bluuebunny/crossref_metadata_2025_split huggingface dataset:
Androgen Insensitivity
Authors: McEwan Iain J 
Published: July 2018

Abstract

Androgen insensitivity is an X‐linked disorder of defective or absent virilisation in 46, XY individuals owing to complete or partial resistance to androgens in androgen‐dependent tissues and organs. The syndrome is part of a group of disorders of sex development (DSD). The molecular cause of the syndrome is mutations in the androgen receptor gene (locus: Xq11–12), resulting either in the absence of an androgen receptor protein or in the production of a mutant receptor with partial or complete loss of its activity. Androgen insensitivity displays a broad phenotypic and genotypic spectrum. The phenotype can vary from complete (CAIS, complete androgen insensitivity syndrome), partial (PAIS, partial androgen insensitivity syndrome) to mild (MAIS, mild androgen insensitivity syndrome). More than 450 different mutations in the androgen receptor gene have been reported. The majority of mutations are single‐base substitutions. However, deletions (1–6 bp), partial or complete gene deletions (>10 bp), insertions or duplications are also found.

Key Concepts

Androgens and the androgen receptor are indispensable for expression of the male phenotype.

The androgen receptor is a ligand‐dependent transcription factor and belongs to the family of nuclear receptors.

Despite two different ligands (testosterone and 5α‐dihydrotestosterone), only one androgen receptor cDNA has been identified and cloned.

A highly polymorphic (CAG)

n

‐CAA repeat, encoding a polyglutamine stretch, in exon 1 of the androgen receptor gene is used for identification of X‐chromosomes for carrier detection in pedigree analyses.

Variations in the polyglutamine stretch modulate androgen receptor transcriptional activity.

End‐organ resistance to androgens has been designated as androgen insensitivity syndrome (AIS) and is distinct from other XY disorders of sex development.

Defects in the androgen receptor gene can prevent normal development of both the internal and external male structures in 46, XY individuals.

End‐organ resistance to androgens is X‐linked, and only 46, XY individuals are affected.

AR gene mutations are transmitted in an X‐linked manner, but in 30% of the cases, mutations arise
de novo
.

A number of cases of AIS present with no identifiable mutation in the androgen receptor, which has been estimated at between 25% and 33% of individuals presenting with androgen resistance.
Relevance of Copy Number Variation to Human Genetic Disease
Authors: Torres Fátima , Lopes Fátima , Maciel Patrícia 
Published: July 2018

Abstract

Genomic rearrangements leading to the appearance of copy number variations (CNVs) are frequent and widespread events, mostly as a consequence of the inherent repeat architecture of the human genome. It is currently accepted that these structural variants represent a major genetic component underlying our phenotypic diversity and also play an important role in human disease. CNVs can lead to disease by means of gene dosage effect, gene disruption, gene fusion and other effects on gene function, including position effect mechanisms. Recurrent CNVs with common breakpoints define genomic disorders that frequently involve the contribution of multiple genes and are associated with a particular phenotype, although most of them exhibit variable expressivity and incomplete penetrance. These rearrangements are presently unavoidable elements when studying the genetic basis of syndromes and complex diseases, such as cancer, metabolism disorders, neurodegenerative and neurodevelopmental disorders.

Key Concepts

The detection and identification of recurrent CNVs has allowed the definition of previously unidentified genomic disorders.

Many CNV‐associated disorders show incomplete penetrance and variable expressivity.

An adequate estimation of CNV‐associated odds ratio of disease is of utmost relevance for genetic counselling.

These disorders usually affect multiple genes, and even though in some cases there is a key gene recognised as the main contributor to the disease features, others are contiguous gene syndromes, that is result from the contribution of dosage changes in multiple genes.

Animal/hiPSC models are helping to understand the pathogenic mechanisms by which CNVs cause disease.

hiPSC models are also being used for drug discovery and development.
Origins of Human Aneuploidy
Authors: Delhanty Joy DA 
Published: July 2018

Abstract

At birth, at least 1% of humans have a clinically significant chromosomal abnormality. However, this represents a small fraction of those originally conceived as by the time of birth, natural selection has eliminated the vast majority of abnormal embryos and foetuses.

There are three stages in development when aneuploidy may arise: during gamete formation, at fertilisation or during the early stages of embryo development. Gamete formation differs significantly between males and females, affecting the incidence of aneuploid gametes, which is fourfold higher in females than in males. Molecular cytogenetic techniques have revealed the extent of full and mosaic aneuploidy in embryos created by
in vitro
fertilisation (IVF), explaining the high level of arrested development affecting these embryos. Maternal age is the most significant factor affecting the incidence of aneuploidy, but genetic anomalies in the parents are also important.

Key Concepts

Chromosomally abnormal conceptions are very high in humans, but the effects are lethal in almost all cases.

Aneuploidy may arise at three developmental stages: during gamete formation, at fertilisation or during embryogenesis.

Gamete formation (oogenesis or spermatogenesis) differs considerably between the sexes as males produce sperm throughout adult life, whereas females are born with a finite set of oogonia.

These differences are reflected in the fourfold higher aneuploidy rate in females versus males.

Maternal age is the most significant factor affecting the incidence of aneuploidy, but genetic variation, particularly chromosomal rearrangement, in a parent is also an important factor.
Therapeutic and Other Misconceptions in Clinical Trials for Paediatric Genetic Disorders
Authors: Woods Simon 
Published: July 2018

AbstractPaediatric research is ethically complex because it involves subjects unable to consent for themselves. As some conditions only affect children, it is necessary to involve children in research so that treatments can be developed. Paediatric genomic research requires parental consent for children with serious, often progressive and frequently life‐threatening conditions. A body of evidence identifies the various vulnerabilities associated with the process of informed consent. Commonly misconceptions about the nature of research, especially those that mistake research for treatment, the ‘therapeutic misconception’, can occur. Serious misconceptions about research potentially undermine the validity of consent. Various factors increase the likelihood of therapeutic and other serious misconceptions, which include the complexity of the research, the timing and context of decisions. Researchers may also contribute to misconceptions, for example by being too optimistic about the benefits of research. Wider factors such as the ‘promissory’ hyperbole that accompanies public discussion of bioscience research also encourage inflated expectations of research. Researchers ought to be conscious of these factors but should not deny parents the opportunity to exercise parental responsibility in giving consent nor deny them the capacity for hope alongside a realistic understanding of the aims and limitations of research.Key ConceptsInformed consent for clinical research is an important ethico‐legal concept, but it is vulnerable to several serious flaws which may undermine the validity of the consent.In research ethics, the ‘therapeutic misconception’ is commonly observed in which research participants falsely believe that the aim of the research is to provide beneficial treatment.Paediatric genomics research is a complex area of research in which appropriate support for parental decisions is needed to help them to navigate complex information and to understand the aims of the research.Clinicians who are also active in paediatric research ought to be aware of the influence they can exert over parents invited to participate in genomics research.A disposition to hope for benefit from research may be an important coping mechanism, for parents and researchers should distinguish between a disposition to hope and a serious therapeutic misconception.Researchers and policymakers should attend to the language they use in the public discussion of developing areas of biomedicine, avoiding ‘promissory’ claims which may encourage a therapeutic misconception.
Reducing seed waste and increasing value of dynamic intraoperative implantation of Pd‐103 seeds in prostate brachytherapy
Authors: Taylor Peter K. , Riegel Adam C. 
Published: July 2018

AbstractSeveral nomograms exist for ordering palladium‐103 seeds for permanent prostate seed implants (PSI). Excess seeds from PSIs pose additional radiation safety risks and increase the cost of care. This study compared five nomograms to clinical data from dynamic modified‐peripheral intraoperative PSI to determine (a) the cause of excess seeds and (b) the optimal nomogram for our institution. Pre‐ and intraoperative patient data were collected for monotherapy PSIs and compiled into a clinical database. All patients were prescribed 125 Gy with dose coverage of D90% = 100% to the planning target volume (PTV) using 103Pd seeds with mean air‐kerma strength () of 2 U. Seeds were ordered based upon an in‐house nomogram as a function of preoperative prostate volume and prescription dose. Preoperative prostate volume was assessed with transrectal ultrasound. If any of the following four conditions were not met: (a) preoperative volume = intraoperative volume, (b) D90% = 100%, (c) , and (d) seed ordering matched the in‐house nomogram, then a normalization factor was applied to the number of seeds used intraoperatively to meet all four conditions. Four published nomograms, an in‐house nomogram, and the normalized number of implanted seeds for each patient were plotted against intraoperative prostate volume. Of the 226 patients, 223 had excess seeds at the completion of their PSI. On average, 25.7 ± 9.9% of ordered seeds were not implanted. Excess seeds were separated into two categories, accounted‐for excess, determined by the four normalization factors, and residual excess, assumed to be due to overordering. The upper 99.9% CI linear fit of the normalized clinical data plus a 5% “cushion” may provide a more reasonable nomogram for 103Pd seed ordering for our institution. Nomograms customized for individual institutions may reduce seed waste, thereby reducing radiation safety risks and increasing the value of prostate brachytherapy.
Association Between Knee Load and Pain: Within‐Patient, Between‐Knees, Case–Control Study in Patients With Knee Osteoarthritis
Authors: Birmingham Trevor B. , Marriott Kendal A. , Leitch Kristyn M. , Moyer Rebecca F. , Lorbergs Amanda L. , Walton Dave M. , Willits Kevin , Litchfield Robert B. , Getgood Alan , Fowler Peter J. , Giffin J. Robert 
Published: July 2018

ObjectiveThe association between knee loading and pain in patients with knee osteoarthritis is reported to be low and of questionable importance, but may be confounded by several factors that differ between patients. We aimed to elucidate the association between dynamic knee load and pain by minimizing confounding using a study design that was within the same patient, with knees discordant for pain.MethodsA total of 265 patients with knees discordant for pain (530 knees) rated the pain in each knee before and after walking for 6 minutes, and then underwent 3‐dimensional gait analysis.ResultsThe peak knee adduction moment and knee adduction impulse (proxies for medial knee loading) were associated with increased pain (odds ratio [OR] 2.43 [95% confidence interval (95% CI) 1.77–3.33] and OR 6.62 [95% CI 3.46–12.7], respectively) and remained significant after controlling for radiographic disease severity. When split into quartiles, ORs indicated knees in the highest loading quartile had greater odds of experiencing increased pain with walking (OR 4.7 95% CI 2.3–9.5] for peak adduction moment; OR 9.0 [95% CI 4.0–20.1] for adduction impulse) compared to knees in the lowest loading quartile.ConclusionWhen between‐patient confounding is minimized, there is a strong association between medial knee load and increased knee pain during walking.
Barriers and Facilitators of Vigorous Cardiorespiratory Training in Axial Spondyloarthritis: Surveys Among Patients, Physiotherapists, and Rheumatologists
Authors: Niedermann Karin , Nast Irina , Ciurea Adrian , Vliet Vlieland Thea , van Bodegom‐Vos Leti 
Published: July 2018

ObjectiveVigorous cardiorespiratory training (CRT) in patients with axial spondyloarthritis (SpA) is effective, safe. and feasible; however, it has not yet been adopted in axial SpA exercise programs. Therefore, the aim of this study was to explore the barriers and facilitators for vigorous CRT among patients, physiotherapists, and rheumatologists.MethodsStakeholder‐specific surveys were used to examine perceptions of barriers and facilitators to vigorous CRT, with categories organized according to the recommendations proposed by Grol and Wensing. Respondents chose the 3 most important barrier and facilitator categories and rated individual items on a 4‐point scale. Frequencies and proportions were calculated, and ratings between active and inactive patients were compared.ResultsAmong all patients (n = 575 [response rate 34%]), the top 3 barrier categories were “low motivation” (n = 317 [59%]), “unsuccessful timing in daily routine” (n = 292 [55%]), and “hindering disease symptoms” (n = 272 [51%]). The top 3 facilitator categories were “high motivation” (n = 248 [47%]), “good organizational conditions” (n = 217 [41%]), and “facilitating disease symptoms” (n = 209 [40%]). More inactive patients than active patients chose “low motivation” as a barrier (P = 0.01). Among physiotherapists (n = 40 [response rate 48%]), the top 3 barrier categories were “heterogeneous groups” (n = 26 [70%]), “difficult organizational conditions” (n = 19 [51%]), and “low perceived motivation” (n = 19 [51%]). Among physiotherapists, the top 3 facilitator categories were “knowledge” (n = 20 [54%]), “homogeneous group composition,” and “high perceived motivation” (both n = 17 [46%]). For rheumatologists (n = 73 [response rate 17%], with 54 [74%] answering barrier items and 68 [93%] answering facilitator items), the strongest barriers included “not enough information” (n = 25 [47%]) and “anticipated or perceived disinterest of patient” (n = 27 [50%]). The strongest facilitators reported by rheumatologists included “exercise important topic even in limited consultation time” (n = 65 [96%]) and “clear evidence for effectiveness of flexibility exercises” (n = 62 [91%]).ConclusionThe identified facilitators and barriers will guide the development of stakeholder‐specific implementation strategies.
Efficient Photocarrier Transfer and Effective Photoluminescence Enhancement in Type I Monolayer MoTe2/WSe2 Heterostructure
Authors: Yamaoka Takao , Lim Hong En , Koirala Sandhaya , Wang Xiaofan , Shinokita Keisuke , Maruyama Mina , Okada Susumu , Miyauchi Yuhei , Matsuda Kazunari 
Published: July 2018

AbstractArtificial van der Waals heterostructures of 2D layered materials are attractive from the viewpoint of the possible discovery of new physics together with improved functionalities. Stacking various combinations of atomically thin semiconducting transition metal dichalcogenides, MX2 (M = Mo, W; X = S, Se, Te) with a hexagonal crystal structure, typically leads to the formation of a staggered Type II band alignment in the heterostructure, where electrons and holes are confined in different layers. Here, the comprehensive studies are performed on heterostructures prepared from monolayers of WSe2 and MoTe2 using differential reflectance, photoluminescence (PL), and PL excitation spectroscopy. The MoTe2/WSe2 heterostructure shows strong PL from the MoTe2 layer at ≈1.1 eV, which is different from the quenched PL from the WSe2 layer. Moreover, enhancement of PL intensity from the MoTe2 layer is observed because of the near‐unity highly efficient photocarrier transfer from WSe2 to MoTe2. These experimental results suggest that the MoTe2/WSe2 heterostructure has a Type I band alignment where electrons and holes are confined in the MoTe2 layer. The findings extend the diversity and usefulness of ultrathin layered heterostructures based on transition metal dichalcogenides, leading to possibilities toward future optoelectronic applications.
Synergistic Compositional–Mechanical–Thermal Effects Leading to a Record High zT in n‐Type V2VI3 Alloys Through Progressive Hot Deformation
Authors: Hu Lipeng , Zhang Yang , Wu Haijun , Liu Yamei , Li Junqin , He Jian , Ao Weiqin , Liu Fusheng , Pennycook Stephen John , Zeng Xierong 
Published: July 2018

AbstractHere a progressive hot deformation procedure that endows the benchmark n‐type V2VI3 thermoelectric materials with short range disorder (multiple defects), long range order (crystallinity), and strong texture (nearly orientation order) is reported. Not only it is rare for these structural features to coexist but also these structural features elicit the synergistic compositional–mechanical–thermal effects, i.e., a profound interplay among the counts, magnitude, and temperature of hot deformation in relation to the as formed point defects, dislocations, textures, strain clusters, and distortions. Using progressively larger die sets and relatively low hot deformation temperature, rich multiscale microstructures concurrently with a high level of texture comparable to that of zone melted ingot are obtained. The strong donor‐like effect significantly increases the majority carrier concentration, suppressing the detrimental bipolar effect. In addition, the multiscale microstructures yield an ultralow lattice thermal conductivity ≈0.31 W m−1 K−1 at 405 K. A record zT ≈ 1.3 at 450 K are attained in progressively hot deformed n‐type Bi1.95Sb0.05Te2.3Se0.7 through the synergistic effects. These results not only promise a better pairing between n‐type and p‐type legs in device fabrication but also bring our understanding of n‐type V2VI3 alloys and hot deformation technique to a new level.
Addressing Unmet Clinical Needs with 3D Printing Technologies
Authors: Ghosh Udayan , Ning Shen , Wang Yuzhu , Kong Yong Lin 
Published: July 2018

AbstractRecent advances in 3D printing have enabled the creation of novel 3D constructs and devices with an unprecedented level of complexity, properties, and functionalities. In contrast to manufacturing techniques developed for mass production, 3D printing encompasses a broad class of fabrication technologies that can enable 1) the creation of highly customized and optimized 3D physical architectures from digital designs; 2) the synergistic integration of properties and functionalities of distinct classes of materials to create novel hybrid devices; and 3) a biocompatible fabrication approach that facilitates the creation and cointegration of biological constructs and systems. This progress report describes how these capabilities can potentially address a myriad of unmet clinical needs. First, the creation of 3D‐printed prosthetics to regain lost functionalities by providing structural support for skeletal and tubular organs is highlighted. Second, novel drug delivery strategies aided by 3D‐printed devices are described. Third, the advancement of medical research heralded by 3D‐printed tissue/organ‐on‐chips systems is discussed. Fourth, the developments of 3D‐printed tissue and organ regeneration are explored. Finally, the potential for seamless integration of engineered organs with active devices by leveraging the versatility of multimaterial 3D printing is envisioned.
Acceleration of Diabetic Wound Regeneration using an In Situ–Formed Stem‐Cell‐Based Skin Substitute
Authors: Dong Yixiao , Rodrigues Melanie , Kwon Sun Hyung , Li Xiaolin , A Sigen , Brett Elizabeth Anne , Elvassore Nicola , Wang Wenxin , Gurtner Geoffrey C. 
Published: July 2018

AbstractChronic diabetic ulcers are a common complication in patients with diabetes, often leading to lower limb amputations and even mortality. Stem cells have shown promise in promoting cutaneous wound healing by modulating inflammation, angiogenesis, and re‐epithelialization. However, more effective delivery and engraftment strategies are needed to prolong transplanted stem cell lifespan and their pro‐healing functions in a chronic wound environment to improve skin regeneration. In this study, an injectable poly(ethylene glycol) (PEG)–gelatin‐based hydrogel system is examined to create a functional stem cell niche for the delivery of adipose‐derived stem cells (ASCs) into diabetic wounds. Human ASCs are encapsulated into the in situ crosslinked hydrogels and cultured in a 3D topography. The encapsulated cells are well attached and spread inside the hydrogels, retaining viability, proliferation, and metabolic activity up to three weeks in vitro. Allogeneic ASCs are delivered to diabetic wounds by this hydrogel vehicle. It is found that stem cell retention is significantly improved in vivo with vehicle‐mediated delivery. The ASC‐hydrogel‐based treatment decreases inflammatory cell infiltration, enhances neovascularization, and remarkably accelerates wound closure in diabetic mice. Together, these findings suggest this conveniently‐applicable ASC‐hydrogel‐based skin substitute provides a promising potential for the treatment of chronic diabetic wounds.
Tracking the Fate of Porous Silicon Nanoparticles Delivering a Peptide Payload by Intrinsic Photoluminescence Lifetime
Authors: Jin Yusung , Kim Dokyoung , Roh Hajung , Kim Sojeong , Hussain Sazid , Kang Jinyoung , Pack Chan‐Gi , Kim Jun Ki , Myung Seung‐Jae , Ruoslahti Erkki , Sailor Michael J. , Kim Song Cheol , Joo Jinmyoung 
Published: July 2018

AbstractA nanoparticle system for systemic delivery of therapeutics is described, which incorporates a means of tracking the fate of the nanocarrier and its residual drug payload in vivo by photoluminescence (PL). Porous silicon nanoparticles (PSiNPs) containing the proapoptotic antimicrobial peptide payload, D[KLAKLAK]2, are monitored by measurement of the intrinsic PL intensity and the PL lifetime of the nanoparticles. The PL lifetime of the PSiNPs is on the order of microseconds, substantially longer than the nanosecond lifetimes typically exhibited by conventional fluorescent tags or by autofluorescence from cells and tissues; thus, emission from the nanoparticles is readily discerned in the time‐resolved PL spectrum. It is found that the luminescence lifetime of the PSiNP host decreases as the nanoparticle dissolves in phosphate‐buffered saline solution (37 °C), and this correlates with the extent of release of the peptide payload. The time‐resolved PL measurement allows tracking of the in vivo fate of PSiNPs injected (via tail vein) into mice. Clearance of the nanoparticles through the liver, kidneys, and lungs of the animals is observed. The luminescence lifetime of the PSiNPs decreases with increasing residence time in the mice, providing a measure of half‐life for degradation of the drug nanocarriers.