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The growing world population, changing dietary habits, and increasing pressure on agricultural resources are drivers for the development of novel foods (including new protein sources as well as existing protein sources that are produced or used in an alternative way or in a different concentration). These changes, coupled with consumer inclination to adopt new dietary trends, may heighten the intake of unfamiliar proteins, or escalate consumption of specific ones, potentially amplifying the prevalence of known and undiscovered food allergies. Assessing the allergenicity of novel or modified protein-based foods encounters several challenges, including uncertainty surrounding acceptable risks and assessment criteria for determining safety. Moreover, the available methodological tools for gathering supportive data exhibit significant gaps. This paper synthesises these challenges, addressing the varied interpretations of "safe" across jurisdictions and societal attitudes towards allergenic risk. It proposes a comprehensive two-part framework for allergenicity assessment: the first part emphasises systematic consideration of knowledge and data requirements, while the second part proposes the application of a generic assessment approach, integrating a Threshold of Allergological Concern. This combined framework highlights areas that require attention to bridge knowledge and data gaps, and it delineates research priorities for its development and implementation.

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BACKGROUND: The purpose of this randomized trial is to evaluate the early removal of postoperative drains after robot-assisted minimally invasive oesophagectomy (RAMIE). Evidence is lacking about feasibility, associated pain, recovery, and morbidity. METHODS/DESIGN: This is a randomized controlled multicentric trial involving 72 patients undergoing RAMIE. Patients will be allocated into two groups. The "intervention" group consists of 36 patients. In this group, abdominal and chest drains are removed 3 h after the end of surgery in the absence of contraindications. The control group consists of 36 patients with conventional chest drain management. These drains are removed during the further postoperative course according to a standard algorithm. The primary objective is to investigate whether postoperative pain measured by NRS on the second postoperative day can be significantly reduced in the intervention group. Secondary endpoints are the intensity of pain during the first week, analgesic use, number of postoperative chest X-ray and CT scans, interventions, postoperative mobilization (steps per day as measured with an activity tracker), postoperative morbidity and mortality. DISCUSSION: Until now, there have been no trials investigating different intraoperative chest drain strategies in patients undergoing RAMIE for oesophageal cancer with regard to perioperative complications until discharge. Minimally invasive approaches combined with enhanced recovery after surgery (ERAS) protocols lower morbidity but still include the insertion of chest drains. Reduction and early removal have been proposed after pulmonary surgery but not after RAMIE. The study concept is based on our own experience and the promising current results of the RAMIE procedure. Therefore, the presented randomized controlled trial will provide statistical evidence of the effectiveness and feasibility of the "drainless" RAMIE. TRIAL REGISTRATION: ClinicalTrials.gov NCT05553795. Registered on 23 September 2022.

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Over the Ross Sea shelf, annual primary production is limited by dissolved iron (DFe) supply. Here, a major source of DFe to surface waters is thought to be vertical resupply from the benthos, which is assumed most prevalent during winter months when katabatic winds drive sea ice formation and convective overturn in coastal polynyas, although the impact of these processes on water-column DFe distributions has not been previously documented. We collected hydrographic data and water-column samples for trace metals analysis in the Terra Nova Bay and Ross Ice Shelf polynyas during April-May 2017 (late austral fall). In the Terra Nova Bay polynya, we observed intense katabatic wind events, and surface mixed layer depths varied from ∼250 to ∼600 m over lateral distances <10 km; there vertical mixing was just starting to excavate the dense, iron-rich Shelf Waters, and there was also evidence of DFe inputs at shallower depths in the water column. In the Ross Ice Shelf polynya, wind speeds were lower, mixed layers were <300 m deep, and DFe distributions were similar to previous, late-summer observations, with concentrations elevated near the seafloor. Corresponding measurements of dissolved manganese and zinc, and particulate iron, manganese, and aluminum, suggest that deep DFe maxima and some mid-depth DFe maxima primarily reflect sedimentary inputs, rather than remineralization. Our data and model simulations imply that vertical resupply of DFe in the Ross Sea occurs mainly during mid-late winter, and may be particularly sensitive to changes in the timing and extent of sea ice production.

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The development of queen and worker castes in honey bees is induced by differential nutrition, with future queens and workers receiving diets that are qualitatively and quantitatively different. We monitored the gene expression of 14 genes for components of the insulin/insulin-like signalling and TOR pathways in honey bee larvae from 40-88 h after hatching. We compared normally fed queen and normally fed worker larvae and found that three genes showed expression differences in 40-h-old larvae. Genes that show such early differences in expression may be part of the mechanism that transduces nutrition level into a hormone signal. We then compared changes in expression after shifts in diet with those in normally developing queens and workers. Following a shift to the worker diet, the expression of 9/14 genes was upregulated in comparison with queens. Following a shift to the queen diet, expression of only one gene changed. The honey bee responses may function together as a homeostatic mechanism buffering larvae from caste-disrupting variation in nutrition. The different responses would be part of the canalization of both the queen and worker developmental pathways, and as such, a signature of advanced sociality.

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Previous studies found associations between children and sex in child sex offenders (CSOs) using the Implicit Association Test (IAT). We used a modification of this task, the Single Category-Implicit Association Test (SC-IAT) to unravel child-sex associations in CSOs. Using the SC-IAT, we were able to test whether CSOs indeed hold stronger child-sex associations relative to adult-sex associations, compared to adult sex offenders and nonoffenders. Furthermore, we examined whether contact CSOs differed from noncontact CSOs in their child-sex associations. The hypothesis that CSOs would have stronger child-sex associations, relative to their adult-sex associations, than adult sex offenders and nonoffenders was confirmed. No difference between contact CSOs and noncontact CSOs was found. Although the Sex SC-IAT was able to distinguish CSOs from nonoffenders, the sensitivity and specificity of the test was poor (AUC of .65) and needs refinement. The results of this study support the existence of a child-sex association as a distinctive characteristic of CSOs. These findings are discussed in the context of theories on deviant cognitions in CSOs and risk for sexual offending.

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The feasibility of using a retailer fidelity card scheme to estimate food additive intake was investigated in an earlier study. Fidelity card survey information was combined with information provided by the retailer on levels of the food colour Sunset Yellow (E110) in the foods to estimate a daily exposure to the additive in the Swiss population. As with any dietary exposure method the fidelity card scheme is subject to uncertainties and in this paper the impact of uncertainties associated with input variables including the amounts of food purchased, the levels of E110 in food, the proportion of food purchased at the retailer, the rate of fidelity card usage, the proportion of foods consumed outside of the home and bodyweights and with systematic uncertainties was assessed using a qualitative, deterministic and probabilistic approach. An analysis of the sensitivity of the results to each of the probabilistic inputs was also undertaken. The analysis identified the key factors responsible for uncertainty within the model and demonstrated how the application of some simple probabilistic approaches can be used quantitatively to assess uncertainty.

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Alfentanil (ALF) is a validated probe for hepatic, first-pass, and intestinal cytochrome P450 (CYP) 3A activity, using plasma clearances, single-point concentrations, and noninvasive pupil diameter change (miosis). Assessing intravenous (i.v.) and oral drug disposition typically requires separate dosing. This investigation evaluated concurrent administration of oral deuterated and i.v. unlabeled ALF to assess both intestinal and hepatic CYP3A, and compare sequential and simultaneous dosing. ALF disposition was evaluated after strong hepatic and/or intestinal CYP3A induction and inhibition by rifampin, ketoconazole, and grapefruit juice. Using plasma ALF concentrations and area under the curve (AUC), clearance, or single-point concentrations, both simultaneous and sequential dosing provided equivalent results and detected hepatic and intestinal CYP3A induction and inhibition. Miosis better detected CYP3A modulation with sequential vs. simultaneous dosing. These results show that concurrent administration of oral deuterated and i.v. ALF, either sequentially or simultaneously, is an efficient and effective approach to assessing hepatic and intestinal CYP3A activity.

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OBJECTIVE: We investigated whether psychopathology in HIV-positive patients was associated with more negative fundamental assumptions than in healthy controls. In addition, we explored whether psychopathology and negative fundamental assumptions in HIV-positive patients were associated with lower CD4 T-lymphocyte counts. METHOD: Self-rating questionnaires to assess depressive symptoms, posttraumatic stress symptoms, alcohol abuse, general psychopathology and fundamental assumptions, were completed by 123 HIV-positive patients and 84 uninfected clinic attendees at three primary health care clinics in the Western Cape, South Africa. CD4 T-lymphocyte counts were obtained from chart records. RESULTS: HIV-positive patients reported more depressive and posttraumatic symptoms than uninfected individuals. However when controlling for socio-economic status, the number of traumatic events experienced and other potential confounds, no differences remained. Fundamental assumptions (FA) were mainly positive in both HIV-positive patients and controls and no correlations were found between fundamental assumptions, psychiatric symptoms and CD4 levels. However, in infected patients FA and psychopathology were negatively associated with all participants scoring in the positive range of the FA scale. CONCLUSION: The positive scores on the FA scale indicate that positive assumptions are related to less psychopathology. Longitudinal studies investigating the association between the valence of fundamental assumptions and HIV morbidity are needed.

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Objective: We investigated whether psychopathology in HIV-positive patients was associated with more negative fundamental assumptions than in healthy controls. In addition; we explored whether psychopathology and negative fundamental assumptions in HIV-positive patients were associated with lower CD4 T-lymphocyte counts. Method: Self-rating questionnaires to assess depressive symptoms; posttraumatic stress symptoms; alcohol abuse; general psychopathology and fundamental assumptions; were completed by 123 HIV-positive patients and 84 uninfected clinic attendees at three primary health care clinics in the Western Cape; South Africa. CD4 T-lymphocyte counts were obtained from chart records. Results: HIV-positive patients reported more depressive and posttraumatic symptoms than uninfected individuals. However when controlling for socio-economic status; the number of traumatic events experienced and other potential confounds; no differences remained. Fundamental assumptions (FA) were mainly positive in both HIV-positive patients and controls and no correlations were found between fundamental assumptions; psychiatric symptoms and CD4 levels. However; in infected patients FA and psychopathology were negatively associated with all participants scoring in the positive range of the FA scale. Conclusion: The positive scores on the FA scale indicate that positive assumptions are related to less psychopathology. Longitudinal studies investigating the association between the valence of fundamental assumptions and HIV morbidity are needed

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Female honeybees have two castes, queens and workers. Developmental fate is determined by larval diet. Coding sequences made available through the Honey Bee Genome Sequencing Consortium allow for a pathway-based approach to understanding caste determination. We examined the expression of several genes of the insulin signalling pathway, which is central to regulation of growth based on nutrition. We found one insulin-like peptide expressed at very high levels in queen but not worker larvae. Also, the gene for an insulin receptor was expressed at higher levels in queen larvae during the 2nd larval instar. These results demonstrate that the insulin pathway is a compelling candidate for pursing the relationship between diet and downstream signals involved in caste determination and differentiation.

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Stem cells tantalise. They alone have the capacity to divide exponentially, recreate the stem cell compartment as well as create differentiated cells to build tissues. They should be the natural candidates to provide a renewable source of cells for transplantation. Does the reality support the promise of this exciting alternative to conventional therapies for metabolic and degenerative liver disease? Can techniques be developed to provide the large number of cells that could be required? Must there be "space" in the liver to accept the cells? To what extent is the liver immunoprivileged, and is immunosuppression necessary for stem cell therapy? Is it better to use haematopoietic stem cells, fetal stem cells, mesenchymal cells, embryonic stem cells, hepatocytes or all of the above, but for different disease indications? This paper discusses why the exploration of stem cells for the treatment of liver disease is of great potential, and delineates some of the hurdles that need to be overcome before patients see benefits from laboratory-based research into stem cell transplantation and function.

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Storage proteins have been found to play a major role in insect metamorphosis and egg production and are accumulated during the actively feeding larval stage. Yet few studies have focused on how nutrition affects storage protein levels. Three storage proteins were identified in male and female Heliothis virescens pupae, one arylphorin and two putative high-methionine hexamers. Storage proteins were quantified in early pupae and in pharate adults. Storage protein levels peaked in 48-h pupae and were more abundant in females across all stages. Both male and female pharate adults retained a portion of total storage protein levels and females retained greater levels overall. In females, post-eclosion protein reserves will likely be used toward egg manufacturing, while the role of protein reserves in males remains speculative. In our previous study of H. virescens larvae, we found that protein-derived growth in females progressively increased as dietary protein levels increased. Our present data show that levels of storage protein also increased progressively along with dietary protein levels. This suggests that females allocated protein, in excess of adult tissue formation needs, toward storage protein. Our study is the first to demonstrate how responsive storage protein levels can be in face of varying levels of dietary protein.

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Fourth-instar larvae of the autogenous mosquito, Aedes atropalpus, synthesize three hexamerins or hexameric storage proteins which are distinguished by different methionine and aromatic amino-acid contents. One protein, Hexamerin-1.2 (AatHex-1.2) is only found in female larvae and pupae. In order to investigate the molecular basis for this sex-specific accumulation, we have cloned and sequenced the cDNA encoding AatHex-1.2 and isolated and sequenced over 1 kb of the 5' flanking region of the AatHex-1.2 gene. The AatHex-1.2 transcript encodes a 81.6-kDa hexamerin subunit which contains 19.8% phenylalanine, tyrosine and tryptophan and 8.6% methionine residues. The single-copy AatHex-1.2 gene consists of three exons and two small introns located at its 5' end. A 2.3-kb AatHex-1.2 mRNA accumulates only in female larvae and pupae and is expressed at very low levels in adult female mosquitoes. The temporal expression profile of this transcript is typical of other mosquito hexamerin genes, with rapid disappearance of the mRNA shortly after pupation. Hence this is the first observation of exclusively female-specific gene activity during preadult development of an insect. In the 5' flanking region of the AatHex-1.2 gene, we identified putative binding sites for transcription factors, such as GATA, C/EBP and Doublesex, typically involved in fat body- and female-specific gene activity in Diptera. These findings suggest that mechanisms for sex-specific transcription in the fat body may be well conserved between flies and mosquitoes.

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The mechanism of Fas antigen-induced hepatocyte apoptosis was investigated. Using a monoclonal antibody directed against the Fas antigen, apoptosis was induced in freshly isolated murine hepatocytes within 90 minutes of antibody addition as assessed by plasma membrane bleb formation, chromatin condensation, and DNA fragmentation. Pretreatment of the cells with the caspase inhibitors, N-acetyl-Asp-Glu-Val-Asp aldehyde (Ac-DEVD-CHO), benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (Z-VAD-FMK), or Z-Asp-2,6-dichlorobenzoyloxymethylketone inhibited anti-Fas-mediated apoptosis. Likewise, the serine protease inhibitors, N-tosyl-L-phenyl chloromethyl ketone (TPCK) and 3,4-dichloroisocoumarin (DCI), prevented apoptosis, whereas N-tosyl-L-lysine chloromethyl ketone (TLCK), Ac-Leu-Leu-L-norleucinal, Ac-Leu-Leu-L-methional, and trans-epoxysuccinyl-L-leucylamido-(4-guanidino)butane were without effect. Examination of CED-3/caspase-3-related caspases revealed that pro-caspases-3 (CPP32) and -7 (Mch-3alpha) were rapidly processed after Fas antigen stimulation. Caspase-7 was further cleaved to form the catalytically active subunits. In contrast, the p17 subunit of caspase-3 was not detected, indicating slow formation or rapid degradation. The activation of CED-3-related caspases was further confirmed by an increase in the rate of Z-DEVD-7-amino-4-trifluoromethylcoumarin (Z-DEVD-AFC) hydrolysis that was sensitive to Ac-DEVD-CHO and was inhibited by pretreatment of the cells with TPCK but not by DCI. In contrast, no increase in the rates of hydrolysis of Z-YVAD-AFC, a substrate for caspase-1, was detected. Investigation of the in situ proteolytic cleavage of the CED-3 related caspases substrate, poly(ADP-ribose) polymerase, revealed that this protein was not degraded in hepatocytes undergoing Fas-mediated apoptosis. Taken together, our results show that processing of caspases, in particular, caspases-7 and -3, occurs during Fas-induced apoptosis of mouse hepatocytes and suggest a role of these proteases as well as serine protease(s) in the apoptotic response.

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We have compared twelve sulphone analogues of dapsone in terms of inhibition both of zymosan-mediated human neutrophil respiratory burst and inhibition of interleukin-1-stimulated neutrophil adhesion to transformed human umbilical vein endothelial cells. Overall, there was a good correlation between the respective rank orders of compound potency in the two test systems. The most effective compounds in terms of respiratory burst and adherence inhibition were the 2-nitro-4-amino-, 2-hydroxy-4-aminopropyl-, and 2-methoxy-4-aminoethyl- derivatives. In general, potency was inversely associated with lipophilicity; compounds with bulky side-chains, e.g. the 2-methyl-4-aminopentyl, 2-methyl-4-aminohexyl and the 2-hydroxymethyl-4-aminoethyl derivatives, were less potent. A 2-hydroxy-4-amino- derivative was the exception, however, with low lipophilicity and relatively low potency. All of the compounds tested showed comparable or greater inhibition in both the neutrophil-mediated assays compared with dapsone. Some of the compounds might, because of their good tissue penetration and lower toxicity than dapsone, have the potential to undergo further development.

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Four novel combined dapsone and trimethoprim analogues, K-120, K-150, K-138 and DRS-506, have been compared with dapsone in their methaemoglobin forming abilities as well as their anti-inflammatory properties using rat and human tissues in vitro. All four compounds formed consistently less methaemoglobin compared with dapsone in both the rat and human microsomes. Using human microsomes from five livers, K-120 was significantly less toxic than the other analogues in three of the five livers (P < 0.01). DRS-506 and K-138 both inhibited the human neutrophil respiratory burst to a significantly greater degree compared with dapsone at 0.5 mM (P < 0.01), while K-120 and K-150 showed no significant effect at 0.5 mM. At 1 mM, DRS-506, K-120 and K-138 were more potent than dapsone (P < 0.01), although K-150 appeared to increase the neutrophil activation. All four analogues caused a significant reduction in neutrophil adhesion to human umbilical vein cells at 0.1 mM. In view of its efficacy and low toxicity, K-120 shows considerable promise for future clinical evaluation.

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