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Abstract Chitosans are promising biopolymers for diverse applications, with material properties and bioactivities depending i.a. on their pattern of acetylation (PA). Commercial chitosans are typically produced by heterogeneous deacetylation of chitin, but whether this process yields chitosans with a random or block-wise PA has been debated for decades. Using a combination of recently developed in vitro assays and in silico modeling surprisingly revealed that both hypotheses are wrong; instead, we found a more regular PA in heterogeneously deacetylated chitosans, with acetylated units overrepresented at every third position in the polymer chain. Compared to random-PA chitosans produced by homogeneous deacetylation of chitin or chemical N-acetylation of polyglucosamine, this regular PA increases the elicitation activity in plants, and generates different product profiles and distributions after enzymatic and chemical cleavage. A regular PA may be beneficial for some applications but detrimental for others, stressing the relevance of the production process for product development.

Abstract Autophagy is relevant for diverse processes in eukaryotic cells, making its regulation of fundamental importance. The formation and maturation of autophagosomes require a complex choreography of numerous factors. The endosomal sorting complex required for transport (ESCRT) is implicated in the final step of autophagosomal maturation by sealing of the phagophore membrane. ESCRT-III components were shown to mediate membrane scission by forming filaments that interact with cellular membranes. However, the molecular mechanisms underlying the recruitment of ESCRTs to non-endosomal membranes remain largely unknown. Here we focus on the ESCRT-associated protein ALG2-interacting protein X (ALIX) and identify Ca2+-dependent lipid binding protein 1 (CaLB1) as its interactor. Our findings demonstrate that CaLB1 interacts with AUTOPHAGY8 (ATG8) and PI(3)P, a phospholipid found in autophagosomal membranes. Moreover, CaLB1 and ALIX localize with ATG8 on autophagosomes upon salt treatment and assemble together into condensates. The depletion of CaLB1 impacts the maturation of salt-induced autophagosomes and leads to reduced delivery of autophagosomes to the vacuole. Here, we propose a crucial role of CaLB1 in augmenting phase separation of ALIX, facilitating the recruitment of ESCRT-III to the site of phagophore closure thereby ensuring efficient maturation of autophagosomes.

Emerging data suggest that air pollution is a persistent source of neuroinflammation, reactive oxygen species (ROS), and neuropathology that contributes to central nervous system (CNS) disorders. Previous research using animal models has shown that exposure to diesel exhaust causes considerable disruption of the blood-brain barrier (BBB), leading to marked neuroinflammation. However, the effects of biodiesel exhaust on cerebrovascular integrity and neuroinflammation have not been explored previously. Therefore, in this study, 8-week-old BALB/c mice were exposed to biodiesel exhaust (derived from canola biodiesel or tallow biodiesel) and compared with control mice that were exposed to air or mineral diesel exhaust. Consistently with previous findings, the integrity of the BBB was significantly disrupted by exposure to mineral diesel exhaust. Tallow and canola biodiesel exhaust exposure resulted in no BBB disruption. Moreover, both tallow and canola biodiesels significantly attenuated oxidative stress in the brain. The data collectively suggest that biodiesel exhaust may exert significantly less detrimental effects on brain function, compared to mineral diesel.

Abstract The human adrenal gland is a complex endocrine tissue. Studies on adrenal renewal have been limited to animal models or human foetuses. Enhancing our understanding of adult human adrenal homeostasis is crucial for gaining insights into the pathogenesis of adrenal diseases, such as adrenocortical tumours. Here, we present a comprehensive cellular genomics analysis of the adult human normal adrenal gland, combining single‐nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland homeostasis. As expected, we identified primary cells of the various zones of the adrenal cortex and medulla, but we also uncovered additional cell types. They constitute the adrenal microenvironment, including immune cells, mostly composed of a large population of M2 macrophages, and new cell populations, including different subpopulations of vascular‐endothelial cells and cortical‐neuroendocrine cells. Utilizing spatial transcriptome and pseudotime trajectory analysis, we support evidence of the centripetal dynamics of adrenocortical cell maintenance and the essential role played by Wnt/β‐catenin, sonic hedgehog, and fibroblast growth factor pathways in the adult adrenocortical homeostasis. Furthermore, we compared single‐nuclei transcriptional profiles obtained from six healthy adrenal glands and twelve adrenocortical adenomas. This analysis unveiled a notable heterogeneity in cell populations within the adenoma samples. In addition, we identified six distinct adenoma‐specific clusters, each with varying distributions based on steroid profiles and tumour mutational status. Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal‐related pathologies.

Abstract Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options.

Abstract The thorough characterization of chitosan-cleaving enzymes is crucial to unveil structure–function relationships of this promising class of biomolecules for both, enzymatic fingerprinting analyses and to use the enzymes as biotechnological tools to produce tailor-made chitosans for diverse applications. Analyzing polymeric substrates as well as oligomeric products has been established as an effective way to understand the actions of enzymes, but it currently requires separate, rather laborious methods to obtain the full picture. Here, we present ultra high performance size exclusion chromatography coupled to refractive index and mass spectrometry detection (UHPSEC-RI-MS) as a straightforward method for the semi-quantitative analysis of chitosan oligomers of up to ten monomers in length. Additionally, the method allows to determine the average molecular weight of the remaining polymers and its distribution. By sampling live from an ongoing enzymatic reaction, UHPSEC-RI-MS offers the unique opportunity to analyze polymers and oligomers simultaneously—i.e., to monitor the molecular weight reduction of the polymeric substrate over the course of the digestion, while at the same time analyzing the emerging oligomeric products in a semi-quantitative manner. In this way, a single simple analysis yields detailed insights into an enzyme’s action on a given substrate.

Abstract Estimation of mortality rates and mortality rate ratios (MRR) of diseased and non-diseased individuals is a core metric of disease impact used in chronic disease epidemiology. Estimation of mortality rates is often conducted through retrospective linkage of information from nationwide surveys such as the National Health Interview Survey (NHIS) and death registries. These surveys usually collect information on disease status during only one study visit. This infrequency leads to missing disease information (with right censored survival times) for deceased individuals who were disease-free at study participation, and a possibly biased estimation of the MRR because of possible undetected disease onset after study participation. This occurrence is called “misclassification of disease status at death (MicDaD)” and it is a potentially common source of bias in epidemiologic studies. In this study, we conducted a simulation analysis with a high and a low incidence setting to assess the extent of MicDaD-bias in the estimated mortality. For the simulated populations, MRR for diseased and non-diseased individuals with and without MicDaD were calculated and compared. Magnitude of MicDaD-bias depends on and is driven by the incidence of the chronic disease under consideration; our analysis revealed a noticeable shift towards underestimation for high incidences when MicDaD is present. Impact of MicDaD was smaller for lower incidence (but associated with greater uncertainty in the estimation of MRR in general). Further research can consider the amount of missing information and potential influencers such as duration and risk factors of the disease.

Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. Polo-like kinase 1 (PLK1) is a promising drug target; PLK1 inhibitors (PLK1i) have been investigated in solid cancers and are more effective in TP53-mutated cases. We evaluated PLK1 expression in ACC samples and the efficacy of two PLK1i in ACC cell lines with different genetic backgrounds. PLK1 protein expression was investigated by immunohistochemistry in tissue samples and correlated with clinical data. The efficacy of rigosertib (RGS), targeting RAS/PI3K, CDKs and PLKs, and poloxin (Pol), specifically targeting the PLK1 polo-box domain, was tested in TP53-mutated NCI-H295R, MUC-1, and CU-ACC2 cells and in TP53 wild-type CU-ACC1. Effects on proliferation, apoptosis, and viability were determined. PLK1 immunostaining was stronger in TP53-mutated ACC samples vs wild-type (P = 0.0017). High PLK1 expression together with TP53 mutations correlated with shorter progression-free survival (P = 0.041). NCI-H295R showed a time- and dose-dependent reduction in proliferation with both PLK1i (P < 0.05 at 100 nM RGS and 30 μM Pol). In MUC-1, a less pronounced decrease was observed (P < 0.05 at 1000 nM RGS and 100 μM Pol). 100 nM RGS increased apoptosis in NCI-H295R (P < 0.001), with no effect on MUC-1. CU-ACC2 apoptosis was induced only at high concentrations (P < 0.05 at 3000 nM RGS and 100 μM Pol), while proliferation decreased at 1000 nM RGS and 30 μM Pol. CU-ACC1 proliferation reduced, and apoptosis increased, only at 100 μM Pol. TP53-mutated ACC cell lines demonstrated better response to PLK1i than wild-type CU-ACC1. These data suggest PLK1i may be a promising targeted treatment of a subset of ACC patients, pre-selected according to tumour genetic signature.

The use of gas diffusion electrodes (GDEs) in microbial fuel cells (MFCs) can improve their cell performance, but tends to cause fouling. In order to allow long-term stable operation, the search for antifouling methods is necessary. Therefore, an antibacterial coating with ammonium compounds is investigated. Within the first 30 days of operation, the maximum measured power density of a GDE with antibacterial ionomer was 606 mW m−2. The GDE without an antifouling treatment could only reach a maximum of 284 mW m−2. Furthermore, there was an optimum in the loading amount with ionomer below 2.6 mg cm−2. Further investigations showed that additional aeration of the GDEs by a fan had a negative effect on their performance. Despite the higher performance, the antibacterial coating could not prevent biofilm growth at the surface of the GDE. The thickness of the biofilm was only reduced by 14–16%. However, the weight of the biofilm on the treated GDEs was 62–80% less than on a GDE without an antifouling treatment. Consequently, the coating cannot completely prevent fouling, but possibly leads to a lower density of the biofilm or prevents clogging of the pores inside the electrodes and improves their long-term stability.

An air-sea interaction field campaign was conducted in September of 2017 within the warm and cold eddy region of the western Northwest Pacific (WNP) (17.5˚-20.5˚N, 127.5˚E-133.5˚E). Both near-surface oceanic and atmospheric conditions in addition to ocean heat content (OHC) were examined to better understand the mechanisms governing high heat flux magnitudes responsible for rapidly intensifying tropical cyclones. Observations from this experiment indicate that the latent heat flux (LHF) under modest wind conditions reached 400 W m-2 within the vicinity of a warm eddy, with OHC higher than 100 kJ cm-2 of warm eddy region being 2~3 times as large as that of cold eddy region. These high OHC and a resultant high LHF in the warm eddy, comparable to the magnitude of LHF in the North Equatorial Current, may explain the mechanism of why tropical cyclones over a warm eddy in eddy-rich zones often rapidly intensify in the WNP. A month later typhoon Lan rapidly intensified into a super typhoon, while passing over the boundary region of warm and cold eddies during the observation period. Results from this study illustrate that both the wind-normalized LHF and the difference (Qs-Qa) between the specific humidity at air (Qa) and at the sea surface (Qs), closely correlate with OHC patterns, which suggests that the ocean looks likely to control the spatial pattern of LHF. Overall, both the ocean and weather conditions govern the pattern of specific humidity difference between the air-sea interface, with large OHC over the warm eddy controlling higher Qs and the pattern of Qa depending on the pattern of wind direction. Qa as a factor impacting LHF magnitude is strongly linked to wind direction in the experimental area, that is, the drier northwesterly flow and southeasterly moist wind, resulting in the enhanced contrast of specific humidity at cold eddy region.

Parathyroid carcinoma (PC) is an ultra‐rare malignancy with a high risk of recurrence after surgery. Tumour‐directed systemic treatments for PC are not established. We used whole‐genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (a) immune checkpoint inhibition with pembrolizumab based on high tumour mutational burden and a single‐base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like) overactivation; (b) multi‐receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 (Fibroblast Growth Factor Receptor 1) and RET (Ret Proto‐Oncogene) and, (c) later in the course of the disease, PARP (Poly(ADP‐Ribose) Polymerase) inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome‐wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra‐rare cancers based on insight into disease biology.

Background/Objectives: Recent studies provide the first indications of the impact of climate factors on human health, especially with individuals already grappling with internal and neurological conditions being particularly vulnerable. In the face of escalating climate change, our research delves into the specific influence of a spectrum of climatic factors and seasonal variations on the hospital admissions of patients receiving treatment for epileptic seizures at our clinic in Kaiserslautern. Methods: Our study encompassed data from 9366 epilepsy patients who were admitted to hospital due to epileptic seizures. We considered seven climate parameters that Germany’s National Meteorological Service made available. We employed the Kruskal–Wallis test to examine the correlation between the frequency of admittance to our hospital in the mentioned patient group and seasons. Furthermore, we used conditional Poisson regression and distributed lag linear models (DLMs) to scrutinize the coherence of the frequency of patient admittance and the investigated climate parameters. The mentioned parameters were also analyzed in a subgroup analysis regarding the gender and age of patients and the classification of seizures according to ILAE 2017. Results: Our results demonstrate that climatic factors, such as precipitation and air pressure, can increase the frequency of hospital admissions for seizures in patients with general-onset epilepsy. In contrast, patients with focal seizures are less prone to climatic changes. Consequently, admittance to the hospital for seizures is less affected by climatic factors in the latter patient group. Conclusions: The present study demonstrated that climatic factors are possible trigger factors for the provocation of seizures, particularly in patients with generalized seizures. This was determined indirectly by analyzing the frequency of seizure-related emergency admissions and their relation to prevailing climate factors. Our study is consistent with other studies showing that climate factors, such as cerebral infarcts or cerebral hemorrhages, influence patients’ health.

Summary: The expression of pro-lymphangiogenic VEGF-C in primary tumors is associated with sentinel lymph node metastasis in most solid cancer types. However, the impact of VEGF-C on distant organ metastasis remains unclear. Perivascular tumor-associated macrophages (TAMs) play a crucial role in guiding hematogenous spread of cancer cells by establishing metastatic pathways within the tumor microenvironment. This process supports breast cancer cell intravasation and metastatic dissemination. We show here that VEGF-C-expressing TAMs reduce the dissemination of mammary cancer cells to the lungs while concurrently increasing lymph node metastasis. These TAMs express podoplanin and interact with normalized tumor blood vessels expressing VEGFR3. Moreover, clinical data suggest inverse association between VEGF-C-expressing TAMs and breast cancer malignancy. Thus, our study elucidates the paradoxical role of VEGF-C-expressing TAMs in redirecting cancer cells to preferentially disseminate to lymph nodes rather than to lungs, partially achieved by normalizing tumor blood vessels and promoting lymphangiogenesis.

Abstract This article proposes a four-layered diagram that displays as an overview of the current field of historical time studies according to the following branches of investigation: 1) the metaphysics of natural time, 2) the metaphysics of historical time, 3) the regimes of historicity, and 4) historiographical regimes. By defining these fields and their connections, identifying essential concepts, revealing the questions they address, and sketching tendencies that have emerged since the 2000s, this article tackles historical temporality as a theoretical and historiographical subject. This framework, which portrays the state of the art in temporal studies, allows for the presentation and classification of the variety of contributions gathered in this special edition.