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Luigino Dal Maso,1 Armando Santoro,2,3 Elisabetta Iannelli,4,5 Paolo De Paoli,6 Carla Minoia,7 Monica Pinto,8 Alexia Francesca Bertuzzi,3 Diego Serraino,1 Roberta De Angelis,9 Annalisa Trama,10 Riccardo Haupt,11 Gabriella Pravettoni,12,13 Maria Perrone,14 Francesco De Lorenzo,4,5 Paolo Tralongo15 On behalf of the Alliance Against Cancer (ACC) Survivorship Care and Nutritional Support Working Group1Cancer Epidemiology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy; 2Department of Biomedical Sciences, Humanitas University, Milan, Italy; 3IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Milan, Italy; 4Italian Federation of Cancer Patients Organisations (FAVO), Rome, Italy; 5Italian Association of Cancer Patients (Aimac), Rome, Italy; 6Alleanza Contro il Cancro, Rome, Italy; 7SC Haematology, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy; 8Rehabilitation Medicine Unit, Strategic Health Services Department, Istituto Nazionale Tumori-IRCCS Fondazione G. Pascale, Naples, Italy; 9Department of Oncology and Molecular Medicine, Italian National Institute of Health (ISS), Rome, Italy; 10Evaluative Epidemiology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy; 11DOPO Clinic, Department of Pediatric Haematology/Oncology, IRCCS Istituto Giannina Gaslini, Genoa, Italy; 12Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; 13Applied Research Division for Cognitive and Psychological Science, IEO European Institute of Oncology IRCCS, Milan, Italy; 14Psychology Unit, IRCCS Regina Elena Cancer Institute, Rome, Italy; 15Medical Oncology Unit, Umberto I Hospital, Department of Oncology, RAO, Siracusa, ItalyCorrespondence: Luigino Dal Maso, Epidemiologia Oncologica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini 2, Aviano (PN), 33081, Italy, Tel +39 0434 659354, Email epidemiology@cro.it Paolo Tralongo, Medical Oncology Unit, Umberto I Hospital, Department of Oncology, RAO, Via Giuseppe Testaferrata 1, Siracusa, 96100, Italy, Tel +39 0931 724 464, Email paolo.tralongo@asp.sr.itAbstract: A multidisciplinary panel of experts and cancer patients developed a position paper to highlight recent evidence on “cancer cure” (ie, the possibility of achieving the same life expectancy as the general population) and discuss the consequences of this concept on follow-up and rehabilitation strategies. The aim is to inform clinicians, patients, and health-care policy makers about strategies of survivorship care for cured cancer patients and consequences impacting patient lives, spurring public health authorities and research organizations to implement resources to the purpose. Two identifiable, measurable, and reproducible indicators of cancer cure are presented. Cure fraction (CF) is > 60% for breast and prostate cancer patients, > 50% for colorectal cancer patients, and > 70% for patients with melanoma, Hodgkin lymphoma, and cancers of corpus uteri, testis (> 90%), and thyroid. CF was > 65% for patients diagnosed at ages 15– 44 years and 30% for those aged 65– 74 years. Time-to-cure was consistently < 1 year for thyroid and testicular cancer patients and < 10 years for patients with colorectal and cervical cancers, melanoma, and Hodgkin lymphoma. The working group agrees that the evidence allows risk stratification of cancer patients and implementation of personalized care models for timely diagnosis, as well as treatment of possible cancer relapses or related long-term complications, and preventive measures aimed at maintaining health status of cured patients. These aspects should be integrated to produce an appropriate follow-up program and survivorship care plan(s), avoiding stigma and supporting return to work, to a reproductive life, and full rehabilitation. The “right to be forgotten” law, adopted to date only in a few European countries, may contribute to these efforts for cured patients.Keywords: cancer cure, survivorship, time-to-cure, personalized care models, right to be forgotten

Roberto Burro,1 Ugo Savardi,1 Maria Antonietta Annunziata,2 Paolo De Paoli,2 Ivana Bianchi3 1Department of Human Sciences, University of Verona, 37129 Verona, Italy; 2National Cancer Institute IRCCS “Centro di Riferimento Oncologico” (CRO), 33080 Aviano (PN), Italy; 3Department of Humanities (section Philosophy and Human Sciences), University of Macerata, 62100 Macerata, Italy Background: Healthcare staff should be aware of the importance that patients may attach to the words that are used to convey information. This is relevant in terms of the patients’ understanding. Modeling how people understand the information conveyed in a medical context may help health practitioners to better appreciate the patients’ approach. Purpose: 1) Analyze the participants’ self-reported perception of the type of information provided in an oncological scenario in terms of three dimensions: impairment to their health, risks associated with the disease itself and commitment required to undergo the treatment; and 2) show the benefits of using Rasch scaling for the analysis of the data. Starting from a survey, Rasch scaling produces a unidimensional logit-interval scale relating to the extent to which each item conveys a latent dimension. These were related to structure, in particular concerning communication by means of opposite vs. unipolar language. Subjects and methods: The participants rated 82 items of information in a questionnaire regarding their perception of impairment to their health (H) and the risks (R) and commitment relating to the treatment prescribed (T). Results: The scaling produced an item bank for healthcare staff to consult in order to estimate the importance the recipient would be likely to attach to the vocabulary used and the likely impact of the information in terms of the patient’s condition. Furthermore, the use of opposites was generally associated with a clearer impression of whether the information given was generally only very negative or slightly negative, whereas ‘neutral’ information was often perceived as being very negative. Actual findings: Is possible to estimate people’s understanding more precisely (in terms of H, R and T) which can help healthcare practitioners to modulate the way they convey information. Limitations: The participants in the study were healthy volunteers and the context was simulated. Keywords: Rasch model, simulated oncological scenario, perceived severity of impairment to health, perception of risk, perceived commitment to the treatment, opposites

Roberto Burro,1 Ugo Savardi,1 Maria Antonietta Annunziata,2 Paolo De Paoli,2 Ivana Bianchi3 1Department of Human Sciences, University of Verona, Verona, Italy; 2National Cancer Institute IRCCS ‘Centro di Riferimento Oncologico’ (CRO), Aviano, Italy; 3Department of Humanities (Section Philosophy and Human Sciences), University of Macerata, Macerata, Italy Background: An extensive body of literature has demonstrated that many patients who have been asked to participate in clinical trials do not fully understand the informed consent forms. A parallel independent study has demonstrated that opposites have a special status in human cognitive organization: they are common to all-natural languages and are intuitively and naturally understood and learnt.Purpose: The study investigates whether, and how, the use of opposites impacts on doctor–patient communication: does using the terms “small–large” to describe a nodule (ie, bipolar communication) rather than speaking in terms of centimeters (ie, unipolar communication) affect a patient’s understanding of the situation? And is it better to speak of “common–rare” side effects (ie, bipolar communication) instead of the number of people who have suffered from particular side effects (ie, unipolar communication)?Methods: Two questionnaires were created and used, one presenting the information in terms of opposites (ie, bipolar communication) and another using unipolar communication.Results: The participants’ perception of their situation (in terms of feeling healthy–ill, being at high–low risk, and their treatment requiring high–low commitment) varied in the two conditions. Moreover, self-reported levels of understanding and satisfaction with how the information was communicated were higher when opposites were used.Limitations: Since this is the first study that addresses the merits of using bipolar structures versus unipolar structures in doctor–patient communication, further work is needed to consolidate and expand on the results, involving not only simulated but also real diagnostic contexts.Conclusion: The encouraging results imply that further testing of the use of opposites in informed consent forms and in doctor–patient communication is strongly advisable. Keywords: opposites, bipolar, unipolar, informed consent, doctor–patient communication, understanding, satisfaction

Enriching geospatial data, particularly through address geocoding, is fundamental to many geospatial analytical solutions, facilitating resource allocation, accessibility assessment, and urban development planning. This paper explores the address geocoding approaches from traditional GIS-based methods to advanced data-driven solutions, emphasising their accuracy, efficiency, and complementarity. Geospatial data enrichment challenges are explored using the SemTUI framework and QGIS platform. SemTUI employs a data-driven approach that facilitates interactive semantic enrichment and address reconciliation. QGIS is utilised for address geocoding, using the MMQGIS plugin with two geocoding web services provided by OSM and Google. The comparison between SemTUI and QGIS workflows highlights their complementary strengths. SemTUI offers intuitive interfaces and an automated solution, while QGIS provides advanced geospatial visualisation and analysis capabilities. Practical applications in supply-demand analysis of social amenities and walkability index calculation demonstrate the significance of geocoding in urban planning. Further research efforts are focused on enhancing the integration between SemTUI and QGIS to improve the precision and performance of address geocoding and further spatial data analysis.

Abstract The growth factor Neuregulin-1 (NRG1) has pleiotropic roles in proliferation and differentiation of the stem cell niche in different tissues. It has been implicated in gut, brain and muscle development and repair. Six isoform classes of NRG1 and over 28 protein isoforms have been previously described. Here we report a new class of NRG1, designated NRG1-VII to denote that these NRG1 isoforms arise from a myeloid-specific transcriptional start site (TSS) previously uncharacterized. Long-read sequencing was used to identify eight high-confidence NRG1-VII transcripts. These transcripts presented major structural differences from one another, through the use of cassette exons and alternative stop codons. Expression of NRG1-VII was confirmed in primary human monocytes and tissue resident macrophages and induced pluripotent stem cell-derived macrophages (iPSC-derived macrophages). Isoform switching via cassette exon usage and alternate polyadenylation was apparent during monocyte maturation and macrophage differentiation. NRG1-VII is the major class expressed by the myeloid lineage, including tissue-resident macrophages. Analysis of public gene expression data indicates that monocytes and macrophages are a primary source of NRG1. The size and structure of class VII isoforms suggests that they may be more diffusible through tissues than other NRG1 classes. However, the specific roles of class VII variants in tissue homeostasis and repair have not yet been determined.

Alicerçados na Teoria Histórico-Cultural, objetivamos analisar as contribuições de intervenções em aulas de ciências no ensino de estudantes autistas em processos inclusivos. Em nossa investigação, no período de 1943 até 2022, identificamos 19 trabalhos (oito nacionais e 11 internacionais) que desenvolveram ações pedagógicas na Educação Básica em aulas de ciências com estudantes autistas em escolas comuns. A partir das contribuições dos artigos e referenciais teóricos, defendemos que a organização de atividades de estudos, em aulas de ciências, articuladas em projetos de inclusão escolar que integram o(a) estudante autista em múltiplas experiências sociais, pode se beneficiar de conhecimentos científicos como uma ferramenta importante para promover a ampliação da comunicação, com ou sem fala, e para fomentar o desenvolvimento da consciência do mundo e de si, além de aprimorar a compreensão do que significa ser autista e assumir protagonismos. Convidamos as pesquisas da área a aprofundarem e ampliarem as contribuições.

RESUMO: A partir de pesquisas nacionais e internacionais do período de 1943 a 2022, este manuscrito teve por objetivo discutir perspectivas de inclusão de pessoas autistas em aulas de ciências. Trata-se de uma investigação bibliográfica que resultou em 19 artigos (oito nacionais e 11 internacionais) submetidos a uma análise sob orientação teórico-metodológica da Teoria Histórico-Cultural e do Materialismo Histórico-Dialético. Percebemos que, majoritariamente, as pesquisas de intervenção pedagógica ocorreram em salas de Atendimento Educacional Especializado sem a relação com os pares da sala de aula comum. Muitas delas como ações pedagógicas estanques sem uma proposta articulada e continuada em projetos escolares. Identificamos poucas justificativas acerca do ensino de conhecimentos de ciências em contribuições para a superação de interrupções explicitadas - a dificuldade de pessoas com autismo em relação a comunicação e vínculos sociais. Apontamos a necessidade de ampliação de investigações na área de ensino de ciências com estudantes no espectro autista.

In this manuscript I build upon an initial body of research developing procedures for leveraging large language models (LLMs) in qualitative data analysis, by carrying out thematic analysis (TA) with LLMs. TA is used to identify patterns by means of initial labelling of qualitative data followed by the organisation of the labels/codes by themes. First, I propose a new set of LLM prompts for initial coding and generation of themes. These new prompts are different from the typical prompts deployed for such analysis in that they are entirely open-ended and rely on TA language. Second, I investigate the process of removing duplicate initial codes through a comparative analysis of the codes of each interview against a cumulative codebook. Third, I explore the construction of thematic maps from the themes elicited by the LLM. Fourth, I evaluate the themes produced by the LLM against the themes produced manually by humans. For conducting this research, I employed a commercial LLM via an application program interface (API). Two datasets of open access semi-structured interviews were analysed to demonstrate the methodological possibilities of this approach. I conclude with practical reflections on performing TA with LLM, enhancing our knowledge of the field.

Abstract Background A major obstacle faced by families with rare diseases is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years and causal variants are identified in under 50%, even when capturing variants genome-wide. To aid in the interpretation and prioritization of the vast number of variants detected, computational methods are proliferating. Knowing which tools are most effective remains unclear. To evaluate the performance of computational methods, and to encourage innovation in method development, we designed a Critical Assessment of Genome Interpretation (CAGI) community challenge to place variant prioritization models head-to-head in a real-life clinical diagnostic setting. Methods We utilized genome sequencing (GS) data from families sequenced in the Rare Genomes Project (RGP), a direct-to-participant research study on the utility of GS for rare disease diagnosis and gene discovery. Challenge predictors were provided with a dataset of variant calls and phenotype terms from 175 RGP individuals (65 families), including 35 solved training set families with causal variants specified, and 30 unlabeled test set families (14 solved, 16 unsolved). We tasked teams to identify causal variants in as many families as possible. Predictors submitted variant predictions with estimated probability of causal relationship (EPCR) values. Model performance was determined by two metrics, a weighted score based on the rank position of causal variants, and the maximum F-measure, based on precision and recall of causal variants across all EPCR values. Results Sixteen teams submitted predictions from 52 models, some with manual review incorporated. Top performers recalled causal variants in up to 13 of 14 solved families within the top 5 ranked variants. Newly discovered diagnostic variants were returned to two previously unsolved families following confirmatory RNA sequencing, and two novel disease gene candidates were entered into Matchmaker Exchange. In one example, RNA sequencing demonstrated aberrant splicing due to a deep intronic indel in ASNS, identified in trans with a frameshift variant in an unsolved proband with phenotypes consistent with asparagine synthetase deficiency. Conclusions Model methodology and performance was highly variable. Models weighing call quality, allele frequency, predicted deleteriousness, segregation, and phenotype were effective in identifying causal variants, and models open to phenotype expansion and non-coding variants were able to capture more difficult diagnoses and discover new diagnoses. Overall, computational models can significantly aid variant prioritization. For use in diagnostics, detailed review and conservative assessment of prioritized variants against established criteria is needed.

RESUMO Este ensaio teórico teve por objetivo identificar contribuições da organização do conhecimento científico na sistematização do ensino em ciências, para a constituição humana típica e atípica. Isso foi realizado a partir de ponderações entre textos da área de Ensino de Ciências e pressupostos da Teoria Histórico-Cultural. Assim, apresentamos reflexões acerca de discussões que polarizam a educação de pessoas com deficiência ou autismo no direcionamento curricular, em relação às habilidades funcionais e acadêmicas. A partir da análise de limitações, possibilidades e estratégias educacionais para aulas de ciências, concluímos que as habilidades funcionais, que envolvem conhecimentos cotidianos, não podem configurar critério de exclusão curricular de habilidades acadêmicas, do conhecimento científico, para a educação de pessoas com desenvolvimento atípico. Compreendemos que uma educação científica escolar com vias ao desenvolvimento integral é indissociável das habilidades da vida diária.

GoTriple is a novel discovery platform for Social Sciences and Humanities (SSH) in Europe. Discovery is a phase of research where scholars seek to locate resources for their work, such as publications or previous projects. The paper details the work done for involving the SSH community in the codesign of GoTriple, focusing on the research discovery activities. It is an investigation of the user needs and barriers toward digital discovery for the SSH community, conducted through codesign. This work encompassed interviews, a questionnaire, codesign workshops and evaluation activities. The paper reports on some outcomes for the codesign and how user needs were identified and served by novel designs supporting discovery for SSH. This process of design is both concerned with creating digital tools for discovery and with the creation of a community of users that could make the platform thrive. The main contribution of the work is therefore the identification of the user needs for digital discovery in SSH and a series of insights on the design with the user community. The paper comprises a report on how codesign principles do support such work.

Novel bis-1,2,4-triazine compounds with potent in vitro activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore and are proposed to act by a novel but as-yet-unknown mechanism of action. This study investigated the activity of the bis-1,2,4-triazine MIPS-0004373 across the mammalian life cycle stages of the parasite and profiled the kinetics of activity against blood and transmission stage parasites in vitro and in vivo. MIPS-0004373 demonstrated rapid and potent activity against P. falciparum, with excellent in vitro activity against all asexual blood stages. Prolonged in vitro drug exposure failed to generate stable resistance de novo, suggesting a low propensity for the emergence of resistance. Excellent activity was observed against sexually committed ring stage parasites, but activity against mature gametocytes was limited to inhibiting male gametogenesis. Assessment of liver stage activity demonstrated good activity in an in vitro P. berghei model but no activity against Plasmodium cynomolgi hypnozoites or liver schizonts. The bis-1,2,4-triazine MIPS-0004373 efficiently cleared an established P. berghei infection in vivo, with efficacy similar to that of artesunate and chloroquine and a recrudescence profile comparable to that of chloroquine. This study demonstrates the suitability of bis-1,2,4-triazines for further development toward a novel treatment for acute malaria.

Abstract After the introduction of highly active antiretroviral therapies (HAART), an increased incidence of insulin resistance, diabetes mellitus (DM), and cardiovascular diseases has been described. The impact of such conditions on mortality in the post-HAART era has been also assessed in various modes in the literature. In this paper, we report on the death risks for DM, myocardial infarction, and chronic ischemic heart diseases that were investigated among 9662 Italian AIDS cases diagnosed between 1999 and 2005. Death certificates reporting DM, myocardial infarction, and chronic ischemic heart diseases were reviewed to identify the underlying cause of death, and to compare the observed numbers of deaths with the expected ones from the sex- and age-matched, general population of Italy. Person-years at risk of death were computed from date of AIDS diagnosis up to date of death or to December 31, 2006. Standardized mortality ratios (SMR) and their 95% confidence intervals (CI) were computed. DM and cardiovascular diseases were the cause of death for 43 out of 3101 deceased AIDS cases (i.e., 1.4% of all deaths). In comparison with the general population, the risks of death were 6.4-fold higher for DM (95% CI:3.5-10.8), 2.3-fold higher for myocardial infarction (95% CI:1.4-3.7) and 3.0 for chronic ischemic heart diseases (95% CI: 1.5-5.2).

This review highlights -omics research in Solanaceae family, with a particular focus on resilient traits. Extensive research has enriched our understanding of Solanaceae genomics and genetics, with historical varietal development mainly focusing on disease resistance and cultivar improvement but shifting the emphasis towards unveiling resilience mechanisms in genebank-preserved germplasm is nowadays crucial. Collecting such information, might help researchers and breeders developing new experimental design, providing an overview of the state of the art of the most advanced approaches for the identification of the genetic elements laying behind resilience. Building this starting point, we aim at providing a useful tool for tackling the global agricultural resilience goals in these crops.

The multifaceted nature of climate change is increasing the urgency to select resilient grapevine varieties, or generate new, fitter cultivars, to withstand a multitude of new challenging conditions. The attainment of this goal is hindered by the limiting pace of traditional breeding approaches, which require decades to result in new selections. On the other hand, marker-assisted breeding has proved useful when it comes to traits governed by one or few genes with great effects on the phenotype, but its efficacy is still restricted for complex traits controlled by many loci. On these premises, innovative strategies are emerging which could help guide selection, taking advantage of the genetic diversity within the Vitis genus in its entirety. Multiple germplasm collections are also available as a source of genetic material for the introgression of alleles of interest via adapted and pioneering transformation protocols, which present themselves as promising tools for future applications on a notably recalcitrant species such as grapevine. Genome editing intersects both these strategies, not only by being an alternative to obtain focused changes in a relatively rapid way, but also by supporting a fine-tuning of new genotypes developed with other methods. A review on the state of the art concerning the available genetic resources and the possibilities of use of innovative techniques in aid of selection is presented here to support the production of climate-smart grapevine genotypes.

Abstract Background The aging of the Italian population will unavoidably lead to a growing number of persons diagnosed and living with cancer. A comprehensive description of the burden of cancer mortality among Italian elderly (65-84 years of age) in the last four decades has not been carried out yet. Cancer mortality rates were used to describe time trends between 1970-2008. Methods Mortality counts, provided by the Italian National Institute of Statistics, were grouped according to data availability: in quinquennia from 1970-74 through 1995-99, and in 2000-03 and 2006-08 groups. Age-standardized rates (world population) were computed by calendar periods while annual percent changes (APCs) were computed for elderly and middle aged (35-64 years) people for the period 1995-2008. Results The number of cancer deaths in elderly nearly doubled between 1970-74 (31,400 deaths/year in men, and 24,000 in women) and 2006-08 (63,000 deaths/year in men, and 42,000 in women). Overall cancer mortality rates peaked during the quinquennia 1985-89 and 1990-94 (about 1,500/100,000 in men and 680 in women) and declined thereafter. Throughout 1995-2008 cancer mortality rates decreased by -1.6%/year in men and -0.9%/year in women. These decreases were mainly driven by cancers of the stomach, bladder, prostate, and lung (APC = -3.3%, -2.7%, -2.5%, -2.2%, respectively) in men, and by cancers of the stomach, bladder, and breast (APC = -3.5%, -1.9%, -1.1%, respectively) in women. Conversely, increases in mortality rates between 1995 and 2008 were recorded for lung cancer (APC = +0.6%) in women, cutaneous melanoma (APC = +1.7%) in men, and pancreatic cancer (APC = +0.6% in men and +0.9% in women). Conclusions Overall favorable trends in cancer mortality were observed among Italian elderly between 1995 and 2008. Early diagnosis, improved efficacy of anti-cancer treatments and management of comorbidities are the most likely explanations of these positive observations. However, enduring preventive interventions against the most common risk factor (e.g. cigarette smoking), early diagnosis, and access to care should be reconsidered and extended to match the reductions of cancer mortality recorded in the elderly with those in the middle aged.

Abstract The development and maintenance of adequate shared infrastructures is considered a major goal for academic centers promoting translational research programs. Among infrastructures favoring translational research, centralized facilities characterized by shared, multidisciplinary use of expensive laboratory instrumentation, or by complex computer hardware and software and/or by high professional skills are necessary to maintain or improve institutional scientific competitiveness. The success or failure of a shared resource program also depends on the choice of appropriate institutional policies and requires an effective institutional governance regarding decisions on staffing, existence and composition of advisory committees, policies and of defined mechanisms of reporting, budgeting and financial support of each resource. Shared Resources represent a widely diffused model to sustain cancer research; in fact, web sites from an impressive number of research Institutes and Universities in the U.S. contain pages dedicated to the SR that have been established in each Center, making a complete view of the situation impossible. However, a nation-wide overview of how Cancer Centers develop SR programs is available on the web site for NCI-designated Cancer Centers in the U.S., while in Europe, information is available for individual Cancer centers. This article will briefly summarize the institutional policies, the organizational needs, the characteristics, scientific aims, and future developments of SRs necessary to develop effective translational research programs in oncology. In fact, the physical build-up of SRs per se is not sufficient for the successful translation of biomedical research. Appropriate policies to improve the academic culture in collaboration, the availability of educational programs for translational investigators, the existence of administrative facilitations for translational research and an efficient organization supporting clinical trial recruitment and management represent essential tools, providing solutions to overcome existing barriers in the development of translational research in biomedical research centers.

Biological engineering of microorganisms to produce value-added chemicals is a promising route to sustainable manufacturing. However, overproduction of metabolic intermediates at high titer, rate, and yield from inexpensive substrates is challenging in non-model systems where limited information is available regarding metabolic flux and its control in production conditions. Integrated multi-omic analyses of engineered strains offers an in-depth look at metabolites and proteins directly involved in growth and production of target and non-target bioproducts. Here we applied multi-omic analyses to overproduction of the polymer precursor 3-hydroxypropionic acid (3HP) in the filamentous fungus Aspergillus pseudoterreus. A synthetic pathway consisting of aspartate decarboxylase, beta-alanine pyruvate transaminase, and 3HP dehydrogenase was designed and built for A. pseudoterreus. Strains with single- and multi-copy integration events were isolated and multi-omics analysis consisting of intracellular and extracellular metabolomics and targeted and global proteomics was used to interrogate the strains in shake-flask and bioreactor conditions. Production of a variety of co-products (organic acids and glycerol) and oxidative degradation of 3HP were identified as metabolic pathways competing with 3HP production. Intracellular accumulation of nitrogen as 2,4-diaminobutanoate was identified as an off-target nitrogen sink that may also limit flux through the engineered 3HP pathway. Elimination of the high-expression oxidative 3HP degradation pathway by deletion of a putative malonate semialdehyde dehydrogenase improved the yield of 3HP by 3.4 × after 10 days in shake-flask culture. This is the first report of 3HP production in a filamentous fungus amenable to industrial scale biomanufacturing of organic acids at high titer and low pH.

Human life intimately depends on plants for food, biomaterials, health, energy, and a sustainable environment. Various plants have been genetically improved mostly through breeding, along with limited modification via genetic engineering, yet they are still not able to meet the ever-increasing needs, in terms of both quantity and quality, resulting from the rapid increase in world population and expected standards of living. A step change that may address these challenges would be to expand the potential of plants using biosystems design approaches. This represents a shift in plant science research from relatively simple trial-and-error approaches to innovative strategies based on predictive models of biological systems. Plant biosystems design seeks to accelerate plant genetic improvement using genome editing and genetic circuit engineering or create novel plant systems through de novo synthesis of plant genomes. From this perspective, we present a comprehensive roadmap of plant biosystems design covering theories, principles, and technical methods, along with potential applications in basic and applied plant biology research. We highlight current challenges, future opportunities, and research priorities, along with a framework for international collaboration, towards rapid advancement of this emerging interdisciplinary area of research. Finally, we discuss the importance of social responsibility in utilizing plant biosystems design and suggest strategies for improving public perception, trust, and acceptance.

Abstract Background Engagement of CD40 promotes survival of undifferentiated nasopharyngeal carcinoma (UNPC) cells and similar effects are induced by the EBV oncoprotein LMP-1 that is expressed in a fraction of cases. Considering that CD40 may be activated also by the soluble isoform of CD40L (sCD40L), we investigated the serum levels of sCD40L in a series of 61 UNPC patients from Italy, a non-endemic area for this disease. Results At diagnosis, serum samples of UNPC patients contained significantly higher levels of sCD40L than age-matched healthy controls (p < 0.001). High levels of sCD40L (i.e., >18 ng/ml) were more frequently found in patients + lymphoid cells admixed to neoplastic UNPC cells were detected in cases with high serum levels of sCD40L, suggesting that sCD40L is probably produced within the tumor mass. Conclusion sCD40L may contribute to CD40 activation in UNPC cells, particularly of LMP-1-negative cases, further supporting the crucial role of CD40 signalling in the pathogenesis of UNPC. sCD40L levels may be useful to identify UNPC patients with occult distant metastases at presentation.

Diabetes mellitus is clinically defined by chronic hyperglycemia. Sex differences in the presentation and outcome of diabetes exist with premenopausal women having a reduced risk of developing diabetes, relative to men, or women after menopause. Accumulating evidence shows a protective role of estrogens, specifically 17-beta estradiol, in the maintenance of pancreatic beta cell health; however, the mechanisms underlying this protection are still unknown. To elucidate these potential mechanisms, we used a pancreatic beta cell line (BTC6) and a mouse model of hyperglycemia-induced atherosclerosis, the ApoE−/−:Ins2+/Akita mouse, exhibiting sexual dimorphism in glucose regulation. In this study we hypothesize that 17-beta estradiol protects pancreatic beta cells by modulating the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. We observed that ovariectomized female and male ApoE−/−:Ins2+/Akita mice show significantly increased expression of apoptotic UPR markers. Sham operated female and ovariectomized female ApoE−/−:Ins2+/Akita mice supplemented with exogenous 17-beta estradiol increased the expression of adaptive UPR markers compared to non-supplemented ovariectomized female ApoE−/−:Ins2+/Akita mice. These findings were consistent to what was observed in cultured BTC6 cells, suggesting that 17-beta estradiol may protect pancreatic beta cells by repressing the apoptotic UPR and enhancing the adaptive UPR activation in response to pancreatic ER stress.

Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder. Diagnosis can take a long time, especially in the presence of confounding factors, and it is, to some extent, a process of exclusion. AOSD has life-threating complications ranging from asymptomatic to severe, such as macrophage activation syndrome (MAS), which is also referred to as hemophagocytic lymphohistocytosis (HLH). This condition is correlated with cytokine storm production and monocyte/macrophage overactivation and typically occurs with rash, pyrexia, pancytopenia, hepatosplenomegaly and systemic involvement. Exitus occurs in approximately 10% of cases. For the treatment of MAS-HLH, the Histiocyte Society currently suggests high-dose corticosteroids, with the possible addition of cyclosporine A, anti-interleukin (IL)-1, or IL-6 biological drugs; the inclusion of etoposide is recommended for the most severe conditions. In all cases, a multidisciplinary collaboration involving the resources and expertise of several specialists (e.g., rheumatologist, infectiologist, critical care medicine specialist) is advised. Herein, we provide a detailed description of the clinical case of a previously healthy young woman in which MAS developed as a dramatic onset manifestation of AOSD and whose diagnosis posed a real clinical challenge; the condition was finally resolved by applying the HLH-94 protocol (i.e., etoposide in combination with dexamethasone).