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Introduction The empty pelvis syndrome is a significant source of morbidity following pelvic exenteration surgery. It remains poorly defined with research in this field being heterogeneous and of low quality. Furthermore, there has been minimal engagement with patient representatives following pelvic exenteration with respect to the empty pelvic syndrome. ‘PelvEx—Beating the empty pelvis syndrome’ aims to engage both patient representatives and healthcare professionals to achieve an international consensus on a core outcome set, pathophysiology and mitigation of the empty pelvis syndrome.Methods and analysis A modified-Delphi approach will be followed with a three-stage study design. First, statements will be longlisted using a recent systematic review, healthcare professional event, patient and public engagement, and Delphi piloting. Second, statements will be shortlisted using up to three rounds of online modified Delphi. Third, statements will be confirmed and instruments for measurable statements selected using a virtual patient-representative consensus meeting, and finally a face-to-face healthcare professional consensus meeting.Ethics and dissemination The University of Southampton Faculty of Medicine ethics committee has approved this protocol, which is registered as a study with the Core Outcome Measures in Effectiveness Trials Initiative. Publication of this study will increase the potential for comparative research to further understanding and prevent the empty pelvis syndrome.Trial registration number NCT05683795.

The evolution of language has fascinated anthropologists, psychologists and biologists for centuries, seeking to infer language origins from the communication of primates, our closest living relatives. Capacity for intentional signalling is a key feature of transition to language in our hominin ancestors, facilitating complex social dynamics in complex social groups. However whether vocal, gestural and bimodal signals are differentiated according to intentional use and hence complex sociality has not been studied, making unclear the modality of language evolution. We addressed this question in wild chimpanzees. We found that larger social network size was associated with a larger network of gestural but not vocal or bimodal signals. Response waiting was more common in association with gestures than vocalizations, but elaborations were more common in vocal than gestural or bimodal signals. Overall, chimpanzees were more likely to manage weak social bonds through vocalizations, whereas strong social bonds were managed through gestures and bimodal signals. However, when social bonds were weak, gestures accompanied by response waiting were more likely to elicit approaches than vocalizations accompanied by elaboration, which elicited avoidance. This suggests that gestures were the primary modality of language evolution and that the use of more sophisticated gestural signalling led to evolution of complex social groups of hominin ancestors. This article is part of the theme issue 'Cognition, communication and social bonds in primates'.

Renin, encoded by REN, is an essential enzyme in the renin-angiotensin aldosterone system (RAAS) which is responsible for the maintenance of blood pressure homeostasis. Transcriptional regulation of REN has been linked to enhancer-promoter crosstalk, cAMP response element-binding protein (CREB), the active metabolite of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), and a less well-characterized intronic silencer element. We hypothesized that in addition to these, differential DNA methylation is linked to REN expression and influenced by 1,25(OH) 2 D 3 . REN expressing cells (HEK293) were used to elucidate the effect of 1,25(OH) 2 D 3 on REN methylation and expression as quantified by methylation-sensitive qPCR and RT-qPCR, respectively. In vitro 1,25(OH) 2 D 3 supplementation (10 nM) induced significant hypomethylation of the REN silencer (P < 0.050), which was linked to a significant reduction in REN expression (P < 0.010) but had no effect on enhancer methylation. In addition, 1,25(OH) 2 D 3 increased VDR (P < 0.05), as well as TET1 (P < 0.05) expression, suggesting an association between 1,25(OH) 2 D 3 and DNA methylation. Thus, it appears that the silencer element, which is controlled by DNA methylation and influenced by 1,25(OH) 2 D 3 , plays an essential role in regulating REN expression., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Feed supplements are concentrated cell culture media that contain a variety of nutrients, which can be added during a bioprocess. During fed-batch cultivation, feed media are typically added to a growing cell culture to maximize cell and product concentrations. In this study, only a single shot of feed medium was added on day 0 to a basal cell culture medium and compared to non-supplemented basal medium (feed-spiked at day 0 versus control experiments) by cultivation of a recombinant mAb expressing CHO cell line in batch mode under controlled conditions in a bioreactor. Since the feed-spike at day 0 was based on existing medium components without introducing additional supplements, a desirable process with decreased complexity was generated. Unlike cells in basal medium, feed-spiked cultures reached almost 2× higher peak cell concentrations (10 × 10 6 c/mL vs. 18 × 10 6 c/mL) and 3× higher antibody concentrations (0.8 g/L vs. 2.4 g/L). Batch process time and the integral over the viable cell count were similar for both process types. Constantly high cell-specific production rates in feed-spiked cultures (70 pg/cell/day) compared to continuously declining rates in basal medium (from 70 to 10 pg/cell/day) were responsible for an overall 70% higher cell-specific production rate and the higher product concentrations. To associate gene expression patterns to different process proceedings, transcriptome analysis was performed using microarrays. Several transcripts that are involved with glutamine de novo synthesis and citric acid cycle were significantly upregulated on several days in feed-spiked cultures. The top identified gene ontology (GO) terms related well to cell cycle and primary metabolism, cellular division as well as nucleobase formation or regulation, which indicated a more active proliferative state for feed-spiked cultures. KEGG biochemical pathway analysis and Gene set enrichment analysis (GSEA) further confirmed these findings from a complementary perspective. Moreover, several interesting gene targets, which have not yet been associated with recombinant protein expression, were identified that related to a higher proliferative state, growth, protein synthesis, cell-size control, metabolism, cell survival as well as genes that are associated with the control of the mammalian target of rapamycin (mTOR) in feed-spiked cultures. Analysis of critical product quality attributes (i.e. glycosylation, charge variants and size distribution) showed that feed-spiking did not change antibody quality., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

The current study investigated the extent to which the concurrent presentation of pleasant and unpleasant odors could modulate the perceptual saliency of happy facial expressions in an emotional visual search task. Whilst a search advantage for happy faces was found in the no odor and unpleasant odor conditions, it was abolished under the pleasant odor condition. Furthermore, phasic properties of visual search performance revealed the malleable nature of this happiness advantage. Specifically, attention towards happy faces was optimized at the start of the visual search task for participants presented with pleasant odors, but diminished towards the end. This pattern was reversed for participants in the unpleasant odor condition. These patterns occur through the emotion-inducing capacities of odors and highlight the circumstances in which top-down factors can override perceptually salient facial features in emotional visual search.

In this study, eight commercially available, chemically defined Chinese hamster ovary (CHO) cell culture media from different vendors were evaluated in batch culture using an IgG-producing CHO DG44 cell line as a model. Medium adaptation revealed that the occurrence of even small aggregates might be a good indicator of cell growth performance in subsequent high cell density cultures. Batch experiments confirmed that the culture medium has a significant impact on bioprocess performance, but high amino acid concentrations alone were not sufficient to ensure superior cell growth and high antibody production. However, some key amino acids that were limiting in most media could be identified. Unbalanced glucose and amino acids led to high cell-specific lactate and ammonium production rates. In some media, persistently high glucose concentrations probably induced the suppression of respiration and oxidative phosphorylation, known as Crabtree effect, which resulted in high cell-specific glycolysis rates along with a continuous and high lactate production. In additional experiments, two of the eight basal media were supplemented with feeds from two different manufacturers in six combinations, in order to understand the combined impact of media and feeds on cell metabolism in a CHO fed-batch process. Cell growth, nutrient consumption and metabolite production rates, antibody production, and IgG quality were evaluated in detail. Concentrated feed supplements boosted cell concentrations almost threefold and antibody titers up to sevenfold. Depending on the fed-batch strategy, fourfold higher peak cell concentrations and eightfold increased IgG titers (up to 5.8 g/L) were achieved. The glycolytic flux was remarkably similar among the fed-batches; however, substantially different specific lactate production rates were observed in the different media and feed combinations. Further analysis revealed that in addition to the feed additives, the basal medium can make a considerable contribution to the ammonium metabolism of the cells. The glycosylation of the recombinant antibody was influenced by the selection of basal medium and feeds. Differences of up to 50 % in the monogalacto-fucosylated (G1F) and high mannose fraction of the IgG were observed.

There are considerable gaps in our knowledge on cell biological effects induced by the heavy metals mercury (Hg) and lead (Pb). In the present study we aimed to explore the effects of these toxicants on proliferation and cell size of primary human amniotic fluid stem (AFS) cells. Monoclonal human AFS cells were incubated with three dosages of Hg and Pb (single and combined treatment; ranging from physiological to cytotoxic concentrations) and the intracellular Hg and Pb concentrations were analyzed, respectively. At different days of incubation the effects of Hg and Pb on proliferation, cell size, apoptosis, and expression of cyclins and the cyclin-dependent kinase inhibitor p27 were investigated. Whereas we found Hg to trigger pronounced effects on proliferation of human AFS cells already at low concentrations, anti-proliferative effects of Pb could only be detected at high concentrations. Exposure to high dose of Hg induced pronounced downregulation of cyclin A confirming the anti-proliferative effects observed for Hg. Co-exposure to Hg and Pb did not cause additive effects on proliferation and size of AFS cells, and on cyclin A expression. Our here presented data provide evidence that the different toxicological effects of Pb and Hg on primary human stem cells are due to different intracellular accumulation levels of these two toxicants. These findings allow new insights into the functional consequences of Pb and Hg for mammalian stem cells and into the cell biological behavior of AFS cells in response to toxicants.