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Plant lignocellulosic biomass, i.e. secondary cell walls of plants, is a vital alternative source for bioenergy. However, the acetylation of xylan in secondary cell walls impedes the conversion of biomass to biofuels. Previous studies have shown that REDUCED WALL ACETYLATION (RWA) proteins are directly involved in the acetylation of xylan but the regulatory mechanism of RWAs is not fully understood. In this study, we demonstrate that overexpression of a Populus trichocarpa PtRWA-C gene increases the level of xylan acetylation and increases the lignin content and S/G ratio, ultimately yielding poplar woody biomass with reduced saccharification efficiency. Furthermore, through gene coexpression network and expression quantitative trait loci (eQTL) analysis, we found that PtRWA-C was regulated not only by the secondary cell wall hierarchical regulatory network but also by an AP2 family transcription factor HARDY (HRD). Specifically, HRD activates PtRWA-C expression by directly binding to the PtRWA-C promoter, which is also the cis-eQTL for PtRWA-C. Taken together, our findings provide insights into the functional roles of PtRWA-C in xylan acetylation and consequently saccharification and shed light on synthetic biology approaches to manipulate this gene and alter cell wall properties. These findings have substantial implications for genetic engineering of woody species, which could be used as a sustainable source of biofuels, valuable biochemicals, and biomaterials.

Background: Rebound pain is believed to involve both nociceptive pain due to insufficient analgesia and hyperalgesia induced by regional anesthesia. Adjuvant's addition could prevent rebound pain. This study aimed to determine if the addition of dexamethasone or clonidine to local anesthetic when performing interscalene block could prevent rebound pain. Methods: This was a multicenter, prospective, parallel grouping, randomized clinical trial conducted with patients receiving a single injection of bupivacaine 0.375% in interscalene block ultrasound guided and general anesthesia for shoulder surgery were randomly assigned to either no additives (control), clonidine (30 mcg), or dexamethasone (4 mg). The primary outcome was rebound pain, defined as sudden onset of pain, moderate to severe intensity (VAS ≥7) without improvement with oral medication, followed by VAS pain at rest, required rescue analgesia, the occurrence of adverse events or complications, and satisfaction survey assessments between groups. Rebound pain and pain at rest were assessed 2, 4, 6, 12, 24, and 48 hours after the procedure. Results: The incidence of rebound pain was not statistically different between groups (p-value = 0.22), with an observed incidence of 41.2% (95% CI 25.9‒57.9), 28.6% (95% CI 16.7‒43.3), and 23.3% (95% CI 12.6‒37.6) in the control, dexamethasone, and clonidine groups, respectively. Additionally, there were no significant differences between the groups in time, from anesthetic blockade to first complaint of pain or the severity of postoperative pain. Conclusion: The administration of dexamethasone or clonidine as perineural adjuncts to local anesthesia in single-injection interscalene blocks did not significantly reduce the incidence of rebound pain.

Creatine transporter deficiency (CTD) is an inborn error of creatine (Cr) metabolism in which Cr is not properly distributed to the brain due to a mutation in the Cr transporter (CrT) SLC6A8 gene. CTD is associated with developmental delays and with neurological disability in children. Dodecyl creatine ester (DCE), as a Cr prodrug, is a promising drug to treat CTD after administration by the nasal route, taking advantage of the nose-to-brain pathway. In this study, the potential adaptive response to energy imbalance in glucose metabolism was investigated in CTD using both SLC6A8-deficient mice (CrT KO) and brain organoids derived from CTD patient cells. Longitudinal brain [18F]FDG PET imaging in CrT KO mice compared to wild-type mice demonstrated that CTD was associated with a significant loss and decline in brain glucose metabolism. In CrT KO mice, intranasal supplementation with DCE for a month significantly mitigated the decline in brain glucose metabolism compared to untreated (vehicle) animals. Mechanistic investigations in CrT KO mice and cerebral organoids derived from CTD patient cells suggest that intracellular trafficking of glucose transporter (Glut) may be altered by lack of activation of AMP-activated protein kinase (AMPK). Consistency between observations in the CrT KO mouse model and cerebral organoids derived from CTD patient cells supports the value of this new model for drug discovery and development. In addition, these results suggest that [18F]FDG PET imaging may offer a unique and minimally-invasive biomarker to monitor the impact of investigational treatment on CTD pathophysiology, with translational perspectives.

ABSTRACT Corticobasal syndrome (CBS) is a rare cause of dementia and comprises varied combinations of subcortical signs (akinetic-rigid parkinsonism, dystonia, or myoclonus) with cortical signs (apraxia, alien hand or cortical sensory deficit), usually asymmetric. We aimed to report and compare the clinical and neuroimaging presentation of two patients diagnosed with CBS. While case 1 had severe non-fluent aphasia associated with mild apraxia and limb rigidity, case 2 had a more posterior cognitive impairment, with a different language pattern associated with marked visuospatial errors and hemineglect. FDG PET played a significant role in diagnosis, suggesting, in the first case, corticobasal degeneration and, in the second, Alzheimer's disease pattern. CBS has been widely studied with the advent of new in vivo methods such as brain FDG PET. Studies that deepen the phenotypic and biomarker heterogeneity of CBS will be of great importance for better classification, prognosis, and treatment of the condition.

Prefoldin (PFD) is a group II chaperonin that is ubiquitously present in the eukaryotic kingdom. Six subunits (PFD1-6) form a jellyfish-like heterohexameric PFD complex and function in protein folding and cytoskeleton organization. However, little is known about its function in plant cell wall-related processes. Here, we report the functional characterization of a PFD gene from Populus deltoides, designated as PdPFD2.2. There are two copies of PFD2 in Populus, and PdPFD2.2 was ubiquitously expressed with high transcript abundance in the cambial region. PdPFD2.2 can physically interact with DELLA protein RGA1_8g, and its subcellular localization is affected by the interaction. In P. deltoides transgenic plants overexpressing PdPFD2.2, the lignin syringyl/guaiacyl ratio was increased, but cellulose content and crystallinity index were unchanged. In addition, the total released sugar (glucose and xylose) amounts were increased by 7.6% and 6.1%, respectively, in two transgenic lines. Transcriptomic and metabolomic analyses revealed that secondary metabolic pathways, including lignin and flavonoid biosynthesis, were affected by overexpressing PdPFD2.2. A total of eight hub transcription factors (TFs) were identified based on TF binding sites of differentially expressed genes in Populus transgenic plants overexpressing PdPFD2.2. In addition, several known cell wall-related TFs, such as MYB3, MYB4, MYB7, TT8 and XND1, were affected by overexpression of PdPFD2.2. These results suggest that overexpression of PdPFD2.2 can reduce biomass recalcitrance and PdPFD2.2 is a promising target for genetic engineering to improve feedstock characteristics to enhance biofuel conversion and reduce the cost of lignocellulosic biofuel production.

We prove that the filtered GRID invariants of Legendrian links in link Floer homology, and consequently their associated invariants in the spectral sequence, obstruct decomposable Lagrangian cobordisms in the symplectization of the standard contact structure on ℝ3, strengthening a result by Baldwin, Lidman, and the fifth author. [ABSTRACT FROM AUTHOR]

Long-lived perennial plants, with distinctive habits of inter-annual growth, defense, and physiology, are of great economic and ecological importance. However, some biological mechanisms resulting from genome duplication and functional divergence of genes in these systems remain poorly studied. Here, we discovered an association between a poplar (Populus trichocarpa) 5-enolpyruvylshikimate 3-phosphate synthase gene (PtrEPSP) and lignin biosynthesis. Functional characterization of PtrEPSP revealed that this isoform possesses a helix-turn-helix motif in the N terminus and can function as a transcriptional repressor that regulates expression of genes in the phenylpropanoid pathway in addition to performing its canonical biosynthesis function in the shikimate pathway. We demonstrated that this isoform can localize in the nucleus and specifically binds to the promoter and represses the expression of a SLEEPER-like transcriptional regulator, which itself specifically binds to the promoter and represses the expression of PtrMYB021 (known as MYB46 in Arabidopsis thaliana), a master regulator of the phenylpropanoid pathway and lignin biosynthesis. Analyses of overexpression and RNAi lines targeting PtrEPSP confirmed the predicted changes in PtrMYB021 expression patterns. These results demonstrate that PtrEPSP in its regulatory form and PtrhAT form a transcriptional hierarchy regulating phenylpropanoid pathway and lignin biosynthesis in Populus.

The treatment of patients suffering from an eating disorder and a comorbid post-traumatic stress disorder is challenging and often leads to poor outcomes. In a randomized control trial, we evaluated to what extent adding Infra-Low Frequency (ILF) neurofeedback could improve symptom reduction within an established inpatient treatment program. In a randomized two-group design, patients suffering from an eating disorder (anorexia nervosa, bulimia nervosa, or binge eating disorder) and comorbid post-traumatic stress disorder (N = 36) were examined while attending an inpatient treatment program in a clinic for psychosomatic disorders. The intervention group received ILF neurofeedback in addition to regular therapy, while the control group received “media-supported relaxation” as a placebo intervention. At the beginning and at the end of their treatment, all participants completed the Eating Disorder Examination-Questionnaire (EDE-Q) as a measure of eating disorder psychopathology and the Impact of Event Scale-Revised (IES-R) in order to assess symptoms of post-traumatic stress. Changes in EDE-Q and IES-R scores over time served as primary outcomes as well as an increase in body mass index in underweight patients. Secondary outcomes were the perceived benefit of the received intervention, global assessment of psychological treatment success, and complications in the course of treatment. Statistical evaluation was carried out with repeated measurement analysis of variance for the primary outcomes and with t-tests and Fisher’s exact test for the secondary outcomes. Our results indicate better treatment outcomes in the ILF neurofeedback group with regard to trauma-associated avoidance as well as with regard to restraint eating and increase in body weight. Furthermore, patients who had received ILF neurofeedback rated the intervention they received and, in tendency, their overall treatment more positively and they experienced fewer complications in the course of treatment. ILF neurofeedback is very well accepted by patients and seems to provide a relevant additional benefit in some aspects of symptom reduction. Findings confirm the feasibility of embedding this treatment approach in an inpatient setting and support the case for a larger study for greater statistical power.Clinical Trial Registration: “Infra-Low Frequency Neurofeedback training in the treatment of patients with eating disorder and comorbid post-traumatic stress disorder”; German Clinical Trials Registry (https://www.drks.de; Identifier: DRKS00027826).

This paper aims the identification of the Organization Designation Authorization (ODA) regulatory approaches adopted by the United States, using the Boeing 737 MAX 8 certification process as a basis, by revising the ODA’s certification role and what can be enhanced on the ODA program, considering the data from the Federal Aviation Administration (FAA), the U.S. Department of Transportation, AND the Office of Inspector General (OIG), and comparing them to the regulatory basis in Europe and in Brazil. An assessment of undue pressure on ODA Unit members and other aspects, such as conflicting restraints, analysing their consequences and roles for the process’ safety, is presented, as well as a comparison with the independent design assurance system adopted by the other two agencies. Therefore, the discussion around the ODA’s aircraft certification processes highlights the ODA model drawbacks, and what can be learned from other models to improve it, so the industry and the society can fully benefit from this system.

Abstract Woody biomass is an important feedstock for biofuel production. Manipulation of wood properties that enable efficient conversion of biomass to biofuel reduces cost of biofuel production. Wood cell wall composition is regulated at several levels that involve expression of transcription factors such as wood‐/secondary cell wall‐associated NAC domains (WND or SND). In Arabidopsis thaliana, SND1 regulates cell wall composition through activation of its down‐stream targets such as MYBs. The functional aspects of SND1 homologs in the woody Populus have been studied through transgenic manipulation. In this study, we investigated the role of PdWND1B, Populus SND1 sequence ortholog, in wood formation using transgenic manipulation through over‐expression or silencing under the control of a vascular‐specific 4‐coumarate‐CoA ligase (4CL) promoter. As compared with control plants, PdWND1B‐RNAi plants were shorter in height, with significantly reduced stem diameter and dry biomass, whereas there were no significant differences in growth and productivity of PdWND1B over‐expression plants. Conversely, PdWND1B over‐expression lines showed a significant reduction in cellulose and increase in lignin content, whereas there was no significant impact on lignin content of downregulated lines. Stem carbohydrate composition analysis revealed a decrease in glucose, mannose, arabinose, and galactose, but an increase in xylose in the over‐expression lines. Transcriptome analysis revealed upregulation of several downstream transcription factors and secondary cell wall related structural genes in the PdWND1B over‐expression lines, partly explaining the observed phenotypic changes in cell wall chemistry. Relative to the control, glucose release efficiency and ethanol production from stem biomass was significantly reduced in over‐expression lines. Our results show that PdWND1B is an important factor determining biomass productivity, cell wall chemistry and its conversion to biofuels in Populus.

Translational methods are needed to monitor the impact of the Alzheimer’s disease (AD) and therapies on brain function in animal models and patients. The formation of amyloid plaques was investigated using [18F]florbetapir autoradiography in a mouse model of AD consisting in unilateral intracerebroventricular (i.c.v) injection of amyloid peptide Aβ25–35. Then, an optimized positron emission tomography (PET) imaging protocol using [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) was performed to estimate brain glucose metabolism: [18F]FDG was injected in awake animals to allow for 40 min brain uptake in freely moving mice. Anesthesia was then induced for 30 min PET acquisition to capture the slow and poorly reversible brain uptake of [18F]FDG. Impact of donepezil (0.25 mg/kg daily, 7 days, orally) on brain function was investigated in AD mice (n = 6 mice/group). Formation of amyloid plaques could not be detected using autoradiography. Compared with sham controls (injection of scramble peptide), significant decrease in [18F]FDG uptake was observed in the AD group in the subcortical volume of the ipsilateral hemisphere. Donepezil restored normal glucose metabolism by selectively increasing glucose metabolism in the affected subcortical volume but not in other brain regions. In mice, [18F]FDG PET imaging can be optimized to monitor impaired brain function associated with i.c.v injection of Aβ25–35, even in the absence of detectable amyloid plaque. This model recapitulates the regional decrease in [18F]FDG uptake observed in AD patients. [18F]FDG PET imaging can be straightforwardly transferred to AD patients and may aid the development of certain therapies designed to restore the altered brain function in AD.

The quantitative relationship between the disruption of the blood-brain barrier (BBB) and the recruitment of glial cells was explored in a mouse model of endotoxemia. [18F]2-Fluoro-2-deoxy-sorbitol ([18F]FDS) PET imaging was used as a paracellular marker for quantitative monitoring of BBB permeability after i.v injection of increasing doses of lipopolysaccharide (LPS) or vehicle (saline, n = 5). The brain distribution of [18F]FDS (V T, mL.cm−3) was estimated using kinetic modeling. LPS dose-dependently increased the brain V T of [18F]FDS after injection of LPS 4 mg/kg (5.2 ± 2.4-fold, n = 4, p < 0.01) or 5 mg/kg (9.0 ± 9.1-fold, n = 4, p < 0.01) but not 3 mg/kg (p > 0.05, n = 7). In 12 individuals belonging to the different groups, changes in BBB permeability were compared with expression of markers of astrocyte (GFAP) and microglial cell (CD11b) using ex vivo immunohistochemistry. Increased expression of CD11b and GFAP expression was observed in mice injected with 3 mg/kg of LPS, which did not increase with higher LPS doses. Quantitative [18F]FDS PET imaging can capture different levels of BBB permeability in vivo. A biphasic effect was observed with the lowest dose of LPS that triggered neuroinflammation without disruptive changes in BBB permeability, and higher LPS doses that increased BBB permeability without additional recruitment of glial cells. [ABSTRACT FROM AUTHOR]

DNK and the Vatican In the hundred issues of DNK several articles paid attention to the possibilities which the Vatican archives hold for the historiography of Dutch Catholicism. Several lists of relevant Vatican sources appeared, and several articles showed a new, although not shocking new, interpretation of specific historical events. This contribution offers an overview and evaluation of these DNK-articles. [ABSTRACT FROM AUTHOR]

Abstract Introduction A rapid transition from a clinical‐based classification to a pathology‐based classification of neurodegenerative conditions, largely promoted by the increasing availability of imaging biomarkers, is emerging. The Framework for Innovative Multi‐tracer molecular Brain Imaging, funded by the EU Joint Program ‐ Neurodegenerative Disease Research 2016 “Working Groups for Harmonisation and Alignment in Brain Imaging Methods for Neurodegeneration,” aimed at providing a roadmap for the applications of established and new molecular imaging techniques in dementia. Methods We consider current and future implications of adopting a pathology‐based framework for the use and development of positron emission tomography techniques. Results This approach will enhance efforts to understand the multifactorial etiology of Alzheimer's disease and other dementias. Discussion The availability of pathology biomarkers will soon transform clinical and research practice. Crucially, a comprehensive understanding of strengths and caveats of these techniques will promote an informed use to take full advantage of these tools.

Abstract Background Plant secondary cell wall is a renewable feedstock for biofuels and biomaterials production. Arabidopsis VASCULAR-RELATED NAC DOMAIN (VND) has been demonstrated to be a key transcription factor regulating secondary cell wall biosynthesis. However, less is known about its role in the woody species. Results Here we report the functional characterization of Populus deltoides WOOD-ASSOCIATED NAC DOMAIN protein 3 (PdWND3A), a sequence homolog of Arabidopsis VND4 and VND5 that are members of transcription factor networks regulating secondary cell wall biosynthesis. PdWND3A was expressed at higher level in the xylem than in other tissues. The stem tissues of transgenic P. deltoides overexpressing PdWND3A (OXPdWND3A) contained more vessel cells than that of wild-type plants. Furthermore, lignin content and lignin monomer syringyl and guaiacyl (S/G) ratio were higher in OXPdWND3A transgenic plants than in wild-type plants. Consistent with these observations, the expression of FERULATE 5-HYDROXYLASE1 (F5H1), encoding an enzyme involved in the biosynthesis of sinapyl alcohol (S unit monolignol), was elevated in OXPdWND3A transgenic plants. Saccharification analysis indicated that the rate of sugar release was reduced in the transgenic plants. In addition, OXPdWND3A transgenic plants produced lower amounts of biomass than wild-type plants. Conclusions PdWND3A affects lignin biosynthesis and composition and negatively impacts sugar release and biomass production.