bluuebunny/crossref_metadata_2025_split huggingface dataset:
Demonstration of the first‐pass metabolism in the skin of the hair dye, 4‐amino‐2‐hydroxytoluene, using the Chip2 skin–liver microphysiological model
Authors: Tao Thi Phuong , Brandmair Katrin , Gerlach Silke , Przibilla Julia , Géniès Camille , Jacques‐Jamin Carine , Schepky Andreas , Marx Uwe , Hewitt Nicola J. , Maschmeyer Ilka , Kühnl Jochen 
Published: February 2021

AbstractWe used TissUse's HUMIMIC Chip2 microfluidic model, incorporating reconstructed skin models and liver spheroids, to investigate the impact of consumer‐relevant application scenarios on the metabolic fate of the hair dye, 4‐amino‐2‐hydroxytoluene (AHT). After a single topical or systemic application of AHT to Chip2 models, medium was analysed for parent and metabolites over 5 days. The metabolic profile of a high dose (resulting in a circuit concentration of 100 μM based on 100% bioavailability) of AHT was the same after systemic and topical application to 96‐well EpiDerm™ models. Additional experiments indicated that metabolic capacity of EpiDerm™ models were saturated at this dose. At 2.5 μM, concentrations of AHT and several of its metabolites differed between application routes. Topical application resulted in a higher Cmax and a 327% higher area under the curve (AUC) of N‐acetyl‐AHT, indicating a first‐pass effect in the EpiDerm™ models. In accordance with in vivo observations, there was a concomitant decrease in the Cmax and AUC of AHT‐O‐sulphate after topical, compared with systemic application. A similar alteration in metabolite ratios was observed using a 24‐well full‐thickness skin model, EpiDermFT™, indicating that a first‐pass effect was also possible to detect in a more complex model. In addition, washing the EpiDermFT™ after 30 min, thus reflecting consumer use, decreased the systemic exposure to AHT and its metabolites. In conclusion, the skin–liver Chip2 model can be used to (a) recapitulate the first‐pass effect of the skin and alterations in the metabolite profile of AHT observed in vivo and (b) provide consumer‐relevant data regarding leave‐on/rinse‐off products.
Hydroxyapatite sonosensitization of ultrasound‐triggered, thermally responsive hydrogels: An on‐demand delivery system for bone repair applications
Authors: Levingstone Tanya , Ali Badriah , Kearney Cathal , Dunne Nicholas 
Published: February 2021

AbstractWhile bones have the innate capability to physiologically regenerate, in certain cases regeneration is suboptimal, too slow, or does not occur. Biomaterials‐based growth factor delivery systems have shown potential for the treatment of challenging bone defects, however, achieving controlled growth factor release remains a challenge. The objective of this study was to develop a thermally responsive hydrogel for bone regeneration capable of ultrasound‐triggered on‐demand delivery of therapeutic agents. Furthermore, it was hypothesized that incorporation of hydroxyapatite (HA) into the hydrogel could increase sonosensitization, augmenting ultrasound sensitivity to enable controlled therapeutic release to the target tissue. Alginate thermally responsive P(Alg‐g‐NIPAAm) hydrogels were fabricated and varying quantities of HA (1, 3, 5, and 7% wt./vol.) incorporated. All hydrogels were highly injectable (maximum injection force below 6.5 N) and rheological characterization demonstrated their ability to gel at body temperature. The study demonstrated the ultrasound‐triggered release of sodium fluorescein (NaF), bovine serum albumin (BSA), and bone morphogenetic protein 2 (BMP‐2) from the hydrogels. Release rates of BSA and BMP‐2 were significantly enhanced in the HA containing hydrogels, confirming for the first time the role of HA as a son sensitizer. Together these results demonstrate the potential of these ultrasound‐triggered thermally responsive hydrogels for on‐demand delivery of therapeutic agents for bone regeneration.
Physical Activity and Psychosocial Factors Associated With Risk of Future Fractures in Middle-Aged Men and Women
Authors: Rogmark Cecilia , Fedorowski Artur , Hamrefors Viktor 
Published: February 2021

ABSTRACT
Identification of risk factors for fractures is important for improving public health. We aimed to identify which factors related to physical activity and psychosocial situation were associated with incident fractures among 30,446 middle-aged women and men, followed from 1991–1996 to 2016, in a prospective population-based cohort study. The association between the baseline variables and first incident fracture was assessed by Cox regression models, and significant risk factors were summed into fracture risk scores. Any first incident fracture affecting spine, thoracic cage, arms, shoulders, hands, pelvis, hips, or legs was obtained from the National Patient Register, using the unique personal identity number of each citizen. A total of 8240 subjects (27%) had at least one fracture during the follow-up of median 20.7 years. Age, female sex, body mass index, previous fracture, reported family history of fracture &gt;50 years (all p &lt; .001), low leisure-time physical activity (p = .018), heavy work (p = .024), living alone (p = .002), smoking (p &lt; .001), and no or high alcohol consumption (p = .005) were factors independently associated with incident fracture. The fracture risk score (0–9 points) was strongly associated with incident fracture (p for trend &lt;.001). Among men without risk factors, the incidence rate was 5.3/1000 person-years compared with 23.2 in men with six or more risk factors (hazard ratio [HR] = 5.5; 95% confidence interval [CI] 3.7–8.2). Among women with no risk factors, the incidence rate was 10.7 compared with 28.4 in women with six or more risk factors (HR = 3.1; 95% CI 2.4–4.0). Even moderate levels of leisure-time physical activity in middle age are associated with lower risk of future fractures. In contrast, heavy work, living alone, smoking, and no or high alcohol consumption increase the risk of fracture. Our results emphasize the importance of these factors in public health initiatives for fracture prevention. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Investigation of oxidant/antioxidant and anti‐inflammatory effects of apigenin on apoptosis in sepsis‐induced rat lung
Authors: Cicek Mustafa , Unsal Velid , Doganer Adem , Demir Mehmet 
Published: February 2021

AbstractWe suppose that apigenin may inhibit the cellular process of sepsis‐induced lung injury, which is considered to be a major cause of morbidity and mortality, and may improve inflammation and oxidative stress. The aim of this study was to investigate the potential protective effect of apigenin in a rat model of polymicrobial sepsis. Eight groups consisting of a total of 64 female Wistar albino rats were used for this study. Pro‐inflammatory (TNF‐α, IL‐1‐β, IL‐6) and anti‐inflammatory (TGF‐β, IL‐10) cytokine levels were measured with the enzyme‐linked immunosorbent assay technique, oxidant/antioxidants parameters were measured using the spectrophotometric method and Bax and Caspase‐3 immunohistochemical methods. TNF‐α, TGF‐β, IL‐1β, and IL‐6 levels significantly increased in the sepsis‐induced group than in the control groups, while IL‐10 levels decreased. Lipid peroxidase (LPO), an oxidative stress marker, increased, while the antioxidant defense parameters of superoxide dismutase (SOD), catalase (CAT) activities, glutathione (GSH) levels decreased. Although Bax and Caspase‐3 immunoreactivity and H score levels significantly increased in the sepsis group, significant decreases were found in the groups treated with apigenin. In conclusion, we are of the opinion that apigenin treatment improves lung injury by inhibiting oxidative stress and inflammatory cell damage.
Adsorptive granulomonocytapheresis alters the gut bacterial microbiota in patients with active ulcerative colitis
Authors: Chen Xiuli , Lou Lian , Tang Haiying , Tan Xiaoyan , Bi Jian , Wu Hao , Li Na , Wang Yingde , Mao Jingwei 
Published: February 2021

AbstractBackgroundUlcerative colitis (UC) is a refractory disease with unclear etiology. Studies have shown that UC is closely associated with gut microbiota dysbiosis. Adsorptive granulomonocytapheresis (GMA) using an Adacolumn has been found to treat UC effectively, but its underlying mechanism of treatment has not been fully elucidated. In this study, we aimed to investigate the influence of GMA on the gut microbiota in patients with active UC.MethodsWe conducted a single‐center prospective analysis of patients with active UC who received GMA therapy and ultimately achieved clinical remission. Stool samples of healthy controls and patients before and after 5 or 10 sessions of GMA therapy were collected. Subsequently, high‐throughput sequencing of the 16S rRNA V3 and V4 gene region of the stool was conducted and clustering of operational taxonomic units and species annotation were performed.ResultsGut microbial profiles in patients with UC were characterized by low bacterial diversity. After 5 or 10 sessions of GMA therapy, the gut microbiota diversity in patients with UC increased and was similar to that of healthy controls. UC was further characterized by increased abundances of Proteobacteria and Bacteroides, as well as decreased abundances of Faecalibacterium, Roseburia, Firmicutes, and Dialister; however, after GMA therapy, the abundance of Bacteroides decreased, whereas those of Faecalibacterium, Roseburia, and Firmicutes increased.ConclusionsActive UC is associated with gut microbiota dysbiosis. GMA therapy exerts a strong regulatory effect on the gut microbiota in patients with UC.
POLR2A blocks osteoclastic bone resorption and protects against osteoporosis by interacting with CREB1
Authors: Liu Chuxiao , Han Yu , Zhao Xingyu , Li Bo , Xu Liwen , Li Dongsong , Li Guangyu 
Published: February 2021

AbstractBone‐resorbing osteoclasts significantly contribute to osteoporosis, and understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss. Here, we report that POLR2A is upregulated during osteoclastogenesis. Functional analyses showed that the inhibition of POLR2A decreased osteoclastogenesis, whereas the overexpression of POLR2A had completely opposite effects in vitro. Notably, the osteoclast‐specific deletion of POLR2A blocks bone resorption in vivo. Furthermore, POLR2A loss‐of‐function suppresses estrogen deficiency‐induced bone resorption. Mechanistically, POLR2A regulates the assembly of CREB1 on the regulatory elements of its target genes. Collectively, using genetic, pharmacological, and disease mouse models, we have identified a previously undescribed protein that interacts with CREB1 to regulate osteoclastic bone resorption.
Circadian clock gene BMAL1 controls testosterone production by regulating steroidogenesis‐related gene transcription in goat Leydig cells
Authors: Xiao Yaoyao , Zhao Lijia , Li Weidong , Wang Xiaoyu , Ma Tiantian , Yang Luda , Gao Lei , Li Cuimei , Zhang Manhui , Yang Dan , Zhang Jing , Jiang Haizhen , Zhao Hongcong , Wang Yiqun , Chao Hsu‐Wen , Wang Aihua , Jin Yaping , Chen Huatao 
Published: February 2021

AbstractTestosterone is produced by Leydig cells (LCs) and undergoes diurnal changes in serum levels in rats, mice, and humans, but little is known in goats. The present study revealed that goat serum testosterone levels displayed diurnal rhythmic changes (peak time at ZT11.2). Immunohistochemical staining showed that BMAL1, a circadian clock protein, is highly expressed in goat LCs. ELISA revealed that both hCG (0–5 IU/ml) and 22R‐OH‐cholesterol (0–30 μM) addition stimulated testosterone synthesis in primary goat LCs in a dose‐dependent manner. Treating goat LCs with hCG (5 IU/ml) significantly increased intracellular cAMP levels. Additionally, real‐time quantitative polymerase chain reaction (PCR) analysis revealed that the circadian clock (BMAL1, PER1, PER2, DBP, and NR1D1) and steroidogenesis‐related genes (SF1, NUR77, StAR, HSD3B2, CYP17A1, CYP11A1, and HSD17B3) showed rhythmic expression patterns in goat LCs following dexamethasone synchronization. Several Bmal1‐Luc circadian oscillations were clearly observed in dexamethasone‐treated goat LCs transfected with the pLV6‐Bmal1‐Luc plasmid. BMAL1 knockdown significantly downregulated mRNA levels of PER2, NR1D1, DBP, StAR, HSD3B2, SF1, NUR77, and GATA4, and dramatically decreased StAR and HSD3B2 protein levels and testosterone production. In contrast, BMAL1 overexpression significantly increased the mRNA and protein expression levels of StAR and HSD17B3 and enhanced testosterone production. Reporter assays revealed that goat BMAL1, or in combination with mouse CLOCK, activated goat HSD17B3 transcription in vitro. These data indicate that BMAL1 contributes to testosterone production by regulating transcription of steroidogenesis‐related genes in goat LCs, providing a basis for further exploring the underlying mechanism by which the circadian clock regulates ruminant reproductive capability.
Generation of biohybrid implants using a multipotent human periodontal ligament cell line and bioactive core materials
Authors: Ono Taiga , Tomokiyo Atsushi , Ipposhi Keita , Yamashita Kozue , Alhasan M Anas , Miyazaki Yudai , Kunitomi Yoshihiro , Tsuchiya Akira , Ishikawa Kunio , Maeda Hidefumi 
Published: February 2021

AbstractWe aimed to generate periodontal ligament (PDL) tissue‐like structures from a multipotent human PDL cell line using three‐dimensional (3D) bioprinting technology and to incorporate these structures with bioactive core materials to develop a new biohybrid implant system. After 3D bioprinting, single‐cell spheroids were able to form 3D tubular structures (3DTBs). We established three types of complexes using 3DTBs and different core materials: 3DTB‐titanium core (TIC), 3DTB‐hydroxyapatite core (HAC), and 3DTB without a core material (WOC). The expressions of PDL‐, angiogenesis‐, cementum‐, and bone‐related genes were significantly increased in the three complexes compared with monolayer‐cultured cells. Abundant collagen fibers and cells positive for the above markers were confirmed in the three complexes. However, more positive cells were detected in HAC than in WOC or TIC. The present results suggest that 3D‐bioprinted structures and hydroxyapatite core materials can function similarly to the PDL and may be useful for the development of a new biohybrid implant system.
Genetic testing for pheochromocytoma and paraganglioma: SDHx carriers’ experiences
Authors: Martins Raquel Gomes , Carvalho Irene Palmares 
Published: February 2021

AbstractPheochromocytoma and paraganglioma are frequently hereditary tumors commonly associated with succinate dehydrogenase (SDHx) pathogenic variants (PV). Genetic testing is recommended to relatives of patients carrying SDHx PV. This study aims to explore the experiences associated with genetic testing for this hereditary condition. Semi‐structured interviews with 38 SDHx PV (tumor‐affected and non‐affected) carriers were transcribed and content‐analyzed. Four ways of living with this genetic alteration emerged from the interviews: ‘living as if not knowing’, ‘preventing others from going through this’, ‘feeling privileged’, and ‘still suffering’. Within each, negative, neutral, and positive reactions to the actual test result emerged initially, in addition to blame and guilt. Recognition of the importance of the genetic test and of the follow‐up occurred in all four, but views on fecundity were divided between having and not having children. Consideration for the four different meanings of carrying an SDHx PV can improve participants’ experiences and clinical practice.
Exploring how mothers of a child with a genetic disorder experience their couple relationship in a low socio‐economic setting
Authors: Haw Tabitha , Henriques Sasha 
Published: February 2021

AbstractHaving a child with a genetic disorder directly impacts a couple's relationship due to increased care demands. Most research on couple relationships in the context of having a child with a disability has been done in well‐resourced, developed countries. In South Africa, the black South African population has been historically disadvantaged resulting in high rates of unemployment and poverty, and disruption of the family system. The purpose of this study was to explore the impact of having a child with a genetic disorder on the couple relationship in a low socio‐economic setting. Thirteen black South African mothers of a child with a confirmed or suspected genetic disorder participated in the study. All participants were recruited while waiting to be seen for a follow‐up appointment by a medical geneticist at a Genetic Clinic in Johannesburg, South Africa between 2016 and 2019. Data were collected through semi‐structured interviews lasting between 25 and 60 min and analyzed using thematic content analysis. Findings showed that mothers of a child with a genetic disorder in this low socio‐economic setting frequently felt unsupported and carried the responsibility of childcare alone. The majority of participants wanted more tangible and emotional support from their partners and without this support they felt isolated and alone. The participants used many different coping strategies to deal with the distress of having a child with a genetic disorder but most frequently they described using 'acceptance'. Participants' partners were more often reported to use escape‐avoidance strategies such as abandonment, denying paternity, withdrawal, and partner‐blame. We suggest that mothers of a child with a genetic disorder should consult with a genetic counselor in addition to a medical geneticist to enable the provision of emotional support.
Coronary artery disease and non‐alcoholic fatty liver disease: Clinical correlation using computed tomography coronary calcium scans
Authors: Kirby Richard S , Halegoua‐DeMarzio Dina 
Published: February 2021

AbstractBackground and AimNon‐alcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) have been explored using coronary angiography, which showed a link between severe NAFLD and cardiovascular disease risk. This study's aim is to determine if computed tomography (CT) coronary artery calcium (CAC) scores used to determine CAD severity in asymptomatic populations can help predict the presence of NAFLD.MethodsThis was a retrospective cross‐sectional study of positive CT CAC scores and liver imaging with either CT; ultrasound; magnetic resonance imaging of the abdomen; or CT of the chest, which included liver images. Drinking 7 or 14 drinks per week for a female or male, respectively, and chronic viral hepatitis diagnosis were the exclusion criteria. CT CAC scores, hepatic steatosis, age, gender, lipid and liver panels, weight, blood pressure, F‐4/BARD scores, and hemoglobin A1c were correlated to CAD severity and NAFLD by logistic regression.ResultsA total of 134 patients with a mean age of 62.3 years (σ = 9.1), with 65% males, body mass index 28.5 (σ = 6.0), and 8% diabetics, were recruited. CAD severity was not associated with the presence of hepatic steatosis (odds ratio 1.96 [95% confidence interval, confidence interval 0.74–5.23] P = 0.36). Adjusted for variables, a link between hepatic steatosis, CAD severity, body mass index over 30 (odds ratio 6.77 [95% confidence interval 1.40–32.66] P = 0.02), and diabetes (odds ratio 9.60 [95% confidence interval 0.56–165.5] P = 0.01) was observed.ConclusionsIn patients with CAD detected using a positive CT CAC scan, we determined that BMI over 30 and diabetes were correlated with the presence of NAFLD. There was no direct relationship between CAD presence and hepatic steatosis presence.
Missed opportunities for sexually transmitted infections testing for HIV pre‐exposure prophylaxis users: a systematic review
Authors: Ong Jason J , Fu Hongyun , Baggaley Rachel C , Wi Teodora E , Tucker Joseph D , Smith M Kumi , Rafael Sabrina , Falconer Jane , Terris‐Prestholt Fern , Mameletzis Ioannis , Mayaud Phillipe 
Published: February 2021

AbstractIntroductionGiven the synergistic relationship between HIV and sexually transmitted infections (STI), the integration of services has the potential to reduce the incidence of both HIV and STIs. We explored the extent to which STI testing has been offered within HIV pre‐exposure prophylaxis (PrEP) programmes worldwide.MethodsWe conducted a systematic review of PrEP programmes implementing STI testing services in nine databases. We approached PrEP implementers for additional unpublished data and implementation details. Descriptive statistics were used to present the characteristics of STI testing within PrEP programmes. Content analysis of the input from PrEP implementers was conducted to summarize the barriers to and facilitators of STI testing.ResultsOf 9,161 citations, 91 studies conducted in 32 countries were included: 69% from high‐income countries (HICs) and 64% from programmes targeting men who have sex with men (MSM) and transgender women (TGW) only. The majority of programmes (70%, 64/91) conducted STI testing before the initiation of PrEP. The most common STIs tested were gonorrhoea (86%, 78/91), chlamydia (84%, 76/91) and syphilis (84%, 76/91). The majority provided STI testing at three‐month intervals (70%, 53/76, for syphilis; 70% 53/78, for chlamydia; 68%, 53/78, for gonorrhoea). Relative to low‐ and middle‐income countries (LMICs), a higher proportion of PrEP programmes in HICs offered testing for gonorrhoea (92% vs. 71%, p < 0.05), chlamydia (92% vs. 64%, p < 0.01), syphilis (87% vs. 75%, p < 0.05), hepatitis A (18% vs. 4%, p < 0.05) and hepatitis C (43% vs. 21%, p < 0.05); offered testing for a higher number of STIs (mean 3.75 vs. 3.04, p < 0.05); and offered triple (throat, genital/urine and anorectal) anatomical site screening (54% vs. 18%, p < 0.001). Common implementation challenges included costs, access to STI diagnostics, programme logistics of integrating STI testing into PrEP delivery models and lack of capacity building for staff involved in PrEP provision.ConclusionsSignificant gaps and challenges remain in the provision of STI testing services within HIV PrEP programmes. We recommend more active integration of STI testing and management into PrEP programmes, supported by standardized practice guidelines, staff capacity building training and adequate funding. This could lead to improved sexual health and HIV outcomes in key populations.
IL-34 and CSF-1, deciphering similarities and differences at steady state and in diseases
Authors: Freuchet Antoine , Salama Apolline , Remy Séverine , Guillonneau Carole , Anegon Ignacio 
Published: February 2021

AbstractAlthough IL-34 and CSF-1 share actions as key mediators of monocytes/macrophages survival and differentiation, they also display differences that should be identified to better define their respective roles in health and diseases. IL-34 displays low sequence homology with CSF-1 but has a similar general structure and they both bind to a common receptor CSF-1R, although binding and subsequent intracellular signaling shows differences. CSF-1R expression has been until now mainly described at a steady state in monocytes/macrophages and myeloid dendritic cells, as well as in some cancers. IL-34 has also 2 other receptors, protein-tyrosine phosphatase zeta (PTPζ) and CD138 (Syndecan-1), expressed in some epithelium, cells of the central nervous system (CNS), as well as in numerous cancers. While most, if not all, of CSF-1 actions are mediated through monocyte/macrophages, IL-34 has also other potential actions through PTPζ and CD138. Additionally, IL-34 and CSF-1 are produced by different cells in different tissues. This review describes and discusses similarities and differences between IL-34 and CSF-1 at steady state and in pathological situations and identifies possible ways to target IL-34, CSF-1, and its receptors.