The S2k guidelines on liver transplantation are the first German language interdisciplinarily developed guidelines on liver transplantation and provide a comprehensive framework for action for the treatment of patients before, during and after transplantation. This article provides a compact overview of selected recommendations from the guidelines that are particularly relevant for the practice. In addition to central aspects of transplantation evaluation, waiting list management and perioperative care, the essential differences to the guidelines of the German Medical Association for management of the waiting list and organ distribution according to Section 16, para. 1, p.1, nos. 2 and 5 of the Transplantation Act are also discussed.

Well-regulated trophoblast proliferation, migration, invasion, and cell turnover are essential for normal placental development in humans and rodents. Given the established role of oxidative stress in placentation and the redox activity of iron, we investigated whether ferroptosis-associated redox signaling contributes to trophoblast function and placental development. Placental iron profiling revealed significantly elevated total and ferrous iron levels in first-trimester human villi compared with term placentas, accompanied by the transcript levels of several iron uptake- and reduction-related genes, including TFRC, DMT1, ZIP8, STEAP3, and STEAP4, which were elevated in first-trimester villi. Murine placentas also exhibited gestational changes in iron abundance and iron-homeostasis-related gene expression. HO-1 protein abundance was highest during early gestation and declined thereafter, suggesting a potential association between heme degradation and gestational iron homeostasis. In contrast, placental labile iron pool (LIP) levels showed only modest, statistically nonsignificant changes across gestation, suggesting a relatively stable redox-active iron pool. Immunofluorescence analyses demonstrated spatially distinct expression of ferroptosis-associated regulators, with ACSL4 enriched in invasive trophoblast populations and GPX4 predominantly localized in surrounding decidual tissues, suggesting regional heterogeneity in ferroptosis-associated molecular features during placentation. Functional studies in HTR-8/SVneo trophoblast cells further demonstrated that mild ferroptosis-associated redox perturbation induced by low-dose erastin or ferrous iron enhanced trophoblast migration and invasion without overt cytotoxicity. These effects were attenuated by ferrostatin-1, deferoxamine mesylate (DFOM), or the mitochondria-targeted antioxidant MitoQ and were blunted following FTH1 and TFRC knockdown, indicating that trophoblast responsiveness depends on iron availability and ferroptosis-associated redox signaling. Importantly, these pro-invasive effects were preserved under physiologically relevant hypoxic conditions. Together, our findings support a model in which gestational changes in placental iron homeostasis are associated with ferroptosis-related molecular features, while experimentally induced iron-dependent redox signaling modulates trophoblast behavior. Rather than inducing overt ferroptotic cell death, sublethal iron-dependent redox perturbation may act as a signaling mechanism influencing trophoblast function during placental development.

Type I interferon induces multiple protein effectors to inhibit viral replication. Among these, the interferon-induced transmembrane protein (IFITM3) and the cholesterol-25-hydroxylase (CH25h) converge on the inhibition of viral entry by altering the behavior of membranes. Here, we dissect the functional and mechanistic relationship between these two membrane-acting effectors using different viruses. When using HIV-1 and vesicular stomatitis virus (VSV), IFITM3 and CH25h restrict viral entry with similar efficiency but act in a largely redundant manner, a finding that is consistent across infection systems, cell types, and entry assays. However, this is not the case for several orthoflaviviruses against which IFITM3, but not CH25h, provides a strong block to infection. We further uncover that the CH25h-25HC axis remodels IFITM3 trafficking by driving partial relocalization of IFITM3 from endolysosomal compartments to the plasma membrane. This occurs by impairing IFITM3 internalization into early endosomes and leads to an increase in its secretion in exosomal vesicles, overall indicating that CH25h contributes to regulate IFITM3 cellular dynamics. Together, these findings reveal that the apparent redundancy of maintaining two distinct effectors targeting the same step of the viral life cycle is not superfluous but instead allows the cell to compensate and, nonetheless, target viruses that may have developed resistance to one of these effectors. Furthermore, the ability of CH25h to remodel IFITM3 trafficking indicates that these two pathways are connected, adding an additional layer of complexity in the biology of IFITM3.IMPORTANCEIFITM3 and CH25h are two potent, broad-acting inhibitors of viral membrane fusion, but their functional connections have not been explored. Here, we show that although their antiviral activities are largely redundant against HIV-1 and vesicular stomatitis virus (VSV), IFITM3 functionally compensates for a relative resistance of orthoflaviviruses toward CH25h. Furthermore, CH25h redistributes IFITM3 from endosomal compartments to the plasma membrane, enhancing its release in exosomal vesicles. Overall, these findings reveal that despite the fact that IFITM3 and CH25h can act redundantly against certain classes of viruses, IFITM3 can functionally compensate for CH25h resistance against other viruses, highlighting why it is important for the cell to maintain two distinct pathways to block virus-to-cell membrane fusion. In addition, these results also reveal how interferon-driven lipid remodeling can reshape the trafficking behavior of IFITM3, leading it to be more present in exosomes, where it could exert paracrine functions that remain to be explored.

Chlamydia psittaci (Cps) causes psittacosis, a zoonotic disease characterized by severe pneumonia and systemic infection, yet its pathogenic mechanisms remain poorly understood. While plasmids are established virulence determinants in C. trachomatis (Ct) and Chlamydia muridarum (Cm), their role in Cps pathogenesis is unknown. Here, we generated a panel of Cps transformants with individual deletions of plasmid genes (pgp1-pgp8) and characterized in vitro and in vivo. Genetic analysis revealed that Pgp1 and Pgp2 are required for plasmid maintenance, whereas Pgp3-Pgp8 are dispensable. Transcriptomic and qRT-PCR analyses identified a subset of chromosomal genes regulated by the Cps plasmid, distinct from those described in Ct and Cm. Pgp4 functions as a central regulator of chromosomal gene expression; however, unlike Ct or Cm, Pgp4 does not affect pgp3 transcript levels but is required for Pgp3 protein expression, indicating post-transcriptional regulation. We further show that Pgp7 positively regulates plasmid-dependent gene expression, whereas Pgp6 and Pgp8 negatively regulate this process. Functionally, the plasmid is a determinant of virulence in a murine lung infection model. Pgp3 is essential for host inflammatory responses and bacterial virulence in vivo. Collectively, these findings demonstrate plasmid-mediated regulation in Cps is distinct from that in other chlamydial species and highlight species-specific regulatory mechanisms underlying chlamydial pathogenesis.

Polylactic acid (PLA) is a bio-based polymer known to exhibit only thermophilic compostability. We recently developed a unique set of compost that can biodegrade PLA at mesophilic conditions, and it exhibited more than 10-fold higher PLA breakdown activity than control composts. Here, we investigated the potential selection of bioactivities related to PLA breakdown in our uniquely trained compost and surveyed the occurrences of those activities in a range of terrestrial and marine environments for comparison. We found that the fraction of PLA-hydrolyzing bacteria in our trained compost was not significantly increased compared to environmental samples. However, PLA-clearing strains isolated from the trained compost were twice as efficient in hydrolyzing PLA compared to those derived from environmental soil, indicating that our trained compost had undergone selection of strains with higher hydrolysis activity. This provides an important insight into PLA-related bioactivity in our trained compost, and it further suggests additional bioactivities that facilitate PLA breakdown most likely exist in our trained compost. Our findings support a multi-step model for mesophilic PLA composting in which several microbial-based bioactivities act synergistically to enhance PLA biodegradation.

Bruising is among the most common physical consequences of violence and a critical form of injury evidence in health, child protection, and criminal justice contexts. Yet for survivors with darker skin tones, bruises are measurably harder to detect and act upon. This disparity has received insufficient research attention but has significant consequences for health, protection, and access to justice. This scoping review mapped the available evidence on bruise ascertainment and documentation in people with darker skin tones exposed to violence, drawing on 21 studies published between 1995 and 2024 across clinical, forensic, and investigative settings. Findings confirm that chromatic contrast between bruised and unbruised tissue decreases at higher melanin levels, rendering standard white-light visual examination unreliable. Alternate light source imaging, cross-polarised photography, and infrared techniques significantly improve detection, yet have not been evaluated in real-world settings with survivor populations. Validated assessment tools, including the Bruise Visibility Scale and TEN-4-FACESp, have not been comprehensively established across skin tones and remain underused in routine practice. Racially and ethnically minoritised survivors face compounded barriers to disclosure and documentation, and inadequate injury evidence has consequences for charging decisions, prosecution outcomes, and sentencing. Police officers appear significantly less likely to identify injuries in Black survivors, and documentation failures reproduce existing inequalities in health and justice. The review identifies critical gaps in practitioner training, interagency protocols, and only limited real-world evaluation of available technologies. A coordinated programme of primary research, including development and evaluation of a complex intervention co-designed with survivors and practitioners, is urgently needed to address these systemic disparities.

Drug-induced seizures are among the most frequent safety concerns for neuroactive drug candidates. Currently, no guidelines are defined for interrogating and mitigating seizure liability. Because of the risks to patient safety during clinical trials, improved nonclinical characterization of seizure liability is an area of intense interest among drug developers and regulators. During the 2022 annual meeting of the American College of Toxicology (ACT), a continuing education course titled "Identifying and Understanding Seizure Liability in Drug Development" addressed challenges in this field. The course (and now this paper) used a series of detailed nonclinical case studies based on the authors' experiences to illustrate core principles and a flexible menu of methods to evaluate potential seizure liability. Key points to consider include lists of (1) procedures for detecting seizures and defining their mechanisms when performing pivotal and/or investigational toxicity studies; (2) constellations of common neurological findings (functional and structural) that indicate potential seizure liability, and in particular (3) event patterns that warrant an electroencephalographic (EEG) study; and (4) major principles for mitigating seizure liability during clinical trials. Taken together, this approach provides a logical workflow by which nonclinical testing of drug-related seizures may be used to best protect patient safety.

Nutrigenomics explores how nutrients interact with the genome to influence metabolic and physiological functions through microbial and molecular mechanisms. Nutrients and bioactive food compounds act as biochemical modulators that regulate gene expression and immune responses, sustaining physiological stability. On the other hand, the gut microbiota create a balanced, complex ecosystem that is vital for maintaining host physiology and metabolic balance. The type and composition of diet directly shape gut microbial communities and populations, which, in turn, influence host gene expression. Disruption of this balance can contribute significantly to various health issues. In this context, the gut microbiota act as both allies and adversaries in human health. This review discusses the current state of nutrigenomics, focusing on the complex interplay among dietary metabolites, microbiota, and genes, and linking this interplay to the genesis and prevention of several chronic diseases. This review provides an overview of the unique composition of the intestinal microbiota and its role in mediating nutrigenomic interactions.

Identifying condition-specific disease drivers from transcriptomic data requires analytical frameworks that capture not only differential expression but also dynamic changes in network organization. Many existing approaches treat genes as independent features or rely primarily on co-expression similarity and hub identification, which can miss context-dependent regulators that drive network rewiring within protein-protein interaction (PPI) networks. To address these limitations, we present a web server DiCE-Ex (Differential Centrality-Ensemble Exploration) designed to prioritize genes whose network roles and topological influence are rewired between conditions, even though some of them may not exhibit large expression changes. DiCE-Ex integrates gene expression data with PPI networks to construct condition-specific weighted interaction networks and systematically evaluates centrality shifts across an ensemble of network measures selected by the user. By focusing on changes in network centrality rather than expression magnitude alone, DiCE-Ex identifies genes that act as key mediators of condition-dependent signalling and regulatory reorganization. Case studies demonstrate that DiCE-Ex successfully recovers known disease modulators while also identifying key nonhub regulators that are overlooked by conventional differential expression analyses, thereby highlighting strong candidates for mechanistic validation and therapeutic development. DiCE-Ex is freely available at https://connect.posit.iu.edu/DiCE-Ex/ with example datasets, comprehensive documents, step-by-step tutorials, and shareable job permalinks.

There is an urgent need to speed up clinical trials for potential disease-modifying therapies that slow progression of Parkinson's disease. The Edmond J Safra Accelerating Clinical Trials in Parkinson's Disease (EJS ACT-PD) initiative set out to develop a patient-centric and inclusive platform trial using an innovative multi-arm, multi-stage (MAMS) design. We describe the work of the EJS ACT-PD consortium, which included over 90 experts including people with Parkinson's disease and care partners across six working groups. There were five key challenges: developing an efficient MAMS trial that meets regulatory requirements and is acceptable to people with Parkinson's; mitigating participant heterogeneity; reducing the risk of simultaneous arm closures; introducing different treatment regimens into a MAMS trial; and maximizing deliverability and accessibility of a MAMS trial. The final design was achieved through an iterative process and critical appraisal of data modelling exploring the impact of participant numbers per arm, trial durations, and endpoints. Every aspect of the design was informed by people with Parkinson's disease and care partners whose advice ensured acceptability, deliverability, and accessibility. The EJS ACT-PD trial will start with one placebo and three treatment arms, each with 400 participants, with a primary endpoint at 3 years powered to detect a 30% reduction in rate of progression of MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I and II summed scores. Interim analyses will test for activity using the summed inverse variance weighted MDS-UPDRS Part I, II, and remote Part III scores. Ineffective arms will be closed, allowing participants to be re-randomized. Cost-effectiveness analysis is embedded. Further promising treatments will be added in future arms, subject to additional funding. To maximize accessibility and inclusivity, the trial will allow for study visits to be conducted remotely based on participant preference. National sites were selected to maximize accessibility and inclusive recruitment with core funded staff placed within experienced trial sites to support training and delivery at less experienced centres. By involving people with Parkinson's and care partners as well as stakeholders with broad scientific expertise, we have developed an inclusive MAMS trial which captures all stages of disease with partial remote delivery and clear design rationales that will significantly speed up the testing of disease-modifying therapies in Parkinson's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by multiple interconnected pathological mechanisms. This narrative review systematically searched major biomedical databases for relevant literature published between 2015 and 2026, using predefined keywords combined with manual supplementary searches. Two independent reviewers performed a qualitative screening based on relevance, involving the iterative review of titles, abstracts, and full texts. A targeted selection of representative, high-quality studies centered on TCM and AD pathogenesis/mechanisms was then conducted. Ultimately, studies were included in the narrative review for the mechanistic synthesis of TCM against AD. This review summarizes seven core AD mechanisms, including the Aβ cascade, Tau abnormalities, Neuroinflammation, Regulated cell death, Synaptic plasticity impairment, Gut microbiota-brain axis imbalance, and Oxidative stress, and critically discusses the multi‑target interventions of TCM via key molecules such as GSK-3β, BACE1, SIRT1, NF‑κB, NLRP3, PINK1/Parkin, AMPK, BDNF, PSD‑95, and the Nrf2/HO‑1 pathway. GSK‑3β and NF‑κB act as central hubs linking Aβ/Tau pathology to neuroinflammation, while AMPK, SIRT1, and Nrf2/HO‑1 regulate metabolic and redox homeostasis, PINK1/Parkin control mitophagy, and BDNF/PSD‑95 determine synaptic integrity. TCM's therapeutic superiority lies in its simultaneous modulation of this entire hierarchical network, representing a multi‑target strategy that conventional single‑target drugs cannot replicate. By concurrently modulating these distinct yet interacting nodes, TCM establishes a synergistic therapeutic network that reduces Aβ deposition, attenuates Tau hyperphosphorylation, and mitigates neuronal damage, offering a novel direction for future AD research.

The hypothalamic-pituitary-gonadal (HPG) axis coordinates reproductive function and incorporates gonadal sex steroid feedback to regulate gonadotropin secretion in a homeostatic manner. In females, ovarian estrogens and progestins act as the primary negative feedback signals to suppress luteinizing hormone (LH) release, whereas in males, androgens, such as testosterone (T), typically provide this feedback. However, androgens can also exert feedback effects on the female HPG axis, particularly in conditions where circulating T levels exceed that of the normal female physiological range. Three clinically relevant examples are anabolic substance abuse, testosterone therapy, and polycystic ovary syndrome (PCOS; recently renamed polyendocrine metabolic ovarian syndrome [PMOS]). Despite shared exposure to "androgen excess," these different hyperandrogenic states are associated with strikingly different neuroendocrine phenotypes. In testosterone therapy and anabolic substance abuse, high exogenous androgen exposure in or above the male physiological range typically suppresses LH secretion and disrupts ovulatory cycling, mimicking enhanced negative feedback on the HPG axis. Conversely, in PMOS, endogenous elevations in T, high for a female but below the male physiological range, are associated with increased LH secretion, acyclicity, and anovulation. The mechanisms underlying these divergent LH outcomes remain unclear but may reflect, in part, differences in the source of androgens (exogenous vs. endogenous), circulating androgen concentrations, and development timing and/or duration of androgen exposure. This review synthesizes current clinical and preclinical evidence to compare distinct models of hyperandrogenemia with respect to the female HPG axis and aims to illuminate how endogenous and exogenous androgens with different features differentially alter female neuroendocrine function.

The average age of childbirth in the UK in 2022 was 30.9 years, having increased by over 3 years in the past 2 decades, and 4 years since 1980. Although a woman's fertility declines markedly in her late-30s and early-40s, more women are now starting their family at this stage of their lives. Related to this, increasing numbers of women are storing their eggs (oocytes) to give them the potential opportunity to have a baby in the future. The number of egg freezing cycles accounts for 5% of in vitro fertilisation (IVF) cycles but the number of cycles using stored eggs is much lower. The use of a technique of rapid freezing called vitrification gives success rates almost as good as using fresh eggs. The reasons behind the increase in egg freezing are complex, but the most common reason given by women storing eggs is that they do not have a partner and are concerned that by the time they do find themselves in a relationship within which they wish to start a family, they may not be able to do so. This paper addresses the growing use of egg freezing and how it may have been promoted. It is essential that women are very clearly informed about the likely success rates of egg freezing, particularly as it is primarily provided by the private sector, with the associated concerns of financial costs and inappropriate or inaccurate marketing. Its success is strongly dependent on the age of the woman at the time of freezing her eggs, with much higher success rates in those under the age of 35 years. The relevant legislation changed in 2022 and now allows women to store eggs for 55 years, although consent for this needs to be renewed every 10 years. This now supports the better success rates when women store eggs at a younger age. We conclude that elective egg freezing provides women with an opportunity to act on the age-related drop in their fertility. At present, most women who are doing this are already in their later 30s when the success rates are limited. We strongly support the need for improved and continuing education of both women and men regarding the decline in female fertility with age.