Miracle-dz/UniFAR-FTUs huggingface dataset:
Local development through the foundational economy? Priority-setting in Danish municipalities

The foundational economy perspective suggests that industries, which provide services essential to all citizens’ well-being and participation in everyday life, should be placed centrally in economic development policy. This article studies the extent to which local governments put emphasis on foundational industries in their strategies for development. Moreover, drivers behind priority-setting are examined. Based on an analysis of all 98 Danish municipalities’ planning strategies and semi-structured interviews with relevant actors from two rural municipalities, we find that foundational industries are to a great extent emphasised, even if they are not characterised as the foundation for economic development. Rather, foundational industries are prioritised in the absence of other options or when municipalities are not compelled to put local job creation as a crucial focus to attract and maintain inhabitants.
Investigating trait variability of gene co-expression network architecture in brain by manipulating genomic signatures of schizophrenia risk

While the role of genomic risk for schizophrenia on brain gene co-expression networks has been described, the patterns of its manifestations are varied and complex. To acquire a deeper understanding of this issue, we implemented a novel approach to network construction by manipulating the RNA-Seq expression input to “integrate” or “remove” the “modulatory” effects of genomic risk for schizophrenia. We created co-expression networks in DLPFC from the adjusted expression input and compared them in terms of gene overlap and connectivity. We used linear regression models to remove variance explained by RNA quality, cell type proportion, age, sex and genetic ancestry. We also created co-expression networks based on the genomic profile of a normative trait, height, as a “negative control”; we also applied the same analytical approach in two independent samples: LIBD Human Brain Repository (HBR) (N=78 brains, European ancestry) and Common Mind Consortium (CMC) (N=116 brains, European ancestry). In addition to direct comparisons, we explored the biological plausibility of the differential gene clusters between co-expression networks by testing them for enrichment in relevant gene ontologies and gene sets of interest (PGC2-CLOZUK GWAS significant loci genes, height GWAS significant loci genes, genes in synaptic ontologies-SynGO and genes of the “druggable genome”). We identify several key aspects of the role of genomic risk for schizophrenia in brain co-expression networks: 1) Variability of co-expression modules with “integration” or “removal” of genomic profiles of complex traits (normal or pathological); 2) Biological plausibility of gene sets represented in the differential co-expression contrasts and potential relevance for illness etiopathogenesis; 3) Non-preferential mapping of schizophrenia GWAS loci genes to network areas apparently influenced by the genomic risk score. Overall, our study supports the notion that genomic risk for schizophrenia has an extensive and non-linear effect on brain gene co-expression networks that possibly manifests as a molecular background for gene-gene, gene-environment interactions that affect various biological pathways.
A Monte Carlo Expectation Maximization Algorithm for Statistical Inference of Weibull Process with Left Censored Data

The Weibull process plays an important role in the failure analysis of repairable systems. In practice, there exists a situation that the data collected are incomplete. Some of the failure data are missing due to various reasons. Statistical inferences of a Weibull process with incomplete data using Monte Carlo expectation maximization algorithm is proposed. The estimation procedures are derived. A case study is performed to illustrate and compare the performances of this algorithm. It is observed that this method is effective and can simplify the estimation.
Effects of Platycodon grandiflorum on Gut Microbiome and Immune System of Immunosuppressed Mouse

Platycodon grandiflorum (PG) has been used as a traditional remedy to control immune related diseases. However, there is limited information about its immune stimulating effects on the immunosuppressed model. The main bioactive components such as saponins are known to con-tribute to controlling immune activity. Thus, we developed an aged red PG (PGS) with 2.6 times of platycodin D, one of the saponins. We treated PG and PGS (PG-diets) to immunosuppressed mice via cyclophosphamide (CPA) injection. After 2weeks of the supplement, 16S rRNA sequencing was performed to investigate the effects of PG-diets on the gut microbiota and immune system in the immune suppressed model. PG-diets groups showed an increased abundance of microorganism in immune-deficient mice compared to the control NC group, indicating PG-diets have a distinct effect on microbial communities. Detection of specific genera related to the immune related biomarkers in PG-diets groups can support their effects on the immune system. Especially, the Akkermansia showed a significant decrease of abundance in response to the CPA treatment in the NC group at the genus level, but its abundance increased in response to the PG-diets treatment in the PG-diets groups. We also found that the modulation of gut microbiome by PG-diets was correlated with body weight as one of important immune biomarkers, though not much difference was found between PG and PGS effects. The results demonstrate that PG-diets may improve the health benefits of immune suppressed mice by altering the gut microbiome.
Sector field ICP: Mass spectrometry for the routine determination of uranium in urine

Nous avons developpe une methode pour la quantification de U dans l'urine au moyen de la spectrometrie ICP - MS avec secteur de champ. Afin de rendre la methode utilisable pour les etudes epidemiologiques,sa fiabilite a due etre combinee a une haute capacite de production. Ainsi, le pre-traitement de l'echantillon a ete limite a 10-fois la dilution avec HNO 3 0.14 M. De plus, la standardisation externe a ete preferee aux techniques d'ajouts de standard ou de dilution isotopique pour la calibration. L'usage d'un standard interne bien choisi (Re) et l'optimisation du debit du gaz porteur, qui vise a minimiser l'effet de matrice sur le rapport d'intensite de 2 3 8 U + sur celui du standard interne 1 8 7 Re + , a permis d'obtenir des resultats exacts. Nous avons demontre la fiabilite de la methode developpee en analysant avec succes un standard certifie (BCR-668 Mussel Tissue) et par l'obtention d'un recouvrement de pres de 100% pour un ajout de 50 ng/L a l'urine. Le resultat pour un echantillon combine d'urine (contenu en U de 1.6 ng/L) n'a montre que des variations faibles et acceptables (′ 10%). La limite de detection a ete etablie a 0.2 ng/L, alors que la the sensibilite se chiffrait a 2000 comptes/ s par ng/L. Pour un niveau de 10 ng/L, la precision est caracterisee par un ecart-type relatif typique de 5%. Avec un temps d'acquisition de moins de trois minutes par echantillon, la methode permet l'analyse d'environ 100 echantillons par journee de travail de 8h. Une etude-pilote a montre que la selection des contenants n'est pas sans importance puisque certains contenants conduisent a des niveaux de blancs eleves qui sont inacceptables. Les concentrations urinaires de U d'environ 3 - 4 ng/L, correspondant a 2 - 3 ng / g en creatinine, apparaissent comme valuers typiques pour des individus non-exposes de Belgique et des Pays-Bas, meme si certaines valeurs (<5%) ont excede 10 ng/L.
Metamodal Coupling of Vibrotactile and Auditory Speech Processing Systems through Matched Stimulus Representations

It has been postulated that the brain is organized by “metamodal,” sensory-independent cortical modules capable of performing tasks (e.g., word recognition) in both “standard” and novel sensory modalities. Still, this theory has primarily been tested in sensory-deprived individuals, with mixed evidence in neurotypical subjects, thereby limiting its support as a general principle of brain organization. Critically, current theories of metamodal processing do not specify requirements for successful metamodal processing at the level of neural representations. Specification at this level may be particularly important in neurotypical individuals, where novel sensory modalities must interface with existing representations for the standard sense. Here we hypothesized that effective metamodal engagement of a cortical area requires congruence between stimulus representations in the standard and novel sensory modalities in that region. To test this, we first used fMRI to identify bilateral auditory speech representations. We then trained 20 human participants (12 female) to recognize vibrotactile versions of auditory words using one of two auditory-to-vibrotactile algorithms. The vocoded algorithm attempted to match the encoding scheme of auditory speech while the token-based algorithm did not. Crucially, using fMRI, we found that only in the vocoded group did trained-vibrotactile stimuli recruit speech representations in the superior temporal gyrus and lead to increased coupling between them and somatosensory areas. Our results advance our understanding of brain organization by providing new insight into unlocking the metamodal potential of the brain, thereby benefitting the design of novel sensory substitution devices that aim to tap into existing processing streams in the brain. SIGNIFICANCE STATEMENT It has been proposed that the brain is organized by “metamodal,” sensory-independent modules specialized for performing certain tasks. This idea has inspired therapeutic applications, such as sensory substitution devices, for example, enabling blind individuals “to see” by transforming visual input into soundscapes. Yet, other studies have failed to demonstrate metamodal engagement. Here, we tested the hypothesis that metamodal engagement in neurotypical individuals requires matching the encoding schemes between stimuli from the novel and standard sensory modalities. We trained two groups of subjects to recognize words generated by one of two auditory-to-vibrotactile transformations. Critically, only vibrotactile stimuli that were matched to the neural encoding of auditory speech engaged auditory speech areas after training. This suggests that matching encoding schemes is critical to unlocking the brain's metamodal potential.
Combined responses of primary coral polyps and their algal endosymbionts to decreasing seawater pH

With coral reefs declining globally, resilience of these ecosystems hinges on successful coral recruitment. However, knowledge of the acclimatory and/or adaptive potential in response to environmental challenges such as ocean acidification (OA) in earliest life stages is limited. Our combination of physiological measurements, microscopy, computed tomography techniques and gene expression analysis allowed us to thoroughly elucidate the mechanisms underlying the response of early life stages of corals, together with their algal partners, to the projected decline in oceanic pH. We observed extensive physiological, morphological and transcriptional changes in surviving recruits, and the transition to a less-skeleton/more-tissue phenotype. We found that decreased pH conditions stimulate photosynthesis and endosymbiont growth, and gene expression potentially linked to photosynthates translocation. Our unique holistic study discloses the previously unseen intricate net of interacting mechanisms that regulate the performance of these organisms in response to OA.
Physiological and genetic analysis of tomato from two cultivars differing in potassium deficiency resistance

Potassium (K) is one of the essential nutrients for tomato. Potassium deficiency will limit tomato growth and yield. So improving the low-K+ (LK) resistance of tomato seems important. Two tomato cultivars (JZ18 and JZ34) differing in LK resistance were obtained to analyze the plant demonstration difference under LK treatment. According to the results, JZ34 showed lower accumulation of ROS, less membrane damage and higher antioxidant enzyme activity after LK treatment. Besides, JZ34 also keeps higher K+/Na+ content, higher Ca2+ and Mg2+ content than JZ18 in both shoots and roots. Our genetic analysis revealed that the two additive-dominance-epistasis major genes plus additive-dominance polygene genetic model (E-1) was the optimum model associated with LK resistance based on root trait. The major QTL intervals were finally obtained by the bulked segregant sequencing (BSA-seq) analysis, which were 2.38 Mb at the end of chromosome 4 and 1.38 Mb at the chromosome 6. This is consistent with the analysis of the genetic model. A total of 8 genes were selected in the two candidate regions, which exhibited close related to ion and antioxidant signaling. These findings provided the inheritance pattern and foundation for further molecular mechanisms study of tomato LK resistance.
The self-regulated response of the Wnt pathway to an oncogenic mutation in β-catenin

Oncogenic mutations in β-catenin can inhibit degradation of β-catenin by preventing phosphorylation of its degron. Degron phosphorylation is mediated by the Axin scaffold, Casein Kinase 1α (CK1α) and Glycogen Synthase Kinase 3 (GSK3). We studied an oncogenic form of β-catenin with a deletion of serine 45 (S45), a site that is phosphorylated by the kinase CK1α. When the S45 site is phosphorylated, it promotes the GSK3-mediated phosphorylations of the β-catenin degron. Deletion of S45 would be expected to prevent GSK3-mediated phosphorylation of the mutant protein and thus block degradation. We found that the S45 mutant was still phosphorylatable by GSK3, and its expression increased the concentration of Axin, restoring the rate of GSK3-mediated phosphorylation to levels comparable to those observed for the wild-type β-catenin. We conclude that there is one core mechanism for creating the phosphodegron for both primed and unprimed β-catenin, which involves the generation of an Axin-GSK3 complex. SIGNIFICANCE Understanding how the Wnt pathway responds to mutations in β-catenin phosphodegron can reveal important properties of the pathway in normal and cancer cells and is valuable for the design of more effective therapeutic strategies.
Immunoprofiling Correlates of Protection Against SHIV Infection in Adjuvanted HIV-1 Pox-Protein Vaccinated Rhesus Macaques

Human immunodeficiency virus type 1 (HIV-1) infection remains a major public health threat due to its incurable nature and the lack of a highly efficacious vaccine. The RV144 vaccine trial is the only clinical study to date that demonstrated significant but modest decrease in HIV infection risk. To improve HIV-1 vaccine immunogenicity and efficacy, we recently evaluated pox-protein vaccination using a next generation liposome-based adjuvant, Army Liposomal Formulation adsorbed to aluminum (ALFA), in rhesus monkeys and observed 90% efficacy against limiting dose mucosal SHIV challenge in male animals. Here, we analyzed binding antibody responses, as assessed by Fc array profiling using a broad range of HIV-1 envelope antigens and Fc features, to explore the mechanisms of ALFA-mediated protection by employing machine learning and Cox proportional hazards regression analyses. We found that Fcγ receptor 2a-related binding antibody responses were augmented by ALFA relative to aluminium hydroxide, and these responses were associated with reduced risk of infection in male animals. Our results highlight the application of systems serology to provide mechanistic insights to vaccine-elicited protection and support evidence that antibody effector responses protect against HIV-1 infection.
Computational Biology and Machine Learning Approaches to Understand Mechanistic Microbiome-Host Interactions

The microbiome, by virtue of its interactions with the host, is implicated in various host functions including its influence on nutrition and homeostasis. Many chronic diseases such as diabetes, cancer, inflammatory bowel diseases are characterized by a disruption of microbial communities in at least one biological niche/organ system. Various molecular mechanisms between microbial and host components such as proteins, RNAs, metabolites have recently been identified, thus filling many gaps in our understanding of how the microbiome modulates host processes. Concurrently, high-throughput technologies have enabled the profiling of heterogeneous datasets capturing community level changes in the microbiome as well as the host responses. However, due to limitations in parallel sampling and analytical procedures, big gaps still exist in terms of how the microbiome mechanistically influences host functions at a system and community level. In the past decade, computational biology and machine learning methodologies have been developed with the aim of filling the existing gaps. Due to the agnostic nature of the tools, they have been applied in diverse disease contexts to analyze and infer the interactions between the microbiome and host molecular components. Some of these approaches allow the identification and analysis of affected downstream host processes. Most of the tools statistically or mechanistically integrate different types of -omic and meta -omic datasets followed by functional/biological interpretation. In this review, we provide an overview of the landscape of computational approaches for investigating mechanistic interactions between individual microbes/microbiome and the host and the opportunities for basic and clinical research. These could include but are not limited to the development of activity- and mechanism-based biomarkers, uncovering mechanisms for therapeutic interventions and generating integrated signatures to stratify patients.
KAI2 regulates seedling development by mediating light‐induced remodelling of auxin transport

The photomorphogenic remodelling of seedling growth upon exposure to light is a key developmental transition in the plant life cycle. The α/β-hydrolase signalling protein KARRIKIN-INSENSITIVE2 (KAI2), a close homologue of the strigolactone receptor DWARF14 (D14), is involved in this process, and kai2 mutants have strongly altered seedling growth as a result1. KAI2 and D14 both act through the MAX2 (MORE AXILLARY BRANCHING2) F-box protein to target proteins of the SMAX1-LIKE (SUPPRESSOR OF MAX2 1) (SMXL) family for degradation, but the signalling events downstream of this step are unclear in both pathways2. Here, we show that kai2 phenotypes arise because of a failure to downregulate auxin transport from the seedling shoot apex towards the root system, rather than a failure to respond to light per se. We demonstrate that KAI2 controls the light-induced remodelling of the PIN-mediated auxin transport system in seedlings, promoting the reduction of PIN3, PIN4, and PIN7 abundance in older tissues, and the increase of PIN1, PIN2, PIN3, and PIN7 abundance in the root meristem, consistent with transition from elongation-mediated growth in the dark to meristematically-mediated growth in the light. We show that removing PIN3, PIN4 and PIN7 from kai2 mutants, or pharmacological inhibition of auxin transport and synthesis, is sufficient to suppress most kai2 seedling phenotypes. KAI2 is not required for the light-mediated changes in PIN gene expression but is required for the changes in PIN protein abundance at the plasma membrane; we thus propose that KAI2 acts to promote vesicle trafficking, consistent with previous suggestions about D14-mediated signalling in the shoot3.
Multi-tissue methylation clocks for age estimation in the common bottlenose dolphin

Accurate identification of individual ages within wild bottlenose dolphins (Tursiops truncatus) is critical for determining population health and the development of population management strategies. As such, we analyzed DNA methylation patterns by applying a custom methylation array (HorvathMammalMethyl40) to both blood (n = 140) and skin samples (n = 87) from known age or approximate age (0 to 57 years) bottlenose dolphins. We present three bottlenose dolphin specific age estimation clocks using combined blood and skin (48 CpGs, R = 0.93, median absolute error = 2.13 years), blood only (64 CpGs, R = 0.97, error= 1.46 years) and skin only (39 CpGs, R = 0.95, error= 2.53). Our sex estimator based on 71 CpGs predicts the sex of any odontocete species with 99.5% accuracy. We characterize individual cytosines that correlate with sex and age in dolphins. The presented epigenetic clocks are expected to be useful for conservation efforts and for studying anthropogenic events.
Visualization of trigeminal ganglion sensory neuronal signaling regulated by Cdk5

The mechanisms underlying facial and oral pain are still incompletely understood, posing major therapeutic challenges. Cyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase involved in pain signaling. However, the regulatory roles of Cdk5 in orofacial pain signaling and the possibility of therapeutic intervention at the level of mouse trigeminal ganglion primary neurons remain elusive. In this study, we used optimized intravital imaging to directly compare trigeminal neuronal activities after mechanical, thermal, and chemical stimulation. We then tested whether facial inflammatory pain in mice could be alleviated by the Cdk5 inhibitor peptide TFP5. We demonstrated regulation of total Ca2+ intensities by Cdk5 activity using transgenic and knockout mouse models. In mice with orofacial inflammation, application of TFP5 specifically decreased total Ca2+ intensities in response to noxious stimuli. It also alleviated inflammation-induced allodynia by inhibiting activation of trigeminal peripheral sensory neurons. Cdk5 inhibitors may provide promising non-opioid candidates for pain treatment.