Oligoasthenoteratozoospermia and Infertility in Mice Deficient for miR-34b/c and miR-449 Loci

Male fertility requires the continuous production of high quality motile spermatozoa in abundance. Alterations in all three metrics cause oligoasthenoteratozoospermia, the leading cause of human sub/infertility. Post-mitotic spermatogenesis inclusive of several meiotic stages and spermiogenesis (terminal spermatozoa differentiation) are transcriptionally inert, indicating the potential importance for the post-transcriptional microRNA (miRNA) gene-silencing pathway therein. We found the expression of miRNA generating enzyme Dicer within spermatogenesis peaks in meiosis with critical functions in spermatogenesis. In an expression screen we identified two miRNA loci of the miR-34 family (miR-34b/c and miR-449) that are specifically and highly expressed in post-mitotic male germ cells. A reduction in several miRNAs inclusive of miR-34b/c in spermatozoa has been causally associated with reduced fertility in humans. We found that deletion of both miR34b/c and miR-449 loci resulted in oligoasthenoteratozoospermia in mice. MiR-34bc/449-deficiency impairs both meiosis and the final stages of spermatozoa maturation. Analysis of miR-34bc-/-;449-/- pachytene spermatocytes revealed a small cohort of genes deregulated that were highly enriched for miR-34 family target genes. Our results identify the miR-34 family as the first functionally important miRNAs for spermatogenesis whose deregulation is causal to oligoasthenoteratozoospermia and infertility

The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease.

The miR-17/92 cluster is among the best-studied microRNA clusters. Interest in the cluster and its members has been increasing steadily and the number of publications has grown exponentially since its discovery with more than 1000 articles published in 2012 alone. Originally found to be involved in tumorigenesis, research work in recent years has uncovered unexpected roles for its members in a wide variety of settings that include normal development, immune diseases, cardiovascular diseases, neurodegenerative diseases and aging. In light of its ever-increasing importance and ever-widening regulatory roles, we review here the latest body of knowledge on the cluster\u27s involvement in health and disease as well as provide a novel perspective on the full spectrum of protein-coding and non-coding transcripts that are likely regulated by its members

Blood Magnesium, and the Interaction with Calcium, on the Risk of High-Grade Prostate Cancer

Ionized calcium (Ca) and magnesium (Mg) compete as essential messengers to regulate cell proliferation and inflammation. We hypothesized that inadequate Mg levels, perhaps relative to Ca levels (e.g. a high Ca/Mg ratio) are associated with greater prostate cancer risk.In this biomarker sub-study of the Nashville Men's Health Study (NMHS), we included 494 NMHS participants, consisting of 98 high-grade (Gleason≥7) and 100 low-grade cancer cases, 133 prostate intraepithelial neoplasia (PIN) cases, and 163 controls without cancer or PIN at biopsy. Linear and logistic regression were used to determine associations between blood Ca, Mg, and the Ca/Mg ratio across controls and case groups while adjusting for potential confounding factors.Serum Mg levels were significantly lower, while the Ca/Mg ratio was significantly higher, among high-grade cases vs. controls (p = 0.04, p = 0.01, respectively). Elevated Mg was significantly associated with a lower risk of high-grade prostate cancer (OR = 0.26 (0.09, 0.85)). An elevated Ca/Mg ratio was also associated with an increased risk of high-grade prostate cancer (OR = 2.81 (1.24, 6.36) adjusted for serum Ca and Mg). In contrast, blood Ca levels were not significantly associated with prostate cancer or PIN.Mg, Ca, or Ca/Mg levels were not associated with low-grade cancer, PIN, PSA levels, prostate volume, or BPH treatment.Low blood Mg levels and a high Ca/Mg ratio were significantly associated with high-grade prostate cancer. These findings suggest Mg affects prostate cancer risk perhaps through interacting with Ca

Structural basis for terminal loop recognition and stimulation of pri-miRNA-18a processing by hnRNP A1

International audiencePost-transcriptional mechanisms play a predominant role in the control of microRNA (miRNA) production. Recognition of the terminal loop of precursor miRNAs by RNA-binding proteins (RBPs) influences their processing; however, the mechanistic basis for how levels of individual or subsets of miRNAs are regulated is mostly unexplored. We previously showed that hnRNP A1, an RBP implicated in many aspects of RNA processing, acts as an auxiliary factor that promotes the Microprocessor-mediated processing of pri-mir-18a. Here, by using an integrative structural biology approach, we show that hnRNP A1 forms a 1:1 complex with pri-mir-18a where both RNA recognition motifs (RRMs) bind to cognate RNA sequence motifs in the terminal loop of pri-mir-18a. Terminal loop binding induces an allosteric destabilization of base-pairing in the pri-mir-18a stem that promotes its downstream processing. Our results highlight terminal loop RNA recognition by RBPs as a potential general principle of miRNA biogenesis and regulation

The diversity of strongly interacting Type IIn supernovae

Context. At late stages, massive stars experience strong mass-loss rates, losing their external layers and thus producing a dense H-rich circumstellar medium (CSM). After the explosion of a massive star, the collision and continued interaction of the supernova (SN) ejecta with the CSM power the SN light curve through the conversion of kinetic energy into radiation. When the interaction is strong, the light curve shows a broad peak and high luminosity that lasts for several months. For these SNe, the spectral evolution is also slower compared to non-interacting SNe. Notably, energetic shocks between the ejecta and the CSM create the ideal conditions for particle acceleration and the production of high-energy (HE) neutrinos above 1 TeV. Aims. We study four strongly interacting Type IIn SNe, 2021acya, 2021adxl, 2022qml, and 2022wed, in order to highlight their peculiar characteristics, derive the kinetic energy of their explosion and the characteristics of the CSM, infer clues on the possible progenitors and their environment, and relate them to the production of HE neutrinos. Methods. We analysed spectro-photometric data of a sample of interacting SNe to determine their common characteristics and derive the physical properties (radii and masses) of the CSM and the ejecta kinetic energies and compare them to HE neutrino production models. Results. The SNe analysed in this sample exploded in dwarf star-forming galaxies, and they are consistent with energetic explosions and strong interaction with the surrounding CSM. For SNe 2021acya and 2022wed, we find high CSM masses and mass-loss rates, linking them to very massive progenitors. For SN 2021adxl, the spectral analysis and less extreme CSM mass suggest a stripped-envelope massive star as a possible progenitor. SN 2022qml is marginally consistent with being a Type Ia thermonuclear explosion embedded in a dense CSM. The mass-loss rates for all the SNe are consistent with the expulsion of several solar masses of material during eruptive episodes in the last few decades before the explosion. Finally, we find that the SNe in our sample are marginally consistent with HE neutrino production

The case of AT2022wtn: a tidal disruption event in an interacting galaxy

We present the results from our multiwavelength monitoring campaign of the transient AT 2022wtn, discovered by the Zwicky Transient Facility in the nucleus of SDSS J232323.79 + 104107.7, the less-massive galaxy in an active merging pair with a mass ratio of $\sim$10:1. AT 2022wtn shows spectroscopic and photometric properties consistent with a X-ray faint N-strong TDE-H + He with a number of peculiarities. Specifically, a 30-d long plateau at maximum luminosity, a corresponding dip in temperature and the development of a double-horned N iii + He ii line profile. Strong and time-evolving velocity offsets in the tidal disruption event (TDE) broad emission lines and the detection of a transient radio emission, indicate the presence of outflows. Overall, the observed properties are consistent with the full disruption of a low-mass star by a $\sim 10^{6}$ M$_{\odot }$ supermassive black hole followed by an efficient disc formation and the launch of a quasi-spherical reprocessing envelope of fast expanding outflowing material. The observed differences between the He ii and the Hydrogen and N iii lines can be explained either with a spatial separation of the lines emitting region or with a late-time reveal of shocks from the returning debris streams, as the photosphere recedes. Finally, we present an extensive analysis of the hosting environment and discuss the implications for the discovery of two TDEs in interacting galaxy pairs, finding indication for an over-representation of TDEs in these systems. The AT 2022wtn host galaxy properties suggest that it is in the early stages of the merger, therefore we may be witnessing the initial enhanced rate of TDEs in interacting galaxies before the post-starburst phase