bluuebunny/crossref_metadata_2025 huggingface dataset:
Mosaic Ring-like Small Supernumerary Marker Chromosome and Gene Mutation in a Male With Intermittent Azoospermia: A Rare Case Report
Authors: Zhang Jianzhong , Li Longyu , Li Qiaoqin , Cai Zhonglin , Wang Binbin , Wang Jing , Li Hongjun
Published: April 2020

This study aimed to report a rare case of intermittent azoospermia and ring-like small supernumerary marker chromosomes (sSMCs). An infertile man was diagnosed with azoospermia presenting a normal male phenotype with complete masculinization. Karyotyping and polymerase chain reaction (PCR) were used to detect 16 sequence-tagged sites on the AZF subregions of the Y chromosome, and 115 candidate genes were screened for mutations. Mutations included single nucleotide variations, insertions, and deletions. Metaphase chromosomes were studied by standard trypsin-Giemsa banding; fluorescent in situ hybridization and PCR were performed to analyze specific Y chromosome regions; gene mutations were detected. Chromosomal analysis detected 117 metaphase cells; a mosaicism with marker 1 and marker 2 sSMCs in 2 metaphase cells (47, X, +mar1x2 karyotype), a mosaicism with marker 2 sSMCs in 14 metaphase cells (46, X, +mar2 karyotype), and a mosaicism with marker 1 sSMCs in 76 metaphase cells (46, X, +mar1 karyotype), coexisting with a 45,X cell line in the remaining 25 metaphase cells. PCR analysis showed the sY160 heterochromosome on the AZFc subregion was absent. Next-generation sequencing identified an asthenozoospermia-specific mutation in GAPDHS (rs2293681), and Sanger sequencing verified this mutation. This gene encodes a protein belonging to the glyceraldehyde-3-phosphate dehydrogenase family of enzymes that play an important role in carbohydrate metabolism. Like its somatic cell counterpart, this sperm-specific enzyme functions in a nicotinamide adenine dinucleotide-dependent manner to remove hydrogen and add phosphate to glyceraldehyde 3-phosphate to form 1,3-diphosphoglycerate. During spermiogenesis, this enzyme may play an important role in regulating the switch between different energy-producing pathways, and it is required for sperm motility and male fertility. A mosaic 46, X, +mar1[76]/45, X[25]/46, X, +mar2[14]/47, X, +mar1x2[2] karyotype could be the main explanation for the azoospermia/severe oligospermia, while the likely pathogenic GAPDHS intron mutation may contribute to the symptom of immotile sperms detected in the semen analysis.
Dose-Dependent Internalization and Externalization Integrity Study of Newly Synthesized 99mTc-Thymoquinone Radiopharmaceutical as Cancer Theranostic Agent
Authors: Tariq Saima , Naqvi Syed Ali Raza , Naz Sumaira , Mubarik Muhammad Samee , Yaseen Muhammad , Riaz Muhammad , Shah Syed Muhammad Ali , Rafi Muhammad , Roohi Samina
Published: April 2020

Thymoquinone (TQ) is a bioactive phytochemical isolated from Nigella sativa and has been investigated for biochemical and biological activities in both in vitro and in vivo models. It is best known for its anticancer activities. Thymoquinone accomplishes anticancer activities through targeting multiple cancer markers including PPAR-γ, PTEN, P53, P73, STAT3, and generation of reactive oxygen species at the cancer cell surface. The radiolabeling of TQ with γ- and β-emitter radionuclide could be used as cancer diagnostic or therapeutic radiopharmaceutical, respectively. In this study, we are reporting the radiolabeling of TQ with technetium-99m (99mTc), stability in saline and blood serum, internalization and externalization of 99mTc-TQ using rhabdomyosarcoma cancer cells line. The quality control study revealed more than 95% labeling yield and stable in blood serum up to 4 hours. In vitro internalization rate was recorded 27.08% ± 0.95% at 1 hour post 2 hours internalization period and comparatively slow externalization. The results of this study are quite encourging and could be investigated for further key preclinical parameters to enter phase I clinical trials.
Small Nucleolar RNA, C/D Box 16 (SNORD16) Acts as a Potential Prognostic Biomarker in Colon Cancer
Authors: He Jun-yan , Liu Xin , Qi Zhen-hua , Wang Qi , Lu Wen-qing , Zhang Qing-tong , He Shu-ya , Wang Zhi-dong
Published: April 2020

Colon cancer (CC) is considered one of the most common and lethal malignancies occurring both in male and female. Its widespread prevalence demonstrates the need for novel diagnostic and prognostic biomarkers for CC. Emerging evidence has shown that small nucleolar RNAs play critical roles in tumor development. In this study, we investigated the expression profile and functions of SNORD16 in CC. Our data showed that SNORD16, rather than its host gene (RPL4), was upregulated in CC cell lines. Compared to matched adjacent normal tissues, CC tissues showed higher SNORD16 expression levels, and no correlation was found between SNORD16 and RPL4. Patients with high SNORD16 expression levels had a worse prognosis, and multivariate analysis showed the high SNORD16 expression was an independent prognostic factor for CC. In vitro gain- and loss-of-function studies revealed that SNORD16 can promote cell growth, proliferation, migration, and invasion of CC cells by inhibiting apoptosis. These results suggested that SNORD16 has an oncogenic role in CC and might be a novel diagnostic and prognostic biomarker for CC.
Non-Dose-Dependent Changes in Liver Enzyme Levels of Children With Epilepsy on Treatment With Sodium Valproate
Authors: Adedapo Aduragbenro Deborah A. , Demaki Winifred Eseoghene , Lagunju IkeOluwa
Published: April 2020

Background:

Sodium valproate (VPA) is considered as the drug of choice for the treatment of generalized epilepsy in children. Sodium Valproate may be hepatotoxic.

Aim:

To assess the level of derangement of liver enzymes in children with epilepsy on treatment with sodium valproate.

Methods:

A cohort study. One hundred fifty-three children, comprising 51 with epilepsy on treatment with VPA (group I), 51 with epilepsy on treatment with other antiepileptic drugs (AEDs) but not VPA (group II), and 51 with nonconvulsive disorders (group III) had liver function tests performed for them. Data were analyzed by SPSS version 23.0.

Results:

There were 85 males and 68 females, aged 6 months to 14 years (median = 7.0 years). There was no significant difference in the mean plasma levels of alanine transaminase (ALT), alkaline phosphatase, and gamma glutamyl transferase across the three groups of children. The mean aspartate transaminase level was significantly higher in children in group III. There was a statistically significant negative correlation between the duration of AED therapy and the mean serum level of AST ( r = −0.266, P = 0.016). The serum ALT level showed a statistically significant positive correlation with the duration of AED therapy ( r = 0.268, P = 0.015).

Conclusion:

Sodium valproate monotherapy does not appear to be associated with significant hepatotoxicity in children in our cohort.
Research on static and dynamics mechanical characteristics of flexible bearing in harmonic reducer
Authors: Caizhi Zhu , Xiaojing Wang , Zhaolun Li , Jun Liu , Jiaqi Zheng
Published: April 2020

Flexible bearing is an important component of harmonic reducer which is widely used in automation equipment, especially in industrial robots. Studying its mechanical characteristics has great significance. In this article, the theoretical model of contact force between rolling elements and outer ring is established based on three bending moment equations, and the characteristics of CSF-40-80 flexible bearing are also studied by finite element method analysis. Analysis of equivalent stress at static state has shown that it already has large equivalent stress before load and that external load has a great influence on it. The dynamic and contact characteristics of it after actual assembly are also presented in this article. The displacements and velocities at different locations at different times of the movement are found to be different, which can provide a reference for the manufacture of flexible bearing.
The Nomological Net of the HEXACO Model of Personality: A Large-Scale Meta-Analytic Investigation
Authors: Zettler Ingo , Thielmann Isabel , Hilbig Benjamin E. , Moshagen Morten
Published: April 2020

Based on lexical studies, the HEXACO (honesty-humility, emotionality, extraversion, agreeableness, conscientiousness, and openness to experience) model of personality has been proposed as a model of basic personality structure that summarizes individual differences in six broad trait dimensions. Although research across various fields relies on the HEXACO model increasingly, a comprehensive investigation of the nomological net of the HEXACO dimensions is missing entirely. Thus, it remains unclear whether each HEXACO dimension accounts for individual variation across theoretically relevant outcome criteria. We close this gap through a large-scale meta-analytic investigation, testing whether each HEXACO dimension is uniquely linked to one broad and theoretically relevant outcome domain. Results from 426 individual meta-analyses, 436 independent samples, and 3,893 effect-size estimates corroborate this unique mapping. Specifically, honesty-humility maps onto the outcome domain of exploitation, emotionality onto insecurity, extraversion onto sociality, agreeableness versus anger onto obstruction, conscientiousness onto duty, and openness to experience onto exploration. Overall, the current investigation provides a comprehensive empirical test of the (breadth of) content captured by the HEXACO dimensions and allows for a broad specification of the nomological net of the HEXACO model overall.
Return to Work Following Tibial Tubercle Osteotomy for Patellofemoral Osteoarthritis and Pain
Authors: Agarwalla Avinesh , Liu Joseph N. , Wu Hao-Hua , Kalbian Irene L. , Garcia Grant H. , Shubin Stein Beth E.
Published: April 2020

Purpose

To evaluate the ability of patients to return to work following anteromedialization (AMZ) tibial tubercle osteotomy (TTO) due to isolated patellofemoral osteoarthritis or pain.

Methods

Consecutive patients undergoing AMZ TTO were reviewed retrospectively at a minimum of 1 year postoperatively. Patients completed a subjective work questionnaire, a visual analog scale for pain, as well as a Kujala questionnaire and satisfaction questionnaire.

Results

Fifty-seven patients (61 knees; average age: 32.7 ± 9.6 years) were contacted at an average follow-up of 4.86 ± 2.84 years postoperatively. The preoperative Kujala score improved from 55.7 ± 17.8 to 84.6 ± 15.8 at final follow-up ( P < 0.001). Thirty-seven patients (64.9%) were employed within 3 years prior to surgery and 34 patients (91.9%) were able to return to work by 2.8 ± 2.6 months postoperatively. However, only 27 patients (73.0%) of patients were able to return to the same level of occupational intensity. Patients who held sedentary, light-, medium-, or high-intensity occupations were able to return to work at a rate of 100.0%, 93.8%, 77.8%, and 100.0% by 2.2 months, 3.0 months, 3.1 months, and 4.0 months, postoperatively. No patients underwent revision TTO or conversion to arthroplasty by the time of final follow-up.

Conclusion

In patients with focal patellofemoral osteoarthritis or pain, AMZ TTO provides a high rate of return to work (91.9%) by 2.8 ± 2.6 months postoperatively. Patients with higher intensity occupations may take longer to return to work than those with less physically demanding occupations.

Level of Evidence

III.
Endurance exercise training in pulmonary hypertension increases skeletal muscle electron transport chain supercomplex assembly
Authors: McCullough Danielle J. , Kue Nouaying , Mancini Thomas , Vang Alexander , Clements Richard T. , Choudhary Gaurav
Published: April 2020

Pulmonary hypertension is associated with pronounced exercise intolerance (decreased V ċ O2 max) that can significantly impact quality of life. The cause of exercise intolerance in pulmonary hypertension remains unclear. Mitochondrial supercomplexes are large respiratory assemblies of individual electron transport chain complexes which can promote more efficient respiration. In this study, we examined pulmonary hypertension and exercise‐induced changes in skeletal muscle electron transport chain protein expression and supercomplex assembly. Pulmonary arterial hypertension was induced in rats with the Sugen/Hypoxia model (10% FiO2, three weeks). Pulmonary arterial hypertension and control rats were assigned to an exercise training protocol group or kept sedentary for one month. Cardiac function and V ċ O2 max were assessed at the beginning and end of exercise training. Red (Type 1—oxidative muscle) and white (Type 2—glycolytic muscle) gastrocnemius were assessed for changes in electron transport chain complex protein expression and supercomplex assembly via SDS‐ and Blue Native‐PAGE. Results showed that pulmonary arterial hypertension caused a significant decrease in V ċ O2 max via treadmill testing that was improved with exercise (P < 0.01). Decreases in cardiac output and pulmonary acceleration time due to pulmonary arterial hypertension were not improved with exercise. Pulmonary arterial hypertension reduced expression in individual electron transport chain complex protein expression (NDUFB8 (CI), SDHB (CII), Cox IV (CIV), but not UQCRC2 (CIII), or ATP5a (CV)) in red gastrocnemius muscle. Both red gastrocnemius and white gastrocnemius electron transport chain expression was unaffected by exercise. However, non‐denaturing Blue Native‐PAGE analysis of mitochondrial supercomplexes demonstrated increases with exercise training in pulmonary arterial hypertension in the red gastrocnemius but not white gastrocnemius muscle. Pulmonary arterial hypertension‐induced exercise intolerance is improved with exercise and is associated with muscle type specific alteration in mitochondrial supercomplex assembly and expression of mitochondrial electron transport chain proteins.
Clinical outcomes of nonagenarians with acute myocardial infarction who undergo percutaneous coronary intervention
Authors: Nishihira Kensaku , Watanabe Nozomi , Kuriyama Nehiro , Shibata Yoshisato
Published: April 2020

Background

With increases in life expectancy, percutaneous coronary intervention is being performed more often, even in elderly patients with acute myocardial infarction. However, the optimal management of nonagenarians with acute myocardial infarction is uncertain. This study sought to investigate clinical outcomes of nonagenarians who undergo percutaneous coronary intervention.

Methods

Of 2640 consecutive patients with acute myocardial infarction hospitalised within 24 hours after symptom onset in 2009–2018, we prospectively analysed 96 nonagenarians (median age 92 years; interquartile range 91–94) who underwent percutaneous coronary intervention.

Results

The median follow-up period was 375 days. Inhospital major bleeding (Bleeding Academic Research Consortium type 3 or 5) and inhospital death occurred in 15.6% and 17.7% of patients, respectively. The proportion of patients with frailty increased during hospitalisation, from 43.8% (mild frailty 37.5%; moderate to severe frailty 6.3%) at admission to 60.7% (mild frailty 46.8%; moderate to severe frailty 13.9%) at discharge (P < 0.01). The cumulative incidence of all-cause mortality was 22.2% at 180 days and 27.5% at 365 days. After adjusting for confounders, cardiogenic shock (hazard ratio (HR) 2.85; 95% confidence interval (CI) 1.07–7.64) and final thrombolysis in myocardial infarction flow grade less than 3 (HR 2.45; 95% CI 1.03–5.58) were associated with higher mid-term mortality and cardiac rehabilitation (HR 0.25; 95% CI, 0.13–0.50) was associated with lower mid-term mortality.

Conclusions

The mid-term mortality of selected nonagenarians with acute myocardial infarction who undergo percutaneous coronary intervention is reasonable, but older patients have high rates of inhospital major bleeding and progression of frailty. This study provides physicians, patients and families with important information for therapeutic decision-making.
The nociceptive flexion reflex: a scoping review and proposed standardized methodology for acquisition in those affected by chronic pain
Authors: Linde Lukas D , Duarte Felipe CK , Esmaeili Hamid , Hamad Abdul , Masani Kei , Kumbhare Dinesh A
Published: April 2020

The nociceptive flexion reflex (NFR) is used in neurophysiological research as an objective measure of nociception. NFR thresholds are reduced in numerous chronic pain pathologies, which are indicative of common central hyperexcitability within conditions. However, variation exists in both the NFR assessment and determinants of NFR threshold among research groups. Our purpose was to provide a review of the recent literature to (a) confirm the NFR threshold’s efficacy in identifying those with chronic pain compared to controls and (b) provide a narrative synthesis on the current methodology used to assess the NFR in clinical populations. We conducted a review of multiple databases (MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Google Scholar and Cochrane Library), including articles that reported controlled clinical studies of humans, in English, comparing NFR thresholds within chronic pain conditions to matched control subjects, published since the last NFR review in 2010. Our search resulted in nine studies included in our narrative synthesis and eight studies included in a meta-analysis. There was a significant pooled standardized mean difference in NFR threshold between chronic pain conditions and controls (−0.94, 95% confidence interval (CI) −1.33 to −0.55, p < 0.0001), with substantial heterogeneity of pooled estimates ( I2 = 87%, τ2 = 0.41, Q = 76.13, the degrees of freedom (df) = 11, p < 0.0001). Significant variations in participant positioning, stimulation parameters and determinants of the NFR threshold were evident among included studies. We provided a narrative synthesis on the methodologies of included studies, as a recommendation for future studies in the assessment of the NFR in chronic pain.
Unconventional Surgical Intervention for Left Ventricular Pseudoaneurysm Associated With Staphylococcus aureus in a Pediatric Patient
Authors: Chavarri Fernando , Pinto Miguel , Torres Yeli , Adrianzén Valeria , de Guzmán Ivan Niño , Esqueche Eduardo
Published: April 2020

Ventricular pseudoaneurysms are very unusual in children. A six-year-old child developed left ventricular pseudoaneurysm associated with methicillin-sensitive Staphylococcus aureus. The patient responded favorably to antibiotic therapy and ventriculoplasty through an unconventional surgery due to the constrictive pericarditis.
Determinants of Capital Structure with Reference to Select Indian Companies: A Panel Data Regression Analysis
Authors: Kaur Rajbinder , Chattopadhyay Arup Kumar , Rakshit Debdas
Published: April 2020

This article mainly focuses on the analysis of determinants of capital structure of 50 Bombay Stock Exchange (BSE)-listed sample companies, choosing 5 sample companies from each of 10 industries, namely cement, computer hardware, large heavy engineering, fertiliser, fast-moving consumer goods (FMCG), large electric equipment, mining/mineral, textile, large tyres and pharmaceutical over 15 years’ time period ranging from 1999–2000 to 2013–2014, applying panel data regression technique. Our study has first made industry-wise empirical analysis of capital structure with respect to eight firm-specific determinants, viz. profitability, size, growth, tangibility, non-debt tax shield, liquidity, uniqueness and income variation. Subsequently, we have made a comparative analysis of selected determinants of capital structure across selected industries to determine their capital structure behaviour in view of three prominent capital structure theories, namely Pecking Order Theory, Trade-Off Theory and Agency Cost Theory. The regression analysis concludes that the Pecking Order Theory and the Trade-Off Theory mostly describe the observed relationship of independent factors with capital structure of the selected Indian industries. Profitability emerges as a significant determinant in devising the capital structure of the selected industries and reveals that greater proportion of profits is likely to raise the internal fund for financing future investment projects and, therefore, less dependent on external borrowings.
Which Aspects of Education Matter for Early Adult Mortality? Evidence from the High School and Beyond Cohort
Authors: Warren John Robert , Muller Chandra , Hummer Robert A. , Grodsky Eric , Humphries Melissa
Published: April 2020

What dimensions of education matter for people’s chances of surviving young adulthood? Do cognitive skills, noncognitive skills, course-taking patterns, and school social contexts matter for young adult mortality, even net of educational attainment? The authors analyze data from High School and Beyond, a nationally representative cohort of about 25,000 high school students first interviewed in 1980. Many dimensions of education are associated with young adult mortality, and high school students’ math course taking retains its association with mortality net of educational attainment. This work draws on theories and measures from sociological and educational research and enriches public health, economic, and demographic research on educational gradients in mortality that has relied almost exclusively on ideas of human capital accumulation and measures of degree attainment. The findings also call on social and education researchers to engage together in research on the lifelong consequences of educational processes, school structures, and inequalities in opportunities to learn.
Beyond the green panopticon: New directions in research exploring environmental governmentality
Authors: Fletcher Robert , Cortes-Vazquez Jose A
Published: April 2020

This introduction to the special collection explores how a revised or expanded understanding of ‘environmentality’ can further our analysis of the evermore complex terrain of environmental politics today. We offer an outline of the literature from which the discussion emerges and how the subsequent articles both engage with and depart from it. We describe the origin of the ‘green governmentality’ discussion following the rise of global sustainable development discourse. We then explain how this initial exploration was subsequently complicated by introduction of two further lines of investigation: (1) attention to the micropolitics of community-based natural resource management; and (2) extrapolation from this to describe the different forms of green governmentality within which such local practices are situated as well as the multiple scales at which environmental governance is exercised. Following this, we outline a range of critiques to which this burgeoning research has also been subject and the fruitful lines of future research to which they point. We finish by describing how the various contributions to this collection engage with different aspects of this multifaceted discussion as the basis for further engagement by other researchers in the years ahead.
Evaluation of Antimalarial Activity of Methanolic Root Extract of Myrica salicifolia A Rich (Myricaceae) Against Plasmodium berghei–Infected Mice
Authors: Kifle Zemene Demelash , Adinew Getnet Mequanint , Mengistie Mestayet Geta , Gurmu Abyot Endale , Enyew Engidaw Fentahun , Goshu Bahiru Tenaw , Amare Gedefaw Getenet
Published: April 2020

Background.

The management and control of malaria has become gradually challenging due to the spread of drug-resistant parasites, lack of effective vaccine, and the resistance of vector to insecticides. Consequently, novel agents are urgently needed from different sources including from medicinal plants. In Ethiopia and Uganda, Myrica salicifolia root is traditionally claimed for the treatment of malaria. The aim of this study was to evaluate the in vivo antimalarial activity of root crude extract of M salicifolia.

Methods.

The parasite, Plasmodium berghei was used in this study since it is an appropriate parasite that is most commonly used because of its higher accessibility. A 4-day suppressive test was employed to evaluate the antimalarial effect of crude extract against early infection. The curative and prophylactic effect of the crude extract was further tested by Rane’s test and residual infection procedure. Parasitemia, survival time, packed cell volume, body weight, and rectal temperature of mice were used as evaluation parameters. Windows SPSS version 24 was used to analyze the data and analysis of variance followed by Tukey’s honestly significant difference to compare results between groups.

Results.

The root crude extract of M salicifolia significantly ( P < .05-.0001) suppressed parasitemia. The crude extract exhibited a chemosuppression of 40.90.

Conclusion.

The development of new antimalarial agents and the finding supports the traditional claims and previous in vitro studies.
E-commerce and Digital Connectivity: Unleashing the Potential for Greater India–ASEAN Integration
Authors: Majumdar Shouvik Kishore , Sarma Angana Parashar , Majumdar Srishti
Published: April 2020

Digital connectivity and e-commerce are emerging as important drivers to connect small and medium enterprises (SMEs) in developing countries to their domestic and global markets. India and the Association of Southeast Asian Nations (ASEAN) have emerged as fastest growing e-commerce and digital markets. Studies show that digital connectivity and e-commerce will help SMEs and marginalised groups in the two economies to diversify their client base at lower costs, while consumers will have access to a wide range of products. To support digitalisation and e-commerce, several initiatives have been taken by the governments in India and ASEAN. Many of them are related to enhancing cross-country trade and collaboration. The ASEAN–India Partnership for Peace, Progress and Shared Prosperity 2016–2020 is one such initiative. However, SMEs so far have not gained much from such initiatives. This article provides an overview of the current status of digtalisation and e-commerce in India and ASEAN. It examines their comparative positions in terms of technology adaptation and policy regimes and then presents the participation of these countries in bilateral, plurilateral and multilateral agreements and forums. Apart from infrastructure issues, restrictive regulations like data localisation requirements and lack of standards along with the defensive position of countries in international forums is adversely impacting the ability of their SMEs to scale up. The article provides recommendations on use of technology to help SMEs to scale up through a joint innovative knowledge sharing and e-commerce platform.
The obligate need for accuracy in reporting preclinical studies relevant to clinical trials: autologous germline mitochondrial supplementation for assisted human reproduction as a case study
Authors: Tilly Jonathan L. , Woods Dori C.
Published: April 2020

A now large body of work has solidified the central role that mitochondria play in oocyte development, fertilization, and embryogenesis. From these studies, a new technology termed autologous germline mitochondrial energy transfer was developed for improving pregnancy success rates in assisted reproduction. Unlike prior clinical studies that relied on the use of donor, or nonautologous, mitochondria for microinjection into eggs of women with a history of repeated in vitro fertilization failure to enhance pregnancy success, autologous germline mitochondrial energy transfer uses autologous mitochondria collected from oogonial stem cells of the same woman undergoing the fertility treatment. Initial trials of autologous germline mitochondrial energy transfer during - in vitro fertilization at three different sites with a total of 104 patients indicated a benefit of the procedure for improving pregnancy success rates, with the birth of children conceived through the inclusion of autologous germline mitochondrial energy transfer during in vitro fertilization. However, a fourth clinical study, consisting of 57 patients, failed to show a benefit of autologous germline mitochondrial energy transfer– in vitro fertilization versus in vitro fertilization alone for improving cumulative live birth rates. Complicating this area of work further, a recent mouse study, which claimed to test the long-term safety of autologous mitochondrial supplementation during in vitro fertilization, raised concerns over the use of the procedure for reproduction. However, autologous mitochondria were not actually used for preclinical testing in this mouse study. The unwarranted fears that this new study’s erroneous conclusions could cause in women who have become pregnant through the use of autologous germline mitochondrial energy transfer during- in vitro fertilization highlight the critical need for accurate reporting of preclinical work that has immediate bearing on human clinical studies.
UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells
Authors: Swenson Samantha A. , Gilbreath Tyler J. , Vahle Heather , Hynes-Smith R. Willow , Graham Jared H. , Law Henry C.-H. , Amador Catalina , Woods Nicholas T. , Green Michael R. , Buckley Shannon M.
Published: April 2020

Coordination of a number of molecular mechanisms including transcription, alternative splicing, and class switch recombination are required to facilitate development, activation, and survival of B cells. Disruption of these pathways can result in malignant transformation. Recently, next-generation sequencing has identified a number of novel mutations in mantle cell lymphoma (MCL) patients including mutations in the ubiquitin E3 ligase UBR5. Approximately 18% of MCL patients were found to have mutations in UBR5, with the majority of mutations within the HECT domain of the protein that can accept and transfer ubiquitin molecules to the substrate. Determining if UBR5 controls the maturation of B cells is important to fully understand malignant transformation to MCL. To elucidate the role of UBR5 in B-cell maturation and activation, we generated a conditional mutant disrupting UBR5′s C-terminal HECT domain. Loss of the UBR5 HECT domain leads to a block in maturation of B cells in the spleen and upregulation of proteins associated with messenger RNA splicing via the spliceosome. Our studies reveal a novel role of UBR5 in B-cell maturation by stabilization of spliceosome components during B-cell development and suggests UBR5 mutations play a role in MCL transformation.
LUBAC accelerates B-cell lymphomagenesis by conferring resistance to genotoxic stress on B cells
Authors: Jo Tomoyasu , Nishikori Momoko , Kogure Yasunori , Arima Hiroshi , Sasaki Katsuhiro , Sasaki Yoshiteru , Nakagawa Tomoko , Iwai Fumie , Momose Shuji , Shiraishi Aki , Kiyonari Hiroshi , Kagaya Noritaka , Onuki Tetsuo , Shin-ya Kazuo , Yoshida Minoru , Kataoka Keisuke , Ogawa Seishi , Iwai Kazuhiro , Takaori-Kondo Akifumi
Published: April 2020

The linear ubiquitin chain assembly complex (LUBAC) is a key regulator of NF-κB signaling. Activating single-nucleotide polymorphisms of HOIP, the catalytic subunit of LUBAC, are enriched in patients with activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL), and expression of HOIP, which parallels LUBAC activity, is elevated in ABC-DLBCL samples. Thus, to clarify the precise roles of LUBAC in lymphomagenesis, we generated a mouse model with augmented expression of HOIP in B cells. Interestingly, augmented HOIP expression facilitated DLBCL-like B-cell lymphomagenesis driven by MYD88-activating mutation. The developed lymphoma cells partly shared somatic gene mutations with human DLBCLs, with increased frequency of a typical AID mutation pattern. In vitro analysis revealed that HOIP overexpression protected B cells from DNA damage-induced cell death through NF-κB activation, and analysis of the human DLBCL database showed that expression of HOIP positively correlated with gene signatures representing regulation of apoptosis signaling, as well as NF-κB signaling. These results indicate that HOIP facilitates lymphomagenesis by preventing cell death and augmenting NF-κB signaling, leading to accumulation of AID-mediated mutations. Furthermore, a natural compound that specifically inhibits LUBAC was shown to suppress the tumor growth in a mouse transplantation model. Collectively, our data indicate that LUBAC is crucially involved in B-cell lymphomagenesis through protection against DNA damage–induced cell death and is a suitable therapeutic target for B-cell lymphomas.
Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma
Authors: Perez Cristina , Botta Cirino , Zabaleta Aintzane , Puig Noemi , Cedena Maria-Teresa , Goicoechea Ibai , Alameda Daniel , San José-Eneriz Edurne , Merino Juana , Rodríguez-Otero Paula , Maia Catarina , Alignani Diego , Maiso Patricia , Manrique Irene , Lara-Astiaso David , Vilas-Zornoza Amaia , Sarvide Sarai , Riillo Caterina , Rossi Marco , Rosiñol Laura , Oriol Albert , Blanchard María-Jesús , Rios Rafael , Sureda Anna , Martin Jesus , Martinez Rafael , Bargay Joan , de la Rubia Javier , Hernandez Miguel-Teodoro , Martinez-Lopez Joaquin , Orfao Alberto , Agirre Xabier , Prosper Felipe , Mateos Maria-Victoria , Lahuerta Juan-José , Blade Joan , San-Miguel Jesús F. , Paiva Bruno
Published: April 2020

Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14−CD15+CD33+HLADR− cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC–related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial
Authors: Voorhees Peter M. , Kaufman Jonathan L. , Laubach Jacob , Sborov Douglas W. , Reeves Brandi , Rodriguez Cesar , Chari Ajai , Silbermann Rebecca , Costa Luciano J. , Anderson Larry D. , Nathwani Nitya , Shah Nina , Efebera Yvonne A. , Holstein Sarah A. , Costello Caitlin , Jakubowiak Andrzej , Wildes Tanya M. , Orlowski Robert Z. , Shain Kenneth H. , Cowan Andrew J. , Murphy Sean , Lutska Yana , Pei Huiling , Ukropec Jon , Vermeulen Jessica , de Boer Carla , Hoehn Daniela , Lin Thomas S. , Richardson Paul G.
Published: April 2020

Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10−5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.
Interplay of erythropoietin, fibroblast growth factor 23, and erythroferrone in patients with hereditary hemolytic anemia
Authors: van Vuren Annelies. J. , Eisenga Michele F. , van Straaten Stephanie , Glenthøj Andreas , Gaillard Carlo A. J. M. , Bakker Stephan J. L. , de Borst Martin H. , van Wijk Richard , van Beers Eduard J.
Published: April 2020

Recently, erythropoietin (EPO) was identified as regulator of fibroblast growth factor 23 (FGF23). Proteolytic cleavage of biologically active intact FGF23 (iFGF23) results in the formation of C-terminal fragments (cFGF23). An increase in cFGF23 relative to iFGF23 suppresses FGF receptor signaling by competitive inhibition. EPO lowers the i:cFGF23 ratio, thereby overcoming iFGF23-mediated suppression of erythropoiesis. We investigated EPO-FGF23 signaling and levels of erythroferrone (ERFE) in 90 patients with hereditary hemolytic anemia (www.trialregister.nl [NL5189]). We show, for the first time, the importance of EPO-FGF23 signaling in hereditary hemolytic anemia: there was a clear correlation between total FGF23 and EPO levels (r = +0.64; 95% confidence interval [CI], 0.09-0.89), which persisted after adjustment for iron load, inflammation, and kidney function. There was no correlation between iFGF23 and EPO. Data are consistent with a low i:cFGF23 ratio. Therefore, as expected, we report a correlation between EPO and ERFE in a diverse set of hereditary hemolytic anemias (r = +0.47; 95% CI, 0.14-0.69). There was no association between ERFE and total FGF23 or iFGF23, which suggests that ERFE does not contribute to the connection between FGF23 and EPO. These findings open a new area of research and might provide potentially new druggable targets with the opportunity to ameliorate ineffective erythropoiesis and the development of disease complications in hereditary hemolytic anemias.
Associations of bedtime, sleep duration, and sleep quality with semen quality in males seeking fertility treatment: a preliminary study
Authors: Hvidt Julius Edward Miller , Knudsen Ulla Breth , Zachariae Robert , Ingerslev Hans Jakob , Philipsen Marie Tholstrup , Frederiksen Yoon
Published: April 2020

Background

Poor sleep has been linked to a number of adverse health outcomes. Recent studies suggest that late bedtimes, short or long sleep durations, and poor sleep quality may impair semen quality. No study has previously explored all three factors in relation to semen quality.

Results

One hundred and four men and their partners treated at three fertility clinics in Denmark between 2010 and 2012 completed an online-version of the Pittsburgh Sleep Quality Index (PSQI). The results of the semen analyses conducted at the fertility clinics were self-reported and categorised as normal or reduced.

Early bedtime (< 10:30 PM) was more often associated with normal semen quality compared with both regular (10:30 PM-11:29 PM) and late (≥11:30 PM) bedtime (OR: 2.75, 95%CI: 1.1–7.1,p = 0.04 and OR: 3.97, 95%CI: 1.2–13.5,p = 0.03). Conventional sleep duration (7.5–7.99 h) was more often associated with normal semen quality than both short (7.0–7.49 h) and very short (< 7.0 h) sleep duration (OR: 1.36, 95% CI: 1.2–12.9,p = 0.03 and OR: 6.18, 95%CI: 1.6–24.2,p = 0.01). Although poor sleep quality was associated with reduced semen quality in the descriptive statistics (p = 0.04), no differences were found between optimal (PSQI ≤6) and either borderline (PSQI 7–8) or poor (PSQI ≥9) sleep quality (OR: 1.19, 95%CI: 0.4–3.4,p = 0.75 and OR: 2.43, 95%CI: 0.8–7.1,p = 0.11) in multivariate regression models.

Conclusion

Early bedtimes (< 10:30 PM) and conventional sleep duration (7.5–7.99 h) were associated with self-reported normal semen quality. The role of subjective sleep quality remains uncertain.
Dual graph convolutional neural network for predicting chemical networks
Authors: Harada Shonosuke , Akita Hirotaka , Tsubaki Masashi , Baba Yukino , Takigawa Ichigaku , Yamanishi Yoshihiro , Kashima Hisashi
Published: April 2020

Background

Predicting of chemical compounds is one of the fundamental tasks in bioinformatics and chemoinformatics, because it contributes to various applications in metabolic engineering and drug discovery. The recent rapid growth of the amount of available data has enabled applications of computational approaches such as statistical modeling and machine learning method. Both a set of chemical interactions and chemical compound structures are represented as graphs, and various graph-based approaches including graph convolutional neural networks have been successfully applied to chemical network prediction. However, there was no efficient method that can consider the two different types of graphs in an end-to-end manner.

Results

We give a new formulation of the chemical network prediction problem as a link prediction problem in a graph of graphs (GoG) which can represent the hierarchical structure consisting of compound graphs and an inter-compound graph. We propose a new graph convolutional neural network architecture called dual graph convolutional network that learns compound representations from both the compound graphs and the inter-compound network in an end-to-end manner.

Conclusions

Experiments using four chemical networks with different sparsity levels and degree distributions shows that our dual graph convolution approach achieves high prediction performance in relatively dense networks, while the performance becomes inferior on extremely-sparse networks.
Maladaptive plasticity facilitates evolution of thermal tolerance during an experimental range shift
Authors: Leonard Aoife M. , Lancaster Lesley T.
Published: April 2020

Background

Many organisms are responding to climate change with dramatic range shifts, involving plastic and genetic changes to cope with novel climate regimes found at higher latitudes. Using experimental lineages of the seed beetle Callosobruchus maculatus, we simulated the initial phase of colonisation to progressively cooler and/or more variable conditions, to investigate how adaptation and phenotypic plasticity contribute to shifts in thermal tolerance during colonisation of novel climates.

Results

We show that heat and cold tolerance rapidly evolve during the initial stages of adaptation to progressively cooler and more variable climates. The evolved shift in cold tolerance is, however, associated with maladaptive plasticity under the novel conditions, resulting in a pattern of countergradient variation between the ancestral and novel, fluctuating thermal environment. In contrast, lineages exposed to progressively cooler, but constant, temperatures over several generations expressed only beneficial plasticity in cold tolerances and no evolved response.

Conclusions

We propose that thermal adaptation during a range expansion to novel, more variable climates found at high latitudes and elevations may typically involve genetic compensation arising from maladaptive plasticity in the initial stages of adaptation, and that this form of (countergradient) thermal adaptation may represent an opportunity for more rapid and labile evolutionary change in thermal tolerances than via classic genetic assimilation models for thermal tolerance evolution (i.e., selection on existing reaction norms). Moreover, countergradient variation in thermal tolerances may typically mask cryptic genetic variability for these traits, resulting in apparent evolutionary stasis in thermal traits.
GWAS and co-expression network combination uncovers multigenes with close linkage effects on the oleic acid content accumulation in Brassica napus
Authors: Yao Min , Guan Mei , Zhang Zhenqian , Zhang Qiuping , Cui Yixin , Chen Hao , Liu Wei , Jan Habib U. , Voss-Fels Kai P. , Werner Christian R. , He Xin , Liu Zhongsong , Guan Chunyun , Snowdon Rod J. , Hua Wei , Qian Lunwen
Published: April 2020

Background

Strong artificial and natural selection causes the formation of highly conserved haplotypes that harbor agronomically important genes. GWAS combination with haplotype analysis has evolved as an effective method to dissect the genetic architecture of complex traits in crop species.

Results

We used the 60 KBrassicaInfinium SNP array to perform a genome-wide analysis of haplotype blocks associated with oleic acid (C18:1) in rapeseed. Six haplotype regions were identified as significantly associated with oleic acid (C18:1) that mapped to chromosomes A02, A07, A08, C01, C02, and C03. Additionally, whole-genome sequencing of 50 rapeseed accessions revealed three genes (BnmtACP2-A02, BnABCI13-A02 and BnECI1-A02) in theA02 chromosome haplotype region and twogenes(BnFAD8-C02 and BnSDP1-C02) in theC02 chromosome haplotype region that were closely linked to oleic acid content phenotypic variation. Moreover, the co-expression network analysis uncovered candidate genes from these two different haplotype regions with potential regulatory interrelationships with oleic acid content accumulation.

Conclusions

Our results suggest that several candidate genes are closely linked, which provides us with an opportunity to develop functional haplotype markers for the improvement of the oleic acid content in rapeseed.
A chromosome-scale assembly of the smallest Dothideomycete genome reveals a unique genome compaction mechanism in filamentous fungi
Authors: Wang Bo , Liang Xiaofei , Gleason Mark L. , Hsiang Tom , Zhang Rong , Sun Guangyu
Published: April 2020

Background

The wide variation in the size of fungal genomes is well known, but the reasons for this size variation are less certain. Here, we present a chromosome-scale assembly of ectophytic Peltaster fructicola, a surface-dwelling extremophile, based on long-read DNA sequencing technology, to assess possible mechanisms associated with genome compaction.

Results

At 18.99 million bases (Mb), P. fructicola possesses one of the smallest known genomes sequence among filamentous fungi. The genome is highly compact relative to other fungi, with substantial reductions in repeat content, ribosomal DNA copies, tRNA gene quantity, and intron sizes, as well as intergenic lengths and the size of gene families. Transposons take up just 0.05% of the entire genome, and no full-length transposon was found. We concluded that reduced genome sizes in filamentous fungi such as P. fructicola, Taphrina deformans and Pneumocystis jirovecii occurred through reduction in ribosomal DNA copy number and reduced intron sizes. These dual mechanisms contrast with genome reduction in the yeast fungus Saccharomyces cerevisiae, whose small and compact genome is associated solely with intron loss.

Conclusions

Our results reveal a unique genomic compaction architecture of filamentous fungi inhabiting plant surfaces, and broaden the understanding of the mechanisms associated with compaction of fungal genomes.