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The Omicron strains of SARS-CoV-2 pose a significant challenge to the development of effective antibody-based treatments as immune evasion has compromised most available immune therapeutics. Therefore, in the ‘arms race’ with the virus, there is a continuing need to identify new biologics for the prevention or treatment of SARS-CoV-2 infections. Here, we report the isolation of nanobodies that bind to the Omicron BA.1 spike protein by screening nanobody phage display libraries previously generated from llamas immunized with either the Wuhan or Beta spike proteins. The structure and binding properties of three of these nanobodies (A8, H6 and B5-5) have been characterized in detail providing insight into their binding epitopes on the Omicron spike protein. Trimeric versions of H6 and B5-5 neutralized the SARS-CoV-2 variant of concern BA.5 both in vitro and in the hamster model of COVID-19 following nasal administration. Thus, either alone or in combination could serve as starting points for the development of new anti-viral immunotherapeutics.

Although whistleblowing is thought to represent an effective mechanism for detecting and uncovering doping in sport, it has yet to become a widely adopted practice. Understanding the factors that encourage or discourage whistleblowing is of vital importance for the promotion of this practice and the development of pedagogical material to enhance the likelihood of whistleblowing. The current study employed a qualitative methodology to explore the personal and organisational factors that underpin intentions to blow the whistle or that may lead to engagement in whistleblowing behaviours in sport. Thirty-three competitive athletes across a range of sports took part in a semi-structured interview which sought to explore what they would do should they encounter a doping scenario. Content analysis revealed that whistleblowing is a dynamic process characterised by the interaction of a range of personal and organisational factors in determining the intention to report PED use. These factors included moral reasoning, a desire to keep the matter “in-house”, perceived personal costs, institutional attitudes to doping, and social support. Analysis revealed a number of “intervening events”, including a perceived lack of organisational protection (e.g., ethical leadership) within some sporting sub-cultures, which present an important obstacle to whistleblowing. The intention to report doping was underpinned by a “fairness-loyalty trade-off” which involved athletes choosing to adhere to either fairness norms (which relate to a sense that all people and groups are treated equally) or loyalty norms (which reflect preferential treatment towards an in-group) when deciding whether they would blow the whistle. The promotion of fairness norms that emphasise a group's collective interests might encourage athletes to view whistleblowing as a means of increasing group cohesiveness and effectiveness and thereby increase the likelihood of this practice.

Retirement from sport is widely reported as a challenging time of transition in the lives of elite athletes and is one that has been explored from a range of different perspectives both by sport psychologists and socio-cultural scholars of sport. However, of late, a small number of scholars have considered athlete career transition within the context of religion and spirituality, identifying the religious identity and belief of athletes as central to their transition experiences. That said, this work does not go as far as developing a theological understanding of sports retirement. Here, we explore and frame the phenomenon of sports retirement through the theological lens put forward by the neo-Franciscan priest, Richard Rohr in his book Falling Upward: A Spirituality for the Two Halves of Life. In this paper, we suggest how Rohr’s ideas might help develop an alternative and more nuanced understanding of sports retirement, building on those currently promoted in sport psychology and the sociology of sport the literature.

One aspect of sports retirement that has been overlooked until recently is the manner in which retired athletes relate to, and seek to redefine, the meaning of exercise in their post-sport lives. In this article, three Foucauldian scholars present and analyze a series of vignettes concerning their own sense-making and meaning-making about exercise following their long-term involvement in high-performance soccer (authors one and two) and distance running (author three). In doing so, this paper aims to underline the problematic legacy of high-performance sport for retiring athletes' relationship to movement and exercise, and to highlight how social theory, and Foucauldian theorization in particular, can serve to open new spaces and possibilities for thinking about sports retirement.

Blowing the whistle on corruption or wrongdoing can facilitate the detection, investigation, and then prosecution of a violation that may have otherwise gone undetected. The purpose of this systematic review was to identify the factors that are associated with intentions to blow the whistle on wrongdoing. We searched Academic Search Premier, CINAHL Complete, Education Research Complete, ERIC, Medline, PsycARTICLES, PsycINFO, Regional Business News, and SPORTDiscus in January 2020. The quality of evidence was assessed using the Cochrane risk of bias tool. Of the 9,136 records identified, 217 studies were included in this systematic review. We identified 8 dimensions, 26 higher-order themes, and 119 lower-order themes. The whistleblowing dimensions were personal factors, organizational factors, cost and benefits, outcome expectancies, the offense, reporting, the wrongdoer, and social factors. Based on the findings, it is apparent that organizations should empower, educate, protect, support, and reward those who blow the whistle, in order to increase the likelihood on individuals blowing the whistle on corruption and wrongdoing. A combined approach may increase whistleblowing intentions, although research is required to test this assertion. From a policy perspective, more consistent protection is required across different countries.

Pediatric MLL-rearranged acute myeloid leukemia (AML) has a generally unfavorable outcome, primarily due to relapse and drug resistance. To overcome these difficulties, new therapeutic agents are urgently needed. Yet, implementing novel drugs for clinical use is a time-consuming, laborious, costly and high-risk process. Therefore, we applied a drug-repositioning strategy by screening drug libraries, comprised of >4000 compounds that are mostly FDA-approved, in a high-throughput format on primary MLL-rearranged AML cells. Here we identified pyrvinium pamoate (pyrvinium) as a novel candidate drug effective against MLL-rearranged AML, eliminating all cell viability at

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (KMT2A-rearranged infant ALL patient samples (n = 2). The most effective drugs were then tested on non-leukemic whole bone marrow samples (n = 2) to select drugs with a favorable therapeutic index for bone marrow toxicity. The identified agents frequently belonged to several recurrent drug classes, including BCL-2, histone deacetylase, topoisomerase, microtubule, and MDM2/p53 inhibitors, as well as cardiac glycosides and corticosteroids. The in vitro efficacy of these drug classes was successfully validated in additional primary KMT2A-rearranged infant ALL samples (n = 7) and KMT2A-rearranged ALL cell line models (n = 5). Based on literature studies, most of the identified drugs remarkably appeared to lead to activation of p53 signaling. In line with this notion, subsequent experiments showed that forced expression of wild-type p53 in KMT2A-rearranged ALL cells rapidly led to apoptosis induction. We conclude that KMT2A-rearranged infant ALL cells are vulnerable to p53 activation, and that drug-induced p53 activation may represent an essential condition for successful treatment results. Moreover, the present study provides an attractive collection of approved drugs that are highly effective against KMT2A-rearranged infant ALL cells while showing far less toxicity towards non-leukemic bone marrow, urging further (pre)clinical testing.

This article describes the radiation facilities and associated sample preparation, management, and analysis equipment currently in place at the Dalton Cumbrian Facility, a facility which opened in 2011 to support the UK’s nuclear industry. Examples of measurements performed using these facilities are presented to illustrate their versatility and the breadth of research they make possible. Results are presented from research which furthers our understanding of radiation damage to polymeric materials, radiolytic yield of gaseous products in situations relevant to nuclear materials, radiation chemistry in light water reactor cooling systems, material chemistry relevant to immobilization of nuclear waste, and radiation-induced corrosion of fuel cladding elements. Applications of radiation chemistry relevant to health care are also described. Research concerning the mechanisms of radioprotection by dietary carotenoids is reported. An ongoing open-labware project to develop a suite of modular sample handling components suited to radiation research is described, as is the development of a new neutron source able to provide directional beams of neutrons.

Conventional wisdom dictates that the use of GPS surveillance technology in sport to assist athletic performance is an overwhelminglypositive phenomenon. Specifically, the health and performance benefits of the application of GPS and surveillance technologies have been well documented across a range of field sports. Previous research into the developmental implications of GPS surveillance in professional rugby league (Jones, Marshall, & Denison, 2016) has identified that there are some significant unintended consequencesof their use for elite athletes. We utilised the disciplinary analysis of Foucault to investigate the experiences of academy soccer playersin relation to wearable GPS technology. Five academy players took part in semi-structured group interviews as part of a wider study into the effects of surveillance technologies within an academy setting. We suggest that the now normalised and increasingly ubiqui- tous use of GPS surveillance technology within this particular British soccer academy is seen as relatively insignificant by its players. However, we also report that GPS use does act to impose discipline on academy players and may well have unforeseen and potentially problematic implications for academy players’ development experience.

Existing literature on the work of sports chaplains has focused primarily on practitioner accounts of chaplaincy with elite athletes. While these narratives provide useful descriptions of personal experience and practical application, they are largely devoid of theoretical grounding. This paper seeks to address this imbalance by proposing the need for sports chaplains to have a more critical understanding of sport and its relational dynamics. We begin by problematizing some of the historical assumptions underpinning elite sport, especially in relation to identity formation. We then explore some of the moral dilemmas which may be experienced by Christian athletes who inhabit contemporary sporting contexts. In line with the work of established sociological scholars, we then move to a critical analysis of performance-based identity and how an understanding of sociological concepts and ideas might assist chaplains in their work with elite athletes. The paper concludes by identifying sports chaplains as key figures in the disruption of performance-based identity.

Oxygen depletion in the ocean interior may be closely linked to atmospheric CO2level, yet robust proxies are scarce. Here, using foraminiferal I/Ca as a proxy for oxygenation changes, the authors show that oxygen depletion in the upper waters of the high latitude Southern Ocean occurred during glacials.

Purpose: The broad aim of this paper is to use Noddings' theory of ethical care to analyse mentors' caring experiences. More specifically, it aims to analyse how physical education (PE) mentors provide care, how they are cared for and how this impacts their role within the context of secondary PE initial teacher training (ITT). Design/methodology/approach: Semi-structured interviews were used to generate data from 17 secondary PE mentors within the same university ITT partnership in the north-west of England. Questions focused on the mentors' experiences of care and the impact this had on their wellbeing and professional practice. A process of thematic analysis was used to identify, analyse and report patterns in the data. Findings: The participants reflected established definitions of mentoring by prioritising the aim of developing the associate teachers' (ATs) teaching rather than explicitly providing support for their wellbeing. This aim could be challenging for mentors who face personal and professional difficulties while supporting the training of an AT. Mentors frequently referred to the support of their departmental colleagues in overcoming these difficulties and the importance of developing interdependent caring relationships. Receiving care did not impede mentors from providing support for others; it heightened awareness and increased their desire to develop caring habits. Originality/value: Teacher wellbeing has drawn greater attention in recent years and is increasingly prioritised in public policy. These findings highlight the value of mentor wellbeing and how caring professional relationships can mitigate the pressures associated with performativity and managing a demanding workload.

Lesson study is a collaborative and contextualised approach to professional learning that involves small groups of teachers working together to design and reflect on the teaching of a research lesson. Although it is a well-established approach to professional learning in classroom-based subjects, research on its effectiveness within physical education (PE) initial teacher training (ITT) and in the general practice of PE teachers is scarce. This study examines the views of 18 secondary PE associate teachers (ATs) who completed a lesson study cycle as part of their one-year postgraduate ITT programme. A questionnaire and semi-structured interviews--conducted at the end of the lesson study and six months later at the end of the programme--were used to generate data. Thematic analysis was then used to interrogate the data and identify patterns of response. The findings revealed that the ATs benefitted from the experience in similar ways to established teachers. They developed their understanding of lesson research and engaged in elevated levels of critical reflection that helped to change and develop their approaches to teaching and learning. Moreover, the ATs recognised that their learning was enhanced when they could rehearse the phases of the cycle before starting the lesson study in their placement school. They also understood the value of a mentor who could support their progress and ensure their full engagement in all phases of the lesson study cycle. These findings have implications for providers of ITT as the considered inclusion of lesson study contributed to the immediate aim of developing ATs' teaching competencies while also promoting the skills needed for them to manage their own ongoing learning as fully qualified teachers.

MOZAIC-IAGOS data are used to assess the ability of the MACC reanalysis (REAN) to reproduce distributions of ozone (O3) and carbon monoxide (CO), along with vertical and inter-annual variability in the upper troposphere/lower stratosphere region (UTLS) over Europe for the period 2003–2010. A control run (CNTRL, without assimilation) is compared with the MACC reanalysis (REAN, with assimilation) to assess the impact of assimilation. On average over the period, REAN underestimates ozone by 60 ppbv in the lower stratosphere (LS), whilst CO is overestimated by 20 ppbv. In the upper troposphere (UT), ozone is overestimated by 50 ppbv, while CO is partly over or underestimated by up to 20 ppbv. As expected, assimilation generally improves model results but there are some exceptions. Assimilation leads to increased CO mixing ratios in the UT which reduce the biases of the model in this region but the difference in CO mixing ratios between LS and UT has not changed and remains underestimated after assimilation. Therefore, this leads to a significant positive bias of CO in the LS after assimilation. Assimilation improves estimates of the amplitude of the seasonal cycle for both species. Additionally, the observations clearly show a general negative trend of CO in the UT which is rather well reproduced by REAN. However, REAN misses the observed inter-annual variability in summer. The O3–CO correlation in the Ex-UTLS is rather well reproduced by the CNTRL and REAN, although REAN tends to miss the lowest CO mixing ratios for the four seasons and tends to oversample the extra-tropical transition layer (ExTL region) in spring. This evaluation stresses the importance of the model gradients for a good description of the mixing in the Ex-UTLS region, which is inherently difficult to observe from satellite instruments.

The search for novel anticancer therapeutics with the ability to overcome multi-drug resistance (MDR) mechanisms is of high priority. A class of molecules that show potential in overcoming MDR are the N-alkylated isatins. In particular 5,7-dibromo-N-alkylisatins are potent microtubule destabilizing agents that act to depolymerize microtubules, induce apoptosis and inhibit primary tumor growth in vivo. In this study we evaluated the ability of four dibrominated N-alkylisatin derivatives and the parent compound, 5,7-dibromoisatin, to circumvent MDR. All of the isatin-based compounds examined retained potency against the MDR cell lines; U937VbR and MES-SA/Dx5 and displayed bioequivalent dose-dependent cytotoxicity to that of the parental control cell lines. We show that one mechanism by which the isatin-based compounds overcome MDR is by circumventing P-glycoprotein (P-gp) mediated drug efflux. Thus, as the isatin-based compounds are not susceptible to extrusion from P-gp overexpressing tumor cells, they represent a promising alternative strategy as a stand-alone or combination therapy for treating MDR cancer.

Nature Communications 7: Article number: 11146 (2016); Published: 31 March 2016; Updated: 26 April 2016 In Fig. 3 of this Article, data in panel ‘a’ were inadvertently partially obscured during the production process. The correct version of Fig. 3 now appears in the PDF and HTML versions of the Article.

This arts-based research considers creativity in the professional lives of English teachers in a school in England within the context of a progressively performative education system. In addition, it explores how found poetry can represent participants' voices in an illuminating and authentic manner. The teachers who participated in the study were able to scrutinise, reflect and comment upon the content of poems created from the words found in an initial interview transcript. This recursive process supports a credible way of seeing and knowing the teachers' voices in a representation that gives a deeper understanding of the participants' creative experiences. The construction, interrogation, and presentation of the found poems reveal that the teachers of English believe they have reduced freedom to be creative or to act with agency in their professional lives. The reduced freedom to be creative stems from the normalising practices of working within a culture of performance. The restrictions are both tangible and self-imposed by the participants.