Insight
is our reward

Publications in Applied Sciences by NOMIS researchers

NOMIS Researcher(s)

Published in

December 1, 2021

Background: The rapid expansion of the CRISPR toolbox through tagging effector domains to either enzymatically inactive Cas9 (dCas9) or Cas9 nickase (nCas9) has led to several promising new gene editing strategies. Recent additions include CRISPR cytosine or adenine base editors (CBEs and ABEs) and the CRISPR prime editors (PEs), in which a deaminase or reverse transcriptase are fused to nCas9, respectively. These tools hold great promise to model and correct disease-causing mutations in animal and plant models. But so far, no widely-available tools exist to automate the design of both BE and PE reagents. Results: We developed PnB Designer, a web-based application for the design of pegRNAs for PEs and guide RNAs for BEs. PnB Designer makes it easy to design targeting guide RNAs for single or multiple targets on a variant or reference genome from organisms spanning multiple kingdoms. With PnB Designer, we designed pegRNAs to model all known disease causing mutations available in ClinVar. Additionally, PnB Designer can be used to design guide RNAs to install or revert a SNV, scanning the genome with one CBE and seven different ABE PAM variants and returning the best BE to use. PnB Designer is publicly accessible at http://fgcz-shiny.uzh.ch/PnBDesigner/ Conclusion: With PnB Designer we created a user-friendly design tool for CRISPR PE and BE reagents, which should simplify choosing editing strategy and avoiding design complications.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Bioinformatics

NOMIS Researcher(s)

Published in

August 1, 2021

Spin qubits are considered to be among the most promising candidates for building a quantum processor. Group IV hole spin qubits are particularly interesting owing to their ease of operation and compatibility with Si technology. In addition, Ge offers the option for monolithic superconductor–semiconductor integration. Here, we demonstrate a hole spin qubit operating at fields below 10 mT, the critical field of Al, by exploiting the large out-of-plane hole g-factors in planar Ge and by encoding the qubit into the singlet-triplet states of a double quantum dot. We observe electrically controlled g-factor difference-driven and exchange-driven rotations with tunable frequencies exceeding 100 MHz and dephasing times of 1 μs, which we extend beyond 150 μs using echo techniques. These results demonstrate that Ge hole singlet-triplet qubits are competing with state-of-the-art GaAs and Si singlet-triplet qubits. In addition, their rotation frequencies and coherence are comparable with those of Ge single spin qubits, but singlet-triplet qubits can be operated at much lower fields, emphasizing their potential for on-chip integration with superconducting technologies.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Nanoscience & Nanotechnology

NOMIS Researcher(s)

Published in

July 1, 2021

Effective fisheries management is necessary for the long-term sustainability of fisheries and the economic benefits that they provide, but focusing only on ecological sustainability risks disregarding ultimate goals related to well-being that must be achieved through broader social policy. An analysis of global landings data shows that average fishing wages in 36%–67% of countries, home to 69%–95% of fishers worldwide, are likely below their nationally determined minimum living wage (which accounts for costs of food, shelter, clothing, health and education). Furthermore, even if all fisheries in every country were perfectly managed to achieve their Maximum Sustainable Yield, a common sustainability target, average incomes of fishers in up to 49 countries—70% of fishers worldwide—would still not meet minimum living wages. Access to decent work and livelihoods are fundamental human rights, including for all fisherfolk around the world, and strategies to support their well-being must therefore integrate a much wider set of perspectives, disciplines and institutions. Key first steps for fisheries researchers are to more fully recognize and estimate fisheries benefits to households—including income from women and/or alternative employment, unreported landings, or shadow values of subsistence catch—and to help identify and learn from economic equity outcomes in rebuilt fisheries around the world.

Research field(s)
Applied Sciences, Agriculture, Fisheries, Fisheries & Forestry, Fisheries

NOMIS Researcher(s)

Published in

April 1, 2021

To improve the prognosis of cancer patients, methods of local cancer detection and treatment could be implemented. For that, iron-based nanomaterials (IBN) are particularly well-suited due to their biocompatibility and the various ways in which they can specifically target a tumor, i.e. through passive, active or magnetic targeting. Furthermore, when it is needed, IBN can be associated with well-known fluorescent compounds, such as dyes, clinically approved ICG, fluorescent proteins, or quantum dots. They may also be excited and detected using well-established optical methods, relying on scattering or fluorescent mechanisms, depending on whether IBN are associated with a fluorescent compound or not. Systems combining IBN with optical methods are diverse, thus enabling tumor detection in various ways. In addition, these systems provide a wealth of information, which is inaccessible with more standard diagnostic tools, such as single tumor cell detection, in particular by combining IBN with near-field scanning optical microscopy, dark-field microscopy, confocal microscopy or super-resolution microscopy, or the highlighting of certain dynamic phenomena such as the diffusion of a fluorescent compound in an organism, e.g. using fluorescence lifetime imaging, fluorescence resonance energy transfer, fluorescence anisotropy, or fluorescence tomography. Furthermore, they can in some cases be complemented by a therapeutic approach to destroy tumors, e.g. when the fluorescent compound is a drug, or when a technique such as photo-thermal or photodynamic therapy is employed. This review brings forward the idea that iron-based nanomaterials may be associated with various optical techniques to form a commercially available toolbox, which can serve to locally detect or treat cancer with a better efficacy than more standard medical approaches. Statement of Significance: New tools should be developed to improve cancer treatment outcome. For that, two closely-related aspects deserve to be considered, i.e. early tumor detection and local tumor treatment. Here, I present various types of iron-based nanomaterials, which can achieve this double objective when they interact with a beam of light under specific and accurately chosen conditions. Indeed, these materials are biocompatible and can be used/combined with most standard microscopic/optical methods. Thus, these systems enable on the one hand tumor cell detection with a high sensitivity, i.e. down to single tumor cell level, and on the other hand tumor destruction through various mechanisms in a controlled and localized manner by deciding whether or not to apply a beam of light and by having these nanomaterials specifically target tumor cells.

Research field(s)
Applied Sciences, Engineering, Biomedical Engineering

NOMIS Researcher(s)

Published in

February 1, 2021

Achieving temporally precise, noninvasive control over specific neural cell types in the deep brain would advance the study of nervous system function. Here we use the potent channelrhodopsin ChRmine to achieve transcranial photoactivation of defined neural circuits, including midbrain and brainstem structures, at unprecedented depths of up to 7 mm with millisecond precision. Using systemic viral delivery of ChRmine, we demonstrate behavioral modulation without surgery, enabling implant-free deep brain optogenetics.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Biotechnology

NOMIS Researcher(s)

January 1, 2021

A transdisciplinary project examining agroecological management alternatives in Malawi utilized mixed methods to learn from and about farmer knowledge of biodiversity. Wild biodiversity was assessed on 96 farms within a study area of 16 villages. Forty-two farmers from the 96 farms were involved in the photovoice sub-study discussed here. They received camera training then took photographs of plants and animals that were meaningful to them; subsequently 42 interviews were conducted with farmers to discuss the photos and elicit greater understanding of their perceptions about insects and pest management. Workshops were then utilized to discuss findings, facilitate horizontal knowledge exchange among project stakeholders, and encourage farmers to co-design experiments testing ecological management strategies. The photographs were used in the workshops to expand knowledge about pests and natural enemies. Combining photovoice interviews with workshops and field visits supported a process of co-constructing agroecological knowledge.

Research field(s)
Applied Sciences, Agriculture, Agronomy & Agriculture, Fisheries & Forestry, Agronomy & Agriculture

NOMIS Researcher(s)

September 21, 2020

Quantum illumination is a sensing technique that employs entangled signal-idler beams to improve the detection efficiency of low-reflectivity objects in environments with large thermal noise. The advantage over classical strategies is evident at low signal brightness, a feature which could make the protocol an ideal prototype for non-invasive scanning or low-power short-range radar. Here we experimentally investigate the concept of quantum illumination at microwave frequencies, by generating entangled fields using a Josephson parametric converter which are then amplified to illuminate a room-temperature object at a distance of 1 meter. Starting from experimental data, we simulate the case of perfect idler photon number detection, which results in a quantum advantage compared to the relative classical benchmark. Our results highlight the opportunities and challenges on the way towards a first room-temperature application of microwave quantum circuits.

Research field(s)
Applied Sciences, Information & Communication Technologies, Networking & Telecommunications

NOMIS Researcher(s)

Published in

May 1, 2020

DISCOVER-seq (discovery of in situ Cas off-targets and verification by sequencing) is a broadly applicable approach for unbiased CRISPR–Cas off-target identification in cells and tissues. It leverages the recruitment of DNA repair factors to double-strand breaks (DSBs) after genome editing with CRISPR nucleases. Here, we describe a detailed experimental protocol and analysis pipeline with which to perform DISCOVER-seq. The principle of this method is to track the precise recruitment of MRE11 to DSBs by chromatin immunoprecipitation followed by next-generation sequencing. A customized open-source bioinformatics pipeline, BLENDER (blunt end finder), then identifies off-target sequences genome wide. DISCOVER-seq is capable of finding and measuring off-targets in primary cells and in situ. The two main advantages of DISCOVER-seq are (i) low false-positive rates because DNA repair enzyme binding is required for genome edits to occur and (ii) its applicability to a wide variety of systems, including patient-derived cells and animal models. The whole protocol, including the analysis, can be completed within 2 weeks.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Bioinformatics

NOMIS Researcher(s)

Published in

May 1, 2020

Aging of the circulatory system correlates with the pathogenesis of a large spectrum of diseases. However, it is largely unknown which factors drive the age-dependent or pathological decline of the vasculature and how vascular defects relate to tissue aging. The goal of the study is to design a multianalytical approach to identify how the cellular microenvironment (i.e., fibroblasts) and serum from healthy donors of different ages or Alzheimer disease (AD) patients can modulate the functionality of organ-specific vascular endothelial cells (VECs). Long-living human microvascular networks embedding VECs and fibroblasts from skin biopsies are generated. RNA-seq, secretome analyses, and microfluidic assays demonstrate that fibroblasts from young donors restore the functionality of aged endothelial cells, an effect also achieved by serum from young donors. New biomarkers of vascular aging are validated in human biopsies and it is shown that young serum induces angiopoietin-like-4, which can restore compromised vascular barriers. This strategy is then employed to characterize transcriptional/functional changes induced on the blood–brain barrier by AD serum, demonstrating the importance of PTP4A3 in the regulation of permeability. Features of vascular degeneration during aging and AD are recapitulated, and a tool to identify novel biomarkers that can be exploited to develop future therapeutics modulating vascular function is established.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Nanoscience & Nanotechnology

NOMIS Researcher(s)

Published in

March 1, 2020

Extracellular vesicles (EVs) are endogenous membrane-derived vesicles that shuttle bioactive molecules between glia and neurons, thereby promoting neuronal survival and plasticity in the central nervous system (CNS) and contributing to neurodegenerative conditions. Although EVs hold great potential as CNS theranostic nanocarriers, the specific molecular factors that regulate neuronal EV uptake and release are currently unknown. A combination of patch-clamp electrophysiology and pH-sensitive dye imaging is used to examine stimulus-evoked EV release in individual neurons in real time. Whereas spontaneous electrical activity and the application of a high-frequency stimulus induce a slow and prolonged fusion of multivesicular bodies (MVBs) with the plasma membrane (PM) in a subset of cells, the neurotrophic factor basic fibroblast growth factor (bFGF) greatly increases the rate of stimulus-evoked MVB-PM fusion events and, consequently, the abundance of EVs in the culture medium. Proteomic analysis of neuronal EVs demonstrates bFGF increases the abundance of the v-SNARE vesicle-associated membrane protein 3 (VAMP3, cellubrevin) on EVs. Conversely, knocking-down VAMP3 in cultured neurons attenuates the effect of bFGF on EV release. The results determine the temporal characteristics of MVB-PM fusion in hippocampal neurons and reveal a new function for bFGF signaling in controlling neuronal EV release.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Nanoscience & Nanotechnology

NOMIS Researcher(s)

Published in

November 1, 2019

The average judgment of large numbers of people has been found to be consistently better than the best individual response. But what motivates individuals when they make collective decisions? While it is a popular belief that individual incentives promote out-of-the-box thinking and diverse solutions, the exact role of motivation and reward in collective intelligence remains unclear. Here we examined collective intelligence in an interactive group estimation task where participants were rewarded for their individual or group’s performance. In addition to examining individual versus collective incentive structures, we controlled whether participants could see social information about the others’ responses. We found that knowledge about others’ responses reduced the wisdom of the crowd and, crucially, this effect depended on how people were rewarded. When rewarded for the accuracy of their individual responses, participants converged to the group mean, increasing social conformity, reducing diversity and thereby diminishing their group wisdom. When rewarded for their collective performance, diversity of opinions and the group wisdom increased. We conclude that the intuitive association between individual incentives and individualist opinion needs revising.

Research field(s)
Applied Sciences, Information & Communication Technologies, Artificial Intelligence & Image Processing

NOMIS Researcher(s)

Published in

January 1, 2019

Motivation Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia. Results We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified. Availability and implementation Datasets and scripts for reproduction of results are available through: Https://nalab.stanford.edu/multiomics-pregnancy/.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Bioinformatics

NOMIS Researcher(s)

Published in

December 20, 2018

Biomarkers of aging can be used to assess the health of individuals and to study aging and age-related diseases. We generate a large dataset of genome-wide RNA-seq profiles of human dermal fibroblasts from 133 people aged 1 to 94 years old to test whether signatures of aging are encoded within the transcriptome. We develop an ensemble machine learning method that predicts age to a median error of 4 years, outperforming previous methods used to predict age. The ensemble was further validated by testing it on ten progeria patients, and our method is the only one that predicts accelerated aging in these patients.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Bioinformatics

NOMIS Researcher(s)

Published in

March 1, 2014

Background Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile. Objective We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region. Methods We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features. Results We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment. Conclusion These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients. © 2014 Elsevier HS Journals, Inc.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Optoelectronics & Photonics