Biology subjects

Weiss, F.

Publications and source records attributed to Weiss, F..

16 recordsLinked to original sources

bioRxiv2026

Laser-integrated nanophotonic neural probes with on-chip sensors for addressable photostimulation

Studying the role of individual neurons in behavior and disease requires tools for controlling neural activity with high spatiotemporal resolution. Implantable nanophotonic neural probes are capable of delivering targeted photostimulation to enable genetically distinct neurons to be selectively controlled, yet face barriers to achieving scalable emitter densities and lack sensors for monitoring feedback signals relevant to device operation. To address this, we developed laser-integrated nanophotonic neural probes, which feature hybrid-integrated laser diodes (LD) and thermo-optic photonics switches for scalable emitter addressing and on-chip sensors for monitoring optical power and temperature during photo-stimulation. Devices were fabricated at a commercial silicon photonics foundry on 200-mm diameter silicon-on-insulator (SOI) wafers in an active visible-light platform and were controlled using a custom-developed electronic circuit board. Each device features a hybrid-integrated InGaN LD which couples 450-nm light into a reconfigurable photonic switching tree for delivering spatially resolved photostimulation through 16 emitters along a 3-mm implantable shank. Using the on-chip photodetectors, we demonstrate how devices can enable switching tree calibration as well as output power monitoring during photostimulation. Furthermore, using the on-chip temperature sensors, we show how device temperature perturbations resulting from LD and thermo-optic switch activation can be directly monitored during photostimulation to ensure temperature fluctuations remain below 1 {degrees}C. We validate our design by delivering high spatiotemporal photostimulation during an in vivo optogenetic experiment with simultaneous Neuropixels recording to monitor evoked responses. Overall, these scalable integrated devices offer a pathway for neuroscientists to conduct fiberless optogenetic experiments with greater control and precision.

neuroscience↗

bioRxiv2026

Orally Bioavailable SARS-CoV-2 Protease Inhibitors Bearing a Hydroxymethyl Ketone Warhead

The use of covalent warheads targeting the catalytic cysteine has been a cornerstone in coronavirus main protease (Mpro) inhibitor development, where various electrophilic motifs have been used including aldehydes, nitriles, ketoamides, and hydroxymethyl ketones (HMKs). Recent efforts have been mostly centered around nitrile warheads, given the success of compounds like Nirmatrelvir and Ensitrelvir in the clinic. However, finding and advancing alternative chemotypes with differentiating chemical and pharmacological profiles is essential for future pandemic preparedness. Among such alternatives, HMKs hold special interest because they balance reduced intrinsic electrophilicity with an excellent selectivity profile. Nevertheless, early HMK-based compounds, such as the clinical-stage Mpro inhibitor PF-00835231, suffered from poor oral bioavailability and therefore required intravenous administration, with or without prodrug derivatization of the hydroxyl group. Here, we describe our efforts in advancing the HMK field via the discovery of mCMX110, a lead that has superior potency, increased unbound exposure in vivo, and favorable oral bioavailability in preclinical studies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/725542v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@40222aorg.highwire.dtl.DTLVardef@831b88org.highwire.dtl.DTLVardef@184a910org.highwire.dtl.DTLVardef@779095_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Retargeted adenoviruses for local IgA and CD47 blocker production as a novel cancer therapy

Despite advances in IgG-based cancer immunotherapy, challenges remain in effectively engaging innate immune responses against solid tumors. Here, IgA antibodies hold promise due to their ability to activate neutrophils and macrophages. We present a novel retargeted adenovirus-mediated approach that transforms cancer cells into "biofactories" for localized production of monomeric or dimeric IgA antibodies and a CD47 blocker to potentiate the effect of IgA antibodies. With our approach tumor cells effectively produced IgA antibodies against tumor antigens such as EGFR or EpCAM and a soluble SIRP-Fc fusion protein, which blocks the CD47-SIRP axis. In a perfused tumor-on-a-chip model, locally produced IgA triggered neutrophil- and macrophage-mediated tumor cell killing, further potentiated by SIRP-Fc co-production. In FcRI-transgenic, tumor-bearing mice, intratumoral adenoviral injection induced strong local IgA and SIRP-Fc expression, immune cell infiltration, and more than 50% tumor volume reduction after a single treatment. We found that dimeric IgA exerts stronger effects than monomeric IgA, which is of particular interest since dimeric IgA necessitates a local production approach. Together, these results demonstrate that adenovirus-mediated, tumor-restricted delivery of IgA antibodies and CD47 blockade effectively engages innate immune mechanisms, providing a promising new avenue to enhance cancer immunotherapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/686998v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@183dd88org.highwire.dtl.DTLVardef@452624org.highwire.dtl.DTLVardef@1cb10e8org.highwire.dtl.DTLVardef@c2fa85_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Genome-replicating HC-AdV, a novel high-capacity adenoviral vector class featuring enhanced in situ payload expression

High-capacity adenoviral (HC-AdV) vectors offer large transgene capacities and long-term expression of therapeutics, but require high doses due to limited transgene expression. In contrast, replication-competent AdV (RC-AdV) vectors enhance in situ transgene expression by genome replication and increased transcription from amplified genomes. Yet, RC-AdVs are constrained by minimal payload capacity, progeny formation, and toxic protein expression leading to rapid host cell death. To address these limitations, we developed a novel, genome-replicating HC-AdV vector. Therefore, we investigated AdV genome replication independently of progeny particle formation, and developed cell-based trans-replication assays, enabling us to probe the requirement for individual AdV proteins in AdV genome replication. We identified seven AdV proteins from the early transcriptional units which promote potent replication of HC-AdV genomes. We then created a genome-replicating HC-AdV vector by encoding an engineered minimal replication system that functionally reconstitutes AdV genome replication. Host cell transduction with our genome-replicating HC-AdV promoted cis-replication of the delivered HC-AdV genome and up to 20-fold increased reporter fluorescence. Our novel vector retained a large transgene capacity (22 kb) and, unlike RC-AdVs, did not induce a cytopathic effect nor host cell killing. Together, these data describe a novel delivery platform potentially allowing more efficacious vaccination and vector-mediated therapies.

biochemistry↗

bioRxiv2025

Motivating Effects of Negative-hedonic Valence Encoded in Engrams

Engrams are neuronal alterations that encode associations between environmental contexts and subjectively rewarding or aversive experiences within sparsely activated neuronal assemblies that regulate behavioral responses. How positive- or negative-hedonic states are represented in brain neurocircuits is a fundamental question relevant for understanding the processing of emotionally meaningful stimuli that drive appropriate or maladaptive behavior, respectively. It is well-known that animals avoid noxious stimuli and experiences. Little is known, however, how the conditioning of environmental or contextual stimuli to behavior that leads to amelioration of dysphoric states establishes powerful associations leading to compulsive maladaptive behavior. Here we have studied engrams that encode the conditioned effects of alcohol-related stimuli associated with the reversal of the dysphoric withdrawal state in alcohol dependent rats and document the recruitment of engrams in the paraventricular nucleus of the thalamus (PVT), the central nucleus of the amygdala (CeA), and the Dorsal Striatum (DS). The findings suggest that the encoding of associations between reversal of negative hedonic states and environmental contexts in these engrams may serve as a neural mechanism for compulsive alcohol seeking and vulnerability to relapse associated with dysregulation of reward to a pathological allostatic level.

neuroscience↗

bioRxiv2024

Medial prefrontal cortical neurotransmitters reactive to relapse-promoting and relapse-suppressing cues in rats trained to self-administer cocaine or alcohol

Environmental cues conditioned to signal drug availability (S+) or omission (S-) activate specific neurons (neuronal ensembles/engram cells) within the medial prefrontal cortex (mPFC) to promote and suppress drug relapse in rats. However, the neurochemical source of such cue-specific activation remains unknown. In this study, we determined extracellular neurotransmitter fluctuations reactive to S+ vs. S- in the infralimbic (IL) and prelimbic (PL) cortices of male rats trained to lever-press for cocaine or alcohol self-administration. In cocaine- or alcohol-trained rats exposed to S+, no significant neurotransmitter fluctuations were observed in IL or PL. In cocaine-trained rats exposed to S-, glutamate, serotonin, taurine and adenosine were increased in PL but not in IL. In alcohol-trained rats exposed to S-, glutamate was increased, while dopamine and GABA were decreased, in IL but not in PL. Although S+ reactive neurotransmitters driving neuronal activation in mPFC remains to be elucidated, glutamate is likely the source of such activation by S- in rats trained to self-administer cocaine or alcohol. While drugs used for self-administration and cue-conditioning appear to dictate the type and anatomical specificity of S- evoked neurotransmission within mPFC, glutamate may serve as a common therapeutic target to mimic relapse-suppression by S- across cocaine and alcohol use disorders (CUD and AUD). In contrast, serotonin, taurine and adenosine may serve as the targets in CUD, while dopamine and GABA may serve as the targets in AUD.

neuroscience↗

bioRxiv2024

Identification of mCMQ069, a novel antimalarial with potential for a single-dose cure and/or 28-day chemoprevention

In efforts towards eliminating malaria, a discovery program was initiated to identify a novel antimalarial using KAF156 as a starting point. Following the most recent TCP/TPP guidelines, we have identified mCMQ069 with a predicted single oral dose for treatment ([~]40-106 mg) and one-month chemoprevention ([~]96-216 mg). We have improved unbound MPC and predicted human clearance by 18-fold and 10-fold respectively when compared to KAF156.

microbiology↗

bioRxiv2024

Dendritic cell targeting in lymph nodes with engineered modular adapters improves HAdV5 and HC-HAdV5 tumor vaccination by co-secretion of IL-2v and IL-21

Adenoviral vectors demonstrate encouraging clinical outcomes for B- and T-cell vaccines. With such approaches, multiple payloads can be delivered, beyond the antigen itself. Nevertheless, the human adenoviral vector serotype C5 (HAdV5) exhibits limited transduction efficiency to dendritic cells (DC), therefore necessitating very high viral loads. Targeting antigen-presenting cells (APC) has remained challenging. To solve this problem, we developed a versatile platform that employs modular retargeting adapters to enhance transduction of specific cell types, including challenging host cells. By rational design, we constructed a dual-adapter for DC-SIGN and CD11c and demonstrate successful targeting of HAdV5 to human and murine DCs. Our in vivo characterization highlights improved and specific transduction of DCs in draining lymph nodes. Moreover, a tumor vaccination study showcases the advantageous co-expression of T cell stimulatory cytokines (IL-2v or IL-21) locally in lymph nodes alongside a potent tumor antigen. Lymph node-directed gene therapy at significantly reduced vector loads circumvents potential systemic toxicity of stimulating payloads. Our proposed low-dosage DC-targeted vaccine offers an effective solution for patients and also minimizes potential adenovirus-related side-effects. The robust immunogenicity of HC-HAdV5, with its large coding capacity (37 kbp DNA), opens up exciting possibilities for future therapeutic combination strategies.

biochemistry↗

bioRxiv2023

Osteopontin in colitis-associated carcinoma

Patients with ulcerative colitis (UC) and Crohns disease (CD) face a lifelong risk of developing colitis-associated carcinoma (CAC). Current insights into CAC development originate from murine CAC models, while human CAC studies primarily focus on mutational analysis of patient samples. Although the mutational landscape reveals distinct patterns and frequencies compared to colorectal cancer, it falls short in elucidating the inflammatory mechanisms of CAC development. Consequently, we adopted a multi-omics approach to unravel CAC carcinogenesis from an immunological perspective. Our data revealed a robust upregulation of SPP1 gene in CAC at both RNA and protein levels, expressed by CD68+ macrophages. In vitro OPN stimulation demonstrated no direct effect on intestinal epithelial organoids. However, the mutually exclusive spatial location of SPP1/OPN+ macrophages and CD8+ T cells suggests a crucial indirect role of SPP1/OPN in mediating an immunosuppressive tumour microenvironment.

cancer biology↗

bioRxiv2023

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Covalent Warhead

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof towards human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = PaxlovidTM), CMX990 has distinctly differentiated potency ([~]5x more potent in primary cells) and human in vitro clearance (>4x better microsomal clearance and >10x better hepatocyte clearance), with good in vitro-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

microbiology↗

bioRxiv2023

Cebranopadol, a novel long-acting opioid agonist with low abuse liability, to treat opioid use disorder: Preclinical evidence of efficacy

The gold standard pharmacological treatment for opioid use disorder (OUD) consists of maintenance therapy with long-acting opioid agonists such as buprenorphine and methadone. Despite these compounds having demonstrated substantial efficacy, a significant number of patients do not show optimal therapeutic responses. Moreover, the abuse liability of these medications remains a major concern. Cebranopadol, is a new, long-acting pan-opioid agonist that also activates the nociception/orphanin FQ NOP receptor. Here we used rats to explore the therapeutic potential of this agent in OUD. First, in operant intravenous self-administration experiments we compared the potential abuse liability of cebranopadol with the prototypical opioid heroin. Under a fixed ratio 1 (FR1) contingency, rats maintained responding for heroin (1, 7, 20, 60 g/inf) to a larger extent than cebranopadol (0.03, 0.1, 0.3, 1.0, 6.0 g/inf). When the contingency was switched to a progressive ratio (PR) reinforcement schedule, heroin maintained responding at high levels at all except the lowest dose. Conversely, in the cebranopadol groups responding decreased drastically and the break point (BP) did not differ from saline controls. Next, we demonstrated that oral administration of cebranopadol (0, 25, 50 g/kg) significantly attenuated drug self-administration independent of heroin dose (1, 7, 20, 60 g/inf). Cebranopadol also reduced the break point for heroin (20 g/inf). Furthermore, in a heroin self-administration training extinction/reinstatement paradigm, pretreatment with cebranopadol significantly attenuated yohimbine stress-induced reinstatement of drug seeking. Together, these data indicate that cebranopadol has limited abuse liability compared to heroin and is highly efficacious in attenuating opioid self-administration and stress-induced reinstatement, suggesting clinical potential of this compound for OUD treatment.

pharmacology and toxicology↗

bioRxiv2023

Sulfate limitation increases specific pDNA yield in E. coli fed-batch processes

Plasmid DNA (pDNA) is a key biotechnological product whose importance became apparent in the last years due to its role as a raw material in the messenger ribonucleic acid (mRNA) vaccine manufacturing process. In pharmaceutical production processes, cells need to grow in the defined medium in order to guarantee the highest standards of quality and repeatability. However, often these requirements result in low product titer, productivity, and yield. In this study, we used constraint-based metabolic modeling to optimize the average volumetric productivity of pDNA production in a fed-batch process. We identified a set of 13 nutrients in the growth medium that are essential for cell growth but not for pDNA replication. When these nutrients are depleted in the medium, cell growth is stalled and pDNA production is increased, raising the specific and volumetric yield and productivity. To exploit this effect we designed a three-stage process (1. batch, 2. fed-batch with cell growth, 3. fed-batch without cell growth). The transition between stage 2 and 3 is induced by sulfate starvation. Its onset can be easily controlled via the initial concentration of sulfate in the medium. We validated the decoupling behavior of sulfate and assessed pDNA quality attributes (supercoiled pDNA content) in E. coli with lab-scale bioreactor cultivations. The results showed an increase in supercoiled pDNA to biomass yield by 33 % and an increase of supercoiled pDNA volumetric productivity by 13 % upon limitation of sulfate. In conclusion, even for routinely manufactured biotechnological products such as pDNA, simple changes in the growth medium can significantly improve the yield and quality. HighlightsO_LIGenome-scale metabolic models predict growth decoupling strategies. C_LIO_LISulfate limitation decouples cell growth from pDNA production. C_LIO_LISulfate limitation increases the specific supercoiled pDNA yield by 33 % and the volumetric productivity by 13 %. C_LIO_LIWe propose that sulfate limitation improves the biosynthesis of over 25 % of naturally secreted products in E. coli. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/527815v4_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@68fdccorg.highwire.dtl.DTLVardef@ee8e8dorg.highwire.dtl.DTLVardef@1d0f99eorg.highwire.dtl.DTLVardef@b42744_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2022

Multi-site assessment of reproducibility in high-content live cell imaging data

High-content image-based cell phenotyping provides fundamental insights in a broad variety of life science areas. Striving for accurate conclusions and meaningful impact demands high reproducibility standards, even more importantly with the advent of data sharing initiatives. However, the sources and degree of biological and technical variability, and thus the reproducibility and usefulness of meta-analysis of results from live-cell microscopy have not been systematically investigated. Here, using high content data describing features of cell migration and morphology, we determine the sources of variability across different scales, including between laboratories, persons, experiments, technical repeats, cells and time points. Significant technical variability occurred between laboratories, providing low value to direct meta-analysis on the data from different laboratories. However, batch effect removal markedly improved the possibility to combine image-based datasets of perturbation experiments. Thus, reproducible quantitative high-content cell image data and meta-analysis depend on standardized procedures and batch correction applied to studies of perturbation effects.

cell biology↗

bioRxiv2019

Genome-wide analysis of diet and gene interactions in Drosophila uncovers the glucose transporter, CG4607, as a diet-responsive gene.

Genetic and environmental factors play a major role in metabolic health. However, they do not act in isolation, as a change in an environmental factor such as diet may exert different effects based on an individuals genotype. Here, we sought to understand how such gene-diet interactions influenced nutrient storage and utilisation, a major determinant of metabolic disease. We subjected the Drosophila Genetic Reference Panel (DGRP), comprising 200 genetically divergent inbred fly strains, to diets varying in sugar, fat and protein. We assessed starvation resistance, a holistic phenotype of nutrient storage and utilisation that can be robustly measured. Diet influenced the starvation resistance of each strain, but this effect varied markedly between strains. This demonstrates that genetics plays a major role in the response to diet. Furthermore, heritability analysis revealed that the greatest variability arose from diets either high in sugar or high in protein. To uncover the genetic underpinnings of this variation, we mapped 1,239 diet-responsive SNPs in 534 genes, 325 of which have human orthologues. Using whole-body knockdown, we confirmed that 30 candidate genes were required for glucose tolerance, storage and utilization. In particular, we characterised CG4607, a GLUT6/GLUT8 homolog, as a key protein involved in sugar tolerance. Overall, this provides strong evidence that genetics is a major contributor to how individuals respond to diets of varying nutrient composition. It is likely that a similar principle may be applied to metabolic disease in higher organisms thus supporting the case for nutrigenomics as an important health strategy.

genetics↗

bioRxiv2019

No atypical white-matter structures in grapheme- or color-sensitive areas in synesthetes

Grapheme-color synesthetes experience colors when presented with written language characters. In this study diffusion-weighted imaging was used to investigate white matter alterations in color-and grapheme-processing brain areas in synesthetes as a possible factor for the color sensations. Regions of interest were defined by means of neuroanatomical atlantes, functional localizer tasks and retinotopic mapping. None of the regions showed differences in white matter structure between synesthetes and a control population, as revealed by fractional anisotropy and mean diffusivity measures. Quite the contrary, the data broadly supported the null hypothesis of no group differences in white matter microstructure. This finding is in line with recent studies suggesting no atypical neuroanatomy in grapheme-color synesthetes.

neuroscience↗

bioRxiv2017

A rainfall-manipulation experiment with 517 Arabidopsis thaliana accessions

The gold standard for studying natural selection and adaptation in the wild is to quantify lifetime fitness of individuals from natural populations that have been grown together in a common garden, or that have been reciprocally transplanted. By combining fitness values with species traits and genome sequences, one can infer selection coefficients at the genetic level. Here we present a rainfall-manipulation experiment with 517 whole-genome sequenced natural accessions of the plant Arabidopsis thaliana spanning the global distribution of the species. The experiments were conducted in two field stations in contrasting climates, in the Mediterranean and in Central Europe, where we built rainout shelters and simulated high and low rainfall. Using custom image analysis we quantified fitness- and phenology-related traits for 23,154 pots, which contained about 14,500 plants growing independently, and over 310,000 plants growing in small populations (max. 30 plants). This large field experiment dataset, which associates fitness and ecologically-relevant traits with genomes, will provide an important resource to test eco-evolutionary genetic theories and to understand the potential evolutionary impacts of future climates on an important plant model species.

evolutionary biology↗