The breakthrough paradox: How focusing on one form of innovation jeopardizes the advancement of science: How focusing on one form of innovation jeopardizes the advancement of science.

Research needs a balance of risk-taking in "breakthrough projects" and gradual progress. For building a sustainable knowledge base, it is indispensable to provide support for both.

Successful implementation of a stakeholder engagement program for pharmacoepidemiologic research.

PURPOSE: Rigorously conducted pharmacoepidemiologic research requires methodologically complex study designs and analysis yet evaluates problems of high importance to patients and clinicians. Despite this, participation in and mechanisms for stakeholder engagement in pharmacoepidemiologic research are not well-described. Here, we describe our approach and lessons learned from engaging stakeholders, of varying familiarity with research methods, in a rigorous multi-year pharmacoepidemiologic research program evaluating the comparative effectiveness of diabetes medications. METHODS: We recruited 5 patient and 4 clinician stakeholders; each was compensated for their time. Stakeholders received initial formal training in observational research and pharmacoepidemiologic methods sufficient to enable contribution to the research project. After onboarding, stakeholder engagement meetings were held virtually, in the evening, 2-3 times annually. Each was approximately 90 min and focused on 1-2 specific questions about the project, with preparatory materials sent in advance. RESULTS: Stakeholder meeting attendance was high (89%-100%), and all stakeholders engaged with the research project, both during and between meetings. Stakeholders reported positive experiences with meetings, satisfaction, and interest in the research project and its findings, and dedication to the success of the project's goals. They affirmed the value of receiving materials to review in advance and the effectiveness of a virtual platform. Their contributions included prioritizing and suggesting research questions, optimizing written evidence briefs for a lay audience, and guidance on broader topics such as research audience and methods of dissemination. CONCLUSIONS: Stakeholder engagement in pharmacoepidemiologic research using complex study designs and analysis is feasible, acceptable, and positively impacts the research project.

Identification of a UDP-glucosyltransferase conferring deoxynivalenol resistance in Aegilops tauschii and wheat.

Aegilops tauschii is the diploid progenitor of the wheat D subgenome and a valuable resource for wheat breeding, yet, genetic analysis of resistance against Fusarium head blight (FHB) and the major Fusarium mycotoxin deoxynivalenol (DON) is lacking. We treated a panel of 147 Ae. tauschii accessions with either Fusarium graminearum spores or DON solution and recorded the associated disease spread or toxin-induced bleaching. A k-mer-based association mapping pipeline dissected the genetic basis of resistance and identified candidate genes. After DON infiltration nine accessions revealed severe bleaching symptoms concomitant with lower conversion rates of DON into the non-toxic DON-3-O-glucoside. We identified the gene AET5Gv20385300 on chromosome 5D encoding a uridine diphosphate (UDP)-glucosyltransferase (UGT) as the causal variant and the mutant allele resulting in a truncated protein was only found in the nine susceptible accessions. This UGT is also polymorphic in hexaploid wheat and when expressed in Saccharomyces cerevisiae only the full-length gene conferred resistance against DON. Analysing the D subgenome helped to elucidate the genetic control of FHB resistance and identified a UGT involved in DON detoxification in Ae. tauschii and hexaploid wheat. This resistance mechanism is highly conserved since the UGT is orthologous to the barley UGT HvUGT13248 indicating descent from a common ancestor of wheat and barley.

Pyramiding Fusarium head blight resistance QTL from T. aestivum, T. dicoccum and T. dicoccoides in durum wheat.

KEY MESSAGE: FHB resistance of durum wheat was improved by introgression of Fhb1 and resistance genes from emmer wheat and by selection against adverse alleles of elite durum wheat. Durum wheat is particularly susceptible to Fusarium head blight (FHB) and breeding for resistance is impeded by the low genetic variation within the elite gene pool. To extend the genetic basis for FHB resistance in durum wheat, we analyzed 603 durum wheat lines from crosses of elite durum wheat with resistance donors carrying resistance alleles derived from Triticum aestivum, T. dicoccum and T. dicoccoides. The lines were phenotyped for FHB resistance, anthesis date, and plant height in artificially inoculated disease nurseries over 5 years. A broad variation was found for all traits, while anthesis date and plant height strongly influenced FHB severities. To correct for spurious associations, we adjusted FHB scorings for temperature fluctuations during the anthesis period and included plant height as a covariate in the analysis. This resulted in the detection of seven quantitative trait loci (QTL) affecting FHB severities. The hexaploid wheat-derived Fhb1 QTL was most significant on reducing FHB severities, highlighting its successful introgression into several durum wheat backgrounds. For two QTL on chromosomes 1B and 2B, the resistance alleles originated from the T. dicoccum line Td161 and T. dicoccoides accessions Mt. Hermon#22 and Mt. Gerizim#36, respectively. The other four QTL featured unfavorable alleles derived from elite durum wheat that increased FHB severities, with a particularly negative effect on chromosome 6A that simultaneously affected plant height and anthesis date. Therefore, in addition to pyramiding resistance genes, selecting against adverse alleles present in elite durum wheat could be a promising avenue in breeding FHB-resistant durum wheat.

Fusarium head blight resistance in European winter wheat: insights from genome-wide transcriptome analysis.

BACKGROUND: Fusarium head blight (FHB) is a devastating disease of wheat worldwide. Resistance to FHB is quantitatively controlled by the combined effects of many small to medium effect QTL. Flowering traits, especially the extent of extruded anthers, are strongly associated with FHB resistance. RESULTS: To characterize the genetic basis of FHB resistance, we generated and analyzed phenotypic and gene expression data on the response to Fusarium graminearum (Fg) infection in 96 European winter wheat genotypes, including several lines containing introgressions from the highly resistant Asian cultivar Sumai3. The 96 lines represented a broad range in FHB resistance and were assigned to sub-groups based on their phenotypic FHB severity score. Comparative analyses were conducted to connect sub-group-specific expression profiles in response to Fg infection with FHB resistance level. Collectively, over 12,300 wheat genes were Fusarium responsive. The core set of genes induced in response to Fg was common across different resistance groups, indicating that the activation of basal defense response mechanisms was largely independent of the resistance level of the wheat line. Fg-induced genes tended to have higher expression levels in more susceptible genotypes. Compared to the more susceptible non-Sumai3 lines, the Sumai3-derivatives demonstrated higher constitutive expression of genes associated with cell wall and plant-type secondary cell wall biogenesis and higher constitutive and Fg-induced expression of genes involved in terpene metabolism. Gene expression analysis of the FHB QTL Qfhs.ifa-5A identified a constitutively expressed gene encoding a stress response NST1-like protein (TraesCS5A01G211300LC) as a candidate gene for FHB resistance. NST1 genes are key regulators of secondary cell wall biosynthesis in anther endothecium cells. Whether the stress response NST1-like gene affects anther extrusion, thereby affecting FHB resistance, needs further investigation. CONCLUSION: Induced and preexisting cell wall components and terpene metabolites contribute to resistance and limit fungal colonization early on. In contrast, excessive gene expression directs plant defense response towards programmed cell death which favors necrotrophic growth of the Fg pathogen and could thus lead to increased fungal colonization.

"I was able to eat what I am supposed to eat"-- patient reflections on a medically-tailored meal intervention: a qualitative analysis.

BACKGROUND: Medically-tailored meal programs that provide home-delivered medically-appropriate food are an emerging intervention when type 2 diabetes co-occurs with food insecurity (limited or uncertain access to nutritious food owing to cost). We sought to understand the experiences of medically-tailored meal program participants. METHODS: We conducted semi-structured interviews with participants in a randomized trial of medically-tailored meals (NCT02426138) until reaching content saturation. Participants were adults (age > 20 years) with type 2 diabetes in eastern Massachusetts, and the interviews were conducted from April to July 2017. Interviews were transcribed verbatim and coded by two independent reviewers. We determined emergent themes using content analysis. RESULTS: Twenty individuals were interviewed. Their mean age was 58 (SD: 13) years, 60.0% were women, 20.0% were non-Hispanic black, and 15.0% were Hispanic. Key themes were 1) satisfaction and experience with medically-tailored meals 2) food preferences and cultural appropriateness, 3) diabetes management and awareness, and 4) suggestions for improvement and co-interventions. Within these themes, participants were generally satisfied with medically-tailored meals and emphasized the importance of receiving culturally appropriate food. Participants reported several positive effects of medically-tailored meals, including improved quality of life and ability to manage diabetes, and stress reduction. Participants suggested combining medically-tailored meals with diabetes self-management education or lifestyle interventions. CONCLUSIONS: Individuals with diabetes and food insecurity expressed satisfaction with the medically-tailored meal program, and reported that participation reduced stress and the burden of diabetes management. Suggestions to help ensure the success of medically-tailored meal programs included a strong emphasis on culturally acceptability and accommodating taste preferences for provided foods, and combining medically-tailored meals with diabetes education or lifestyle intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT02426138.

Chitosan Hydrochloride Decreases Fusarium graminearum Growth and Virulence and Boosts Growth, Development and Systemic Acquired Resistance in Two Durum Wheat Genotypes.

Fusarium head blight (FHB) is a devastating disease for cereals. FHB is managed by fungicides at anthesis, but their efficacy is variable. Conventional fungicides accumulate in the soil and are dangerous for animal and human health. This study assayed the antifungal ability of chitosan hydrochloride against Fusarium graminearum. Chitosan reduced F. graminearum growth and downregulated the transcript of the major genes involved in the cell growth, respiration, virulence, and trichothecenes biosynthesis. Chitosan promoted the germination rate, the root and coleoptile development, and the nitrogen balance index in two durum wheat genotypes, Marco Aurelio (FHB-susceptible) and DBC480 (FHB-resistant). Chitosan reduced FHB severity when applied on spikes or on the flag leaves. FHB severity in DBC480 was of 6% at 21 dpi after chitosan treatments compared to F. graminearum inoculated control (20%). The elicitor-like property of chitosan was confirmed by the up-regulation of TaPAL, TaPR1 and TaPR2 (around 3-fold). Chitosan decreased the fungal spread and mycotoxins accumulation. This study demonstrated that the non-toxic chitosan is a powerful molecule with the potential to replace the conventional fungicides. The combination of a moderately resistant genotype (DBC480) with a sustainable compound (chitosan) will open new frontiers for the reduction of conventional compounds in agriculture.

[Assisted living facilities in inpatient and outpatient settings]. / Wohn- und Hausgemeinschaften in stationären und ambulanten Settings.

BACKGROUND AND OBJECTIVE: Assisted living (AL) facilities for older people in need of support in outpatient and inpatient settings differ from nursing homes due to the orientation towards autonomy of the residents and the normality of living and everyday routines, very similar to living at home. The conceptual framework, here defined as AL, is characterized by a homelike small-scale environment and the keeping of one's own household and manageability. The presence of personnel in a new personal mix supports qualities, such as social participation, meaningful activities and functional support. The study examined how this frame of reference impacts the quality of life of residents and reflects the perspectives of further development of housing options. MATERIAL AND METHODS: Over a period of 9 months (2006-2007) 8 AL facilities with 73 residents and a classical nursing home with 18 residents were examined in terms of behavioral competence, subjective well-being, perceived quality of life and objective environment. Established multidimensional person and environment-related assessment instruments were applied. Specific organizational questions were explored through qualitative interviews. RESULTS: Despite a formal inpatient or outpatient classification, the residents living in AL facilities showed significantly higher values for well-being and showed significantly less agitated, challenging behavior compared to the nursing home. In particular, people with dementia benefited from the specific quality of AL, which is reflected in relevant dimensions. CONCLUSION: The findings indicate that AL represents a concept that can be used as a basis for new housing offers and a new type of care infrastructure. It provides connecting factors to the leading principle of shared responsibility.

Medically Tailored Meal Delivery for Diabetes Patients with Food Insecurity: a Randomized Cross-over Trial.

BACKGROUND: Food insecurity, defined as inconsistent food access owing to cost, leads to poor health. OBJECTIVE: To test whether a medically tailored meal delivery program improved dietary quality in individuals with type 2 diabetes and food insecurity. DESIGN: Randomized cross-over clinical trial. PARTICIPANTS: Forty-four adults with diabetes, hemoglobin A1c > 8.0%, and food insecurity (defined as at least one positive item on the two-item "Hunger Vital Sign"). INTERVENTION: In the Community Servings: Food as Medicine for Diabetes cross-over clinical trial (NCT02426138), conducted from June 2015 to July 2017, we randomly assigned the order of "on-meals" (home delivery of 10 meals/week for 12 weeks delivered by Community Servings, a non-profit organization) and "off-meals" (12 weeks usual care and a Choose MyPlate healthy eating brochure) periods. MAIN MEASURES: The primary outcome was Healthy Eating Index 2010 score (HEI), assessed by three 24-h food recalls in both periods. Higher HEI score (range 0-100; clinically significant difference 5) represents better dietary quality. Secondary outcomes included food insecurity and self-reported hypoglycemia. KEY RESULTS: Mean "on-meal" HEI score was 71.3 (SD 7.5) while mean "off-meal" HEI score was 39.9 (SD 7.8) (difference 31.4 points, p < 0.0001). Participants experienced improvements in almost all sub-categories of HEI score, with increased consumption of vegetables, fruits, and whole grains and decreased solid fats, alcohol, and added sugar consumption. Participants also reported lower food insecurity (42% "on-meal" vs. 62% "off-meal," p = 0.047), less hypoglycemia (47% "on-meal" vs. 64% "off-meal," p = 0.03), and fewer days where mental health interfered with quality of life (5.65 vs. 9.59 days out of 30, p = 0.03). CONCLUSIONS: For food-insecure individuals with diabetes, medically tailored meals improved dietary quality and food insecurity and reduced hypoglycemia. Longer-term studies should evaluate effects on diabetes control (e.g., hemoglobin A1c) and patient-reported outcomes (e.g., well-being).

Fine-mapping of the Fusarium head blight resistance QTL Qfhs.ifa-5A identifies two resistance QTL associated with anther extrusion.

KEY MESSAGE: Fine-mapping separated Qfhs.ifa-5A into a major QTL mapping across the centromere and a minor effect QTL positioned at the distal half of 5AS. Both increase Fusarium resistance and anther extrusion. The Fusarium head blight (FHB) resistance QTL Qfhs.ifa-5A resides in the low-recombinogenic pericentromeric region of chromosome 5A making fine-mapping particularly arduous. Qfhs.ifa-5A primarily contributes resistance to fungal entry with the favorable allele descending from the highly Fusarium resistant cultivar Sumai-3. Fine-mapping a near-isogenic recombinant inbred line population partitioned the Qfhs.ifa-5A interval into 12 bins. Near-isogenic lines recombining at the interval were phenotyped for FHB severity, anther retention and plant height. Composite interval mapping separated the initially single QTL into two QTL. The major effect QTL Qfhs.ifa-5Ac mapped across the centromere and the smaller effect QTL Qfhs.ifa-5AS mapped to the distal half of 5AS. Although Qfhs.ifa-5Ac and Qfhs.ifa-5AS intervals were as small as 0.1 and 0.2 cM, their corresponding physical distances were large, comprising 44.1 Mbp and 49.2 Mbp, respectively. Sumai-3 alleles at either QTL improved FHB resistance and increased anther extrusion suggesting a pleiotropic effect of anthers on resistance. This hypothesis was supported by greenhouse experiments using the susceptible cultivar Remus and its resistant near-isogenic line NIL3 carrying the entire Qfhs.ifa-5A segment. By manually removing anthers prior to spray inoculation both, Remus and NIL3 became almost equally resistant in the early phase of the disease development and were significantly less diseased than variants without anther manipulation. At late time points the positive effect of the anther removal became smaller for Remus and disappeared completely for NIL3. Results affirm that absence of anthers enhanced resistance to initial infection but did not protect plants from fungal spreading within spikes.

Exploring and exploiting the genetic variation of Fusarium head blight resistance for genomic-assisted breeding in the elite durum wheat gene pool.

KEY MESSAGE: Genomic selection had a higher selection response for FHB resistance than phenotypic selection, while association mapping identified major QTL on chromosome 3B unaffected by plant height and flowering date. Fusarium head blight (FHB) is one of the most destructive diseases of durum wheat. Hence, minimizing losses in yield, quality and avoiding contamination with mycotoxins are of pivotal importance, as durum wheat is mostly used for human consumption. While growing resistant varieties is the most promising approach for controlling this fungal disease, FHB resistance breeding in durum wheat is hampered by the limited variation in the elite gene pool and difficulties in efficiently combining the numerous small-effect resistance quantitative trait loci (QTL) in the same line. We evaluated an international collection of 228 genotyped durum wheat cultivars for FHB resistance over 3 years to investigate the genetic architecture and potential of genomic-assisted breeding for FHB resistance in durum wheat. Plant height was strongly positively correlated with FHB resistance and led to co-localization of plant height and resistance QTL. Nevertheless, a major QTL on chromosome 3B independent of plant height was identified in the same chromosomal interval as reported for the prominent hexaploid resistance QTL Fhb1, though haplotype analysis highlighted the distinctiveness of both QTL. Comparison between phenotypic and genomic selection for FHB resistance revealed a superior prediction ability of the former. However, simulated selection experiments resulted in higher selection responses when using genomic breeding values for early generation selection. An earlier identification of the most promising lines and crossing parents was feasible with a genomic selection index, which suggested a much faster short-term population improvement than previously possible in durum wheat, complementing long-term strategies with exotic resistance donors.

Fusarium Head Blight in Durum Wheat: Recent Status, Breeding Directions, and Future Research Prospects.

Fusarium head blight (FHB) is a major fungal disease affecting wheat production worldwide. Since the early 1990s, FHB, caused primarily by Fusarium graminearum, has become one of the most significant diseases faced by wheat producers in Canada and the United States. The increasing FHB problem is likely due to the increased adoption of conservation tillage practices, expansion of maize production, use of susceptible wheat varieties in rotation, and climate variability. Durum wheat (Triticum turgidum sp. durum) is notorious for its extreme susceptibility to FHB and breeding for resistance is complicated because sources of FHB resistance are rare in the primary gene pool of tetraploid wheat. Losses due to this disease include yield, test weight, seed quality, food and feed quality, and when severe, market access. More importantly, it is the contamination with mycotoxins, such as deoxynivalenol, in Fusarium-infected durum kernels that causes the most serious economic as well as food and feed safety concerns. Several studies and thorough reviews have been published on germplasm development and breeding for FHB resistance and the genetics and genomics of FHB resistance in bread or common wheat (T. aestivum); however, similar reviews have not been conducted in durum wheat. Thus, the aim of this review is to summarize and discuss the recent research efforts to mitigate FHB in durum wheat, including quantitative trait locus mapping, genome-wide association studies, genomic prediction, mutagenesis and characterization of genes and pathways involved in FHB resistance. It also highlights future directions, FHB-resistant germplasm, and the potential role of morphological traits to enhance FHB resistance in durum wheat.

Indomethacin promotes survival of new neurons in the adult murine hippocampus accompanied by anti-inflammatory effects following MPTP-induced dopamine depletion.

BACKGROUND: Parkinson's disease (PD) is characterized by dopaminergic cell loss and inflammation in the substantia nigra (SN) leading to motor deficits but also to hippocampus-associated non-motor symptoms such as spatial learning and memory deficits. The cognitive decline is correlated with impaired adult hippocampal neurogenesis resulting from dopamine deficit and inflammation, represented in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) mouse model of PD. In the inflammatory tissue, cyclooxygenase (COX) is upregulated leading to an ongoing inflammatory process such as prostaglandin-mediated increased cytokine levels. Therefore, inhibition of COX by indomethacin may prevent the inflammatory response and the impairment of adult hippocampal neurogenesis. METHODS: Wildtype C57Bl/6 and transgenic Nestin-GFP mice were treated with MPTP followed by short-term or long-term indomethacin treatment. Then, aspects of inflammation and neurogenesis were evaluated by cell counts using immunofluorescence and immunohistochemical stainings in the SN and dentate gyrus (DG). Furthermore, hippocampal mRNA expression of neurogenesis-related genes of the Notch, Wnt, and sonic hedgehog signaling pathways and neurogenic factors were assessed, and protein levels of serum cytokines were measured. RESULTS: Indomethacin restored the reduction of the survival rate of new mature neurons and reduced the amount of amoeboid CD68+ cells in the DG after MPTP treatment. Indomethacin downregulated genes of the Wnt and Notch signaling pathways and increased neuroD6 expression. In the SN, indomethacin reduced the pro-inflammatory cellular response without reversing dopaminergic cell loss. CONCLUSION: Indomethacin has a pro-neurogenic and thereby restorative effect and an anti-inflammatory effect on the cellular level in the DG following MPTP treatment. Therefore, COX inhibitors such as indomethacin may represent a therapeutic option to restore adult neurogenesis in PD.

High-resolution mapping of the pericentromeric region on wheat chromosome arm 5AS harbouring the Fusarium head blight resistance QTL Qfhs.ifa-5A.

The Qfhs.ifa-5A allele, contributing to enhanced Fusarium head blight resistance in wheat, resides in a low-recombinogenic region of chromosome 5A close to the centromere. A near-isogenic RIL population segregating for the Qfhs.ifa-5A resistance allele was developed and among 3650 lines as few as four recombined within the pericentromeric C-5AS1-0.40 bin, yielding only a single recombination point. Genetic mapping of the pericentromeric region using a recombination-dependent approach was thus not successful. To facilitate fine-mapping the physically large Qfhs.ifa-5A interval, two gamma-irradiated deletion panels were generated: (i) seeds of line NIL3 carrying the Qfhs.ifa-5A resistance allele in an otherwise susceptible background were irradiated and plants thereof were selfed to obtain deletions in homozygous state and (ii) a radiation hybrid panel was produced using irradiated pollen of the wheat line Chinese Spring (CS) for pollinating the CS-nullisomic5Atetrasomic5B. In total, 5157 radiation selfing and 276 radiation hybrid plants were screened for deletions on 5AS and plants containing deletions were analysed using 102 5AS-specific markers. Combining genotypic information of both panels yielded an 817-fold map improvement (cR/cM) for the centromeric bin and was 389-fold increased across the Qfhs.ifa-5A interval compared to the genetic map, with an average map resolution of 0.77 Mb/cR. We successfully proved that the RH mapping technique can effectively resolve marker order in low-recombining regions, including pericentromeric intervals, and simultaneously allow developing an in vivo panel of sister lines differing for induced deletions across the Qfhs.ifa-5A interval that can be used for phenotyping.

p27kip1 Is Required for Functionally Relevant Adult Hippocampal Neurogenesis in Mice.

We asked whether cell-cycle associated protein p27kip1 might be involved in the transition of precursor cells to postmitotic maturation in adult hippocampal neurogenesis. p27kip1 was expressed throughout the dentate gyrus with a strong nuclear expression in early postmitotic, calretinin-positive neurons and neuronally determined progenitor cells (type-3 and some type-2b), lower or absent expression in radial glia-like precursor cells (type-1) and type-2a cells and essentially no expression in granule cells. This suggested a transitory role in late proliferative and early postmitotic phases of neurogenesis. Inconsistent with a role limited to cell cycle arrest the acute stimuli, voluntary wheel running (RUN), environmental enrichment (ENR) and kainate-induced seizures increased p27kip1 expressing cells. Sequential short-term combination of RUN and ENR yielded more p27kip1 cells than either stimulus alone, indicating an additive effect. In vitro, p27kip1 was lowly expressed by proliferating precursor cells but increased upon differentiation. In p27kip1-/- mice neurogenesis was reduced in vivo, whereas the number of proliferating cells was increased. Accordingly, the microdissected dentate gyrus of p27kip1-/- mice generated more colonies in the neurosphere assay and an increased number of larger spheres with the differentiation potential unchanged. In p27kip1-/- monolayer cultures, proliferation was increased and cell cycle genes were upregulated. In the Morris water maze p27kip1-/- mice learned the task but were specifically impaired in the reversal phase explainable by the decrease in adult neurogenesis. We conclude that p27kip1 is involved in the decisive step around cell-cycle exit and plays an important role in activity-regulated and functionally relevant adult hippocampal neurogenesis. Stem Cells 2017;35:787-799.

MR elastography detection of early viscoelastic response of the murine hippocampus to amyloid ß accumulation and neuronal cell loss due to Alzheimer's disease.

PURPOSE: To investigate in vivo viscoelastic parameters related to early histopathological changes in the hippocampus and the cortex in early, preclinical Alzheimer's disease (AD) stages. MATERIALS AND METHODS: Magnetic resonance elastography (MRE) was applied to female APP23 mice, an established transgenic mouse model of AD, at three different stages early in disease progression. To investigate the potential therapeutic effects of physical, cognitive, and social stimulation on brain viscoelasticity and histopathological characteristics, MRE was also applied after exposing young APP23 mice to environmentally enriched cage conditions (ENR), for 1, 12, or 24 weeks, which corresponds to adolescent, young-adult, and adult age at the time of analysis. RESULTS: Viscosity in the hippocampus of APP23 mice is lower than in controls (CTR) (P = 0.005) and does not increase with age, as in CTR mice (adolescent vs. young-adult: P = 1.000, vs. adult: P = 0.493, young-adult vs. adult: P = 1.000). Hippocampal cell numbers decrease with disease progression in APP23 mice (P < 0.001). Elasticity in the hippocampus is also reduced in APP23 mice (P = 0.024) but increases (P = 0.027) with disease progression. ENR in APP23 mice transiently increased hippocampal cell numbers (P = 0.002) but not viscosity (P = 0.838). CONCLUSION: MRE detects alterations in viscoelasticity in the hippocampus related to early histopathological changes in the APP23 mouse model of AD. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:105-114.

QTL mapping of Fusarium head blight resistance in three related durum wheat populations.

KEY MESSAGE: The QTL Fhb1 was successfully introgressed and validated in three durum wheat populations. The novel germplasm and the QTL detected will support improvement of Fusarium resistance in durum wheat. Durum wheat (Triticum durum Desf.) is particularly susceptible to Fusarium head blight (FHB) and breeding for resistance is hampered by limited genetic variation within this species. To date, resistant sources are mainly available in a few wild relative tetraploid wheat accessions. In this study, the effect of the well-known hexaploid wheat (Triticum aestivum L.) quantitative trait locus (QTL) Fhb1 was assessed for the first time in durum wheat. Three F7-RIL mapping populations of about 100 lines were developed from crosses between the durum wheat experimental line DBC-480, which carries an Fhb1 introgression from Sumai-3, and the European T. durum cultivars Karur, Durobonus and SZD1029K. The RILs were evaluated in field experiments for FHB resistance in three seasons using spray inoculation and genotyped with SSR as well as genotyping-by-sequencing markers. QTL associated with FHB resistance were identified on chromosome arms 2BL, 3BS, 4AL, 4BS, 5AL and 6AS at which the resistant parent DBC-480 contributed the positive alleles. The QTL on 3BS was detected in all three populations centered at the Fhb1 interval. The Rht-B1 locus governing plant height was found to have a strong effect in modulating FHB severity in all populations. The negative effect of the semi-dwarf allele Rht-B1b on FHB resistance was compensated by combining with Fhb1 and additional resistance QTL. The successful deployment of Fhb1 in T. durum was further substantiated by assessing type 2 resistance in one population. The efficient introgression of Fhb1 represents a significant step forward for enhancing FHB resistance in durum wheat.

Melatonin restores hippocampal neural precursor cell proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice.

Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder "jet lag" disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro-neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag-induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro-neurogenic stimuli melatonin (8 mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate "jet lag" by shortening the dark period every third day by 6 hours for 3 weeks. We found that "jet lag" simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (~23%). While melatonin prevented both the cellular (~1%) as well as the cognitive deficits (~5%), environmental enrichment only preserved precursor cell proliferation (~12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag-induced consequences. Instead, melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to.

Oxidation of Monolignols by Members of the Berberine Bridge Enzyme Family Suggests a Role in Plant Cell Wall Metabolism.

Plant genomes contain a large number of genes encoding for berberine bridge enzyme (BBE)-like enzymes. Despite the widespread occurrence and abundance of this protein family in the plant kingdom, the biochemical function remains largely unexplored. In this study, we have expressed two members of the BBE-like enzyme family from Arabidopsis thaliana in the host organism Komagataella pastoris. The two proteins, termed AtBBE-like 13 and AtBBE-like 15, were purified, and their catalytic properties were determined. In addition, AtBBE-like 15 was crystallized and structurally characterized by x-ray crystallography. Here, we show that the enzymes catalyze the oxidation of aromatic allylic alcohols, such as coumaryl, sinapyl, and coniferyl alcohol, to the corresponding aldehydes and that AtBBE-like 15 adopts the same fold as vanillyl alcohol oxidase as reported previously for berberine bridge enzyme and other FAD-dependent oxidoreductases. Further analysis of the substrate range identified coniferin, the glycosylated storage form of coniferyl alcohol, as a substrate of the enzymes, whereas other glycosylated monolignols were rather poor substrates. A detailed analysis of the motifs present in the active sites of the BBE-like enzymes in A. thaliana suggested that 14 out of 28 members of the family might catalyze similar reactions. Based on these findings, we propose a novel role of BBE-like enzymes in monolignol metabolism that was previously not recognized for this enzyme family.

Mouse model of CADASIL reveals novel insights into Notch3 function in adult hippocampal neurogenesis.

Could impaired adult hippocampal neurogenesis be a relevant mechanism underlying CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)? Memory symptoms in CADASIL, the most common hereditary form of vascular dementia, are usually thought to be primarily due to vascular degeneration and white matter lacunes. Since adult hippocampal neurogenesis, a process essential for the integration of new spatial memory occurs in a highly vascularized niche, we considered dysregulation of adult neurogenesis as a potential mechanism for the manifestation of dementia in CADASIL. Analysis in aged mice overexpressing Notch3 with a CADASIL mutation, revealed vascular deficits in arteries of the hippocampal fissure but not in the niche of the dentate gyrus. At 12 months of age, cell proliferation and survival of newborn neurons were reduced not only in CADASIL mice but also in transgenic controls overexpressing wild type Notch3. At 6 months, hippocampal neurogenesis was altered in CADASIL mice independent of overt vascular abnormalities in the fissure. Further, we identified Notch3 expression in hippocampal precursor cells and maturing neurons in vivo as well as in cultured hippocampal precursor cells. Overexpression and knockdown experiments showed that Notch3 signaling negatively regulated precursor cell proliferation. Notch3 overexpression also led to deficits in KCl-induced precursor cell activation. This suggests a cell-autonomous effect of Notch3 signaling in the regulation of precursor proliferation and activation and a loss-of-function effect in CADASIL. Consequently, besides vascular damage, aberrant precursor cell proliferation and differentiation due to Notch3 dysfunction might be an additional independent mechanism for the development of hippocampal dysfunction in CADASIL.