Biology subjects

Fuchs, K.

Publications and source records attributed to Fuchs, K..

10 recordsLinked to original sources

bioRxiv2024

Prefrontal orchestration: a cortical network for rodent motor inhibition

Goal-directed action control and behavioral flexibility are prerequisites for effective, adaptive behavior. Both abilities rely on functional motor inhibition, which is linked to the prefrontal cortex (PFC), where distinct subsections collaborate in functional networks. How these PFC subsections interact and which roles they play during motor inhibition remains incompletely understood. In this study, we employed an action-preparation task in rats, combined with bidirectional optogenetic interventions, opto-fMRI, single unit electrophysiology and local field potential synchrony measurements across PFC subsections. Our findings support a clear and simple model of action inhibition within the prefrontal network. This model suggests prelimbic cortex (PL) as an input-dependent switch between motor inhibition and execution, modulated by an infralimbic cortex (IL)-dominated network. This distribution of tasks allows the PL to mediate goal-directed action while the IL ensures behavioral flexibility. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/618207v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@147ab98org.highwire.dtl.DTLVardef@52b6f9org.highwire.dtl.DTLVardef@6ab566org.highwire.dtl.DTLVardef@1ab5044_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Behavioral measurements were conducted alongside optogenetic modulation of PL, IL or VO. Inhibitory modulation led to varying effects on performance, while excitatory ChR2 stimulation of PL, IL or VO led to analogous effects on proactive motor inhibition. To identify shared nodes recruited by ChR2 stimulation of distinct PFC subareas, we performed whole-brain mapping with opto-fMRI. This revealed an overlapping activation volume spanning PFC, BF, Fr, Cg2, and M2. Notably, this common activation volume closely outlined the entirety of the IL-recruited regions; IL excitation also produced robust behavioral effects. Multisite recordings revealed task performance-dependent PL-IL delta synchrony. PCA of single-unit activity during behavior revealed varied neural patterns among PFC subsections, highlighting PL to have the most the homogenous input-driven activity. The findings can be interpreted as PL acting as an input-dependent switch between motor inhibition and execution, modulated by IL to maintain behavioral flexibility. C_FIG

neuroscience↗

bioRxiv2024

Uterus and cervix anatomical changes and cervix stiffness evolution throughout pregnancy

The coordinated biomechanical performance, such as uterine stretch and cervical barrier function, within maternal reproductive tissues facilitates healthy human pregnancy and birth. Quantifying normal biomechanical function and detecting potentially detrimental biomechanical dysfunction (e.g., cervical insufficiency, uterine overdistention, premature rupture of membranes) is difficult, largely due to minimal data on the shape and size of maternal anatomy and material properties of tissue across gestation. This study quantitates key structural features of human pregnancy to fill this knowledge gap and facilitate three-dimensional modeling for biomechanical pregnancy simulations to deeply explore pregnancy and childbirth. These measurements include the longitudinal assessment of uterine and cervical dimensions, fetal weight, and cervical stiffness in 47 low-risk pregnancies at four time points during gestation (late first, middle second, late second, and middle third trimesters). The uterine and cervical size were measured via 2-dimensional ultrasound, and cervical stiffness was measured via cervical aspiration. Trends in uterine and cervical measurements were assessed as time-course slopes across pregnancy and between gestational time points, accounting for specific participants. Patient-specific computational solid models of the uterus and cervix, generated from the ultrasonic measurements, were used to estimate deformed uterocervical volume. Results show that for this low-risk cohort, the uterus grows fastest in the inferior-superior direction from the late first to middle second trimester and fastest in the anterior-posterior and left-right direction between the middle and late second trimester. Contemporaneously, the cervix softens and shortens. It softens fastest from the late first to the middle second trimester and shortens fastest between the late second and middle third trimester. Alongside the fetal weight estimated from ultrasonic measurements, this work presents holistic maternal and fetal patient-specific biomechanical measurements across gestation.

bioengineering↗

bioRxiv2024

Macrophages foster adaptive anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction

Tumor-associated macrophages (TAMs) shape the tumor microenvironment (TME) and exert a decisive impact on anti-tumor immunity. Understanding TAM function is therefore critical to understand anti-tumor immune responses and to design immunotherapies. Here, we describe the transcription factor ZEB1, a well-known driver of epithelial-to-mesenchymal transition, as an intrinsic regulator of TAM function in adaptive anti-tumor immunity. By combining cell type-specific deletion of Zeb1 with syngeneic models of colorectal and pancreatic cancer, we discovered an unexpected function of ZEB1 in the TAM-mediated control of T cell trafficking. ZEB1 supports secretion of a subset of chemokines including CCL2 and CCL22 by promoting their transcription and translation as well as by safeguarding protein processing. ZEB1 thereby elevates cytotoxic T cell (CTL) recruitment in vitro and in vivo and fosters immunosurveillance during tumor as well as lung metastatic outgrowth. Our study spotlights ZEB1 as a crucial facilitator of adaptive anti-tumor immunity and uncovers a potential therapeutic window of opportunity for cytokine-guided enhancement of CTL infiltration into tumors and metastases.

cancer biology↗

bioRxiv2023

Life and death in Trypillia times: Interdisciplinary analyses of the exceptional human remains from the settlement of Kosenivka, Ukraine (3700-3600 BCE)

We present an interdisciplinary analysis of finds from the Trypillia settlement of Kosenivka, Ukraine (ca. 3700-3600 BCE, Trypillia C1), that links information on human, faunal, and botanical remains with archaeological data to provide exceptionally detailed insights into life and death at a Trypillia mega-site. We obtained osteological, palaeopathological, and histotaphonomic data from human bone fragments; performed carbon and nitrogen stable isotopic analysis of human and animal bone to calculate food webs with the software FRUITS; and modelled newly generated radiocarbon dates to refine the sites chronology. The biological profile of seven identified individuals, some of whom suffered from disease symptoms common in the Chalcolithic, represents a demographic cross-section of the population. The analysis of perimortem cranial trauma suffered by two individuals suggest cases of interpersonal conflict. Food web calculations demonstrate the large contribution of cereals to the protein component of the human diet, which is supported by dental observations, and we suggest that livestock were a major manure producer for crop cultivation. The most probable scenario for the formation of the Kosenivka find assemblage is a deathly fire event. This makes the site a rare example where the archaeological and osteological results can be used to reconstruct a minimum number of house inhabitants. Following a literature review, we contextualise our analysis by discussing the general lack of human remains from Early and Middle Trypillia sites. The individuals from Kosenivka form part of the less than 0.05% of the total estimated Trypillia population that is represented skeletally; its members were deposited within settlements in the Middle Trypillia stage (until C1), preceding the shift to extramural burials in its late phase (C2). Our detailed results indicate the huge explanatory potential that has yet to be unlocked in the rare and often poorly preserved bioarchaeological archives of the Cucuteni-Trypillia phenomenon.

evolutionary biology↗

bioRxiv2023

ZEB1-dependent modulation of fibroblast polarization governs inflammation and immune checkpoint blockade sensitivity in colorectal cancer

The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specific Zeb1 deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers is reduced upon fibroblast-specific loss of Zeb1. Single-cell transcriptomics, histological and in vitro characterization reveal a crucial role in CAF polarization, promoting myofibroblastic features whilst restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, pointing to a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis.

cancer biology↗

bioRxiv2022

Chitin oligomers directly promote lymphoid innate and adaptive immune cell activation

BackgroundChitin is a highly abundant N-acetyl-glucosamine (GlcNAc) polysaccharide which has been linked to immune responses in the context of fungal infections and allergic asthma, especially T helper 2 (Th2) immune responses. Unfortunately, due to the frequent use of crude chitin preparations of unknown purity and degree of polymerization there is still great uncertainty how chitin activates different parts of the human immune system. ObjectiveWe recently identified chitin oligomers of six GlcNAc units as the smallest immunologically active chitin motif and the innate immune receptor TLR2 as primary chitin sensor on human and murine myeloid cells, but the response of lymphoid cells to oligomeric chitin has not been investigated and was addressed here. MethodsFlow cytometric analysis of primary human immune cells upon stimulation with oligomeric chitin. For detailed Methods, please see the Methods section in this articles Online Repository at www.jacionline.org. ResultHere we report that chitin oligomers also activate immune responses by both primary lymphoid innate and adaptive immune cells: Notably, chitin oligomers activated Natural Killer (NK) cells and B lymphocytes. Moreover, the maturation of dendritic cells enabled CD8 T cell recall responses. ConclusionsOur results suggest that chitin oligomers not only trigger immediate innate responses in limited range of myeloid cells but exert critical activities across the entire human immune system. Key messagesChitin oligomers are microbe-associated molecular patterns involved in TLR2-dependent fungal recognition by myeloid immune cells. Here we show that lymphoid cells, most notably Natural Killer (NK) cells and B cells, are activated by oligomeric chitin. Oligomeric chitin also promotes antigen-presenting cell (APC) maturation and CD8 T cell recall responses. Capsule summaryOligomeric chitin is a novel microbe-associated molecular patterns involved in TLR2-dependent fungal recognition by myeloid innate immune cells. Here we show that lymphoid innate and adaptive immune responses are also promoted by oligomeric chitin.

immunology↗

bioRxiv2021

An increase in surface hydrophobicity mediates chaperone activity in N-chlorinated proteins

Under physiological conditions, Escherichia coli RidA is an enamine/imine deaminase, which promotes the release of ammonia from reactive enamine/imine intermediates. However, when modified by hypochlorous acid (HOCl), as produced by the host defense, RidAHOCl turns into a potent chaperone-like holdase that can effectively protect the proteome of E. coli during oxidative stress. We previously reported that the activation of RidAs chaperone-like function coincides with the addition of at least seven and up to ten chlorine atoms. These atoms are reversibly added to basic amino acids in RidAHOCl and removal by reducing agents leads to inactivation. Nevertheless, it remains unclear, which residues in particular need to be chlorinated for activation. Here, we employ a combination of LC-MS/MS analysis, a chemo-proteomic approach, and a mutagenesis study to identify residues responsible for RidAs chaperone-like function. Through LC-MS/MS of digested RidAHOCl, we obtained direct evidence of the chlorination of one arginine residue (and, coincidentally, two tyrosine residues), while other N- chlorinated residues could not be detected, presumably due to the instability of the modification and its potential interference with a proteolytic digest. Therefore, we established a chemoproteomic approach using 5-(dimethylamino) naphthalene-1-sulfinic acid (DANSO2H) as a probe to label N-chlorinated lysines. Using this probe, we were able to detect the N-chlorination of six additional lysine residues. Moreover, using a mutagenesis study to genetically probe the role of single arginine and lysine residues, we found that the removal of arginines R105 and R128 leads to a substantial reduction of RidAHOCls chaperone activity. These results, together with structural analysis, confirm that the chaperone activity of RidA is concomitant with the loss of positive charges on the protein surface, leading to an increased overall protein hydrophobicity. Molecular modelling of RidAHOCl and the rational design of a RidA variant that shows chaperone activity even in the absence of HOCl further supports our hypothesis. Our data provide a molecular mechanism for HOCl-mediated chaperone activity found in RidA and a growing number of other HOCl-activated chaperones.

biochemistry↗

bioRxiv2019

Neolithic genomes reveal a distinct ancient HLA allele pool and population transformation in Europe

The Wartberg culture (WBC, 3,500-2,800 BCE) dates to the Late Neolithic period, a time of important demographic and cultural transformations in western Europe. We perform a genome-wide analysis of 42 individuals who were interred in a WBC collective burial in Niedertiefenbach, Germany (3,300-3,200 cal. BCE). Our results highlight that the Niedertiefenbach population indeed emerged at the beginning of the WBC. This farming community was genetically heterogeneous and carried a surprisingly large hunter-gatherer ancestry component (40%). We detect considerable differences in the human leukocyte antigen gene pool between contemporary Europeans and the Niedertiefenbach individuals whose immune response was primarily geared towards defending viral infections.

evolutionary biology↗

bioRxiv2018

The genetic prehistory of the Greater Caucasus

Archaeogenetic studies have described the formation of Eurasian steppe ancestry as a mixture of Eastern and Caucasus hunter-gatherers. However, it remains unclear when and where this ancestry arose and whether it was related to a horizon of cultural innovations in the 4th millennium BCE that subsequently facilitated the advance of pastoral societies likely linked to the dispersal of Indo-European languages. To address this, we generated genome-wide SNP data from 45 prehistoric individuals along a 3000-year temporal transect in the North Caucasus. We observe a genetic separation between the groups of the Caucasus and those of the adjacent steppe. The Caucasus groups are genetically similar to contemporaneous populations south of it, suggesting that - unlike today - the Caucasus acted as a bridge rather than an insurmountable barrier to human movement. The steppe groups from Yamnaya and subsequent pastoralist cultures show evidence for previously undetected farmer-related ancestry from different contact zones, while Steppe Maykop individuals harbour additional Upper Palaeolithic Siberian and Native American related ancestry.

genomics↗

bioRxiv2018

The fungal ligand chitin directly binds and signals inflammation dependent on oligomer size and TLR2

Chitin is a highly abundant polysaccharide and linked to fungal infection and asthma. Unfortunately, its polymeric structure has hampered the identification of immune receptors directly binding chitin and signaling immune activation and inflammation, because purity, molecular structure and molarity are not well definable for a polymer typically extracted from biomass. Therefore, by using defined chitin (N-acetyl-glucosamine) oligomers, we identified six subunit long chitin chains as the smallest immunologically active motif and the innate immune receptor Toll-like receptor (TLR) 2 as the primary fungal chitin receptor on human and murine immune cells. Chitin oligomers directly bound TLR2 with nanomolar affinity and showed both overlapping and distinct signaling outcomes compared to known mycobacterial TLR2 ligands. Conversely, chitin oligomers shorter than 6 subunits were inactive or showed antagonistic effects on chitin/TLR2-mediated signaling, hinting to a size-dependent sensing/activation system unexpectedly conserved in plants and humans. Since blocking the chitin-TLR2 interaction effectively prevented chitin-mediated inflammation in vitro and in vivo, our study highlights the chitin TLR2 interaction as a potential target for developing novel therapies in chitin-related pathologies and fungal disease.

immunology↗