bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Testosterone Treatment on Bone Microarchitecture and Bone Mineral Density in Men: A 2-Year RCT
Authors: Ng Tang Fui Mark , Hoermann Rudolf , Bracken Karen , Handelsman David J , Inder Warrick J , Stuckey Bronwyn G A , Yeap Bu B , Ghasem-Zadeh Ali , Robledo Kristy P , Jesudason David , Zajac Jeffrey D , Wittert Gary A , Grossmann Mathis 
Published: March 2021

Abstract

Context
Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown.

Objective
We aimed to determine the effect of testosterone treatment on bone microarchitecture using high resolution–peripheral quantitative computed tomography (HR-pQCT).

Methods
Men ≥ 50 years of age were recruited from 6 Australian centers and were randomized to receive injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program. The primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (1 center). Secondary endpoints included other HR-pQCT parameters and bone remodeling markers. Areal BMD (aBMD) was measured by dual-energy x-ray absorptiometry (DXA) in 601 men (5 centers). Using a linear mixed model for repeated measures, the mean adjusted differences (95% CI) at 12 and 24 months between groups are reported as treatment effect.

Results
Over 24 months, testosterone treatment, versus placebo, increased tibial cortical vBMD, 9.33 mg hydroxyapatite (HA)/cm3) (3.96, 14.71), P &lt; 0.001 or 3.1% (1.2, 5.0); radial cortical vBMD, 8.96 mg HA/cm3 (3.30, 14.62), P = 0.005 or 2.9% (1.0, 4.9); total tibial vBMD, 4.16 mg HA/cm3 (2.14, 6.19), P &lt; 0.001 or 1.3% (0.6, 1.9); and total radial vBMD, 4.42 mg HA/cm3 (1.67, 7.16), P = 0.002 or 1.8% (0.4, 2.0). Testosterone also significantly increased cortical area and thickness at both sites. Effects on trabecular architecture were minor. Testosterone reduced bone remodeling markers CTX, −48.1 ng/L [−81.1, −15.1], P &lt; 0.001 and P1NP, −6.8 μg/L[−10.9, −2.7], P &lt; 0.001. Testosterone significantly increased aBMD at the lumbar spine, 0.04 g/cm2 (0.03, 0.05), P &lt; 0.001 and the total hip, 0.01 g/cm2 (0.01, 0.02), P &lt; 0.001.

Conclusion
In men ≥ 50 years of age, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.
The Impact of Low-dose Gliclazide on the Incretin Effect and Indices of Beta-cell Function
Authors: Cordiner Ruth L M , Mari Andrea , Tura Andrea , Pearson Ewan R 
Published: March 2021

AbstractAims/HypothesisStudies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low-dose gliclazide on beta-cell function and incretin action in patients with T2DM.MethodsPaired oral glucose tolerance tests and isoglycemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low-dose gliclazide in 16 subjects with T2DM (hemoglobin A1c &lt; 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration.ResultsA single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 61.2) to 54.99% (34.8, 72.8; P = 0.049). Gliclazide increased beta-cell glucose sensitivity by 46% [control 22.61 ± 3.94, gliclazide 33.11 ± 7.83 (P = 0.01)] as well as late-phase incretin potentiation [control 0.92 ± 0.05, gliclazide 1.285 ± 0.14 (P = 0.038)].Conclusions/InterpretationLow-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling shows that low plasma concentrations of gliclazide potentiate late-phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low-dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycemia.
IL-38 Exerts Anti-Inflammatory and Antifibrotic Effects in Thyroid-Associated Ophthalmopathy
Authors: Shi Lu , Ye Huijing , Huang Jun , Li Yanbing , Wang Xing , Xu Zhihui , Chen Jingqiao , Xiao Wei , Chen Rongxin , Yang Huasheng 
Published: March 2021

Abstract

Context
Thyroid-associated ophthalmopathy (TAO) is an organ-specific autoimmune disease closely associated with Graves’ disease. IL-38, a novel cytokine in the IL-1 superfamily, has been reported to be involved in the pathogenesis of various autoimmune diseases.

Objective
We aimed to evaluate the relationship between IL-38 and TAO disease activity and its role in inflammation and fibrosis in TAO.

Methods
Blood samples and orbital connective tissues were collected from TAO patients and controls. Orbital fibroblasts were isolated from patients with TAO. Enzyme-linked immunosorbent assay, immunohistochemistry, flow cytometry, immunofluorescence, quantitative real-time PCR and Western blot analysis were performed.

Results
Here, we demonstrated that IL-38 levels decreased in the circulation and orbital connective tissues of patients with TAO compared with the controls, and levels were negatively correlated with the clinical activity score. In vitro, potent anti-inflammatory and antifibrotic effects of IL-38 were observed. Furthermore, we revealed that IL-38 can counteract the phosphorylation of star molecules in multiple classical pathways.

Conclusion
IL-38 plays a protective role in TAO and is associated with its pathogenesis. Our data suggest that IL-38 may be a promising marker of TAO disease activity and a potential target for TAO therapy.
Association of Genetically Predicted Serum Estradiol With Risk of Thromboembolism in Men: A Mendelian Randomization Study
Authors: Nethander Maria , Quester Johan , Vandenput Liesbeth , Ohlsson Claes 
Published: March 2021

Abstract

Context
An association was recently reported between genetic markers related to high testosterone and increased risk of thromboembolism in men, but a possible causal role of estradiol for risk of thromboembolism in men remains unknown.

Objective
This work aimed to determine whether endogenous estradiol has a causal role in thromboembolism in men.

Methods
A 2-sample mendelian randomization study using gene-based genetic instruments assessed the association between endogenous estradiol genetically predicted by 22 variants in the aromatase CYP19A1 gene region and the risk of thromboembolism (5815 cases) in 170 593 unrelated men of White ancestry in the UK Biobank. The main outcome measure included thromboembolism based on self-reports, hospital episodes, and death.

Results
Endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with the risk of thromboembolism (odds ratio per SD increase in estradiol 0.74; 95% CI, 0.62-0.90). In contrast, genetic variants in the JMJD1C gene, used as a predictor of high endogenous testosterone, were associated with an increased risk of thromboembolism (odds ratio per SD increase in testosterone 1.39; 95% CI, 1.12-1.72). Subsequent explorative analyses evaluating potential repercussions of thromboembolism revealed that endogenous estradiol genetically predicted by variants in the CYP19A1 gene region was inversely associated with the risk of ischemic stroke (0.68; 95% CI, 0.49-0.95) but not myocardial infarction (0.97; 95% CI, 0.84-1.13).

Conclusion
Genetically predicted estradiol was inversely associated with the risk of thromboembolism and ischemic stroke in men. The ratio between testosterone and estradiol, determined by CYP19A1 activity, may contribute to the overall impact of sex steroids on thromboembolism in men.
Implications of an Improved Model of the TSH Receptor Transmembrane Domain (TSHR-TMD-TRIO)
Authors: Mezei Mihaly , Latif Rauf , Das Bhaskar , Davies Terry F 
Published: March 2021

Abstract
The thyroid-stimulating hormone receptor (TSHR) is a G-protein-coupled receptor group A family member with 7 transmembrane helices. We generated 3 new models of its entire transmembrane region using a 600 ns molecular simulation. The simulation started from our previously published model, which we have now revised by also modeling the intracellular loops and the C-terminal tail, adding internal waters and embedding it into a lipid bilayer with a water layer and with ions added to complete the system. We have named this model TSHR-TMD-TRIO since 3 representative dominant structures were then extracted from the simulation trajectory and compared with the original model. These structures each showed small but significant changes in the relative positions of the helices. The 3 models were also used as targets to dock a set of small molecules that are known active compounds including a new TSHR antagonist (BT362), which confirmed the appropriateness of the model with some small molecules showing significant preference for one or other of the structures.
Mice lacking PC1/3 expression in POMC-expressing cells do not develop obesity
Authors: Shakya Manita , Gahlot Surbhi , White Anne , Verchere C Bruce , Low Malcolm J , Lindberg Iris 
Published: March 2021

Abstract
Pro-opiomelanocortin (POMC) neurons form an integral part of the central melanocortin system regulating food intake and energy expenditure. Genetic and pharmacological studies have revealed that defects in POMC synthesis, processing, and receptor signaling lead to obesity. It is well established that POMC is extensively processed by a series of enzymes, including prohormone convertases PC1/3 and PC2, and that genetic insufficiency of both PC1/3 and POMC is strongly associated with obesity risk. However, whether PC1/3-mediated POMC processing is absolutely tied to body weight regulation is not known. To investigate this question, we generated a Pomc-CreER T2; Pcsk1 lox/lox mouse model in which Pcsk1 is specifically and temporally knocked out in POMC-expressing cells of adult mice by injecting tamoxifen at eight weeks of age. We then measured the impact of Pcsk1 deletion on POMC cleavage to ACTH and α-MSH, and on body weight. In whole pituitary, POMC cleavage was significantly impacted by the loss of Pcsk1, while hypothalamic POMC-derived peptide levels remained similar in all genotypes. However, intact POMC levels were greatly elevated in Pomc-CreER T2; Pcsk1 lox/lox mice. Males expressed two-fold greater levels of pituitary PC1/3 protein than females, consistent with their increased POMC cleavage. Past studies show that mice with germline removal of PC1/3 do not develop obesity, while mice expressing mutant PC1/3 forms do develop obesity. We conclude that obesity pathways are not disrupted by PC1/3 loss solely in POMC-expressing cells, further disfavoring the idea that alterations in POMC processing underlie obesity in PCSK1 deficiency.
Senolytics: Potential for Alleviating Diabetes and Its Complications
Authors: Palmer Allyson K , Tchkonia Tamar , Kirkland James L 
Published: March 2021

Abstract
Therapeutics that target cellular senescence, including novel “senolytic” compounds, hold significant promise for treating or preventing obesity-induced metabolic dysfunction, type 2 diabetes, and the multiple complications of diabetes and obesity. Senolytics selectively clear senescent cells, which accumulate with aging and obesity and represent a fundamental mechanism of aging that contributes to metabolic dysfunction and diabetes pathogenesis. In addition to improving metabolic function, targeting senescent cells holds promise as a preventive strategy to reduce the incidence and severity of diabetes complications. The intermittent administration schedule used for senolytic therapy may confer benefits in terms of improving adherence and limiting adverse effects. It is necessary to design effective clinical trials that will safely translate discoveries from preclinical models into human studies that may pave the way for a novel therapeutic class for treating obesity, diabetes, and their complications. In this review, we outline what is known regarding the role of cellular senescence in the pathogenesis of type 2 diabetes and its complications, present evidence from preclinical models that targeting cellular senescence is beneficial, review senolytic drugs, and outline the features of clinical trials investigating the role of targeting senescent cells for diabetes.
Are mitochondria the main contributor of reactive oxygen species in cells?
Authors: Zhang Yufeng , Wong Hoi Shan 
Published: March 2021

ABSTRACT
Physiologists often assume that mitochondria are the main producers of reactive oxygen species (ROS) in cells. Consequently, in biomedicine, mitochondria are considered as important targets for therapeutic treatments, and in evolutionary biology, they are considered as mediators of life-history tradeoffs. Surprisingly, data supporting such an assumption are lacking, at least partially due to the technical difficulties in accurately measuring the level of ROS produced by different subcellular compartments in intact cells. In this Commentary, we first review three potential reasons underlying the misassumption of mitochondrial dominance in the production of cellular ROS. We then introduce some other major sites/enzymes responsible for cellular ROS production. With the use of a recently developed cell-based assay, we further discuss the contribution of mitochondria to the total rate of ROS release in cell lines and primary cells of different species. In these cells, the contribution of mitochondria varies between cell types but mitochondria are never the main source of cellular ROS. This indicates that although mitochondria are one of the significant sources of cellular ROS, they are not necessarily the main contributor under normal conditions. Intriguingly, similar findings were also observed in cells under a variety of stressors, life-history strategies and pathological stages, in which the rates of cellular ROS production were significantly enhanced. Finally, we make recommendations for designing future studies. We hope this paper will encourage investigators to carefully consider non-mitochondrial sources of cellular ROS in their study systems or models.
Fractal analysis of the trabecular bone pattern in the presence/absence of metal artifact–producing objects: Comparison of cone-beam computed tomography with panoramic and periapical radiography
Authors: Vadiati Saberi Bardia , Khosravifard Negar , Nooshmand Kowsar , Dalili Kajan Zahra , Ghaffari Mohammad Ebrahim 
Published: March 2021

Objectives: The effect of metallic objects on the fractal dimension (FD), bone area fraction (BAF) and gray scale values (GSVs) of cone-beam CT (CBCT) images was assessed. Also, FD, BAF and GSV were compared among CBCT, digital periapical and panoramic radiographies. Methods: Digital periapical and panoramic radiographs were acquired from six blocks of bovine rib. Additionally, different arrangements of titanium implants and intracanal metallic posts were created in the bone blocks and CBCT scans were taken from the different implant-root arrangements. The three radiographical modalities were compared by analysis of variance. Pairwise comparisons between the modalities were performed by the Tukey test (significance level set at 0.05). Results: Different root-implant arrangements in the CBCT images revealed no significant differences in the FD (p = 0.920), BAF and GSV values (p = 0.623). FD differed significantly among the three modalities (p < 0.001). Significant differences were found between CBCT and each of the periapical and panoramic techniques (p < 0.001), while no remarkable differences were observed in the FD of the periapical and panoramic images (p = 0.294). BAF and GSV showed significantly different results among the three radiographical techniques (p < 0.001). The difference was remarkable between CBCT and periapical (p < 0.001), CBCT and panoramic (p < 0.001) and periapical and panoramic (p = 0.008). Conclusion: Presence of titanium implants and intracanal posts does not produce different results in the fractal analysis (FA) of the CBCT images. The trabecular bone pattern is best assessed by FA of the periapical radiographs followed by the panoramic and CBCT techniques, respectively.
Level of development, foreign direct investment and domestic investment in food manufacturing
Authors: Djokoto Justice Gameli 
Published: March 2021

Background: Whilst the literature on the complementarity and substitutability of foreign direct investment (FDI) on domestic investment (DI) is not uncommon, the facet of food manufacturing is non-existent. This paper fills this void by investigating the effect of FDI on DI in the food manufacturing sector for developing, economies in transition and developed countries. Methods: Using an unbalanced panel data of 49 countries from 1993 to 2016, from FAOSTAT, estimated by the system generalised method of moments (GMM), the Wald statistics for the short and long-run effects of FDI on DI were computed for the development groups. Results: Developed economies experienced a crowd-out effect of FDI on DI in the short run, whilst the others experienced no significant effect. In the case of the long run, food manufacturing sectors of all three development groups exhibited a crowd-out effect. The effect in the long run for all development groups together is a crowd-in. Analysing all country groups together could mask the results of the various country groups. Conclusions: A review of investment policies to priorities FDI entry mode that favour domestic investment is needed. Improvement of the investment regulatory and administrative efficiency among others are recommended.
The Effect of Peer Gender on Major Choice in Business School
Authors: Zölitz Ulf , Feld Jan 
Published: March 2021

Business degrees are popular and lead to high earnings. Female business graduates, however, earn less than their male counterparts. These gender differences can be traced back to university, where women shy away from majors like finance that lead to high earnings. In this paper, we investigate how the gender composition of peers in business school affects women’s and men’s major choices and labor market outcomes. We find that women who are randomly assigned to teaching sections with more female peers become less likely to choose male-dominated majors like finance and more likely to choose female-dominated majors like marketing. After graduation, these women end up in jobs where their earnings grow more slowly. Men, on the other hand, become more likely to choose male-dominated majors and less likely to choose female-dominated majors when they had more female peers in business school. However, men’s labor market outcomes are not significantly affected. Taken together, our results show that studying with more female peers in business school increases gender segregation in educational choice and affects labor market outcomes. This paper was accepted by Axel Ockenfels, decision analysis.
Drivers, Riders, and Service Providers: The Impact of the Sharing Economy on Mobility
Authors: Benjaafar Saif , Bernhard Harald , Courcoubetis Costas , Kanakakis Michail , Papafragkos Spyridon 
Published: March 2021

It is widely believed that ride sharing, the practice of sharing a car such that more than one person travels in the car during a journey, has the potential to significantly reduce traffic by filling up cars more efficiently. We introduce a model in which individuals may share rides for a certain fee, paid by the rider(s) to the driver through a ride-sharing platform. Collective decision making is modeled as an anonymous nonatomic game with a finite set of strategies and payoff functions among individuals who are heterogeneous in their income. We examine how ride sharing is organized and how traffic and ownership are affected if a platform, which chooses the seat rental price to maximize either revenue or welfare, is introduced to a population. We find that the ratio of ownership to usage costs determines how ride sharing is organized. If this ratio is low, ride sharing is offered as a peer-to-peer (P2P) service, and if this ratio is high, ride sharing is offered as a business-to-customer (B2C) service. In the P2P case, rides are initiated by drivers only when the drivers need to fulfill their own transportation requirements. In the B2C case, cars are driven all the time by full-time drivers taking rides even if these are not motivated by their private needs. We show that, although the introduction of ride sharing may reduce car ownership, it can lead to an increase in traffic. We also show that traffic and ownership may increase as the ownership cost increases and that a revenue-maximizing platform might prefer a situation in which cars are driven with only a few seats occupied, causing high traffic. We contrast these results with those obtained for a social welfare-maximizing platform. This paper was accepted by Charles Corbett, operations management.
Mental health and Islamic religion online: An intertextual analysis
Authors: Al Zidjaly Najma 
Published: March 2021

In this article, the discursive construction of mental health and the role religion plays in its representation are examined using four psychological consultations collected in fall 2016 from Islamweb.net, the largest network for Islamic information. Using computer mediated discourse analysis (Herring 2004), intertextuality was identified as a communicative strategy psychologists draw upon to turn mental health consultations into platforms to perpetuate Islamic authoritative discourses (e. g. submission to God, prayer, and collectivity). Mental illnesses were also constructed within the Islamic context as supernatural and cured by religion, rather than as conditions treated through medical and psychological intervention. Intertextually, the authoritative discourses are evoked overtly through direct quotations from the books of Islam and covertly through referencing certain ritualistic discourses (words, themes, and practices) in the opening, main, and closing sections of the consultations. Permeating consultations with religious discourse, and cementing them with the speech acts of warning, scolding, and advice to not think or act otherwise, create religious authority in the context of health online. These actions also maintain Islamic authoritative discourses, and reaffirm Islamic cultural identity, while blurring the lines between medicine and religion online.
On the rise of domain adverbials in Italian: the history of the -mente parlando construction
Authors: Grübl Klaus 
Published: March 2021

This paper investigates the history of -mente parlando, a construction that can be used in modern Italian either as a style disjunct (e. g. rigorosamente parlando ‘strictly speaking’) or as a domain adverbial (e. g. economicamente parlando ‘economically speaking’). This functional difference will be accounted for synchronically as a case of constructional polysemy, with different semantic types of adjectives (mainly relational vs non-relational) occurring in the -mente slot leading to a different reading of the whole construction. Diachronically, the constructional polysemy appears to be the result of a metonymic shift from the older STYLE reading to the newer DOMAIN interpretation. A corpus-based investigation will analyze the syntactic, pragmatic and discursive conditions from which the different uses arose. While both variants are attested from the 14th century on, a massive expansion of domain adverbials formed by -mente parlando is observed only in the first half of the 19th century, a tendency which can be explained as a new fashion for “rationalist” discourse organization and which corresponds to similar evolutions described for 19th-century English, French and Spanish.