BioTechMed-Graz

Phase singularities are a common problem in image reconstruction with auto-calibrated sensitivities due to an inherent ambiguity of the estimation problem. The purpose of this work is to develop a method for detecting and correcting phase poles in non-linear inverse (NLINV) reconstruction of MR images and coil sensitivity maps. Phase poles are detected in individual coil sensitivity maps by computing the curl in each pixel. A weighted average of the curl in each coil is computed to detect phase poles. Phase pole detection and correction is then integrated into the iteratively regularized Gauss-Newton method of the NLINV algorithm. In addition, we demonstrate the algorithm can also remove phase poles in ESPIRiT coil sensitivity maps. Phase pole correction is evaluated for reconstruction of accelerated Cartesian MPRAGE data of the brain and interactive radial real-time MRI of the human heart. For both applications, phase pole correction can be used for estimation of coil sensitivity profiles free from singularities. For NLINV, we demonstrate reliable and efficient estimation even from very small ( ) auto-calibration (AC) regions. With the proposed method, phase poles can be reliably removed in reconstructions and coil sensitivities.

Mitochondrial calcium ([Ca2+]mito) homeostasis is a key regulator of cellular physiology, controlling signal transduction, energy metabolism, and cell survival. To examine how these processes change with age in vivo, we used the pharyngeal muscle of Caenorhabditis elegans (C. elegans) as a tractable model for studying [Ca2+]mito dynamics. We introduced electric field stimulation as a robust trigger for [Ca2+]mito uptake that overcomes limitations of compound stimulation, which relies on pharyngeal pumping and endoplasmic reticulum store filling and is typically confined to single-stimulus protocols. In contrast, electric field stimulation enables physiologically relevant repeated excitation that challenges [Ca2+]mito uptake and recovery. Stimulation with 10V for 10s reliably evoked reproducible [Ca2+]mito transients in the pharyngeal muscle of C. elegans and produced higher responder rates than compound stimulation. Basal [Ca2+]mito increased with age, and the first field-evoked transient was significantly larger in aged animals, an effect not detected with pharmacological triggers. Repeated pulses unmasked cumulative [Ca2+]mito loading and incomplete recovery in aged pharynx, indicative of [Ca2+]mito overload, which was attenuated by inhibition of the mitochondrial Ca2+ uniporter (MCU) with mitoxantrone. Regional analyses identified the corpus as a hotspot for electric field-evoked [Ca2+]mito uptake and overload, while MCU inhibition reduced repeated responses in both corpus and posterior bulb. Electric field stimulation enables precise, repeated in vivo probing of [Ca2+]mito uptake and recovery, revealing overload in the C. elegans pharynx. This approach identified age-enhanced, MCU-dependent, and region-specific [Ca2+]mito loading, providing a pathophysiologically relevant readout of impaired Ca2+ handling that may contribute to age-related muscle dysfunction.

Skin barrier dysfunction is central to inflammation and susceptibility to infection in atopic dermatitis (AD). Cutaneous T-cell lymphoma (CTCL) shares clinical similarities with AD and is also associated with a high prevalence of Staphylococcus aureus (S. aureus) colonisation. However, the mechanisms driving skin barrier damage in CTCL and the contribution of bacteria remain poorly understood. We investigate how the interplay between S. aureus (and staphylococcal enterotoxins (SEs)) and primary malignant- and non-malignant T cells affects keratinocyte expression of skin barrier proteins; invitro, in an EL4 murine lymphoma model of bacteria-driven tumour progression, and in CTCL patient lesions colonised with SE-producing S. aureus before and after bacterial eradication by antibiotic treatment. S. aureus and SEs activate malignant and non-malignant T cells to release barrier-repressing cytokines, including IL-4, IL-13, IL-22, and OSM, and JAK-dependent downregulation of filaggrin and loricrin in keratinocytes. In the EL4 model, bacteria-colonised tumour-bearing mice show significant filaggrin loss in tumour-adjacent epidermis, whereas antibiotic-treated mice maintain near-normal expression. Clinically, antibiotic eradication of SE-producing S. aureus partially restores filaggrin and loricrin expression in three of four patients, paralleling reduced inflammatory signalling. SE-producing S. aureus promotes skin barrier impairment in CTCL through cytokine-driven, JAK-dependent repression of structural proteins in keratinocytes. These findings identify microbial-immune crosstalk as a contributor to CTCL skin pathology and provide mechanistic rationale for strategies targeting S. aureus colonisation as adjunctive therapy in CTCL.

The placenta and uterus are essential to healthy human pregnancy, yet their complex adaptation and function remain difficult to study, particularly during the second trimester. Historical collections of placenta in situ specimens, including the Boyd, Dixon, and Carnegie Collections, provide rare access to placental and uterine anatomy across developmental stages and pathological conditions. Due to advancements in obstetric care, the preparation and extent of specimens in these collections is uncommon nowadays. They therefore offer a unique window into pregnancy that contemporary imaging cannot fully reproduce. This review article briefly summarizes these historical collections and examines how they can be integrated with modern imaging, machine learning, and multiscale modeling to extend their research utility. Advances in computational methods support the digitization and 3D reconstruction of 2D histological sections, helping to mitigate issues such as tissue deformation, staining variability, and missing sections. In addition, machine learning approaches enable automated segmentation, facilitating more detailed characterization of utero-placental structures and associated physiological functions. Image-based multiscale modeling can link microscale features, such as villous capillary architecture, to organ-scale responses including global perfusion and oxygen transport, while enabling efficient computation when enhanced with physics-informed neural networks or neural operators. These methods preserve the scientific value of legacy specimens while enabling new avenues for studying pregnancy complications such as preeclampsia and fetal growth restriction. By combining legacy resources with contemporary analytical techniques in an interdisciplinary framework, a more thorough understanding of placental biology and maternal-fetal health can be achieved that may inform future research and clinical applications.

Patatin‐like phospholipase (PNPLA) domain‐containing proteins are essential enzymes involved in lipid metabolism, membrane remodeling, and signaling pathways across various organisms. This review focuses on the structural and functional characteristics of four selected PNPLA proteins from different organisms with experimental 3D structures or biochemical data on protein–protein interactions that facilitate their co‐activation mechanism, namely VipD, ExoU, PNPLA9, and PNPLA2 (also known as ATGL). VipD and ExoU, phospholipases from Legionella pneumophila and Pseudomonas aeruginosa, respectively, are multidomain proteins and utilize distinct mechanisms for host cell interaction and pathogenesis. VipD binds to Rab proteins, underscoring the critical role of Rab5 in upregulating its enzymatic activity and contributing to the pathogenicity. ExoU requires ubiquitin for activation and exhibits an inhibited structure when complexed with its chaperone SpcU. PNPLA9, a calcium‐independent phospholipase A2, is predominantly expressed in the human brain, with mutations linked to neurodegenerative disorders and inflammation. The crystal structure of the Chinese hamster ortholog of PNPLA9 reveals a dimerization mechanism required for its catalytic activity, along with specific regions identified for membrane interaction and substrate binding. PNPLA2 is known for its triacylglycerol hydrolytic activity and is regulated by protein–protein interactions, particularly with the co‐activator ABHD5, which is crucial for its activation. This review highlights the diversity and conserved architectural segments of PNPLA proteins, reflecting their varied biological roles and regulatory mechanisms. Understanding the diverse protein–protein interactions that activate these enzymes is crucial for elucidating their roles in physiological and pathological contexts.

Purpose: Physical activity has consistently shown positive effects on psychological functioning and brain structure – particularly within the hippocampus, a region implicated in both exercise and mood regulation. Clinical findings suggest reduced hippocampal volume in individuals with depression compared to healthy controls. However, longitudinal intervention studies on young, healthy populations remain scarce. This preregistered study aimed to investigate the biological and social mechanisms driving structural brain, affective, and fitness-related changes during a running intervention, with a novel comparison between individual and group-based running formats. Methods: A four-week longitudinal intervention included 129 participants aged 18–35 who engaged in less than the WHO-recommended 150 minutes/week of aerobic activity. Participants were randomly assigned to one of three groups: (1) individual running, (2) small group running, or (3) waiting control. The running route, frequency, and duration were identical across intervention groups. Assessments were conducted at three timepoints and included magnetic resonance imaging (MRI), psychometric evaluations, electrocardiography (ECG), and estimated V̇O₂max via the UKK Walking Test. Preliminary Results: Previous intervention studies conducted in our laboratory have demonstrated significant volumetric changes in subfields of the hippocampus, which were associated with a reduction in depressive symptoms. In this study, we will follow up on these results by not only examining intervention-related volumetric changes in the hippocampus subfields but also by taking into account a broad range of psychometric measures and cardiac responses to gain insights into various facets of wellbeing induced by physical activity. It is anticipated that the study presented here, with a larger sample and a more rigorous methodological design, will more specifically bolster the results from previous research. Conclusion: Taken together, the findings of our laboratory suggest that regular running induces beneficial changes in brain and mood in previously rather inactive young adults. This work highlights the holistic benefits of running and supports its promotion as a tool for maintaining mental and brain health. Support/Funding Source: This research was funded by the Austrian Science Fund (FWF).

Eukaryotic ribosome synthesis is a highly complex, multistep process that is best characterized in the yeast Saccharomyces cerevisiae. It is orchestrated by >200 ribosome assembly factors and 75 small nucleolar ribonucleoproteins (snoRNPs), which guide site-specific chemical modifications of precursor rRNA (pre-rRNA). While canonical box C/D snoRNPs guide 2′-O-methylation, the atypical box C/D snoRNPs snR4 and snR45 guide acetylation of 18S rRNA residues C1280 and C1773, respectively, catalyzed by the acetyltransferase Kre33. Here, we identify and characterize Ynl050c/Sni445 as a novel ribosome assembly factor and previously unrecognized auxiliary component of the snR4 and snR45 box C/D snoRNPs. Sni445 associates with snR4 and snR45 in their free form and is required for their stable incorporation into 90S pre-ribosomes. Genetic interactions link Sni445 and the snR4 and snR45 snoRNAs to ribosomal proteins Rps20 (uS10) and Rps14 (uS11), which are positioned near the respective acetylation sites in the 40S subunit. Moreover, Sni445 physically interacts with Kre33 within the 90S pre-ribosome, and its absence abolishes acetylation of C1280 and C1773. Our findings suggest that Sni445 facilitates the recruitment of snR4 and snR45 snoRNPs to 90S particles and might promote their interaction with Kre33, thereby enabling the site-specific acetylation of 18S rRNA by Kre33.

Structural predictions have reached unprecedented accuracy. They leverage sequence‐specific data to capture all potential interactions a sequence has evolved to fulfill. AlphaFold derives information from three sources: learned parameters capturing intrinsic amino acid secondary structure and environment propensity; models of related proteins providing structural templates; and aligned sequences encoding profiles and concerted evolutionary changes of residues involved in contacts. However, function demands dynamic changes; hence not all possible interactions can coexist simultaneously. Comprehensive information entails contradictions, which resolved in favor of the better‐informed structure will silence less stable states and associations. Here, we introduce a method using all three channels to include prior knowledge: site‐specific variants, predefined alignments and templates. Selecting information relevant to a particular state delimits the functional context of a prediction. Our program VAIRO allows us to rescue asymmetric and weaker interactions to complete the view of molecular assemblies in the architecture of a bacterial surface layer, and reveals otherwise inaccessible dynamic states in a pneumococcal multimeric membrane protein complex. VAIRO is distributed via the python package index (PyPI) (https://pypi.org/project/vairo) and the code is also available on Github (https://github.com/arcimboldo-team/vairo).

Fungal infections pose a significant global health threat with rising morbidity and mortality rates. However, the repertoire of effective antifungal drugs remains narrow, a challenge that is further exacerbated by the increasing emergence of (multi)drug-resistant strains. This underscores the urgent need for novel therapeutic strategies. Among them, antifungal peptides (AFPs) have emerged as a promising alternative. AFPs are small, naturally occurring peptides produced by a wide range of organisms, including plants, animals, fungi, and bacteria, as part of their innate immune defense. In addition, synthetic and semisynthetic variants have also been engineered. We here underscore the potential of AFPs as viable candidates for the development of next-generation antifungal therapies. In particular, we advocate their multimodal advantage that spans beyond standalone activity, including their synergistic and immune-regulatory potential.

Lytic polysaccharide monooxygenases catalyse the H 2 O 2 -dependent cleavage of polysaccharides. An optical H 2 O 2 sensor allows for real-time monitoring of enzyme activity and avoids the determination of oxidised reaction products.