bluuebunny/crossref_metadata_2025_split huggingface dataset:
The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype
Authors: Averdunk Luisa , Sticht Heinrich , Surowy Harald , Lüdecke Hermann-Josef , Koch-Hogrebe Margarete , Alsaif Hessa S. , Kahrizi Kimia , Alzaidan Hamad , Alawam Bashayer S. , Tohary Mohamed , Kraus Cornelia , Endele Sabine , Wadman Erin , Kaplan Julie D. , Efthymiou Stephanie , Najmabadi Hossein , Reis André , Alkuraya Fowzan S. , Wieczorek Dagmar 
Published: September 2021

Abstract
Pathogenic variants in aminoacyl-tRNA synthetases (ARS1) cause a diverse spectrum of autosomal recessive disorders. Tyrosyl tRNA synthetase (TyrRS) is encoded by YARS1 (cytosolic, OMIM*603,623) and is responsible of coupling tyrosine to its specific tRNA. Next to the enzymatic domain, TyrRS has two additional functional domains (N-Terminal TyrRSMini and C-terminal EMAP-II-like domain) which confer cytokine-like functions. Mutations in YARS1 have been associated with autosomal-dominant Charcot-Marie-Tooth (CMT) neuropathy type C and a heterogenous group of autosomal recessive, multisystem diseases. We identified 12 individuals from 6 families with the recurrent homozygous missense variant c.1099C > T;p.(Arg367Trp) (NM_003680.3) in YARS1. This variant causes a multisystem disorder with developmental delay, microcephaly, failure to thrive, short stature, muscular hypotonia, ataxia, brain anomalies, microcytic anemia, hepatomegaly, and hypothyroidism. In silico analyses show that the p.(Arg367Trp) does not affect the catalytic domain responsible of enzymatic coupling, but destabilizes the cytokine-like C-terminal domain. The phenotype associated with p.(Arg367Trp) is distinct from the other biallelic pathogenic variants that reside in different functional domains of TyrRS which all show some common, but also divergent clinical signs [(e.g., p.(Phe269Ser)—retinal anomalies, p.(Pro213Leu)/p.(Gly525Arg)—mild ID, p.(Pro167Thr)—high fatality)]. The diverse clinical spectrum of ARS1-associated disorders is related to mutations affecting the various non-canonical domains of ARS1, and impaired protein translation is likely not the exclusive disease-causing mechanism of YARS1- and ARS1-associated neurodevelopmental disorders.

Key messages

The missense variant p.(Arg367Trp) in YARS1 causes a distinct multisystem disorder.

p.(Arg367Trp) affects a non-canonical domain with cytokine-like functions.

Phenotypic heterogeneity associates with the different affected YARS1 domains.

Impaired protein translation is likely not the exclusive mechanism of ARS1-associated disorders.
Diabetic pregnancy as a novel risk factor for cardiac dysfunction in the offspring—the heart as a target for fetal programming in rats
Authors: Schütte Till , Kedziora Sarah M. , Haase Nadine , Herse Florian , Alenina Natalia , Müller Dominik N. , Bader Michael , Schupp Michael , Dechend Ralf , Golic Michaela , Kräker Kristin 
Published: September 2021

Abstract
Aims/hypothesis
The impact of diabetic pregnancy has been investigated extensively regarding offspring metabolism; however, little is known about the influence on the heart. We aimed to characterise the effects of a diabetic pregnancy on male adult offspring cardiac health after feeding a high-fat diet in an established transgenic rat model.

Methods
We applied our rat model for maternal type 2 diabetes characterised by maternal insulin resistance with hyperglycaemia and hyperinsulinaemia. Diabetes was induced preconceptionally via doxycycline-induced knock down of the insulin receptor in transgenic rats. Male wild-type offspring of diabetic and normoglycaemic pregnancies were raised by foster mothers, followed up into adulthood and subgroups were challenged by a high-fat diet. Cardiac phenotype was assessed by innovative speckle tracking echocardiography, circulating factors, immunohistochemistry and gene expression in the heart.

Results
When feeding normal chow, we did not observe differences in cardiac function, gene expression and plasma brain natriuretic peptide between adult diabetic or normoglycaemic offspring. Interestingly, when being fed a high-fat diet, adult offspring of diabetic pregnancy demonstrated decreased global longitudinal (−14.82 ± 0.59 vs −16.60 ± 0.48%) and circumferential strain (−23.40 ± 0.57 vs −26.74 ± 0.34%), increased relative wall thickness (0.53 ± 0.06 vs 0.37 ± 0.02), altered cardiac gene expression, enlarged cardiomyocytes (106.60 ± 4.14 vs 87.94 ± 1.67 μm), an accumulation of immune cells in the heart (10.27 ± 0.30 vs 6.48 ± 0.48 per fov) and higher plasma brain natriuretic peptide levels (0.50 ± 0.12 vs 0.12 ± 0.03 ng/ml) compared with normoglycaemic offspring on a high-fat diet. Blood pressure, urinary albumin, blood glucose and body weight were unaltered between groups on a high-fat diet.

Conclusions/interpretation
Diabetic pregnancy in rats induces cardiac dysfunction, left ventricular hypertrophy and altered proinflammatory status in adult offspring only after a high-fat diet. A diabetic pregnancy itself was not sufficient to impair myocardial function and gene expression in male offspring later in life. This suggests that a postnatal high-fat diet is important for the development of cardiac dysfunction in rat offspring after diabetic pregnancy. Our data provide evidence that a diabetic pregnancy is a novel cardiac risk factor that becomes relevant when other challenges, such as a high-fat diet, are present.

Graphical abstract
Problems associated with the use of the term “antibiotics”
Authors: Seifert Roland , Schirmer Bastian 
Published: September 2021

AbstractThe term “antibiotics” is a broadly used misnomer to designate antibacterial drugs. In a recent article, we have proposed to replace, e.g., the term “antibiotics” by “antibacterial drugs”, “antibiosis” by “antibacterial therapy”, “antibiogram” by “antibacteriogram”, and “antibiotic stewardship” by “antibacterial stewardship” (Seifert and Schirmer Trends Microbiol, 2021). In the present article, we show that many traditional terms related to antibiotics are used much more widely in the biomedical literature than the respective scientifically precise terms. This practice should be stopped. Moreover, we provide arguments to end the use of other broadly used terms in the biomedical literature such as “narrow-spectrum antibiotics” and “reserve antibiotics”, “chemotherapeutics”, and “tuberculostatics”. Finally, we provide several examples showing that antibacterial drugs are used for non-antibacterial indications and that some non-antibacterial drugs are used for antibacterial indications now. Thus, the increasing importance of drug repurposing renders it important to drop short designations of drug classes such as “antibiotics”. Rather, the term “drug” should be explicitly used, facilitating the inclusion of newly emerging indications such as antipsychotic and anti-inflammatory. This article is part of an effort to implement a new rational nomenclature of drug classes across the entire field of pharmacology.
European Hedgehogs (Erinaceus europaeus L.) as a Reservoir of Dermatophytes in Poland
Authors: Gnat Sebastian , Łagowski Dominik , Dyląg Mariusz , Nowakiewicz Aneta 
Published: September 2021

AbstractThe European hedgehog (Erinaceus europaeus Linnaeus) frequently colonises areas located close to human life in cities, as these are more suitable nest sites offering an abundance of food and allowing avoidance of predators. However, urbanisation has a significant impact on the epidemiology of infectious diseases, including dermatophytoses, the primary source of which are wild animals. In this study, we determined the spectrum of dermatophytes isolated from the European hedgehog and assessed their susceptibility profile to antifungal drugs. Symptomatic and asymptomatic dermatophyte infections were observed in 7.7% and 8% of the 182 examined free-living hedgehogs, respectively. In the pool of the isolated dermatophyte strains, Trichophyton erinacei was dominant (29.9%), followed by Trichophyton mentagrophytes (17.9%), Trichophyton benhamiae (13.4%), Nannizzia gypsea (11.9%), Microsporum canis (10.4%), Nannizzia nana (7.5%), Paraphyton cookei (6.0%), and Nannizzia fulva (3.0%). Susceptibility tests revealed the highest activity of luliconazole and the lowest of activity fluconazole among the azole drugs applied. Although terbinafine generally exhibited high efficacy, two Trichophyton mentagrophytes isolates showed resistance to this drug (MIC = 2 µg/ml) resulting from missense mutations in the SQLE gene corresponding to the amino acid substitution Leu393Phe. Summarising, our study has also revealed that such wildlife animals as hedgehogs can be a reservoir of pathogenic human dermatophytes, including harmful strains resistant to commonly used antifungal drugs.
Graphical Abstract
Marine dissolved organic matter: a vast and unexplored molecular space
Authors: Catalá Teresa S. , Shorte Spencer , Dittmar Thorsten 
Published: September 2021

Abstract
Marine dissolved organic matter (DOM) comprises a vast and unexplored molecular space. Most of it resided in the oceans for thousands of years. It is among the most diverse molecular mixtures known, consisting of millions of individual compounds. More than 1 Eg of this material exists on the planet. As such, it comprises a formidable source of natural products promising significant potential for new biotechnological purposes. Great emphasis has been placed on understanding the role of DOM in biogeochemical cycles and climate attenuation, its lifespan, interaction with microorganisms, as well as its molecular composition. Yet, probing DOM bioactivities is in its infancy, largely because it is technically challenging due to the chemical complexity of the material. It is of considerable interest to develop technologies capable to better discern DOM bioactivities. Modern screening technologies are opening new avenues allowing accelerated identification of bioactivities for small molecules from natural products. These methods diminish a priori the need for laborious chemical fractionation. We examine here the application of untargeted metabolomics and multiplexed high-throughput molecular-phenotypic screening techniques that are providing first insights on previously undetectable DOM bioactivities.

Key points
• Marine DOM is a vast, unexplored biotechnological resource.
• Untargeted bioscreening approaches are emerging for natural product screening.
• Perspectives for developing bioscreening platforms for marine DOM are discussed.
Myocardial injury detected by T1 and T2 mapping on CMR predicts subsequent cancer therapy–related cardiac dysfunction in patients with breast cancer treated by epirubicin-based chemotherapy or left-sided RT
Authors: Tahir Enver , Azar Manuella , Shihada Sahar , Seiffert Katharina , Goy Yvonne , Beitzen-Heineke Antonia , Molwitz Isabel , Muellerleile Kai , Stehning Christian , Schön Gerhard , Adam Gerhard , Petersen Cordula , Müller Volkmar , Lund Gunnar K. 
Published: September 2021

Abstract
Objectives
Cancer therapy-related cardiac dysfunction (CTRCD) is a relevant clinical problem and needs early prediction. This study aimed to analyze myocardial injury using serial laboratory and cardiac magnetic resonance imaging (CMR) parameters after epirubicin-based chemotherapy compared with left-sided radiotherapy and to study their value for early prediction of CTRCD.

Methods
Sixty-six consecutive women (53 ± 13 years) including n = 39 with epirubicin-based chemotherapy and n = 27 with left-sided radiotherapy were prospectively studied by 3 T CMR including left ventricular (LV) mass and volumes for ejection fraction (LVEF), as well as feature-tracking with global longitudinal strain (GLS) and T1/T2 mapping. CMR was performed at baseline, at therapy completion (follow-up 1, FU1), and after 13 ± 2 months (FU2). CTRCD was defined as LVEF decline of at least 10% to < 55% or a > 15% GLS change at FU2.

Results
T1 and T2 increased at FU1 after epirubicin-based chemotherapy, but not after left-sided radiotherapy. CTRCD occurred in 20% of patients after epirubicin-based chemotherapy and in 4% after left-sided radiotherapy. T1 at FU1 was the best single parameter to predict CTRCD with an area under the curve (AUC) of 0.712 (CI 0.587–0.816, p = 0.005) with excellent sensitivity (100%, 66–100%), but low specificity (44%, 31–58%). Combined use of increased T1 and LVEF ≤ 60% at FU1 improved AUC to 0.810 (0.695–0.896) resulting in good sensitivity (78%, 44–95%) and specificity (84%, 72–92%).

Conclusion
Only epirubicin-based chemotherapy, but not left-sided radiotherapy, resulted in increased T1/T2 myocardial relaxation times as a marker of myocardial injury. Combined use of CMR parameters may allow an early prediction of subsequent CTCRD.

Key Points
• Myocardial T1 and T2 relaxation times increased at FU1 after epirubicin-based chemotherapy, but not after left-sided radiotherapy.
• Cancer therapy–related cardiac dysfunction (CTRCD) occurred in 20% of patients after epirubicin-based chemotherapy and in 4% after left-sided radiotherapy.
• Combined use of increased T1 and reduced LVEF had an AUC of 0.810 (0.695–0.896) to predict CTRCD with good sensitivity (78%, 44–95%) and specificity (84%, 72–92%).
Importing genetically altered animals: ensuring quality
Authors: Birling M.-C. , Fray M. D. , Kasparek P. , Kopkanova J. , Massimi M. , Matteoni R. , Montoliu L. , Nutter L. M. J. , Raspa M. , Rozman J. , Ryder E. J. , Scavizzi F. , Voikar V. , Wells S. , Pavlovic G. , Teboul L. 
Published: September 2021

AbstractThe reproducibility of research using laboratory animals requires reliable management of their quality, in particular of their genetics, health and environment, all of which contribute to their phenotypes. The point at which these biological materials are transferred between researchers is particularly sensitive, as it may result in a loss of integrity of the animals and/or their documentation. Here, we describe the various aspects of laboratory animal quality that should be confirmed when sharing rodent research models. We also discuss how repositories of biological materials support the scientific community to ensure the continuity of the quality of laboratory animals. Both the concept of quality and the role of repositories themselves extend to all exchanges of biological materials and all networks that support the sharing of these reagents.
Sedimentological evidence for seiching in a swell-dominated headland-bay system: Table Bay, Western Cape, South Africa
Authors: Woodborne Mike , Flemming Burg 
Published: September 2021

AbstractTable Bay, South Africa, is a typical headland-bay system with a shoreline that can be described by a logarithmic spiral. A peculiarity and unique feature of Table Bay is the juxtaposition of Robben Island opposite its headland. As a consequence, the bathymetry defines an ellipsoidal basin which was postulated to potentially resonate in the form of long-period standing waves (seiches). One aim of this study, therefore, was to investigate whether any evidence for such resonant oscillations could be detected in the geomorphology and sediment distribution patterns. Indeed, the ellipsoidal shape of the basin can be framed by two converging log-spirals with their centres located opposite each other, one off Robben Island and the other on the Cape Town side of the bay. The so-called apex line, which divides the two spirals into equal parts is aligned SW–NE, i.e. more or less parallel to the direction of ocean wave propagation. The distribution patterns of all sedimentary parameters were found to be characterised by a strikingly similar trend to either side of the apex line. This supports the hypothesis that the basin of Table Bay appears to resonate in the form of a mode 1 standing wave, with the node positioned above the apex line in the centre of the bay. The maximum period of such a standing wave was calculated to be around 37 min. The study demonstrates that large-scale sediment distribution patterns can reveal the existence of specific hydrodynamic processes in coastal embayments. It is recommended that this phenomenon be investigated in greater detail aimed at verifying the existence of resonant oscillations in Table Bay and, in the event, at establishing its precise nature and trigger mechanism.
Apocrine lesions of the breast
Authors: Quinn Cecily M. , D’Arcy Clare , Wells Clive 
Published: September 2021

AbstractApocrine change is recognised in benign, atypical and malignant lesions of the breast. Apocrine metaplasia, a frequent finding in the breast of women over the age of 25 years, is most commonly seen in benign cysts with a simple or papillary configuration. Apocrine change is also recognised in other benign lesions including sclerosing adenosis, now known as apocrine adenosis. Apocrine atypia usually refers to cytological atypia in which there is at least threefold variation in nuclear size but architectural atypia may also occur. The distinction between atypical apocrine hyperplasia and non-high-grade apocrine ductal carcinoma in situ may be difficult due to the relative rarity of these entities and the lack of validated diagnostic criteria. Lobular carcinoma in situ (LCIS) with apocrine change is considered to be a variant of pleomorphic LCIS. An apocrine variant of encapsulated papillary carcinoma is also recognised. Apocrine change is described in invasive carcinoma, including no special type, lobular, micropapillary and mucinous variants. The recent WHO 2019 update recognises ‘carcinoma with apocrine differentiation’ as a special type breast carcinoma based on the presence of apocrine morphology in at least 90% of the tumour. Tumours with apocrine morphology are usually but not always hormone receptor negative. Human epidermal growth factor receptor 2 (HER-2) status is variable. Molecular studies have identified breast tumours with apocrine features and high expression of androgen receptor mRNA including ‘luminal androgen receptor tumours’ and ‘molecular apocrine tumours’. The term ‘pure apocrine carcinoma’ has been proposed to describe an invasive carcinoma with apocrine morphology that is oestrogen and progesterone receptor negative and androgen receptor positive. HER-2 status may be positive or negative. This article reviews the pathology of benign, atypical and malignant apocrine lesions of the breast, with emphasis on diagnostic criteria including an approach to evaluation of apocrine lesions on needle core biopsy, and recent advances in our understanding of invasive apocrine carcinoma.
Detailed clinical features and genotype–phenotype correlation in an OTOF-related hearing loss cohort in Japan
Authors: Iwasa Yoh-ichiro , Nishio Shin-ya , Yoshimura Hidekane , Sugaya Akiko , Kataoka Yuko , Maeda Yukihide , Kanda Yukihiko , Nagai Kyoko , Naito Yasushi , Yamazaki Hiroshi , Ikezono Tetsuo , Matsuda Han , Nakai Masako , Tona Risa , Sakurai Yuika , Motegi Remi , Takeda Hidehiko , Kobayashi Marina , Kihara Chiharu , Ishino Takashi , Morita Shin-ya , Iwasaki Satoshi , Takahashi Masahiro , Furutate Sakiko , Oka Shin-ichiro , Kubota Toshinori , Arai Yasuhiro , Kobayashi Yumiko , Kikuchi Daisuke , Shintani Tomoko , Ogasawara Noriko , Honkura Yohei , Izumi Shuji , Hyogo Misako , Ninoyu Yuzuru , Suematsu Mayumi , Nakayama Jun , Tsuchihashi Nana , Okami Mayuri , Sakata Hideaki , Yoshihashi Hiroshi , Kobayashi Taisuke , Kumakawa Kozo , Yoshida Tadao , Esaki Tomoko , Usami Shin-ichi 
Published: September 2021

AbstractMutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype–phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype–phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a “typical” phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85–90% of the patients showed a hearing level of 20–39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed “true” auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype–phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype–phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.
Classification of NF1 microdeletions and its importance for establishing genotype/phenotype correlations in patients with NF1 microdeletions
Authors: Kehrer-Sawatzki Hildegard , Cooper David N. 
Published: September 2021

AbstractAn estimated 5–11% of patients with neurofibromatosis type-1 (NF1) harbour large deletions encompassing the NF1 gene and flanking regions. These NF1 microdeletions are subclassified into type 1, 2, 3 and atypical deletions which are distinguishable from each other by their extent and by the number of genes included within the deletion regions as well as the frequency of mosaicism with normal cells. Most common are type-1 NF1 deletions which encompass 1.4-Mb and 14 protein-coding genes. Type-1 deletions are frequently associated with overgrowth, global developmental delay, cognitive disability and dysmorphic facial features which are uncommon in patients with intragenic pathogenic NF1 gene variants. Further, patients with type-1 NF1 deletions frequently exhibit high numbers of neurofibromas and have an increased risk of malignant peripheral nerve sheath tumours. Genes located within the type-1 NF1 microdeletion interval and co-deleted with NF1 are likely to act as modifiers responsible for the severe disease phenotype in patients with NF1 microdeletions, thereby causing the NF1 microdeletion syndrome. Genotype/phenotype correlations in patients with NF1 microdeletions of different lengths are important to identify such modifier genes. However, these correlations are critically dependent upon the accurate characterization of the deletions in terms of their extent. In this review, we outline the utility as well as the shortcomings of multiplex ligation-dependent probe amplification (MLPA) to classify the different types of NF1 microdeletion and indicate the importance of high-resolution microarray analysis for correct classification, a necessary precondition to identify those genes responsible for the NF1 microdeletion syndrome.