Biology subjects

Goetz, S.

Publications and source records attributed to Goetz, S..

12 recordsLinked to original sources

bioRxiv2026

Spatial Recruitment Model for Motor Potentials Evoked By Transcranial Magnetic Stimulation (TMS) for In-Silico Testing and Tuning of Closed-Loop Procedures

The primary motor cortex has a prominent role in transcranial magnetic stimulation (TMS). It is one of few locations that provide directly observable responses, and its physiology serves as model or reference for almost all other TMS targets, e.g., through the motor threshold and spatial targeting relative to its position. It furthermore sets the safety limits for the entire brain. Its easily detectable responses have led to closed-loop methods for a range of aspects, e.g., for automated thresholding, amplitude tracking, and targeting. The high variability of brain stimulation methods would substantially benefit from fast unbiased closed-loop methods. However, the development of more potent methods would early on in the design phase require proper models that allowed tuning and testing with sufficient conditions but without a high number of experiments, which are time-consuming and expensive or even impossible at the needed scale. On the one hand, theoretical researchers without access to experiments miss realistic spatial response models of brain stimulation to develop better methods. On the other hand, subjects should potentially not be exposed to early closed-loop-methods without sufficient prior testing. After all, initial, poorly tuned feed-back as needed for closed-loop operation is known to demonstrate erratic behavior. To bridge this gap, we developed a digital-twin-style population model that generates motor evoked potentials in response to virtual stimuli and includes statistical information on spatial (coil position and orientation) as well as pulse-strength-dependent neural recruitment in the population to represent inter- and intra-individual variability. The population data were extracted from a combination of datasets of healthy and depressed subjects to reach large numbers and wide coverage. The model allows users to simulate different subjects and millions of runs for software-in-the loop testing. The model provides all code open-source to stimulate further development.

neuroscience↗

bioRxiv2026

Regulated conformational transitions in seipin define a functional ER–lipid droplet interface

Lipid droplets (LDs) are key organelles in cellular lipid homeostasis that form at the endoplasmic reticulum (ER) through a sequence of membrane rearrangements. While seipin emerged as an essential protein complex for LD biogenesis, how seipin-mediated LD formation proceeds beyond the initial step of neutral lipid nucleation remains unknown. Using a combination of in vitro and in-cell cryogenic electron microscopy (cryo-EM), ultrastructural expansion microscopy, molecular simulations and tailored genetic perturbations, we show that the seipin transmembrane domains undergo large-scale conformational rearrangements that define the architecture of the ER-LD interface and enable LD growth. Cryo-EM of purified Xenopus seipin revealed coexistence of two states: a compact "closed" conformation, consistent with early LD biogenesis, and an "open" conformation in which the transmembrane helices splay out laterally. Molecular dynamics simulations indicate that this open state induces local membrane curvature and promotes triacylglycerol accumulation. We identify conserved flexible linkers between the seipin luminal and transmembrane regions that act as mechanical hinges, enabling this conformational transition. We demonstrate that mutations in these hinge regions hinder seipin opening and affect LD formation in yeast and human cells. Analysis of native ER-LD contacts in human cells using light microscopy and cryo-electron tomography confirms that the seipin complex opens to establish stereotypical ~21-nm necks connecting the ER bilayer and LD monolayer. Moreover, we identify the liver-enriched microprotein SMLR1 as an inhibitor of this seipin conformational transition, providing a regulatory mechanism for seipin-dependent lipid storage in a tissue-specific manner. Together, these data establish seipin opening as a key structural rearrangement at the ER-LD interface that is essential for LD biogenesis and growth.

Cell Biology↗

bioRxiv2025

To join or not to join: handling biological replicates in long-read RNA sequencing data

Long-read RNA sequencing (lrRNA-seq) has revolutionized transcriptomics facilitating the study of alternative splicing and resulting in identification of thousands of novel transcripts. While isoform identification has received significant attention, the handling of biologically replicated lrRNA-seq datasets remains less explored. However, how multiple samples are combined in a lrRNA-seq study may strongly impact transcript identification. This study defines and evaluates two strategies for obtaining consensus transcriptomes from multi-sample lrRNA-seq data: "Join & Call", where reads from all samples are combined before transcript identification, and "Call & Join", where transcript identification is performed on individual samples before combining the resulting annotations. We applied these strategies to a highly replicated dataset of mouse brain and kidney tissues, using both PacBio and ONT technologies, across six widely used transcript reconstruction tools. Our results indicate that the optimal strategy depends on the chosen computational tool and research objective. We found that Join & Call is generally more suitable for discovering rarely occurring, novel isoforms, as pooling evidence increases confidence in calling lowly-expressed transcripts. Conversely, Call & Join is computationally more efficient and often preferable for highly replicated datasets when the investigation of rare novel transcripts is not the primary objective. Our findings provide a conceptual and practical framework for multi-sample transcriptome reconstruction, guiding best practices in the context of increasingly large-scale lrRNA-seq studies.

bioinformatics↗

bioRxiv2024

MicrobiomeKG: Bridging Microbiome Research and Host Health Through Knowledge Graphs

The microbiome represents a complex community of trillions of microorganisms residing in various body parts, and plays critical roles in maintaining host health and well-being. Understanding the interactions between microbiota and host offers valuable insights into potential strategies to promote health, including microbiome-targeted interventions. We have created MicrobiomeKG, a Knowledge Graph for microbiome research, bridging various taxa and microbial pathways with host health. This novel knowledge graph derives algorithmically-generated knowledge assertions from the supplemental tables supporting published microbiome papers, and is deployed for integrative analysis and hypothesis generation via the Biomedical Data Translator ecosystem.

bioinformatics↗

bioRxiv2024

Functional traits and phylogeny predict vertical foraging in terrestrial mammals and birds

Earths ecosystems are characterized by numerous gradients related to the distribution of environmental conditions and resources. Niche theory predicts that animals will evolve traits to exploit changing resource availability and environmental conditions across these gradients. Much work has been done examining how animal traits like body mass and diet change across gradients from regional to global scales. Environmental and resource gradients in the vertical dimension tend to exhibit strong changes over relatively short distances due to the influence of elevation and vegetation. Vegetation structure may be an especially important vertical axis as it contributes to strong gradients in micro- climate, food resources, and predation risk. To investigate interrelationships between the vertical niche and its presumed drivers, we use functional traits, phylogenies, and predation risk to predict the vertical foraging niche for 4,828 mammals and 9,437 birds globally. To provide biogeographic context to the predictive analysis, we use species ranges to map geographic distributions of the vertical foraging niche and relationships between the niche and its presumed drivers. Linking trait databases with species range maps revealed distinct global distributions of vertical foraging niches for mammals and birds. The most important predictors of these niches varied by taxon but there were several systematic relationships. Diet, body mass, and phylogeny were strong predictors of vertical foraging niche across mammal and bird species. Percent fruit in diet exhibited progressively more positive relationships with higher canopy foraging positions. Predation pressure was relatively unimportant in predicting most vertical foraging niches for birds and mammals but displayed a positive trend with arboreal foraging. Geographic hotspots for the importance of fruit in both mammal and bird diets included the Andes-Amazon transition zone, the Amazon Basin, and New Guinea. Our results provide support for the theory of resource driven vertical niche partitioning but also reveal that vertical niches are strongly associated with phylogeny, suggesting niche conservatism in numerous mammal and bird families. Geographic patterns in variable importance values suggest multiple mechanisms behind spatial structure in eco- evolutionary relationships, including latitudinal gradients in vegetation structure and composition, historical patterns of island isolation (in Southeast Asia), and the influence of habitat heterogeneity driven by tectonic processes (in South America).

ecology↗

bioRxiv2022

TTBK2 controls cilium stability through actin and the centrosomal compartment

The serine-threonine kinase Tau Tubulin Kinase 2 (TTBK2) is a key regulator of the assembly of primary cilia, which are vital signaling organelles. TTBK2 is also implicated in the stability of the assembled cilium, through mechanisms that remain to be defined. Here, we use mouse embryonic fibroblasts (MEFs) derived from Ttbk2fl/fl; UBC-CreERT+ embryos (hereafter Ttbk2cmut) to dissect the role of TTBK2 in cilium stability. This system depletes TTBK2 levels after cilia formation, allowing us to assess the molecular changes to the assembled cilium over time. As a consequence of Ttbk2 deletion, the ciliary axoneme is destabilized and primary cilia are lost within 48-72 hours following recombination. Axoneme destabilization involves an increased frequency of cilia breaks and is partially driven by altered actin dynamics and a reduction in axonemal microtubule modifications. At the same time, we find that TTBK2 is required to regulate the composition of the centriolar satellites and to maintain the basal body pools of intraflagellar transport (IFT) proteins. Altogether, our results reveal parallel pathways by which TTBK2 maintains cilium stability.

cell biology↗

bioRxiv2021

Microbial Biotextiles for a Circular Materials Economy

The synthesis and bottom-up assembly of nanocellulose by microbes offers unique advantages to tune and meet key design criteria--rapid renewability, low toxicity, scalability, performance, and degradability--for multi-functional, circular economy textiles. However, development of green processing methods that meet these criteria remains a major research challenge. Here, we harness microbial biofabrication of nanocellulose and draw inspiration from ancient textile techniques to engineer sustainable biotextiles with a circular life cycle. The unique molecular self-organization of microbial nanocellulose (MC) combined with bio-phosphorylation with a lecithin treatment yields a compostable material with superior mechanical and flame-retardant properties. Specifically, treatment of MC with a lecithin-phosphocholine emulsion makes sites available to modulate cellulose cross-linking through hydroxyl, phosphate and methylene groups, increasing the interaction between cellulose chains. The resultant bioleather exhibits enhanced tensile strength and high ductility. Bio-phosphorylation with lecithin also redirects the combustion pathway from levoglucosan production towards the formation of foaming char as an insulating oxygen barrier, for outstanding flame retardance. Controlled color modulation is demonstrated with natural dyes. Life cycle impact assessment reveals that MC bioleather has up to an order of magnitude lower carbon footprint than conventional textiles, and a thousandfold reduction in the carcinogenic impact of leather production. Eliminating the use of hazardous substances, these high performance materials disrupt linear production models and strategically eliminate its toxicity and negative climate impacts, with widespread application in fashion, interiors and construction. Importantly, the biotextile approach developed in this study demonstrates the potential of biofabrication coupled with green chemistry for a circular materials economy.

bioengineering↗

bioRxiv2020

The Casein Kinase II catalytic subunit CSNK2A1 interacts with TTBK2 to regulate ciliary trafficking and stability

Cilia biogenesis is a complex, multi-step process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified a kinase that acts as a key regulator of ciliogenesis, TTBK2. Here, using CRISPR kinome screening, we identify the CK2 subunit CSNK2A1 as an important modulator of TTBK2 function in cilia trafficking. Super-resolution microscopy reveals that CSNK2A1 is a centrosomal protein concentrated at the mother centriole and associated with the distal appendages where it physically interacts with TTBK2. Further, Csnk2a1 knockout partially corrects defects in cilia formation and length in Ttbk2 hypomorphic cells. Csnk2a1 mutant cilia are longer than those of control cells and exhibit instability, particularly at the tip. Csnk2a1 mutant cilia also abnormally accumulate key cilia assembly and SHH-related proteins including IFT, GLI2, KIF7, and Smoothened (SMO). De novo mutations of Csnk2a1 were recently linked to the human genetic disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Consistent with the role of CSNK2A1 in cilium stability, we find that expression of OCNDS-associated Csnk2a1 variants in wild-type cells cause ciliary structural defects. Our findings provide new insights into mechanisms involved in ciliary length regulation, trafficking, and stability that in turn shed light on the significance and implications of cilia instability in human disease. SIGNIFICANCE STATEMENTPrimary cilia (PC) are sensory organelles that play essential roles during development and adulthood. Abnormal functioning of PC causes human disorders called ciliopathies. Hence, a thorough understanding of the molecular regulation of PC is critical. Our findings highlight CSNK2A1 as a novel modulator of cilia trafficking and stability, tightly related to TTBK2 function. Enriched at the centrosome, CSNK2A1 prevents abnormal accumulation of key ciliary proteins, instability at the tip, and aberrant activation of the Sonic Hedgehog pathway. Further, we establish that Csnk2a1 mutations associated with Okur-Chung neurodevelopmental disorder (OCNDS) alter cilia morphology. Thus, we report a potential linkage between CSNK2A1 ciliary function and OCNDS.

cell biology↗

bioRxiv2020

Change in terrestrial human footprint drives continued loss of intact ecosystems

Our ability to map humanitys influence across Earth has evolved, thanks to powerful computing, a network of earth observing satellites, and new bottom-up census and crowd-sourced data. Here, we provide the latest temporally inter-comparable maps of the terrestrial Human Footprint, and assessment of change in human pressure at global, biome, and ecoregional scales. In 2013, 42% of terrestrial Earth could be considered relatively free of anthropogenic disturbance, and 25% could be classed as wilderness (the least degraded end of the human footprint spectrum). Between 2000 and 2013, 1.9 million km2 - an area the size of Mexico - of land relatively free of human disturbance became highly modified. The majority of this occurred within tropical and subtropical grasslands, savannah, and shrubland ecosystems, but the rainforests of Southeast Asia also underwent rapid modification. Our results show that humanitys footprint is eroding Earths last intact ecosystems, and greater efforts are urgently needed to retain them.

ecology↗

bioRxiv2020

Only 40% of the world's forests are in good health

Many global environmental agendas, including halting biodiversity loss, reversing land degradation, and limiting climate change, depend upon retaining forests with high ecological integrity, yet the scale and degree of forest modification remains poorly quantified and mapped. By integrating data on observed and inferred human pressures and an index of lost connectivity, we generate the first globally-consistent, continuous index of forest condition as determined by degree of anthropogenic modification. Globally, only 17.4 million km2 of forest (40.5%) have high landscape level integrity (mostly found in Canada, Russia, the Amazon, Central Africa and New Guinea) and only 27% of this area is found in nationally-designated protected areas. Of the forest in protected areas, only 56% has high landscape level integrity. Ambitious policies that prioritize the retention of forest integrity, especially in the most intact areas, are now urgently needed alongside current efforts aimed at halting deforestation and restoring the integrity of forests globally.

ecology↗

bioRxiv2018

Design of Transcranial Magnetic Stimulation Coils with Optimal Trade-off between Depth, Focality, and Energy

BackgroundTranscranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique used for research and clinical applications. Existent TMS coils are limited in their precision of spatial targeting (focality), especially for deeper targets.\n\nObjectiveThis paper presents a methodology for designing TMS coils to achieve optimal trade-off between the depth and focality of the induced electric field (E-field), as well as the energy required by the coil.\n\nMethodsA multi-objective optimization technique is used for computationally designing TMS coils that achieve optimal trade-offs between stimulation focality, depth, and energy (fdTMS coils). The fdTMS coil winding(s) maximize focality (minimize stimulated volume) while reaching a target at a specified depth and not exceeding predefined peak E-field strength and required coil energy. Spherical and MRI-derived head models are used to compute the fundamental depth-focality trade-off as well as focality-energy trade-offs for specific target depths.\n\nResultsAcross stimulation target depths of 1.0-3.4 cm from the brain surface, the stimulated volume can be theoretically decreased by 42%-55% compared to existing TMS coil designs. The stimulated volume of a figure-8 coil can be decreased by 36%, 44%, or 46%, for matched, doubled, or quadrupled energy. For matched focality and energy, the depth of a figure-8 coil can be increased by 22%.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC=\"FIGDIR/small/300616_fig8.gif\" ALT=\"Figure 8\">\nView larger version (14K):\norg.highwire.dtl.DTLVardef@af0b5org.highwire.dtl.DTLVardef@4118d8org.highwire.dtl.DTLVardef@1c61f80org.highwire.dtl.DTLVardef@3e23fa_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 8.C_FLOATNO Energy, W, vs. spread, S1/2, curves for hand knob stimulation for a conventional figure-8 coil and optimized fdTMS coil on a 32 x 32 cm square plane.\n\nC_FIG ConclusionComputational design of TMS coils could enable more selective targeting of the induced E-field. The presented results appear to be the first significant advancement in the depth-focality trade-off of TMS coils since the introduction of the figure-8 coil three decades ago, and likely represent the fundamental physical limit.\n\nDECLARATION OF INTERESTThe fdTMS technology described in this paper is subject to a provisional patent application by Duke University with the authors as inventors. Additionally: L.J.G. is inventor on a patent pertaining to the design of focal multicoil TMS systems. S.M.G. is inventor on patents and patent applications; he has received royalties from Rogue Research, TU Muenchen, and Porsche; furthermore, he has been provided with research support and patent fee reimbursement from Magstim Co. A.V.P. is inventor on patents and patent applications, and has received research and travel support as well as patent royalties from Rogue Research; research and travel support, consulting fees, as well as equipment loan from Tal Medical / Neurex; patent application and research support from Magstim; and equipment loans from MagVenture, all related to technology for transcranial magnetic stimulation.

bioengineering↗

bioRxiv2018

Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.

Spinocerebellar ataxia type 11 (SCA11) is a rare, dominantly inherited human ataxia characterized by atrophy of Purkinje neurons in the cerebellum. SCA11 is caused by mutations in the gene encoding the Serine/Threonine kinase Tau tubulin kinase 2 (TTBK2) that result in premature truncations of the protein. We previously showed that TTBK2 is a key regulator of the assembly of primary cilia in vivo. However, the mechanisms by which the SCA11-associated mutations disrupt TTBK2 function, and whether they interfere with ciliogenesis were unknown. In this work, we present evidence that SCA11-associated mutations are dominant negative alleles and that the resulting truncated protein (TTBK2SCA11) interferes with the function of full length TTBK2 in mediating ciliogenesis. A Ttbk2 allelic series revealed that upon partial reduction of full length TTBK2 function, TTBK2SCA11 can interfere with the activity of the residual wild-type protein to decrease cilia number and interrupt cilia-dependent Sonic hedgehog (SHH) signaling. Our studies have also revealed new functions for TTBK2 after cilia initiation in the control of cilia length, trafficking of a subset of SHH pathway components, including Smoothened (SMO), and cilia stability. These studies provide a molecular foundation to understand the cellular and molecular pathogenesis of human SCA11, and help account for the link between ciliary dysfunction and neurodegenerative diseases.\n\nAuthor SummaryDefects in primary cilia structure and function are linked to a number of recessive genetic disorders, now collectively referred to as ciliopathies. Most of the characteristics of these disorders arise from disruptions to embryonic development, with the requirements for primary cilia in adult tissues being less well-defined. We previously showed that a kinase associated with an adult-onset neurodegenerative condition is required for cilium assembly and ciliary signaling during development. Here, we show that the human disease-associated mutations act as mild dominant negatives, interfering with the function of the full length protein in cilia formation and ciliary signaling.

cell biology↗