Biology subjects

Voss, M.

Publications and source records attributed to Voss, M..

14 recordsLinked to original sources

bioRxiv2026

Determination of diagnostic cycle threshold (Ct) cut-offs for qPCR-based prevalence surveys of soil-transmitted helminth infections

WHO guidelines for control of soil-transmitted helminths (STH) rely on coproscopic methods to assess population prevalence. In low-prevalence and light-intensity STH settings, quantitative PCR (qPCR) has higher sensitivity and specificity for detection. For qPCR to accurately identify transmissible infections of public health significance, it is essential to interpret the qPCR cycle threshold (Ct) results. As part of the DeWorm3 community-based cluster randomized trial on interrupting STH transmission, we conducted population-based surveys using high-throughput qPCR and aimed to establish appropriate Ct cut-offs to detect transmissible infections. Experimental approaches including egg and genome-equivalent spiking experiments were hindered by inefficient fecal DNA extraction despite optimization efforts. The Ct results for 29,980 samples (pre-intervention, cross-sectional surveys) revealed a bimodal distribution for two of the four species tested, N. americanus and A. lumbricoides. The first peak was assumed to represent transmissible infections, and the second peak to represent indeterminate or non-transmissible infections. Using a finite mixture model, we defined true qPCR positivity as any Ct result with a [≥]5% chance of belonging to the first peak. This approach yielded Ct cut-offs of 34.4398 for N. americanus and 28.57587 for A. lumbricoides. For hookworms, sensitivity of qPCR was 96.7%, compared to 73.2% for Kato-Katz and moderate- to heavy-intensity infections (median Ct: 19.1, interquartile range [IQR]: 17.9-19.8) were differentiated from light-intensity infections and Kato-Katz negative samples (25.3, IQR: 22.5-27.9). Our findings demonstrate the feasibility and utility of evidence-based Ct cut-offs to identify transmissible STH infections in large scale surveys, and to categorize infection intensity as programmatically relevant. Author SummaryQuantitative PCR (qPCR) has been used for the detection of soil-transmitted helminths but with limited emphasis on determining cycle threshold (Ct) cut-offs to accurately identify transmissible infections which are of public health significance. When qPCR is used to assess interventions, or, in the future, to potentially make programmatic decisions, it will be crucial to validate positivity criteria to avoid underestimation (false negatives) or overestimation (false positives) of results. As part of the DeWorm3 trial, a community-based cluster randomized trial on interrupting transmission of STH, we developed and applied a validated STH qPCR to test 29,980 samples collected pre-intervention and explored experimental approaches to establish assay-specific Ct cut-offs. The Ct values from these samples showed a bimodal distribution for N. americanus and A. lumbricoides, suggesting the presence of two distinct groups. For this reason, a statistical approach with a finite mixture model was employed to determine Ct cut-offs that differentiated epidemiologically relevant, transmissible, egg-positive STH infections from those that are likely to represent detection of non-transmissible DNA or indeterminate results. While our data were applied in three different country settings, India, Benin and Malawi, it is important to note that no single Ct cut-off may be applicable across all epidemiological scenarios. Our findings demonstrate the feasibility of developing evidence-based Ct cut-offs with high sensitivity to accurately detect transmissible STH infections in large scale surveys.

microbiology↗

bioRxiv2025

Integrated histopathologic modeling of detailed tumor subtypes and actionable biomarkers

Accurate cancer subtyping with accompanying molecular characterization is critical for precision oncology. While machine learning approaches have been applied to both digital pathology and cancer genomics, previous work has been limited in sample size and has typically aggregated granular cancer subtypes into coarse groupings, likely obfuscating informative molecular and prognostic associations and phenotypic variation of more detailed tumor subtypes. Accordingly, we collated 378,123 hematoxylin and eosin (H&E)-stained whole-slide images (WSIs) with matched targeted DNA clinical sequencing results and OncoTree detailed cancer subtypes from a real-world cohort of 71,142 patients. Using this scaled, granular dataset and a cancer subtype knowledge graph, we developed Mosaic: a family of calibrated machine learning models using H&E WSI embeddings to classify tumors and identify molecular phenotypes across 163 detailed subtypes. The cancer subtyping module (Aeon) achieved an area under the receiver operating characteristic curve (AUROC) of 0.992 overall, with 161/163 subtypes reaching an AUROC [≥] 0.90 and improved performance over a state-of-the-art genomics-based classifier. The genomic inference module (Paladin) achieved an AUROC [≥] 0.80 for 167 pairs of detailed subtypes and genomic targets. We further used the learned histopathologic representations to i) identify key associations of the histopathologic embeddings with clinical biomarkers; ii) identify unsupervised sub-clusters of tumors with genomic determinants of tumor phenotype; iii) specify granular diagnoses for cancers of unknown primary, evaluated by genomic associations and expected clinical outcome distributions; iv) annotate functional significance for variants of uncertain significance (VUS); and v) identify cases that mimic the phenotypic effect of known DNA variants on H&E in the absence of detectable DNA alterations. Taken together, this work advances our understanding of phenotypic variation of granular tumor subtypes, their relevance to enhanced diagnostics, and their potential utility in risk stratification with multimodal machine learning in cancer.

cancer biology↗

bioRxiv2024

Accessing the specific capacity of TIL-derived CD8 T-cells to suppress tumor recurrence in resectable HBV-HCC patients

BackgroundHepatocellular carcinoma represents a significant global health challenge, affecting over a million patients annually, arising mainly from chronic liver diseases, with a majority being related to viral infections. However, despite the groundbreaking clinical results of immune checkpoint blockades and adoptive cell therapies, we still face non-responders accompanied by high rebound rates after resection. Considering that the main concern is to overcome a highly specialized immunosuppressive tumor microenvironment of the individual patient, the characterization of the particular tumor microenvironment and the source of the immune cells used in ACT is of immense importance. Approved ACT therapies mainly use modified peripheral blood cells from individuals. At the same time, tumor-infiltrating lymphocytes are underrepresented even if they have garnered interest due to their potential to target tumor-specific antigens more effectively. MethodsIn this study, we employed allogenic and autologous immune cell sources for expansion and stimulation, resulting in adoptive T-cell transfer experiments determining the effector cell differentiation and the related anti-tumor effects by the possible implementation of re-stimulation. ResultsWe determined a high success rate in expanding and stimulating tumor-infiltrating lymphocytes with consistent CD8 T-cell fractions from HCC patients. To showcase the effectiveness of stimulated T-cells from different sources, we generated cell lines derived from the margin and center of an HBV-induced HCC with a highly immune-suppressive TME. We found effective immune responses supported by cell death induction, ferroptosis, proptosis and apoptosis triggered by all sources of T-cells depending on the area of derived tumor cells. ConclusionEffector T-cell fractions derived from tumor-infiltrating lymphocytes present a viable source for cell-based immune therapy combined with immune checkpoint inhibitors in HCC patients, especially after resection, to suppress rebound strategies of the parental tumor on an individual level.

immunology↗

bioRxiv2024

Ex-vivo expansion of patient-derived PBMCs preferentially results in effector memory T-cell proliferation with restored autologous efficiency in HBV-HCC

BackgroundT-cell-based therapies achieved milestones in targeting solid tumors, such as hepatocellular carcinoma, by leveraging the cytotoxic potential of effector memory T-cells. However, a key challenge lies in the ex-vivo expansion of functional memory T-cells while simultaneously preventing over-differentiation into senescent TEMRA cells. MethodsPBMC derived from 10 HCC patients and two healthy donors were used for expansion in small bioreactors equipped with a permeable membrane for 2 weeks. During expansion, surface marker composition, cytokine and chemokine production were observed. Enriched T-cell subsets from three patients with chronic HBV infection were analysed in detail. We extracted the enriched complement of one chronically infected patient to elucidate the therapeutic potential. ResultsWe successfully expanded the effector T-cell subsets for all investigated samples and consistently enriched the cell amount over time. Subsequently, we showed that the expanded patient-derived T-cells showed functionality against autologous liver cancer-derived cells by inducing receptor and protein-mediated cell death. ConclusionWe showed the consistent ex-vivo expansion of T-cell subsets of initial patient-derived PBMCs. The enriched subsets exhibit cytotoxic functionality and shift to cytolytic TEMRA cells in an immune evasion setting in the context of chronic HBV-infected patient-derived liver cancer cells.

immunology↗

bioRxiv2023

Global functional connectivity of cognitive control network predicts task-switching performance in older adults

Executive Function (EF) is a complex higher order cognitive process that involves integrating subprocesses of attention, working memory, inhibition, and task switching and known to be one of the first cognitive functions to be affected by age related declines. Global Functional Connectivity (GFC), a measure of whole brain connectivity in brain networks such as the Cognitive Control Network (CCN), has been shown to measure the maintained EF abilities in older adults with cognitive impairment. However, this relationship has not been explored in a sample comprised of mostly cognitively normal older adults nor with the use of an experimental EF task sensitive to sub-processes most sensitive to aging. Task-switch paradigm studies have shown age-related deficits in holding and responding to rule sets while inhibiting another rule set in working memory (i.e., mixing cost). The present study aims to elucidate the relationship seen in EF performance using GFC and leveraging a task-switch paradigm that manipulates response overlap to increase cognitive demands on switching between tasks (e.g., mixing cost). Results show that greater negative DMN GFC coincides with older adults lower mixing costs, not CCN GFC. Findings indicate that DMN GFC, not CCN, may be important for EF performance in older adults.

neuroscience↗

bioRxiv2023

Antigenic cartography using variant-specific hamster sera reveals substantial antigenic variation among Omicron subvariants

SARS-CoV-2 has developed substantial antigenic variability. As the majority of the population now has pre-existing immunity due to infection or vaccination, the use of experimentally generated animal immune sera can be valuable for measuring antigenic differences between virus variants. Here, we immunized Syrian hamsters by two successive infections with one of eight SARS-CoV-2 variants. Their sera were titrated against 14 SARS-CoV-2 variants and the resulting titers visualized using antigenic cartography. The antigenic map shows a condensed cluster containing all pre-Omicron variants (D614G, Alpha, Delta, Beta, Mu, and an engineered B.1+E484K variant), and a considerably more distributed positioning among a selected panel of Omicron subvariants (BA.1, BA.2, BA.4/5, the BA.5 descendants BF.7 and BQ.1.18; the BA.2.75 descendant BN.1.3.1; and the BA.2-derived recombinant XBB.2). Some Omicron subvariants were as antigenically distinct from each other as the wildtype is from the Omicron BA.1 variant. The results highlight the potential of using variant-specifically infected hamster sera for the continued antigenic characterisation of SARS-CoV-2.

immunology↗

bioRxiv2023

Functional genomics identifies extension of complex N-glycans as a mechanism to evade lysis by natural killer cells

Somatic mutations can lead to the transformation of healthy cells into malignant cells and allow their evasion from immune surveillance. To uncover genes that play a role in the detection and lysis of tumor cells by natural killer (NK) cells, a B lymphoblastoid cell line was subjected to a genome-wide CRISPR screen. Among the top hits that facilitated NK evasion was SPPL3, which encodes an intramembrane protease that cleaves transmembrane glycosyltransferases in the Golgi apparatus. SPPL3-deficient cells accumulated glycosyltransferases, such as acetylglucosaminyltransferase 5 (MGAT5), and displayed increased N-glycosylation. Binding of NK receptors NKG2D and CD2 to their corresponding ligands MICB and CD58, and binding of rituximab to CD20, was disrupted by SPPL3-deletion. Inhibition of N-glycan maturation restored receptor binding and sensitivity to NK cells. To elucidate the mechanism of this resistant phenotype, a secondary CRISPR screen was performed in SPPL3-deficient cells. This screen identified glycosyltransferases that catalyze the formation of highly branched N-glycans and N-acetyl-lactosamine (LacNAc) extensions as key regulators that prevent killing. A significant enrichment of poly-LacNAc-containing tetra-antennary species was confirmed by glycoproteomic analysis. These findings provide mechanistic insight into how SPPL3 deletions have been linked to cancer.

immunology↗

bioRxiv2022

An Interplay of Phytoplankton Donor Species and Transformation of Released Compounds over Time Defines Bacterial Communities Following Phytoplankton DOMp Pulses

Phytoplankton-bacteria interactions are stimulated by phytoplankton-released dissolved organic matter (DOMp). Two factors that shape the accompanying bacterial community are i) the "donor" phytoplankton species, defining the initial composition of released DOMp, and ii) the DOMp transformation over time. We added phytoplankton DOM from two globally abundant species - the diatom Skeletonema marinoi and the cyanobacterium Prochlorococcus MIT9312 - to natural bacterial communities in the Eastern Mediterranean and determined the bacterial responses over a time-course of 72 h in terms of cell numbers, bacterial production (BP), alkaline phosphatase activity (APA), and changes in active bacterial community compositions based on rRNA amplicon sequencing. Both DOMp types were demonstrated to serve the bacterial community as carbon and potentially phosphorus source. Diatom-derived DOM induced higher BP and lower APA compared to cyanobacterium DOM after 24 h, but not after 48 and 72 h of incubation, and also maintained higher Shannon diversities over the course of the experiment, indicating a better bacterial accessibility and broader disposability of diatom derived DOM. Bacterial communities significantly differed between DOMp types as well as different incubation times, pointing to a certain bacterial specificity for the DOMp donor as well as a successive utilization of phytoplankton DOM by different bacterial taxa. The highest differences in bacterial community composition with DOMp types occurred shortly after additions, suggesting a high specificity towards highly bioavailable DOMp compounds. We conclude that phytoplankton associated bacterial communities are strongly shaped by an interplay between phytoplankton donor and the transformation of its released DOMp over time. IMPORTANCEPhytoplankton-bacteria interactions maintain biogeochemical cycles of global importance. Phytoplankton photosynthetically fix carbon dioxide and subsequently release the synthesized compounds as dissolved organic matter (DOMp), which becomes processed and recycled by heterotrophic bacteria. Yet, the combined effect of the phytoplankton donor species and time-dependent transformation of DOMp compounds on the accessibility to the bacterial community has not been explored until now. The diatom Skeletonema marinoi and the cyanobacterium Prochlorococcus MIT9312 are globally important phytoplankton species, and our study revealed that DOMp of both species was selectively incorporated by the bacterial community. The donor species had the highest impact shortly after DOMp appropriation, and its effect diminished over time. Our results improve the understanding of biogeochemical cycles between phytoplankton and bacteria, and solve yet unresolved questions of phytoplankton-bacteria interactions.

microbiology↗

bioRxiv2022

Significant organic carbon acquisition by Prochlorococcus in the oceans

Marine phytoplankton are responsible for about half of the photosynthesis on Earth. Many are mixotrophs, combining photosynthesis with heterotrophic assimilation of organic carbon but the relative contribution of these two carbon sources is not well quantified. Here, single-cell measurements reveal that Prochlorococcus at the base of the photic zone in the Eastern Mediterranean Sea are obtaining only ~20% of carbon required for growth by photosynthesis. Consistently, laboratory-calibrated evaluations of Prochlorococcus photosynthesis indicate that carbon fixation is systematically too low to support published in situ growth rates in the deep photic layer of the Pacific Ocean. Furthermore, agent-based model simulations show that mixotrophic cells maintain realistic growth rates and populations 10s of meters deeper than obligate photo-autotrophs, deepening the nutricline and Deep Chlorophyll Maximum by ~20 m. Time-series of Prochlorococcus ecotype-abundance from the subtropical North Atlantic and North Pacific suggest that up to 30% of the Prochlorococcus cells live where light intensity is not enough to sustain obligate photo-autotrophic populations during warm, stratified periods. Together, these data and models suggest that mixotrophy underpins the ecological success of a large fraction of the global Prochlorococcus population and its collective genetic diversity.

microbiology↗

bioRxiv2021

Brain structure and function predict adherence to an exercise intervention in older adults

Individualized and precision medicine approaches to exercise for cognitive and brain health in aging have the potential to improve intervention efficacy. Predicting adherence to an exercise intervention in older adults prior to its commencement will allow for adaptive and optimized approaches that could save time (no need to demonstrate failure before changing course) and money (cost of de-implementing approaches that do not work for certain individuals) which ultimately could improve health outcomes (e.g., preventative medicine approaches prior to the onset of symptoms). Individual differences in brain structure and function in older adults are potential proxies of brain and brain reserve or maintenance and may provide strong predictions of adherence. We hypothesized that brain-based measures would predict adherence to a six-month randomized controlled trial of exercise in older adults, alone and in combination with psychosocial, cognitive and health measures. In 131 older adults (aged 65.79 {+/-} 4.65 years, 63% female) we found, using regularized elastic net regression within a nested cross-validation framework, that brain structure (cortical thickness and cortical surface area) in somatosensory, inferior temporal, and inferior frontal regions and functional connectivity (degree count) in primary information processing (somatosensory, visual), executive control, default, and attentional networks, predicted exercise adherence (R2 = 0.15, p < 0.001). Traditional survey and clinical measures such as gait and walking self-efficacy, biological sex and perceived stress also predicted adherence (R2 = 0.06, p = 0.001) but a combined multimodal model achieved the highest predictive strength (R2 = 0.22, p <0.001). Neuroimaging features alone can predict adherence to a structured group-based exercise intervention in older adults which suggests there is substantial utility of these measures for future research into precision medicine approaches. The best performing model contained multimodal features suggesting that each modality provided independent relevant information in the prediction of exercise adherence.

neuroscience↗

bioRxiv2021

Phytoplankton exudates provide full nutrition to a subset of accompanying heterotrophic bacteria via carbon, nitrogen and phosphorus allocation

Marine bacteria rely on phytoplankton exudates as carbon sources (DOCp). Yet, it is unclear to what extent phytoplankton exudates also provide nutrients such as phytoplankton-derived N and P (DONp, DOPp). We address these questions by exudate addition experiments from the ubiquitous pico-cyanobacterium Prochlorococcus to contrasting ecosystems in the Eastern Mediterranean - a coastal and an open-ocean, oligotrophic station. Nutrient addition did not lower the incorporation of exudate DONp, nor did it reduce alkaline phosphatase activity, suggesting that bacterial communities are able to exclusively cover their nitrogen and phosphorus demands with organic forms provided by phytoplankton exudates. Approximately half of the cells in each ecosystem took up detectable amounts of Prochlorococcus-derived C and N, yet based on 16S rRNA sequencing different bacterial genera were responsible for the observed exudate utilization patterns. In the coastal community, several phylotypes of Aureimarina, Psychrosphaera and Glaciecola responded positively to the addition of phytoplankton exudates, whereas phylotypes of Pseudoalteromonas increased and dominated the open ocean communities. Together, our results strongly indicate that phytoplankton exudates provide coastal and open-ocean bacterial communities with organic carbon, nitrogen and phosphorus, and that phytoplankton exudate serve a full-fledged meal for specific members of the accompanying bacterial community in the nutrient-poor eastern Mediterranean.

ecology↗

bioRxiv2019

Distinctive tasks of different cyanobacteria and associated bacteria in carbon as well as nitrogen fixation and cycling in a late stage Baltic Sea bloom

Cyanobacteria and associated heterotrophic bacteria hold key roles in carbon as well as nitrogen fixation and cycling in the Baltic Sea due to massive cyanobacterial blooms each summer. The species specific activities of different cyanobacterial species as well as the N- and C-exchange of associated heterotrophic bacteria in these processes, however, are widely unknown. Within one time series experiment we tested the cycling in a natural, late stage cyanobacterial bloom by adding 13C bi-carbonate and 15N2, and performed sampling after 10 min, 30 min, 1 h, 6 h and 24 h in order to determine the fixing species as well as the fate of the fixed carbon and nitrogen in the associations. Uptake of 15N and 13C isotopes by the most abundant cyanobacterial species as well as the most abundant associated heterotrophic bacterial groups was then analysed with a NanoSIMS. Overall, the filamentous, heterocystous species Dolichospermum sp., Nodularia sp., and Aphanizomenon sp. revealed no or erratic uptake of carbon and nitrogen, indicating mostly inactive cells. In contrary, non-heterocystous Pseudanabaena sp. dominated the nitrogen and carbon fixation, with uptake rates up to 1.49 {+/-} 0.47 nmol N h-1 l-1 and 2.55 {+/-} 0.91 nmol C h-1 l-1. Associated heterotrophic bacteria dominated the subsequent nitrogen cycling with uptake rates up to 1.2 {+/-} 1.93 fmol N h-1 cell -1, but were also indicative for fixation of di-nitrogen.

ecology↗

bioRxiv2019

Prochlorococcus rely on microbial interactions rather than on chlorotic resting stages to survive long-term stress

Many microorganisms produce resting cells with very low metabolic activity that allow them to survive phases of prolonged nutrient or energy stress. In cyanobacteria and some eukaryotic phytoplankton, the production of resting stages is accompanied by a loss of photosynthetic pigments, a process termed chlorosis. Here, we show that a chlorosis-like process occurs under multiple stress conditions in axenic laboratory cultures of Prochlorococcus, the dominant phytoplankton linage in large regions of the oligotrophic ocean and a global key player in ocean biogeochemical cycles. In Prochlorococcus strain MIT9313, chlorotic cells show reduced metabolic activity, measured as C and N uptake by NanoSIMS. However, unlike many other cyanobacteria, chlorotic Prochlorococcus cells are not viable and do not re-grow under axenic conditions when transferred to new media. Nevertheless, co-cultures with a heterotrophic bacterium, Alteromonas macleodii HOT1A3, allowed Prochlorococcus to survive nutrient starvation for months. We propose that reliance on co-occurring heterotrophic bacteria, rather than the ability to survive extended starvation as resting cells, underlies the ecological success of Prochlorococcus. ImportanceThe ability of microorganisms to withstand long periods of nutrient starvation is key to their survival and success under highly fluctuating conditions as is common in nature. Therefore, one would expect this trait to be prevalent among organisms in the nutrient-poor open ocean. Here, we show that this is not the case for Prochlorococcus, a globally abundant and ecologically impactful marine cyanobacterium. Instead, Prochlorococcus rely on co-occurring heterotrophic bacteria to survive extended phases of nutrient and light starvation. Our results highlight the power of microbial interactions to drive major biogeochemical cycles in the ocean and elsewhere with consequences at the global scale.

microbiology↗

bioRxiv2017

Surgically disconnected temporal pole exhibits resting functional connectivity with remote brain regions

Functional connectivity, as measured by resting-state fMRI, has proven a powerful method for studying brain systems in the context of behavior, development, and disease states. However, the relationship of functional connectivity to structural connectivity remains unclear. If functional connectivity relies on structural connectivity, then anatomical isolation of a brain region should eliminate functional connectivity with other brain regions. We tested this by measuring functional connectivity of the surgically disconnected temporal pole in resection patients (N=5; mean age 37; 2F, 3M). Functional connectivity was evaluated based on coactivation of whole-brain fMRI data with the average low-frequency BOLD signal from disconnected tissue in each patient. In sharp contrast to our prediction, we observed significant functional connectivity between the disconnected temporal pole and remote brain regions in each disconnection case. These findings raise important questions about the neural bases of functional connectivity measures derived from the fMRI BOLD signal.

neuroscience↗