bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors
Authors: Saad Fred , Bögemann Martin , Suzuki Kazuhiro , Shore Neal 
Published: February 2021

Abstract
Background
Nonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as a rising prostate-specific antigen concentration, despite castrate levels of testosterone with ongoing androgen-deprivation therapy or orchiectomy, and no detectable metastases by conventional imaging. Patients with nmCRPC progress to metastatic disease and are at risk of developing cancer-related symptoms and morbidity, eventually dying of their disease. While patients with nmCRPC are generally asymptomatic from their disease, they are often older and have chronic comorbidities that require long-term concomitant medication. Therefore, careful consideration of the benefit–risk profile of potential treatments is required.

Methods
In this review, we will discuss the rationale for early treatment of patients with nmCRPC to delay metastatic progression and prolong survival, as well as the factors influencing this treatment decision. We will focus on oral pharmacotherapy with the second-generation androgen receptor inhibitors, apalutamide, enzalutamide, and darolutamide, and the importance of balancing the clinical benefit they offer with potential adverse events and the consequential impact on quality of life, physical capacity, and cognitive function.

Results and conclusions
While the definition of nmCRPC is well established, the advent of next-generation imaging techniques capable of detecting hitherto undetectable oligometastatic disease in patients with nmCRPC has fostered debate on the criteria that inform the management of these patients. However, despite these developments, published consensus statements have maintained that the absence of metastases on conventional imaging suffices to guide such therapeutic decisions. In addition, the prolonged metastasis-free survival and recently reported positive overall survival outcomes of the three second-generation androgen receptor inhibitors have provided further evidence for the early use of these agents in patients with nmCRPC in order to delay metastases and prolong survival. Here, we discuss the benefit–risk profiles of apalutamide, enzalutamide, and darolutamide based on the data available from their pivotal clinical trials in patients with nmCRPC.
Differential longitudinal changes of neuronal and glial damage markers in anorexia nervosa after partial weight restoration
Authors: Hellerhoff Inger , King Joseph A. , Tam Friederike I. , Pauligk Sophie , Seidel Maria , Geisler Daniel , Bahnsen Klaas , Kretschmann Nicole , Akgün Katja , Roessner Veit , Ziemssen Tjalf , Ehrlich Stefan 
Published: February 2021

AbstractAtrophic brain changes in acute anorexia nervosa (AN) are often visible to the naked eye on computed tomography or magnetic resonance imaging scans, but it remains unclear what is driving these effects. In neurological diseases, neurofilament light (NF-L) and tau protein have been linked to axonal damage. Glial fibrillary acidic protein (GFAP) has been associated with astroglial injury. In an attempt to shed new light on factors potentially underlying past findings of structural brain alterations in AN, the current study investigated serum NF-L, tau protein, and GFAP levels longitudinally in AN patients undergoing weight restoration. Blood samples were obtained from 54 acutely underweight, predominantly adolescent female AN patients and 54 age-matched healthy control participants. AN patients were studied in the severely underweight state and again after short-term partial weight restoration. Group comparisons revealed higher levels of NF-L, tau protein, and GFAP in acutely underweight patients with AN compared to healthy control participants. Longitudinally, a decrease in NF-L and GFAP but not in tau protein levels was observed in AN patients upon short-term partial weight restoration. These results may be indicative of ongoing neuronal and astroglial injury during the underweight phase of AN. Normalization of NF-L and GFAP but not tau protein levels may indicate an only partial restoration of neuronal and astroglial integrity upon weight gain after initial AN-associated cell damage processes.
Individual inflammatory marker abnormalities or inflammatory marker scores to identify primary care patients with unexpected weight loss for cancer investigation?
Authors: Nicholson B. D. , Oke J. L. , Aveyard P. , Hamilton W. T. , Hobbs F. D. R. 
Published: February 2021

Abstract
Background
Combinations of inflammatory markers are used as prognostic scores in cancer patients with cachexia. We investigated whether they could also be used to prioritise patients attending primary care with unexpected weight loss for cancer investigation.

Methods
We used English primary care electronic health records data linked to cancer registry data from 12,024 patients with coded unexpected weight loss. For each individual inflammatory marker and score we estimated the sensitivity, specificity, likelihood ratios, positive predictive value (PPV) and the area under the curve along with 95% confidence intervals for a cancer diagnosis within six months.

Results
The risk of cancer associated with two abnormal inflammatory markers combined in a score was higher than the risk associated with individual inflammatory marker abnormalities. However, the risk of cancer in weight loss associated with individual abnormalities, notably a raised C-reactive protein, was sufficient to trigger further investigation for cancer under current NICE guidelines.

Conclusions
If scores including pairs of inflammatory marker abnormalities were to be used, in preference to individual abnormalities, fewer people would be investigated to diagnose one cancer with fewer false positives, but fewer people with cancer would be diagnosed overall.
Evaluating the potential of novel genetic approaches for the treatment of Duchenne muscular dystrophy
Authors: Himič Vratko , Davies Kay E. 
Published: February 2021

AbstractDuchenne muscular dystrophy (DMD) is an X-linked progressive muscle-wasting disorder that is caused by a lack of functional dystrophin, a cytoplasmic protein necessary for the structural integrity of muscle. As variants in the dystrophin gene lead to a disruption of the reading frame, pharmacological treatments have only limited efficacy; there is currently no effective therapy and consequently, a significant unmet clinical need for DMD. Recently, novel genetic approaches have shown real promise in treating DMD, with advancements in the efficacy and tropism of exon skipping and surrogate gene therapy. CRISPR-Cas9 has the potential to be a ‘one-hit’ curative treatment in the coming decade. The current limitations of gene editing, such as off-target effects and immunogenicity, are in fact partly constraints of the delivery method itself, and thus research focus has shifted to improving the viral vector. In order to halt the loss of ambulation, early diagnosis and treatment will be pivotal. In an era where genetic sequencing is increasingly utilised in the clinic, genetic therapies will play a progressively central role in DMD therapy. This review delineates the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable.
Dry anophthalmic socket syndrome – morphological alterations in meibomian glands
Authors: Rokohl Alexander C. , Trester Marc , Naderi Parsa , Loreck Niklas , Zwingelberg Sarah , Bucher Franziska , Pine Keith R. , Heindl Ludwig M. 
Published: February 2021

Abstract
Purpose
To evaluate morphological alterations of meibomian glands (MGs) in the dry anophthalmic socket syndrome (DASS).

Methods
Fifteen unilateral anophthalmic patients wearing cryolite glass prosthetic eyes were enrolled. All patients with clinical blepharitis or other significant eyelid abnormalities were excluded. In vivo laser scanning confocal microscopy (LSCM) of the MGs in the lower eyelids both on the anophthalmic side and the healthy fellow eye was performed to quantify acinar unit density, acinar unit diameter, acinar unit area, meibum secretion reflectivity, the inhomogeneous appearance of the glandular interstice, and inhomogeneous appearance of the acinar walls.

Results
The lower eyelids of the anophthalmic sockets revealed a significant reduction of the acinar unit density (p = 0.003) as well as a significantly more inhomogeneous appearance of the periglandular interstices (p = 0.018) and the acinar unit walls (p = 0.015) than the healthy fellow eyelid. However, there were no significant differences regarding the acinar unit diameter, acinar unit area, and meibum secretion reflectivity of the MGs on the anophthalmic side compared to the healthy fellow eyelid (p ≥ 0.05, respectively).

Conclusions
The eyelids of anophthalmic sockets without clinical blepharitis demonstrate a reduced density of MG acinar units and a more inhomogeneous appearance of the periglandular interstices and the acinar unit walls. This can cause meibomian gland dysfunction contributing to DASS and suggests early treatment of these symptomatic patients, even in the clinical absence of any blepharitis signs.
The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes
Authors: Davydova Erna , Shimazu Tadahiro , Schuhmacher Maren Kirstin , Jakobsson Magnus E. , Willemen Hanneke L. D. M. , Liu Tongri , Moen Anders , Ho Angela Y. Y. , Małecki Jędrzej , Schroer Lisa , Pinto Rita , Suzuki Takehiro , Grønsberg Ida A. , Sohtome Yoshihiro , Akakabe Mai , Weirich Sara , Kikuchi Masaki , Olsen Jesper V. , Dohmae Naoshi , Umehara Takashi , Sodeoka Mikiko , Siino Valentina , McDonough Michael A. , Eijkelkamp Niels , Schofield Christopher J. , Jeltsch Albert , Shinkai Yoichi , Falnes Pål Ø. 
Published: February 2021

AbstractPost-translational methylation plays a crucial role in regulating and optimizing protein function. Protein histidine methylation, occurring as the two isomers 1- and 3-methylhistidine (1MH and 3MH), was first reported five decades ago, but remains largely unexplored. Here we report that METTL9 is a broad-specificity methyltransferase that mediates the formation of the majority of 1MH present in mouse and human proteomes. METTL9-catalyzed methylation requires a His-x-His (HxH) motif, where “x” is preferably a small amino acid, allowing METTL9 to methylate a number of HxH-containing proteins, including the immunomodulatory protein S100A9 and the NDUFB3 subunit of mitochondrial respiratory Complex I. Notably, METTL9-mediated methylation enhances respiration via Complex I, and the presence of 1MH in an HxH-containing peptide reduced its zinc binding affinity. Our results establish METTL9-mediated 1MH as a pervasive protein modification, thus setting the stage for further functional studies on protein histidine methylation.
Genetic predictors of participation in optional components of UK Biobank
Authors: Tyrrell Jessica , Zheng Jie , Beaumont Robin , Hinton Kathryn , Richardson Tom G. , Wood Andrew R. , Davey Smith George , Frayling Timothy M. , Tilling Kate 
Published: February 2021

AbstractLarge studies such as UK Biobank are increasingly used for GWAS and Mendelian randomization (MR) studies. However, selection into and dropout from studies may bias genetic and phenotypic associations. We examine genetic factors affecting participation in four optional components in up to 451,306 UK Biobank participants. We used GWAS to identify genetic variants associated with participation, MR to estimate effects of phenotypes on participation, and genetic correlations to compare participation bias across different studies. 32 variants were associated with participation in one of the optional components (P < 6 × 10−9), including loci with links to intelligence and Alzheimer’s disease. Genetic correlations demonstrated that participation bias was common across studies. MR showed that longer educational duration, older menarche and taller stature increased participation, whilst higher levels of adiposity, dyslipidaemia, neuroticism, Alzheimer’s and schizophrenia reduced participation. Our effect estimates can be used for sensitivity analysis to account for selective participation biases in genetic or non-genetic analyses.
Salmonella Typhimurium reprograms macrophage metabolism via T3SS effector SopE2 to promote intracellular replication and virulence
Authors: Jiang Lingyan , Wang Peisheng , Song Xiaorui , Zhang Huan , Ma Shuangshuang , Wang Jingting , Li Wanwu , Lv Runxia , Liu Xiaoqian , Ma Shuai , Yan Jiaqi , Zhou Haiyan , Huang Di , Cheng Zhihui , Yang Chen , Feng Lu , Wang Lei 
Published: February 2021

AbstractSalmonella Typhimurium establishes systemic infection by replicating in host macrophages. Here we show that macrophages infected with S. Typhimurium exhibit upregulated glycolysis and decreased serine synthesis, leading to accumulation of glycolytic intermediates. The effects on serine synthesis are mediated by bacterial protein SopE2, a type III secretion system (T3SS) effector encoded in pathogenicity island SPI-1. The changes in host metabolism promote intracellular replication of S. Typhimurium via two mechanisms: decreased glucose levels lead to upregulated bacterial uptake of 2- and 3-phosphoglycerate and phosphoenolpyruvate (carbon sources), while increased pyruvate and lactate levels induce upregulation of another pathogenicity island, SPI-2, known to encode virulence factors. Pharmacological or genetic inhibition of host glycolysis, activation of host serine synthesis, or deletion of either the bacterial transport or signal sensor systems for those host glycolytic intermediates impairs S. Typhimurium replication or virulence.
The mechanism for the enhanced piezoelectricity in multi-elements doped (K,Na)NbO3 ceramics
Authors: Gao Xiaoyi , Cheng Zhenxiang , Chen Zibin , Liu Yao , Meng Xiangyu , Zhang Xu , Wang Jianli , Guo Qinghu , Li Bei , Sun Huajun , Gu Qinfen , Hao Hua , Shen Qiang , Wu Jinsong , Liao Xiaozhou , Ringer Simon P. , Liu Hanxing , Zhang Lianmeng , Chen Wen , Li Fei , Zhang Shujun 
Published: February 2021

Abstract(K,Na)NbO3 based ceramics are considered to be one of the most promising lead-free ferroelectrics replacing Pb(Zr,Ti)O3. Despite extensive studies over the last two decades, the mechanism for the enhanced piezoelectricity in multi-elements doped (K,Na)NbO3 ceramics has not been fully understood. Here, we combine temperature-dependent synchrotron x-ray diffraction and property measurements, atomic-scale scanning transmission electron microscopy, and first-principle and phase-field calculations to establish the dopant–structure–property relationship for multi-elements doped (K,Na)NbO3 ceramics. Our results indicate that the dopants induced tetragonal phase and the accompanying high-density nanoscale heterostructures with low-angle polar vectors are responsible for the high dielectric and piezoelectric properties. This work explains the mechanism of the high piezoelectricity recently achieved in (K,Na)NbO3 ceramics and provides guidance for the design of high-performance ferroelectric ceramics, which is expected to benefit numerous functional materials.
Complete and cooperative in vitro assembly of computationally designed self-assembling protein nanomaterials
Authors: Wargacki Adam J. , Wörner Tobias P. , van de Waterbeemd Michiel , Ellis Daniel , Heck Albert J. R. , King Neil P. 
Published: February 2021

AbstractRecent advances in computational methods have enabled the predictive design of self-assembling protein nanomaterials with atomic-level accuracy. These design strategies focus exclusively on a single target structure, without consideration of the mechanism or dynamics of assembly. However, understanding the assembly process, and in particular its robustness to perturbation, will be critical for translating this class of materials into useful technologies. Here we investigate the assembly of two computationally designed, 120-subunit icosahedral complexes in detail using several complementary biochemical methods. We found that assembly of each material from its two constituent protein building blocks was highly cooperative and yielded exclusively complete, 120-subunit complexes except in one non-stoichiometric regime for one of the materials. Our results suggest that in vitro assembly provides a robust and controllable route for the manufacture of designed protein nanomaterials and confirm that cooperative assembly can be an intrinsic, rather than evolved, feature of hierarchically structured protein complexes.
Human heart-forming organoids recapitulate early heart and foregut development
Authors: Drakhlis Lika , Biswanath Santoshi , Farr Clara-Milena , Lupanow Victoria , Teske Jana , Ritzenhoff Katharina , Franke Annika , Manstein Felix , Bolesani Emiliano , Kempf Henning , Liebscher Simone , Schenke-Layland Katja , Hegermann Jan , Nolte Lena , Meyer Heiko , de la Roche Jeanne , Thiemann Stefan , Wahl-Schott Christian , Martin Ulrich , Zweigerdt Robert 
Published: February 2021

AbstractOrganoid models of early tissue development have been produced for the intestine, brain, kidney and other organs, but similar approaches for the heart have been lacking. Here we generate complex, highly structured, three-dimensional heart-forming organoids (HFOs) by embedding human pluripotent stem cell aggregates in Matrigel followed by directed cardiac differentiation via biphasic WNT pathway modulation with small molecules. HFOs are composed of a myocardial layer lined by endocardial-like cells and surrounded by septum-transversum-like anlagen; they further contain spatially and molecularly distinct anterior versus posterior foregut endoderm tissues and a vascular network. The architecture of HFOs closely resembles aspects of early native heart anlagen before heart tube formation, which is known to require an interplay with foregut endoderm development. We apply HFOs to study genetic defects in vitro by demonstrating thatNKX2.5-knockout HFOs show a phenotype reminiscent of cardiac malformations previously observed in transgenic mice.
Nickel excess affects phenology and reproductive attributes of Asterella wallichiana and Plagiochasma appendiculatum growing in natural habitats
Authors: Sharma Anil , Bhagat Madhu , Urfan Mohammad , Ahmed Bilal , Langer Anima , Ali Villayat , Vyas Dhiraj , Yadav Narendra Singh , Hakla Haroon Rashid , Sharma Shubham , Pal Sikander 
Published: February 2021

AbstractBryophytes are potent metal absorbers, thriving well on heavy metal (HM)-polluted soils. Mechanisms controlling uptake, compartmentalization and impacts of HMs on bryophytes life cycle are largely unknown. The current study is an effort to decipher mechanisms of nickel (Ni) excess-induced effects on the phenological events of two bryophytes, Asterella wallichiana and Plagiochasma apendiculatum growing in natural habitats. Observations revealed Ni-excess induced negative impacts on abundance, frequency of occurrence of reproductive organs, population viability and morphological traits, spore viability and physiological attributes of both the liverworts. Results led us conclude that P. appendiculatum survived better with the lowest impact on its life cycle events than A. wallichiana under Ni excess in natural habitats. Our findings collectively provide insights into the previously unknown mechanisms of Ni-induced responses in liverworts with respect to phenological attributes, as well as demonstrate the potential of P. appendiculatum to survive better in Ni excess habitats.
Ancient mitogenomics elucidates diversity of extinct West Indian tortoises
Authors: Kehlmaier Christian , Albury Nancy A. , Steadman David W. , Graciá Eva , Franz Richard , Fritz Uwe 
Published: February 2021

AbstractWe present 10 nearly complete mitochondrial genomes of the extinct tortoiseChelonoidis alburyorumfrom the Bahamas. While our samples represent morphologically distinct populations from six islands, their genetic divergences were shallow and resembled those among Galápagos tortoises. Our molecular clock estimates revealed that divergence among Bahamian tortoises began ~ 1.5 mya, whereas divergence among the Galápagos tortoises (C. nigercomplex) began ~ 2 mya. The inter-island divergences of tortoises from within the Bahamas and within the Galápagos Islands are much younger (0.09–0.59 mya, and 0.08–1.43 mya, respectively) than the genetic differentiation between any other congeneric pair of tortoise species. The shallow mitochondrial divergences of the two radiations on the Bahamas and the Galápagos Islands suggest that each archipelago sustained only one species of tortoise, and that the taxa currently regarded as distinct species in the Galápagos should be returned to subspecies status. The extinct tortoises from the Bahamas have two well-supported clades: the first includes one sample from Great Abaco and two from Crooked Island; the second clade includes tortoises from Great Abaco, Eleuthera, Crooked Island, Mayaguana, Middle Caicos, and Grand Turk. Tortoises belonging to both clades on Great Abaco and Crooked Island suggest late Holocene inter-island transport by prehistoric humans.
Structural and morphological tuning of Cu-based metal oxide nanoparticles by a facile chemical method and highly electrochemical sensing of sulphite
Authors: Sudha Velayutham , Murugadoss Govindhasamy , Thangamuthu Rangasamy 
Published: February 2021

AbstractA facile one-step chemical method is introduced for the successful synthesis of Cu2O, CuO and CuNa2(OH)4crystal structures and their electrochemical properties were also investigated. X-ray diffraction studies revealed that these copper-based oxide nanoparticles display different crystal structures such as cubic (Cu2O), monoclinic (CuO) and orthorhombic [CuNa2(OH)4]. The microstructural information of nanoparticles was investigated by transmission electron microscopy. It shows attractive morphologies of different orientation such as rod like structure, nanobeads and well-aligned uniform nanorod for Cu2O, CuO and CuNa2(OH)4, respectively. Electrochemical sensing of sulphite (SO32−) on these three copper-based oxide modified electrodes was investigated. Among the three different crystal structures, CuO shows promising electrocatalytic activity towards oxidation of sulphite. A linear variation in peak current was obtained for SO32−oxidation from 0.2 to 15 mM under the optimum experimental condition. The sensitivity and detection limit were in the order of 48.5 µA cm−2 mM−1and 1.8 µM, respectively. Finally, practical utility of CuO modified electrode was demonstrated for the estimation of sulphite in commercial wine samples.