Biology subjects

Harder, L.

Publications and source records attributed to Harder, L..

7 recordsLinked to original sources

bioRxiv2026

UV photogrammetry for transparent and composite surfaces

Transparent and composite surfaces pose a fundamental challenge for stereo photogrammetry: optically smooth glass produces no detectable surface features under visible illumination, making three-dimensional reconstruction impossible without surface preparation. This excludes optical components such as lenses and cover glasses, composite assemblies, and semi-translucent biological specimens from non-contact geometric measurement. Here we show that coherent speckle illumination at 266 nm overcomes this limitation by exploiting wavelength-dependent scatter enhancement, generating sufficient backscattered signal on surfaces that are entirely invisible under visible illumination. We developed a multispectral stereo system and evaluated three illumination modalities under identical acquisition conditions. On transparent glass, both visible modalities produce complete reconstruction failure, recovering only non-transparent holder structures. Ultraviolet speckle illumination at 266 nm enables dense reconstruction of the same surfaces. We demonstrate recovery of an uncoated plano-convex lens with a fitted radius of 30.946 mm and point-cloud standard deviation of 106.5 {micro}m, defect detection on a transparent cover glass without surface preparation, and reconstruction of a semi-translucent biological specimen. On metrology-grade reference objects, ultraviolet speckle achieves a standard deviation of 116 {micro}m and completeness exceeding 93%, approaching the performance of optimised visible structured illumination. These results establish ultraviolet speckle photogrammetry as an enabling approach of optical metrology to otherwise uncooperative surfaces, with relevance to optical manufacturing inspection and biological surface analysis.

biophysics↗

bioRxiv2025

A novel key player in cognitive striatal processes: the Pthlh interneurons

Interneurons in the dorsal striatum provide essential modulatory control over the projecting neurons, known as medium spiny neurons (MSNs), regulating the output of this brain structure, which is critical for motor control, decision-making, and learning. The diversity of interneurons has been recently determined based on single-cell transcriptomic analyses identifying novel populations as the Pthlh-expressing interneurons, one of the most abundant and distinctive inhibitory populations in the human and mouse striatum. Here, we generated a novel Pthlhcre knock-in mouse line that enables comprehensive study of this critical population. Quantitative histological analyses show that this line effectively targets the Pthlh interneuron class, which appears as a stable population across age, sex and the anterior-posterior axis. To elucidate their functional role, we performed selective chemogenetic inhibition of Pthlh interneurons, which caused significant impairments in striatum-dependent cognitive functions and reduced exploratory behaviorur. Importantly, selective silencing did not affect basal locomotion, motor coordination, or anxiety-like behavior. Monosynaptic rabies tracing revealed that Pthlh interneurons receive dense local input from MSN subtypes and diverse long-range afferents from thalamic and different cortical regions. We further confirm that this population displays electrophysiological heterogeneity encompassing fast-spiking and fast-spiking-like phenotypes. Overall, our findings establish Pthlh interneurons as a major inhibitory class essential for cognitive processing--but not gross motor function--acting as key integrators of local MSN feedback and thalamocortical signals. The novel Pthlhcre mouse line provides a valuable resource for future studies of inhibitory diversity in basal ganglia function and related neurological disorders.

neuroscience↗

bioRxiv2025

Oligodendroglia vulnerability in the human dorsal striatum in Parkinson's disease

Oligodendroglia are the responsible cells for myelination in the central nervous system and their involvement in Parkinsons disease (PD) is poorly understood. We performed snRNA-seq and image-based spatial transcriptomics of human caudate nucleus and putamen (dorsal striatum) from PD and Control brain donors to elucidate the diversity of oligodendroglia and how they are affected by the disease. We have defined fifteen subclasses, from precursor to mature cells, four of which are disease-associated. These PD-specific populations are characterized by the overexpression of heat shock proteins and distinct expression signatures, including immune responses and myelination alterations. We have also identified disruptions in cell communication and oligodendrocyte development, evidenced by changes in neurotransmitter receptors expression and cell adhesion molecules. These transcriptomic changes correlated with impaired myelin integrity and altered oligodendrocyte distribution in the striatum. Thus, we uncover oligodendroglia as a critical cell type in PD and a potential new therapeutic target.

neuroscience↗

bioRxiv2024

Thyroid hormone receptor beta (THRB) dependent regulation of diurnal hepatic lipid metabolism in adult male mice

Thyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In the liver, high TH action protects against steatosis by enhancing cholesterol and triglyceride turnover, with thyroid hormone receptor beta (THRB) signaling playing a pivotal role. This study probed the potential interaction between THRB action and another critical regulator of liver energy metabolism, the circadian clock. Liver transcriptome analysis of THRB deficient (THRBKO) mice under normal chow conditions revealed a markedly modest impact of THRB deletion. Temporal transcriptome and lipidome profiling uncovered significant alterations in diurnal metabolic rhythms attributable to THRB deficiency pointing to a pro-steatotic state with elevated levels of cholesterol, tri- and diacylglycerides, and fatty acids. These findings were confirmed by THRB agonization in hepatocytes under steatosis-promoting conditions in vitro. Integration of transcriptome profiles from THRBKO mice and mice with induced high or low TH action identified a subset of TH responsive but THRB insensitive genes implicated in immune processes. In summary, our study reveals a complex time-of-day dependent interaction of different TH-related signals in the regulation of liver physiology indicating an opportunity for chronopharmacological approaches to TH/THR(B) manipulation in fatty liver diseases.

physiology↗

bioRxiv2023

Tuning of liver circadian transcriptome rhythms by thyroid hormone state in male mice

Thyroid hormones (THs) are important regulators of systemic energy metabolism. In the liver, they stimulate lipid and cholesterol turnover and increase systemic energy bioavailability. It is still unknown how the TH state interacts with the circadian clock, another important regulator of energy metabolism. We addressed this question using a mouse model of hypothyroidism and performed circadian analyses. Low TH levels decreased locomotor activity, food intake, and body temperature mostly in the active phase. Concurrently, liver transcriptome profiling showed only subtle effects compared to elevated TH conditions. Comparative circadian transcriptome profiling revealed alterations in mesor, amplitude, and phase of transcript levels in the livers of low-TH mice. Genes associated with cholesterol uptake, biosynthesis, and bile acid secretion showed reduced mesor. Increased and decreased cholesterol levels in the serum and liver were identified, respectively. Combining data from low- and high-TH conditions allowed the identification of 516 genes with mesor changes as molecular markers of the liver TH state. These genes participate in many known TH-associated processes. We further explored these genes and created a unique expression panel that can assess liver TH state in a time-of-day dependent manner. Our findings suggest that the liver has a low TH state under physiological conditions. Circadian profiling reveals genes as potential markers of liver TH state in one-time point studies.

physiology↗

bioRxiv2023

Interneuron diversity in the human dorsal striatum

Deciphering the striatal interneuron diversity is key to understanding the basal ganglia circuit and to untangle the complex neurological and psychiatric diseases affecting this brain structure. We performed single-nucleus RNA-sequencing (snRNA-seq) of postmortem human caudate nucleus (CN) and putamen (Pu) samples to elucidate the diversity and abundance of interneuron populations and their transcriptional structure in the human dorsal striatum. We propose a new taxonomy of striatal interneurons with eight main classes. We provide specific markers for all subclasses and validated some of them with quantitative in situ fluorescence hybridization, such as a novel PTHLH-expressing population that exhibits different abundance and gene expression between CN and Pu. For the most abundant interneuron populations in human striatum, PTHLH and TAC3, we found matching known mouse interneuron populations based on key functional genes such as ion channels and synaptic receptors. Remarkably, human TAC3 and mouse Th populations share important similarities including the expression of the neuropeptide tachykinin 3. Finally, we were able to integrate our dataset with several prior smaller human striatal snRNA-seq studies, thus supporting the generalizability of this new harmonized taxonomy.

neuroscience↗

bioRxiv2022

Rewiring of liver diurnal transcriptome rhythms by triiodothyronine (T3) supplementation

Diurnal (i.e., 24-hour) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day dependent manner. 24-hour transcriptome profiling of liver tissue identified 37 robustly and time independently T3 associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10 - 15 % of the liver transcriptome as rhythmic in control and T3 groups, but only 4 % of the liver transcriptome (1,033 genes) were rhythmic across both conditions - amongst these several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In sum, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

physiology↗