Lateral frontoparietal functional connectivity based on individual sulcal morphology.

A salient neuroanatomical feature of the human brain is its pronounced cortical folding, and there is mounting evidence that sulcal morphology is relevant to functional brain architecture and cognition. Recent studies have emphasized putative tertiary sulci (pTS): small, shallow, late-developing, and evolutionarily new sulci that have been posited to serve as functional landmarks in association cortices. A fruitful approach to characterizing brain architecture has been to delineate regions based on transitions in fMRI-based functional connectivity profiles; however, exact regional boundaries can change depending on the data used to generate the parcellation. As sulci are fixed neuroanatomical structures, here, we propose to anchor functional connectivity to individual-level sulcal anatomy. We characterized fine-grained patterns of functional connectivity across 42 sulci in lateral prefrontal (LPFC) and lateral parietal cortices (LPC) in a pediatric sample (N = 43; 20 female; ages 7-18). Further, we test for relationships between pTS morphology and functional network architecture, focusing on depth as a defining characteristic of these shallow sulci, and one that has been linked to variability in cognition. We find that 1) individual sulci have distinct patterns of connectivity, but nonetheless cluster together into groups with similar patterns - in some cases with distant rather than neighboring sulci, 2) there is moderate agreement in cluster assignments at the group and individual levels, underscoring the need for individual-level analyses, and 3) across individuals, greater depth was associated with higher network centrality for several pTS. These results highlight the importance of considering individual sulcal morphology for understanding functional brain organization. Significance Statement: A salient, and functionally relevant, feature of the human brain is its pronounced cortical folding. However, the links between sulcal anatomy and brain function are still poorly understood - particularly for small, shallow, individually variable sulci in association cortices. Here, we explore functional connectivity among individually defined sulci in lateral prefrontal and parietal regions. We find that individual sulci have distinct patterns of connectivity but nonetheless cluster together into groups with similar connectivity - in some cases spanning lateral prefrontal and parietal sulci. We further show that the network centrality of specific sulci is positively associated with their depth, thereby helping to bridge the gap between individual differences in brain anatomy and functional networks leveraging the sulcal anatomy of the individual.

Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum.

OBJECTIVE: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. METHODS: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. RESULTS: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. INTERPRETATION: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

Cichorium intybus L. Hairy Roots as a Platform for Antimicrobial Activity.

Industrial chicory is an important crop for its high dietary fibre content. Besides inulin, chicory taproots contain interesting secondary metabolite compounds, which possess bioactive properties. Hairy roots are differentiated plant cell cultures that have shown to be feasible biotechnological hosts for the production of several plant-derived molecules. In this study, hairy roots of industrial chicory cultivars were established, and their potential as a source of antimicrobial ingredients was assessed. It was shown that hot water extracts of hairy roots possessed antimicrobial activity against relevant human microbes, whereas corresponding chicory taproots did not show activity. Remarkably, a significant antimicrobial activity of hot water extracts of chicory hairy roots towards methicillin-resistant Staphylococcus aureus was observed, indicating a high potential of hairy roots as a host for production of antimicrobial agents.

Maternal psychological distress associates with alterations in resting-state low-frequency fluctuations and distal functional connectivity of the neonate medial prefrontal cortex.

Prenatal stress exposure (PSE) has been observed to exert a programming effect on the developing infant brain, possibly with long-lasting consequences on temperament, cognitive functions and the risk for developing psychiatric disorders. Several prior studies have revealed that PSE associates with alterations in neonate functional connectivity in the prefrontal regions and amygdala. In this study, we explored whether maternal psychological symptoms measured during the 24th gestational week had associations with neonate resting-state network metrics. Twenty-one neonates (nine female) underwent resting-state fMRI scanning (mean gestation-corrected age at scan 26.95 days) to assess fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo). The ReHo/fALFF maps were used in multiple regression analysis to investigate whether maternal self-reported anxiety and/or depressive symptoms associate with neonate functional brain features. Maternal psychological distress (composite score of depressive and anxiety symptoms) was positively associated with fALFF in the neonate medial prefrontal cortex (mPFC). Anxiety and depressive symptoms, assessed separately, exhibited similar but weaker associations. Post hoc seed-based connectivity analyses further showed that distal connectivity of mPFC covaried with PSE. No associations were found between neonate ReHo and PSE. These results offer preliminary evidence that PSE may affect functional features of the developing brain during gestation.

Enzyme-treated chicory for cosmetics: application assessment and techno-economic analysis.

Chicory (Cichorium intybus L.) is an important industrial crop that produces large quantities of the dietary fiber inulin in its roots. Following inulin extraction, the bagasse is typically used as animal feed, but it contains numerous bioactive secondary metabolites with potential applications in healthcare and cosmetic products. Here we assessed the antimicrobial properties of chicory biomass pre-treated with various enzymes alone and in combination to release the bioactive compounds and increase their bioavailability. We found that pre-treatment significantly increased the antimicrobial activity of this industrial by-product, yielding an extract that inhibited typical skin pathogens in a cosmetic formula challenge test. We also evaluated the valorization of chicory biomass as a bioactive cosmetic ingredient. Economic feasibility was estimated by combining our experimental results with a conceptual techno-economic analysis. Our results suggest that chicory biomass can be utilized for the sustainable production of efficacious cosmetic ingredients.

Maternal sensitivity at the age of 8 months associates with local connectivity of the medial prefrontal cortex in children at 5 years of age.

The quality of mother-child interaction, especially maternal sensitivity in caregiving behavior, plays an important role in a child's later socioemotional development. Numerous studies have indicated associations between poor mother-child interaction and offspring brain structure and function, but more knowledge on how variation in the characteristics of early caregiving is associated with children's brain structure and function is needed. We investigated whether maternal sensitivity at 8 or 30 months is associated with functional connectivity in a child's brain at 5 years of age based on the FinnBrain Birth Cohort Study (17 and 39 mother-child dyads at 8 and 30 months, respectively, with an overlap of 13 dyads). Maternal sensitivity was assessed during a free play interaction using the Emotional Availability Scales at 8 and 30 months of the children's age. Task-free functional magnetic resonance imaging (fMRI) was acquired at the age of 5 years in 7-min scans while watching the Inscapes movie. Regional homogeneity (ReHo) maps were created from the fMRI data, and multiple regression analysis was performed to assess the relation between maternal sensitivity and ReHo. Maternal sensitivity at the age of 8 months was positively associated with children's ReHo values within the medial prefrontal cortex. Distal connectivity of this region showed no significant association with maternal sensitivity in a seed-based connectivity analysis. No associations were found between maternal sensitivity during toddlerhood and brain functional connectivity. Together, these results suggest that maternal sensitivity, especially in infancy, may influence offspring brain functional connectivity. However, studies with larger sample sizes are warranted.

Improving yield of a recombinant biologic in a Brassica hairy root manufacturing process.

Hairy root systems have proven to be a viable alternative for recombinant protein production. For recalcitrant proteins, maximizing the productivity of hairy root cultures is essential. The aim of this study was to optimize a Brassica rapa rapa hairy root process for secretion of alpha- l-iduronidase (IDUA), a biologic of medical value. The process was first optimized with hairy roots expressing eGFP. For the biomass optimization, the highest biomass yields were achieved in modified Gamborg B5 culture medium. For the secretion induction, the optimized secretion media was obtained with additives (1.5 g/l PVP + 1 mg/l 2,4- d + 20.5 g/l KNO3 ) resulting in 3.4 fold eGFP secretion when compared to the non-induced control. These optimized conditions were applied to the IDUA-expressing hairy root clone, confirming that the highest yields of secreted IDUA occurred when using the defined additive combination. The functionality of the IDUA protein, secreted and intracellular, was confirmed with an enzymatic activity assay. A > 150-fold increase of the IDUA activity was observed using an optimized secretion medium, compared with a non-induced medium. We have proven that our B. rapa rapa hairy root system can be harnessed to secrete recalcitrant proteins, illustrating the high potential of hairy roots in plant molecular farming.

Tailoring sensory properties of plant cell cultures for food use.

The nutritional value of Rowan (Sorbus aucuparia L.) and Arctic bramble (Rubus arcticus L.) plant cell cultures in terms of protein and dietary fibre contents is very good, ∼ 18-22% and âˆ¼ 28-29% on dry matter basis, respectively. The aim of this study was to evaluate various processing methods and formulation to modulate sensory profiles of these plant cell cultures for food purposes. For fresh unprocessed plant cell cultures, treatment with sugar or sugar in combination with citric acid significantly improved the mouthfeel and flavour. The sugar and sugar + citric acid treated plant cell culture samples were perceived more moist, softer, less sandy and they had a less coarse mouthfeel when compared to untreated plant cell cultures. Freeze-drying produced sweet, intense, berry-like flavour and resulted in most promising sensory attributes for the studied plant cell cultures. When freeze-dried Rowan plant cell culture was further processed, the most balanced sweetness/sourness ratio was reached by using 9.5 % (w/w) sucrose and 0.1 % (w/w) citric acid or 4.8 % w/w fructose and 0.1 % w/w citric acid. We conclude that formulation and processing can greatly improve the performance of plant cell cultures for food use.

Life cycle assessment of plant cell cultures.

A novel food such as plant cell culture (PCC) is an important complementary asset for traditional agriculture to tackle global food insecurity. To evaluate environmental impacts of PCC, a life cycle assessment was applied to tobacco bright yellow-2 and cloudberry PCCs. Global warming potential (GWP), freshwater eutrophication potential (FEUP), marine eutrophication potential, terrestrial acidification potential (TAP), stratospheric ozone depletion, water consumption and land use were assessed. The results showed particularly high contributions (82-93%) of electricity consumption to GWP, FEUP and TAP. Sensitivity analysis indicated that using wind energy instead of the average Finnish electricity mix reduced the environmental impacts by 34-81%. Enhancement in the energy efficiency of bioreactor mixing processes and reduction in cultivation time also effectively improved the environmental performance (4-47% reduction of impacts). In comparison with other novel foods, the environmental impacts of the PCC products studied were mostly comparable to those of microalgae products but higher than those of microbial protein products produced by autotrophic hydrogen-oxidizing bacteria. Assayed fresh PCC products were similar or close to GWP of conventionally grown food products and, with technological advancements, can be highly competitive.

Maternal pre-pregnancy BMI associates with neonate local and distal functional connectivity of the left superior frontal gyrus.

Maternal obesity/overweight during pregnancy has reached epidemic proportions and has been linked with adverse outcomes for the offspring, including cognitive impairment and increased risk for neuropsychiatric disorders. Prior neuroimaging investigations have reported widespread aberrant functional connectivity and white matter tract abnormalities in neonates born to obese mothers. Here we explored whether maternal pre-pregnancy adiposity is associated with alterations in local neuronal synchrony and distal connectivity in the neonate brain. 21 healthy mother-neonate dyads from uncomplicated pregnancies were included in this study (age at scanning 26.14 ± 6.28 days, 12 male). The neonates were scanned with a 6-min resting-state functional magnetic resonance imaging (rs-fMRI) during natural sleep. Regional homogeneity (ReHo) maps were computed from obtained rs-fMRI data. Multiple regression analysis was performed to assess the association of pre-pregnancy maternal body-mass-index (BMI) and ReHo. Seed-based connectivity analysis with multiple regression was subsequently performed with seed-ROI derived from ReHo analysis. Maternal adiposity measured by pre-pregnancy BMI was positively associated with neonate ReHo values within the left superior frontal gyrus (SFG) (FWE-corrected p < 0.005). Additionally, we found both positive and negative associations (p < 0.05, FWE-corrected) for maternal pre-pregnancy BMI and seed-based connectivity between left SFG and prefrontal, amygdalae, basal ganglia and insular regions. Our results imply that maternal pre-pregnancy BMI associates with local and distal functional connectivity within the neonate left superior frontal gyrus. These findings add to the evidence that increased maternal pre-pregnancy BMI has a programming influence on the developing neonate brain functional networks.

Chicory Extracts and Sesquiterpene Lactones Show Potent Activity against Bacterial and Fungal Pathogens.

Chicory (Cichorium intybus L.) is an important industrial crop cultivated mainly to extract the dietary fiber inulin. However, chicory also contains bioactive compounds such as sesquiterpene lactones and certain polyphenols, which are currently discarded as waste. Plants are an important source of active pharmaceutical ingredients, including novel antimicrobials that are urgently needed due to the global spread of drug-resistant bacteria and fungi. Here, we tested different extracts of chicory for a range of bioactivities, including antimicrobial, antifungal and cytotoxicity assays. Antibacterial and antifungal activities were generally more potent in ethyl acetate extracts compared to water extracts, whereas supercritical fluid extracts showed the broadest range of bioactivities in our assays. Remarkably, the chicory supercritical fluid extract and a purified fraction thereof inhibited both methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Pseudomonas aeruginosa IBRS P001. Chicory extracts also showed higher antibiofilm activity against the yeast Candida albicans than standard sesquiterpene lactone compounds. The cytotoxicity of the extracts was generally low. Our results may thus lead to the development of novel antibacterial and antifungal preparations that are both effective and safe for human use.

Inactivation of the germacrene A synthase genes by CRISPR/Cas9 eliminates the biosynthesis of sesquiterpene lactones in Cichorium intybus L.

Chicory (Cichorium intybus var. sativum) is an industrial crop species cultivated for the production of a fructose polymer inulin, which is used as a low-calorie sweetener and prebiotic. Besides, inulin chicory taproots also accumulate sesquiterpene lactones (STLs). These are bitter tasting compounds, which need to be removed during inulin extraction, resulting in additional costs. In this work, we describe chicory lines where STL accumulation is almost completely eliminated. Genome editing using the CRISPR/Cas9 system was used to inactivate four genes that encode the enzyme that performs the first dedicated step in STL synthesis, germacrene A synthase (CiGAS). Chicory lines were obtained that carried null mutations in all four CiGAS genes. Lines lacking functional CiGAS alleles showed a normal phenotype upon greenhouse cultivation and show nearly complete elimination of the STL synthesis in the roots. It was shown that the reduction in STLs could be attributed to mutations in genetically linked copies of the CiGAS-short gene and not the CiGAS-long gene, which is relevant for breeding the trait into other cultivars. The inactivation of the STL biosynthesis pathway led to increase in phenolic compounds as well as accumulation of squalene in the chicory taproot, presumably due to increased availability of farnesyl pyrophosphate (FFP). These results demonstrate that STLs are not essential for chicory growth and that the inhibition of the STL biosynthesis pathway reduced the STL levels chicory which will facilitate inulin extraction.

Contributions of the international plant science community to the fight against human infectious diseases - part 1: epidemic and pandemic diseases.

Infectious diseases, also known as transmissible or communicable diseases, are caused by pathogens or parasites that spread in communities by direct contact with infected individuals or contaminated materials, through droplets and aerosols, or via vectors such as insects. Such diseases cause ˜17% of all human deaths and their management and control places an immense burden on healthcare systems worldwide. Traditional approaches for the prevention and control of infectious diseases include vaccination programmes, hygiene measures and drugs that suppress the pathogen, treat the disease symptoms or attenuate aggressive reactions of the host immune system. The provision of vaccines and biologic drugs such as antibodies is hampered by the high cost and limited scalability of traditional manufacturing platforms based on microbial and animal cells, particularly in developing countries where infectious diseases are prevalent and poorly controlled. Molecular farming, which uses plants for protein expression, is a promising strategy to address the drawbacks of current manufacturing platforms. In this review article, we consider the potential of molecular farming to address healthcare demands for the most prevalent and important epidemic and pandemic diseases, focussing on recent outbreaks of high-mortality coronavirus infections and diseases that disproportionately affect the developing world.

Contributions of the international plant science community to the fight against infectious diseases in humans-part 2: Affordable drugs in edible plants for endemic and re-emerging diseases.

The fight against infectious diseases often focuses on epidemics and pandemics, which demand urgent resources and command attention from the health authorities and media. However, the vast majority of deaths caused by infectious diseases occur in endemic zones, particularly in developing countries, placing a disproportionate burden on underfunded health systems and often requiring international interventions. The provision of vaccines and other biologics is hampered not only by the high cost and limited scalability of traditional manufacturing platforms based on microbial and animal cells, but also by challenges caused by distribution and storage, particularly in regions without a complete cold chain. In this review article, we consider the potential of molecular farming to address the challenges of endemic and re-emerging diseases, focusing on edible plants for the development of oral drugs. Key recent developments in this field include successful clinical trials based on orally delivered dried leaves of Artemisia annua against malarial parasite strains resistant to artemisinin combination therapy, the ability to produce clinical-grade protein drugs in leaves to treat infectious diseases and the long-term storage of protein drugs in dried leaves at ambient temperatures. Recent FDA approval of the first orally delivered protein drug encapsulated in plant cells to treat peanut allergy has opened the door for the development of affordable oral drugs that can be manufactured and distributed in remote areas without cold storage infrastructure and that eliminate the need for expensive purification steps and sterile delivery by injection.

Neuroimaging in genetic frontotemporal dementia and amyotrophic lateral sclerosis.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have a strong clinical, genetic and pathological overlap. This review focuses on the current understanding of structural, functional and molecular neuroimaging signatures of genetic FTD and ALS. We overview quantitative neuroimaging studies on the most common genes associated with FTD (MAPT, GRN), ALS (SOD1), and both (C9orf72), and summarize visual observations of images reported in the rarer genes (CHMP2B, TARDBP, FUS, OPTN, VCP, UBQLN2, SQSTM1, TREM2, CHCHD10, TBK1).

Plant cell cultures as food-aspects of sustainability and safety.

KEY MESSAGE: Sustainability and safety aspects of plant cell cultures as food are presented. Applicability of dairy side streams as carbon source and use of natural growth enhancers in cultivation are shown. Biotechnologically produced cellular products are currently emerging to replace and add into the portfolio of agriculturally derived commodities. Plant cell cultures used for food could supplement current food production. However, still many aspects need to be resolved before this new food concept can enter the market. Issues related to sustainability and safety for human consumption are relevant for both consumers and regulators. In this study, two plant cell cultures, deriving from arctic bramble (Rubus arcticus) and birch (Betula pendula), were cultivated using lactose-rich dairy side streams as alternative carbon sources to replace sucrose. Biomasses were comparable to those of original plant cell culture media when up to 83% and 75% of the original sucrose was replaced by these side streams for arctic bramble and birch cell cultures, respectively. Furthermore, nutritional composition or sensory properties were not compromised. Synthetic plant growth regulators were replaced by natural components, such as coconut water and IAA for several subculture cycles. Finally, it was shown that only trace amounts of free growth regulators are present in the cells at the harvesting point and assessment by freshwater crustaceans assay indicated that toxicity of the cells was not exceeding that of traditionally consumed bilberry fruit.

Resting-state networks of the neonate brain identified using independent component analysis.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been successfully used to probe the intrinsic functional organization of the brain and to study brain development. Here, we implemented a combination of individual and group independent component analysis (ICA) of FSL on a 6-min resting-state data set acquired from 21 naturally sleeping term-born (age 26 ± 6.7 d), healthy neonates to investigate the emerging functional resting-state networks (RSNs). In line with the previous literature, we found evidence of sensorimotor, auditory/language, visual, cerebellar, thalmic, parietal, prefrontal, anterior cingulate as well as dorsal and ventral aspects of the default-mode-network. Additionally, we identified RSNs in frontal, parietal, and temporal regions that have not been previously described in this age group and correspond to the canonical RSNs established in adults. Importantly, we found that careful ICA-based denoising of fMRI data increased the number of networks identified with group-ICA, whereas the degree of spatial smoothing did not change the number of identified networks. Our results show that the infant brain has an established set of RSNs soon after birth.

Hairy Root Cultures-A Versatile Tool With Multiple Applications.

Hairy roots derived from the infection of a plant by Rhizobium rhizogenes (previously referred to as Agrobacterium rhizogenes) bacteria, can be obtained from a wide variety of plants and allow the production of highly diverse molecules. Hairy roots are able to produce and secrete complex active glycoproteins from a large spectrum of organisms. They are also adequate to express plant natural biosynthesis pathways required to produce specialized metabolites and can benefit from the new genetic tools available to facilitate an optimized production of tailor-made molecules. This adaptability has positioned hairy root platforms as major biotechnological tools. Researchers and industries have contributed to their advancement, which represents new alternatives from classical systems to produce complex molecules. Now these expression systems are ready to be used by different industries like pharmaceutical, cosmetics, and food sectors due to the development of fully controlled large-scale bioreactors. This review aims to describe the evolution of hairy root generation and culture methods and to highlight the possibilities offered by hairy roots in terms of feasibility and perspectives.

Biotransformation of Cyclodextrine-Complexed Semisynthetic Betulin Derivatives by Plant Cells.

In this study, three semisynthetic betulonic acid-based compounds, 20(29)-dihydrolup-2-en[2,3-d]isoxazol-28-oic acid, 1-betulonoylpyrrolidine, and lupa-2,20(29)-dieno[2,3-b]pyrazin-28-oic acid, were studied in biotransformation experiments using Nicotiana tabacum and Catharanthus roseus cell suspension cultures. Biotransformation was performed using cyclodextrin to aid dissolving poorly water-soluble substrates. Several new derivatives were found, consisting of oxidized and glycosylated (pentose- and hexose-conjugated) products.