Advances in grape phenotyping: pigment characterization by reflectance and theoretical chemistry

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π-Stacked polyphenolic dimers: A case study using dispersion-corrected methods

The accuracy of dispersion-corrected calculations (DFT-D2, DFT-D3 and DFT-NL) is assessed here, with large basis sets (def2-QZVP) to avoid incompleteness effects, for the most stable structure of a real-world polyphenol dimer chosen as an appropriate model. Natural polyphenols form such complexes with π-stacking playing a key stabilizing role. Our benchmark calculations predict its existence favored by 22–24 kcal/mol with respect to the isolated monomers, mainly driven by both π–π and H-bonding interactions. The adequate comparison of lower-cost DFT-based methods allowed bracketing their expected accuracy. These results thus pave the way towards reliable studies of challenging aggregation processes of natural products.The work in Alicante is supported by the ‘Ministerio de Educación y Ciencia’ of Spain and the ‘European Regional Development Fund’ through project CTQ2011-27253. The work in Mons is supported by the Belgian National Fund for Scientific Research (FNRS). The work in Limoges is supported by the ‘Conseil Régional du Limousin’ and COST actions FA1003 ‘East–West Collaboration for Grapevine Diversity Exploration and Mobilization of Adaptive Traits for Breeding’ and CM0804 ‘Chemical Biology with Natural Products’. The work in Malaysia is supported by Akademi Sains Malaysia through the SAGA Grant C20 and by the Ministry of Higher Education through the Grant 600-RMI/ST/FRGS 5/3/Fst (4/2011). The authors gratefully acknowledge the support by the Operational Program Research and Development for Innovation–European Regional Development Fund (Project CZ.1.05/2.1.00/03.0058 of the Ministry of Education, Youth and Sports of the Czech Republic). I.B. gratefully thanks the ‘Association Djerbienne de France’ (ADF) for the financial support

Stabilizing and Modulating Color by Copigmentation: Insights from Theory and Experiment

Natural anthocyanin pigments/dyes and phenolic copigments/co-dyes form noncovalent complexes, which stabilize and modulate (in particular blue, violet, and red) colors in flowers, berries, and food products derived from them (including wines, jams, purees, and syrups). This noncovalent association and their electronic and optical implications constitute the copigmentation phenomenon. Over the past decade, experimental and theoretical studies have enabled a molecular understanding of copigmentation. This review revisits this phenomenon to provide a comprehensive description of the nature of binding (the dispersion and electrostatic components of π–π stacking, the hydrophobic effect, and possible hydrogen-bonding between pigment and copigment) and of spectral modifications occurring in copigmentation complexes, in which charge transfer plays an important role. Particular attention is paid to applications of copigmentation in food chemistry.P.T. thanks the “Conseil Régional du Limousin” for financial support and CALI (CAlcul en LImousin). Financial support from the Czech Science Foundation (P208/12/G016), the Ministry of Education, Youth and Sports of the Czech Republic (project LO1305), and the Operational Program Education for Competitiveness-European Social Fund (project CZ.1.07/2.3.00/20.0058 of the Ministry of Education, Youth and Sports of the Czech Republic) is also gratefully acknowledged. The work at IMDEA was supported by the Spanish Ministerio de Economía y Competitividad (MINECO; project CTQ2014-58801)

Pituitary models

pre-printPituitary tumor animal models provide researchers a microenvironment that simulates the clinical situation; however, in comparison with astrocytoma and meningioma tumor research where intracranial xenograft transplantations are increasingly being used to test various therapeutic modalities, in vivo therapeutic research on pituitary animal models focuses on direct drug therapy to the tumor because of the lack of established intracranial pituitary tumor models. The rat subcutaneous prolactin-secreting pituitary model allows investigators to noninvasively measure tumor size and the effect of direct tumor-guided therapy in a serial manner and is considered biologically relevant because it has proven to be histologically, immunocytochemically, and ultrastructurally consistent with human pituitary tumors

GHRH secretion from a pancreatic neuroendocrine tumor causing gigantism in a patient with MEN1.

Summary: A male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare. Learning points: It is important to diagnose gigantism and its underlying cause (pituitary vs ectopic) early in order to prevent further growth and avoid unnecessary pituitary surgery. The most common primary tumour sites in ectopic acromegaly include the lung (53%) and the pancreas (34%) (1): 76% of patients with a pNET secreting GHRH showed a MEN1 mutation (1). Plasma GHRH testing is readily available in international laboratories and can be a useful diagnostic tool in distinguishing between pituitary acromegaly mediated by GH and ectopic acromegaly mediated by GHRH. Positive GHRH immunostaining in the NET tissue confirms the diagnosis. Distinguishing between pituitary (somatotroph) hyperplasia secondary to ectopic GHRH and pituitary adenoma is difficult and requires specialist neuroradiology input and consideration, especially in the MEN1 setting. It is important to note that the vast majority of GHRH-secreting tumours (lung, pancreas, phaeochromocytoma) are expected to be visible on cross-sectional imaging (median diameter 55 mm) (1). Therefore, we suggest that a chest X-ray and an abdominal ultrasound checking the adrenal glands and the pancreas should be included in the routine work-up of newly diagnosed acromegaly patients

Aggressive pituitary tumours and carcinomas, characteristics and management of 171 patients.

OBJECTIVE: To describe clinical and pathological characteristics and treatment outcomes in a large cohort of aggressive pituitary tumours (APT)/pituitary carcinomas (PC). DESIGN: Electronic survey August 2020-May 2021. RESULTS: 96% of 171 (121 APT, 50 PC), initially presented as macro/giant tumours, 6 were microadenomas (5 corticotroph). Ninety-seven tumours, initially considered clinically benign, demonstrated aggressive behaviour after 5.5 years (IQR: 2.8-12). Of the patients, 63% were men. Adrenocorticotrophic hormone (ACTH)-secreting tumours constituted 30% of the APT/PC, and the gonadotroph subtypes were under-represented. Five out of 13 silent corticotroph tumours and 2/6 silent somatotroph tumours became secreting. Metastases were observed after median 6.3 years (IQR 3.7-12.1) from diagnosis. At the first surgery, the Ki67 index was ≥3% in 74/93 (80%) and ≥10% in 38/93 (41%) tumours. An absolute increase of Ki67 ≥ 10% after median of 6 years from the first surgery occurred in 18/49 examined tumours. Tumours with an aggressive course from outset had higher Ki67, mitotic counts, and p53. Temozolomide treatment in 156/171 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1%, and progressive disease in 32.2% of the patients. Treatment with bevacizumab, immune checkpoint inhibitors, and peptide receptor radionuclide therapy resulted in partial regression in 1/10, 1/6, and 3/11, respectively. Median survival in APT and PC was 17.2 and 11.3 years, respectively. Tumours with Ki67 ≥ 10% and ACTH-secretion were associated with worse prognosis. CONCLUSION: APT/PCs exhibit a wide and challenging spectrum of behaviour. Temozolomide is the first-line chemotherapy, and other oncological therapies are emerging. Treatment response continues to be difficult to predict with currently studied biomarkers

Mutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas.

CONTEXT: Limited screening suggests that three germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are not involved in sporadic pituitary tumorigenesis. Multiple novel mutations of this gene have since been identified in familial isolated pituitary adenoma cohorts. OBJECTIVE: The objective of the study was to undertake full AIP coding sequence screening to assess for the presence of germline and somatic mutations in European Union subjects with sporadic pituitary tumors. DESIGN: The study design was the analysis of DNA from peripheral blood lymphocytes and analysis of exons 1-6 and paraexonic intron sequences of AIP. Multiplex ligation-dependent probe amplification was used to screen separate sporadic pituitary tumor tissue samples for discrete and extensive deletions or mutations of the AIP gene. Setting: The study was conducted in university tertiary referral Clinical Genetics, Molecular Biology, and Endocrinology Departments. RESULTS: In 107 patients [prolactinomas (n =49), nonfunctioning tumors (n = 29), somatotropinomas (n = 26), ACTH-secreting tumors (n = 2), TSH-secreting tumors (n = 1)], no germline mutations of AIP were demonstrated. Among a group of 41 tumor samples from other subjects, a novel AIP mutation (R22X) was found in one sample in which the corresponding allele was deleted; follow-up screening of the patient demonstrated a germline R22X AIP mutation. CONCLUSIONS: AIP mutations do not appear to play a prominent role in sporadic pituitary tumorigenesis in this population of European subjects

Evidence of cerebellar involvement in the onset of a manic state

We described the cerebello-cerebral functional connectivity in a subject who developed a manic state after a cerebellar lesion. Whole brain investigation, performed by means of an advanced MRI examination, evidenced an isolated lesion involving the left lobules VI, VIIa (crus I), and IX and the posterior area of the vermis. The cerebello-cerebral functional connectivity analysis detected a pattern of altered connectivity in specific areas of the prefrontal-striatal-thalamic circuits that are typically altered in bipolar subjects during the manic state. Specifically, a pattern of hypo-connectivity was found between the cerebellum and cerebral regions known to be implicated in emotion modulation and social interaction. Conversely, a pattern of hyper-connectivity was found between the cerebellum and posterior cerebral cortical regions that are involved in sensorimotor functions. The present study represents the first evidence that dysregulation of cerebral networks consequent to a cerebellar lesion is at the root of bipolar disorder, at least the manic state, and provides a new framework for interpreting cerebellar modulation in the regulation of mood in specific psychiatric conditions

Three LIF-dependent signatures and gene clusters with atypical expression profiles, identified by transcriptome studies in mouse ES cells and early derivatives

<p>Abstract</p> <p>Background</p> <p>Mouse embryonic stem (ES) cells remain pluripotent <it>in vitro </it>when grown in the presence of the cytokine Leukaemia Inhibitory Factor (LIF). Identification of LIF targets and of genes regulating the transition between pluripotent and early differentiated cells is a critical step for understanding the control of ES cell pluripotency.</p> <p>Results</p> <p>By gene profiling studies carried out with mRNAs from ES cells and their early derivatives treated or not with LIF, we have identified i) LIF-dependent genes, highly expressed in pluripotent cells, whose expression level decreases sharply upon LIF withdrawal [<it>Pluri </it>genes], ii) LIF induced genes [<it>Lifind </it>genes] whose expression is differentially regulated depending upon cell context and iii) genes specific to the reversible or irreversible committed states. In addition, by hierarchical gene clustering, we have identified, among eight independent gene clusters, two atypical groups of genes, whose expression level was highly modulated in committed cells only. Computer based analyses led to the characterization of different sub-types of <it>Pluri </it>and <it>Lifind </it>genes, and revealed their differential modulation by <it>Oct4 </it>or <it>Nanog </it>master genes. Individual knock down of a selection of <it>Pluri </it>and <it>Lifind </it>genes leads to weak changes in the expression of early differentiation markers, in cell growth conditions in which these master genes are still expressed.</p> <p>Conclusion</p> <p>We have identified different sets of LIF-regulated genes depending upon the cell state (reversible or irreversible commitment), which allowed us to present a novel global view of LIF responses. We are also reporting on the identification of genes whose expression is strictly regulated during the commitment step. Furthermore, our studies identify sub-networks of genes with a restricted expression in pluripotent ES cells, whose down regulation occurs while the master knot (composed of OCT4, SOX2 and NANOG) is still expressed and which might be down-regulated together for driving cells towards differentiation.</p