bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel homozygous variant in REN in a family presenting with classic features of disorders involving the renin–angiotensin pathway, without renal tubular dysgenesis
Authors: Dilliott Allison A. , Wang Jian , Brown Emma , Singh Gagandeep , Shkrum Michael J. , Clin Madeleine , Rupar Charles Anthony , Hegele Robert A. , Siu Victoria Mok 
Published: August 2020

AbstractAutosomal recessively inherited pathogenic variants in genes associated with the renin–angiotensin–aldosterone system (RAAS) result in early onset oligohydramnios and clinical features of the Potter sequence, typically in association with proximal renal tubules dysgenesis. We describe two siblings and a first cousin who had severe oligohydramnios in the second trimester, and presented at birth with loose skin, wide fontanelles and sutures, and pulmonary insufficiency. Two had refractory hypotension during their brief lives and one received palliative care after birth. All were found to have a homozygous nonsense variant, REN: c.891delG; p.Tyr287*, on exome sequencing. Autopsy limited to the genitourinary system in two of the children revealed normal renal tubular histology in both. Immunoblotting confirmed diminished expression of renin within cultured skin fibroblasts. To our knowledge, this is the first identification of an association between biallelic variants in REN and oligohydramnios in the absence of renal tubular dysgenesis. Due to its role in the RAAS, it has previously been proposed that the decreased expression of REN results in hypotension, ischemia, and decreased urine production. We suggest sequencing of genes in the RAAS, including REN, should be considered in cases of severe early onset oligohydramnios, even when renal morphology and histology are normal.
The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN‐associated AMC as a type of viable fetal akinesia deformation sequence
Authors: Mis Emily K. , Al‐Ali Samir , Ji Weizhen , Spencer‐Manzon Michele , Konstantino Monica , Khokha Mustafa K. , Jeffries Lauren , Lakhani Saquib A. 
Published: August 2020

AbstractRecessive variants in the GLDN gene, which encodes the gliomedin protein and is involved in nervous system development, have recently been associated with Arthrogryposis Multiplex Congenita (AMC), a heterogenous condition characterized by congenital contractures of more than one joint. Two cohorts of patients with GLDN‐associated AMC have previously been described, evolving the understanding of the condition from lethal to survivable with the provision of significant neonatal support. Here, we describe one additional patient currently living with the syndrome, having one novel variant, p.Leu365Phe, for which we provide functional data supporting its pathogenicity. We additionally provide experimental data for four other previously reported variants lacking functional evidence, including p.Arg393Lys, the second variant present in our patient. We discuss unique and defining clinical features, adding calcium‐related findings which appear to be recurrent in the GLDN cohort. Finally, we compare all previously reported patients and draw new conclusions about scope of illness, with emphasis on the finding of pulmonary hypoplasia, suggesting that AMC secondary to GLDN variants may be best fitted under the umbrella of fetal akinesia deformation sequence (FADS).
Birth prevalence of achondroplasia: A systematic literature review and meta‐analysis
Authors: Foreman Pamela K. , van Kessel Femke , van Hoorn Rosa , van den Bosch Judith , Shediac Renée , Landis Sarah 
Published: August 2020

AbstractAchondroplasia is a genetic disorder that results in disproportionate short stature. The true prevalence of achondroplasia is unknown as estimates vary widely. This systematic literature review and meta‐analysis was conducted to better estimate worldwide achondroplasia birth prevalence. PubMed, Embase, Scielo, and Google Scholar were searched, complemented by manual searching, for peer‐reviewed articles published between 1950 and 2019. Eligible articles were identified by two independent researchers using predefined selection criteria. Birth prevalence estimates were extracted for analysis, and the quality of evidence was assessed. A meta‐analysis using a quality effects approach based on the inverse variance fixed effect model was conducted. The search identified 955 unique articles, of which 52 were eligible and included. Based on the meta‐analysis, the worldwide birth prevalence of achondroplasia was estimated to be 4.6 per 100,000. Substantial regional variation was observed with a considerably higher birth prevalence reported in North Africa and the Middle East compared to other regions, particularly Europe and the Americas. Higher birth prevalence was also reported in specialized care settings. Significant heterogeneity (HigginsI2of 84.3) was present and some indication of publication bias was detected, based on visual asymmetry of the Doi plot with a Furuya‐Kanamori index of 2.73. Analysis of pooled data from the current literature yields a worldwide achondroplasia birth prevalence of approximately 4.6 per 100,000, with considerable regional variation. Careful interpretation of these findings is advised as included studies are of broadly varying methodological quality.
Congenital ichthyosis in Prader–Willi syndrome associated with maternal chromosome 15 uniparental disomy: Case report and review of autosomal recessive conditions unmasked by UPD
Authors: Muthusamy Karthik , Macke Erica L. , Klee Eric W. , Tebben Peter J. , Hand Jennifer L. , Hasadsri Linda , Marcou Cherisse A. , Schimmenti Lisa A. 
Published: August 2020

AbstractPrader–Willi syndrome (PWS) is a prototypic genetic condition related to imprinting. Causative mechanisms include paternal 15q11‐q13 deletion, maternal chromosome 15 uniparental disomy (UPD15), Prader–Willi Syndrome/Angelman Syndrome (PWS/AS) critical region imprinting defects, and complex chromosomal rearrangements. Maternal UPD15‐related PWS poses risks of concomitant autosomal recessive (AR) disorders when the mother carries a pathogenic variant in one of the genes on chromosome 15 associated with autosomal recessive inherited disease. Co‐occurrence of autosomal recessive conditions in the setting of UPD leads to increased complexity of the clinical phenotype, and may delay the diagnosis of PWS. We report a patient with PWS and associated congenital ichthyosis due to maternal UPD15, and a homozygous novel pathogenic variant in ceramide synthase 3 (CERS3). We also review the literature of associated disorders reported in the setting of maternal UPD15‐related PWS and provide a summary of the previously described CERS3 variants. This represents the second case of autosomal recessive congenital ichthyosis (ARCI) in the setting of PWS and UPD15. There needs to be a high index of suspicion of this genetic mechanism when there is unexpected phenotype or evolution of the clinical course in a patient with PWS.
Update of the genotype and phenotype ofKMT2DandKDM6Aby genetic screening of 100 patients with clinically suspected Kabuki syndrome
Authors: Murakami Hiroaki , Tsurusaki Yoshinori , Enomoto Keisuke , Kuroda Yukiko , Yokoi Takayuki , Furuya Noritaka , Yoshihashi Hiroshi , Minatogawa Mari , Abe‐Hatano Chihiro , Ohashi Ikuko , Nishimura Naoto , Kumaki Tatsuro , Enomoto Yumi , Naruto Takuya , Iwasaki Fuminori , Harada Noriaki , Ishikawa Aki , Kawame Hiroshi , Sameshima Kiyoko , Yamaguchi Yu , Kobayashi Masahisa , Tominaga Makiko , Ishikiriyama Satoshi , Tanaka Toshiaki , Suzumura Hiroshi , Ninomiya Shinsuke , Kondo Akane , Kaname Tadashi , Kosaki Kenjiro , Masuno Mitsuo , Kuroki Yoshikazu , Kurosawa Kenji 
Published: August 2020

AbstractKabuki syndrome is characterized by a variable degree of intellectual disability, characteristic facial features, and complications in various organs. Many variants have been identified in two causative genes, that is, lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A). In this study, we present the results of genetic screening of 100 patients with a suspected diagnosis of Kabuki syndrome in our center from July 2010 to June 2018. We identified 76 variants (43 novel) inKMT2Dand 4 variants (3 novel) inKDM6Aas pathogenic or likely pathogenic. Rare variants included a deep splicing variant (c.14000‐8C>G) confirmed by RNA sequencing and an 18% mosaicism level for aKMT2Dmutation. We also characterized a case with a blended phenotype consisting of Kabuki syndrome, osteogenesis imperfecta, and 16p13.11 microdeletion. We summarized the clinical phenotypes of 44 patients including a patient who developed cervical cancer of unknown origin at 16 years of age. This study presents important details of patients with Kabuki syndrome including rare clinical cases and expands our genetic understanding of this syndrome, which will help clinicians and researchers better manage and understand patients with Kabuki syndrome they may encounter.
Pre‐ and postnatal findings in a patient with a recombinant chromosome rec(8)(qter→q21.11::p23.3→qter) due to a paternal pericentric inversion inv(8)(p23.3q21.11) and review of the literature
Authors: Habhab Wisam , Mau‐Holzmann Ulrike , Singer Sylke , Rieß Angelika , Kagan Karl‐Oliver , Gerbig Ines , Schäferhoff Karin , Dufke Andreas , Kehrer Martin 
Published: August 2020

AbstractRecombinant chromosome 8 (Rec8) syndrome (San Luis Valley [SLV] syndrome; OMIM #179613) is a rare chromosome disorder associated with intellectual disability, congenital heart defects, variable skeletal and urogenital anomalies, and dysmorphic features. It is characterized by a partial terminal deletion of 8p and a partial terminal duplication of 8q, which is usually due to meiotic recombination of a pericentric inversion of chromosome 8 of a healthy carrier parent. There are only few reports of cases with breakpoints defined at the molecular level by molecular karyotyping. We report on a case of Rec8 syndrome with previously unreported breakpoints in a male fetus with intrauterine growth restriction, hypogenesis of the corpus callosum, bilateral cleft lip/palate, and congenital heart defect. Cytogenetic analysis revealed a recombinant chromosome 8 [46,XY,rec(8)(qter→q21.11::p23.3→qter)] secondary to a paternal pericentric inversion [46,XY,inv(8)(p23.3q21.11)]. Molecular karyotyping correspondingly showed a terminal copy number loss of 1.4 Mb (arr[hg19] 8p23.3(158048_1514749)×1) and a terminal copy number gain of chromosome band 8q21.11q24.3 of 69.8 Mb (arr[hg19] 8q21.11q24.3(76477367_146295771)×3). To our knowledge, this is the fourth reported case diagnosed prenatally. We describe the postnatal clinical course of the male newborn. Furthermore, we review and compare the phenotypic features and breakpoints of 74 reported Rec8/SLV cases.
Tuberous sclerosis complex (TSC), lymphangioleiomyomatosis, and COVID‐19: The experience of a TSC clinic in Italy
Authors: Peron Angela , La Briola Francesca , Bruschi Fabio , Terraneo Silvia , Vannicola Chiara , Previtali Roberto , Perazzoli Sabrina , Morenghi Emanuela , Bulfamante Gaetano , Vignoli Aglaia , Canevini Maria Paola 
Published: August 2020

AbstractIndividuals with comorbidities are at higher risk of coronavirus disease 2019 (COVID‐19) and worse outcome, but little information has been available about patients with genetic diseases and COVID‐19. This study aims at evaluating the presence and outcome of COVID‐19 in a cohort of Italian patients with tuberous sclerosis complex (TSC) and/or lymphangioleiomyomatosis (LAM), and at reviewing the possible effects of mTOR inhibitors on SARS‐CoV‐2 infection. We included 102 unselected individuals with a diagnosis of TSC and/or LAM assessed between January 1, 2020 and April 24, 2020 (29% children, 71% adults). Twenty‐six patients were on mTOR inhibitors. Demographic data, TSC manifestations, presence, and outcomes in individuals with confirmed or suspected SARS‐CoV‐2 infection were evaluated. Health status and outcomes of all patients on mTOR inhibitors were assessed. One patient with severe TSC had polymerase chain reaction (PCR)‐confirmed SARS‐CoV‐2 infection, was admitted to ICU, and died. Nine additional patients either met the definition of suspect case or presented with at least two of the most common symptoms of SARS‐CoV‐2 infection. All recovered fully. None of the patients treated with mTOR inhibitors for their underlying comorbidities was diagnosed with COVID‐19, and those who showed suspicious respiratory symptoms recovered fully. This cohort study provides preliminary information on COVID‐19 in people with TSC in Italy and suggests feasibility to systematically evaluate the role of mTOR inhibitors in SARS‐CoV‐2 infection.
Spondyloepiphyseal dysplasia type Stanescu: Expanding the clinical and molecular spectrum of a very rare type II collagenopathy
Authors: Travessa André M. , Díaz‐González Francisca , Mirco Teresa , Oliveira‐Ramos Filipa , Parrón‐Pajares Manuel , Heath Karen E. , Sousa Ana Berta 
Published: August 2020

AbstractSpondyloepiphyseal dysplasia type Stanescu (SED‐S) is a very rare type II collagenopathy. We describe an 8‐year‐old boy who presented with short trunk, C2‐C3 vertebral fusion, hand, foot, leg and thigh pain, stiffness and limited joint mobility, and waddling gait. Radiographs showed platyspondyly with anterior wedging and endplate irregularities, broad femoral necks, and large epiphyses and epiphyseal equivalents. Differential diagnosis included progressive pseudorheumatoid dysplasia and SED‐S. A skeletal dysplasia custom‐designed NGS panel was performed and the heterozygous pathogenic variant c.620G>A; p.(Gly207Glu) in COL2A1 was detected, establishing the diagnosis of SED‐S. Vertebral fusions, observed in our patient, have not been previously described in this dysplasia. This variant has not been previously associated with SED‐S, but was reported in two other families with spondyloepiphyseal dysplasia. Thus, this case expands the clinical and mutational spectrum of SED‐S and demonstrates that SED‐S significantly overlaps with other skeletal dysplasias.
Indigenous women's experiences of domestic and family violence, help‐seeking and recovery in regional Queensland
Authors: Meyer Silke , Stambe Rose‐Marie 
Published: August 2020

AbstractIndigenous women are disproportionately affected by the prevalence and severity of domestic and family violence (DFV) perpetrated by men against women in Australia. The impact of their experiences is further exacerbated by the level of social and cultural marginalisation affecting Indigenous communities, families and individuals along with regional, rural or remote living. The pervasive, ongoing impact of colonisation, dispossession and transgenerational trauma continues to shape the experiences of Indigenous women and their communities, including their help‐seeking decisions and opportunities, and their level of trust in and access to adequate and culturally sensitive support services. In this paper, we explore the experiences of Indigenous women affected by DFV in two regional Australian settings through face‐to‐face interviews with women (n = 13) and community stakeholders (n = 18). The findings of this study highlight the complex role of social and cultural marginalisation, spiritual (dis)connectedness and role of family as both a stressor and a protective factor. Implications for policy and practice are discussed.
Precision prevention of Alzheimer's and other dementias: Anticipating future needs in the control of risk factors and implementation of disease‐modifying therapies
Authors: Frisoni Giovanni B. , Molinuevo José Luis , Altomare Daniele , Carrera Emmanuel , Barkhof Frederik , Berkhof Johannes , Delrieu Julien , Dubois Bruno , Kivipelto Miia , Nordberg Agneta , Schott Jonathan M. , van der Flier Wiesje M. , Vellas Bruno , Jessen Frank , Scheltens Philip , Ritchie Craig 
Published: August 2020

AbstractEmpirical evidence suggests that a fair proportion of dementia cases are preventable, that some preventive actions can be taken immediately, and others may soon be implemented. Primary prevention may target cognitively normal persons with modifiable risk factors through lifestyle and multiple domain interventions (including general cardiovascular health). While the effect on individuals may be modest, it might have a large societal impact by decreasing overall dementia incidence by up to 35%. Secondary prevention will target cognitively normal persons at high risk of dementia due to Alzheimer's disease pathology with future anti‐amyloid, anti‐tau, or other drugs. This approach is likely to have major benefits to both individuals and society. Memory clinics will need structural and functional changes to adapt to novel technologies and increased patients’ demands, and brand‐new services may need to be developed with specific skills on risk profiling, risk communication, and personalized risk reduction plans.
Redox Dyshomeostasis Strategy for Hypoxic Tumor Therapy Based on DNAzyme‐Loaded Electrophilic ZIFs
Authors: Li Yanli , Zhao Peiran , Gong Teng , Wang Han , Jiang Xingwu , Cheng Hui , Liu Yanyan , Wu Yelin , Bu Wenbo 
Published: August 2020

AbstractRedox homeostasis is one of the main reasons for reactive oxygen species (ROS) tolerance in hypoxic tumors, limiting ROS‐mediated tumor therapy. Proposed herein is a redox dyshomeostasis (RDH) strategy based on a nanoplatform, FeCysPW@ZIF‐82@CAT Dz, to disrupt redox homeostasis, and its application to improve ROS‐mediated hypoxic tumor therapy. Once endocytosed by tumor cells, the catalase DNAzyme (CAT Dz) loaded zeolitic imidazole framework‐82 (ZIF‐82@CAT Dz) shell can be degraded into Zn2+as cofactors for CAT Dz mediated CAT silencing and electrophilic ligands for glutathione (GSH) depletion under hypoxia, both of which lead to intracellular RDH and H2O2accumulation. These “disordered” cells show reduced resistance to ROS and are effectively killed by ferrous cysteine‐phosphotungstate (FeCysPW) induced chemodynamic therapy (CDT). In vitro and in vivo data demonstrate that the pH/hypoxia/H2O2triple stimuli responsive nanocomposite can efficiently kill hypoxic tumors. Overall, the RDH strategy provides a new way of thinking about ROS‐mediated treatment of hypoxic tumors.
Enzymatic Building‐Block Synthesis for Solid‐Phase Automated Glycan Assembly
Authors: Marchesi Andrea , Parmeggiani Fabio , Louçano João , Mattey Ashley P. , Huang Kun , Gupta Tanistha , Salwiczek Mario , Flitsch Sabine L. 
Published: August 2020

AbstractAutomated chemical oligosaccharide synthesis is an attractive concept that has been successfully applied to a large number of target structures, but requires excess quantities of suitably protected and activated building blocks. Herein we demonstrate the use of biocatalysis to supply such reagents for automated synthesis. By using the promiscuous NmLgtB‐B β1‐4 galactosyltransferase from Neisseria meningitidis we demonstrate fast and robust access to the LacNAc motif, common to many cell‐surface glycans, starting from either lactose or sucrose as glycosyl donors. The enzymatic product was shown to be successfully incorporated as a complete unit into a tetrasaccharide target by automated assembly.
Multivalent‐Interaction‐Driven Assembly of Discrete, Flexible, and Asymmetric Supramolecular Protein Nano‐Prisms
Authors: Han Suyeong , Kim Yu‐na , Jo Gyunghee , Kim Young Eun , Kim Ho Min , Choi Jeong‐Mo , Jung Yongwon 
Published: August 2020

AbstractCurrent approaches to design monodisperse protein assemblies require rigid, tight, and symmetric interactions between oligomeric protein units. Herein, we introduce a new multivalent‐interaction‐driven assembly strategy that allows flexible, spaced, and asymmetric assembly between protein oligomers. We discovered that two polygonal protein oligomers (ranging from triangle to hexagon) dominantly form a discrete and stable two‐layered protein prism nanostructure via multivalent interactions between fused binding pairs. We demonstrated that protein nano‐prisms with long flexible peptide linkers (over 80 amino acids) between protein oligomer layers could be discretely formed. Oligomers with different structures could also be monodispersely assembled into two‐layered but asymmetric protein nano‐prisms. Furthermore, producing higher‐order architectures with multiple oligomer layers, for example, 3‐layered nano‐prisms or nanotubes, was also feasible.
Reversible Soft Mechanochemical Control of Biaryl Conformations through Crosslinking in a 3D Macromolecular Network
Authors: Kelber Julien B. , Bensalah‐Ledoux Amina , Zahouani Sarah , Baguenard Bruno , Schaaf Pierre , Chaumont Alain , Guy Stephan , Jierry Loïc 
Published: August 2020

AbstractTuning the dihedral angle (DA) of axially chiral compounds can impact biological activity, catalyst efficiency, molecular motor performance, or chiroptical properties. Herein, we report gradual, controlled, and reversible changes in molecular conformation of a covalently linked binaphthyl moiety within a 3D polymeric network by application of a macroscopic stretching force. We managed direct observation of DA changes by measuring the circular dichroism signal of an optically pure BINOL‐crosslinked elastomer network. Stretching the elastomer resulted in a widening of the DA between naphthyl rings when the BINOL was doubly grafted to the elastomer network; no effect was observed when a single naphthyl ring of the BINOL was grafted to the elastomer network. We have determined that ca. 170 % extension of the elastomers led to the transfer of a mechanical force to the BINOL moiety of 2.5 kcal mol−1 Å−1 (ca. 175 pN) in magnitude and results in the opening of the DA of BINOL up to 130°.
Cucurbituril‐Based Biomacromolecular Assemblies
Authors: Liu Yao‐Hua , Zhang Ying‐Ming , Yu Hua‐Jiang , Liu Yu 
Published: August 2020

AbstractThe construction of controlled biomacromolecular assemblies has become a thriving area of supramolecular chemistry. In this context, cucurbiturils (CBs), a class of macrocyclic receptors having robust skeletons, hydrophobic cavities, and carbonyl‐laced portals, have been drawn into the limelight because of their advantageous molecular recognition characteristics with a variety of biomacromolecules, including peptides, nucleic acids, and proteins. In this minireview, we focus on the impressive advances in CB‐based biomacromolecular assemblies, such as in biosensors and assays, the regulation of biochemical reactions, and the treatment of serious diseases. CB‐promoted subcellular bioimaging has also been demonstrated in different organelles. The case studies presented herein demonstrate the numerous applications, from fundamental research to translational applications, of diverse CB‐based supra/biomacromolecular architectures.
Compaction of RNA Duplexes in the Cell**
Authors: Collauto Alberto , von Bülow Sören , Gophane Dnyaneshwar B. , Saha Subham , Stelzl Lukas S. , Hummer Gerhard , Sigurdsson Snorri T. , Prisner Thomas F. 
Published: August 2020

AbstractThe structure and flexibility of RNA depends sensitively on the microenvironment. Using pulsed electron‐electron double‐resonance (PELDOR)/double electron‐electron resonance (DEER) spectroscopy combined with advanced labeling techniques, we show that the structure of double‐stranded RNA (dsRNA) changes upon internalization into Xenopus lævis oocytes. Compared to dilute solution, the dsRNA A‐helix is more compact in cells. We recapitulate this compaction in a densely crowded protein solution. Atomic‐resolution molecular dynamics simulations of dsRNA semi‐quantitatively capture the compaction, and identify non‐specific electrostatic interactions between proteins and dsRNA as a possible driver of this effect.