bluuebunny/crossref_metadata_2025 huggingface dataset:
INHERITANCE DISTRIBUTION FOR "KHUNTHA MUSHKIL" (SISSY) IN ISLAM:
Authors: Abizar Mukhammad Hafidz
Published: July 2021

This article is result of library research with a normative legal approach. Legal materials and data were obtained from Islamic legal norms regarding inheritance and khuntsa obtained from the texts of the Qur'an and Hadith, as well as the opinions of the jurists. This thesis discusses the distribution of khuntsa inheritance based on the opinion of Imam Ali As-Shobuni and Imam Abu Hanifah. People who do not have a clear gender status, not male and not female, are called khuntsa in Islamic law. One of the problems of khuntsa is in determining the right of inheritance. The Qur'an does not clearly state the portion of khuntha inheritance. This study concludes that in the unclear gender of khuntsa, it can be determined by two things, namely first, signs of maturity and second, where does urine come from. This argument is put forward using the istidlal theory used by Imam Ali As-Shobuni and Imam Abu Hanifah. If a khuntsa has a clear gender status, then this status follows the law of inheritance

Keyword : Khuntha mushkil, sissy, inheritance.

 

Abstrak

Artikel ini adalah hasil dari penelitian kepustakaan dengan pendekatan hukum normatif. Bahan hukum dan data diperoleh dari norma- norma hukum Islam tentang kewarisan dan khuntsa yang diperoleh dari nash al-Qur‟an dan Hadits, serta pendapat para fuqaha‟.  Tesis   ini   mendiskusikan pembagian  warisan  khuntsa  berdasarkan  pendapat  Imam Ali  As-Shobuni  dan     Imam  Abu  Hanifah.  orang  yang  tidak mempunyai status jenis kelamin yang jelas, bukan laki-laki dan bukan perempuan disebut dengan istilah khuntsa dalam hukum islam. Salah satu dari permasalahan  khuntsa  adalah dalam hal menentukan hak kewarisannya.  Al-Qur‟an  tidak menyebutkan secara jelas bagian waris khuntha. Penelitian ini menyimpulkan bahwa dalam ketidak jelasan jenis kelamin khuntsa, dapat ditentukan dengan dua hal, yaitu pertama, tanda-tanda kedewasaannya dan kedua, darimana ia mengeluarkan air kencing. Argumen ini diajukan dengan menggunakan teori istidlal yang digunakan oleh  Imam Ali  As-Shobuni  dan     Imam  Abu  Hanifah. Bila seorang khuntsa telah jelas status jenis kelaminnya, maka status ini mengikuti pada hukum kewarisannya.

Kata Kunci : Khuntha mushkil, banci, pembagian waris
HAPPY FAMILY ("SAKINAH" ) OF TAHFID PESANTREN ALUMNI: Marriage Counseling Approach
Authors: Machmudz Machmudz
Published: July 2021

This article is a result of a qualitative field research. This article discusses efforts to form a sakinah family. The research location is Jombang Regency. The data of this research are alumni of Madrasatul Qur'an Islamic boarding school Tebuireng Jombang who are domiciled in Jombang Regency. This study concludes that marriage counseling to maintain household harmony, one of which can be done independently through istiqamahan interacting with the Qur'an. This argument is based on data from the family of alumni who have memorized the Koran PP. Madrasataul Qur'an Tebuireng in Diwek district, Jombang. The alumni practice the routine of memorizing the Qur'an, always remembering Allah (taqarrub), tadarus Al-Qur`an every day, praying in congregation, being open between family members. The alumni carry out several family functions, namely educational, religious, protective, economic, and recreational functions.

Keywords: marriage counseling, happy family, pesantren alumni.

 

Abstrak

Artikel ini adalah hasil penelitian kualitatif lapangan. Artikel ini mendiskusikan upaya membentuk keluarga sakinah. Lokasi penelitian berada Kabupaten Jombang. Data penelitian ini adalah alumni pondok pesantren Madrasatul Qur’an Tebuireng Jombang yang berdomisili di Kabupaten Jombang. Penelitian ini menyimpulkan bahwa konseling pernikahan untuk menjaga keharmonisan rumah tangga salah satunya dapat dilakukan secara mandiri melalui keistiqamahan berinteraksi dengan Al-Qur’an. Argumen ini didasarkan pada data Keluarga alumni penghafal Al-Qur`an PP. Madrasataul Qur`an Tebuireng di kecamatan Diwek Jombang. Para alumni mempraktekkan rutinitas menghafal Al-Qur`an, selalu bedzikir kepada Allah (taqarrub), tadarus Al-Qur`an setiap hari, shalat berjamaah, bersikap terbuka antar anggota keluarga. Para alumni menjalankan beberapa fungsi keluarga, yakni fungsi edukatif, religi, protektif, ekonomis, dan rekreatif.

Kata Kunci: konseling perkawinan, keluarga bahagia, alumni pesantren.
The Riemann Hypothesis
Authors: Vega Frank
Published: July 2021

For every prime number $p_{n}$, we define the sequence $X_{n} = \frac{\prod_{q \mid N_{n}} \frac{q}{q-1}}{e^{\gamma} \times \log\log N_{n}}$, where $N_{n} = \prod_{k = 1}^{n} p_{k}$ is the primorial number of order $n$ and $\gamma \approx 0.57721$ is the Euler-Mascheroni constant. The Nicolas theorem states that the Riemann hypothesis is true if and only if the $X_{n} > 1$ holds for all prime $p_{n} > 2$. For every prime number $p_{k}$, $X_{k} > 1$ is called the Nicolas inequality. We show if the sequence $X_{n}$ is strictly decreasing for $n$ big enough, then the Riemann hypothesis should be true. Moreover, we demonstrate that the sequence $X_{n}$ is indeed strictly decreasing when $n \to \infty$. Notice that, Choie, Planat and Sol{\'e} in the preprint paper arXiv:1012.3613 have a proof that the Cram{\'e}r conjecture is false when $X_{n}$ is strictly decreasing for $n$ big enough. This paper is an extension of their result.
Robin Criterion on Divisibility
Authors: Vega Frank
Published: July 2021

Robin criterion states that the Riemann Hypothesis is true if and only if the inequality $\sigma(n) < e^{\gamma } \times n \times \log \log n$ holds for all $n > 5040$, where $\sigma(n)$ is the sum-of-divisors function and $\gamma \approx 0.57721$ is the Euler-Mascheroni constant. This is known as the Robin inequality. We show that the Robin inequality is true for all $n > 5040$ which are not divisible by any prime number between $2$ and $953$. In addition, from the possible smallest counterexample $n > 5040$ of the Robin inequality, we prove that necessarily $\log(n)^{\beta} < 1.26 \times \log(N_{m})$, where $N_{m} = \prod_{k = 1}^{m} q_{k}$ is the primorial number of order $m$ and $\beta = \prod_{i = 1}^{m} \frac{q_{i}^{a_{i} + 1}}{q_{i}^{a_{i} + 1} - 1}$ when $n$ is an Hardy-Ramanujan integer of the form $\prod_{i=1}^{m} q_{i}^{a_{i}}$.
Plasma Spray vs. Electrochemical Deposition: Toward a Better Osteogenic Effect of Hydroxyapatite Coatings on 3D-Printed Titanium Scaffolds
Authors: Sun Yang , Zhang Xing , Luo Mingran , Hu Weifan , Zheng Li , Huang Ruqi , Greven Johannes , Hildebrand Frank , Yuan Feng
Published: July 2021

Surface modification of three-dimensional (3D)-printed titanium (Ti) scaffolds with hydroxyapatite (HA) has been a research hotspot in biomedical engineering. However, unlike HA coatings on a plain surface, 3D-printed Ti scaffolds have inherent porous structures that influence the characteristics of HA coatings and osteointegration. In the present study, HA coatings were successfully fabricated on 3D-printed Ti scaffolds using plasma spray and electrochemical deposition, named plasma sprayed HA (PSHA) and electrochemically deposited HA (EDHA), respectively. Compared to EDHA scaffolds, HA coatings on PSHA scaffolds were smooth and continuous. In vitro cell studies confirmed that PSHA scaffolds have better potential to promote bone mesenchymal stem cell adhesion, proliferation, and osteogenic differentiation than EDHA scaffolds in the early and late stages. Moreover, in vivo studies showed that PSHA scaffolds were endowed with superior bone repair capacity. Although the EDHA technology is simpler and more controllable, its limitation due to the crystalline and HA structures needs to be improved in the future. Thus, we believe that plasma spray is a better choice for fabricating HA coatings on implanted scaffolds, which may become a promising method for treating bone defects.
Mechanical Parameters and Trajectory of Two Chinese Cervical Manipulations Compared by a Motion Capture System
Authors: Huang Xuecheng , Lin Dongxin , Liang Zeyu , Deng Yuping , He Zaopeng , Wang Mian , Tan Jinchuan , Li Yikai , Yang Yang , Huang Wenhua
Published: July 2021

Objective: To compare the mechanical parameters and trajectory while operating the oblique pulling manipulation and the cervical rotation–traction manipulation.

Methods: An experimental research measuring kinematics parameter and recording motion trajectories of two cervical manipulations were carried out. A total of 48 healthy volunteers participated in this study, who were randomly divided into two groups of 24 representing each of the two manipulations. A clinician performed two manipulations in two groups separately. A motion capture system was used to monitor and analyze kinematics parameters during the operation.

Results: The two cervical manipulations have similar thrust time, displacement, mean velocity, max velocity, and max acceleration. There were no significant differences in active and passive amplitudes between the two cervical rotation manipulations. The thrust amplitudes of the oblique pulling manipulation and the cervical rotation–traction manipulation were 5.735 ± 3.041° and 2.142 ± 1.742°, respectively. The thrust amplitudes of the oblique pulling manipulation was significantly greater than that of the cervical rotation–traction manipulation (P < 0.001).

Conclusion: Compared with the oblique pulling manipulation, the cervical rotation–traction manipulation has a less thrust amplitudes.
Contribution of Low-Level Acoustic and Higher-Level Lexical-Semantic Cues to Speech Recognition in Noise and Reverberation
Authors: Warzybok Anna , Rennies Jan , Kollmeier Birger
Published: July 2021

Masking noise and reverberation strongly influence speech intelligibility and decrease listening comfort. To optimize acoustics for ensuring a comfortable environment, it is crucial to understand the respective contribution of bottom-up signal-driven cues and top-down linguistic-semantic cues to speech recognition in noise and reverberation. Since the relevance of these cues differs across speech test materials and training status of the listeners, we investigate the influence of speech material type on speech recognition in noise, reverberation and combinations of noise and reverberation. We also examine the influence of training on the performance for a subset of measurement conditions. Speech recognition is measured with an open-set, everyday Plomp-type sentence test and compared to the recognition scores for a closed-set Matrix-type test consisting of syntactically fixed and semantically unpredictable sentences (c.f. data by Rennies et al., J. Acoust. Soc. America, 2014, 136, 2642–2653). While both tests yield approximately the same recognition threshold in noise in trained normal-hearing listeners, their performance may differ as a result of cognitive factors, i.e., the closed-set test is more sensitive to training effects while the open-set test is more affected by language familiarity. All experimental data were obtained at a fixed signal-to-noise ratio (SNR) and/or reverberation time set to obtain the desired speech transmission index (STI) values of 0.17, 0.30, and 0.43. respectively, thus linking the data to STI predictions as a measure of pure low-level acoustic effects. The results confirm the consistent difference between robustness to reverberation observed in the literature between the matrix type sentences and the Plomp-type sentences, especially for poor and medium speech intelligibility. The robustness of the closed-set matrix type sentences against reverberation disappeared when listeners had no a priori knowledge about the speech material (sentence structure and words used), thus demonstrating the influence of higher-level lexical-semantic cues in speech recognition. In addition, the consistent difference between reverberation- and noise-induced recognition scores of everyday sentences for medium and high STI conditions and the differences between Matrix-type and Plomp-type sentence scores clearly demonstrate the limited utility of the STI in predicting speech recognition in noise and reverberation.
Time-Dependent Internalization of S100B by Mesenchymal Stem Cells via the Pathways of Clathrin- and Lipid Raft-Mediated Endocytosis
Authors: Zhang Ying , Zhu Jing , Xu Hao , Yi Qin , Yan Liang , Ye Liang , Zhang Xinyuan , Xie Min , Tan Bin
Published: July 2021

Mesenchymal stem cells (MSCs) are promising tools for cancer therapy, but there is a risk of malignant transformation in their clinical application. Our previous work revealed that the paracrine protein S100B in the glioma microenvironment induces malignant transformation of MSCs and upregulates intracellular S100B, which could affect cell homeostasis by interfering with p53. The purpose of this study was to investigate whether extracellular S100B can be internalized by MSCs and the specific endocytic pathway involved in S100B internalization. By using real-time confocal microscopy and structured illumination microscopy (SIM), we visualized the uptake of fluorescently labeled S100B protein (S100B-Alexa488) and monitored the intracellular trafficking of internalized vesicles. The results showed that S100B-Alexa488 was efficiently internalized into MSCs in a time-dependent manner and transported through endolysosomal pathways. After that, we used chemical inhibitors and RNA interference approaches to investigate possible mechanisms involved in S100B-Alexa488 uptake. The internalization of S100B-Alexa488 was inhibited by pitstop-2 or dyngo-4a treatment or RNA-mediated silencing of clathrin or dynamin, and the lipid raft-mediated endocytosis inhibitors nystatin and MβCD. In conclusion, our findings show that clathrin and lipid rafts contribute to the internalization of S100B-Alexa488, which provides promising interventions for the safe application of MSCs in glioma therapy.
CircFAM120B Blocks the Development of Colorectal Cancer by Activating TGF-Beta Receptor II Expression via Targeting miR-645
Authors: Yu You , Lei Xiao
Published: July 2021

Circular RNAs (circRNAs) are implicated in various human cancers, including colorectal cancer (CRC). The objective of this study was to investigate the function and regulatory mechanism of a novel circRNA, circFAM120B, in CRC development. The expression of circFAM120B, miR-645 and TGF-beta receptor II (TGFBR2) mRNA was detected by quantitative real-time polymerase chain reaction. Cellular biological functions, including cell proliferation, migration/invasion, and glycolysis metabolism, were assessed using CCK-8 assay, colony formation assay, transwell assay, and glycolysis stress test, respectively. Glycolysis progression was also monitored by lactate production and glucose consumption. The expression of glycolysis-related markers and TGFBR2 at the protein level was detected by western blot. The interaction between miR-645 and circFAM120B or TGFBR2 was predicted by bioinformatics analysis and verified by pull-down assay, dual-luciferase reporter assay and RIP assay. In vivo animal experiments were performed to further explore the function of circFAM120B. The expression of circFAM120B was decreased in CRC tissues and cells. CircFAM120B overexpression blocked CRC cell proliferation, migration/invasion, and glycolysis metabolism. MiR-645 was a target of circFAM120B, and miR-645 restoration reversed the effects of circFAM120B overexpression. In addition, TGFBR2 was a target of miR-645, and miR-645 inhibition-suppressed CRC cell proliferation, migration/invasion and glycolysis were restored by TGFBR2 knockdown. Moreover, circFAM120B activated the expression of TGFBR2 by targeting miR-645. TGFBR2 also blocked tumor growth in vivo by targeting the miR-645/TGFBR2 axis. CircFAM120B inhibited CRC progression partly by mediating the miR-645/TGFBR2 network, which explained the potential mechanism of circFAM120B function in CRC.
DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder
Authors: Bam Sophia , Buchanan Erin , Mahony Caitlyn , O’Ryan Colleen
Published: July 2021

Autism spectrum disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including pathways that affect mitochondrial function. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the etiology of ASD. We measured DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), as well as five genes involved in regulating mitochondrial homeostasis to examine mitochondrial dysfunction in an ASD cohort of South African children. Using targeted Next Generation bisulfite sequencing, we found differential methylation (p < 0.05) at six key genes converging on mitochondrial biogenesis, fission and fusion in ASD, namely PGC-1α, STOML2, MFN2, FIS1, OPA1, and GABPA. PGC-1α, the transcriptional regulator of biogenesis, was significantly hypermethylated at eight CpG sites in the gene promoter, one of which contained a putative binding site for CAMP response binding element 1 (CREB1) (p = 1 × 10–6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter and there was a positive correlation between methylation at PGC-1α CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD. Furthermore, DNA methylation at PGC-1α CpG#1 and mtDNA copy number correlated significantly (p < 0.05) with levels of urinary organic acids associated with mitochondrial dysfunction, oxidative stress, and neuroendocrinology. Our data show differential methylation in ASD at six key genes converging on PGC-1α-dependent regulation of mitochondrial biogenesis and function. We demonstrate that methylation at the PGC-1α promoter is associated with elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored role for DNA methylation in regulating specific pathways involved in mitochondrial biogenesis, fission and fusion contributing to mitochondrial dysfunction in ASD.
Ovary Development: Insights From a Three-Dimensional Imaging Revolution
Authors: Soygur Bikem , Laird Diana J.
Published: July 2021

The ovary is an indispensable unit of female reproduction and health. However, the study of ovarian function in mammals is hindered by unique challenges, which include the desynchronized development of oocytes, irregular distribution and vast size discrepancy of follicles, and dynamic tissue remodeling during each hormonal cycle. Overcoming the limitations of traditional histology, recent advances in optical tissue clearing and three-dimensional (3D) visualization offer an advanced platform to explore the architecture of intact organs at a single cell level and reveal new relationships and levels of organization. Here we summarize the development and function of ovarian compartments that have been delineated by conventional two-dimensional (2D) methods and the limits of what can be learned by these approaches. We compare types of optical tissue clearing, 3D analysis technologies, and their application to the mammalian ovary. We discuss how 3D modeling of the ovary has extended our knowledge and propose future directions to unravel ovarian structure toward therapeutic applications for ovarian disease and extending female reproductive lifespan.
ELMO1 Regulates RANKL-Stimulated Differentiation and Bone Resorption of Osteoclasts
Authors: Liang Xinyue , Hou Yafei , Han Lijuan , Yu Shuxiang , Zhang Yunyun , Cao Xiumei , Yan Jianshe
Published: July 2021

Bone homeostasis is a metabolic balance between the new bone formation by osteoblasts and old bone resorption by osteoclasts. Excessive osteoclastic bone resorption results in low bone mass, which is the major cause of bone diseases such as rheumatoid arthritis. Small GTPases Rac1 is a key regulator of osteoclast differentiation, but its exact mechanism is not fully understood. ELMO and DOCK proteins form complexes that function as guanine nucleotide exchange factors for Rac activation. Here, we report that ELMO1 plays an important role in differentiation and bone resorption of osteoclasts. Osteoclast precursors derived from bone marrow monocytes (BMMs) of Elmo1–/–mice display defective adhesion and migration during differentiation. The cells also have a reduced activation of Rac1, p38, JNK, and AKT in response to RANKL stimulation. Importantly, we show that bone erosion is alleviated in Elmo1–/–mice in a rheumatoid arthritis mouse model. Taken together, our results suggest that ELMO1, as a regulator of Rac1, regulates osteoclast differentiation and bone resorption bothin vitroandin vivo.
BRAF Mutation as a Potential Therapeutic Target for Checkpoint Inhibitors: A Comprehensive Analysis of Immune Microenvironment in BRAF Mutated Colon Cancer
Authors: Cen Shuyi , Liu Kun , Zheng Yu , Shan Jianzhen , Jing Chao , Gao Jiale , Pan Hongming , Bai Zhigang , Liu Zhen
Published: July 2021

BRAF mutated colon cancer presents with poor survival, and the treatment strategies are controversial. The tumor microenvironment, which plays a key role in tumorigenesis as well as responses to treatments, of this subtype is largely unknown. In the present study, we analyzed the differences of immune microenvironments between BRAF mutated and BRAF wild-type colon cancer utilizing datasets from The Cancer Genome Atlas and Gene Expression Omnibus and confirmed the findings by tissue specimens of patients. We found that BRAF mutated colon cancer had more stromal cells, more immune cell infiltration, and lower tumor purity. Many immunotherapeutic targets, including PD-1, PD-L1, CTLA-4, LAG-3, and TIM-3, were highly expressed in BRAF mutated patients. BRAF mutation was also correlated with higher proportions of neutrophils and macrophages M1, and lower proportions of plasma cells, dendritic cells resting, and T cells CD4 naïve. In conclusion, our study demonstrates a different pattern of the immune microenvironment in BRAF mutated colon cancer and provides insights into the future use of checkpoint inhibitors in this subgroup of patients.
Diabetic Uterine Environment Leads to Disorders in Metabolism of Offspring
Authors: Dong Ming-Zhe , Li Qian-Nan , Fan Li-Hua , Li Li , Shen Wei , Wang Zhen-Bo , Sun Qing-Yuan
Published: July 2021

Aims

Research evidence indicates that epigenetic modifications of gametes in obese or diabetic parents may contribute to metabolic disorders in offspring. In the present study, we sought to address the effect of diabetic uterine environment on the offspring metabolism.

Methods

Type 2 diabetes mouse model was induced by high-fat diet combined with streptozotocin (STZ) administration. We maintained other effect factors constant and changed uterine environment by zygote transfers, and then determined and compared the offspring numbers, symptoms, body weight trajectories, and metabolism indices from different groups.

Result

We found that maternal type 2 diabetes mice had lower fertility and a higher dystocia rate, accompanying the increased risk of offspring malformations and death. Compared to only a pre-gestational exposure to hyperglycemia, exposure to hyperglycemia both pre- and during pregnancy resulted in offspring growth restriction and impaired metabolism in adulthood. But there was no significant difference between a pre-gestational exposure group and a no exposure group. The deleterious effects, no matter bodyweight or glucose tolerance, could be rescued by transferring the embryos from diabetic mothers into normal uterine environment.

Conclusion

Our data demonstrate that uterine environment of maternal diabetes makes critical impact on the offspring health.
Identify Inflammatory Bowel Disease-Related Genes Based on Machine Learning
Authors: Ye Lili , Lin Yongwei , Fan Xing-di , Chen Yaoming , Deng Zengli , Yang Qian , Lei Xiaotian , Mao Jizong , Cui Chunhui
Published: July 2021

The patients of Inflammatory bowel disease (IBD) are increasing worldwide. IBD has the characteristics of recurring and difficult to cure, and it is also one of the high-risk factors for colorectal cancer (CRC). The occurrence of IBD is closely related to genetic factors, which prompted us to identify IBD-related genes. Based on the hypothesis that similar diseases are related to similar genes, we purposed a SVM-based method to identify IBD-related genes by disease similarities and gene interactions. One hundred thirty-five diseases which have similarities with IBD and their related genes were obtained. These genes are considered as the candidates of IBD-related genes. We extracted features of each gene and implemented SVM to identify the probability that it is related to IBD. Ten-cross validation was applied to verify the effectiveness of our method. The AUC is 0.93 and AUPR is 0.97, which are the best among four methods. We prioritized the candidate genes and did case studies on top five genes.
Stability of Maleimide-PEG and Mono-Sulfone-PEG Conjugation to a Novel Engineered Cysteine in the Human Hemoglobin Alpha Subunit
Authors: Cooper Chris E. , Bird Matthew , Sheng XiaoBo , Choi Ji-Won , Silkstone Gary G.A. , Simons Michelle , Syrett Natalie , Piano Riccardo , Ronda Luca , Bettati Stefano , Paredi Gianluca , Mozzarelli Andrea , Reeder Brandon J.
Published: July 2021

In order to use a Hemoglobin Based Oxygen Carrier as an oxygen therapeutic or blood substitute, it is necessary to increase the size of the hemoglobin molecule to prevent rapid renal clearance. A common method uses maleimide PEGylation of sulfhydryls created by the reaction of 2-iminothiolane at surface lysines. However, this creates highly heterogenous mixtures of molecules. We recently engineered a hemoglobin with a single novel, reactive cysteine residue on the surface of the alpha subunit creating a single PEGylation site (βCys93Ala/αAla19Cys). This enabled homogenous PEGylation by maleimide-PEG with >80% efficiency and no discernible effect on protein function. However, maleimide-PEG adducts are subject to deconjugation via retro-Michael reactions and cross-conjugation to endogenous thiol species in vivo. We therefore compared our maleimide-PEG adduct with one created using a mono-sulfone-PEG less susceptible to deconjugation. Mono-sulfone-PEG underwent reaction at αAla19Cys hemoglobin with > 80% efficiency, although some side reactions were observed at higher PEG:hemoglobin ratios; the adduct bound oxygen with similar affinity and cooperativity as wild type hemoglobin. When directly compared to maleimide-PEG, the mono-sulfone-PEG adduct was significantly more stable when incubated at 37°C for seven days in the presence of 1 mM reduced glutathione. Hemoglobin treated with mono-sulfone-PEG retained > 90% of its conjugation, whereas for maleimide-PEG < 70% of the maleimide-PEG conjugate remained intact. Although maleimide-PEGylation is certainly stable enough for acute therapeutic use as an oxygen therapeutic, for pharmaceuticals intended for longer vascular retention (weeks-months), reagents such as mono-sulfone-PEG may be more appropriate.
Pro-inflammatory Vascular Stress in Spontaneously Hypertensive Rats Associated With High Physical Activity Cannot Be Attenuated by Aldosterone Blockade
Authors: Schreckenberg Rolf , Wolf Annemarie , Troidl Christian , Simsekyilmaz Sakine , Schlüter Klaus-Dieter
Published: July 2021

The effect of high physical activity, performed as voluntary running wheel exercise, on inflammation and vascular adaptation may differ between normotensive and spontaneously hypertensive rats (SHRs). We investigated the effects of running wheel activity on leukocyte mobilization, neutrophil migration into the vascular wall (aorta), and transcriptional adaptation of the vascular wall and compared and combined the effects of high physical activity with that of pharmacological treatment (aldosterone antagonist spironolactone). At the start of the 6th week of life, before hypertension became established in SHRs, rats were provided with a running wheel over a period of 10-months'. To investigate to what extent training-induced changes may underlie a possible regression, controls were also generated by removal of the running wheel for the last 4 months. Aldosterone blockade was achieved upon oral administration of Spironolactone in the corresponding treatment groups for the last 4 months. The number of circulating blood cells was quantified by FACS analysis of peripheral blood. mRNA expression of selected proteins was quantified by RT-PCR. Histology and confocal laser microscopy were used to monitor cell migration. Although voluntary running wheel exercise reduced the number of circulating neutrophils in normotensive rats, it rather increased it in SHRs. Furthermore, running wheel activity in SHRs but not normotensive rats increased the number of natural killer (NK)-cells. Except of the increased expression of plasminogen activator inhibitor (PAI)-1 and reduction of von Willebrand factor (vWF), running wheel activity exerted a different transcriptional response in the vascular tissue of normotensive and hypertensive rats, i.e., lack of reduction of the pro-inflammatory IL-6 in vessels from hypertensive rats. Spironolactone reduced the number of neutrophils; however, in co-presence with high physical activity this effect was blunted. In conclusion, although high physical activity has beneficial effects in normotensive rats, this does not predict similar beneficial effects in the concomitant presence of hypertension and care has to be taken on interactions between pharmacological approaches and high physical activity in hypertensives.
Translation, Cultural Adaptation, and Reproducibility of the Physical Activity Readiness Questionnaire for Everyone (PAR-Q+): The Brazilian Portuguese Version
Authors: Schwartz Juliano , Oh Paul , Takito Monica Y. , Saunders Bryan , Dolan Eimear , Franchini Emerson , Rhodes Ryan E. , Bredin Shannon S. D. , Coelho Josye P. , dos Santos Pedro , Mazzuco Melina , Warburton Darren E. R.
Published: July 2021

Background: The Physical Activity Readiness Questionnaire for Everyone (PAR-Q+) is the international standard for pre-participation risk stratification and screening. In order to provide a practical and valid screening tool to facilitate safe engagement in physical activity and fitness assessments for the Brazilian population, this study aimed to translate, culturally adapt, and verify the reproducibility of the evidence-based PAR-Q+ to the Brazilian Portuguese language.

Method: Initially, the document was translated by two independent translators, before Brazilian experts in health and physical activity evaluated the translations and produced a common initial version. Next, two English native speakers, fluent in Brazilian Portuguese and accustomed to the local culture, back-translated the questionnaire. These back translations were assessed by the organization in charge of the PAR-Q+, then a final Brazilian version was approved. A total of 493 Brazilians between 5 and 93 yr (39.9 ± 25.4 yr), 59% female, with varying levels of health and physical activity, completed the questionnaire twice, in person or online, 1–2 weeks apart. Cronbach's alpha was used to calculate the internal consistency of all items of the questionnaire, and the Kappa statistic was used to assess the individual reproducibility of each item of the document. Additionally, the intraclass correlation coefficient and its 95% confidence interval (CI) were used to verify the general reproducibility (reliability) of the translated version.

Results: The Brazilian version had an excellent internal consistency (0.993), with an almost perfect agreement in 93.8% of the questions, and a substantial agreement in the other 6.2%. The translated version also had a good to excellent total reproducibility (0.901, 95% CI: 0.887–0.914).

Conclusion: The results show this translation is a valid and reliable screening tool, which may facilitate a larger number of Brazilians to start or increase physical activity participation in a safe manner.
3D Collagen-Nanocellulose Matrices Model the Tumour Microenvironment of Pancreatic Cancer
Authors: Curvello Rodrigo , Kast Verena , Abuwarwar Mohammed H. , Fletcher Anne L. , Garnier Gil , Loessner Daniela
Published: July 2021

Three-dimensional (3D) cancer models are invaluable tools designed to study tumour biology and new treatments. Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of cancer, has been progressively explored with bioengineered 3D approaches by deconstructing elements of its tumour microenvironment. Here, we investigated the suitability of collagen-nanocellulose hydrogels to mimic the extracellular matrix of PDAC and to promote the formation of tumour spheroids and multicellular 3D cultures with stromal cells. Blending of type I collagen fibrils and cellulose nanofibres formed a matrix of controllable stiffness, which resembled the lower profile of pancreatic tumour tissues. Collagen-nanocellulose hydrogels supported the growth of tumour spheroids and multicellular 3D cultures, with increased metabolic activity and matrix stiffness. To validate our 3D cancer model, we tested the individual and combined effects of the anti-cancer compound triptolide and the chemotherapeutics gemcitabine and paclitaxel, resulting in differential cell responses. Our blended 3D matrices with tuneable mechanical properties consistently maintain the growth of PDAC cells and its cellular microenvironment and allow the screening of anti-cancer treatments.
A Protocol Study to Establish Psychological Outcomes From the Use of Wearables for Health and Fitness Monitoring
Authors: Folkvord Frans , van Breugel Amy , de Haan Sanneke , de Wolf Marcella , de Boer Marjolein , Abeele Mariek Vanden
Published: July 2021

Background: The last few decades people have increasingly started to use technological tools for health and activity monitoring, such as tracking apps and wearables. The main assumption is that these tools are effective in reinforcing self-empowerment because they support better-informed lifestyle decision-making. However, experimental research assessing the effectiveness of the technological tools on such psychological outcomes is limited.

Methods and Design: Three studies will be conducted. First, we will perform a systematic review to examine the experimental evidence on the effects of self-tracking apps on psychological outcome measurements. Second, we will conduct a longitudinal field experiment with a between subject design. Participants (N = 150) begin a 50-day exercise program, either with or without the aid of the self-tracking app Strava. Among those who use Strava, we vary between those who use all features and those who use a limited set of features. Participants complete questionnaires at baseline, at 10, 25, and 50 days, and provide details on what information has been tracked via the platform. Third, a subset of participants is interviewed to acquire additional qualitative data. The study will provide a rich set of data, enabling triangulation, and contextualization of the findings.

Discussion: People increasingly engage in self-tracking whereby they use technological tools for health and activity monitoring, although the effects are still unknown. Considering the mixed results of the existing evidence, it is difficult to draw firm conclusions, showing more research is needed to develop a comprehensive understanding.

Trial registration: Netherlands Trial registration: NL9402, received on 20 April 2021; https://www.trialregister.nl/trial/9402.
Multi-state Risk-Based Maintenance Analysis of Redundant Safety Systems Using the Markov Model and Fault Tree Method
Authors: Mohammadhasani F. , Pirouzmand A.
Published: July 2021

The risk-based maintenance strategy has received special attention in the safe operation of nuclear power plants. Simultaneous quantification of the positive and negative effects of maintenance activities and components degradation effect makes it possible to accurately evaluate the risk criterion for safety systems of nuclear power plants. However, it is difficult to integrate the effects of maintenance and components degradation into the standard reliability approaches. A straightforward approach for considering components degradation and different maintenance policies is to make use of Markov maintenance models. In this article, the effectiveness of maintenance activities (including changes in the surveillance test intervals and alteration in the different maintenance policies) on the components unavailability with considering aging effects is quantified using Markov maintenance models and then by coupling these models and the fault tree method, the risk measure is upgraded from the component level to the system level. The proposed models are applied to evaluate the unavailability of two safety systems of VVER-1000/V446 nuclear power plants as case studies. The results show that the Markov method due to its multi-state nature is effective in the conservative evaluation of risk measures so that the unavailability computed by the coupling process is higher than the original unavailability (calculated by system fault tree using PSA data of nuclear power plants) for all maintenance policies. In addition, this study illustrates that the developed Markov maintenance models could be applied to the large-scale whole plant level and provides a proper transition from the classical PSA methods to new techniques. This approach integrates the effects of maintenance strategies and components degradation. Also, it provides a practical and a more accurate tool to determine the technical specification of a real nuclear power plant from the risk point of view.
Photovoltaic Power Station Electromagnetic Environment Complexity Evaluation Utilizing Logarithmic Morphological Gradient Spectrum
Authors: Xi Hua-chen , Li Bing , Mai Wen-hui , Xu Xiong , Wang Ya
Published: July 2021

In this paper, a feature extraction method for evaluating the complexity of the Electromagnetic Environment (EME) of the photovoltaic power station is presented by using logarithmic morphological gradient spectrum (LMGS) based on the mathematical morphological theory. We use LMGS to evaluate electromagnetic environment signals. We also explored the impact of structure element (SE) on the MS, MGS, and LMGS. Three types of SE, mean the line SE, square SE and diamond SE, are utilized and compared for computing the LMGS. EME signals with four complexity degrees are simulated to evaluate the effectiveness of the presented method. The experimental results have shown that the feature extraction scheme proposed in this paper is a reasonable method to classify the complexity of EME.
SWCC of Calcareous Silty Sand Under Different Fines Contents and dry Densities
Authors: Shen Jian-Hua , Hu Ming-Jian , Wang Xing , Zhang Chen-Yang , Xu Dong-Sheng
Published: July 2021

Investigating the soil-water characteristics of calcareous soil has a great significance for preventing geological disasters on island-reefs as well as maintaining the foundation stability of hydraulic-filled island-reefs. In this study, calcareous silty sands with different fines contents and dry densities were studied to reveal their effects on the soil-water characteristics of calcareous soil on hydraulic-filled island-reefs. The soil-water characteristic curve (SWCC) of the calcareous silty sand was measured using a pressure plate apparatus. Taking into account the porous meso-structure, the effects of fines content and dry density on the SWCC of calcareous silty sand were analyzed, and the applicability of existing SWCC models to calcareous silty sand was verified. A SWCC model suitable for assessing soil-water characteristic of calcareous silty sand was proposed. Results of this study provide some reference for quantifying the water-holding capacity of calcareous silty sand.
The Evidential Statistics of Genetic Assembly: Bootstrapping a Reference Sequence
Authors: Toquenaga Yukihiko , Gagné Takuya
Published: July 2021

The reference sequences play an essential role in genome assembly, like type specimens in taxonomy. Those references are also samples obtained at some time and location with a specific method. How can we evaluate or discriminate uncertainties of the reference itself and assembly methods? Here we bootstrapped 50 random read data sets from a small circular genome of aEscherichia colibacteriophage, phiX174, and tried to reconstruct the reference with 14 free assembly programs. Nine out of 14 assembly programs were capable of circular genome reconstruction. Unicycler correctly reconstructed the reference for 44 out of 50 data sets, but each reconstructed contig of the failed six data sets had minor defects. The other assembly software could reconstruct the reference with minor defects. The defect regions differed among the assembly programs, and the defect locations were far from randomly distributed in the reference genome. All contigs of Trinity included one, but Minia had two perfect copies other than an imperfect reference copy. The centroid of contigs for assembly programs except Unicycler differed from the reference with 75bases at most. Nonmetric multidimensional scaling (NMDS) plots of the centroids indicated that even the reference sequence was located slightly off from the estimated location of the true reference. We propose that the combination of bootstrapping a reference, making consensus contigs as centroids in an edit distance, and NMDS plotting will provide an evidential statistic way of genetic assembly for non-fragmented base sequences.
Iberian Protected Areas Capture Regional Functional, Phylogenetic and Taxonomic Diversity of Most Tetrapod Groups
Authors: Llorente-Culebras Sonia , Molina-Venegas Rafael , Barbosa A. Márcia , Carvalho Silvia B. , Rodríguez Miguel Á. , Santos Ana M. C.
Published: July 2021

Protected areas (PAs) have been created with the purpose of preserving biodiversity, acting as refuges from anthropogenic pressures. Traditionally, PAs have been designed and managed to represent mainly taxonomic diversity, ignoring other diversity facets such as its functional and phylogenetic components. Yet, functional and phylogenetic diversity are, respectively, connected with species’ roles on ecosystems and evolutionary history held within communities. Here, we focused on the amphibian, reptile, resident breeding bird, and non-flying mammal faunas of the national and natural parks of the Iberian Peninsula, to evaluate whether these PAs are adequately representing regional functional, phylogenetic, and taxonomic diversity of each group. Specifically, we computed functional and phylogenetic diversity within each PA, and then compared those values to the ones obtained from a random assembly of species from the regional pool, that was defined as the region encompassing the PA and a neighboring area of 50 km beyond its boundary. We also calculated the proportion of species in each regional pool that were present within the PAs. In general, the functional and phylogenetic diversity of amphibians, reptiles and non-flying mammals found within PAs did not differ significantly from random expectations generated from the species pertaining to the regional pool, although a few PAs showed a higher diversity. In contrast, resident breeding birds presented lower functional and phylogenetic diversity than expected by chance in many of the PAs, which could relate to climatic variables and the habitat specificity of some species. The proportion of species from the regional pools that are present in the PAs was high for amphibians, reptiles and mammals, and slightly lower for birds. These results suggest that the Iberian natural and national parks are effectively capturing the functional, phylogenetic and taxonomic diversity of most tetrapod assemblages present at the regional level. Future studies should identify priority areas to expand the representation of these biodiversity components, and assess potential effects of climate and land-use changes on current patterns.
Causal Relationship Between Parathyroid Hormone and the Risk of Osteoarthritis: A Mendelian Randomization Study
Authors: Huang Guiwu , Zhong Yanlin , Li Wenchang , Liao Weiming , Wu Peihui
Published: July 2021

Background

Previous studies have demonstrated an inverse association between parathyroid hormone (PTH) and the risk of osteoarthritis (OA). However, it remains unknown whether such association reflects causality. We aimed to apply a Mendelian randomization (MR) approach to investigate the causal association between PTH and OA.

Materials and Methods

We performed a two-sample MR analysis using summary statistics from 13 cohorts (PTH, N = 29,155) and a recent genome-wide association study meta-analysis (OA, N = 455,221) by the UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). MR analyses were carried out mainly using the inverse-variance-weighted method. Sensitivity analyses were performed to test the robustness of the associations using the weighted median method, the MR–Egger method, and “leave-one-out” analysis. Analyses were performed again to test whether the associations remained statistically significant after excluding any outlier variants that were detected using the MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) test.

Results

Five single-nucleotide polymorphisms (SNPs) were selected as instrumental variables at the genome-wide significance threshold (p < 5 × 10–8). The causal effect between PTH and OA was genetically predicted using the inverse-variance-weighted method (odds ratio = 0.67, 95% confidence interval: 0.50–0.90; p = 0.008). This result was borne out using the weighted median method (odds ratio = 0.73, 95% confidence interval: 0.60–0.90; p = 0.004). The causality remained robust after discarding the outlier variants as well as SNPs associated with confounding factors.

Conclusion

MR analysis supported a potential causative relationship between decreased serum circulating PTH and a higher risk of hip and knee OA.
ARG2, MAP4K5 and TSTA3 as Diagnostic Markers of Steroid-Induced Osteonecrosis of the Femoral Head and Their Correlation With Immune Infiltration
Authors: Yu Rongguo , Zhang Jiayu , Zhuo Youguang , Hong Xu , Ye Jie , Tang Susu , Liu Nannan , Zhang Yiyuan
Published: July 2021

Background

The diagnosis for steroid-induced osteonecrosis of the femoral head (SONFH) is hard to achieve at the early stage, which results in patients receiving ineffective treatment options and a poor prognosis for most cases. The present study aimed to find potential diagnostic markers of SONFH and analyze the effect exerted by infiltration of immune cells in this pathology.

Materials and Methods

R software was adopted for identifying differentially expressed genes (DEGs) and conducting functional investigation based on the microarray dataset. Then we combined SVM-RFE, WGCNA, LASSO logistic regression, and random forest (RF) algorithms for screening the diagnostic markers of SONFH and further verification by qRT-PCR. The diagnostic values were assessed through receiver operating characteristic (ROC) curves. CIBERSORT was then adopted for assessing the infiltration of immune cells and the relationship of infiltration-related immune cells and diagnostic markers.

Results

We identified 383 DEGs overall. This study found ARG2, MAP4K5, and TSTA3 (AUC = 0.980) to be diagnostic markers of SONFH. The results of qRT-PCR showed a statistically significant difference in all markers. Analysis of infiltration of immune cells indicated that neutrophils, activated dendritic cells and memory B cells were likely to show the relationship with SONFH occurrence and progress. Additionally, all diagnostic markers had different degrees of correlation with T cell follicular helper, neutrophils, memory B cells, and activated dendritic cells.

Conclusion

ARG2, MAP4K5, and TSTA3 are potential diagnostic genes for SONFH, and infiltration of immune cells may critically impact SONFH occurrence and progression.