Biology subjects

Konrad, D.

Publications and source records attributed to Konrad, D..

6 recordsLinked to original sources

bioRxiv2025

Drivers of individual plant species contributions to β-diversity are scale-dependent

Species introductions and native extirpations are driving biotic homogenisation in plant communities by reducing {beta}-diversity. Individual species vary in their contributions to {beta}-diversity (Species Contribution to {beta}-Diversity; species-{beta}), yet our understanding of how species characteristics shape these contributions remains limited. Additionally, although the ecological processes influencing {beta}-diversity are known to vary with spatial scale, we lack understanding of how species contributions, or their underlying determinants, change across scales. Here, we modelled how plant functional traits, phylogenetic relatedness, and introduction status influence their contributions to {beta}-diversity using plant community data from 429 plots surveyed from 2017-2023 across three nested spatial scales (up to 1 km2) in nine sites spanning four countries. We extended the analysis to broader spatial extents (100 km2 to the entire UK) using GBIF occurrence data. We found that functional traits associated with competitive ability influenced species-{beta}, but the direction and strength of their effects varied with scale. Likewise, phylogenetic novelty increased species-{beta} at small scales but reduced it at larger ones. After accounting for traits and phylogeny, introduced species consistently contributed less to {beta}-diversity than native species--especially at broader spatial extents. These results demonstrate that species ecological and evolutionary characteristics shape their contributions to {beta}-diversity, but that these effects are scale-dependent. Our findings highlight the importance of scale-explicit approaches in understanding both the determinants of {beta}-diversity, and how we can combat its loss to mitigate biotic homogenisation.

ecology↗

bioRxiv2025

ASK1 overexpression protects from HFD-induced body weight gain via FGF21

People with obesity are at high risk to develop metabolic complications such as type 2 diabetes and metabolic dysfunction-associated fatty liver disease (MAFLD). We previously reported that the apoptosis signal-regulating kinase 1 (ASK1) regulates the development of MAFLD, since high fat diet (HFD)-fed mice with liver-specific ASK1 depletion and overexpression revealed increased and blunted development of MAFLD, respectively. Herein we identify a protective role of liver-expressed ASK1 in the context of diet-induced obesity. When fed a HFD for 20 weeks, liver-specific ASK1 overexpressing mice (ASK1+hep) were resistant to obesity and showed improved glucose metabolism as well as increased energy expenditure compared to control animals. Moreover, HFD-fed ASK1+hep mice had higher BAT activity as well as increased browning of inguinal WAT, as suggested by increased UCP1 levels. The latter may be induced by the hepatokine fibroblast growth factor (FGF21), a hormone that is mainly produced in the liver and is known to reduce body weight via increasing energy expenditure. In line with an important role of FGF21, its plasma levels were significantly increased in HFD-fed ASK1+hep mice and they negatively correlated with body weight. Mechanistically, we propose that the transcription factor ATF4 is activated via HFD-induced ASK1-p38 signaling in hepatocytes, subsequently promoting hepatic Fgf21 gene expression. Supporting this hypothesis, p38 inhibition resulted in a more pronounced reduction in Fgf21 expression in ASK1+hep hepatocytes compared to controls, while silencing of ATF4 in primary hepatocytes significantly decreased Fgf21 transcript levels in ASK1+hep hepatocytes but not in hepatocytes derived from control mice. In conclusion, we have uncovered a yet undescribed axis between hepatic ASK1 and FGF21 which positively affects body weight and glucose metabolism.

physiology↗

bioRxiv2025

High fat high sucrose exposure during lactation but not during the post-weaning period programs impaired glucose homeostasis

Nutrition during critical developmental windows plays a pivotal role in shaping long-term metabolic health. Exposure to a Western diet in early life may lead to altered metabolic programing, potentially influencing the risk to develop obesity and type 2 diabetes. In particular, an early exposure to an obesogenic diet may induce a metabolic program that only emerges upon dietary challenges later in life. Accordingly, understanding the long-term impact of nutritional insults in different stages of early life may provide strategies for primary prevention. Therefore, the present study aimed to determine which time window in the post-natal period is most critical for long-term metabolic health. To this end, pups born to lean mouse dams were exposed to a high-fat, high-sucrose (HFHS) diet for 3 weeks during lactation or in the post-weaning period. Thereafter, mice were either fed a regular chow diet until the age of 30 weeks or exposed to a second bout of HFHS diet for the last 12 weeks. Metabolic health and development of obesity was assessed by regular monitoring of glucose homeostasis and body weight gain. 12 week-old mice with lactational exposure to a HFHS diet revealed a significantly impaired glucose tolerance compared to control mice, while glucose tolerance of post -weaning exposed mice was similar to the control group. Moreover, a second bout of HFHS diet impaired glucose tolerance and increased body and adipose tissue weight in mice with lactational exposure to a significant greater extent than in post-weaning exposed mice. Hence, exposure to HFHS during lactation but not during the post-weaning period programs impaired glucose homeostasis, suggesting that the lactational window may be more critical in terms of metabolic programing.

physiology↗

bioRxiv2024

Chemical tools to expand the ligandable proteome: diversity-oriented synthesis-based photoreactive stereoprobes

Chemical proteomics enables the global assessment of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range of small molecules explored by chemical proteomics has, however, been limited. Here, we describe a diversity-oriented synthesis (DOS)-inspired library of stereochemically-defined compounds bearing diazirine and alkyne units for UV light-induced covalent modification and click chemistry enrichment of interacting proteins, respectively. We find that these photo-stereoprobes interact in a stereoselective manner with hundreds of proteins from various structural and functional classes in human cells and demonstrate that these interactions can form the basis for high-throughput screening-compatible nanoBRET assays. Integrated phenotypic analysis and chemical proteomics identified photo-stereoprobes that modulate autophagy by engaging the mitochondrial serine protease CLPP. Our findings show the utility of photo-stereoprobes for expanding the ligandable proteome, furnishing target engagement assays, and discovering and characterizing bioactive small molecules by cell-based screening.

biochemistry↗

bioRxiv2022

Thiazides induce glucose intolerance through inhibition of mitochondrial carbonic anhydrase 5b in β-cells

Thiazides are associated with glucose intolerance and new onset diabetes mellitus, but the molecular mechanisms remain elusive. The aim of this study was to decipher the molecular basis of thiazide-induced glucose intolerance. In mice, hydrochlorothiazide induced a pathological glucose tolerance, characterized by reduced first phase insulin secretion but normal insulin sensitivity. In vitro, thiazides inhibited glucose-and sulfonylurea-stimulated insulin secretion in islets and the murine {beta}-cell line Min6 at pharmacologically relevant concentrations. Inhibition of insulin secretion by thiazides was CO2/HCO3--dependent, not additive to unselective carbonic anhydrase (CA) inhibition with acetazolamide and independent of extracellular potassium. In contrast, insulin secretion was unaltered in islets of mice lacking the known molecular thiazide targets NCC (SLC12A3) or NDCBE (SLC4A8). CA expression profiling with subsequent knock-down of individual CA isoforms suggested mitochondrial CA5b as molecular target. In support of these findings, thiazides significantly attenuated Krebs cycle anaplerosis through reduction of mitochondrial oxalacetate synthesis. CA5b KO mice were resistant to thiazide-induced glucose intolerance, and insulin secretion of islets isolated from CA5b KO mice was unaffected by thiazides. In summary, our study reveals attenuated insulin secretion due to inhibition of the mitochondrial CA5b isoform in {beta}-cells as molecular mechanism of thiazide-induced glucose intolerance.

physiology↗

bioRxiv2020

In vivo photopharmacology enabled by multifunctional fibers

To reversibly manipulate neural circuits with increased spatial and temporal control, photoswitchable ligands can add an optical switch to a target receptor or signaling cascade. This approach, termed photopharmacology, has been enabling to molecular neuroscience, however, its application to behavioral experiments has been impeded by a lack of integrated hardware capable of delivering both light and compounds to deep brain regions in moving subjects. Here, we devise a hybrid photochemical genetic approach to target neurons using a photoswitchable agonist of capsaicin receptor (TRPV1), red-AzCA-4. Using the thermal drawing process we created multifunctional fibers that can deliver viruses, photoswitchable ligands, and light to deep brain regions in awake, freely moving mice. We implanted our fibers into the ventral tegmental area (VTA), a midbrain hub of the mesolimbic pathway, and used them to deliver a transgene coding for TRPV1. This sensitized excitatory VTA neurons to red-AzCA-4, and allowed us to optically control conditioned place preference using a mammalian ion-channel, thus extending applications of photopharmacology to behavioral experiments. Applied to endogenous receptors, our approach may accelerate studies of molecular mechanisms underlying animal behavior.

neuroscience↗