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Mona Mokhtari, Michael Jackson, Alistair Brown, David Ackerley, Nigel Ritson, Robert A Keyzers, Andrew Munkacsi
Pathogenic fungi continue to develop resistance against current antifungal drugs. To explore the potential of agricultural waste products as a source of novel antifungal compounds, we obtained an unbiased GC-MS profile of 151 compounds from 16 commercial and experimental cultivars of feijoa peels. Multivariate analysis correlated 93% of the compound profile with antifungal bioactivity. Of 18 compounds that significantly correlated with antifungal activity, five had not previously been described from feijoa...
March 16, 2018: Journal of Agricultural and Food Chemistry
Naoyuki Kitao, Akinobu Nakamura, Hideaki Miyoshi, Hiroshi Nomoto, Kiyohiko Takahashi, Kazuno Omori, Kohei Yamamoto, Kyu Yong Cho, Yasuo Terauchi, Tatsuya Atsumi
OBJECTIVE: We investigated whether glucokinase and insulin receptor substrate-2 were required for beta cell proliferation induced by short-term high-fat (HF) diet feeding, as has been shown for long-term HF diet. METHODS: Eight-week-old C57BL/6 J mice were exposed to either a standard chow (SC) or HF diet. After 1 week on the diet, histopathological beta cell proliferation and gene expression in isolated islets were examined. Additionally, 8-week-old beta cell-specific glucokinase haploinsufficient (Gck+/- ) and Irs2 knockout (Irs2-/- ) mice were exposed to either an SC or HF diet...
March 12, 2018: Metabolism: Clinical and Experimental
Jovana Kovacevic, Gregoire Maroteaux, Desiree Schut, Maarten Loos, Mohit Dubey, Julika Pitsch, Esther Remmelink, Bastijn Koopmans, James Crowley, L Niels Cornelisse, Patrick F Sullivan, Susanne Schoch, Ruud F Toonen, Oliver Stiedl, Matthijs Verhage
De novo heterozygous mutations in STXBP1/Munc18-1 cause early infantile epileptic encephalopathies (EIEE4, OMIM #612164) characterized by infantile epilepsy, developmental delay, intellectual disability, and can include autistic features. We characterized the cellular deficits for an allelic series of seven STXBP1 mutations and developed four mouse models that recapitulate the abnormal EEG activity and cognitive aspects of human STXBP1-encephalopathy. Disease-causing STXBP1 variants supported synaptic transmission to a variable extent on a null background, but had no effect when overexpressed on a heterozygous background...
March 12, 2018: Brain: a Journal of Neurology
Antoine Guérin, Gaspard Kerner, Nico Marr, Janet G Markle, Florence Fenollar, Natalie Wong, Sabri Boughorbel, Danielle T Avery, Cindy S Ma, Salim Bougarn, Matthieu Bouaziz, Vivien Beziat, Erika Della Mina, Carmen Oleaga-Quintas, Tomi Lazarovt, Lisa Worley, Tina Nguyen, Etienne Patin, Caroline Deswarte, Rubén Martinez-Barricarte, Soraya Boucherit, Xavier Ayral, Sophie Edouard, Stéphanie Boisson-Dupuis, Vimel Rattina, Benedetta Bigio, Guillaume Vogt, Frédéric Geissmann, Lluis Quintana-Murci, Damien Chaussabel, Stuart G Tangye, Didier Raoult, Laurent Abel, Jacinta Bustamante, Jean-Laurent Casanova
Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity...
March 14, 2018: ELife
Hema Singh, Pradeep Tiwari, Vijay Bhavi, Praveen Singh Chaudhary, Prashanth Suravajhala, M Krishna Mohan, Sandeep Kumar Mathur
Background: Human height is a classic polygenic trait and currently available data explains only 10% of the phenotypic variation in height. Almost 60%-80% of the children coming to pediatric and endocrinology outpatient department for the evaluation of short stature are still labeled as idiopathic. Objectives: The aim of this study is to identify various chromosomal alterations causing idiopathic short stature (ISS) and short stature with dysmorphic features not pertaining to known genetic syndromes...
January 2018: Indian Journal of Endocrinology and Metabolism
Luye Qin, Kaijie Ma, Zi-Jun Wang, Zihua Hu, Emmanuel Matas, Jing Wei, Zhen Yan
Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits...
March 12, 2018: Nature Neuroscience
Xue-Ping Wang, Ya-Lan Liu, Ling-Yun Mei, Chu-Feng He, Zhi-Jie Niu, Jie Sun, Yu-Lin Zhao, Yong Feng, Hua Zhang
Mutation in the gene encoding microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome 2 (WS2), an autosomal dominantly inherited syndrome with auditory-pigmentary abnormalities, which is clinically and genetically heterogeneous. Haploinsufficiency may be the underlying mechanism for WS2. However, the mechanisms explaining the genotypic and phenotypic variations in WS2 caused by MITF mutations are unclear. A previous study revealed that MITF interacts with LEF-1, an important factor in the Wnt signaling pathway, to regulate its own transcription through LEF-1-binding sites on the MITF promoter...
March 12, 2018: Journal of Human Genetics
Ana Valero-Jiménez, Joaquín Zúñiga, José Cisneros, Carina Becerril, Alfonso Salgado, Marco Checa, Ivette Buendía-Roldán, Criselda Mendoza-Milla, Miguel Gaxiola, Annie Pardo, Moisés Selman
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by epithelial cell activation, expansion of the fibroblast population and excessive extracellular matrix accumulation. The mechanisms are incompletely understood but evidence indicates that the deregulation of several proteases contributes to its pathogenesis. Transmembrane protease serine 4 (TMPRSS4) is a novel type II transmembrane serine protease that may promote migration and facilitate epithelial to mesenchymal transition (EMT), two critical processes in the pathogenesis of IPF...
2018: PloS One
Amrutha Swaminathan, Marilou Bouffard, Meijiang Liao, Sarah Ryan, Janis Bennion Callister, Stuart M Pickering-Brown, Gary Alan Barclay Armstrong, Pierre Drapeau
Large expansions of hexanucleotide GGGGCC (G4C2) repeats (hundreds to thousands) in the first intron of the chromosome 9 open reading frame 72 (C9orf72) locus are the strongest known genetic factor associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Different hypotheses exist about the underlying disease mechanism including loss-of-function by haploinsufficiency, toxicity arising as a result of RNA or dipeptide repeats (DPRs). Five different DPRs are produced by repeat-associated non-ATG-initiated (RAN) translation of the G4C2 repeats...
March 8, 2018: Human Molecular Genetics
Yukiko Kuroda, Ikuko Ohashi, Takuya Naruto, Kazumi Ida, Yumi Enomoto, Toshiyuki Saito, Jun-Ichi Nagai, Kenji Kurosawa
Ehlers-Danlos syndrome classical type (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and joint hypermobility. The condition typically results from mutations in COL5A1 or COL5A2 leading to the functional haploinsufficiency. Here, we report of a 24-year-old male with mild intellectual disability, dysmorphic features, and a phenotype consistent with cEDS. A copy number variant-calling algorithm from panel sequencing data identified the deletions exons 2-11 and duplications of exons 12-67 within COL5A1...
March 9, 2018: Congenital Anomalies
Raji P Grewal, Kinsi Oberoi, Leema Reddy Peddareddygari
Charcot-Marie-Tooth disease type 4C, an autosomal recessive genetic neuropathy, is caused by mutations in the SH3TC2 (SH3 domain and tetratricopeptide repeats 2) gene. Interestingly, although mutations in this gene have been observed in European gypsies, a population that originated in India, there are few publications describing Indian patients. We report our analysis of a 50-year-old woman of Asian Indian descent with onset of progressive distal weakness and sensory loss in childhood. A clinical examination revealed the presence of a neuropathy with pes cavus without spinal abnormalities...
January 2018: Case Reports in Neurology
T Smol, F Petit, A Piton, B Keren, D Sanlaville, A Afenjar, S Baker, E C Bedoukian, E J Bhoj, D Bonneau, E Boudry-Labis, S Bouquillon, O Boute-Benejean, R Caumes, N Chatron, C Colson, C Coubes, C Coutton, F Devillard, A Dieux-Coeslier, M Doco-Fenzy, L J Ewans, L Faivre, E Fassi, M Field, C Fournier, C Francannet, D Genevieve, I Giurgea, A Goldenberg, A K Green, A M Guerrot, D Heron, B Isidor, B A Keena, B L Krock, P Kuentz, E Lapi, N Le Meur, G Lesca, D Li, I Marey, C Mignot, C Nava, A Nesbitt, G Nicolas, C Roche-Lestienne, T Roscioli, V Satre, A Santani, M Stefanova, S Steinwall Larsen, P Saugier-Veber, S Picker-Minh, C Thuillier, A Verloes, G Vieville, M Wenzel, M Willems, S Whalen, Y A Zarate, A Ziegler, S Manouvrier-Hanu, V M Kalscheuer, B Gerard, Jamal Ghoumid
Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies...
March 6, 2018: Neurogenetics
J Lévy, D Haye, N Marziliano, G Casu, F Guimiot, C Dupont, N Teissier, B Benzacken, P Gressens, E Pipiras, A Verloes, A-C Tabet
Ephrin B2, one of the ligand of the EphB receptors, is involved in a complex signaling pathway regulating the development of the nervous system, neuronal migration, erythropoiesis and vasculogenesis. We report a patient with a de novo variant in EFNB2 and a family in which segregates a 610-kb deletion at chromosome 13q33 encompassing only ARGLU1 and EFNB2 genes. The de novo variant was observed in a patient with anal stenosis, hypoplastic left ventricle and mild developmental delay. The deletion was identified in 2 sibs with congenital heart defect and mild developmental delay...
March 6, 2018: Clinical Genetics
Frederik Heldt, Hannah Wallaschek, Tim Ripperger, Susanne Morlot, Thomas Illig, Thomas Eggermann, Brigitte Schlegelberger, Caroline Scholz, Doris Steinemann
We report here on the first family with short stature and Silver-Russell-like phenotype due to a microdeletion in 12q14.3. The Netchine-Harbison clinical scoring system was used for the clinical diagnosis of Silver-Russell syndrome (SRS). The three affected first-degree relatives (index patient, mother and brother) presented with prenatal and postnatal growth retardation, feeding difficulties, a prominent forehead and a failure to thrive but did not show relative macrocephaly. In addition, our index patient showed dysmorphic facial features, periodically increased sweating, and scoliosis...
March 1, 2018: European Journal of Medical Genetics
Petra Liskova, Lubica Dudakova, Cerys J Evans, Karla E Rojas Lopez, Nikolas Pontikos, Dimitra Athanasiou, Hodan Jama, Josef Sach, Pavlina Skalicka, Viktor Stranecky, Stanislav Kmoch, Caroline Thaung, Martin Filipec, Michael E Cheetham, Alice E Davidson, Stephen J Tuft, Alison J Hardcastle
In a large family of Czech origin, we mapped a locus for an autosomal-dominant corneal endothelial dystrophy, posterior polymorphous corneal dystrophy 4 (PPCD4), to 8q22.3-q24.12. Whole-genome sequencing identified a unique variant (c.20+544G>T) in this locus, within an intronic regulatory region of GRHL2. Targeted sequencing identified the same variant in three additional previously unsolved PPCD-affected families, including a de novo occurrence that suggests this is a recurrent mutation. Two further unique variants were identified in intron 1 of GRHL2 (c...
March 1, 2018: American Journal of Human Genetics
Stephen L Greene, Chung How Kau, Somsak Sittitavornwong, Kathlyn Powell, Noel K Childers, Mary MacDougall, Ejvis Lamani
Cleidocranial dysplasia (CCD, MIM 119600) is a rare autosomal dominant disorder affecting bone, cartilage, craniofacial growth, and tooth formation leading to supernumerary teeth. Few reports delineate the genotype-phenotype correlations related to the variations in craniofacial morphology and patterning of the dentition and the complexity of treating patient's malocclusion. Successful management of the craniofacial deformities in patients with CCD requires a multidisciplinary team of healthcare specialists...
March 1, 2018: Journal of Craniofacial Surgery
Lin Zhou, Liang Zhou, Li-da Su, Sheng-Long Cao, Ya-Jun Xie, Na Wang, Chong-Yu Shao, Ya-Nan Wang, Jia-Huan Zhou, John K Cowell, Ying Shen
Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that glutamatergic transmission is altered in LGI1 mutant mice and seizures can be reduced by restoring LGI1 function. Yet, the mechanism underlying ADLTE is unclear. Here, we propose that seizures in male LGI1-/- mice are due to non-synaptic epileptiform activity in cortical neurons. We examined the intrinsic excitability of pyramidal neurons in the temporal cortex of male LGI1-/- mice and found that the voltage-gated K+ channel Kv1...
February 28, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Irene Sangrador, Xavier Molero, Fiona Campbell, Sebastià Franch-Expósito, Maria Rovira-Rigau, Esther Samper, Manuel Domínguez Fraile, Cristina Fillat, Antoni Castells, Eva C Vaquero
The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic KrasG12D and Trp53 mutations (KPC) were crossed with Zeb1 haploinsufficient mice (Z+/-)...
February 28, 2018: Cancer Research
Georgios Kellaris, Kamal Khan, Shahid M Baig, I-Chun Tsai, Francisca Millan Zamora, Paul Ruggieri, Marvin R Natowicz, Nicholas Katsanis
BACKGROUND: Intellectual disability (ID) is a common condition with a population prevalence frequency of 1-3% and an enrichment for males, driven in part by the contribution of mutant alleles on the X-chromosome. Among the more than 500 genes associated with ID, DDX3X represents an outlier in sex specificity. Nearly all reported pathogenic variants of DDX3X are de novo, affect mostly females, and appear to be loss of function variants, consistent with the hypothesis that haploinsufficiency at this locus on the X-chromosome is likely to be lethal in males...
March 1, 2018: Human Genomics
Anas Alzahrani, Yoon Chi, Kenneth W Finnson, Meryem Blati, Bertrand Lussier, Mohit Kapoor, Stephane Roy, Anie Philip
Transforming growth factor (TGF)-β is a multifunctional growth factor with potent pro-fibrotic effects. Endoglin is a TGF-β co-receptor that strongly regulates TGF-β signaling in a variety of cell types. Although aberrant regulation of TGF-β signaling is known to play a key role in fibrotic diseases such as scleroderma and impaired cartilage repair, the significance of endoglin function in regulating these processes is poorly understood. Here we examined whether endoglin haploinsufficiency regulates extracellular (ECM) protein expression and fibrotic responses during bleomycin induced skin fibrosis and surgically induced osteoarthritis, using endoglin-heterozygous (Eng+/-) mice and wild-type (Eng+/+) littermates...
March 2018: Journal of Cell Communication and Signaling
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