bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction
Authors: Perkins Emma M. , Burr Karen , Banerjee Poulomi , Mehta Arpan R. , Dando Owen , Selvaraj Bhuvaneish T. , Suminaite Daumante , Nanda Jyoti , Henstridge Christopher M. , Gillingwater Thomas H. , Hardingham Giles E. , Wyllie David J. A. , Chandran Siddharthan , Livesey Matthew R. 
Published: March 2021

Abstract
Background
Physiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harbouring the C9ORF72 repeat expansion (C9ORF72RE) mutation – the most common genetic impairment causal to ALS and FTD. Noting that perturbations in cortical function are evidenced pre-symptomatically, and that the cortex is associated with widespread pathology, cortical dysfunction is thought to be an early driver of neurodegenerative disease progression. However, our understanding of how altered network function manifests at the cellular and molecular level is not clear.

Methods
To address this we have generated cortical neurons from patient-derived iPSCs harbouring C9ORF72RE mutations, as well as from their isogenic expansion-corrected controls. We have established a model of network activity in these neurons using multi-electrode array electrophysiology. We have then mechanistically examined the physiological processes underpinning network dysfunction using a combination of patch-clamp electrophysiology, immunocytochemistry, pharmacology and transcriptomic profiling.

Results
We find that C9ORF72RE causes elevated network burst activity, associated with enhanced synaptic input, yet lower burst duration, attributable to impaired pre-synaptic vesicle dynamics. We also show that the C9ORF72RE is associated with impaired synaptic plasticity. Moreover, RNA-seq analysis revealed dysregulated molecular pathways impacting on synaptic function. All molecular, cellular and network deficits are rescued by CRISPR/Cas9 correction of C9ORF72RE. Our study provides a mechanistic view of the early dysregulated processes that underpin cortical network dysfunction in ALS-FTD.

Conclusion
These findings suggest synaptic pathophysiology is widespread in ALS-FTD and has an early and fundamental role in driving altered network function that is thought to contribute to neurodegenerative processes in these patients. The overall importance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic plasticity, synaptic vesicle stores, and network propagation, which directly impact upon cortical function.
Central precocious puberty in a girl with LEGIUS syndrome: an accidental association?
Authors: Orlandi Valentina , Cavarzere Paolo , Palma Laura , Gaudino Rossella , Antoniazzi Franco 
Published: March 2021

Abstract
Background
Central precocious puberty is a condition characterized by precocious activation of the hypothalamic-pituitary-gonadal axis. It may be idiopathic or secondary to organic causes, including syndromes such as Neurofibromatosis type 1 (NF1).

Case presentation
We presented a girl of 6 years and 10 months with almost 11 café-au-lait skin macules, without other clinical or radiological signs typical of NF1, and with a central precocious puberty. Genetic analysis evidenced the new variant NM-152594.2:c.304delAp. (Thr102Argfs*19) in SPRED1 gene, which allowed to diagnose Legius syndrome.

Conclusions
We report for the first time a case of central precocious puberty in a girl with Legius syndrome. The presence of central precocious puberty in a child with characteristic café-au-lait macules should suggest pediatricians to perform genetic analysis in order to reach a definitive diagnosis. Further studies on timing of puberty in patients with RASopathies are needed to better elucidate if this clinical association is casual or secondary to their clinical condition.
Systematic review of available software for multi-arm multi-stage and platform clinical trial design
Authors:   on behalf of EU-PEARL (EU Patient-cEntric clinicAl tRial pLatforms) Consortium, Meyer Elias Laurin , Mesenbrink Peter , Mielke Tobias , Parke Tom , Evans Daniel , König Franz 
Published: March 2021

Abstract
Background
In recent years, the popularity of multi-arm multi-stage, seamless adaptive, and platform trials has increased. However, many design-related questions and questions regarding which operating characteristics should be evaluated to determine the potential performance of a specific trial design remain and are often further complicated by the complexity of such trial designs.

Methods
A systematic search was conducted to review existing software for the design of platform trials, whereby multi-arm multi-stage trials were also included. The results of this search are reported both on the literature level and the software level, highlighting the software judged to be particularly useful.

Results
In recent years, many highly specialized software packages targeting single design elements on platform studies have been released. Only a few of the developed software packages provide extensive design flexibility, at the cost of limited access due to being commercial or not being usable as out-of-the-box solutions.

Conclusions
We believe that both an open-source modular software similar to OCTOPUS and a collaborative effort will be necessary to create software that takes advantage of and investigates the impact of all the flexibility that platform trials potentially provide.
Records of three mammal tick species parasitizing an atypical host, the multi-ocellated racerunner lizard, in arid regions of Xinjiang, China
Authors: Zhou Qi , Li Jiao , Guo Xianguang , Liu Jinlong , Song Qi , Gong Xiong , Chen Han , Zhang Jianhui , He Jinlei , Zheng Zhiwan , Chen Dali , Chen Jianping 
Published: March 2021

Abstract
Background
Ticks are ectoparasites that feed on blood of a broad taxonomical range of terrestrial and flying vertebrates and are distributed across a wide range of environmental settings. To date, the species identity, diversity, and relationships among the ticks on lizards in China have been poorly understood.

Methods
In this study, 30 ticks, collected from the multi-ocellated racerunner (Eremias multiocellata) lizard in the Tarim Basin and adjacent Yanqi Basin of the Xinjiang Uygur Autonomous Region in China, were identified by morphological observation and confirmed by DNA-based techniques. The mitochondrially encoded 12S rRNA, 16S rRNA, and COI gene fragments of ticks were amplified and sequenced. To understand the genetic polymorphisms, 47 ticks collected from hedgehogs and 1 from brushwood in the Tarim Basin were also included. Species identification was based on both morphological and molecular characters. The median-joining network approach was used to evaluate the intraspecific genealogies of the ticks and their relatedness with the geographical origin or hosts.

Results
The sequence similarity analysis confirmed that the 30 ticks belong to three genera and three species including 11 individuals of Hyalomma asiaticum, 3 of Rhipicephalus turanicus, and 16 of Haemaphysalis sulcata. A network approach revealed paraphyletic populations of R. turanicus and Hy. asiaticum at the intraspecies level regarding geographical origin and low host specificity. For R. turanicus and Hy. asiaticum, common ancestry was observed between COI sequences from lizards and other sequence types from different hosts and countries.

Conclusions
To our knowledge, our study is the first to conduct a molecular survey of ticks from lizards in the arid regions of Xinjiang, China. Eremias multiocellata is an atypical host of the three tick species. Notably, two species of ticks, Hy. asiaticum and R. turanicus, have been collected and identified from lizards in China for the first time. Star-like networks suggest both of them might have experienced recent population expansion. The discoveries are closely related to the geographical environments in Xinjiang and will provide information for the control of ticks and tick-borne pathogens in Northwest China.

Graphical Abstract
DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother–newborn pairs
Authors: Xu Richard , Hong Xiumei , Zhang Boyang , Huang Wanyu , Hou Wenpin , Wang Guoying , Wang Xiaobin , Igusa Tak , Liang Liming , Ji Hongkai 
Published: March 2021

AbstractBackgroundMaternal smoking affects more than half a million pregnancies each year in the US and is known to result in fetal growth restriction as measured by lower birthweight and its associated long-term consequences. Maternal smoking also has been linked to altered fetal DNA methylation (DNAm). However, what remains largely unexplored is whether these DNAm alterations are merely markers of smoking exposure or if they also have implications for health outcomes. This study tested the hypothesis that fetal DNAm mediates the effect of maternal smoking on newborn birthweight.MethodsThis study included mother–newborn pairs from a US predominantly urban, low-income multi-ethnic birth cohort. DNAm in cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip. After standard quality control and normalization procedures, an epigenome-wide association study (EWAS) of maternal smoking was performed using linear regression models, controlling for maternal age, education, race, parity, pre-pregnancy body mass index, alcohol consumption, gestational age, maternal pregestational/gestational diabetes, child sex, cord blood cell compositions and batch effects. To quantify the degree to which cord DNAm mediates the smoking-birthweight association, the VanderWeele-Vansteelandt approach for single mediator and structural equational model for multiple mediators were used, adjusting for pertinent covariates.ResultsThe study included 954 mother–newborn pairs. Among mothers, 165 (17.3%) ever smoked before or during pregnancy. Newborns with smoking exposure had on average 258 g lower birthweight than newborns without exposure (P < 0.001). Using a false discovery rate (FDR) < 0.05 as the significance cutoff, the EWAS identified 38 differentially methylated CpG sites associated with maternal smoking. Of those, 17 CpG sites were mapped to previously reported genes:GFI1, AHRR, CYP1A1, and CNTNAP2;8 of those, located in the first three genes, were Bonferroni significantly associated with newborn birthweight and mediated the smoking-birthweight association. The combined mediation effect of the three genes explained 67.8% of the smoking-birthweight association.ConclusionsOur study not only lends further support that maternal smoking alters fetal DNAm in a multiethnic population, but also suggests that fetal DNAm substantially mediates the maternal smoking–birthweight association. Our findings, if further validated, indicate that DNAm modification is likely an important pathway by which maternal smoking impairs fetal growth and, perhaps, even long-term health outcomes.
Controversy of indomethacin eye drops in the treatment of rheumatoid arthritis-induced corneal ulceration: a case report
Authors: Nicoară Simona Delia , Damian Ioana 
Published: March 2021

Abstract
Background
Perforation of the cornea is a rare finding in patients with rheumatoid arthritis (RA). Addressing a perforated cornea associated with RA is challenging, since its pathogenesis is not fully elucidated. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) were developed to prevent cystoid macular edema following cataract surgery in patients at risk. Their prescription in inflammation of the anterior segment of the eye may induce negative effects on the ocular surface. We bring into focus a corneal perforation in a patient with RA who used indomethacin eye drops to treat corneal ulceration, but responded promptly to drug discontinuation and initiation of topical cyclosporine 0.1%. Our aim is to emphasize two issues: the contraindication of topical indomethacin in corneal defects, and the immediate positive impact of topical cyclosporine 0.1% on corneal healing.

Case presentation
A 73-year-old Caucasian woman with a 13-year history of RA was treated for corneal ulceration in her oculus sinister (OS) with topical indomethacin and gentamicin. The patient was being treated with systemic immunosuppression and NSAIDs for the underlying RA and artificial tears in both eyes. No bandage contact lens was used. After 3 weeks of treatment, perforation of the left cornea occurred and the patient was referred to our hospital. Upon admission, visual acuity (VA) in the OS was 20/630. Slit lamp examination of the OS revealed paracentral corneal perforation, iris plugging the perforation site, shallow anterior chamber, clear aqueous humor, and clear lens. Anterior segment optical coherence tomography showed the inclavated iris in the perforation site and minimum corneal thickness of 101 µm. Topical NSAIDs were discontinued and topical treatment was initiated with tobramycin, tropicamide 1%, phenylephrine 10%, and artificial tears five times a day, and occlusive patch. For 5 days, there was no improvement, so topical cyclosporine 0.1% was started, one drop every evening. Within 7 days, the cornea had healed, the iris was liberated from the perforation site, the minimum corneal thickness increased to 250 µm, VA improved to 20/25, and the patient was free of symptoms.

Conclusions
The main “takeaway” lessons from this case are that topical indomethacin should not be prescribed in cases of inflammation of the anterior segment of the eye, and that topical cyclosporine was efficacious in healing corneal perforation in our patient.
The joint use of 99mTc-MAA-SPECT/CT and cone-beam CT optimizes radioembolization planning
Authors: Rodríguez-Fraile Macarena , Ezponda Ana , Grisanti Fabiana , Morán Verónica , Calvo Marta , Berián Pablo , de la Cuesta Antonio Martínez , Sancho Lidia , Iñarrairaegui Mercedes , Sangro Bruno , Bilbao José Ignacio 
Published: March 2021

Abstract
Purpose
To determine which imaging method used during radioembolization (RE) work-up: contrast-enhanced computed tomography (CECT), 99mTc-MAA-SPECT/CT or cone beam-CT (CBCT), more accurately predicts the final target volume (TgV) as well as the influence that each modality has in the dosimetric calculation.

Methods
TgVs from 99mTc-MAA-SPECT/CT, CECT and CBCT were consecutively obtained in 24 patients treated with RE and compared with 90Y PET/CT TgV. Using the TgVs estimated by each imaging modality and a fictitious activity of 1 GBq, the corresponding absorbed doses by tumor and non-tumoral parenchyma were calculated for each patient. The absorbed doses for each modality were compared with the ones obtained using 90Y PET/CT TgV.

Results
99mTc-MAA-SPECT/CT predicted 90Y PET/CT TgV better than CBCT or CECT, even for selective or superselective administrations. Likewise, 99mTc-MAA-SPECT/CT showed dosimetric values more similar to those obtained with 90Y PET/CT. Nevertheless, CBCT provided essential information for RE planning, such as ensuring the total coverage of the tumor and, in cases with more than one feeding artery, splitting the activity according to the volume of tumor perfused by each artery.

Conclusion
The joint use of 99mTc-MAA-SPECT/CT and CBCT optimizes dosimetric planning for RE procedures, enabling a more accurate personalized approach.
Engineering a lipoxygenase from cyclocybe aegerita towards long chain polyunsaturated fatty acids
Authors: Karrer Dominik , Gand Martin , Rühl Martin 
Published: March 2021

AbstractThe basidiomycetous lipoxygenase Lox1 fromCyclocybe aegeritacatalyzes the oxygenation of polyunsaturated fatty acids (PUFAs) with a high preference towards the C18-PUFA linoleic acid (C18:2 (ω-6)). In contrast, longer PUFAs, generally not present in the fungal cell such as eicosatrienoic acid (C20:3(ω-3)) and docosatrienoic acid (C22:3 (ω-3)), are converted with drastically lower activities. With site-directed mutagenesis, we were able to create two variants with enhanced activities towards longer chain PUFAs. The W330L variant showed a ~ 20 % increased specific activity towards C20:3(ω-3), while a ~ 2.5-fold increased activity against C22:3 (ω-3) was accomplished by the V581 variant.
Centrosome-phagy: implications for human diseases
Authors: Wu Qi , Yu Xin , Liu Le , Sun Shengrong , Sun Si 
Published: March 2021

AbstractAutophagy is a prominent mechanism to preserve homeostasis and the response to intracellular or extracellular stress. Autophagic degradation can be selectively targeted to dysfunctional subcellular compartments. Centrosome homeostasis is pivotal for healthy proliferating cells, but centrosome aberration is a hallmark of diverse human disorders. Recently, a process called centrosome-phagy has been identified. The process involves a panel of centrosomal proteins and centrosome-related pathways that mediate the specific degradation of centrosomal components via the autophagic machinery. Although autophagy normally mediates centrosome homeostasis, autophagy defects facilitate ageing and multiple human diseases, such as ciliopathies and cancer, which benefit from centrosome aberration. Here, we discuss the molecular systems that trigger centrosome-phagy and its role in human disorders.
Cognitive rehabilitation interventions after stroke: protocol for a systematic review and meta-analysis of randomized controlled trials
Authors: Zhao Qing , Wang Xue , Wang Tao , Dmytriw Adam A. , Zhang Xiao , Yang Kun , Luo Jichang , Bai Xuesong , Jiang Nan , Yang Bin , Ma Yan , Jiao Liqun , Xie Yunyan 
Published: March 2021

Abstract
Background
Stroke is the second leading cause of death worldwide, and 53.4% of stroke survivors suffer from post-stroke cognitive impairment. Post-stroke cognitive impairment can increase hospitalization rate and cost of care and decrease the quality of life of stroke patients. To date, multiple cognitive rehabilitation interventions have been tested in stroke populations with post-stroke cognitive impairment. However, the most efficacious intervention has not been established. This systematic review aims to compare the efficacy of cognitive rehabilitation interventions for patients with post-stroke cognitive impairment.

Methods
We will search MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, PubMed, and clinical trial registries to identify eligible randomized clinical trials with no restrictions in the date of publication and language. Studies conducted with patients aged 18 or over, with the presence of cognitive impairment after being diagnosed with stroke will be included. Studies will be restricted to randomized controlled trials comparing a cognitive rehabilitation intervention with another intervention. The primary outcome is any clinical changes in the general or specific cognitive domain (e.g., executive function, attention, memory, or perception). The secondary outcomes that will be collected include adverse effects (e.g., stroke, disability, or mortality) and quality of life. Two independent reviewers will assess articles to identify trials eligible for inclusion. Data extraction and risk of bias assessment of the included studies will also be done independently. Any discrepancies will be solved by discussion, or a third reviewer will be consulted if necessary. A meta-analysis will be carried out if appropriate.

Discussion
This systematic review for patients with post-stroke cognitive impairment will assess the efficacy of cognitive rehabilitation interventions. And our results will help clinical decision-making and support the development of clinical practice guidelines.

Trial registration
Systematic review registration: PROSPERO CRD42020173988
Parent-directed intervention versus controls whilst their child waits for diagnostic assessment: a systematic review protocol
Authors: Bernie C. , Mitchell M. , Williams K. , May T. 
Published: March 2021

AbstractBackgroundWaiting lists are an ongoing issue for publicly funded community and hospital-based health services. Parents and caregivers are instrumental supports in the health and well-being of young and school-aged children, yet little is known about the way they can be supported during waiting periods. Given mounting evidence about the value of early intervention in physical and mental health literature, and waits for some public health services extending past 12 months, it is both timely and warranted to explore interim interventions that may be applied in this period.MethodsIntervention studies that have applied an educational programme, information, group-based support or individualised therapy to primary caregivers of children (heron referred to as parent-directed interventions), waiting for diagnostic assessment at any inpatient or outpatient health service and aged between 1 and 12 years of age, will be reviewed. These will include intervention studies of any type that have included more than 5 participants or participant groups and where a control or comparison group has been included. Abstract screening, full-text review, data extraction and risk of bias will be conducted by two reviewers. Relevant databases in health and education will be systematically searched using key words and Medical Subject Headings (MeSH) and grey literature will be explored. Databases will include PubMed, Ovid for MEDLINE and PsycINFO, EBSCO for the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and the Education Resources Information Center (ERIC). Covidence© will be used to support abstract and full text screening, which will be completed by two main reviewers. Results will be tabulated, summarised and meta-analysed using a random-effects model, in any instance where concordant outcome measures have been applied. Results will be published and reported in line with PRISMA reporting guidelines.DiscussionGiven little is known about effective support for families when children are awaiting diagnostic assessment for any medical, developmental or behavioural condition, the authors will synthesise existing evidence about parent-directed interventions in this period. It is hoped that by understanding the existing evidence interventions that are proven to be effective will be adopted and intervention innovation can occur.Systematic review registrationPROSPERO 2020 CRD42020159360