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Most language use is displaced, referring to past, future, or hypothetical events, posing the challenge of how children learn what words refer to when the referent is not physically available. One possibility is that iconic cues that imagistically evoke properties of absent referents support learning when referents are displaced. In an audio-visual corpus of caregiver-child dyads, English-speaking caregivers interacted with their children (N = 71, 24-58 months) in contexts in which the objects talked about were either familiar or unfamiliar to the child, and either physically present or displaced. The analysis of the range of vocal, manual, and looking behaviors caregivers produced suggests that caregivers used iconic cues especially in displaced contexts and for unfamiliar objects, using other cues when objects were present.

Abstract An effective vaccine against hepatitis C virus (HCV) should elicit both humoral and cellular immune responses. Previously, we characterized a bivalent vaccine candidate against hepatitis B (HBV) and HCV using chimeric HBV-HCV virus-like particles (VLP), in which the highly conserved epitope of HCV E2 glycoprotein (residues 412–425) was inserted into the hydrophilic loop of HBV small surface antigen (sHBsAg). While sHBsAg_412–425 elicited cross-neutralizing antibodies, it did not trigger a T-cell response against HCV. Thus, this study aimed to develop a vaccine candidate engaging both arms of adaptive immune response, potentially offering stronger protection against HCV. We evaluated the immunogenicity of minicircle (MC) DNA vaccines encoding sHBsAg_412–425 and HCV nonstructural (NS) proteins in BALB/c mice. Co-administration of sHBsAg_412–425 and NS induced a potent T-cell response, especially against NS3 and high titers of antibodies specific to HCV E2. Additionally, these antibodies recognized native HCV envelope glycoprotein heterodimers (E1E2) across multiple HCV genotypes and showed binding profiles to E1E2 alanine mutants comparable to the broadly neutralizing AP33 antibody. Overall, the findings demonstrate that MC DNA vaccine incorporating both sHBsAg_412–425 and HCV NS protein sequences induces robust, T-cell and AP33-like antibody responses, highlighting its potential as pan-genotypic prophylactic vaccine against HCV.

A low response rate in surveys makes the research more expensive and time consuming, but it also, or even more importantly, constitutes a major methodological problem. Therefore, researchers use all kinds of measures in order to increase the response rate. This article describes four experiments (three field studies and one on-line experiment) designed to test a specific technique intended for this purpose. The technique consists in suggesting, to a respondent, that the study requires individuals with a certain rare quality that they have. In the case of the first study, which was conducted during the pandemic, respondents were told that it required people wearing exactly the type of face mask as theirs (or people without a face mask). In the second study, tall people were asked to complete a survey. Some of them were told right away that only tall individuals were considered suitable candidates for the study. In both cases, this technique significantly improved the response rate. However, the employed technique proved ineffective in both Study 3 and Study 4. In these instances, participants likely perceived that their refusal wouldn’t pose any inconvenience to the researchers. Consequently, we can posit that the efficacy of the ’we are looking for people like you’ social influence technique hinges on respondents feeling compelled to respond affirmatively to the research invitation. The assumption is that declining may potentially create challenges for the researchers, prompting a sense of obligation among participants.

Abstract Background 6 − 4 photoproducts are the second most common UV-induced DNA lesions after cyclobutane pyrimidine dimers. In plants, they are mainly repaired by photolyases in a process called photoreactivation. While pyrimidine dimers can be deleterious, leading to mutagenesis or even cell death, 6 − 4 photoproducts can activate specific signaling pathways. Therefore, their removal is particularly important, especially for plants exposed to high UV intensities due to their sessile nature. Although photoreactivation in nuclear DNA is well-known, its role in plant organelles remains unclear. In this paper we analyzed the activity and localization of GFP-tagged AtUVR3, the 6 − 4 photoproduct specific photolyase. Results Using transgenic Arabidopsis with different expression levels of AtUVR3, we confirmed a positive trend between these levels and the rate of 6 − 4 photoproduct removal under blue light. Measurements of 6 − 4 photoproduct levels in chloroplast and nuclear DNA of wild type, photolyase mutants, and transgenic plants overexpressing AtUVR3 showed that the photoreactivation is the main repair pathway responsible for the removal of these lesions in both organelles. The GFP-tagged AtUVR3 was predominantly located in nuclei with a small fraction present in chloroplasts and mitochondria of transgenic Arabidopsis thaliana and Nicotiana tabacum lines. In chloroplasts, this photolyase co-localized with the nucleoid marked by plastid envelope DNA binding protein. Conclusions Photolyases are mainly localized in plant nuclei, with only a small fraction present in chloroplasts and mitochondria. Despite this unbalanced distribution, photoreactivation is the primary mechanism responsible for the removal of 6 − 4 photoproducts from nuclear and chloroplast DNA in adult leaves. The amount of the AtUVR3 photolyase is the limiting factor influencing the photoreactivation rate of 6 − 4 photoproducts. The efficient photoreactivation of 6 − 4 photoproducts in 35S: AtUVR3-GFP Arabidopsis and Nicotiana tabacum is a promising starting point to evaluate whether transgenic crops overproducing this photolyase are more tolerant to high UV irradiation and how they respond to other abiotic and biotic stresses under field conditions.

Abstract Background Transcultural nursing recognises the significance of cultural backgrounds in providing patients with quality care. This study investigates the opinions of master’s students in nursing and midwifery regarding the attitudes of Jehovah’s Witnesses towards refusing blood transfusions. Methods 349 master’s students in nursing and midwifery participated in a quantitative study and were surveyed via the Web to evaluate their awareness of the stance of Jehovah’s Witnesses on blood transfusions and the ethical and legal dilemmas associated with caring for Jehovah’s Witness (JW) patients. Results The study yielded three significant findings. It unequivocally demonstrates that nursing and midwifery students possess inadequate knowledge regarding Jehovah’s Witnesses’ stance on blood transfusions and their acceptance of specific blood products and medical procedures. Despite being cognisant of the ethical and legal dilemmas of caring for JW patients, students lack an understanding of patients’ autonomy to reject blood transfusions and their need for bloodless medicine. Students also articulated educational needs regarding cultural competencies regarding the Jehovah’s Witnesses’ beliefs on blood transfusions and non-blood management techniques. Conclusions Healthcare professionals need the knowledge and skills necessary to provide holistic, patient-centred and culturally sensitive care. This study emphasises the urgent need for university curricula and nursing postgraduate training to include modules on transcultural nursing and strategies for minimising blood loss.

Abstract The use of patient‐reported outcomes (PROMs) of quality of life (QOL) is common in cachexia trials. Patients' self‐report on health, functioning, wellbeing, and perceptions of care, represent important measures of efficacy. This review describes the frequency, variety, and reporting of QOL endpoints used in cancer cachexia clinical trials. Electronic literature searches were performed in Medline, Embase, and Cochrane (1990–2023). Seven thousand four hundred thirty‐five papers were retained for evaluation. Eligibility criteria included QOL as a study endpoint using validated measures, controlled design, adults (>18 years), ≥40 participants randomized, and intervention exceeding 2 weeks. The Covidence software was used for review procedures and data extractions. Four independent authors screened all records for consensus. Papers were screened by titles and abstracts, prior to full‐text reading. PRISMA guidance for systematic reviews was followed. The protocol was prospectively registered via PROSPERO (CRD42022276710). Fifty papers focused on QOL. Twenty‐four (48%) were double‐blind randomized controlled trials. Sample sizes varied considerably (n = 42 to 469). Thirty‐nine trials (78%) included multiple cancer types. Twenty‐seven trials (54%) featured multimodal interventions with various drugs and dietary supplements, 11 (22%) used nutritional interventions alone and 12 (24%) used a single pharmacological intervention only. The median duration of the interventions was 12 weeks (4–96). The most frequent QOL measure was the EORTC QLQ‐C30 (60%), followed by different FACIT questionnaires (34%). QOL was a primary, secondary, or exploratory endpoint in 15, 31 and 4 trials respectively, being the single primary in six. Statistically significant results on one or more QOL items favouring the intervention group were found in 18 trials. Eleven of these used a complete multidimensional measure. Adjustments for multiple testing when using multicomponent QOL measures were not reported. Nine trials (18%) defined a statistically or clinically significant difference for QOL, five with QOL as a primary outcome, and four with QOL as a secondary outcome. Correlation statistics with other study outcomes were rarely performed. PROMs including QOL are important endpoints in cachexia trials. We recommend using well‐validated QOL measures, including cachexia‐specific items such as weight history, appetite loss, and nutritional intake. Appropriate statistical methods with definitions of clinical significance, adjustment for multiple testing and few co‐primary endpoints are encouraged, as is an understanding of how interventions may relate to changes in QOL endpoints. A strategic and scientific‐based approach to PROM research in cachexia trials is warranted, to improve the research base in this field and avoid the use of QOL as supplementary measures.

Studies have shown the importance of caregivers’ multimodal behaviours (e.g., prosody, gestures, gaze) on children’s word learning. However, most studies focus on only one specific behaviour (e.g., only prosody). Here, we investigate which multimodal behaviours used by caregivers best predict children’s word learning and vocabulary growth. Using data from the ECOLANG corpus, we analysed caregiver behaviour in semi-naturalistic interactions with their child (3 to 4 years old) in which they talked about known and unknown toys. We analysed caregivers’ (n=36) use of multimodal cues while labelling the objects, specifically their use of yes/no questions, pitch, representational gestures, pointing, object manipulations and gaze. Caregivers’ pitch, use of yes/no questions and pointing predicted children’s word learning. In particular, higher pitch when labelling unknown toys predicted immediate word learning. The degree to which caregivers used higher pitch when producing the label for known compared to unknown toys predicted both immediate learning and vocabulary growth. Furthermore, the degree to which caregivers used yes/no questions more for unknown toys predicted immediate learning, while the frequency of yes/no questions when naming unknown toys predicted vocabulary growth. Lastly, caregiver pointing also predicted immediate label learning and vocabulary growth, but in the opposite direction from prosody: the more they pointed towards known toys, the better children’s learning of novel toy labels. Other behaviours did not predict word learning. Overall, these results provide evidence for the important role of multimodal caregiver behaviours, particularly prosody, on children’s lexical development.

Abstract Background A major contributing factor to glioblastoma (GBM) development and progression is its ability to evade the immune system by creating an immune-suppressive environment, where GBM-associated myeloid cells, including resident microglia and peripheral monocyte-derived macrophages, play critical pro-tumoral roles. However, it is unclear whether recruited myeloid cells are phenotypically and functionally identical in GBM patients and whether this heterogeneity is recapitulated in patient-derived orthotopic xenografts (PDOXs). A thorough understanding of the GBM ecosystem and its recapitulation in preclinical models is currently missing, leading to inaccurate results and failures of clinical trials. Methods Here, we report systematic characterization of the tumor microenvironment (TME) in GBM PDOXs and patient tumors at the single-cell and spatial levels. We applied single-cell RNA sequencing, spatial transcriptomics, multicolor flow cytometry, immunohistochemistry, and functional studies to examine the heterogeneous TME instructed by GBM cells. GBM PDOXs representing different tumor phenotypes were compared to glioma mouse GL261 syngeneic model and patient tumors. Results We show that GBM tumor cells reciprocally interact with host cells to create a GBM patient-specific TME in PDOXs. We detected the most prominent transcriptomic adaptations in myeloid cells, with brain-resident microglia representing the main population in the cellular tumor, while peripheral-derived myeloid cells infiltrated the brain at sites of blood–brain barrier disruption. More specifically, we show that GBM-educated microglia undergo transition to diverse phenotypic states across distinct GBM landscapes and tumor niches. GBM-educated microglia subsets display phagocytic and dendritic cell-like gene expression programs. Additionally, we found novel microglial states expressing cell cycle programs, astrocytic or endothelial markers. Lastly, we show that temozolomide treatment leads to transcriptomic plasticity and altered crosstalk between GBM tumor cells and adjacent TME components. Conclusions Our data provide novel insights into the phenotypic adaptation of the heterogeneous TME instructed by GBM tumors. We show the key role of microglial phenotypic states in supporting GBM tumor growth and response to treatment. Our data place PDOXs as relevant models to assess the functionality of the TME and changes in the GBM ecosystem upon treatment. Graphical Abstract

Abstract There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when comparing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary intake as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guidance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40–628). Forty‐nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most frequently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appetite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24‐h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge's g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as primary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not validated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials.

Możliwość bezpośredniego kontaktu z przyrodą wpływa na jakość życia mieszkańców miast, m.in. poprzez wykorzystanie rekreacyjne terenów zieleni. O ile wynikające z tego korzyści dla psychofizycznego dobrostanu człowieka są stosunkowo dobrze rozpoznane, o tyle zdecydowanie mniej wiadomo na temat negatywnych doświadczeń związanych z wizytami na terenach zieleni w mieście. W kontekście zrównoważonego planowania i zarządzania rekreacją istotne zaś jest pozyskanie kompleksowej wiedzy o postrzeganiu tych terenów przez ich użytkowników, a zwłaszcza o relacjach, jakie zachodzą między różnymi rodzajami doświadczeń. Niniejszy artykuł wypełnia tę lukę poprzez wykorzystanie kartowania partycypacyjnego w celu rozpoznania pozytywnych i negatywnych aspektów doświadczania miejskiego krajobrazu nadrzecznego na przykładzie Wisły w Warszawie. Na podstawie opinii mieszkańców zidentyfikowano wiązki pozytywnych doświadczeń oraz grupy negatywnych doświadczeń wynikających z pobytów nad rzeką. Poddano ocenie oddziaływanie wskazywanych negatywnych doświadczeń na intensywność pozytywnych doświadczeń. Pozytywne doświadczenia wynikają z postrzegania krajobrazu nadrzecznego jako: (1) przestrzeni oswojonej, miejsca intelektualnego złączenia z przyrodą; (2) przestrzeni interakcji społecznych; (3) przestrzeni aktywnego spędzania czasu i odkrywania przyrody. W kontekście negatywnych doświadczeń respondenci wskazują na większe znaczenie społecznych niż przyrodniczych aspektów funkcjonowania miejskiego krajobrazu nadrzecznego. Dodatkowo negatywne doświadczenia istotnie wpływają na ocenę pozytywnych doświadczeń. Uzyskane wyniki mogą stanowić podstawę do identyfikacji i właściwego zaspokajania najistotniejszych potrzeb mieszkańców miasta wobec terenów nadrzecznych jako przestrzeni spędzania czasu wolnego.

Visiting urban green and blue spaces improves the quality of life in cities as it helps to preserve human-nature bonds. In this context, the role of urban parks and forests has been well-recognised; however, much less is known about the landscapes of inland water bodies. To fill this gap, the study aimed to identify spatiotemporal patterns of recreational activities in the urban riverscape in relation to the visitors’ residential proximity. Also, survey results were combined with spatial and remote sensing data to determine how the spatial characteristics of the riverscape affect its recreational use. The case of Warsaw, Poland, was used. The results indicated that the riverscape serves as a local park for the neighbouring communities, while it is rather a warm-weekend attraction for far-living ones. Visitors concentrate in the city centre, and spread out along the communication paths; however, spatial patterns of the magnitude of particular activities also show interbank differences. Spatial error models of drivers of riverscape recreation revealed (1) the multifaceted role of trees in densely visited areas and (2) the importance of physical availability for contact with the urban river. These findings expand knowledge on the recreational use of urban rivers by exploring its place-related motivations.

Abstract Alzheimer’s disease (AD) progression and pathology show pronounced sex differences, but the factors driving these remain poorly understood. To gain insights into early AD-associated molecular changes and their sex dependency for tau pathology in the cortex, we performed single-cell RNA-seq in the THY-Tau22 AD mouse model. By examining cell type-specific and cell type-agnostic AD-related gene activity changes and their sex-dimorphism for individual genes, pathways and cellular sub-networks, we identified both statistically significant alterations and interpreted the upstream mechanisms controlling them. Our results confirm several significant sex-dependent alterations in gene activity in the THY-Tau22 model mice compared to controls, with more pronounced alterations in females. Both changes shared across multiple cell types and cell type-specific changes were observed. The differential genes showed significant over-representation of known AD-relevant processes, such as pathways associated with neuronal differentiation, programmed cell death and inflammatory responses. Regulatory network analysis of these genes revealed upstream regulators that modulate many of the downstream targets with sex-dependent changes. Most key regulators have been previously implicated in AD, such as Egr1, Klf4, Chchd2, complement system genes, and myelin-associated glycoproteins. Comparing with similar data from the Tg2576 AD mouse model and human AD patients, we identified multiple genes with consistent, cell type-specific and sex-dependent alterations across all three datasets. These shared changes were particularly evident in the expression of myelin-associated genes such as Mbp and Plp1 in oligodendrocytes. In summary, we observed significant cell type-specific transcriptomic changes in the THY-Tau22 mouse model, with a strong over-representation of known AD-associated genes and processes. These include both sex-neutral and sex-specific patterns, characterized by consistent shifts in upstream master regulators and downstream target genes. Collectively, these findings provide insights into mechanisms influencing sex-specific susceptibility to AD and reveal key regulatory proteins that could be targeted for developing treatments addressing sex-dependent AD pathology.

Data sovereignty has emerged as a critical concern for enterprises, cloud service providers (hyperscalers), end-users, and policymakers at both national and international levels. In response, cloud-based distributed computing models have been proposed as frameworks to enforce data sovereignty requirements. This study aims to evaluate and enhance data sovereignty practices within public cloud environments. Through a comprehensive literature review, we analyze existing reference architectures and solutions that address data sovereignty, identifying the technological and economic constraints they impose, such as increased computational costs associated with specific frameworks and cryptographic measures. To address these challenges, we propose an abstract data sovereignty model designed to aid system designers and architects in developing compliant cloud-based systems. Additionally, we conduct computational experiments assessing the performance of the IDS connector, a key data sovereignty tool, deployed on the Google Cloud Platform and Microsoft Azure. Results reveal that while the geographic location of the software significantly impacts performance, the choice of cloud platform minimally influences the IDS connector’s efficiency. These findings offer insights into optimizing data sovereignty strategies for cloud solutions, with implications for future system design and policy development.

Anion-exchange-membrane water electrolyzers (AEMWEs) in principle operate without soluble electrolyte using earth-abundant catalysts and cell materials and thus lower the cost of green H2 . Current systems lack competitive performance and the durability needed for commercialization. One critical issue is a poor understanding of catalyst-specific degradation processes in the electrolyzer. While non-platinum-group-metal (non-PGM) oxygen-evolution catalysts show excellent performance and durability in strongly alkaline electrolyte, this has not transferred directly to pure-water AEMWEs. Here, AEMWEs with five non-PGM anode catalysts are built and the catalysts' structural stability and interactions with the alkaline ionomer are characterized during electrolyzer operation and post-mortem. The results show catalyst electrical conductivity is one key to obtaining high-performing systems and that many non-PGM catalysts restructure during operation. Dynamic Fe sites correlate with enhanced degradation rates, as does the addition of soluble Fe impurities. In contrast, electronically conductive Co3 O4 nanoparticles (without Fe in the crystal structure) yield AEMWEs from simple, standard preparation methods, with performance and stability comparable to IrO2 . These results reveal the fundamental dynamic catalytic processes resulting in AEMWE device failure under relevant conditions, demonstrate a viable non-PGM catalyst for AEMWE operation, and illustrate underlying design rules for engineering anode catalyst/ionomer layers with higher performance and durability.

Abstract Neuroinflammation in the brain contributes to the pathogenesis of Parkinson’s disease (PD), but the potential dysregulation of peripheral immunity has not been systematically investigated for idiopathic PD (iPD). Here we showed an elevated peripheral cytotoxic immune milieu, with more terminally-differentiated effector memory (TEMRA) CD8 T, CD8+ NKT cells and circulating cytotoxic molecules in fresh blood of patients with early-to-mid iPD, especially females, after analyzing > 700 innate and adaptive immune features. This profile, also reflected by fewer CD8+FOXP3+ T cells, was confirmed in another subcohort. Co-expression between cytotoxic molecules was selectively enhanced in CD8 TEMRA and effector memory (TEM) cells. Single-cell RNA-sequencing analysis demonstrated the accelerated differentiation within CD8 compartments, enhanced cytotoxic pathways in CD8 TEMRA and TEM cells, while CD8 central memory (TCM) and naïve cells were already more-active and transcriptionally-reprogrammed. Our work provides a comprehensive map of dysregulated peripheral immunity in iPD, proposing candidates for early diagnosis and treatments.