Search

Abstract Although sex determination is a fundamental process in vertebrate development, it is very plastic. Diverse genes became major sex determinants in teleost fishes. Deciphering how individual sex-determining genes orchestrate sex determination can reveal new actors in sexual development. Here, we demonstrate that the Y-chromosomal copy of the TGF-β family member gdf6 (gdf6Y) in Nothobranchius furzeri, an emerging model organism in aging research, gained the function of the male sex determinant through allelic diversification while retaining the skeletal developmental function shared with the X-chromosomal gdf6 allele (gdf6X). Concerning sex determination, gdf6Y is expressed by somatic supporting cells of the developing testes. There it induces the male sex in a germ cell-independent manner in contrast to sex determination in zebrafish and the medaka. Looking for downstream effectors of Gdf6Y, we identified besides TGF-β signaling modulators, especially the inhibitor of DNA binding genes id1/2/3, the mRNA decay activator zfp36l2 as a new GDF6 signaling target.

Abstract We consider a class of singlet scalar extensions of the Standard Model of particle physics in which the scalar couples only to off-shell states. As a result, low-order tree-level processes involving the singlet scalar vanish, providing a unique phenomenology that may allow to evade existing constraints on new singlet scalar fields. We describe search strategies for such states at the Large Hadron Collider and identify the parameter space that can be explored in the future.

Abstract Extrapolations of sensitivity to new interactions and standard model parameters critically inform the programme at the Large Hadron Collider (LHC) and potential future collider cases. To this end, statistical considerations based on inclusive quantities and established analysis strategies typically give rise to a sensitivity scaling with the square root of the luminosity, $$\sqrt{\mathcal {L}}$$ L . This suggests only a mild sensitivity improvement for LHC’s high-luminosity phase, compared to the collected data up to the year 2025. We discuss representative analyses in top quark, Higgs boson and electroweak gauge boson phenomenology and provide clear evidence that the assumption that the sensitivity in searches and measurement scales only with $$\sqrt{\mathcal {L}}$$ L at the High-Luminosity LHC is overly conservative at best, and unrealistic in practice. As kinematic coverage enables more targeted search strategies with sufficient statistical sensitivity, employing a multitude of features in data dispels the scaling based on more inclusive selections.

Abstract This study introduces a novel Graph Neural Network (GNN) architecture that leverages infrared and collinear (IRC) safety and equivariance to enhance the analysis of collider data for Beyond the Standard Model (BSM) discoveries. By integrating equivariance in the rapidity-azimuth plane with IRC-safe principles, our model significantly reduces computational overhead while ensuring theoretical consistency in identifying BSM scenarios amidst Quantum Chromodynamics backgrounds. The proposed GNN architecture demonstrates superior performance in tagging semi-visible jets, highlighting its potential as a robust tool for advancing BSM search strategies at high-energy colliders.

Abstract The top quark as the heaviest particle in the Standard Model (SM) defines an important mass scale for Higgs physics and the electroweak scale itself. It is therefore a well-motivated degree of freedom which could reveal the presence of new interactions beyond the SM. Correlating modifications of the top-Higgs interactions in the 2-Higgs-Doublet Model (2HDM), we analyse effective field theory deformations of these interactions from the point of view of a strong first-order electroweak phase transition (SFOEWPT). We show that such modifications are compatible with current Higgs data and that an SFOEWPT can be tantamount to a current overestimate of exotic Higgs searches’ sensitivity at the LHC in t t ¯ $$ t\overline{t} $$ and four top quark final states. We argue that these searches remain robust from the point of accidental signal-background interference so that the current experimental strategy might well lead to 2HDM-like discoveries in the near future.

Abstract We consider what multiple Higgs interactions may yet reveal about the scalar sector. We estimate the sensitivity of a Feynman topology-templated analysis of weak boson fusion Higgs pair production at present and future colliders — where the signal is a function of the Higgs coupling modifiers κ V , κ 2V , and κ λ . While measurements are statistically limited at the LHC, they are under general perturbative control at present and future colliders, departures from the SM expectation give rise to a significant future potential for BSM discrimination in κ 2V . We explore the landscape of BSM models in the space of deviations in κ V , κ 2V , and κ λ , highlighting models that have measurable order-of-magnitude enhancements in either κ 2V or κ λ , relative to their deviation in the single Higgs coupling κ V .

Abstract We study the intersection of flavour and collider physics for Two-Higgs-Doublet models of Type I and II. Drawing from the flavour precision-LHC exotics search complementarity, we also provide a projection of the future sensitivity that can be achieved in light of currently available analyses. On the one hand, we find that the parameter space of the 2HDM can be explored significantly further with more data from the LHC with some complementarity with flavour physics. On the other hand, flavour physics results alongside their projections remain powerful tools to constrain the model space in regions where direct sensitivity to new states via exotics searches is lost. Our results further high-light the recently observed flavour physics anomalies as important drivers of new physics searches in the future; we also touch on implications for a strong first order electroweak phase transition.

Abstract Constraints on quartic interactions of the Higgs boson with gauge bosons have been obtained by the experimental LHC collaborations focussing on the so-called κ framework of flat rescalings of SM-like interactions in weak boson fusion (WBF) Higgs pair production. While such approaches are admissible to obtain a qualitative picture of consistency with the SM when the statistical yield is low, once more statistics become available a more theoretically consistent framework of limit setting is desirable. Reviewing the constraints provided at the Large Hadron Collider, we first show that these limits are robust when considered in a leading order context. Turning to radiative corrections, we demonstrate the limitations of this approach in the SM, and by adopting Higgs effective field theory techniques, we clarify the sensitivity from single Higgs measurements to rescalings of quartic Higgs-gauge couplings. We then discuss avenues for sensitivity improvements of WBF analyses employing Graph Neural Networks to combat the large contributing backgrounds.

Abstract It is well-known that type II two Higgs doublet models (2HDMs) can struggle to facilitate a strong first-order electroweak phase transition in the early universe whilst remaining theoretically appealing scenarios for many reasons. We analyse this apparent shortfall from the perspective of additional new physics. Starting from a consistent dimension-6 effective field theory Higgs potential extension, we identify the Higgs potential extensions that provide the necessary additional contributions required to achieve a strong first-order electroweak phase transition and trace their phenomenological implications for the Large Hadron Collider. In passing, we critically assess the reliability of the dimension-6 approximation depending on the expected 2HDM phenomenology. In particular, we focus on the role of Higgs pair production (resonant and non-resonant) and interference effects expected in top final states, which are the prime candidates of 2HDM exotics discoveries.

Abstract We explore the potential of Graph Neural Networks (GNNs) to improve the performance of high-dimensional effective field theory parameter fits to collider data beyond traditional rectangular cut-based differential distribution analyses. In this study, we focus on a SMEFT analysis of pp → t t ¯ $$ t\overline{t} $$ production, including top decays, where the linear effective field deformation is parametrised by thirteen independent Wilson coefficients. The application of GNNs allows us to condense the multidimensional phase space information available for the discrimination of BSM effects from the SM expectation by considering all available final state correlations directly. The number of contributing new physics couplings very quickly leads to statistical limitations when the GNN output is directly employed as an EFT discrimination tool. However, a selection based on minimising the SM contribution enhances the fit’s sensitivity when reflected as a (non-rectangular) selection on the inclusive data samples that are typically employed when looking for non-resonant deviations from the SM by means of differential distributions.

Body pigmentation is a limitation for in vivo imaging and thus for the performance of longitudinal studies in biomedicine. A possibility to circumvent this obstacle is the employment of pigmentation mutants, which are used in fish species like zebrafish and medaka. To address the basis of aging, the short-lived African killifish Nothobranchius furzeri has recently been established as a model organism. Despite its short lifespan, N. furzeri shows typical signs of mammalian aging including telomere shortening, accumulation of senescent cells, and loss of regenerative capacity. Here, we report the generation of a transparent N. furzeri line by the simultaneous inactivation of three key loci responsible for pigmentation. We demonstrate that this stable line, named klara, can serve as a tool for different applications including behavioral experiments and the establishment of a senescence reporter by integration of a fluorophore into the cdkn1a (p21) locus and in vivo microscopy of the resulting line.

Abstract We devise an autoencoder based strategy to facilitate anomaly detection for boosted jets, employing Graph Neural Networks (GNNs) to do so. To overcome known limitations of GNN autoencoders, we design a symmetric decoder capable of simultaneously reconstructing edge features and node features. Focusing on latent space based discriminators, we find that such setups provide a promising avenue to isolate new physics and competing SM signatures from sensitivity-limiting QCD jet contributions. We demonstrate the flexibility and broad applicability of this approach using examples of W bosons, top quarks, and exotic hadronically-decaying exotic scalar bosons.

Improving the sensitivity to CP-violation in the Higgs sector is one of the pillars of the precision Higgs programme at the Large Hadron Collider. We present a simple method that allows CP-sensitive observables to be directly constructed from the output of neural networks. We show that these observables have improved sensitivity to CP-violating effects in the production and decay of the Higgs boson, when compared to the use of traditional angular observables alone. The kinematic correlations identified by the neural networks can be used to design new analyses based on angular observables, with a similar improvement in sensitivity.

Anomaly detection through employing machine learning techniques has emerged as a novel powerful tool in the search for new physics beyond the Standard Model. Historically similar to the development of jet observables, theoretical consistency has not always assumed a central role in the fast development of algorithms and neural network architectures. In this work, we construct an infrared and collinear safe autoencoder based on graph neural networks by employing energy-weighted message passing. We demonstrate that whilst this approach has theoretically favorable properties, it also exhibits formidable sensitivity to non-QCD structures.

We consider a wide range of UV scenarios with the aim of informing searches for CP violation at the TeV scale using effective field theory techniques. We demonstrate that broad theoretical assumptions about the nature of UV dynamics responsible for CP violation map out a small subset of relevant operators at the TeV scale. Concretely, this will allow us to reduce the number of free parameters that need to be considered in experimental investigations, thus enhancing analyses' sensitivities. In parallel, reflecting the UV dynamics' Wilson coefficient hierarchy will enable a streamlined theoretical interpretation of such analyses in the future. We demonstrate a minimal approach to analysing CP violation in this context using a Monte Carlo study of a combination of weak boson fusion Higgs and electroweak diboson production, which provide complementary information on the relevant EFT operators.

The Wilms tumor suppressor gene Wt1 encodes a zinc finger transcription factor, which is highly conserved among vertebrates. It is a key regulator of urogenital development and homeostasis but also plays a role in other organs including the spleen and the heart. More recently additional functions for Wt1 in the mammalian central nervous system have been described. In contrast to mammals, bony fish possess two paralogous Wt1 genes, namely wt1a and wt1b. By performing detailed in situ hybridization analyses during zebrafish development, we discovered new expression domains for wt1a in the dorsal hindbrain, the caudal medulla and the spinal cord. Marker analysis identified wt1a expressing cells of the dorsal hindbrain as ependymal cells of the choroid plexus in the myelencephalic ventricle. The choroid plexus acts as a blood-cerebrospinal fluid barrier and thus is crucial for brain homeostasis. By employing wt1a mutant larvae and a dye accumulation assay with fluorescent tracers we demonstrate that Wt1a is required for proper choroid plexus formation and function. Thus, Wt1a contributes to the barrier properties of the choroid plexus in zebrafish, revealing an unexpected role for Wt1 in the zebrafish brain.

Sizeable exotic Higgs boson production through gluon fusion via top quark loops is correlated with large Higgs decay probabilities into top quark final states, if these are kinematically accessible. It is known that gg→S→tt¯ is particularly susceptible to signal-background interference effects that can significantly impact discovery sensitivities. In such an instance, identifying more robust signatures to enhance the discovery sensitivity becomes necessary, shifting phenomenological focus to final states that show a reduced destructive signal-background interference. In this work, we discuss the phenomenological relevance of signal-signal and signal-background interference effects for decay chains. In particular, we identify asymmetric cascade decays in models of scalar extensions of the SM Higgs sector as new promising candidates. In parallel, characteristic interference patterns can provide a formidable tool for indirect CP spectroscopy of BSM sectors if a discovery is made in the future. This motivates associated searches at present and future colliders as robust discovery modes of new physics, in addition to serving as a sensitive tool for the reconstruction of the underlying UV electroweak potential.

Abstract We study, from theoretical and phenomenological angles, the Higgs boson oblique parameter Ĥ, as the hallmark of off-shell Higgs physics. Ĥ is defined as the Wilson coefficient of the sole dimension-6 operator that modifies the Higgs boson propagator, within a Universal EFT. Theoretically, we describe self-consistency conditions on Wilson coefficients, derived from the Källén-Lehmann representation. Phenomenologically, we demonstrate that the process gg → h ∗ → V V is insensitive to propagator corrections from Ĥ, and instead advertise four-top production as an effective high-energy probe of off-shell Higgs behaviour, crucial to break flat directions in the EFT.

Central pattern generator (CPG) networks coordinate the generation of rhythmic activity such as locomotion and respiration. Their development is driven by various transcription factors, one of which is the Wilms tumor protein (Wt1). It is present in dI6 neurons of the mouse spinal cord, and involved in the coordination of locomotion. Here we report about the presence of Wt1 in neurons of the caudoventral medulla oblongata and their impact on respiration. By employing immunohistofluorescence staining, we were able to characterize these Wt1 positive (+) cells as dB4 neurons. The temporal occurrence of Wt1 suggests a role for this transcription factor in the differentiation of dB4 neurons during embryonic and postnatal development. Conditional knockout of Wt1 in these cells caused an altered population size of V0 neurons already in the developing hindbrain, leading to a decline in the respiration rate in the adults. Thereby, we confirmed and extended the previously proposed similarity between dB4 neurons in the hindbrain and dI6 neurons of the spinal cord, in terms of development and function. Ablation of Wt1+ dB4 neurons resulted in the death of neonates due to the inability to initiate respiration, suggesting a vital role for Wt1+ dB4 neurons in breathing. These results expand the role of Wt1 in the CNS and show that, in addition to its function in differentiation of dI6 neurons, it also contributes to the development of dB4 neurons in the hindbrain that are critically involved in the regulation of respiration.

The Weinberg angle is an important parameter in Grand Unified Theories (GUT) as its size is crucially influenced by the assumption of unification. In scenarios with different steps of symmetry breaking, in particular in models that involve gauge-Higgs unification, the connection of the ultraviolet theory and the TeV scale-relevant, effective Standard Model description is an important test of the models' validity. In this work, we consider a 6D gauge-Higgs unification GUT scenario and explore the TeV scale-GUT relation using a detailed RGE analysis in the 4D and 5D regimes of the theory, including constraints from LHC measurements. We show that such can be consistent with unification in the light of current constraints, while the Weinberg angle likely translates into concrete conditions on the fermion sector in the higher dimensional setup.

We perform a comprehensive study of collider aspects of a Higgs portal scenario that is protected by an unbroken Z2 symmetry. If the mass of the Higgs portal scalar is larger than half the Higgs mass, this scenario becomes very difficult to detect. We provide a detailed investigation of the model's parameter space based on analyses of the direct collider sensitivity at the LHC as well as at future lepton and hadron collider concepts and analyse the importance of these searches for this scenario in the context of expected precision Higgs and electroweak measurements. In particular we also consider the associated electroweak oblique corrections that we obtain in a first dedicated two-loop calculation for comparisons with the potential of, e.g., GigaZ. The currently available collider projections corroborate an FCC-hh 100 TeV as a very sensitive tool to search for such a weakly-coupled Higgs sector extension, driven by small statistical uncertainties over a large range of energy coverage. Crucially, however, this requires good theoretical control. Alternatively, Higgs signal-strength measurements at an optimal FCC-ee sensitivity level could yield comparable constraints.

CP-violation in the Higgs sector remains a possible source of the baryon asymmetry of the universe. Recent differential measurements of signed angular distributions in Higgs boson production provide a general experimental probe of the CP structure of Higgs boson interactions. We interpret these measurements using the Standard Model Effective Field Theory and show that they do not distinguish the various CP-violating operators that couple the Higgs and gauge fields. However, the constraints can be sharpened by measuring additional CP-sensitive observables and exploiting phase-space-dependent effects. Using these observables, we demonstrate that perturbatively meaningful constraints on CP-violating operators can be obtained at the LHC with luminosities of O(100/fb). Our results provide a roadmap to a global Higgs boson coupling analysis that includes CP-violating effects. Keywords: Higgs boson, Effective field theory, CP-violation, LHC

Abstract Machine Learning is a powerful tool to reveal and exploit correlations in a multi-dimensional parameter space. Making predictions from such correlations is a highly non-trivial task, in particular when the details of the underlying dynamics of a theoretical model are not fully understood. Using adversarial networks, we include a priori known sources of systematic and theoretical uncertainties during the training. This paves the way to a more reliable event classification on an event-by-event basis, as well as novel approaches to perform parameter fits of particle physics data. We demonstrate the benefits of the method explicitly in an example considering effective field theory extensions of Higgs boson production in association with jets.

Abstract Higgs pair production is a crucial phenomenological process in deciphering the nature of the TeV scale and the mechanism underlying electroweak symmetry breaking. At the Large Hadron Collider, this process is statistically limited. Pushing the energy frontier beyond the LHC’s reach will create new opportunities to exploit the rich phenomenology at higher centre-of-mass energies and luminosities. In this work, we perform a comparative analysis of the $$hh+\text {jet}$$ hh+jet channel at a future 100 TeV hadron collider. We focus on the $$hh\rightarrow b\bar{b} b\bar{b}$$ hh→bb¯bb¯ and $$hh \rightarrow b\bar{b} \tau ^+\tau ^-$$ hh→bb¯τ+τ- channels and employ a range of analysis techniques to estimate the sensitivity potential that can be gained by including this jet-associated Higgs pair production to the list of sensitive collider processes in such an environment. In particular, we observe that $$hh \rightarrow b\bar{b} \tau ^+\tau ^-$$ hh→bb¯τ+τ- in the boosted regime exhibits a large sensitivity to the Higgs boson self-coupling and the Higgs self-coupling could be constrained at the 8% level in this channel alone.

Age-associated organ failure and degenerative diseases have a major impact on human health. Cardiovascular dysfunction has an increasing prevalence with age and is one of the leading causes of death. In contrast to humans, zebrafish have extraordinary regeneration capacities of complex organs including the heart. In addition, zebrafish has recently become a model organism in research on aging. Here, we have compared the ventricular transcriptome as well as the regenerative capacity after cryoinjury of old and young zebrafish hearts. We identified the immune system as activated in old ventricles and found muscle organization to deteriorate upon aging. Our data show an accumulation of immune cells, mostly macrophages, in the old zebrafish ventricle. Those immune cells not only increased in numbers but also showed morphological and behavioral changes with age. Our data further suggest that the regenerative response to cardiac injury is generally impaired and much more variable in old fish. Collagen in the wound area was already significantly enriched in old fish at 7 days post injury. Taken together, these data indicate an ‘inflammaging’-like process in the zebrafish heart and suggest a change in regenerative response in the old.

Ageing is associated with a pronounced shift in mortality from cancer to degenerative diseases. Here, the authors show that in concordance with this shift, conserved transcriptional alterations during ageing across four vertebrates align with degenerative diseases but are opposite to those in cancer.

Abstract We present a model-independent study aimed at characterising the nature of possible resonances in the jet-photon or jet-Z final state at hadron colliders. Such resonances are expected in many models of compositeness and would be a clear indication of new physics. At leading order, in the narrow width approximation, the matrix elements are parameterised by just a few constants describing the coupling of the various helicities to the resonance. We present the full structure of such amplitudes up to spin 2 and use them to simulate relevant kinematic distributions that could serve to constrain the coupling structure. This also generalises the signal generation strategy that is currently pursued by ATLAS and CMS to the most general case in the considered channels. While the determination of the P/CP properties of the interaction seems to be out of reach within this framework, there is a wealth of information to be gained about the spin of the resonance and the relative couplings of the helicities.

Abstract While the Higgs characterisation programme is well under way, direct signs for new physics beyond the Standard Model remain elusive. Performing a fit of fully differential Higgs production cross sections at the LHC to a subset of Higgs-relevant effective operators, we discuss the extent to which theoretical uncertainties can limit the sensitivity in such a new physics search programme. Extending the dimension-6 Higgs Effective Field Theory framework by introducing new light degrees of freedom that can contribute to an invisible (or undetectable) Higgs decay width $$h\rightarrow \phi \phi $$ h → ϕ ϕ , we show how differential coupling fits can disentangle effects from non-Standard Model couplings and an invisible decay width, as present in many new physics scenarios, such as Higgs-portal dark matter. Including the so-called off-shell measurement that has been advocated as a sensitive determination of the Higgs width in the $$\kappa $$ κ framework, we show explicitly that this method does not provide complementary sensitivity for scale-separated new physics $$\Lambda \gg m_h \gg m_\phi $$ Λ ≫ m h ≫ m ϕ , which is favoured in beyond the Standard Model scenarios that relate astrophysics and collider phenomenology in the light of non-observation of new physics during run 1 of the LHC.

Abstract We investigate a recently proposed UV-complete composite Higgs scenario in the light of the first LHC runs. The model is based on a SU(4) gauge group with global flavour symmetry breaking SU(5) → SO(5), giving rise to pseudo Nambu-Goldstone bosons in addition to the Higgs doublet. This includes a real and a complex electroweak triplet with exotic electric charges. Including these, as well as constraints on other exotic states, we show that LHC measurements are not yet sensitive enough to significantly constrain the model’s low energy constants. The Higgs potential is described by two parameters which are on the one hand constrained by the LHC measurement of the Higgs mass and Higgs decay channels and on the other hand can be computed from correlation functions in the UV-complete theory. Hence to exclude the model at least one constant needs to be determined and to validate the Higgs potential both constants need to be reproduced by the UV-theory. Due to its UV-formulation, a certain number of low energy constants can be computed from first principle numerical simulations of the theory formulated on a lattice, which can help in establishing the validity of this model. We assess the potential impact of lattice calculations for phenomenological studies, as a preliminary step towards Monte Carlo simulations.

Abstract We perform a comparative study of the reach of future $$e^+e^-$$ e + e - collider options for the scale of non-resonant new physics effects in the top quark sector, phrased in the language of higher-dimensional operators. Our focus is on the electroweak top quark pair production process $$e^+e^- \rightarrow Z^*/\gamma \rightarrow t\bar{t} $$ e + e - → Z ∗ / γ → t t ¯ , and we study benchmark scenarios at the ILC and CLIC. We find that both are able to constrain mass scales up to the few $$\text {TeV}$$ TeV range in the most sensitive cases, improving by orders of magnitude on the forecast capabilities of the LHC. We discuss the role played by observables such as forward–backward asymmetries, and making use of different beam polarisation settings, and highlight the possibility of lifting a degeneracy in the allowed parameter space by combining top observables with precision Z-pole measurements from LEP1.

In this paper we argue that monojet and monophoton searches can be a sensitive test of very highly ionizing particles such as particles with charges ≳150e and more generally particles that do not reach the outer parts of the detector. 8 TeV monojet data from the CMS experiment excludes such objects with masses in the range ≲650 GeV and charges ≳100e. This nicely complements searches for highly ionizing objects at ALICE, ATLAS, CMS and LHCb. Expected improvements in these channels will extend the sensitivity range to m≲750 GeV. This search strategy can directly be generalised to other particles that strongly interact with the detector material, such as e.g. magnetic monopoles.

Abstract We provide a comprehensive analysis of the power of including top quark-polarisation information to kinematically challenging top pair resonance searches, for which ATLAS and CMS start losing sensitivity. Following the general modelling and analysis strategies pursued by the experiments, we analyse the semi-leptonic and the di-lepton channels and show that including polarisation information can lead to large improvements in the limit setting procedures with large data sets. This will allow us to set stronger limits for parameter choices where sensitivity from the invariant mass of the top pair is not sufficient. This highlights the importance of spin observables as part of a more comprehensive set of observables to gain sensitivity to BSM resonance searches.

We perform a detailed investigation of a Grand Unified Theory (GUT)-inspired theory of gauge-Higgs unification. Scanning the model's parameter space with adapted numerical techniques, we contrast the scenario's low energy limit with existing SM and collider search constraints. We discuss potential modifications of di-Higgs phenomenology at hadron colliders as sensitive probes of the gauge-like character of the Higgs self-interactions and find that for phenomenologically viable parameter choices modifications of the order of 20% compared to the SM cross section can be expected. While these modifications are challenging to observe at the LHC, a future 100 TeV hadron collider might be able to constrain the scenario through more precise di-Higgs measurements. We point out alternative signatures that can be employed to constrain this model in the near future.

Summary: Organ regeneration is preceded by the recruitment of innate immune cells, which play an active role during repair and regrowth. Here, we studied macrophage subtypes during organ regeneration in the zebrafish, an animal model with a high regenerative capacity. We identified a macrophage subpopulation expressing Wilms tumor 1b (wt1b), which accumulates within regenerating tissues. This wt1b+ macrophage population exhibited an overall pro-regenerative gene expression profile and different migratory behavior compared to the remainder of the macrophages. Functional studies showed that wt1b regulates macrophage migration and retention at the injury area. Furthermore, wt1b-null mutant zebrafish presented signs of impaired macrophage differentiation, delayed fin growth upon caudal fin amputation, and reduced cardiomyocyte proliferation following cardiac injury that correlated with altered macrophage recruitment to the regenerating areas. We describe a pro-regenerative macrophage subtype in the zebrafish and a role for wt1b in organ regeneration. : Sanz-Morejón et al. identify Wilms tumor 1b (Wt1b)+ macrophages with a pro-regenerative gene signature in injured fins and hearts in the zebrafish. They show that Wt1b controls macrophage migration and differentiation. Regeneration is impaired in wt1b mutants, supporting a role for this gene, likely within macrophages, in organ regeneration. Keywords: heart regeneration, zebrafish, macrophages, Wilms tumor 1b, fin regeneration

Neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s diseases (PD), are complex heterogeneous diseases with highly variable patient responses to treatment. Due to the growing evidence for ageing-related clinical and pathological commonalities between AD and PD, these diseases have recently been studied in tandem. In this study, we analysed transcriptomic data from AD and PD patients, and stratified these patients into three subclasses with distinct gene expression and metabolic profiles. Through integrating transcriptomic data with a genome-scale metabolic model and validating our findings by network exploration and co-analysis using a zebrafish ageing model, we identified retinoids as a key ageing-related feature in all subclasses of AD and PD. We also demonstrated that the dysregulation of androgen metabolism by three different independent mechanisms is a source of heterogeneity in AD and PD. Taken together, our work highlights the need for stratification of AD/PD patients and development of personalised and precision medicine approaches based on the detailed characterisation of these subclasses.

We investigate the prospects to systematically improve generic effective field theory-based searches for new physics in the top sector during LHC run 2 as well as the high luminosity phase. In particular, we assess the benefits of high momentum transfer final states on top EFT-fit as a function of systematic uncertainties in comparison with sensitivity expected from fully-resolved analyses focusing on tt¯ production. We find that constraints are typically driven by fully-resolved selections, while boosted top quarks can serve to break degeneracies in the global fit. This demystifies and clarifies the importance of high momentum transfer final states for global fits to new interactions in the top sector from direct measurements.

We study Higgs production through weak boson fusion with subsequent decay to bottom quarks. By combining jet substructure techniques and matrix element methods in different limits we motivate this channel as a probe of the bottom-Yukawa interactions in the boosted regime. In particular we ameliorate the “no-go” results of cut-and-count analyses in this channel. After applying a data-driven reconstruction approach we find that the Higgs-bottom coupling can be limited to 0.82

The correlation of on- and off-shell Higgs boson production at the LHC in gg→h⁎→ZZ has been used to bound the Higgs width. We propose an alternative complementary constraint which is only possible through the combination of LEP and LHC measurements. Precision electroweak measurements at LEP allow for the determination of indirect constraints on Higgs couplings to vector bosons by considering one-loop processes involving virtual Higgs exchange. As the indirect constraint is model dependent we will consider two specific models which modify the Higgs couplings and width, and our results will apply specifically to these models. By combining these LEP constraints with current LHC 8 TeV Higgs measurements a stronger limit on the Higgs width can be achieved than with LHC data alone. Looking to the future, a more robust constraint can be achieved by correlating LEP measurements with WBF Higgs production followed by Higgs decays to WW and ZZ. We will discuss the model dependence of this method in comparison to other proposed methods.

Searches for multi-Higgs final states allow to constrain parameters of the SM (or extensions thereof) that directly relate to the mechanism of electroweak symmetry breaking. Multi-Higgs production cross sections, however, are small and the phenomenologically accessible final states are challenging to isolate in the busy multi-jet hadron collider environment of the LHC run 2 and HL-LHC. This makes the necessity to extend the list of potentially observable production mechanisms obvious. Most of the phenomenological analyses in the past have focused on gg→hh+jets; in this paper we study pp→tt¯hh at the HL-LHC and find that this channel for h→bb¯ and semi-leptonic and hadronic top decays has the potential to provide an additional handle to constrain the Higgs trilinear coupling in a global fit at the end of the high luminosity phase. Keywords: Di-Higgs, Self-coupling, Trilinear

Regenerative therapy for degenerative spine disorders requires the identification of cells that can slow down and possibly reverse degenerative processes. Here, we identify an unanticipated wound-specific notochord sheath cell subpopulation that expresses Wilms Tumor (WT) 1b following injury in zebrafish. We show that localized damage leads to Wt1b expression in sheath cells, and that wt1b+cells migrate into the wound to form a stopper-like structure, likely to maintain structural integrity. Wt1b+sheath cells are distinct in expressing cartilage and vacuolar genes, and in repressing a Wt1b-p53 transcriptional programme. At the wound, wt1b+and entpd5+ cells constitute separate, tightly-associated subpopulations. Surprisingly, wt1b expression at the site of injury is maintained even into adult stages in developing vertebrae, which form in an untypical manner via a cartilage intermediate. Given that notochord cells are retained in adult intervertebral discs, the identification of novel subpopulations may have important implications for regenerative spine disorder treatments.

If the LHC run 2 will not provide conclusive hints for new resonant Physics beyond the Standard Model, dedicated and consistent search strategies at high momentum transfers will become the focus of searches for anticipated deviations from the Standard Model expectation. We discuss the phenomenological importance of QCD and electroweak corrections in bounding higher dimensional operators when analysing energy-dependent differential distributions. In particular, we study the impact of RGE-induced operator running and mixing effects on measurements performed in the context of an Effective Field Theory extension of the SM. Furthermore, we outline a general analysis strategy which allows a RGE-improved formulation of constraints free of theoretical shortcomings that can arise when differential distributions start to probe the new interaction scale. We compare the numerical importance of such a programme against the standard analysis approach which is widely pursued at present.

The original version of this Article contained an error in the spelling of the author Jule Müller, which was incorrectly given as Julia Müller. Additionally, in Fig. 4a, the blue-red colour scale for fold change in ageing/disease regulation included a blue stripe in place of a red stripe at the right-hand end of the scale. These errors have been corrected in both the PDF and HTML versions of the Article.

Mutations in the human EYA1 gene have been associated with several human diseases including branchio-oto (BO) and branchio-oto-renal (BOR) syndrome, as well as congenital cataracts and ocular anterior segment anomalies. BOR patients suffer from severe malformations of the ears, branchial arches and kidneys. The phenotype of Eya1-heterozygous mice resembles the symptoms of human patients suffering from BOR syndrome. The Eya1 gene encodes a multifunctional protein that acts as a protein tyrosine phosphatase and a transcriptional coactivator. It has been shown that Eya1 interacts with Six transcription factors, which are also required for nuclear translocation of the Eya1 protein. We investigated the effects of seven disease-causing Eya1 missense mutations on Eya1 protein function, in particular cellular localization, ability to interact with Six proteins, and protein stability. We show here that the BOR-associated Eya1 missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of the Eya1 protein in mammalian cells. Moreover, Six proteins lead to a significant stabilization of Eya1, which is caused by Six-mediated protection from proteasomal degradation. In case of the mutant L550P, loss of interaction with Six proteins leads to rapid protein degradation. Our observations suggest that protein destabilization constitutes a novel disease causing mechanism for Eya1.