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The resolution of causal genetic variants informs understanding of disease biology. We used regulatory quantitative trait loci (QTLs) from the BLUEPRINT, GTEx and eQTLGen projects to fine-map putative causal variants for 12 immune-mediated diseases. We identify 340 unique loci that colocalize with high posterior probability (≥98%) with regulatory QTLs and apply Bayesian frameworks to fine-map associations at each locus. We show that fine-mapping credible sets derived from regulatory QTLs are smaller compared to disease summary statistics. Further, they are enriched for more functionally interpretable candidate causal variants and for putatively causal insertion/deletion (INDEL) polymorphisms. Finally, we use massively parallel reporter assays to evaluate candidate causal variants at the ITGA4 locus associated with inflammatory bowel disease. Overall, our findings suggest that fine-mapping applied to disease-colocalizing regulatory QTLs can enhance the discovery of putative causal disease variants and enhance insights into the underlying causal genes and molecular mechanisms.

Genomic medicine enables the identification of patients with rare or ultra-rare monogenic forms of inflammatory bowel disease (IBD) and supports clinical decision making. Patients with monogenic IBD frequently experience extremely early onset of treatment-refractory disease, with complex extraintestinal disease typical of immunodeficiency. Since more than 100 monogenic disorders can present with IBD, new genetic disorders and variants are being discovered every year, and as phenotypic expression of the gene defects is variable, adaptive genomic technologies are required. Monogenic IBD has become a key area to establish the concept of precision medicine. Clear guidance and standardised, affordable applications of genomic technologies are needed to implement exome or genome sequencing in clinical practice. This joint British Society of Gastroenterology and British Society of Paediatric Gastroenterology, Hepatology and Nutrition guideline aims to ensure that testing resources are appropriately applied to maximise the benefit to patients on a national scale, minimise health-care disparities in accessing genomic technologies, and optimise resource use. We set out the structural requirements for genomic medicine as part of a multidisciplinary team approach. Initiation of genomic diagnostics should be guided by diagnostic criteria for the individual patient, in particular the age of IBD onset and the patient's history, and potential implications for future therapies. We outline the diagnostic care pathway for paediatric and adult patients. This guideline considers how to handle clinically actionable findings in research studies and the impact of consumer-based genomics for monogenic IBD. This document was developed by multiple stakeholders, including UK paediatric and adult gastroenterology physicians, immunologists, transplant specialists, clinical geneticists, scientists, and research leads of UK genetic programmes, in partnership with patient representatives of several IBD and rare disease charities.

Cell death is one of the failure modes of mammalian cell culture. Apoptosis is a regulated cell death process mainly observed in cell culture. Timely detection of apoptosis onset allows opportunities for preventive controls that ensure high productivity and consistent product quality. Capacitance spectroscopy captures the apoptosis-related cellular properties changes and thus quantifies the percentage of dying cells. This study demonstrated a quantification model that measures the percentage of apoptotic cells using a capacitance spectrometer in an at-line setup. When predicting the independent test set collected from bench-scale bioreactors, the root-mean-squared error of prediction was 8.8% (equivalent to 9.9% of the prediction range). The predicted culture evolution trajectory aligned with measured values from the flow cytometer. Furthermore, this method alarms cell death onset earlier than the traditional viability test, that is, the trypan blue exclusion test. Compared to flow cytometry (the traditional early cell death detection method), this method is rapid, simple, and less labor-intensive. In addition, this at-line setup can be easily transferred between scales (e.g., lab-scale for development to manufacturing scale), which benefits process transfers between facilities, scale-up, and other process transitions.

Retrospective analysis of historic data for cell culture processes is a powerful tool to develop further process understanding. In particular, deploying retrospective analyses can identify important cell culture process parameters for controlling critical quality attributes, e.g., afucosylation, for the production of monoclonal antibodies (mAbs). However, a challenge of analyzing large cell culture data is the high correlation between regressors (particularly media composition), which makes traditional analyses, such as analysis of variance and multivariate linear regression, inappropriate. Instead, partial least-squares regression (PLSR) models, in combination with machine learning techniques such as variable importance metrics, are an orthogonal or alternative approach to identifying important regressors and overcoming the challenge of a highly covariant data structure. A specific workflow for the retrospective analysis of cell culture data is proposed that covers data curation, PLS regression, model analysis, and further steps. In this study, the proposed workflow was applied to data from four mAb products in an industrial cell culture process to identify significant process parameters that influence the afucosylation levels. The PLSR workflow successfully identified several significant parameters, such as temperature and media composition, to enhance process understanding of the relationship between cell culture processes and afucosylation levels.

Interacting proteins tend to have similar functions, influencing the same organismal traits. Interaction networks can be used to expand the list of candidate trait-associated genes from genome-wide association studies. Here, we performed network-based expansion of trait-associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share an underlying genetic and biological process. We identified 73 pleiotropic gene modules linked to multiple traits, enriched in genes involved in processes such as protein ubiquitination and RNA processing. In contrast to gene deletion studies, pleiotropy as defined here captures specifically multicellular-related processes. We show examples of modules linked to human diseases enriched in genes with known pathogenic variants that can be used to map targets of approved drugs for repurposing. Finally, we illustrate the use of network expansion scores to study genes at inflammatory bowel disease genome-wide association study loci, and implicate inflammatory bowel disease-relevant genes with strong functional and genetic support., Nature Genetics, 55 (3), ISSN:1061-4036, ISSN:1546-1718

Nature-based solutions (NbS) can be beneficial to help human communities build resilience to climate change bymanaging and mitigating related hydro-meteorological hazards (HMHs). Substantial research has been carriedout in the past on the detection and assessment of HMHs and their derived risks. Yet, knowledge on the performanceand functioning of NbS to address these hazards is severely lacking. The latter is exacerbated by thelack of practical and viable approaches that would help identify and select NbS for specific problems. The EUfundedOPERANDUM project established seven Open-Air Laboratories (OALs) across Europe to co-develop,test, and generate an evidence base from innovative NbS deployed to address HMHs such as flooding,droughts, landslides, erosion, and eutrophication. Herein, we detail the original approaches that each OAL followedin the process of identifying and selecting NbS for specific hazards with the aim of proposing a novel,generic framework for selecting NbS. We found that the process of selecting NBS was overall complex andcontext-specific in all the OALs, and it comprised 26 steps distributed across three stages: (i) Problem recognition,(ii) NbS identification, and (iii) NbS selection. We also identified over 20 selection criteria which, in mostcases, were shared across OALs and were chiefly related to sustainability aspects. All the identified NbS wererelated to the regulation of the water cycle, and they were mostly chosen according to three main factors: (i)hazard type, (ii) hazard scale, and (iii) OAL size. We noticed that OALs exposed to landslides and erosion selectedNbS capable to manage water budgets within the soil compartment at the local or landscape scale, while OALsexposed to floods, droughts, and eutrophication selected approaches to managing water transport and storage atthe catchment scale. We successfully portrayed a synthesis of the stages and steps followed in the OALs’ NbSselection process in a framework. The framework, which reflects the experiences of the stakeholders involved, isinclusive and integrated, and it can serve as a basis to inform NbS selection processes whilst facilitating theorganisation of diverse stakeholders working towards finding solutions to natural hazards. We animate the futuredevelopment of the proposed framework by integrating financial viability steps. We also encourage studieslooking into the implementation of the proposed framework through quantitative approaches integrating multicriteriaanalyses.

Somatic evolution of cells within the body is well known to lead to cancers. However, spread of somatic mutations within a tissue over time may also contribute to the pathogenesis of non-neoplastic diseases. Recent years have seen the publication of many studies aiming to characterize somatic evolution in healthy tissues. A logical next step is to extend such work to diseased conditions. As our understanding of the interplay between somatic mutations and non-neoplastic disease grows, opportunities for the joint study of germline and somatic variants will present themselves. Here, we present our thoughts on the utility of somatic mutations for understanding both the causes and consequences of common complex disease and the challenges that remain for the joint study of the soma and germline.

Previous work developed a quantitative model using capacitance spectroscopy in an at-line setup to predict the dying cell percentage measured from a flow cytometer. This work aimed to transfer the at-line model to monitor lab-scale bioreactors in real-time, waiving the need for frequent sampling and enabling precise controls.Due to the difference between the at-line and in-line capacitance probes, direct application of the at-line model resulted in poor accuracy and high prediction bias. A new model with a variable range and offering similar spectral shape across all probes was first constructed, improving prediction accuracy. Moreover, the global calibration method included the variance of different probes and scales in the model, reducing prediction bias. External parameter orthogonalization, a preprocessing method, also mitigated the interference from feeding, which further improved model performance. The root-mean-square error of prediction of the final model was 6.56% (8.42% of the prediction range) with an RThe culture evolution trajectory predicted by the in-line model captured the cell death and alarmed cell death onset earlier than the trypan blue exclusion test. Additionally, the incorporation of at-line spectra following orthogonal design into the calibration set was shown to generate calibration models that are more robust than the calibration models constructed using the in-line spectra only. This is advantageous, as at-line spectral collection is easier, faster, and more material-sparing than in-line spectra collection. This article is protected by copyright. All rights reserved.

Purpose This paper aims to present a theoretical model for restructuring Colombia’s educational initiatives in response to current socioeconomic needs. More equitable and decolonized education could help learners decouple their capacities to imagine the future from colonialized paradigms, thereby opening spaces for more active engagement in their own futures. Design/methodology/approach The authors take a critical, postmodern approach focused on empowering people to transcend constraints from a colonial past and recognizing that the purpose of knowledge, although reflecting power and social relationships, is to help people improve society. Notions of situated and futures literacies nourish an approach toward a decolonized and glocalized educational model. Findings The current Colombian educational system tends to favor a single focus – local, national or international – at the expense of the others. The authors argue that educational policy and planning should account for three realms of knowledge: locally situated literacies, nationally situated literacies and globally situated literacies. Originality/value Deconstructing obsolete and colonized methodologies could not only help prepare Colombian learners for active engagement both within and beyond their modern-day borders but could also help transform other educational systems originally designed to support societies and economies that no longer exist, including those of the Global North.

Somatic mutations are hypothesised to play a role in many non-neoplastic diseases. These diseases may also shape the somatic mutation landscape of affected tissues after onset. We performed whole-exome sequencing of 1182 microbiopsies dissected from lesional and non-lesional epidermis from 111 patients with psoriasis, a chronic inflammatory disease of the skin, to search for evidence that somatic mutations in keratinocytes may influence the disease process and to characterise the effects of the disease on the mutation landscape of the epidermis. We show that psoriasis is associated with increased mutation burden of the cell-intrinsic signatures SBS1 and SBS5 but not of UV-light, which remains the dominant mutagen in psoriatic skin. Despite the hyperproliferation of keratinocytes that characterises psoriasis, lesional skin remains highly polyclonal, showing no evidence of spread of clones carrying potentially pathogenic mutations. We find that the selection forces operating in the epidermis remain mostly unchanged in psoriasis and the mutational landscape continues to be dominated by clones carrying mutations in genes recurrently mutated in normal squamous epithelia. There is evidence of positive selection in previously reported driver genes, NOTCH1, NOTCH2, TP53, FAT1 and PPM1D and we also identify four driver genes (GXYLT1, CHEK2, ZFP36L2 and EEF1A1), that have not been previously described in studies of normal skin but which we hypothesise are selected for in squamous epithelium irrespective of disease status. We describe the mutagenic effects of psoralens, a class of chemicals previously found in some sunscreens and which remain a part of a common photochemotherapy treatment for psoriasis (psoralens and UV-A, PUVA). Psoralens leave a distinct mutational signature in the genomes of exposed cells that is tightly linked with transcription, showing evidence of both transcription-coupled repair and transcription-coupled damage. These results suggest that somatic mutations in keratinocytes are unlikely to influence the pathogenesis of psoriasis and that while psoriasis has only modest effect on the mutation landscape of the skin, PUVA treatment has the potential to exert a unique and larger effects.

Fredric Schiffer,1,2 Alaptagin Khan,1,2 Kyoko Ohashi,1,2 Laura C Hernandez Garcia,1,2 Carl M Anderson,1,2 Lisa D Nickerson,1,3 Martin H Teicher1,2 1Department of Psychiatry, Harvard Medical School, Boston, MA, USA; 2Developmental Biopsychiatry Research Program, McLean Hospital, Belmont, MA, USA; 3McLean Imaging Center, McLean Hospital, Belmont, MA, USACorrespondence: Fredric Schiffer, Developmental Biopsychiatry Research Program, McLean Hospital, Belmont, MA, USA, Tel +1 617 855 2970, Fax +1 617 855 3712, Email fschiffer@mclean.harvard.eduPurpose: Conventional theories of hemispheric emotional valence (HEV) postulate fixed hemispheric differences in emotional processing. Schiffer’s dual brain psychology proposes that there are prominent individual differences with a substantial subset showing a reversed laterality pattern. He further proposed that hemispheric differences were more akin to differences in personality than in emotional processing. This theory is supported by findings that unilateral treatments, such as transcranial magnetic stimulation, are effective if they accurately target individual differences in laterality. The aim of this paper was to assess if a computer test of hemispheric emotional valence (CTHEV) could effectively identify individual differences in HEV and to ascertain if these individual differences were associated with underlying differences in brain structure and connectivity.Patients and Methods: The CTHEV was administered to 50 (18 male/32 female) right-handed participants, aged 18– 19 years, enrolled in a study assessing the neurobiological effects of childhood maltreatment. Based on a literature review, we determined whether CTHEV correlated with lateralized volumes of the nucleus accumbens, amygdala, hippocampus, and subgenual anterior cingulate as well as volume of the corpus callosum.Results: CTHEV scores correlated with laterality indices of the nucleus accumbens (p = 0.00016), amygdala (p = 0.0138) and hippocampus (p = 0.031). A positive left hemispheric valence was associated with a larger left-sided nucleus accumbens and hippocampus and a smaller left amygdala. We identified four eigenvector network centrality DTI measures that predict CTHEV, most notably the left amygdala, and found that CTHEV results correlated with total and segment-specific corpus callosal volumes.Conclusion: Individual differences in HEV can be readily assessed by computer test and correlate with differences in brain structure and connectivity that could provide a mechanistic understanding. These findings provide further support for a revised understanding of HEV and provide a tool that could be used to guide lateralized brain treatments.Keywords: cerebral laterality, brain structure, personality, Dual-Brain Psychology, corpus callosum

Near infrared spectroscopy (NIRS) is often used during the tablet coating process to assess coating thickness. As the coating process proceeds, the increase and decrease in NIRS signal from both the coating formulation and tablet core has been related to coating thickness. Partial least-squares models are often generated relating NIRS spectra to reference coating thickness measurements for in-line and/or at-line monitoring of the coating process. This study investigated the effect of the reference coating thickness measurements on the accuracy of the model. The two primary reference techniques used were weight gain-based coating thickness and terahertz-based coating thickness. Most NIRS coating thickness models currently use weight gain-based reference values; however, terahertz-time-of-flight spectroscopy (THz-TOF) offers a more direct reference coating thickness measurement. Results showed that the accuracy of the NIRS coating thickness model significantly improved when terahertz-based coating thickness measurements were used as reference when compared to weight gain-based coating thickness measurements. Therefore, the application of THz-TOF as a reference method is further demonstrated.

This paper proposes the design of an instructional model, referred to as the universal genre sphere, for teaching academic writing in a manner appropriate to all learners, but developed especially with consideration for the needs of English as additional language students with or without diagnosed learning differences. Despite growing research on, variously, second-language writing, English as an additional language and learning differences, there has been relatively little work that explores approaches to the intersections of these topics. Thus, the proposed universal genre sphere model is founded on the pillars of universal design for learning and the tenets of the genre-based approach, especially the teaching-learning cycle, to create more equitable and inclusive, as well as effective, learning environments. The universal genre sphere balances inclusive design that draws upon students’ interests, while breaking learning into manageable and adjustable segments, thus making academic writing more accessible to a greater number of learners. The combination of universal design for learning and the genre-based approach represents an opportunity to create a shift in second-language writing instruction (and, potentially, in L1 writing instruction) that aligns with the principles of inclusive education by reducing barriers in the classroom and providing students with multiple pathways to participate, which could do much to advance knowledge about more inclusive, equitable and effective writing instruction for all learners.

Background and aims Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut homeostasis. Methods To build a taxonomy model we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by: (1) overlapping syndromic features; (2) response to hematopoietic stem cell transplantation; (3) bulk RNA-seq of 32 tissues; (4) single-cell RNA-seq of >50 cell subsets from the intestine of healthy individuals and IBD patients (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4). Results Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8+ T cells, neutrophils, epithelial subsets and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mTOR activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD. Conclusion Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses.

As continuous manufacturing (CM) processes are developed, process analytical technology (PAT) via NIR spectroscopy has become an integral tool in process monitoring. NIR spectroscopy requires the deployment of complex multivariate models to extract the relevant information. The model of choice for the pharmaceutical industry is Partial Least Squares (PLS). However, the development of PLS can be burdensome due to the time and resource intensive requirements of calibration. To overcome this challenge, calibration-free/minimal calibration approaches have become of increasing interest. Iterative optimization technology (IOT) algorithms are a favorable calibration-free/minimal calibration approach with only the requirement of pure component spectra for successful active pharmaceutical ingredient (API) quantification. IOT algorithms were utilized to monitor potency trends (qualitative) and API content (quantitative) in a CM system and compared to a traditional PLS model. To overcome the reduced prediction performance of IOT during non-steady state conditions, a novel wavelength method based on variable importance in projection scores was employed. Overall, the success and value of IOT algorithms for application in CM settings was demonstrated.

Extensive knowledge of Chinese hamster ovary (CHO) cell metabolism is required to improve process productivity and culture performance in biopharmaceutical manufacturing. However, CHO cells show a dynamic metabolism during culturing in batch and fed-batch bioreactors. CHO cell metabolism is generally described as taking place in three stages: exponential growth phase, stationary phase, and death phase. This review aims to summarize the trends of central metabolism for CHO cells during each stage. Additional insights into how culture conditions are related to phase transitions and force metabolic rewiring are provided. Understanding of CHO cell metabolism lends itself to improving culture qualities by, for example, identifying sources of toxic byproducts and pathways for cellular engineering. In summary, this review describes the changes in CHO cell central metabolism over the course of the culture. This article is protected by copyright. All rights reserved.

Film coating of nifedipine tablets is commonly performed to reduce photo-degradation. The coating thickness of these tablets is a primary dictating factor of photo-stability. Terahertz spectroscopy enables accurate measurement of coating thickness. This study identifies a method to determine an end-point of a photo-protective coating process by using coating thickness measurements from terahertz time of flight spectroscopy (THz-TOF). For this method, nifedipine tablets, at different coating thicknesses, were placed in a photostability chamber. The illumination conditions of the coated tablets were adjusted based on the time duration of these tablets inside the chamber. A multiple linear regression model was developed with the coating thickness estimates from THz-TOF and illumination conditions information to predict the amount of drug remaining after photo-degradation (percent label claim). The prediction error of this model was 1.03 % label claim in the range of 88.4 to 100.6 % label claim. According to this model, acceptable levels of photo-protection in illumination conditions of up to approximately 700,000 lux hours was achieved at the end of the coating process (approximately 50 µm coating thickness) performed in this study. These results suggest THz-TOF as a viable process analytical technology tool for process understanding and end-point determination of a photo-protective coating process.

Decisions of the United States Supreme Court beginning with Griswold v. Connecticut (1965) have transformed family law in the United States. By characterizing the right to marry as a fundamental constitutional right and procreative decision-making as both a fundamental liberty interest and privacy right, the Court has “deregulated” the institutions of marriage and family.During this same period the Court’s approach to legal questions involving the rights of non-marital cohabitating couples as well as individual procreative decision-making has tended to blur legal distinctions between the family based upon marriage and other living arrangements. The widespread adoption of mutual consent and/or marital breakdown as grounds for the dissolution of marriage in the United States has significantly altered the social dynamics of marriage and further reduces distinctions between marriage and other living arrangements.However, recent decisions by the Court in Hardwick, Michael H., and Webster point to a change of direction in the Court’s view of privacy which may signal a willingness to tolerate greater community involvement in establishing protective regulation of the institutions of marriage and the family based upon it. The Court also appears to be in the process of significantly narrowing the constitutionally recognized right of privacy when viewed as a zone of autonomous decision-making for the individual or non-marital couple., Les décisions de la Cour suprême des États-Unis, à partir de l’arrêt Griswold c. Connecticut (1965), ont transformé le droit de la famille aux États-Unis. En qualifiant le droit au mariage de droit constitutionnel fondamental et le choix de procréer, de liberté fondamentale et de droit inhérent à la vie privée, la cour a procédé à la déréglementation des institutions de la famille et du mariage.Pendant la même période, l’approche de la cour face aux questions impliquant les droits des couples non mariés ainsi que le choix individuel de procréer est venue brouiller les distinctions juridiques entre la famille, fondée sur le mariage, et les autres modes de cohabitation. L’adoption répandue du consentement mutuel et/ou de l’échec du mariage comme motifs de dissolution du mariage aux États-Unis a considérablement altéré la dynamique sociale du mariage et a réduit davantage les distinctions entre le mariage et les autres modes de cohabitation.Cependant, les récentes décisions de la cour dans Hardwick, Michael H. et Webster traduisent un changement de cap dans la définition du droit à la vie privée. Cette nouvelle approche pourrait se révéler plus tolérante face à l’intervention accrue du corps social par le biais d’une législation protectrice de l’institution du mariage et de la famille qui en découle. Parallèlement, la cour semble aller dans le sens d’un rétrécissement du droit constitutionnel à la vie privée lorsqu’analysé sous l’angle de l’autonomie décisionnelle de l’individu ou du couple non marié.

Conservation Trust for North Carolina (CTNC) collaborates with the US National Park Service to preserve land along North Carolina's Blue Ridge Parkway. Escalating pressures from development in the region are threatening the park's scenic views, the primary visitor attraction. A ranked mapping of land parcels for conservation that takes into account visibility is therefore crucial for the park's sustainable management and success. The visibility of parcels within a two mile (3.22 km) buffer of the Parkway was modeled in a GIS-based viewshed decision support system. Using distance decay weightings and LiDAR data to capture obstructive vegetation curtains while driving and at scenic overlooks, a realistic representation of visitor experience was replicated and validated using satellite imagery. This decision support system allows for the efficient allocation of limited conservation resources based on the ranks of over 30,000 parcels within the study area and provides a replicable methodology for similar conservation planning elsewhere.

To develop a robust quantitative calibration model for spectroscopy, different sources of variability that are not directly related to the components of interest should be included in the calibration samples; this variability should be similar to that which is anticipated during validation and routine operation. Moisture content of pharmaceutical samples can vary as a function of supplier, storage conditions, geographic origin or seasonal variation. Additionally, some pharmaceutical operations (e. g., wet granulation) cause exposure of excipients and API to water. Although water is a weak Raman scatterer, moisture variability has an indirect effect on analytical model performance. Because many pharmaceutical components have intrinsic fluorescent characteristics (with broad spectral features), moisture variability may cause spectral artifacts in the form of baseline variation associated with fluorescence quenching. This work investigates the deleterious effects of water quenching on quantitative prediction accuracy of a multivariate calibration algorithm for Raman spectroscopy. To demonstrate this, a formulation composed of acetaminophen, lactose, microcrystalline cellulose, HPMC and magnesium stearate was used. Tablets were manufactured using laboratory scale equipment. A full-factorial design was used to vary acetaminophen (5 levels), and excipient ratios (3 levels) to generate tablets for calibration and testing. Tablet moisture variation was introduced by placing samples in different humidity chambers. Significant spectral effects arising from fluorescence were identified in the Raman spectra and due to moisture variation: the fluorescence related spectral variability caused substantial degradation of the prediction performance for API. The work demonstrated that accounting for moisture variation during method development reduced the prediction error of the multivariate prediction model.

Proteins that interact within molecular networks tend to have similar functions and when perturbed influence the same organismal traits. Interaction networks can be used to expand the list of likely trait associated genes from genome-wide association studies (GWAS). Here, we used improvements in SNP-to-gene mapping to perform network based expansion of trait associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share a common genetic basis as well as the biological processes underlying this. We identified 73 pleiotropic gene modules linked to multiple traits that are enriched in genes involved in processes such as protein ubiquitination and RNA processing. We show examples of modules linked to human diseases enriched in genes with pathogenic variants found in patients or relevant mouse knock-out phenotypes and can be used to map targets of approved drugs for repurposing opportunities. Finally, we illustrate the use of the network expansion scores to study genes at inflammatory bowel disease (IBD) GWAS loci, and implicate IBD-relevant genes with strong functional and genetic support.

Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD), however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequenced data from more than 30,000 CD patients and 80,000 population controls. We observe rare coding variants in established CD susceptibility genes as well as ten genes where coding variation directly implicates the gene in disease risk for the first time.

A material sparing method for near-infrared (NIR) calibration was developed using an offline apparatus coupled with a calibration transfer method to enable a partial least squares (PLS) model to monitor the concentration of active pharmaceutical ingredients (API) in the feed frame of a rotary tablet press. The offline apparatus was designed to simulate the powder flow dynamic and NIRS measurement environment of a tablet-press feed frame. A comprehensive experimental design, including calibration and testing, was employed to determine blend inhomogeneity. NIR spectra were collected at both the feed frame (inline) conditions and the simulator (offline) conditions. The simulator conditions were designed to mimic the density and powder flow in the feed frame during the actual tableting process. The offline data were pretreated by an orthogonalization-based calibration transfer algorithm, a continuum regression filter (CR filter), before being subjected to PLS modeling. This study demonstrated: (1) calibration for inline application can be generated using an offline apparatus, and (2) the CR filter, as an innovative calibration transfer method, can generalize the offline method for multiple feed frame conditions.

The biopharmaceutical industry prefers to culture the mammalian cells in suspension with a serum-free media (SFM) due to improved productivity and process consistency. However, mammalian cells preferentially grow as adherent cells in a complete medium (CM) containing serum. Therefore, cells require adaptation from adherence in CM to suspension culture in SFM. This work proposes an adaptation method that includes media supplementation during the adaption of Chinese hamster ovary cells. As a result, the adaptation was accelerated compared to the traditional repetitive subculturing. Ca2+ /Mg2+ supplementation significantly reduced the doubling time compared to the adaptation without supplementation during the adaptation of adherent cells from 100% CM to 75% CM (p < 0.05). Furthermore, a definitive screening design (DSD) was applied to select essential nutrients during the adaptation from 10% CM to 0% CM. The main effects of Ca2+ and Dulbecco's modified essential medium (DMEM) were found significant to both viable cell density and viability at harvest. Additionally, the interaction term between Ca2+ and DMEM was found significant, which highlights the ability of DSD to capture interaction terms. Eventually, the media supplementation method resulted in adaptation SFM in 27 days, compared to the previously reported 66 days. Additionally, the membrane surface integrin expression was found significantly decreased when adherent cells were adapted to suspension. Moreover, the Ca2+ /Mg2+ supplementation correlated with faster integrin recovery after trypsinization. However, faster integrin recovery did not contribute to the accelerated cell growth when subculturing from 100% CM to 75% CM.

Nature-based solutions (NbS) are increasingly recognized as sustainable approaches to address socio-environmental challenges. Disaster risk reduction (DRR) has benefited by increasingly moving away from purely ‘grey’ infrastructure measures towards NbS, which can better provide cultural, aesthetic, and recreational co-benefits that are highly valued among European citizens. Public acceptance is of particular importance for NbS since they often rely on collaborative implementation, management, and monitoring, as well as protection against competing land uses. Although public engagement is a common goal of NbS projects and found in the IUCN’s core principles of NbS, outreach efforts are rarely based on a sufficient understanding of the (de)motivating factors tied to public perceptions. As a first step, we conducted a systematic literature review to examine how unique NbS characteristics relate to public acceptance through a comparison with grey measures. We identified influential acceptance factors related to individuals, society, and DRR measures. Based on the review, we introduce the PA-NbS framework as a starting point for the systematic consideration, design, and testing of strategies for increasing public acceptance. The PA-NbS highlights the roles of trust, competing interests, and effectiveness of NbS, as well as public perceptions of risk, nature and place.A lack of consideration of these factors may lead to misaligned public expectations and failed participatory initiatives, while jeopardizing the success of NbS projects. Therefore, as a second step, we conducted citizen surveys within three NbS host communities. Distinct NbS being implemented within the OPERANDUM project aim to reduce risk from (socio-)natural hazards in Scotland (landslides and coastal erosion), Finland (eutrophication and algal blooms) and Greece (river flooding). Associations of factors related to risk, nature, and place perceptions with pro-NbS attitudes and behavior were tested to determine how these may be leveraged to increase acceptance. We find that trust is a consistent factor for defining attitudes towards the NbS across the sites. Attitudes are strongly associated with respondents’ commitment to nature and concern for risk, while some skepticism of NbS effectiveness leads to high public demand for relevant evidence. Risk perception and particularly the potential for future impacts are associated with behavioural acceptance (i.e. willingness to engage), along with responsibility for nature and connectedness to place.Current data collection efforts to demonstrate NbS effectiveness for risk reduction are well-positioned to increase public acceptance in Europe. However, recognizing the differences among segments of the public within each site along with distinct hazard types, proposed NbS, and historical, social, and cultural characteristics across the sites is crucial for designing strategies that increase acceptance. An overview of these dynamics leads to evidence-based recommendations for the case-study sites and for successful NbS in Europe.

BACKGROUND AND AIMS: Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology. METHODS: PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population. RESULTS: Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation. CONCLUSIONS: Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.

The tight coupling of the social-ecological system (SES) of the Mississippi Delta calls for balanced natural hazard vulnerability and risk assessments. Most existing assessments have approached these components in isolation. To address this, we apply the Global Delta Risk Index (GDRI) in the Mississippi Delta at high-resolution census tract level. We assess SES spatial patterns of drought, hurricane-force wind, and coastal flood vulnerability and integrate hazard and exposure data for the assessment of coastal flood risk. Moreover, we compare current coastal flood risk to future risk in 2025 based on the modelled effects of flood depth, exposure, and changes in ecosystem area in the context of ongoing efforts under the 2017 Louisiana Coastal Master Plan. Results show that the Master Plan will lead to decreases in risk scores by 2025, but the tracts that are currently the most vulnerable benefit less from risk reduction efforts. Along with our index output, we discuss the need for further advancements in SES methodology and the potential for catastrophic hazard events beyond the model parameters, such as extreme rainfall events and very strong hurricanes. Assessing SES risk components can lead to more targeted policy recommendations, demonstrated by the need for Master Plan projects to consider their unequal spatial effects on vulnerability and risk reduction.

The Sustainable Development Goals (SDGs) were adopted by the United Nations in 2015 as part of the “2030 Agenda for Sustainable Development” and aim to address issues ranging from poverty and economic growth to climate change. Efforts to tackle one issue can support or hinder progress towards others, often with complex systemic interactions. Thus, each of the SDGs and their corresponding targets may contribute as levers or hurdles towards achieving other SDGs and targets. Based on SDG indicator data, we create a systems model considering influence among the SDGs and their targets. Once assessed within a system, we find that more SDGs and their corresponding targets act as levers towards achieving other goals and targets rather than as hurdles. In particular, efforts towards SDGs 5 (Gender Equality) and 17 (Partnerships for the Goals) may accelerate progress, while SDGs 10 (Reduced Inequalities) and 16 (Peace, Justice and Strong Institutions) are shown to create potential hurdles. The model results can be used to help promote supportive interactions and overcome hindering ones in the long term.

Climate change is one factor increasing the risk of hydro-meteorological hazards globally.The use of nature-based solutions (NbS), and more specifically ecosystem-based disasterrisk reduction measures (Eco-DRR), has become a popular response for risk reduction thatalso provides highly-valued co-benefits. Public acceptance is of particular importance forNbS since they often rely on local collaborative implementation, management, andmonitoring, as well as long-term protection against competing societal interests.Although public engagement is a common goal of NbS projects, it is rarely carried outwith a sufficient understanding of the (de)motivating factors tied to public perceptions.Successful collaboration demands consideration of societal attitudes and values in relationto risk, nature, and place. However, existing research does not sufficiently explore thesethemes together, their interactions, and their implications for the public acceptance of NbS.This may lead to misaligned public expectations and failed participatory initiatives, whilejeopardizing the success of NbS projects and their continued funding and uptake. Weconducted citizen surveys within local NbS “host” communities to determine the degree ofpro-NbS attitudes and behavior, associated variables, and how these maybeleveragedtoincreaseacceptance.Wecomparedresultsacrosssites,relyingprimarilyoncorrelationsandregressionmodels along with survey comments and expert knowledge. Three distinctrural NbS being implemented within the OPERANDUM project aim to reduce risk from(socio-)natural hazards in Scotland (landslides and coastal erosion; n = 66 respondents),Finland (eutrophication and algal blooms; n = 204) and Greece (river flooding and waterscarcity; n = 84). Our research thus centers on rural NbS for risk reduction within a large EUproject. Trust in implementers is a consistent factor for defining attitudes towards theNbSacross the sites, and attitudes are strongly associated with respondents’ commitment tonature and behavioral acceptance (i.e., willingness to engage). Behaviorial acceptance ismost consistently predicted by connectedness to place and the extent of expected futureimpacts. Skepticism of NbS effectiveness leads to high public demand for relevantevidence. To increase public acceptance, we recommend greater framing of NbS inrelation to place-based values as well as demonstration of the effectiveness of NbS for riskreduction. However, distinct hazard types, proposed NbS, and historical characteristicsmust be considered for developing strategies aimed at increasing acceptance. Anunderstanding of these characteristics and their interactions leads to evidence-basedrecommendations for our study sites and for successful NbS deployment in Europe andbeyond.

Various frameworks for vulnerability and risk assessment of social-ecological systems (SES) to natural hazards have been developed addressing different contexts. However, none were specifically developed in the context of implementing nature-based solutions (NBS) to hydro-meteorological risks. Since the basic concepts and principles of NBS are mainly focused on ensuring balance between ecological and social benefits, the entire vulnerability and risk assessment process should focus equally on various social and ecological components of a location where an NBS would be implemented. As a part of the OPEn-air laboRAtories for Nature baseD solUtions to Manage hydro-meteo risks (OPERANDUM) project, this research proposes a conceptual framework for vulnerability and risk assessment in the context of NBS to hydro-meteorological risks. This conceptual framework is developed mainly considering the major components of the existing Delta-SES risk assessment framework (Sebesvari et al. 2016) and other similar frameworks proposed in recent studies, as well as the proposed principles for NBS endorsed by International Union for Conservation of Nature (IUCN). The major components of the framework include: (i) the exposure of SES to multiple hydro-meteorological hazards (e.g., flood, drought); (ii) vulnerability of SES that consists of ecosystem susceptibility, social susceptibility, ecosystem robustness, and coping and adaptive capacity of the social system; (iii) risks in the NBS project site determined by the combination of hazard exposure and vulnerability; and (iv) the impacts of hydro-meteorological hazards on the SES surrounding or within the NBS project site. While the basic space of risk assessment would be the NBS project site (usually at the local level within sub-catchments) with specific SES characteristics, this framework also reflects the interrelationships between ecosystem and social system as well as the effects of multiple hazards and risks at local up to the global scales. The framework also considers the changes over time that would capture the maturation time lag of the ecological components of an NBS, as well as the sustainability of the system with the intervention of NBS and other risk reduction measures. An indicator-based risk assessment approach can be used to operationalize the framework. To facilitate that, an indicator library has been developed comprising of indicators for different exposure and vulnerability components of the framework. The proposed framework can be applicable to any geographical conditions where an NBS project is to be implemented to reduce hydro-meteorological risks. The framework can also be tailored for other natural hazards (e.g. geological hazards like earthquake) and anthropogenic hazards (e.g. pollution). We will explain the conceptualisation process of the framework and of the indicator library and how these will be tested within the OPERANDUM project in the context of NBS implementation.Keywords: Nature-based solutions, risk assessment framework, hydro-meteorological hazards, social-ecological systems Reference:Sebesvari, Z., Renaud, F. G., Haas, S., Tessler, Z., Hagenlocher, M., Kloos, J., ... & Kuenzer, C. (2016). A review of vulnerability indicators for deltaic social–ecological systems. Sustainability Science, 11(4), 575-590.