Treatment of cancer in children is increasingly successful but leaves many prepubertal boys suffering from infertility or subfertility later in life. A current strategy to preserve fertility in these ...boys is to cryopreserve a testicular biopsy prior to treatment with the expectation of future technologies allowing for the reintroduction of stem cells and restoration of spermatogenesis. Spermatogonial stem cells (SSCs) form the basis of male reproduction, differentiating into all germ cell types, including mature spermatozoa and can regenerate spermatogenesis following transplantation into an infertile testis. Here, we demonstrate that rat SSCs frozen for more than 20 years can be transplanted into recipient mice and produce all differentiating germ cell types. However, compared with freshly isolated cells or those frozen for a short period of time, long-frozen cells do not colonize efficiently and showed reduced production of spermatids. Single-cell RNA sequencing revealed similar profiles of gene expression changes between short- and long-frozen cells as compared with fresh immediately after thawing. Conversely, following transplantation, long-frozen samples showed enhanced stem cell signaling in the undifferentiated spermatogonia compartment, consistent with self-renewal and a lack of differentiation. In addition, long-frozen samples showed fewer round spermatids with detectable protamine expression, suggesting a partial block of spermatogenesis after meiosis resulting in a lack of elongating spermatids. These findings strongly suggest that prolonged cryopreservation can impact the success of transplantation to produce spermatogenesis, which may not be revealed by analysis of the cells immediately after thawing. Our analysis uncovered persistent effects of long-term freezing not found in other cryopreservation studies that lacked functional regeneration of the tissue and this phenomenon must be accounted for any future therapeutic application.
A 14-year high resolution wave and wind hindcast was carried out for Ireland. The wind was dynamically downscaled from the ERA-Interim reanalysis to a 2.5 km horizontal resolution and 65 vertical ...levels, using the HARMONIE meso-scale model. The wave hindcast was derived using WAVEWATCH III on an unstructured grid with resolution ranging between 10 km offshore and 225 m in the nearshore, forced by the downscaled HARMONIE 10 m winds and ERA-Interim wave spectra. The wind and wave hindcasts were thoroughly validated against available buoy data, including wave buoys in nearshore locations and coastal synoptic stations. In addition, the significant wave heights and winds from the hindcasts were compared against all available altimeter data from the CERSAT database at Ifremer. The quality of both the wind and wave hindcasts was found to be good.
The wave and wind energy resource in coastal areas was assessed, and discussed in terms of water depth, distance to shore, and seasonal and inter-annual variability. In addition, the current study investigates the nearshore wind and wave climate in conjunction with each other, and highlights two issues with relevance to the ocean renewable energy industry: (i) the complementarity between the wind and wave energy resource, and (ii) the accessibility for marine operations. Our study highlights sites around the Irish coast that might have been overlooked in terms of the potential for wind, wave or combined wind/wave energy installations.
•We produce the highest resolution wind and wave atlas for Ireland, covering the same time period.•We examine the energy resource available while taking into account the accessibility levels needed for marine operations.•We estimate the complementarity between the wind and wave energy resource in the nearshore around the entire coastline.•Our study highlights potential new areas suitable for wave, wind and joint wind-wave renewable energy installations.
Retinoic acid (RA) induces spermatogonial differentiation, but the mechanism by which it operates remains largely unknown. We developed a germ cell culture assay system to study genes involved in ...spermatogonial differentiation triggered by RA. Stimulated by RA 8 (Stra8), a RA-inducible gene, is indispensable for meiosis initiation, and its deletion results in a complete block of spermatogenesis at the pre-leptotene/zygotene stage. To interrogate the role of Stra8 in RA mediated differentiation of spermatogonia, we derived germ cell cultures from the neonatal testis of both wild type and Stra8 knock-out mice. We provide the first evidence that Stra8 plays a crucial role in modulating the responsiveness of undifferentiated spermatogonia to RA and facilitates transition to a differentiated state. Stra8-mediated differentiation is achieved through the downregulation of a large portfolio of genes and pathways, most notably including genes involved in the spermatogonial stem cell self-renewal process. We also report here for the first time the role of transcription elongation regulator-1 like (Tcerg1l) as a downstream effector of RA-induced spermatogonial differentiation. Summary sentence The genes stimulated by retinoic acid 8 (Stra8) and transcription elongation regulator-1 like (Tcerg1l) are necessary in early-stage male germ cell differentiation induced by retinoic acid (RA). Stra8 is critical in modulating the responsiveness of undifferentiated spermatogonia to RA.
Spermatogonial stem cell (SSC) culture and transplantation pave the way for clinical restoration of fertility in male prepubertal cancer survivors. In this chapter we detail the steps for isolating ...and freezing testicular tissue along with protocols for the subsequent recovery from cryopreservation and transplantation of cells into a recipient testis. Transplantation of cultured or thawed SSCs provides not only a functional assay for identification of stem cells, a critical tool for the study of the germline stem cell niche in model organisms, but also a framework for reconstitution of spermatogenesis in humans. As proof of concept, the outlined methods have been performed successfully in the murine model and have the potential to be translated to clinical environments.
Objectives
Fibroblast growth factor 9 (FGF9) is expressed by somatic cells in the seminiferous tubules, yet little information exists about its role in regulating spermatogonial stem cells (SSCs).
...Materials and Methods
Fgf9 overexpression lentivirus was injected into mouse testes, and PLZF immunostaining was performed to investigate the effect of FGF9 on spermatogonia in vivo. Effect of FGF9 on SSCs was detected by transplanting cultured germ cells into tubules of testes. RNA‐seq of bulk RNA and single cell was performed to explore FGF9 working mechanisms. SB203580 was used to disrupt p38 MAPK pathway. p38 MAPK protein expression was detected by Western blot and qPCR was performed to determine different gene expression. Small interfering RNA (siRNA) was used to knock down Etv5 gene expression in germ cells.
Results
Overexpression of Fgf9 in vivo resulted in arrested spermatogenesis and accumulation of undifferentiated spermatogonia. Exposure of germ cell cultures to FGF9 resulted in larger numbers of SSCs over time. Inhibition of p38 MAPK phosphorylation negated the SSC growth advantage provided by FGF9. Etv5 and Bcl6b gene expressions were enhanced by FGF9 treatment. Gene knockdown of Etv5 disrupted the growth effect of FGF9 in cultured SSCs along with downstream expression of Bcl6b.
Conclusions
Taken together, these data indicate that FGF9 is an important regulator of SSC proliferation, operating through p38 MAPK phosphorylation and upregulating Etv5 and Bcl6b in turn.
Fibroblast growth factor 9 (FGF9) is expressed by somatic cells in the seminiferous tubules, yet little information exists about its role in regulating spermatogonial stem cells (SSCs). Our data indicate that FGF9 is an important regulator of SSC proliferation, operating through p38 MAPK phosphorylation and upregulating Etv5 and Bcl6b in turn.
Mobile gambling differs from land-based and traditional forms of gambling in that the opportunity to place bets and engage with casinos is constantly present and easily accessible. Instead of going ...to a physical bookmaker or casino, mobile gambling is done quickly and swiftly, anytime, anywhere, with a few taps on a mobile device. Previous studies reveal mobile gambling has managed to reach new audiences especially amongst younger people. Gambling harms can have severe adverse effects on individuals, families and society. However, for a subgroup of highly involved individuals, gambling can be considered a harmonious passion that permits frequent gambling without elevating individual's risks of experience problem gambling manifestations. Combining the Uses and Gratifications (U&G) and Dualistic Model of Passion (DMP) frameworks, the present study aims to determine if and how the different gratifications sought from mobile gambling are susceptible to explaining non-problematic versus problematic patterns in highly involved gamblers. Data were collected over two waves from a global sample of mobile gamblers (N = 327). Results emphasize that the motivational underpinnings of mobile gambling (as measured by the U&G) differ in obsessive versus harmonious passion. Obsessive passion is associated with poor mood and problematic gambling. In contrast, harmonious passion for mobile gambling is associated with positive mood but is unrelated to problematic gambling. Based on these findings, and given that problematic gambling is an internationally relevant public health issue (the prevalence of problem gambling is estimated to range from 0.1% to 5.8% in different countries), we suggest interventions focusing on specific uses and gratifications associated with an obsessive passion for mobile gambling may be effective in reducing problematic usage patterns.
Purpose - The purpose of this paper is to examine how the principles of talent management (TM) can be leveraged to enhance an organization's knowledge management (KM) initiatives.Design methodology ...approach - This paper critically reviews the literature pertaining to the emerging concept of TM and specifically that which focuses on "smart talent management" i.e. the fusion of TM and KM concepts. The authors offer insights as to how TM can benefit KM and then discuss these insights with a focus group of KM practitioners.Findings - The fusion of the two concepts has so far only been considered by human resource scholars who have tended to examine how learnings from the field of KM can be leveraged to advance TM. The authors confront the issue in reverse and identify five KM concerns - identifying key knowledge workers, knowledge creation, knowledge sharing, developing knowledge competencies, and knowledge retention - which they argue can be advanced through the application of TM principles. Their focus group confirms that these KM concerns can benefit from the integration of TM principles, but some more than others.Originality value - The fusion of TM and KM has so far only been considered from a HR perspective. This paper examines the fusion of the two concepts from a KM perspective. Five specific KM concerns which can benefit from the integration of a TM approach are detailed and then validated by a focus group of KM practitioners.
Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an ...isochromosome 12p i(12p) with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis.
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•Comprehensive single-cell transcriptome atlas of normal human male germline development•Transcriptional and open chromatin landscape of seminoma mapped to normal male germline•Altered germline programs, angiogenesis, and MAP kinase signaling pathways in seminoma•An in vitro model of the shaping of seminoma transcriptional programs by isochromosome 12p
Cheng et al. map the single-cell transcriptome and open chromatin landscape of seminoma onto their newly established trajectory of human male germline development. They find that seminoma resembles premigratory/migratory primordial germ cells, and they identify alterations in germline programs and MAP kinase signaling that may be influenced by isochromosome 12p.
As the mean age of parenthood grows, the effect of parental age on genetic disease and child health becomes ever more important. A number of autosomal dominant disorders show a dramatic paternal age ...effect due to selfish mutations: substitutions that grant spermatogonial stem cells (SSCs) a selective advantage in the testes of the father, but have a deleterious effect in offspring. In this paper we present a computational technique to model the SSC niche in order to examine the phenomenon and draw conclusions across different genes and disorders.
We used a Markov chain to model the probabilities of mutation and positive selection with cell divisions. The model was fitted to available data on disease incidence and also mutation assays of sperm donors. Strength of selective advantage is presented for a range of disorders including Apert's syndrome and achondroplasia. Incidence of the diseases was predicted closely for most disorders and was heavily influenced by the site-specific mutation rate and the number of mutable alleles. The model also successfully predicted a stronger selective advantage for more strongly activating gain-of-function mutations within the same gene. Both positive selection and the rate of copy-error mutations are important in adequately explaining the paternal age effect.
C ++/R source codes and documentation including compilation instructions are available under GNU license at https://github.com/anwala/NicheSimulation CONTACT: ewhel001@odu.eduSupplementary information: Supplementary data are available at Bioinformatics online.
Purpose
While the positive health benefits of fitness apps, which motivate and track physical exercise, are widely acknowledged, the adverse connection between these technologies and wellbeing has ...received little attention. The purpose of this paper is to determine how the social dimensions of fitness apps predict the type of passion (harmonious and obsessive) one has for physical exercise, and what the resulting positive and negative implications are for wellbeing.
Design/methodology/approach
Drawing from the theoretical frameworks of social influence and the dual model of passion (DMP), this study develops a model depicting how fitness apps relate to the causes and consequences of harmonious and obsessive passion for exercise. Survey data were collected from 272 fitness app using cyclists and analysed with partial least squares structural equation modelling techniques.
Findings
Different social influence aspects of fitness apps appeal to different types of exercisers. A harmonious passion for physical exercise is predicted by the positive reciprocal benefits attained from one’s fitness app community, while an obsessive passion is predicted by positive recognition. In turn, a harmonious passion for exercise is negatively associated with life burnout, while an obsessive passion strongly affirms that relationship. In addition, the relationship between social influence and life burnout is fully mediated by the type of passion a fitness app user possesses.
Originality/value
Underpinned by the DMP, the study provides a theoretical framework explaining how the use of fitness apps can result in opposing wellness outcomes.
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