Biology subjects

Rapp, M.

Publications and source records attributed to Rapp, M..

11 recordsLinked to original sources

bioRxiv2026

Maftivimab monotherapy is effective in a non-human primate model of Bundibugyo virus disease

The 2026 outbreak of Bundibugyo ebolavirus (BDBV) in the Democratic Republic of the Congo and Uganda has created an urgent need for treatments for BDBV disease, yet the only FDA-approved ebolavirus therapeutics, the monoclonal antibody (mAb) cocktail Inmazeb and the mAb Ebanga, are indicated for Zaire ebolavirus (EBOV). Maftivimab (REGN3479), the most potent neutralizing component of Inmazeb, targets ebolavirus species GPs broadly; however, how it engages BDBV GP, whether it neutralizes BDBV-2026, and whether it protects against BDBV disease in vivo are unknown. Here we show that Maftivimab binds to BDBV-2007 GP with high affinity and potently neutralizes pseudoviruses carrying GP from a 2007 reference strain and the 2026 outbreak lineage. Additionally, a cryo-electron microscopy structure of Maftivimab Fab bound to trimeric BDBV-2007 GP superimposes closely on the EBOV GP:Maftivimab complex; importantly, all GP contact residues are conserved between the 2007 and 2026 BDBV sequences. Finally, in cynomolgus macaques challenged with BDBV-2007, a single dose of Maftivimab monotherapy given 7 days after infection, after the onset of clinical disease, rescued 6 of 6 animals, whereas 5 of 6 placebo-treated animals succumbed. These findings demonstrate that Maftivimab neutralizes BDBV, binds to its epitope on BDBV GP and is efficacious in treating established BDBV disease in the macaque model. The data support its evaluation in clinical trials during the ongoing or future outbreak.

immunology↗

bioRxiv2026

Impaired Control Symptoms in Alcohol Use Disorder Show Convergent Associations Across Behavioral and Neural Markers of Inhibitory Control and Drinking Behavior

Background: Deficits in inhibitory control are considered a central feature of alcohol use disorder (AUD), yet behavioral and neuroimaging findings have been inconsistent. One potential explanation is the marked heterogeneity of AUD, which encompasses multiple symptom dimensions that may differ in their underlying neurocognitive mechanisms. In this study, we investigated whether behavioral and neural markers of inhibitory control are associated with specific DSM-5 AUD symptom domains. Methods: A total of 589 participants (432 with non-treatment seeking AUD, 157 controls) completed a Stop-Signal Task (SST) during fMRI. Associations between DSM-5 symptom domains (impaired control over alcohol use, risky use, social problems, physical dependence) and SST performance, inhibition-related brain activation, and alcohol consumption were examined. Real-life drinking behavior was additionally assessed over 12 months using ecological momentary assessment (EMA). Results: Greater impaired control symptom severity was associated with poorer performance on go trials and diminished post-error slowing during SST. At the neural level, higher impaired control symptom severity was associated with reduced activation across fronto-insular, parietal, cingulate, supplementary motor, and cerebellar regions. In contrast, other symptom domains showed little to no associations with inhibition-related behavioral or neural measures. Higher impaired control symptom severity was associated with greater alcohol consumption across questionnaire-based and EMA-based assessments. Conclusions: In this large cohort, altered behavioral performance and recruitment of inhibition-related brain regions in the SST was selectively linked to impaired control symptoms. These findings highlight the importance of symptom-based approaches for understanding heterogeneity in addiction and may inform the development of more targeted interventions.

neuroscience↗

bioRxiv2025

Impact of port conditions and acclimation capacity of common two-banded seabream juveniles in the bay of Toulon: implications for nursery rehabilitation efforts

Ports are heavily anthropized coastal environments characterized by intense pollution and habitat alterations, creating challenging living conditions for marine organisms, particularly juvenile fish that rely on these areas as nurseries. While recent rehabilitation efforts of the nursery function in ports have focused on structural modifications, the impacts of port chemical and physical pollution are currently disregarded. Using field sampling and caging experiments, we examined the physiological (growth, lipid content, CYP1A-dependent biotransformation activity) and molecular (RNA-seq) responses of juvenile two-banded sea bream (Diplodus vulgaris) by comparing one port site with two adjacent sites from outside of the port, assessing their potential for short-term acclimation to port conditions. Results from individuals sampled in the field revealed distinct physiological and transcriptomic profiles in port juveniles, indicating specific responses to this environment. Notably, alterations related to lipid accumulation, detoxification, hypoxia, and circadian regulation were observed. After one month of caging all the individuals from different locations in the port, juveniles originating from outside the port exhibited stronger transcriptional responses compared to individuals that grew within the port, with higher expression of genes involved in detoxification and lipid metabolism, and a strong overexpression of oncogenes, while individuals originating from the port upregulated genes involved in energy metabolism, suggesting some capacity for short-term acclimation in port-resident juvenile fish. These findings highlight the potential impact of port conditions on juvenile fish health, with implications for the effectiveness of rehabilitation efforts. This study emphasizes the need for further research to inform nursery rehabilitation strategies in polluted ports.

physiology↗

bioRxiv2024

Altered viscoelastic properties of the Nicotiana tabacum BY-2 suspension cell lines adapted to high concentrations of NaCl and mannitol

To survive and grow, plant cells must regulate the properties of their cellular microenvironment in response to ever changing external factors. How the biomechanical balance across the cells internal structures is established and maintained during environmental variations remains a nurturing question. To provide insight into this issue we used two micro-mechanical imaging techniques, namely Brillouin light scattering and BODIPY-based molecular rotors Fluorescence Lifetime Imaging, to study Nicotiana tabacum suspension BY-2 cells long-term adapted to high concentrations of NaCl and mannitol. We discuss our results in terms of molecular crowding in cytoplasm and vacuoles, as well as tension in plasma membrane. The viscoelastic behavior was elucidated relative to cells external environments revealing the difference between the responses of cytoplasm and vacuole in the adapted cells. To understand how sudden changes in osmolarity affect cellular mechanics, the response of control and already adapted cells to further short-term osmotic stimulus was also examined. The applied correlative approach provides evidence that adaptation to hyperosmotic stress leads to different ratios of protoplast and environmental qualities that help to maintain cell integrity. Presented results demonstrate that the viscoelastic properties of protoplasts are an element of plant cells adaptation to high osmolarity.

plant biology↗

bioRxiv2023

A lymph node-to-tumour PD-L1+macrophage circuit antagonizes dendritic cell immunotherapy

Immune-checkpoint blockers (ICB) provide limited benefit against T cell-depleted tumours, calling for therapeutic innovation. Here, we aimed at designing a new type of dendritic cell (DC) vaccine by unbiased computational integration of multi-omics data from cancer patients. In a first attempt, a DC vaccine designed to present tumor antigens from cancer cells succumbing to immunogenic cancer cell death (ICD) and to elicit high type I interferon (IFN) responses failed to induce the regression of mouse tumors lacking T cell infiltrates. In lymph nodes (LNs), instead of activating CD4+ and CD8+T cells, DCs stimulated immunosuppressive PD-L1+LN-associated macrophages (LAMs) via a type I IFN response. Moreover, DC vaccines of this type stimulated pre-existing, T cell-suppressive, PD-L1+tumour-associated macrophages (TAMs). This created a T cell-suppressive circuit of PD-L1+macrophages, spanning across LNs and tumours. Accordingly, DC vaccines synergised with PD-L1 blockade to deplete PD-L1+macrophages, suppress myeloid inflammation affecting the tumor bed and draining lymph nodes, and de-inhibit effector/stem-like memory T cells, eventually causing tumour regression. The synergistic interaction between the DC vaccine and PD-L1 blockade was lost when DCs were manipulated to lose Ifnar1or Ccr7 or when macrophages were depleted. Interestingly, clinical DC vaccines also potentiated lymphocyte-suppressive PD-L1+TAMs in patients bearing T cell-depleted tumours. Altogether, our results reveal the existence of a novel PD-L1+LAM/TAM-driven immunosuppressive pathway that can be elicited by DC vaccines, yet can be subverted for improving the outcome of immunotherapy.

immunology↗

bioRxiv2021

Mg2+-dependent conformational equilibria in CorA: an integrated view on transport regulation

The CorA family of proteins regulates the homeostasis of divalent metal ions in many bacteria, archaea, and eukaryotic mitochondria, making it an important target in the investigation of the mechanisms of transport and its functional regulation. Although numerous structures of open and closed channels are now available for the CorA family, the mechanism of the transport regulation remains elusive. Here, we investigated the conformational distribution and associated dynamic behaviour of the pentameric Mg2+ channel CorA at room temperature using small-angle neutron scattering (SANS) in combination with molecular dynamics (MD) simulations and solid-state nuclear magnetic resonance spectroscopy (NMR). We find that neither the Mg2+-bound closed structure nor the Mg2+-free open forms are sufficient to explain the average conformation of CorA. Our data support the presence of conformational equilibria between multiple states, and we further find a variation in the behaviour of the backbone dynamics with and without Mg2+. We propose that CorA must be in a dynamic equilibrium between different non-conducting states, both symmetric and asymmetric, regardless of bound Mg2+ but that conducting states become more populated in Mg2+-free conditions. These properties are regulated by backbone dynamics and are key to understanding the functional regulation of CorA.

biophysics↗

bioRxiv2021

Structural Basis for Accommodation of Emerging B.1.351 and B.1.1.7 Variants by Two Potent SARS-CoV-2 Neutralizing Antibodies

Emerging SARS-CoV-2 strains, B.1.1.7 and B.1.351, from the UK and South Africa, respectively show decreased neutralization by monoclonal antibodies and convalescent or vaccinee sera raised against the original wild-type virus, and are thus of clinical concern. However, the neutralization potency of two antibodies, 1-57 and 2-7, which target the receptor-binding domain (RBD) of spike, was unaffected by these emerging strains. Here, we report cryo-EM structures of 1-57 and 2-7 in complex with spike, revealing each of these antibodies to utilize a distinct mechanism to bypass or accommodate RBD mutations. Notably, each antibody represented a response with recognition distinct from those of frequent antibody classes. Moreover, many epitope residues recognized by 1-57 and 2-7 were outside hotspots of evolutionary pressure for both ACE2 binding and neutralizing antibody escape. We suggest the therapeutic use of antibodies like 1-57 and 2-7, which target less prevalent epitopes, could ameliorate issues of monoclonal antibody escape.

biochemistry↗

bioRxiv2021

Potent SARS-CoV-2 Neutralizing Antibodies Directed Against Spike N-Terminal Domain Target a Single Supersite

Numerous antibodies that neutralize SARS-CoV-2 have been identified, and these generally target either the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the viral spike. While RBD-directed antibodies have been extensively studied, far less is known about NTD-directed antibodies. Here we report cryo-EM and crystal structures for seven potent NTD-directed neutralizing antibodies in complex with spike or isolated NTD. These structures defined several antibody classes, with at least one observed in multiple convalescent donors. The structures revealed all seven antibodies to target a common surface, bordered by glycans N17, N74, N122, and N149. This site - formed primarily by a mobile {beta}-hairpin and several flexible loops - was highly electropositive, located at the periphery of the spike, and the largest glycan-free surface of NTD facing away from the viral membrane. Thus, in contrast to neutralizing RBD-directed antibodies that recognize multiple non-overlapping epitopes, potent NTD-directed neutralizing antibodies target a single supersite.

biochemistry↗

bioRxiv2021

Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class

Antibodies with heavy chains that derive from the VH1-2 gene constitute some of the most potent SARS-CoV-2-neutralizing antibodies yet identified. To provide insight into whether these genetic similarities inform common modes of recognition, we determined structures of the SARS-CoV-2 spike in complex with three VH1-2-derived antibodies: 2-15, 2-43, and H4. All three utilized VH1-2-encoded motifs to recognize the receptor-binding domain (RBD), with heavy chain N53I enhancing binding and light chain tyrosines recognizing F486RBD. Despite these similarities, class members bound both RBD-up and -down conformations of the spike, with a subset of antibodies utilizing elongated CDRH3s to recognize glycan N343 on a neighboring RBD - a quaternary interaction accommodated by an increase in RBD separation of up to 12 [A]. The VH1-2-antibody class thus utilizes modular recognition encoded by modular genetic elements to effect potent neutralization, with VH-gene component specifying recognition of RBD and CDRH3 component specifying quaternary interactions. HighlightsO_LIDetermine structures of VH1-2-derived antibodies 2-43, 2-15, and H4 in complex with SARS-CoV-2 spike C_LIO_LIDefine a multi-donor VH1-2-antibody class with modular components for RBD and quaternary recognition C_LIO_LIReveal structural basis of RBD-up and RBD-down recognition within the class C_LIO_LIShow somatic hypermutations and avidity to be critical for potency C_LIO_LIDelineate changes in spike conformation induced by CDRH3-mediated quaternary recognition C_LI

immunology↗

bioRxiv2020

Effects of early life stress on bone homeostasis in mice and humans

Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined on bone microarchitecture (CT), metabolism (qPCR), and neuronal stress mediator expression (qPCR) and contrasted with a sample of depressive patients with or without early life stress by analyzing bone mineral density [BMD] (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone micro-CT. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies.

physiology↗

bioRxiv2017

Routine Single Particle CryoEM Sample and Grid Characterization by Tomography

Single particle cryo-electron microscopy (cryoEM) is often performed under the assumption that particles are freely floating away from the air-water interfaces and in thin, vitreous ice. In this study, we performed fiducial-less tomography on over 50 different cryoEM grid/sample preparations to determine the particle distribution within the ice and the overall geometry of the ice in grid holes. Surprisingly, by studying particles in holes in 3D from over 1,000 tomograms, we have determined that the vast majority of particles (approximately 90%) are adsorbed to an air-water interface. The implications of this observation are wide-ranging, with potential ramifications regarding protein denaturation, conformational change, and preferred orientation. We also show that fiducial-less cryo-electron tomography on single particle grids may be used to determine ice thickness, optimal single particle collection areas and strategies, particle heterogeneity, and de novo models for template picking and single particle alignment.

biophysics↗