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Sperm small RNAs are implicated in intergenerational transmission of paternal environmental effects. Small RNAs generated by the cleavage of tRNAs, known as tRNA fragments (tRFs) or tRNA-derived RNAs (tDRs or tsRNAs), are an abundant class of RNAs in mature sperm and can be modulated by environmental conditions. The biogenesis of tRFs in the male reproductive tract remains poorly understood. Angiogenin, a member of the ribonuclease A superfamily (RNase A), cleaves tRNAs to generate tRFs in response to cellular stress. Four paralogs of Angiogenin, namely Rnase9, Rnase10, Rnase11, and Rnase12, are specifically expressed in the epididymis-a long, convoluted tubule where sperm mature and acquire fertility and motility. Here, by generating mice deleted for all four genes (Rnase9-12-/-, termed KO for Knock Out), we report that these genes regulate fertility and small RNA levels. KO male mice are sterile; KO sperm fertilized oocytes in vitro but failed to efficiently fertilize oocytes in vivo due to an inability of sperm to pass through the utero-tubular junction. Intriguingly, there were decreased levels of tRFs and rRNAs (rRNA-derived small RNAs or rsRNAs) in the KO epididymis and epididymal luminal fluid, although RNases 9-12 did not show ribonucleolytic activity in vitro. Importantly, KO sperm showed a dramatic decrease in the levels of tRFs, demonstrating a role of epididymis-specific Rnase9-12 genes in regulating sperm small RNA composition. Together, our results reveal an unexpected role of four epididymis-specific noncanonical ribonuclease A family genes in regulating fertility and small RNA processing.

This article considers the potential ways for coaching and mentoring practices in higher education to support the development of learner autonomy, a key espoused aim of university education. I argue that coaching and mentoring can foster self-regulated learning, critical thinking, and goal-setting among students, empowering them to take greater responsibility for their learning, and that higher education institutions should make greater use of coaching and mentoring practises, particularly for non-traditional learners [what in the UK are identified as 'widening participation' students]. The aim is to stimulate reflection and discussion among higher education practitioners.

This paper explores, from a theoretical basis, the difficulty in defining and assessing learner autonomy in higher education. Although the development of learner autonomy as a key aim of higher education, it is a vague and ill-defined term. As such, the assessment of learner autonomy within university programs of study is highly problematic. The author argues that the authentic assessment of genuine learner autonomy may not be possible within formal credit-bearing programs of higher education. The aim of the paper is to stimulate reflection and discussion so that university teaching staff may reflect and consider whether they can assess autonomy in the programs they are responsible for.

Background/purpose: British, European and American universities are increasingly adopting competency-based learning, yet, there are different and conflicting definitions of competence, competency, and competency-based learning. Consequently, multiple interpretations and understandings are held by educators in respect of what these terms mean, when applied to their own teaching and assessment practices. Therefore, unless informed and considered discussion has taken place amongst staff about their individual understandings and interpretations, any development of new, competency-based assessment processes and procedures, is necessarily problematic. The main purpose of the paper is to stimulate reflection and discussion, so that teaching staff can arrive at a common understanding and interpretation of what competency-based education is, so that they may develop appropriate, authentic and equitable assessment processes. Materials/methods: The methodology used was a systematic review of literature on competence, competency-based learning and the assessment of competency-based learning. Conclusion: This paper provides an overview of the main issues and tensions involved in clearly defining competency within higher education programmes and assessing competence, along with two clear recommendations for practice. The recommendations have significance for all higher education teaching staff involved in programmes of competency-based learning.

Masters and PhD student researchers in the social sciences are often required to explore and explain their positionality, as, in the social world, it is recognized that their ontological and epistemological beliefs influence their research. Yet novice researchers often struggle with identifying their positionality. This paper explores researcher positionality and its influence on and place in the research process. Its purpose is to help new postgraduate researchers better understand positionality so that they may incorporate a reflexive approach to their research and start to clarify their positionality.

This paper provides a critical analysis of the United Kingdom's higher education Key Information Set (KIS), which was implemented following the 2011 UK White Paper 'Students at the Heart of the System'. It argues that one of the central tenets of the KIS -- providing information that students within a free market can make an informed choice and, through this process of consumer choice improve the quality of teaching, is untenable because a central component of the KIS, the National Student Survey (NSS), is unreliable when used for comparing university courses. Further, it argues that the KIS reified a neoliberal perspective about the worth and value of higher education qualification, positioning it as a commodity of value only to the paying individual rather than being something of value to society as a whole. It will be of particular interest to academics and policy makers from outside of the United Kingdom, where governmental and regulatory agencies may be implementing similar policies.

Pre-specified, prescribed or intended Learning Outcomes have been in use throughout higher education programs for over two decades. There is an assumption amongst quality assurance bodies and university program approval and review processes that students engage with them. Yet, learning outcomes may constrain learning, they may not always be understood by learners and their relevance to learning has been questioned. There is anecdotal evidence from lecturers that some students do not understand them and do not use or refer to them. This paper reports on a small-scale research project investigating how university student's use prescribed learning outcomes in their everyday learning and when producing assessed work. No clear differences were found between higher and lower achieving students, yet there were differences between first- and third-year students. Surprisingly, some were able to achieve highly without referring to the outcomes against which they were assessed.

This conceptual paper provides an overview of constructivist education and the development and use of constructivist principles in contemporary higher education, outlining constructivism and some specific facets of student-centered learning. Drawing from first-hand experience and using two examples of current university assessment practice, reflective learning, and learning outcomes, the author argues that, despite claims constructivist pedagogical approaches have become normative practice when it comes to assessment processes, constructivism has not been fully embraced. The question 'is there clear evidence that constructivist principles have been applied to all aspects of university undergraduate study?' is considered. This is important and significant and should be of concern to all educators who espouse constructivist principles in higher education.

Learning outcomes are used throughout assessment processes in higher education. In many countries their use is mandatory, with a frequent assumption that they bring many positive benefits to educational processes. Yet, there are tensions associated with them and their current mode of use has far less flexibility than they should provide. This paper considers from a conceptual basis some of the tensions associated with the use of prescribed pre-articulated learning outcomes and the question of whether learning outcomes, as currently operationalized, provide the benefits they were meant to deliver. This is of significance to educators throughout higher education.

Deoxynucleotide triphosphohydrolases (dNTPases) play a critical role in cellular survival and DNA replication through the proper maintenance of cellular dNTP pools. While the vast majority of these enzymes display broad activity toward canonical dNTPs, such as the dNTPase SAMHD1 that blocks reverse transcription of retroviruses in macrophages by maintaining dNTP pools at low levels, Escherichia coli (Ec)-dGTPase is the only known enzyme that specifically hydrolyzes dGTP. However, the mechanism behind dGTP selectivity is unclear. Here we present the free-, ligand (dGTP)- and inhibitor (GTP)-bound structures of hexameric Ec-dGTPase, including an X-ray free-electron laser structure of the free Ec-dGTPase enzyme to 3.2 Å. To obtain this structure, we developed a method that applied UV-fluorescence microscopy, video analysis, and highly automated goniometer-based instrumentation to map and rapidly position individual crystals randomly located on fixed target holders, resulting in the highest indexing rates observed for a serial femtosecond crystallography experiment. Our structures show a highly dynamic active site where conformational changes are coupled to substrate (dGTP), but not inhibitor binding, since GTP locks dGTPase in its apo- form. Moreover, despite no sequence homology, Ec-dGTPase and SAMHD1 share similar active-site and HD motif architectures; however, Ec-dGTPase residues at the end of the substrate-binding pocket mimic Watson-Crick interactions providing guanine base specificity, while a 7-Å cleft separates SAMHD1 residues from dNTP bases, abolishing nucleotide-type discrimination. Furthermore, the structures shed light on the mechanism by which long distance binding (25 Å) of single-stranded DNA in an allosteric site primes the active site by conformationally "opening" a tyrosine gate allowing enhanced substrate binding.

Most experimental preparations demonstrate a role for dorsolateral striatum (DLS) in stimulus-response, but not outcome-based, learning. Here, we assessed DLS involvement in a touchscreen-based reversal task requiring mice to update choice following a change in stimulus-reward contingencies. In vivo single-unit recordings in the DLS showed reversal produced a population-level shift from excited to inhibited neuronal activity prior to choices being made. The larger the shift, the faster mice reversed. Furthermore, optogenetic photosilencing DLS neurons during choice increased early reversal errors. These findings suggest dynamic DLS engagement may facilitate reversal, possibly by signaling a change in contingencies to other striatal and cortical regions.

While results from many past studies have implicated the bed nucleus of the stria terminalis (BNST) in mediating the expression of sustained negative affect, recent studies have highlighted a more complex role for BNST that includes aspects of fear learning in addition to defensive responding. As BNST is thought to encode ambiguous or unpredictable threat, it seems plausible that it may be involved in encoding early cued fear learning, especially immediately following a first tone-shock pairing when the conditioned stimulus-unconditioned stimulus (CS-US) contingency is not fully apparent. To investigate this, we conducted in vivo electrophysiological recording studies to examine neural dynamics of BNST units during cued fear acquisition and recall. We identified two functionally distinct subpopulations of BNST neurons that encode the intertrial interval (ITI) and may contribute to within- and across-session fear learning. "Ramping" cell activity during cued fear acquisition parallels the increase in freezing expression as mice learn the CS-US contingency, while "Phasic" cells encode postshock (US[subscript post]) periods (30 sec following encounter with footshock) only during early trials. Importantly, the magnitude of Phasic unit responsivity to the first US[subscript post] period predicted not only freezing expression in response to the subsequent CS during acquisition, but also CS freezing evoked 24 h later during CS retrieval. These findings suggest for the first time that BNST activity may serve as an instructive signal during cued fear learning.

Androgenic anabolic steroids (AAS) are commonly abused by young men. Male sex and increased AAS levels are associated with earlier and more severe manifestation of common cardiac conditions, such as atrial fibrillation, and rare ones, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Clinical observations suggest a potential atrial involvement in ARVC. Arrhythmogenic right ventricular cardiomyopathy is caused by desmosomal gene defects, including reduced plakoglobin expression. Here, we analysed clinical records from 146 ARVC patients to identify that ARVC is more common in males than females. Patients with ARVC also had an increased incidence of atrial arrhythmias and P wave changes. To study desmosomal vulnerability and the effects of AAS on the atria, young adult male mice, heterozygously deficient for plakoglobin (Plako+/−), and wild type (WT) littermates were chronically exposed to 5α‐dihydrotestosterone (DHT) or placebo. The DHT increased atrial expression of pro‐hypertrophic, fibrotic and inflammatory transcripts. In mice with reduced plakoglobin, DHT exaggerated P wave abnormalities, atrial conduction slowing, sodium current depletion, action potential amplitude reduction and the fall in action potential depolarization rate. Super‐resolution microscopy revealed a decrease in NaV1.5 membrane clustering in Plako+/− atrial cardiomyocytes after DHT exposure. In summary, AAS combined with plakoglobin deficiency cause pathological atrial electrical remodelling in young male hearts. Male sex is likely to increase the risk of atrial arrhythmia, particularly in those with desmosomal gene variants. This risk is likely to be exaggerated further by AAS use. Key points: Androgenic male sex hormones, such as testosterone, might increase the risk of atrial fibrillation in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), which is often caused by desmosomal gene defects (e.g. reduced plakoglobin expression).In this study, we observed a significantly higher proportion of males who had ARVC compared with females, and atrial arrhythmias and P wave changes represented a common observation in advanced ARVC stages.In mice with reduced plakoglobin expression, chronic administration of 5α‐dihydrotestosterone led to P wave abnormalities, atrial conduction slowing, sodium current depletion and a decrease in membrane‐localized NaV1.5 clusters.5α‐Dihydrotestosterone, therefore, represents a stimulus aggravating the pro‐arrhythmic phenotype in carriers of desmosomal mutations and can affect atrial electrical function. [ABSTRACT FROM AUTHOR]

To present a single-center prospective study of 126 consecutively treated patients who underwent endovascular repair of a thoracoabdominal aortic aneurysm with the physician-modified, nonanatomic-based Unitary Manifold (UM) device. Data were collected from 126 consecutive all-comer patients treated with the physician-modified, nonanatomic-based UM from 2015 to 2023. Treatment was performed at a single center by a single physician under a Physician Sponsored Investigation Exemption G140207. The UM was indicated for repair of all Crawford extents including juxtarenal, pararenal, and short-neck infrarenal aneurysms (<10 mm) in 126 consecutive patients. Patients were not excluded from the study based on presentation, extent of aneurysm or dissection, or history of a spinal cord event. Patients with a thoracoabdominal aortic aneurysm were categorized by Crawford classification: types I and V (3.3%, n = 4), type II (3.3%, n = 4), type III (1%, n = 1), and type IV (93.3%, n = 117). The type IV classification patients were further categorized with 33 (28.2%) true type IV, 68 (58.1%) pararenal or infrarenal, and 16 (13.7%) with dissection. Technical success was 99.2% (n = 125). The most common major adverse event within both 30 days and 365 days of all patients was respiratory failure (11.9%, n = 15, and 13.5%, n = 17, respectively). One patient (0.8%) experienced persistent paraplegia at 365 days. Reintervention for patients at 365 days was 5.6% (n = 7). Of the 444 branches stented, the primary patency rate was remarkably high as only three patients (2.4%) required reintervention due to loss of limb patency within 365 days. Aneurysm enlargement (≥5 mm) occurred in 1.6% (n = 2) patients, and no patients experienced aneurysm rupture. No patients underwent conversion to open repair. The aneurysm-related mortality at 365 days for all patients was 4.0% (n = 5), whereas all-cause mortality was 16.7% (n = 21). Physician-modified endograft device integrity failure was not observed in any patient. The UM device demonstrated remarkable technical surgical success, treatment success, and device patency rates with very reasonable major adverse events and reintervention rates. This study is the most representative example of the general population in comparison with other studies of off-the-shelf devices, with 126 consecutive all-comer patients with diverse pathologies. [ABSTRACT FROM AUTHOR]

A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether selfish genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2(HC)) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2(HC) rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2(HC) is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution.

Cognitive flexibility refers to various processes which enable behaviors to be modified on the basis of a change in the contingencies between stimuli or responses and their associated outcomes. Reversal learning is a form of cognitive flexibility which measures the ability to adjust responding based on a switch in the stimulus--outcome contingencies of, typically two, perceptually distinct stimuli. Reversal tasks have provided valuable insight into the neural basis of cognitive flexibility, implicating brain regions including the lateral orbitofrontal cortex (lOFC) and dorsomedial prefrontal cortex (dmPFC). However, with two-stimulus reversal, it is difficult to determine whether response errors are due excessive perseveration, deficient learning, or other problems with updating. To address this limitation, we developed a mouse three-choice touchscreen-based visual reversal task, in which the contingencies of two stimuli were switched on reversal but a third, simultaneously presented, stimulus was never reinforced. We found that, in male C57BL/6J mice, responding at the previously rewarded stimulus predominated over the newly and never-reinforced stimuli during early reversal. Next, we showed that acute pharmacological inhibition of lOFC, but not dmPFC, impaired early reversal performance, relative to noninactivated controls. Interestingly, however, lOFC inactivation deficits were characterized by increased choice of the never-reinforced stimulus and a decrease in (perseverative-like) responding at the previously rewarded stimulus. These effects are inconsistent with the historical notion of lOFC mediating response inhibition and closer to recent views of the lOFC's role in response/outcome tracking. Overall, these findings provide initial support the utility of this novel paradigm for studying cognitive flexibility and its underlying neural substrates.