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The welfare of animals under human care is often assessed by observing behaviours indicative of stress or discomfort, such as stereotypical behaviour (SB), which often shows as repetitive, invariant pacing. Traditional behaviour monitoring methods, however, are labour-intensive and subject to observer bias. Our study presents an innovative automated approach utilising computer vision and machine learning to non-invasively detect and analyse SB in managed populations, exemplified by a longitudinal study of two polar bears. We designed an animal tracking framework to localise and identify individual animals in the enclosure. After determining their position on the enclosure map via homographic transformation, we refined the resulting trajectories using a particle filter. Finally, we classified the trajectory patterns as SB or normal behaviour using a lightweight random forest approach with an accuracy of 94.9 %. The system not only allows for continuous, objective monitoring of animal behaviours but also provides insights into seasonal variations in SB, illustrating its potential for improving animal welfare in zoological settings. Ultimately, we analysed 607 days for the occurrence of SB, allowing us to discuss seasonal patterns of SB in both the male and female polar bear monitored. This work advances the field of animal welfare research by introducing a scalable, efficient method for the long-term, automated detection and monitoring of stereotypical behaviour, paving the way for its application across various settings and species that can be continuously monitored with cameras. We made the code publicly available at https://github.com/team-vera/stereotypy-detector.

Introduction: Chest wall reconstruction in children continues to be a challenging undertaking, aiming to restore both form and function. An optimal chest wall reconstruction material has not been identified that would provide dynamic chest function and would ideally avoid potential long-term sequelae. Case presentation: A 15-year-old female with Li Fraumeni syndrome and a history of hepatic rhabdomyosarcoma presented with increasing left back and left scapular pain initially attributed to her known scoliosis. Computed tomography revealed a 12 x 6 × 7 cm mass encasing ribs 3–5 extending into the left chest wall and axilla. Image-guided biopsy confirmed a high-grade osteosarcoma without extra-thoracic metastatic disease. She underwent neoadjuvant chemotherapy after which a three-dimensional (3D) anatomic model of the tumor was printed using the post-therapy imaging reconstruction. The surgical team collaborated with Osteobionix (Osteobionics S.L., Santa Lucia de Tirajana, Spain) to create a patient-specific dynamic chest wall reconstruction implant, based on 3D modeling of the planned resection zone. The final implant was 3D printed with a titanium alloy using electron-beam manufacturing technology, sterilized prior to implantation. She underwent left thoracotomy and rib resection with prosthesis fixation to the T3, T4, and T5 vertebral bodies posteriorly and to the sternum anteriorly. More than2 years after the operation, she is doing well without evidence of recurrent disease. She has an excellent cosmetic result, there has been no progression of her scoliosis, and she has returned to competitive sports. Conclusion: Our titanium-based 3D-printed, patient-specific implant seems to be a valuable option for the reconstruction of the chest wall in children who require an extensive chest wall resection.

Melanoma is a metastatic, drug-refractory cancer with the ability to evade immunosurveillance. Cancer immune evasion involves interaction between tumor intrinsic properties and the microenvironment. The transcription factor E2F1 is a key driver of tumor evolution and metastasis. To explore E2F1’s role in immune regulation in presence of aggressive melanoma cells, we established a coculture system and utilized transcriptome and cytokine arrays combined with bioinformatics and structural modeling. We identified an E2F1-dependent gene regulatory network with IL6 as a central hub. E2F1-induced IL-6 secretion unleashes an autocrine inflammatory feedback loop driving invasiveness and epithelial-to-mesenchymal transition. IL-6-activated STAT3 physically interacts with E2F1 and cooperatively enhances IL-6 expression by binding to an E2F1-STAT3-responsive promoter element. The E2F1-STAT3/IL-6 axis strongly modulates the immune niche and generates a crosstalk with CD4+ cells resulting in transcriptional changes of immunoregulatory genes in melanoma and immune cells that is indicative of an inflammatory and immunosuppressive environment. Clinical data from TCGA demonstrated that elevated E2F1, STAT3, and IL-6 correlate with infiltration of Th2, while simultaneously blocking Th1 in primary and metastatic melanomas. Strikingly, E2F1 depletion reduces the secretion of typical type-2 cytokines thereby launching a Th2-to-Th1 phenotype shift towards an antitumor immune response. The impact of activated E2F1-STAT3/IL-6 axis on melanoma-immune cell communication and its prognostic/therapeutic value was validated by mathematical modeling. This study addresses important molecular aspects of the tumor-associated microenvironment in modulating immune responses, and will contribute significantly to the improvement of future cancer therapies.

BackgroundTransforming growth factor (TGF)-ß1 is a pleiotropic cytokine that can promote tumor growth and suppress antitumor immune responses. Latent TGF-ß1 associates with glycoprotein-A repetition predominant (GARP) on the surface of regulatory T cells prior to its activation and release. Livmoniplimab is a monoclonal antibody (mAb) that binds the GARP:TGF-ß1 complex to inhibit activation and release of TGF-ß1. It is in clinical development in combination with budigalimab, an anti-programmed cell death protein 1 Fc-modified mAb. The first-in-human, phase 1, dose-escalation results are presented herein (ClinicalTrials.gov: NCT03821935).MethodsThe dose-escalation phase enrolled adult patients with advanced solid tumors. Patients received escalating doses of livmoniplimab ranging from 3mg to 1500mg, once every 2 weeks (Q2W), as monotherapy or in combination with a 500mg fixed dose of budigalimab Q4W. The primary objective of the dose escalation was to determine the recommended phase 2 dose. Secondary objectives were to assess safety and pharmacokinetics (PK), and exploratory objectives included evaluating preliminary efficacy.ResultsFifty-seven patients enrolled in the dose escalation: 23 in monotherapy cohorts and 34 in combination therapy cohorts. Dose-limiting toxicities were limited, no maximum tolerated dose was reached, and the maximum administered dose of 1500mg was selected for dose expansion. The most common adverse events reported in monotherapy-treated patients were fatigue, anemia, and nausea, and those in combination therapy-treated patients were pruritus, fatigue, nausea, and anemia. Livmoniplimab exhibited dose-proportional PK, and peripheral blood biomarker data demonstrated saturation of the GARP:TGF-ß1 complex on platelets at livmoniplimab doses within the linear PK range. No objective tumor responses were observed in the monotherapy dose escalation. However, the objective response rate was 15% in the combination dose escalation, with a median response duration of 8.4 months.ConclusionLivmoniplimab was well-tolerated as monotherapy and in combination with budigalimab in the dose-escalation phase. Encouraging preliminary efficacy was demonstrated in the combination dose escalation in heavily pretreated patients, supporting further development of this novel drug combination in patients with advanced solid tumors.

Grapevine downy mildew caused by Plasmopara viticola is a deleterious vine disease currently controlled using synthetic and copper-based fungicides. Environmental concerns surrounding such fungicides necessitate sustainable alternatives like grape cane extracts. However, studies into their efficacy and effects on the product remain limited. This study aimed to assess the open-field efficacy of a novel grape cane extract formulation, alone and combined with a copper agent, against downy mildew, and to examine its impact on berry and must composition. The results were compared to standard fungicides frequently used in integrated and organic viticulture. In 2022, the grape cane extract formulation reduced downy mildew severity by 78 % on berry clusters, comparable to the maximum acceptable dose of copper for organic farming in Germany (3 kg/ha/a). Combining the grape cane extract with the copper agent was more effective than the copper agent alone, but not more effective than the grape cane extract alone. In 2023, disease development was marginal, despite artificial inoculation. Compositional differences detectable by FTIR were insignificant between musts derived from all treatments, increased copper levels were observed whenever copper had been applied. The phenolic content in freeze-dried, de-seeded berries of 2022 was significantly lower after copper (14.6 mg/g dry weight DW) and grape cane extract treatments (6.6 mg/g DW) when compared to the control (36.1 mg/g DW), with discrepancies in stilbenoid and flavan-3-ol levels in particular, as analysed by HPLC-DAD. However, these differences were not confirmed in 2023, with results showing no correlations between different treatments and phenolic contents. These findings suggest that applications of the phenolic grape cane extract do not lead to artificially altered levels or relevant residues of the active constituents; i.e., the phenolic compounds in the product. In brief, grape cane extracts might represent a promising natural alternative to controlling grapevine downy mildew, particularly in organic viticulture, which, to date, heavily relies on (eco-)toxic copper-pesticides. Further multi-year studies including wine analyses are warranted to follow the entire flow towards the final product.

The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis. Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expression is enriched for the expression of mitochondrial metabolism genes and exhibits higher mitochondrial respiration compared with CD63lo beta cells. Human and murine pseudo-islets derived from CD63hi beta cells demonstrate enhanced glucose-stimulated insulin secretion compared with pseudo-islets from CD63lo beta cells. We show that CD63hi beta cells are diminished in mouse models of and in humans with type 2 diabetes. Finally, transplantation of pseudo-islets generated from CD63hi but not CD63lo beta cells into diabetic mice restores glucose homeostasis. These findings suggest that loss of a specific subset of beta cells may lead to diabetes. Strategies to reconstitute or maintain CD63hi beta cells may represent a potential anti-diabetic therapy.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

Abstract Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the relationship between rs-FC and the underlying patterns of neural activity in these circuits is therefore vital. Here we introduced inhibitory designer receptors exclusively activated by designer drugs (DREADDs) into the amygdala of two male macaques. We evaluated the causal effect of activating the DREADD receptors on rs-FC and neural activity within circuits connecting amygdala and frontal cortex. Activating the inhibitory DREADD increased rs-FC between amygdala and ventrolateral prefrontal cortex. Neurophysiological recordings revealed that the DREADD-induced increase in fMRI rs-FC was associated with increased local field potential coherency in the alpha band (6.5–14.5 Hz) between amygdala and ventrolateral prefrontal cortex. Thus, our multi-modal approach reveals the specific signature of neuronal activity that underlies rs-FC in fronto-limbic circuits.

Abstract Background Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by the presence of proteinaceous alpha-synuclein (α-syn) inclusions (Lewy bodies), markers of neuroinflammation and the progressive loss of nigrostriatal dopamine (DA) neurons. These pathological features can be recapitulated in vivo using the α-syn preformed fibril (PFF) model of synucleinopathy. We have previously determined that microglia proximal to PFF-induced nigral α-syn inclusions increase in soma size, upregulate major-histocompatibility complex-II (MHC-II) expression, and increase expression of a suite of inflammation-associated transcripts. This microglial response is observed months prior to degeneration, suggesting that microglia reacting to α-syn inclusion may contribute to neurodegeneration and could represent a potential target for novel therapeutics. The goal of this study was to determine whether colony stimulating factor-1 receptor (CSF1R)-mediated microglial depletion impacts the magnitude of α-syn aggregation, nigrostriatal degeneration, or the response of microglial in the context of the α-syn PFF model. Methods Male Fischer 344 rats were injected intrastriatally with either α-syn PFFs or saline. Rats were continuously administered Pexidartinib (PLX3397B, 600 mg/kg), a CSF1R inhibitor, to deplete microglia for a period of either 2 or 6 months. Results CSF1R inhibition resulted in significant depletion (~ 43%) of ionized calcium-binding adapter molecule 1 immunoreactive (Iba-1ir) microglia within the SNpc. However, CSF1R inhibition did not impact the increase in microglial number, soma size, number of MHC-II immunoreactive microglia or microglial expression of Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, and Fcer1g associated with phosphorylated α-syn (pSyn) nigral inclusions. Further, accumulation of pSyn and degeneration of nigral neurons was not impacted by CSF1R inhibition. Paradoxically, long term CSF1R inhibition resulted in increased soma size of remaining Iba-1ir microglia in both control and PFF rats, as well as expression of MHC-II in extranigral regions. Conclusions Collectively, our results suggest that CSF1R inhibition does not impact the microglial response to nigral pSyn inclusions and that CSF1R inhibition is not a viable disease-modifying strategy for PD.

Palaeoclimate information on multiple climate variables at different spatiotemporal scales is becoming increasingly important to understand environmental and societal responses to climate change. A lack of high-quality reconstructions of past hydroclimate has recently been identified as a critical research gap. Speleothems, with their precise chronologies, widespread distribution, and ability to record changes in local to regional hydroclimate variability, are an ideal source of such information. Here, we present a new version of the Speleothem Isotopes Synthesis and AnaLysis database (SISALv3), which has been expanded to include trace element ratios and Sr isotopes as additional, hydroclimate-sensitive geochemical proxies. The oxygen and carbon isotope data included in previous versions of the database have been substantially expanded. SISALv3 contains speleothem data from 365 sites from across the globe, including 95 Mg/Ca, 85 Sr/Ca, 52 Ba/Ca, 25 U/Ca, 29 P/Ca, and 14 Sr-isotope records. The database also has increased spatiotemporal coverage for stable oxygen (892) and carbon (620) isotope records compared with SISALv2 (which consists of 673 and 430 stable oxygen and carbon records, respectively). Additional meta information has been added to improve the machine-readability and filtering of data. Standardized chronologies are included for all new entities along with the originally published chronologies. Thus, the SISALv3 database constitutes a unique resource of speleothem palaeoclimate information that allows regional to global palaeoclimate analyses based on multiple geochemical proxies, permitting more robust interpretations of past hydroclimate and comparisons with isotope-enabled climate models and other Earth system and hydrological models. The database can be accessed at https://doi.org/10.5287/ora-2nanwp4rk (Kaushal et al., 2024).

Abstract Background Psychiatrists face a major ethical challenge when deciding whether to make use of coercive measures in the treatment process of patients suffering from severe and persistent mental illness (SPMI). As India and Switzerland show major cultural, political and financial differences, it is hypothesized that attitudes towards coercive measures among Indian and Swiss psychiatrists will vary too. Exploring differences in attitudes between cultures strengthens the critical reflection on one’s own stances and in consequence, on our way of action. Especially when it comes to situations involving power imbalances between patients and health practitioners, self-reflection is essential to prevent ethically inappropriate behavior. Methods An online survey on aspects of care for patients with SPMI was sent to 3’056 members of the Indian Psychiatric Society between April and June 2020 and to 1’311 members of the Swiss Society for Psychiatry and Psychotherapy between February and March 2016. The respondents’ answers were compared. This article deals with the questionnaire’s items on autonomous decision making and the implementation of coercive measures in clinical practice. More precisely, participating psychiatrists were asked to rate the importance of patient’s autonomy in general and their willingness to apply coercive measures regarding two specific case vignettes depicting a patient with schizophrenia and one with depression. The statistical analysis, namely descriptive data analysis and calculation of arithmetic means, Shapiro Wilks tests and Mann-Whitney U tests, was carried out using IBM SPSS Statistics version 27. Results Answers were received from 206 psychiatrists in India and 457 psychiatrists in Switzerland. Indian participants tended to value autonomous decision making as slightly less important than Swiss participants (62.2% vs. 91%, p =.01). Regarding a case of severe and persistent depression, psychiatrists in the Indian group were on average more in favor of acting against the wishes of the patient (55% vs. 34.1%, p

Abstract Graphene is a promising material for applications as a channel in graphene field-effect transistors (GFETs) which may be used as a building block for optoelectronics, high-frequency devices and sensors. However, these devices require gate insulators which ideally should form atomically flat interfaces with graphene and at the same time contain small densities of traps to maintain high device stability. Previously used amorphous oxides, such as SiO2 and Al2O3, however, typically suffer from oxide dangling bonds at the interface, high surface roughness and numerous border oxide traps. In order to address these challenges, here we use 2 nm thick epitaxial CaF2 as a gate insulator in GFETs. By analyzing device-to-device variability for about 200 devices fabricated in two batches, we find that tens of them show similar gate transfer characteristics. Our statistical analysis of the hysteresis up to 175oC has revealed that while an ambient-sensitive counterclockwise hysteresis can be present in some devices, the dominant mechanism is thermally activated charge trapping by border defects in CaF2 which results in the conventional clockwise hysteresis. We demonstrate that both the hysteresis and bias-temperature instabilities in our GFETs with CaF2 are comparable to similar devices with SiO2 and Al2O3. In particular, we achieve a small hysteresis below 0.01 V for equivalent oxide thickness (EOT) of about 1 nm at the electric fields up to 15 MV cm−1 and sweep times in the kilosecond range. Thus, our results demonstrate that crystalline CaF2 is a promising insulator for highly-stable GFETs.

Reconstructing of past hydroclimates at regional scales during the Common Era (CE) is necessary to place the current warming in the context of natural climate variability. Here we present a composite record of oxygen isotope variations during last 2500 years based on eight stalagmites from four caves in the central Pyrenees (NE Spain) dominated by temperature variations, with the amount of precipitation playing a minor role. The dataset is compared with other Iberian reconstructions that show a high degree of internal coherence with respect to variability at the centennial scale. The Roman Period (RP) (especially 0–200 CE), the Medieval Climate Anomaly (MCA), and part of the Little Ice Age (LIA) represent the warmest periods, while the coldest decades occurred during the Dark Ages (DA) and most of the LIA intervals (e.g., 520–550 CE and 1800–1850 CE). Importantly, the LIA cooling or the MCA warming were not continuous or uniform and exhibited high decadal variability. The Industrial Era (IE) shows an overall warming trend although with marked cycles and partial stabilization during the last 2 decades (1990–2010). The strong coherence between the speleothem data, European temperature reconstructions and global tree-ring data informs about the regional representativeness of this new record as Pyrenean past climate variations. Solar variability, likely through its impact on the North Atlantic Oscillation, and major volcanic eruptions appear to be the two main drivers of climate in southwestern Europe during the past 2.5 millennia.

Abstract Early life factors are important risk factors for breast cancer. The association between weight gain after age 18 and breast cancer risk is inconsistent across previous epidemiologic studies. To evaluate this association, we conducted a meta-analysis according to PRISMA guidelines and the established inclusion criteria. We performed a comprehensive literature search using Medline (Ovid), Embase, Scopus, Cochrane Library, and ClinicalTrials.gov to identify relevant studies published before June 3, 2022. Two reviewers independently reviewed the articles for final inclusion. Seventeen out of 4,725 unique studies met the selection criteria. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS), and all were of moderate to high quality with NOS scores ranging from 5 to 8. We included 17 studies (11 case-control, 6 cohort) in final analysis. In case-control studies, weight gain after age 18 was associated with an increased risk of breast cancer (odds ratio [OR] = 1.25; 95% CI = 1.07–1.48), when comparing the highest versus the lowest categories of weight gain. Menopausal status was a source of heterogeneity, with weight gain after age 18 associated with an increased risk of breast cancer in postmenopausal women (OR = 1.53; 95% CI = 1.40–1.68), but not in premenopausal women (OR = 1.01; 95% CI = 0.92–1.12). Additionally, a 5 kg increase in weight was positively associated with postmenopausal breast cancer risk (OR = 1.12; 95%CI = 1.05–1.21) in case-control studies. Findings from cohort studies were identical, with a positive association between weight gain after age 18 and breast cancer incidence in postmenopausal women (relative risk [RR] = 1.30; 95% CI = 1.09–1.36), but not in premenopausal women (RR = 1.06; 95% CI = 0.92–1.22). Weight gain after age 18 is a risk factor for postmenopausal breast cancer, highlighting the importance of weight control from early adulthood to reduce the incidence of postmenopausal breast cancer.

In large lakes, metal availability sometimes limits the acquisition of nutrients (nitrogen, N and phosphorus, P) in offshore waters that are relatively isolated from tributaries and sediments. We hypothesize that metals may also be important within harmful algal blooms (HABs). HABs occur where nutrient loads are elevated, but bioassays often indicate that phytoplankton in HABs are N or P limited. Nutrient limitation may be exacerbated by corresponding limitations in several metals (i.e. nickel - Ni, molybdenum - Mo, zinc - Zn, and iron - Fe) that facilitate uptake and transformation of oxidized and organic forms of nutrients, such as urea, nitrate and organic phosphorus. The cyanotoxin microcystin has been hypothesized to have a role in metal management, so metal demand may also influence the toxicity of HABs. Here, we used nutrient diffusing substrates to measure how N, P, Ni, Mo, Zn and Fe amendments influenced the growth and toxicity of periphyton. Periphyton was grown suspended in 10 nearshore sites in Lake Michigan and Lake Erie (5 with and 5 without perennial HABs). Outside of blooms, we found no evidence for metal limitation or co-limitation. However, evidence for metal co-limitation was observed in two HABs sites (Zn in Green Bay and Zn, Mo, Ni and Fe in Sandusky Bay). N, P and Zn amendments all stimulated microcystin content in Maumee Bay. These data indicate that nutrient limitation occurs even within blooms, and the availability of metals may have an influence on growth, community composition and toxicity.

Background: Cardiopulmonary resuscitation (CPR) is essential for saving lives during cardiac arrest, but performing CPR in extreme environments poses unique challenges. In scenarios ranging from hypogravity or microgravity to confined spaces like aeroplanes and underwater scenarios, traditional CPR techniques may be inadequate. This scoping review aims to identify alternative chest compression techniques, synthesise current knowledge, and pinpoint research gaps in resuscitation for cardiac arrest in extreme conditions. Methods: PubMed and the Cochrane Register of Controlled Trials as well as the website of ResearchGate was searched to identify relevant literature. Studies were eligible for inclusion if they evaluated alternative chest compression techniques, including manual or mixed CPR approaches, whilst assessing feasibility and effectiveness based on compression depth, rate, and/or impact on rescuer effort. Results: The database search yielded 9499 references. After screening 26 studies covering 6 different extreme environments were included (hypogravity: 2; microgravity: 9, helicopter: 1, aeroplane: 1, confined space: 11; avalanche: 2). 13 alternative chest compression techniques were identified, all of which tested using manikins to simulate cardiac arrest scenarios. Conclusion: To address the unique challenges in extreme environments, novel CPR techniques are emerging. However, evidence supporting their effectiveness remains limited.

BackgroundExtremely preterm (EPT) birth has been related to dysregulation of stress responses and behavioral/learning problems at school age. Early adverse experiences can blunt HPA axis reactivity. We hypothesized that an attenuated cortisol awakening response would be associated with developmental and behavioral problems at school age in EPT children.MethodsThis secondary analysis of a sub-cohort of the SUPPORT study included children born between 24 and 27 weeks, evaluated at 6-7 years with a neurodevelopmental battery and cortisol measures. Differences were tested between EPT and a term-born group. Relationships of cortisol awakening response to test scores were analyzed.ResultsCortisol was measured in 110 EPT and 29 term-born 6-7 year olds. Unadjusted WISC-IV and NEPSY-II scores were significantly worse among EPT children only. Conners Parent Rating Scale behavior scores were significantly worse among EPT children. After adjusting for covariates, blunted cortisol awakening responses were found to be associated with poorer scores on memory tests and greater problems with inattention for the EPT group (p

Necrotizing enterocolitis (NEC) is the leading cause of death caused by gastrointestinal disease in preterm infants. Major risk factors include prematurity, formula feeding, and gut microbial colonization. Microbes have been linked to NEC, yet there is no evidence of causal species, and select probiotics have been shown to reduce NEC incidence in infants. In this study, we evaluated the effect of the probiotic Bifidobacterium longum subsp. infantis (BL. infantis), alone and in combination with a human milk oligosaccharide (HMO)-sialylactose (3'SL)-on the microbiome, and the incidence of NEC in preterm piglets fed an infant formula diet. We studied 50 preterm piglets randomized between 5 treatments: (1) Preterm infant formula, (2) Donor human milk (DHM), (3) Infant formula + 3'SL, (4) Infant formula + BL. infantis, and (5) Infant formula and BL. infantis + 3'SL. NEC incidence and severity were assessed through the evaluation of tissue from all the segments of the GI tract. The gut microbiota composition was assessed both daily and terminally through 16S and whole-genome sequencing (WGS) of rectal stool samples and intestinal contents. Dietary BL. infantis and 3'SL supplementation had no effect, yet DHM significantly reduced the incidence of NEC. The abundance of BL. infantis in the gut contents negatively correlated with disease severity. Clostridium sensu stricto 1 and Clostridium perfringens were significantly more abundant in NEC and positively correlated with disease severity. Our results suggest that pre- and probiotics are not sufficient for protection from NEC in an exclusively formula-based diet. The results highlight the differences in microbial species positively associated with both diet and NEC incidence.

Introduction Mental illness stigma is associated with a range of negative consequences, such as reduced help-seeking for mental health problems. Since stigma affects individual, social, and structural aspects, multilevel interventions such as the Canadian programme The Working Mind have been proven to be the most effective. Given the solid evidence base for The Working Mind, it is our aim to implement and evaluate culturally adapted versions of the programme in German higher education, targeting students, employees and managers.Methods and analysis We will evaluate the programme with regard to its effect on mental illness stigma, openness to mental health problems, willingness to seek help, and positive mental health outcomes. Further, we will investigate the programme’s effectiveness dependent on gender and personal values, various mechanisms of change, and factors facilitating and hindering implementation. The study uses a sequential explanatory mixed-methods evaluation design (QUAN → qual) that consists of three steps: (1) quasi-experimental online survey with programme participants, (2) focus groups with programme participants, and (3) qualitative interviews with programme stakeholders. The quantitative data collected in step 1 will be analysed using 2×3 analysis of variances and a parallel multiple mediation analysis. The results will inform the qualitative data to be collected in steps 2 and 3, which will be analysed using qualitative content analysis.Ethics and dissemination The study was approved by the local Ethics Committee (Ethics Committee of University Medicine Greifswald; BB 098/23). Participants have to provide written consent before taking part in a focus group or interview. As for the online survey, participants have to give their consent by agreeing to an online data protection form before they can start completing the survey. We will publish central results and the anonymised data in an Open Access Journal. Further, the statistical code will be included as a supplement to the paper(s) documenting the results of the study.Trial registration number DRKS00033523.

The response of the haloarchaeal model organism Haloferax volcanii to iron starvation was analyzed at the proteome level by data-independent acquisition mass spectrometry. Cells grown in minimal medium with normal iron levels were compared to those grown under low iron conditions, with samples being separated into membrane and cytoplasmic fractions in order to focus on import/export processes which are frequently associated with metal homeostasis. Iron starvation not only caused a severe retardation of growth but also altered the levels of many proteins. Using a comprehensive annotated spectral library and data-independent acquisition mass spectrometry (DIA-MS), we found that iron starvation resulted in significant changes to both the membrane and the soluble proteomes of Hfx. volcanii. The most affected protein is the RND family permease HVO_A0467, which is 44-fold enriched in cells grown under iron starvation. The gene HVO_A0467 can be deleted suggesting that it is not essential under standard conditions. Compared to wild type cells the deletion strain shows only slight changes in growth and cell morphologies show no differences. Molecular docking predictions indicated that HVO_A0467 may be an exporter of the siderophore schizokinen for which a potential biosynthesis cluster is encoded in the Hfx. volcanii genome. Together, these findings confirm the importance of iron for archaeal cells and suggest HVO_0467 as a siderophore exporter.

BackgroundArginine is a conditionally essential amino acid that is depleted in critically ill or surgical patients. In pediatric and adult patients, sepsis results in an arginine-deficient state, and the depletion of plasma arginine is associated with greater mortality. However, direct supplementation of arginine can result in the excessive production of nitric oxide (NO), which can contribute to the hypotension and macrovascular hypo-reactivity observed in septic shock. Pegylated arginine deiminase (ADI-PEG20, pegargiminase) reduces plasma arginine and generates citrulline that can be transported intracellularly to generate local arginine and NO, without resulting in hypotension, while maintaining microvascular patency. The objective of this study was to assess the efficacy of ADI-PEG20 with and without supplemental intravenous citrulline in mitigating hypovolemic shock, maintaining tissue levels of arginine, and reducing systemic inflammation in an endotoxemic pediatric pig model.MethodsTwenty 3-week-old crossbred piglets were implanted with jugular and carotid catheters as well as telemetry devices in the femoral artery to measure blood pressure, body temperature, heart rate, and respiration rate. The piglets were assigned to one of three treatments before undergoing a 5 h lipopolysaccharide (LPS) infusion protocol. Twenty-four hours before LPS infusion, control pigs (LPS; n=6) received saline, ADI-PEG20 pigs (n=7) received an injection of ADI-PEG20, and seven pigs (ADI-PEG20 + CIT pigs [n=7]) received ADI-PEG20 and 250 mg/kg citrulline intravenously. Pigs were monitored throughout LPS infusion and tissue was harvested at the end of the protocol.ResultsPlasma arginine levels decreased and remained low in ADI-PEG20 + CIT and ADI-PEG20 pigs compared with LPS pigs but tissue arginine levels in the liver and kidney were similar across all treatments. Mean arterial pressure in all groups decreased from 90 mmHg to 60 mmHg within 1 h of LPS infusion but there were no significant differences between treatment groups. ADI-PEG20 and ADI-PEG20 + CIT pigs had less CD45+ infiltrate in the liver and lung and lower levels of pro-inflammatory cytokines in the plasma.ConclusionADI-PEG20 and citrulline supplementation failed to ameliorate the hypotension associated with acute endotoxic sepsis in pigs but reduced systemic and local inflammation in the lung and liver.

BackgroundConsidering the neuromuscular alterations in Achilles tendinopathy (AT), sensorimotor training (SMT) might be beneficial to restore the neuromuscular capacity of the muscle-tendon complex and thereby improve patients' functions and alleviate symptoms. However, there is still a lack of knowledge concerning the effects of SMT on improving functional (e.g., strength) and pain outcomes in this population. Thus, the purpose of this study was to synthesize current evidence to analyze the efficacy of SMT in people with AT.MethodsA systematic electronic search was performed in PubMed, Web of Science, and Cochrane Central Register of Controlled Trials from inception to December 2023. Studies applying SMT in people with AT investigating functional or clinical pain outcomes were considered. Protocols had to incorporate balance, stabilization, proprioception, or vibration training. Patients with insertional or mid-portion AT (≥18 years age) diagnosed with clinical or sonographic evaluation were included.ResultsThe search yielded 823 records. A total of three randomized controlled trials were considered eligible for the analysis. Each trial used a different SMT protocol: balance training, balance with stabilization training, or whole-body vibration training (WBVT) with other co-interventions. Most functional and pain parameters improved compared to baseline. The first study reported a decrease in pain and an increase in performance (i.e., countermovement jump height) and endurance (i.e., number of heel-raises) by 12-week use of a balance training in addition to isometric, concentric/eccentric, and eccentric exercises. The second study evaluated the four weeks effect of SMT (balance and stabilization training plus eccentric exercises) in addition to passive physiotherapy (deep frictions, ice, ultrasound), resulting in an increased plantarflexion peak torque and reduced pain levels. The third study investigating WBVT reported at 12 weeks an increase in flexibility and a decrease in tendon pain.DiscussionSMT in addition to other co-interventions (i.e., eccentric, isometric, concentric/eccentric training, physiotherapy) showed improvements in strength, performance, muscle flexibility, and alleviated clinical outcomes of pain. SMT might therefore be useful as part of a multimodal treatment strategy protocol in patients suffering from AT. However, due to the small number of studies included and the diversity of SMT protocols, the current evidence is weak; its additional effectiveness should be evaluated.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=467698, Identifier CRD42023467698.

The study investigates relative age effects (RAE) in German youth soccer (Youth Bundesliga A: January 2004 to December 2005 and B: January 2006 to December 2007; highest league in German youth soccer) and its persistence in third-division players. Data from the 2022–2023 season (120 teams, 3,174 players) were analyzed using chi-square tests. Significant RAE was found in the A-series (p

Este artigo se propõe a analisar os instrumentos jurídicos disponíveis no âmbito internacional aptos a examinar o mérito de questões climáticas a partir do caso remetido ao Comitê dos Direitos das Crianças por Greta Thunberg et al. Vs. Brasil. Neste norte, o trabalho privilegia o âmbito disciplinar do direito internacional em diálogo com os estudos socioambientais e a ecologia para focalizar a justiça climática como demanda e prerrogativa das novas gerações. A partir do uso do método hipotético-dedutivo questiona-se: os instrumentos jurídicos processuais disponíveis no plano internacional são aptos a resolverem demandas de cunho climático? A hipótese foi elaborada no sentido que os instrumentos processuais disponíveis não se mostram aptos para as demandas climáticas, que possuem características ímpares e urgência inegável, demandando celeridade da tramitação e respostas contundentes, incompatíveis, portanto, com instrumentos processuais à disposição. Verificou-se que os aspectos “tempo”, “alcance” e “obrigatoriedade” são fundamentais para a efetividade do procedimento e decisões dos litígios em matéria climática. Neste sentido, conclui-se que os instrumentos jurídicos disponíveis no plano internacional por muitas vezes não são construídos de forma a possibilitarem, em tempo hábil, respostas contundentes a problemas que necessitam de tratamento urgente.

Introduction: The stable carbon isotope ratio of long-chain alkenones produced by marine haptophyte phytoplankton has often been used to estimate past variations in atmospheric CO2 throughout the Cenozoic. However, previous experimental studies and surveys of alkenones from surface sediment and suspended particulate matter document additional environmental and physiological influences on carbon isotopic fractionation in alkenones.Methods: To clarify the non-CO2 effects on the alkenone carbon isotope fractionations, an important alkenone producer, Gephyrocapsa oceanica, was cultured in laboratory. To separate effects of different environment parameters, G. oceanica was grown in continuous cultures under a matrix of environmental conditions in order to explore the influence of temperature independently of CO2(aq). Through careful manipulation of the media carbon system, we can control the variation of the media CO2(aq) independently of temperature solubility. Carbon isotope fractionations from alkenones, coccolith, and particulate organic carbon were measured from this steady state system.Results and Discussion: We find εp in alkenones and particulate organic carbon inversely correlates with temperature, and temperature affects εp more strongly than CO2(aq). The magnitude of the temperature effect can be explained by higher growth rates at warmer temperatures with a similar growth rate dependence as observed in previous cultures in which growth rate was regulated by other factors. Where the past temperature influence on growth rate could be constrained using the UK’37 alkenone index in the same samples, our finding offers an approach to deconvolve an important physiological factor affecting ancient alkenones εp, and may therefore improve past pCO2 estimates.

Changes in rainfall patterns are a direct consequence of the current climate change. Climate projections indicate an intensification of extreme rainfall events, which will directly affect social, ecological, and economic systems. One of the greatest challenges of climate science is to understand, model, and predict the variability of floods. The uncertainties in projected rainfall are still high, and even higher in Mediterranean areas where the climate is characterized by extreme and sudden rainfall events. The instrumental record is too short to correctly estimate flood return periods. Thus, geological records are required to better understand the long term variability, at millennial to decadal scales, of natural extreme flood events. MODKARST is a MSCA-GF project awarded by the European Union, to develop a quantitative flood database for the Western Mediterranean realm based on speleothems. The action plans to infer past flood events from the last 18 ka based on detrital layers recorded in stalagmites from 5 different caves in the north of Spain, in combination with karst hydraulic models and water-level monitoring. MODKARST will help to better disentangle the relation between flood recurrence and climate changes, and will shed light on how to better predict the variability of floods in the context of present-day global warming.

Abstract Understanding the ability of internal‐ and external‐infesting stored product insects to vector microbes is important for estimating the relative risk that insects pose to postharvest commodities as they move between habitat patches and in the landscape. Thus, the aim of the current study was to evaluate and compare the microbial growth in novel food patches at different dispersal periods by different populations of Sitophilus oryzae (e.g., internal‐infesting) and Lasioderma serricorne (e.g., external‐infesting). Adults of both species collected from laboratory colonies or field‐captured populations were either placed immediately in a novel food patch, or given a dispersal period of 24 or 72 h in a sterilized environment before entering a surrogate food patch. Vectored microbes in new food patches were imaged after 3 or 5 days of foraging, and microbial growth was processed using ImageJ while fungal species were identified through sequencing the ITS4/5 ribosomal subunit. We found that increasing dispersal time resulted in multiple‐fold reductions in microbial growth surrogate food patches by L. serricorne but not S. oryzae. This was likely attributable to higher mobility by S. oryzae than L. serricorne. A total of 20 morphospecies were identified from 13 genera among the 59 sequences, with a total of 23% and 16% classified as Aspergillus and Penicillium spp. Our data suggest that there is a persistent risk of microbial contamination by both species, which has important food safety implications at food facilities.

BackgroundIn sub-Saharan Africa the birth rate among teenage mothers is the highest in the world. In 2021, there would be 6,114,000 births for 15–19-year-olds in this part of the world. In Cameroon, the fertility rate among adolescents aged 15–19 is 24%. However, there is a significant lack of data on the mental health of teenage mothers. Given the biopsychosocial conditions of the perinatal period and adolescence, we hypothesise that the prevalence of mental disorders and the risk of suicide is very high in Cameroon. The aim is therefore to determine the prevalence of perinatal mental disorders and suicide risk among adolescent mothers in urban areas of Cameroon.MethodsFollowing ethical approval of the submitted protocol, we recruited adolescent mothers and data were collected using diagnostic interviews based on the DSM-5, PDM-2 and MINI guidelines. The types of sampling used were typical and incidental. Data were tabulated with Epidata 3.1 and processed with SPSS 25.Results66.4% of adolescent mothers were diagnosed with a mental disorder and 27.4% with suicidal risk. It was found that there was a link between mental disorders and suicidal risk (p

ABSTRACT The Atacama Desert is the oldest and driest desert on Earth, encompassing great temperature variations, high ultraviolet radiation, drought, and high salinity, making it ideal for studying the limits of life and resistance strategies. It is also known for harboring a great biodiversity of adapted life forms. While desertification is increasing as a result of climate change and human activities, it is necessary to optimize soil and water usage, where stress-resistant crops are possible solutions. As many studies have revealed the great impact of the rhizobiome on plant growth efficiency and resistance to abiotic stress, we set up to explore the rhizospheric soils of Suaeda foliosa and Distichlis spicata desert plants. By culturing these soils and using 16S rRNA amplicon sequencing, we address community taxonomy composition dynamics, stability through time, and the ability to promote lettuce plant growth. The rhizospheric soil communities were dominated by the families Pseudomonadaceae, Bacillaceae, and Planococcaceae for S. foliosa and Porphyromonadaceae and Haloferacaceae for D. spicata. Nonetheless, the cultures were completely dominated by the Enterobacteriaceae family (up to 98%). Effectively, lettuce plants supplemented with the cultures showed greater size and biomass accumulation. We identified 12 candidates that could be responsible for these outcomes, of which 5 (Enterococcus, Pseudomonas, Klebsiella, Paenisporosarcina, and Ammoniphilus) were part of the built co-occurrence network. We aim to contribute to the efforts to characterize the microbial communities as key for the plant’s survival in extreme environments and as a possible source of consortia with plant growth promotion traits aimed at agricultural applications.IMPORTANCEThe current scenario of climate change and desertification represents a series of incoming challenges for all living organisms. As the human population grows rapidly, so does the rising demand for food and natural resources; thus, it is necessary to make agriculture more efficient by optimizing soil and water usage, thus ensuring future food supplies. Particularly, the Atacama Desert (northern Chile) is considered the most arid place on Earth as a consequence of geological and climatic characteristics, such as the naturally low precipitation patterns and high temperatures, which makes it an ideal place to carry out research that seeks to aid agriculture in future conditions that are predicted to resemble these scenarios. Our main interest lies in utilizing microorganism consortia from plants thriving under extreme conditions, aiming to promote plant growth, improve crops, and render “unsuitable” soils farmable.

O presente estudo aborda a questão do Transtorno do Espectro Autista (TEA) na Universidade, em especial sobre as implicações da invisibilidade da pessoa com TEA e do capacitismo para a dignidade existencial, no processo ensino-aprendizagem. Realizado por meio de revisão sistemática de dados indiretos disponíveis em publicações científicas, o artigo estrutura o assunto em três unidades. A primeira desenvolve a caracterização da universidade como espaço de convivência. A segunda trata especificamente do Transtorno do Espectro Autista e da invisibilidade social que o acompanha. Por fim, considerando a realidade do processo ensino-aprendizagem, o texto confronta os conceitos de capacitismo e convivência digna. Entre outros aspectos, o estudo indica que, das práticas pedagógicas aos instrumentos de avaliação, o ensino-aprendizagem demanda novas abordagens considerando o cenário das neurodiversidades. As instituições de ensino superior deparam-se com o desafio de prover conteúdos formativos, em uma realidade social orientada por garantias que, entre outros aspectos, reconhecem na individualidade o pressuposto do respeito às diferenças. Nesse contexto, o capacitismo representa um conceito relacionado a barreiras atitudinais que comprometem a dignidade existencial das pessoas com TEA, fato cuja transformação efetiva envolve produção de espaços de diálogo aberto e altero, bem como o reconhecimento do valor positivo das diferenças.