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Mesocosm systems simulating floodplain areas are essential for the understanding of the environmental fate and effects of engineered nanoparticles (ENPs). In such mesocosm studies, the quantification of different types of nanoparticles coexisting in natural systems and containing the same element is often challenging. Such coexistence is expected e.g., for ENPs simultaneously released into the environmental systems. Despite the relevance of the coexistence, little is known about combined behavior and effects of ENPs in the environment. In this study, we developed a method for the quantification and differentiation of silver nanoparticles enriched by 109 Ag isotope ( 109 Ag-NPs) and sulfidized silver nanoparticles with natural isotopic distribution (S-Ag-NPs) in water, soil, and sediment and applied it to evaluate the environmental fate of these nanoparticles introduced simultaneously together with gold (Au-NPs) and titanium dioxide (TiO 2 -NPs) nanoparticles into mesocosms simulating an aquatic-terrestrial transition zone. High nanoparticle recoveries determined in water, sand, and soil spiked with nanoparticle mixtures indicate that the application of isotopically enriched ENPs will allow their differentiation from other nanoparticles containing the same element in environmental compartments even at the concentrations in the range of natural background. The co-accumulation of 109 Ag-NPs, S-Ag-NPs, and Au-NPs in the top layer of sediment and soil and in biofilms observed in mesocosm studies suggests that these compartments can act as effective sinks for these ENPs. We suggest that the hetero-aggregation between different co-occurring ENPs and their high affinity to biota are major mechanisms controlling their fate in the aquatic-terrestrial transition zone. A high co-enrichment of 109 Ag-NPs, S-Ag-NPs, Au-NPs, and TiO 2 -NPs in/on algae, biofilms, leaves, and amphipods suggests an enhanced risk of biomagnification. The findings of this study will contribute to a better understanding of the fate of ENPs and their combined effects in environmental compartments, where the simultaneous presence of diverse nanoparticles is expected., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The complementary breast diagnostics (CMD) include the clinical examination, ultrasound, mammography and magnetic resonance imaging (MRI) of the breast and the assessment of conspicuous findings by interventional methods., Objective: In recent years special breast computed tomography (BCT) systems have been developed and the question arises as to what significance this technology has in comparison to the established MRI procedure., Material and Methods: Presentation of the two dedicated BCT systems with different concepts, which are currently commercially available., Results: In comparison to the Koning® (San Jose, CA, USA) BCT (CBBCT) system there are advantages to the SBCT system from AB-CT® (Erlangen, Germany) such as: 1) direct conversion of the photons at the detector resulting in a reduction of possible data loss, which eliminates an intermediate step as with scintillation imaging, 2) higher resolution, 3) lower patient dose and 4) more precise diagnostics of microcalcification., Conclusion: Based on the CMD the SBCT system includes the indications for MRI in the assessment and opens up new perspectives in terms of recognition and three-dimensional visualization of microcalcification, which is not possible with MRI. It remains to be seen whether SBCT will complement or replace MRI in the clarification or assessment of findings., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: R. Schulz-Wendtland und T. Wacker geben an, dass kein Interessenkonflikt besteht. Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

This manuscript presents a case of a 35-year-old nulligravida premenopausal woman who presented with acute abdominal pain due to pelvic congestion syndrome (PCS). PCS is characterized by multiple pathophysiological mechanisms and various clinical presentations. Our patient was nulliparous with no history of abdominal surgery. However, diagnostic laparoscopy revealed endometriosis lesions on the uterovesical fold. Reporting this unusual case, we focus on the presenting symptoms, the imaging findings, and the final approach by diagnostic laparoscopy., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mpourazanis et al.)

Background: Staphylococcus aureus (SA) colonisation increases the risk of wound infections in surgical procedures. Prevention strategies to date have focused primarily on the hospital, although there are recommendations for pre-hospital decontamination at home, which can be performed by patients themselves. The current study aimed to shift the process of screening and decontamination of SA (methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA)) out of the hospital setting., Methods: Between April 2019 and March 2022, N=8054 (Intervention Group=3390) patients (>18 years) undergoing elective procedures in a hospital in Baden-Württemberg (Germany) were recruited for the study. The intervention consisted of a 5-day decontamination carried out by patients (or their caregivers) in their domestic environment. The analysis comprised a simple arm comparison of colonisation rates at admission between study groups as well as adjusted logistic regressions., Results: After adjustment for relevant risk factors the intervention reduced the risk of SA colonisation at admission statistically significant by 14% (odds ratio: 0.86 (95 % CI: 0.74-0.10; p= 0.046). Rehospitalizations were also significantly less frequent in the intervention group. Signs of wound infection and recolonisation after invasive procedures did not differ significantly between the study groups., Conclusions: The outpatient decontamination measures point towards effectiveness compared to routine care. As results from logistic regressions are based on the Methicillin-Sensitive SA (MSSA), considering it in clinical hygiene management should be discussed. Strict adherence during the pandemic was challenging, potentially underestimating the intervention's overall impact., Competing Interests: Declaration of Competing Interest The authors do not have conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Metal pollution is a global environmental issue with adverse biological effects on wildlife. Long-term studies that span declines in metal emissions due to regulation, resulting in varying levels of environmental contamination, are therefore well-suited to investigate effects of toxic metals, while also facilitating robust analysis by incorporating fluctuating environmental conditions and food availability. Here, we examined a resident population of tawny owls in Norway between 1986 and 2019. Tail feathers from females were collected annually, resulting in over 1000 feathers. Each feather served as an archive of local environmental conditions during molt, including the presence of metals, and their dietary ecology, proxied by stable isotopes of nitrogen (δ 15 N) and carbon (δ 13 C), as well as corticosterone levels (CORTf), the primary avian glucocorticoid and a measure of physiological stress. We analyzed feathers to examine how exposure to toxic metal(loid)s (Al, As, Cd, Hg, and Pb) and variability in dietary proxies modulate CORTf. Using structural equation modelling, we found that increased Al concentrations and δ 15 N values, linked directly to increased CORTf. In opposite, we found that increased Hg concentrations and δ 13 C related to decreased CORTf concentrations. δ 15 N was indirectly linked to CORTf through Al and Hg, while δ 13 C was indirectly linked to CORTf through Hg. This supports our hypothesis that metal exposure and dietary ecology may individually or jointly influence physiological stress. Notably, our results suggest that dietary ecology has the potential to mediate the impact of metals on CORTf, highlighting the importance of considering multiple variables, direct and indirect effects, when assessing stress in wildlife. In conclusion, feathers represent an excellent non-destructive biomonitoring strategy in avian wildlife, providing valuable insights not easily accessible using other methods. Further research is warranted to fully comprehend implications of alterations in CORTf on the tawny owl's health and fitness., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in the present paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Endoplasmic reticulum (ER) stress is one of the major events accompanying myocardial ischemia-reperfusion (IR) injury, as hypoxia and oxidative stress disrupt protein folding in the ER. As a result, the unfolded protein response (UPR) is activated through different sensors including inositol-requiring enzyme 1α (IRE1α) and protein kinase R-like ER kinase (PERK). Failure of the UPR to reduce ER stress induces cellular dysfunction. Matrix metalloproteinase-2 (MMP-2) is a ubiquitous protease that is activated intracellularly in response to oxidative stress and partially localizes near the ER. However, its role in ER homeostasis is unknown. We hypothesized that MMP-2 is involved in the regulation of the UPR and ER stress-mediated apoptosis during IR injury. Isolated mouse hearts subjected to IR injury showed impaired recovery of post-ischemic contractile function compared to aerobically perfused controls. Ventricular extracts from IR hearts had higher levels of glucose-regulated protein-78 and protein disulfide isomerase and lower levels of IRE1α and PERK compared to aerobic controls. MMP-2 inhibitors, ARP-100 or ONO-4817, given 10 min before ischemia, improved cardiac post-ischemic recovery and preserved IRE1α level in hearts subjected to 30 min ischemia/40 min reperfusion. IR also increased the levels of CHOP and mitochondrial Bax and caspase-3 and -9 activities, indicating induction of apoptosis, all of which were attenuated by MMP-2 inhibitors, regardless of the reperfusion time. Immunoprecipitation showed an association between MMP-2 and IRE1α in aerobic and IR hearts. During myocardial IR injury MMP-2 may impair the UPR and induce apoptosis by proteolysis of IRE1α. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in part by preserving IRE1α and preventing the progression to myocardial cell death., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: Radical cystectomy (RC) is the standard treatment for muscle-invasive bladder cancer (MIBC). It is highly invasive and associated with perioperative risks, while bladder-preserving trimodality therapy (TMT) offers a less invasive alternative with preferable quality of life for selected patients. We aimed to compare oncological outcomes of TMT and RC in MIBC patients, and evaluate TMT-specific outcomes., Methods: In December 2023, PubMed, Scopus, and Web of Science were searched for studies on MIBC patients treated with TMT. Pairwise meta-analyses were conducted to compare overall survival (OS) and cancer-specific survival (CSS) between MIBC patients treated with TMT and RC, utilizing hazard ratios (HRs). We included only matched cohort studies to minimize selection bias. TMT-specific outcomes, such as response, recurrence, and toxicity rates, were pooled separately., Key Findings and Limitations: Eighty-seven studies (n = 28 218) were identified. No significant differences in OS (HR: 1.05; 95% confidence interval [CI]: 0.78-1.40) and CSS (HR: 1.05; 95% CI: 0.69-1.58) were found for TMT compared with RC. In patients treated with TMT, the complete response was achieved in 74.4% (95% CI: 69.1-79.1), the estimated rate of intravesical recurrence was 23.1% (95% CI: 19.0-27.7), and the rate of grade ≥3 acute toxicity was 11.4% (95% CI: 4.0-28.4)., Conclusions and Clinical Implications: The oncological outcomes of TMT were comparable with those of RC, with an acceptable toxicity profile. TMT appears as a safe and effective treatment for appropriately selected MIBC patients who want to preserve their bladder. However, evidence from high-volume controlled trials is needed., Patient Summary: Well-selected patients with nonmetastatic muscle-invasive bladder cancer can be treated with "trimodality therapy" to preserve the bladder. So far, the reported outcomes are comparable with those of radical surgery, and we found no signs of excess toxicity., (Copyright © 2024. Published by Elsevier B.V.)

Aims: Hypertension is associated with an increased activity of matrix metalloproteinase (MMP)-2 in the vasculature, which, in turn, proteolyzes extra- and intracellular proteins that lead to vascular dysfunction. The activity of sarcoplasmic reticulum calcium ATPase (SERCA) is decreased in the aortas of hypertensive rats. Increased activity of MMP-2 proteolyzed SERCA in rat heart during ischemia and reperfusion injury, thus impairing cardiac function. Therefore, we examined whether increased activity of MMP-2 in early hypertension contributes to proteolyze SERCA in the aortas, thus leading to maladaptive vascular remodeling and dysfunction., Main Methods: Male Sprague-Dawley rats were submitted to two kidney-one clip (2K-1C) or Sham surgery and treated with doxycycline. Systolic blood pressure (SBP) was assessed by tail-cuff plethysmography. After 7 days, aortas were collected for zymography assays, Western blot to SERCA, ATPase activity assay, vascular reactivity, Ki-67 immunofluorescence and hematoxylin/eosin stain., Key Findings: SBP was increased in 2K-1C rats and doxycycline did not reduce it, but decreased MMP-2 activity and prevented SERCA proteolysis in aortas. Cross sectional area, media to lumen ratio and Ki-67 were all increased in the aortas of hypertensive rats and doxycycline decreased Ki-67. In 2K-1C rats, arterial relaxation to acetylcholine was impaired and doxycycline ameliorated it., Significance: doxycycline reduced MMP-2 activity in aortas of 2K-1C rats and prevented proteolysis of SERCA and its dysfunction, thus ameliorating hypertension-induced vascular dysfunction., Competing Interests: Declaration of competing interest We declare that there are no conflicts of interest associated with this publication., (Copyright © 2024. Published by Elsevier B.V.)

Terrestrial insectivores in riparian areas, such as spiders, can depend on emergent aquatic insects as high-quality prey. However, chemical pollution entering streams from agricultural and urban sources can alter the dynamics and composition of aquatic insect emergence, which may also affect the riparian food web. Few studies have examined the effects of stressor-induced alterations in aquatic insect emergence on spiders, especially in terms of chemical pollution and diet composition. We used DNA metabarcoding of gut content to describe the diet of Tetragnatha montana spiders collected from 10 forested streams with differing levels of pesticide and wastewater pollution. We found that spiders consumed more Chironomidae and fewer other aquatic Diptera, including Tipulidae, Ptychopteridae and Culicidae, at more polluted streams. Pollution-related effects were mainly observed in the spider diet, and were not significant for the number nor composition of flying insects trapped at each site. Our results indicate that the composition of riparian spider diets is sensitive to stream pollution, even in the absence of a change in the overall proportion of aquatic prey consumed. A high reliance on aquatic prey at polluted streams may give spiders an increased risk of dietary exposure to chemical pollutants retained by emergent insects.

Structural disconnectome analyses have provided valuable insights into how a stroke lesion results in widespread network disturbances and how these relate to deficits, recovery patterns, and outcomes. Previous analyses have primarily focused on patients with relatively mild to moderate deficits. However, outcomes vary among survivors of severe strokes, and the mechanisms of recovery remain poorly understood. This study assesses the association between lesion-induced network disconnection and outcome after severe stroke. Thirty-eight ischaemic stroke patients underwent MRI brain imaging early after stroke and longitudinal clinical follow-up. Lesion information was integrated with normative connectome data to infer individual disconnectome profiles on a localized regional and region-to-region pathway level. Ordinal logistic regressions were computed to link disconnectome information to the modified Rankin Scale after 3-6 months. Disconnections of ipsilesional frontal, parietal, and temporal cortical brain areas were significantly associated with a worse motor outcome after a severe stroke, adjusted for the initial deficit, lesion volume, and age. The analysis of the underlying pathways mediating this association revealed location-specific results: For frontal, prefrontal, and temporal brain areas, the association was primarily driven by relatively sparse intrahemispheric disconnections. In contrast, the ipsilesional primary motor cortex, the dorsal premotor cortex, and various parietal brain regions showed a remarkable involvement of either frontoparietal intrahemispheric or additionally interhemispheric disconnections. These results indicate that localized disconnection of multiple regions embedded in the structural frontoparietal network correlates with worse outcomes after severe stroke. Specifically, primary motor and parietal cortices might gain particular importance as they structurally link frontoparietal networks of both hemispheres. These data shed novel light on the significance of distinct brain networks for recovery after a severe stroke., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Objective: Although prostate magnetic resonance imaging (MRI) is increasingly used to diagnose and stage prostate cancer (PCa), the biologic and clinical significance of MRI visibility of the disease is unclear. Our aim was to examine the existing knowledge regarding the molecular correlates of MRI visibility of PCa., Methods: The PubMed, Scopus, and Web of Science databases were queried through November 2023. We defined MRI-visible and MRI-invisible lesions based on the Prostate Imaging Reporting and Data System (PI-RADS) score, and compared these based on the genomic, transcriptomic, and proteomic characteristics., Key Findings and Limitations: From 2015 individual records, 25 were selected for qualitative data synthesis. Current evidence supports the polygenic nature of MRI visibility, primarily influenced by genes related to stroma, adhesion, and cellular organization. Several gene signatures related to MRI visibility were associated with oncologic outcomes, which support that tumors appearing as PI-RADS 4-5 lesions harbor lethal disease. Accordingly, MRI-invisible tumors detected by systematic biopsies were, generally, less aggressive and had a more favorable prognosis; however, some MRI-invisible tumors harbored molecular features of biologically aggressive PCa. Among the commercially available prognostic gene panels, only Decipher was strongly associated with MRI visibility., Conclusions and Clinical Implications: High PI-RADS score is associated with biologically and clinically aggressive PCa molecular phenotypes, and could potentially be used as a biomarker. However, MRI-invisible lesions can harbor adverse features, advocating the continued use of systemic biopsies. Further research to refine the integration of imaging data to prognostic assessment is warranted., Patient Summary: Magnetic resonance imaging visibility of prostate cancer is a polygenic trait. Higher Prostate Imaging Reporting and Data System scores are associated with features of biologically and clinically aggressive cancer., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Recently, a network model of cervical dystonia (CD) has been adopted that implicates nodes and pathways involving cerebellar, basal-ganglia and cortico-cortical connections. Although functional changes in the cerebello-thalamo-cortical network in dystonia have been reported in several studies, structural information of this network remain sparse., Objective: To characterize the structural properties of the cerebellar motor network in isolated CD patients. This includes cerebellar lobules involved in motor processing, the dentate nucleus (DN), the thalamus, and the primary motor cortex (M1)., Methods: Magnetic resonance imaging data of 18 CD patients and 18 healthy control subjects were acquired. In CD patients, the motor part of the Toronto Western Spasmodic Torticollis Rating Scale was assessed to evaluate motor symptom severity. The volume of cerebellar lobules I-VI and VIII, the DN and thalamus, and the cortical thickness (CT) of M1 were determined for a region of interest (ROI)-based quantitative analysis. Volumes/CT of these ROIs were compared between groups and associated with motor symptom severity in patients., Results: The volume of lobule VI and the CT of M1 were reduced in CD patients. The volumes of the other ROIs were not different between groups. No association was identified between the structural properties of lobule VI or M1 and the severity of CD motor symptoms., Conclusion: Atrophy within the cerebellum and M1 contributes to CD's complex motor network pathology. Further investigations are needed to ascertain the mechanisms underlying the local volume loss., (© 2024. The Author(s).)

Proteases are enzymes that induce irreversible post-translational modifications by hydrolyzing amide bonds in proteins. One of these proteases is matrix metalloproteinase-2 (MMP-2), which has been shown to modulate extracellular matrix remodeling and intracellular proteolysis during myocardial injury. However, the substrates of MMP-2 in heart tissue are limited, and lesser known are the cleavage sites. Here, we used degradomics to investigate the substrates of intracellular MMP-2 in rat ventricular extracts. First, we designed a novel, constitutively active MMP-2 fusion protein (MMP-2-Fc) that we expressed and purified from mammalian cells. Using this protease, we proteolyzed ventricular extracts and used subtiligase-mediated N-terminomic labeling which identified 95 putative MMP-2-Fc proteolytic cleavage sites using mass spectrometry. The intracellular MMP-2 cleavage sites identified in heart tissue extracts were enriched for proteins primarily involved in metabolism, as well as the breakdown of fatty acids and amino acids. We further characterized the cleavage of three of these MMP-2-Fc substrates based on the gene ontology analysis. We first characterized the cleavage of sarco/endoplasmic reticulum calcium ATPase (SERCA2a), a known MMP-2 substrate in myocardial injury. We then characterized the cleavage of malate dehydrogenase (MDHM) and phosphoglycerate kinase 1 (PGK1), representing new cardiac tissue substrates. Our findings provide insights into the intracellular substrates of MMP-2 in cardiac cells, suggesting that MMP-2 activation plays a role in cardiac metabolism.

Characterizing cortical plasticity becomes increasingly important for identifying compensatory mechanisms and structural reserve in the ageing population. While cortical thickness (CT) largely contributed to systems neuroscience, it incompletely informs about the underlying neuroplastic pathophysiology. In turn, microstructural characteristics may correspond to atrophy mechanisms in a more sensitive way. Fractional anisotropy, a diffusion tensor imaging (DTI) measure, is inversely related to cortical histologic complexity. Axial diffusivity and radial diffusivity are assumed to be linked to the density of structures oriented perpendicular and parallel to the cortical surface, respectively. We hypothesized (1) that cortical DTI will reveal microstructural correlates for hemispheric specialization, particularly in the language and motor systems, and (2) that lateralization of cortical DTI parameters will show an age effect, paralleling age-related changes in activation, especially in the prefrontal cortex. We analysed data from healthy younger and older adult participants (N = 91). DTI and CT data were extracted from regions of the Destrieux atlas. Diffusion measures showed lateralization in specialized motor, language, visual, auditory and inferior parietal cortices. Age-dependent increased lateralization for DTI measures was observed in the prefrontal, angular, superior temporal and lateral occipital cortex. CT did not show any age-dependent alterations in lateralization. Our observations argue that cortical DTI can capture microstructural properties associated with functional specialization, resembling findings from histology. Age effects on diffusion measures in the integrative prefrontal and parietal areas may shed novel light on the atrophy-related plasticity in healthy ageing., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

In rats decreased bioavailability of nitric oxide induces oxidative stress and right heart failure. Oxidative stress can activate matrix metalloproteinase-2 (MMP2). We addressed the question whether increasing oxidative defense by administration of the SOD mimetic Tempol or direct inhibition of MMP2 activity by SB-3CT mitigates right heart failure. Rats received l-NAME for four weeks and during week three and four treatment groups received either Tempol or SB-3CT in addition. After four weeks heart function was analyzed by echocardiography, organ weights and expression of NPPB and COL1A1 were analyzed, oxidative stress was monitored by DHE-staining and MMP2 activity was quantified by proteolytic auto-activation, zymography, and troponin I degradation. l-NAME induced oxidative stress and MMP2 activity stronger in the right ventricle than in the left ventricle. Troponin I, a MMP2 substrate, was degraded in right ventricles. Tempol reduced oxidative stress and preferentially affected the expression of fibrotic genes (i.e. COL1A1) and fibrosis. Tempol and SB-3CT mitigated right but not left ventricular hypertrophy. Neither SB-3CT nor Tempol alone strongly improved right ventricular function. In conclusion, both MMP2 activity and oxidative stress contribute to right ventricular failure but neither is MMP2 activation linked to oxidative stress nor does oxidative stress and MMP2 activity have common targets., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Natural products (NPs) have long been used as a rich source of bioactive compounds for drug development. Recent technological advancements have revitalised natural products research as evidenced by increased publications in this field. In this editorial review, we highlight key points from the 2020 British Journal of Pharmacology (BJP) practical guide, which outlines standards for natural products research reports, and provide papers published in BJP between years 2020 to 2023 that demonstrate adherence to these guidelines. Looking ahead, we discuss the potential of chemical proteomics approaches to elucidate natural products mechanisms of action and identify therapeutic targets for future research. By fostering innovation, we aim to advance natural products research and contribute to the development of novel therapeutics that will have a significant impact on healthcare., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Linked Articles: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc., (© 2024 British Pharmacological Society.)

Three types of highly promising small RNA therapeutics, namely, small interfering RNAs (siRNAs), microRNAs (miRNAs) and the RNA subtype of antisense oligonucleotides (ASOs), offer advantages over small-molecule drugs. These small RNAs can target any gene product, opening up new avenues of effective and safe therapeutic approaches for a wide range of diseases. In preclinical research, synthetic small RNAs play an essential role in the investigation of physiological and pathological pathways as silencers of specific genes, facilitating discovery and validation of drug targets in different conditions. Off-target effects of small RNAs, however, could make it difficult to interpret experimental results in the preclinical phase and may contribute to adverse events of small RNA therapeutics. Out of the two major types of off-target effects we focused on the hybridization-dependent, especially on the miRNA-like off-target effects. Our main aim was to discuss several approaches, including sequence design, chemical modifications and target prediction, to reduce hybridization-dependent off-target effects that should be considered even at the early development phase of small RNA therapy. Because there is no standard way of predicting hybridization-dependent off-target effects, this review provides an overview of all major state-of-the-art computational methods and proposes new approaches, such as the possible inclusion of network theory and artificial intelligence (AI) in the prediction workflows. Case studies and a concise survey of experimental methods for validating in silico predictions are also presented. These methods could contribute to interpret experimental results, to minimize off-target effects and hopefully to avoid off-target-related adverse events of small RNA therapeutics. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background and Purpose: Cardioprotective miRNAs (protectomiRs) are promising therapeutic tools. Here, we aimed to identify protectomiRs in a translational porcine model of acute myocardial infarction (AMI) and to validate their cardiocytoprotective effect., Experimental Approach: ProtectomiR candidates were selected after systematic analysis of miRNA expression changes in cardiac tissue samples from a closed-chest AMI model in pigs subjected to sham operation, AMI and ischaemic preconditioning, postconditioning or remote preconditioning, respectively. Cross-species orthologue protectomiR candidates were validated in simulated ischaemia-reperfusion injury (sI/R) model of isolated rat ocardiomyocytes and in human AC16 cells as well. For miR-450a, we performed target prediction and analysed the potential mechanisms of action by GO enrichment and KEGG pathway analysis., Key Results: Out of the 220 detected miRNAs, four were up-regulated and 10 were down-regulated due to all three conditionings versus AMI. MiR-450a and miR-451 mimics at 25 nM were protective in rat cardiomyocytes, and miR-450a showed protection in human cardiomyocytes as well. MiR-450a has 3987 predicted mRNA targets in pigs, 4279 in rats and 8328 in humans. Of these, 607 genes are expressed in all three species. A total of 421 common enriched GO terms were identified in all three species, whereas KEGG pathway analysis revealed 13 common pathways., Conclusion and Implications: This is the first demonstration that miR-450a is associated with cardioprotection by ischaemic conditioning in a clinically relevant porcine model and shows cardiocytoprotective effect in human cardiomyocytes, making it a promising drug candidate. The mechanism of action of miR-450a involves multiple cardioprotective pathways., Linked Articles: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Context: Surgery is the gold standard for the local treatment of primary renal cell carcinoma (RCC), but alternatives are emerging. We conducted a systematic review and meta-analysis to assess the results of prospective studies using definitive stereotactic body radiotherapy (SBRT) to treat primary localised RCC., Evidence Acquisition: This review was prospectively registered in PROSPERO (CRD42023447274). We searched PubMed, Embase, Scopus, and Google Scholar for reports of prospective studies published since 2003, describing the outcomes of SBRT for localised RCC. Meta-analyses were performed for local control (LC), overall survival (OS), and rates of adverse events (AEs) using generalised linear mixed models (GLMMs). Outcomes were presented as rates with corresponding 95% confidence intervals (95% CIs). Risk-of-bias was assessed using the ROBINS-I tool., Evidence Synthesis: Of the 2983 records, 13 prospective studies ( n = 308) were included in the meta-analysis. The median diameter of the irradiated tumours ranged between 1.9 and 5.5 cm in individual studies. Grade ≥ 3 AEs were reported in 15 patients, and their estimated rate was 0.03 (95%CI: 0.01-0.11; n = 291). One- and two-year LC rates were 0.98 (95%CI: 0.95-0.99; n = 293) and 0.97 (95%CI: 0.93-0.99; n = 253), while one- and two-year OS rates were 0.95 (95%CI: 0.88-0.98; n = 294) and 0.86 (95%CI: 0.77-0.91; n = 224). There was no statistically significant heterogeneity, and the estimations were consistent after excluding studies at a high risk of bias in a sensitivity analysis. Major limitations include a relatively short follow-up, inhomogeneous reporting of renal function deterioration, and a lack of prospective comparative evidence., Conclusions: The short-term results suggest that SBRT is a valuable treatment method for selected inoperable patients (or those who refuse surgery) with localised RCC associated with low rates of high-grade AEs and excellent LC. However, until the long-term data from randomised controlled trials are available, surgical management remains a standard of care in operable patients.

Aims: To analyse the relevance of body composition and blood markers for long-term outcomes in very old patients after transcatheter aortic valve replacement (TAVR)., Methods and Results: A total of 403 very old patients were characterized with regard to subcutaneous, visceral, and epicardial fat, psoas muscle area, plasma growth differentiation factor 15 (GDF-15), and leptin. Cohorts grouped by body mass index (BMI) were analysed for long-term outcomes. Patients underwent transapical and transfemoral TAVR (similar 30-day/1-year survival). Body mass index >35 kg/m 2 showed increased 2- and 3-year mortality compared with BMI 25-34.9 kg/m 2 but not compared with BMI <25 kg/m 2 . Fat areas correlated positively to BMI (epicardial: R 2 = 0.05, P < 0.01; visceral: R 2 = 0.20, P < 0.001; subcutaneous: R 2 = 0.13, P < 0.001). Increased epicardial or visceral but not subcutaneous fat area resulted in higher long-term mortality. Patients with high BMI (1781.3 mm 2 ± 75.8, P < 0.05) and lean patients (1729.4 ± 52.8, P < 0.01) showed lower psoas muscle area compared with those with mildly elevated BMI (2055.2 ± 91.7). Reduced psoas muscle area and increased visceral fat and epicardial fat areas were independent predictors of long-term mortality. The levels of serum GDF-15 were the highest in BMI >40 kg/m 2 (2793.5 pg/mL ± 123.2) vs. BMI <25 kg/m 2 (2017.6 pg/mL ±130.8), BMI 25-30 kg/m 2 (1881.8 pg/mL ±127.4), or BMI 30-35 kg/m 2 (2054.2 pg/mL ±124.1, all P < 0.05). Increased GDF-15 level predicted mortality (2587 pg/mL, area under the receiver operating characteristic curve 0.94). Serum leptin level increased with BMI without predictive value for long-term mortality., Conclusion: Morbidly visceral and epicardial fat accumulation, reduction in muscle area, and GDF-15 increase are strong predictors of adverse outcomes in very old patients post-TAVR., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Parahydrogen-induced polarization (PHIP) is an emerging technique to enhance the signal of stable isotope metabolic contrast agents for Magnetic Resonance (MR). The objective of this study is to continue establishing 1- 13 C-pyruvate-d 3 , signal-enhanced via PHIP, as a hyperpolarized contrast agent, obtained in seconds, to monitor metabolism in human cancer. Our focus was on human pancreatic and colon tumor xenografts. 1- 13 C-vinylpyruvate-d 6 was hydrogenated using parahydrogen. Thereafter, the polarization of the protons was transferred to 13 C. Following a workup procedure, the free hyperpolarized 1- 13 C-pyruvate-d 3 was obtained in clean aqueous solution. After injection into animals bearing either pancreatic or colon cancer xenografts, slice-selective MR spectra were acquired and analyzed to determine rate constants of metabolic conversion into lactate and alanine. 1- 13 C-pyruvate-d 3 proved to follow the increased metabolic rate to lactate and alanine in the tumor xenografts., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Background: Theta-gamma transcranial alternating current stimulation (tACS) was recently found to enhance thumb acceleration in young, healthy participants, suggesting a potential role in facilitating motor skill acquisition. Given the relevance of motor skill acquisition in stroke rehabilitation, theta-gamma tACS may hold potential for treating stroke survivors., Objective: We aimed to examine the effects of theta-gamma tACS on motor skill acquisition in young, healthy participants and stroke survivors., Methods: In a pre-registered, double-blind, randomized, sham-controlled study, 78 young, healthy participants received either theta-gamma peak-coupled (TGP) tACS, theta-gamma trough-coupled (TGT) tACS or sham stimulation. 20 individuals with a chronic stroke received either TGP or sham. TACS was applied over motor cortical areas while participants performed an acceleration-dependent thumb movement task. Stroke survivors were characterized using standardized testing, with a subgroup receiving additional structural brain imaging., Results: Neither TGP nor TGT tACS significantly modified general motor skill acquisition in the young, healthy cohort. In contrast, in the stroke cohort, TGP diminished motor skill acquisition compared to sham. Exploratory analyses revealed that, independent of general motor skill acquisition, healthy participants receiving TGP or TGT exhibited greater peak thumb acceleration than those receiving sham., Conclusion: Although theta-gamma tACS increased thumb acceleration in young, healthy participants, consistent with previous reports, it did not enhance overall motor skill acquisition in a more complex motor task. Furthermore, it even had detrimental effects on motor skill acquisition in stroke survivors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 University of Twente. Published by Elsevier Inc. All rights reserved.)

Due to an unexpected activation of different zinc (Zn) transporters in a recent prospective clinical study, we have revisited the role of Zn homeostasis and the activation of matrix metalloproteinases (MMPs) in skeletal muscle exposed to the intensive care unit (ICU) condition (immobilization and mechanical ventilation). ICU patients exposed to 12 days ICU condition were followed longitudinally with six repeated muscle biopsies while they showed a progressive preferential myosin loss, i.e., the hallmark of Critical Illness Myopathy (CIM), in parallel with the activation of Zn-transporters. In this study, we have revisited the expression of Zn-transporters and the activation of MMPs in clinical as well as in experimental studies using an established ICU model. MMPs are a group Zn-dependent endopeptidases which do not only target and cleave extracellular proteins but also intracellular proteins including multiple sarcomeric proteins. MMP-9 is of specific interest since the hallmark of CIM, the preferential myosin loss, has also been reported in dilated cardiomyopathy and coupled to MMP-9 activation. Transcriptional activation of Zn-transporters was observed in both clinical and experimental studies as well as the activation of MMPs, in particular MMP-9, in various limb and respiratory muscles in response to long-term exposure to the ICU condition. The activation of Zn-transporters was paralleled by increased Zn levels in skeletal muscle which in turn showed a negative linear correlation with the preferential myosin loss associated with CIM, offering a potential intervention strategy. Thus, activation of Zn-transporters, increased intramuscular Zn levels, and activation of the Zn-dependent MMPs are forwarded as a probable mechanism involved in CIM pathophysiology. These effects were confirmed in different rat strains subjected to a model of CIM and exacerbated by old age. This is of specific interest since old age and muscle wasting are the two factors most strongly associated with ICU mortality., Competing Interests: Declaration of competing interest We declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

The assessment of skin changes in the context of possible child abuse is an important task in forensic medicine. This requires knowledge of pigmentation variants and pigmentation disorders such as congenital dermal melanocytosis, which includes Mongolian spots. Particularly in the case of atypical localization and dark pigmented skin, the differentiation from hematomas can be challenging. A case of two Nigerian siblings with extensive and atypically localized Mongolian spots is reported. The 1.5-year-old girl showed Mongolian spots on her back and the right side of her trunk. The 8-year-old boy showed Mongolian spots only on the back of his thighs. The authors are not aware of any case in which so called Mongolian spots were present exclusively on the back of the thighs and this case is all the more noteworthy as the back of the thigh is a common localization of blunt force trauma., (© 2024. The Author(s).)

Purpose: To evaluate the preferences of dental practitioners for tooth-supported crowns dental ceramics by means of an online survey and to assess the influence of age, gender, years of experience, and dental specialty on those preferences. Materials and Methods: An anonymous questionnaire was delivered online through Google Surveys, targeting 796 dentists. It contained 17 dichotomous, closed questions with two sections. The first section dealt with general characteristics, including age, gender, years of experience, training in prosthodontics, and hours worked per week. The second section included questions regarding preferences of different materials for crowns, and the use of digital workflows. Analyses were carried out with Stata 14.0 software (StataCorp, TX, USA). A significance level of p=0.05 was adopted. Results: 248 surveys were answered. Practitioners in Chile preferred lithium disilicate for the anterior region (55.2%) but also for the posterior area (40.7%), regardless of their age, gender, years since graduation, hours worked per week or any training in prosthodontics. Chilean dentists over 50 years old considered zirconia almost 4 times more than those under 30 years old for anterior crowns (51.85%). 59.68% of dentists take digital impressions, and 37.10% have access to chairside CAD/CAM technology. In this group, 54.4% preferred feldspathic ceramic for anterior and 23.9% for posterior crowns. Conclusions: While there is a wide range of dental ceramic materials, these results provide a snapshot of the current trends in Chile where lithium disilicate is the most preferred ceramic material for tooth-supported crowns, and metal-ceramic is the least preferred material.

The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL) have been shown to promote proliferation of the breast and breast carcinogenesis. The objective of this analysis was to investigate whether tumor-specific RANK and RANKL expression in patients with primary breast cancer is associated with high percentage mammographic density (PMD), which is a known breast cancer risk factor., Methods: Immunohistochemical staining of RANK and RANKL was performed in tissue microarrays (TMAs) from primary breast cancer samples of the Bavarian Breast Cancer Cases and Controls (BBCC) study. For RANK and RANKL expression, histochemical scores (H scores) with a cut-off value of > 0 vs 0 were established. PMD was measured in the contralateral, non-diseased breast. Linear regression models with PMD as outcome were calculated using common predictors of PMD (age at breast cancer diagnosis, body mass index (BMI) and parity) and RANK and RANKL H scores. Additionally, Spearman rank correlations (ρ) between PMD and RANK and RANKL H score were performed., Results: In the final cohort of 412 patients, breast cancer-specific RANK and RANKL expression was not associated with PMD (P = 0.68). There was no correlation between PMD and RANK H score (Spearman's ρ = 0.01, P = 0.87) or RANKL H score (Spearman's ρ = 0.04, P = 0.41). RANK expression was highest in triple-negative tumors, followed by HER2-positive, luminal B-like and luminal A-like tumors, while no subtype-specific expression of RANKL was found., Conclusion: Results do not provide evidence for an association of RANK and RANKL expression in primary breast cancer with PMD., (© 2024. The Author(s).)

The molecular mechanisms of progressive right heart failure are incompletely understood. In this study, we systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery banding (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signature, protein and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome datasets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans., (© 2024. The Author(s).)

Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH.

In 2023, seventy novel drugs received market authorization for the first time in either Europe (by the EMA and the MHRA) or in the United States (by the FDA). Confirming a steady recent trend, more than half of these drugs target rare diseases or intractable forms of cancer. Thirty drugs are categorized as "first-in-class" (FIC), illustrating the quality of research and innovation that drives new chemical entity discovery and development. We succinctly describe the mechanism of action of most of these FIC drugs and discuss the therapeutic areas covered, as well as the chemical category to which these drugs belong. The 2023 novel drug list also demonstrates an unabated emphasis on polypeptides (recombinant proteins and antibodies), Advanced Therapy Medicinal Products (gene and cell therapies) and RNA therapeutics, including the first-ever approval of a CRISPR-Cas9-based gene-editing cell therapy., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

In this study we explore the spatio-temporal trajectory and clinical relevance of microstructural white matter changes within and beyond subcortical stroke lesions detected by free-water imaging. Twenty-seven patients with subcortical infarct with mean age of 66.73 (SD 11.57) and median initial NIHSS score of 4 (IQR 3-7) received diffusion MRI 3-5 days, 1 month, 3 months, and 12 months after symptom-onset. Extracellular free-water and fractional anisotropy of the tissue (FA T ) were averaged within stroke lesions and the surrounding tissue. Linear models showed increased free-water and decreased FA T in the white matter of patients with subcortical stroke (lesion [free-water/FA T , mean relative difference in %, ipsilesional vs. contralesional hemisphere at 3-5 days, 1 month, 3 months, and 12 months after symptom-onset]: +41/-34, +111/-37, +208/-26, +251/-18; perilesional tissue [range in %]: +[5-24]/-[0.2-7], +[2-20]/-[3-16], +[5-43]/-[2-16], +[10-110]/-[2-12]). Microstructural changes were most prominent within the lesion and gradually became less pronounced with increasing distance from the lesion. While free-water elevations continuously increased over time and peaked after 12 months, FA T decreases were most evident 1 month post-stroke, gradually returning to baseline values thereafter. Higher perilesional free-water and higher lesional FA T at baseline were correlated with greater reductions in lesion size (rho = -0.51, p = .03) in unadjusted analyses only, while there were no associations with clinical measures. In summary, we find a characteristic spatio-temporal pattern of extracellular and cellular alterations beyond subcortical stroke lesions, indicating a dynamic parenchymal response to ischemia characterized by vasogenic edema, cellular damage, and white matter atrophy., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction: Despite profitable group effects on functional outcomes after mechanical thrombectomy (MT) in large vessel occlusion (LVO), many patients with successful reperfusion show a non-favorable long-term outcome, highlighting the necessity to identify potential biomarkers predicting outcome variability. In this regard, the role of perfusion mismatch imaging for outcome variability in the early time window within 6 h after symptom onset is a matter of debate. We attempted to investigate under which conditions early perfusion mismatch imaging accounts for variability in functional outcomes after mechanical thrombectomy., Patients and Methods: In a retrospective single-center study, we examined 190 consecutive patients with LVO who were admitted to the Medical Center Lübeck within 6 h after symptom onset, all of whom underwent MT. Perfusion mismatch was quantified by applying the Alberta Stroke Program Early CT score (ASPECTS) on CT-measured cerebral blood flow (CBF-ASPECTS) and subtracting it from an ASPECTS application on cerebral blood volume (CBV-ASPECTS), i.e., ASPECTS mismatch. Using multivariate ordinal regression models, associations between ASPECTS mismatch and modified Rankin Scale (mRS) after 90 days were assessed. Furthermore, the interaction between ASPECTS mismatch and the core lesion volume was calculated to evaluate conditional associations., Results: ASPECTS mismatch did not correlate with functional outcomes when corrected for multiple influencing covariables. However, interactions between ASPECTS mismatch and CBV-ASPECTS [OR: 1.12 (1.06-1.18), p -value < 0.001], as well as NCCT-ASPECTS [OR: 1.15 (1.06-1.25), p -value < 0.001], did show a significant association with functional outcomes. Model comparisons revealed that, profoundly, in patients with large core lesion volumes (CBV-ASPECTS < 6 or NCCT-ASPECTS < 6), perfusion mismatch showed a negative correlation with the mRS., Discussion and Conclusion: Perfusion mismatch imaging within the first 6 h of symptom onset provides valuable insights into the outcome variability of LVO stroke patients receiving thrombectomy but only in patients with large ischemic core lesions., Competing Interests: GR reports compensation from Cardinal Health 200 LLC for consultant services; compensation from Novartis Pharma AG for other services; compensation from AstraZeneca for consultant services; travel support from Boehringer Ingelheim; compensation from Boehringer Ingelheim for consultant services; compensation from Ipsen Pharma SAS for consultant services; and compensation from Bristol-Myers Squibb for consultant services. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Marburg, Rudolf, Matthis, Neumann, Schareck, Schacht, Schulz, Machner, Schramm, Royl and Koch.)

The concept of brain reserve capacity has emerged in stroke recovery research in recent years. Imaging-based biomarkers of brain health have helped to better understand outcome variability in clinical cohorts. Still, outcome inferences are far from being satisfactory, particularly in patients with severe initial deficits. Neurorehabilitation after stroke is a complex process, comprising adaption and learning processes, which, on their part, are critically influenced by motivational and reward-related cognitive processes. Amongst others, dopaminergic neurotransmission is a key contributor to these mechanisms. The question arises, whether the amount of structural reserve capacity in the dopaminergic system might inform about outcome variability after severe stroke. For this purpose, this study analysed imaging and clinical data of 42 severely impaired acute stroke patients. Brain volumetry was performed within the first 2 weeks after the event using the Computational Anatomy Toolbox CAT12, grey matter volume estimates were collected for seven key areas of the human dopaminergic system along the mesocortical, mesolimbic and nigrostriatal pathways. Ordinal logistic regression models related regional volumes to the functional outcome, operationalized by the modified Rankin Scale, obtained 3-6 months after stroke. Models were adjusted for age, lesion volume and initial impairment. The main finding was that larger volumes of the amygdala and the nucleus accumbens at baseline were positively associated with a more favourable outcome. These data suggest a link between the structural state of mesolimbic key areas contributing to motor learning, motivational and reward-related brain networks and potentially the success of neurorehabilitation. They might also provide novel evidence to reconsider dopaminergic interventions particularly in severely impaired stroke patients to enhance recovery after stroke., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The mitochondrial adaptor protein p66Shc has been suggested to control life span in mice via the release of hydrogen peroxide. However, the role of p66Shc in lung aging remains unsolved. Thus, we investigated the effects of p66Shc -/- on the aging of the lung and pulmonary circulation. In vivo lung and cardiac characteristics were investigated in p66Shc -/- and wild type (WT) mice at 3, 12, and 24 months of age by lung function measurements, micro-computed tomography (µCT), and echocardiography. Alveolar number and muscularization of small pulmonary arteries were measured by stereology and vascular morphometry, respectively. Protein and mRNA levels of senescent markers were measured by western blot and PCR, respectively. Lung function declined similarly in WT and p66Shc -/- mice during aging. However, µCT analyses and stereology showed slightly enhanced signs of aging-related parameters in p66Shc -/- mice, such as a decline of alveolar density. Accordingly, p66Shc -/- mice showed higher protein expression of the senescence marker p21 in lung homogenate compared to WT mice of the corresponding age. Pulmonary vascular remodeling was increased during aging, but aged p66Shc -/- mice showed similar muscularization of pulmonary vessels and hemodynamics like WT mice. In the heart, p66Shc -/- prevented the deterioration of right ventricular (RV) function but promoted the decline of left ventricular (LV) function during aging. p66Shc -/- affects the aging process of the lung and the heart differently. While p66Shc -/- slightly accelerates lung aging and deteriorates LV function in aged mice, it seems to exert protective effects on RV function during aging.

Alterations in the cerebellum's morphology in Parkinson's disease (PD) point to its pathophysiological involvement in this movement disorder. Such abnormalities have previously been attributed to different PD motor subtypes. The aim of the study was to relate volumes of specific cerebellar lobules to motor symptom severity, in particular tremor (TR), bradykinesia/rigidity (BR), and postural instability and gait disorders (PIGD) in PD. We performed a volumetric analysis based on T1-weighted MRI images of 55 participants with PD (22 females, median age 65 years, Hoehn and Yahr stage 2). Multiple regression models were fitted to investigate associations between volumes of cerebellar lobules with clinical symptom severity based on MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score and sub-scores for TR, BR, and PIGD; adjusted for age, sex, disease duration, and intercranial volume as cofactors. Smaller volume of lobule VIIb was associated with higher tremor severity (P = 0.004). No structure-function relationships were detected for other lobules or other motor symptoms. This distinct structural association denotes the involvement of the cerebellum in PD tremor. Characterizing morphological features of the cerebellum leads to a better understanding of its role in the spectrum of motor symptoms in PD and contributes further to identifying potential biological markers., (© 2023. The Author(s).)

Nanosized titanium dioxide (nTiO 2 ) is widely used in products, warranting its discharge from various sources into surface water bodies. However, nTiO 2 co-occurs in surface waters with other contaminants, such as metals. Studies with nTiO 2 and metals have indicated that the presence of natural organic matter (NOM) can mitigate their toxicity to aquatic organisms. In addition, "aging" of nTiO 2 can affect toxicity. However, it is a research challenge, particularly when addressing sublethal responses from dietary exposure over multiple generations. We, therefore exposed the alga Desmodesmus subspicatus to nTiO 2 (at concentrations of 0.0, 0.6 and 3.0 mg nTiO 2 /L) in nutrient medium aged for 0 or 3 days with copper (Cu) at concentrations of 0 and 116 µg Cu/L and with NOM at concentrations equivalent to 0 and 8 mg total organic carbon (TOC) per litre. Subsequently, the exposed alga was fed to Daphnia magna for 23 days over two generations and survival, reproduction and body length were assessed as endpoints of toxicity. In parallel, Cu accumulation and depuration from D. magna were measured. The results indicate that the reproduction of D. magna was the most sensitive parameter in this study, being reduced by 30% (at both parental (F 0 ) and filial (F 1 ) generations) and 50% (at F 0 but not F 1 ) due to the dietary Cu exposure in combination with nTiO 2 for 0 and 3 days aging, respectively. There was no relationship between the effects observed on reproduction and Cu body burden in D. magna. Moreover, D. magna from the F 1 generation showed an adaptive response to Cu in the treatment with 3.0 mg nTiO 2 /L aged for 3 days, potentially due to epigenetic inheritance. Unexpectedly, the presence of NOM hardly changed the observed effects, pointing towards the function of algal exopolymeric substances or intracellular organic matter, rendering the NOM irrelevant. Ultimately, the results indicate that the transferability of the impacts observed during the F 0 to the responses in the F 1 generation is challenging due to opposite effect directions. Additional mechanistic studies are needed to unravel this inconsistency in the responses between generations and to support the development of reliable effect models., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Myocardial ischemia-reperfusion (IR) (stunning) injury triggers changes in the proteome and degradome of the heart. Here, we utilize quantitative proteomics and comprehensive degradomics to investigate the molecular mechanisms of IR injury in isolated rat hearts. The control group underwent aerobic perfusion, while the IR injury group underwent 20 min of ischemia and 30 min of reperfusion to induce a stunning injury. As MMP-2 activation has been shown to contribute to myocardial injury, hearts also underwent IR injury with ARP-100, an MMP-2-preferring inhibitor, to dissect the contribution of MMP-2 to IR injury. Using data-independent acquisition (DIA) and mass spectroscopy, we quantified 4468 proteins in ventricular extracts, whereby 447 proteins showed significant alterations among the three groups. We then used subtiligase-mediated N-terminomic labeling to identify more than a hundred specific cleavage sites. Among these protease substrates, 15 were identified following IR injury. We identified alterations in numerous proteins involved in mitochondrial function and metabolism following IR injury. Our findings provide valuable insights into the biochemical mechanisms of myocardial IR injury, suggesting alterations in reactive oxygen/nitrogen species handling and generation, fatty acid metabolism, mitochondrial function and metabolism, and cardiomyocyte contraction.

Background and Purpose: To protect against SARS-CoV-2 infection, the first mRNA-based vaccines, Spikevax (mRNA-1273, Moderna) and Comirnaty (BNT162b2, Pfizer/Biontech), were approved in 2020. The structure and assembly of the immunogen-in both cases, the SARS-CoV-2 spike (S) glycoprotein-are determined by a messenger RNA sequence that is translated by endogenous ribosomes. Cardiac side-effects, which for the most part can be classified by their clinical symptoms as myo- and/or pericarditis, can be caused by both mRNA-1273 and BNT162b2., Experimental Approach: As persuasive theories for the underlying pathomechanisms have yet to be developed, this study investigated the effect of mRNA-1273 and BNT162b2 on the function, structure, and viability of isolated adult rat cardiomyocytes over a 72 h period., Key Results: In the first 24 h after application, both mRNA-1273 and BNT162b2 caused neither functional disturbances nor morphological abnormalities. After 48 h, expression of the encoded spike protein was detected in ventricular cardiomyocytes for both mRNAs. At this point in time, mRNA-1273 induced arrhythmic as well as completely irregular contractions associated with irregular as well as localized calcium transients, which provide indications of significant dysfunction of the cardiac ryanodine receptor (RyR2). In contrast, BNT162b2 increased cardiomyocyte contraction via significantly increased protein kinase A (PKA) activity at the cellular level., Conclusion and Implications: Here, we demonstrated for the first time, that in isolated cardiomyocytes, both mRNA-1273 and BNT162b2 induce specific dysfunctions that correlate pathophysiologically to cardiomyopathy. Both RyR2 impairment and sustained PKA activation may significantly increase the risk of acute cardiac events., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Transportation noise is a ubiquitous urban exposure. In 2018, the World Health Organization concluded that chronic exposure to road traffic noise is a risk factor for ischemic heart disease. In contrast, they concluded that the quality of evidence for a link to other diseases was very low to moderate. Since then, several studies on the impact of noise on various diseases have been published. Also, studies investigating the mechanistic pathways underlying noise-induced health effects are emerging. We review the current evidence regarding effects of noise on health and the related disease-mechanisms. Several high-quality cohort studies consistently found road traffic noise to be associated with a higher risk of ischemic heart disease, heart failure, diabetes, and all-cause mortality. Furthermore, recent studies have indicated that road traffic and railway noise may increase the risk of diseases not commonly investigated in an environmental noise context, including breast cancer, dementia, and tinnitus. The harmful effects of noise are related to activation of a physiological stress response and nighttime sleep disturbance. Oxidative stress and inflammation downstream of stress hormone signaling and dysregulated circadian rhythms are identified as major disease-relevant pathomechanistic drivers. We discuss the role of reactive oxygen species and present results from antioxidant interventions. Lastly, we provide an overview of oxidative stress markers and adverse redox processes reported for noise-exposed animals and humans. This position paper summarizes all available epidemiological, clinical, and preclinical evidence of transportation noise as an important environmental risk factor for public health and discusses its implications on the population level., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Anthropogenic stress alters the linkage between aquatic and terrestrial ecosystems in various ways. Here, we review the contemporary literature on how alterations in aquatic systems through environmental pollution, invasive species and hydromorphological changes carry-over to terrestrial ecosystems and the food webs therein. We consider both the aquatic insect emergence and flooding as pathways through which stressors can propagate from the aquatic to the terrestrial system. We specifically synthesize and contextualize results on the roles of pollutants in the emergence pathway and their top-down consequences. Our review revealed that the emergence and flooding pathway are only considered in isolation and that the overall effects of invasive species or pollutants on food webs at the water-land interface require further attention. While very few recent studies looked at invasive species, a larger number of studies focused on metal transfer compared to pesticides, pharmaceuticals or PCBs, and multiple stress studies up to now left aquatic-terrestrial linkages unconsidered. Recent research on pollutants and emergence used aquatic-terrestrial mesocosms to elucidate the effects of aquatic stressors such as the mosquito control agent Bti, metals or pesticides to understand the effects on riparian spiders. Quality parameters, such as the structural and functional composition of emergent insect communities, the fatty acid profiles, yet also the composition of pollutants transferred to land prove to be important for the effects on riparian spiders. Process-based models including quality of emergence are useful to predict the resulting top-down directed food web effects in the terrestrial recipient ecosystem. In conclusion, we present and recommend a combination of empirical and modelling approaches in order to understand the complexity of aquatic-terrestrial stressor propagation and its spatial and temporal variation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cardiac hypertrophy resulting from sympathetic nervous system activation triggers the development of heart failure. The transcription factor Y-box binding protein 1 (YB-1) can interact with transcription factors involved in cardiac hypertrophy and may thereby interfere with the hypertrophy growth process. Therefore, the question arises as to whether YB-1 influences cardiomyocyte hypertrophy and might thereby influence the development of heart failure. YB-1 expression is downregulated in human heart biopsies of patients with ischemic cardiomyopathy ( n = 8), leading to heart failure. To study the impact of reduced YB-1 in cardiac cells, we performed small interfering RNA (siRNA) experiments in H9C2 cells as well as in adult cardiomyocytes (CMs) of rats. The specificity of YB-1 siRNA was analyzed by a miRNA-like off-target prediction assay identifying potential genes. Testing three high-scoring genes by transfecting cardiac cells with YB-1 siRNA did not result in downregulation of these genes in contrast to YB-1 , whose downregulation increased hypertrophic growth. Hypertrophic growth was mediated by PI3K under PE stimulation, as well by downregulation with YB-1 siRNA. On the other hand, overexpression of YB-1 in CMs, caused by infection with an adenovirus encoding YB-1 (AdYB-1), prevented hypertrophic growth under α-adrenergic stimulation with phenylephrine (PE), but not under stimulation with growth differentiation factor 15 (GDF15; n = 10-16). An adenovirus encoding the green fluorescent protein (AdGFP) served as the control. YB-1 overexpression enhanced the mRNA expression of the Gq inhibitor regulator of G-protein signaling 2 ( RGS2 ) under PE stimulation ( n = 6), potentially explaining its inhibitory effect on PE-induced hypertrophic growth. This study shows that YB-1 protects cardiomyocytes against PE-induced hypertrophic growth. Like in human end-stage heart failure, YB-1 downregulation may cause the heart to lose its protection against hypertrophic stimuli and progress to heart failure. Therefore, the transcription factor YB-1 is a pivotal signaling molecule, providing perspectives for therapeutic approaches.

Freshwater ecosystems subsidize riparian zones with high-quality nutrients via the emergence of aquatic insects. Spiders are dominant consumers of these insect subsidies. However, little is known about the variation of aquatic insect consumption across spiders of different hunting modes, habitat specializations, seasons, and systems. To explore this, we assembled a large stable isotope dataset (n > 1000) of aquatic versus terrestrial sources and six spider species over four points in time adjacent to a lotic and a lentic system. The spiders represent three hunting modes each consisting of a wetland specialist and a habitat generalist. We expected that specialists would feed more on aquatic prey than their generalist counterparts. Mixing models showed that spiders' diet consisted of 17-99% of aquatic sources, with no clear effect of habitat specialization. Averaged over the whole study period, web builders (WB) showed the highest proportions (78%) followed by ground hunters (GH, 42%) and vegetation hunters (VH, 31%). Consumption of aquatic prey was highest in June and August, which is most pronounced in GH and WBs, with the latter feeding almost entirely on aquatic sources during this period. Additionally, the elevated importance of high-quality lipids from aquatic origin during fall is indicated by elemental analyses pointing to an accumulation of lipids in October, which represent critical energy reserves during winter. Consequently, this study underlines the importance of aquatic prey irrespective of the habitat specialization of spiders. Furthermore, it suggests that energy flows vary substantially between spider hunting modes and seasons., (© 2023. The Author(s).)

Streams and their riparian areas are important habitats and foraging sites for bats feeding on emergent aquatic insects. Chemical pollutants entering freshwater streams from agricultural and wastewater sources have been shown to alter aquatic insect emergence, yet little is known about how this impacts insectivorous bats in riparian areas. In this study, we investigate the relationships between the presence of wastewater effluent, in-stream pesticide toxicity, the number of emergent and flying aquatic insects, and the activity and hunting behaviour of bats at 14 streams in southwestern Germany. Stream sites were located in riparian forests, sheltered from direct exposure to pollutants from agricultural and urban areas. We focused on three bat species associated with riparian areas: Myotis daubentonii, M. cf. brandtii, and Pipistrellus pipistrellus. We found that streams with higher pesticide toxicity and more frequent detection of wastewater also tended to be warmer and have higher nutrient and lower oxygen concentrations. We did not observe a reduction of insect emergence, bat activity or hunting rates in association with pesticide toxicity and wastewater detections. Instead, the activity and hunting rates of Myotis spp. were higher at more polluted sites. The observed increase in bat hunting at more polluted streams suggests that instead of reduced prey availability, chemical pollution at the levels measured in the present study could expose bats to pollutants transported from the stream by emergent aquatic insects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Force generation is a crucial element of dexterity and a highly relevant skill of the human motor system. How cerebral and spinal components interact and how spinal activation is associated with the activity in the cerebral primary motor and premotor areas is poorly understood. Here, we conducted combined cortico-spinal functional magnetic resonance imaging during a simple visually guided isometric force generation task in 20 healthy young subjects. Activation was localized in the right cervical spinal cord and left primary motor and premotor areas. The main finding is that spinal activation was negatively correlated with ventral premotor cortex activation. Spinal activation was furthermore significantly correlated with primary motor cortex activation, while increasing target forces led to an increase in the amount of activation. These data indicate that human premotor areas such as the ventral premotor cortex might be functionally connected to the lower cervical spinal cord contributing to distal upper limb functions, a finding that extends our understanding of human motor function beyond the animal literature., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Pesticides enter non-target surface waters as a result of agricultural activities and may reach water bodies in protected areas. We measured in southwestern Germany pesticide concentrations after heavy rainfalls in streams of a drinking water protection area near Hausen (Freiburg) and in the catchment of the Queich (Landau), which originates from the biosphere reserve Palatinate Forest. On average, 32 (n = 21) and 21 (n = 10) pesticides were detected per sample and event in the area of Hausen (n = 56) and in the Queich catchment (n = 17), respectively. The majority of pesticides detected in > 50% of all samples were fungicides, with fluopyram being detected throughout all samples. Aquatic invertebrates exhibited highest risks with 16.1% of samples exceeding mixture toxicity thresholds, whereas risks were lower for aquatic plants (12.9%) and fish (6.5%). Mixture toxicity threshold exceedances indicate adverse ecological effects to occur at half of sites (50%). This study illustrates the presence of pesticide mixtures and highlights ecological risks for aquatic organisms in surface waters of protected areas in Germany., (© 2023. The Author(s).)