HBO1 is required for the maintenance of leukaemia stem cells.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.

Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth.

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.

A natural experimental study of improvements along an urban canal: impact on canal usage, physical activity and other wellbeing behaviours.

BACKGROUND: There are few robust natural experimental studies of improving urban green spaces on physical activity and wellbeing. The aim of this controlled natural experimental study was to examine the impact of green space improvements along an urban canal on canal usage, physical activity and two other wellbeing behaviours (social interactions and taking notice of the environment) among adults in Greater Manchester, UK. The intervention included resurfaced footpaths, removal of encroaching vegetation, improved entrances, new benches and signage. METHODS: Two comparison sites were matched to the intervention site using a systematic five-step process, based on eight correlates of physical activity at the neighbourhood (e.g. population density) and site (e.g. lighting) levels. Outcomes were assessed using systematic observations at baseline, and 7, 12 and 24 months post-baseline. The primary outcome was the change in the number of people using the canal path from baseline to 12 months. Other outcomes were changes in physical activity levels (Sedentary, Walking, Vigorous), Connect and Take Notice behaviours. Data were analysed using multilevel mixed-effects negative binomial regression models, comparing outcomes in the intervention group with the matched comparison group, controlling for day, time of day and precipitation. A process evaluation assessed potential displacement of activity from a separate existing canal path using intercept surveys and observations. RESULTS: The total number of people observed using the canal path at the intervention site increased more than the comparison group at 12 months post-baseline (IRR 2.10, 95% CI 1.79-2.48); there were similar observed increases at 7 and 24 months post-baseline. There was some evidence that the intervention brought about increases in walking and vigorous physical activity, social interactions, and people taking notice of the environment. The process evaluation suggested that there was some displacement of activity, but the intervention also encouraged existing users to use the canal more often. CONCLUSIONS: Urban canals are promising settings for interventions to encourage green space usage and potentially increase physical activity and other wellbeing behaviours. Interventions that improve access to green corridors along canals and provide separate routes for different types of physical activities may be particularly effective and warrant further research. STUDY PROTOCOL: Study protocol published in Open Science Framework in July 2018 before the first follow-up data collection finished ( https://osf.io/zcm7v ). Date of registration: 28 June 2018.

Towards a Theory of Digital Well-Being: Reimagining Online Life After Lockdown.

Global lockdowns during the COVID-19 pandemic have offered many people first-hand experience of how their daily online activities threaten their digital well-being. This article begins by critically evaluating the current approaches to digital well-being offered by ethicists of technology, NGOs, and social media corporations. My aim is to explain why digital well-being needs to be reimagined within a new conceptual paradigm. After this, I lay the foundations for such an alternative approach, one that shows how current digital well-being initiatives can be designed in more insightful ways. This new conceptual framework aims to transform how philosophers of technology think about this topic, as well as offering social media corporations practical ways to design their technologies in ways that will improve the digital well-being of users.

Digital well-being under pandemic conditions: catalysing a theory of online flourishing.

The COVID-19 pandemic has catalysed what may soon become a permanent digital transition in the domains of work, education, medicine, and leisure. This transition has also precipitated a spike in concern regarding our digital well-being. Prominent lobbying groups, such as the Center for Humane Technology (CHT), have responded to this concern. In April 2020, the CHT has offered a set of 'Digital Well-Being Guidelines during the COVID-19 Pandemic.' These guidelines offer a rule-based approach to digital well-being, one which aims to mitigate the effects of moving much of our lives online. The CHT's guidelines follow much recent interest in digital well-being in the last decade. Ethicists of technology have recently argued that character-based strategies and redesigning of online architecture have the potential to promote the digital well-being of online technology users. In this article, I evaluate (1) the CHT's rule-based approach, comparing it with (2) character-based strategies and (3) approaches to redesigning online architecture. I argue that all these approaches have some merit, but that each needs to contribute to an integrated approach to digital well-being in order to surmount the challenges of a post-COVID world in which we may well spend much of our lives online.

Relationships between health outcomes in older populations and urban green infrastructure size, quality and proximity.

BACKGROUND: There is a growing body of literature supporting positive associations between natural environments and better health. The type, quality and quantity of green and blue space ('green-space') in proximity to the home might be particularly important for less mobile populations, such as for some older people. However, considerations of measurement and definition of green-space, beyond single aggregated metrics, are rare. This constitutes a major source of uncertainty in current understanding of public health benefits derived from natural environments. We aimed to improve our understanding of how such benefits are conferred to different demographic groups through a comprehensive evaluation of the physical and spatial characteristics of urban green infrastructure. METHODS: We employed a green infrastructure (GI) approach combining a high-resolution spatial dataset of land-cover and function with area-level demographic and socio-economic data. This allowed for a comprehensive characterization of a densely populated, polycentric city-region. We produced multiple GI attributes including, for example, urban vegetation health. We used a series of step-wise multi-level regression analyses to test associations between population chronic morbidity and the functional, physical and spatial components of GI across an urban socio-demographic gradient. RESULTS: GI attributes demonstrated associations with health in all socio-demographic contexts even where associations between health and overall green cover were non-significant. Associations varied by urban socio-demographic group. For areas characterised by having higher proportions of older people ('older neighbourhoods'), associations with better health were exhibited by land-cover diversity, informal greenery and patch size in high income areas and by proximity to public parks and recreation land in low income areas. Quality of GI was a significant predictor of good health in areas of low income and low GI cover. Proximity of publicly accessible GI was also significant. CONCLUSIONS: The influence of urban GI on population health is mediated by green-space form, quantity, accessibility, and vegetation health. People in urban neighbourhoods that are characterised by lower income and older age populations are disproportionately healthy if their neighbourhoods contain accessible, good quality public green-space. This has implications for strategies to decrease health inequalities and inform international initiatives, such as the World Health Organisation's Age-Friendly Cities programme.

8-Mercaptoguanine Derivatives as Inhibitors of Dihydropteroate Synthase.

Dihydropteroate synthase (DHPS) is an enzyme of the folate biosynthesis pathway, which catalyzes the formation of 7,8-dihydropteroate (DHPt) from 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPPP) and para-aminobenzoic acid (pABA). DHPS is the long-standing target of the sulfonamide class of antibiotics that compete with pABA. In the wake of sulfa drug resistance, targeting the structurally rigid (and more conserved) pterin site has been proposed as an alternate strategy to inhibit DHPS in wild-type and sulfa drug resistant strains. Following the work on developing pterin-site inhibitors of the adjacent enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), we now present derivatives of 8-mercaptoguanine, a fragment that binds weakly within both enzymes, and quantify sub-µm binding using surface plasmon resonance (SPR) to Escherichia coli DHPS (EcDHPS). Eleven ligand-bound EcDHPS crystal structures delineate the structure-activity relationship observed providing a structural framework for the rational development of novel, substrate-envelope-compliant DHPS inhibitors.

Evaluating the impact of improvements in urban green space on older adults' physical activity and wellbeing: protocol for a natural experimental study.

BACKGROUND: Creating or improving urban green space has the potential to be an effective, sustainable and far-reaching way to increase physical activity and improve other aspects of wellbeing in the population. However, there is a dearth of well-conducted natural experimental studies examining the causal effect of changing urban green space on physical activity and wellbeing. This is especially true in older adults and in the United Kingdom. This paper describes a natural experimental study to evaluate the effect of four small-scale urban street greening interventions on older adults' physical activity and wellbeing over a 1-year period, relative to eight matched comparison sites. All sites are located in deprived urban neighbourhoods in Greater Manchester, United Kingdom. METHODS: Components of the interventions include tree and flower planting, and artificial tree decorations. Eight unimproved comparison sites were selected based on a systematic process of matching using several known objective and subjective environmental correlates of physical activity in older adults. The outcome measures are physical activity and two other behavioural indicators of wellbeing (Connect: connecting with other people; and Take Notice: taking notice of the environment), collected using a newly developed observation tool. The primary outcome is Take Notice behaviour due to largest effects on this behaviour being anticipated from improvements in the aesthetic quality of green space at the intervention sites. Baseline data collection occurred in September 2017 before the interventions were installed in November 2017. Follow-up data collection will be repeated in February/ March 2018 (6 months) and September 2018 (12 months). DISCUSSION: The present study permits a rare opportunity to evaluate the causal effects of small-scale changes in urban green space in an understudied population and setting. Although the interventions are expected to have small effects on the outcomes, the present study contributes to developing natural experiment methodology in this field by addressing key methodological weaknesses causing high risk of bias in previous natural experimental studies. Key improvements to reduce risk of bias in the present study are rigorous matching of multiple comparison sites and appropriate statistical control of key confounders. TRIAL REGISTRATION: Retrospectively registered with study ID NCT03575923 . Date of registration: 3 July 2018.

New Lanthanide Tag for the Generation of Pseudocontact Shifts in DNA by Site-Specific Ligation to a Phosphorothioate Group.

Pseudocontact shifts (PCS) generated by paramagnetic lanthanides provide a rich source of long-range structural restraints that can readily be measured by nuclear magnetic resonance (NMR) spectroscopy. Many different lanthanide-binding tags have been designed for site-specific tagging of proteins, but established routes for tagging DNA with a single metal ion rely on difficult chemical synthesis. Here we present a simple and practical strategy for site-specific tagging of inexpensive phosphorothioate (PT) oligonucleotides. Commercially available PT oligonucleotides are diastereomers with S and R stereoconfiguration at the backbone PT site. The respective SP and RP diastereomers can readily be separated by HPLC. A new alkylating lanthanide-binding tag, C10, was synthesized that delivered quantitative tagging yields with both diastereomers. PCSs were observed following ligation with the complementary DNA strand to form double-stranded DNA duplexes. The PCSs were larger for the SP than the RP oligonucleotide and good correlation between back-calculated and experimental PCSs was observed. The C10 tag can also be attached to cysteine residues in proteins, where it generates a stable thioether bond. Ligated to the A28C mutant of ubiquitin, the tag produced excellent fits of magnetic susceptibility anisotropy (Δχ) tensors, with larger tensors than for the tagged PT oligonucleotides, indicating that the tag is not completely immobilized after ligation with a PT group.

Improving the Medical Curriculum in Predoctoral Dental Education: Recommendations From the American Association of Oral and Maxillofacial Surgeons Committee on Predoctoral Education and Training.

Dental procedures are often performed on patients who present with some level of medical fragility. In many dental schools, the exercise of taking a medical history is all too often a transcription of information to the dental chart, with little emphasis on the presurgical risk assessment and the development of a treatment plan appropriate to the medical status of the dental patient. Changes in dentistry, driven by an increasingly medically complex population of dental patients, combined with treatment advances rooted in the biomedical sciences necessitate the adaptation of our dental education to include a stronger background in systemic health. Many predoctoral educators in the American Association of Oral and Maxillofacial Surgeons (AAOMS) have expressed concern about the medical preparedness of our dental students; therefore, the AAOMS and its Committee on Predoctoral Education and Training have provided recommendations for improving the medical curriculum in predoctoral dental education, including a strengthening of training in clinical medicine and biomedical sciences, with specific recommendations for improved training of our dental students and dental faculty.

Installation of a Rigid EDTA-Like Motif into a Protein α-Helix for Paramagnetic NMR Spectroscopy with Cobalt(II) Ions.

Coupling two copies of an iminodiacetic acid-cysteine hybrid ligand to a pair of cysteine residues positioned in an i, i+4 arrangement within a protein α-helix leads to generation of an EDTA-like metal ion-binding motif. Rigid binding of a Co(II) ion by this motif produces pseudo-contact shifts suitable for paramagnetic NMR structural studies.

Ten steps towards integrated decision making for ecological restoration in cities: Rewilding the European beaver (Castor fiber) in Berlin, Germany.

Ensuring a livable city for all within the more-than-human discourse, restoration of urban ecosystems requires careful consideration of both human and non-human needs. However, traditional assessments and therefore most management plans usually fail to include the latter as a core planning requirement. This article presents and explains a 10-step method which simultaneously and actively considers both to identify potential restoration areas within urban ecosystems. To do so, a Strengths-Weaknesses-Opportunities-Threats (SWOT) analysis for the multispecies needs identification is combined with a Multicriteria Spatial Decision Support System (MCSDSS) for the spatial assessment. To validate this method, a case study of Berlin, Germany, an explicitly urban case, is presented. The aim of the study was to evaluate the ecosystem restoration (rewilding) potential of the city's riparian and riverine ecosystems through the enhancement of Eurasian beaver habitats.•Method combining SWOT analysis with MCSDSS for an integrated spatial assessment•Well-suited for multispecies (human and non-human) perspective on urban nature restoration.

Large walking and wellbeing behaviour benefits of co-designed sustainable park improvements: A natural experimental study in a UK deprived urban area.

There is little robust evidence of how sustainable park interventions impact on physical activity and other behaviours important for wellbeing. This controlled natural experimental study aimed to examine the effects of co-designing a sustainable park intervention, in a deprived UK urban area, on walking and other wellbeing behaviours. Behaviour observations were conducted at two intervention sites and two matched comparison sites (n = 4,783). Walking observations (primary outcome), wellbeing behaviours (vigorous, sedentary, social and take notice activities) and demographic characteristics were assessed at pre-intervention, and post-intervention (3 and 15 months). Outcomes were compared between intervention and comparison groups, controlling for pre-intervention using multilevel negative binomial regression models. Additional behaviour observations were conducted in two unchanged nearby sites to assess changes in general local activity. Intercept surveys (n = 623) assessed change in self-reported outdoor space usage at intervention and control areas. Post-intervention, walking increased 203 % at 3 months (IRR 2·03, 95 % CI 1·01-4·09) and 351 % at 15 months (IRR 3·51, 95 % CI 2·07-5·93), for intervention sites relative to comparison sites. Large increases for other wellbeing behaviours were also observed. The proportion of non-white persons increased substantially post-intervention, compared to comparison sites. Nearby unchanged sites showed little evidence of general increased activity. Self-reported outdoor usage increased more in the intervention sites (p=<0·001). Sustainable solutions can yield large increases in walking and wellbeing in deprived areas, especially where interventions are co-designed with residents. More collaborative and robust natural experimental studies like this are needed to better inform decision-makers how to maximise health and wellbeing outcomes from sustainable interventions.

Predictors of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: Insights from a real-world experience.

BACKGROUND: We aimed to investigate factors associated with cytomegalovirus (CMV) viremia and CMV disease and its impact on post-transplant outcomes including overall survival (OS) following allogeneic hematopoietic stem cell transplantation (Allo-SCT). METHODS: We conducted a single-center retrospective study including 452 Allo-SCT recipients (matched unrelated donor, MUD 61%; haploidentical, haplo 39%) from 2016 to 2021. Data were analyzed using SPSS v28. Descriptive (chi-square and t-test), Kaplan-Meier and regression analyses were conducted. RESULTS: The median age was 57 years. Sixty-one percent were males and 84.3% were Caucasians. CMV serostatus was positive in 59.1% of recipients. The median follow-up was 24.4 months. CMV viremia and CMV disease were observed in 181 (40%) and 32 (7%) patients, respectively. Among CMV seropositive recipients, 65% developed CMV viremia and 11% were noted to have CMV disease compared to 4% and 1% in seronegative recipients, respectively (p < 0.001). Patients with CMV disease had significantly lower OS than those without CMV disease (median 14.1 months vs. not reached, p = 0.024); however, OS was not associated with CMV viremia (median not reached in both groups, p = 0.640). Letermovir prophylaxis was used in 66% (n = 176/267) of CMV seropositive recipients, but no impact was observed on the incidence of CMV viremia or CMV disease and OS. CONCLUSIONS: CMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation. Recipient CMV seropositive status was associated with the risk of CMV viremia and CMV disease, and this was not abrogated with the use of Letermovir prophylaxis.

Integrating knowledge on green infrastructure, health and well-being in ageing populations: Principles for research and practice.

Ageing and urbanisation pose significant challenges for public health and urban planning. Ageing populations are at particular risk from hazards arising from urbanisation processes, some of which are in turn exacerbated by climate change. One approach for mitigating the negative effects of urbanisation on ageing populations is the leveraging of the beneficial effects of urban green infrastructure as a public health intervention in the planning process. We assessed the potential of available theoretical frameworks to provide the context for such leverage. This involved active engagement with academics and practitioners specialising in ageing, green infrastructure and health and well-being through a knowledge-brokering approach. We concluded that an integrated and comprehensive framework on the socio-cultural-ecological determinants of health is lacking. To address this, we present a set of principles for overcoming challenges to knowledge integration when working at the intersection of green infrastructure, ageing, health and well-being. Our findings-and the co-production process used to generate them-have wider significance for trans-disciplinary research into the benefits of the natural environment to human health and well-being as well as other complex and interconnected topics associated with global grand challenges.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.

Emotions and Digital Well-Being: on Social Media's Emotional Affordances.

Social media technologies (SMTs) are routinely identified as a strong and pervasive threat to digital well-being (DWB). Extended screen time sessions, chronic distractions via notifications, and fragmented workflows have all been blamed on how these technologies ruthlessly undermine our ability to exercise quintessential human faculties. One reason SMTs can do this is because they powerfully affect our emotions. Nevertheless, (1) how social media technology affects our emotional life and (2) how these emotions relate to our digital well-being remain unexplored. Remedying this is important because ethical insights into (1) and (2) open the possibility of designing for social media technologies in ways that actively reinforce our digital well-being. In this article, we examine the way social media technologies facilitate online emotions because of emotional affordances. This has important implications for evaluating the ethical implications of today's social media platforms, as well as for how we design future ones.

Continuous Positive Airway Pressure-Mandibular Advancement Device Combination Therapy for Moderate-to-Severe Obstructive Sleep Apnea: A Preliminary Study.

OBJECTIVES: The purpose of this pilot study was to determine whether compliance to auto-adjusting positive airway pressure (APAP) improves with the addition of a mandibular advancement device (MAD). Secondary outcome measures included were APAP pressure, subjective daytime sleepiness, apnea-hypopnea index (AHI), and mask leaks. SETTING AND SAMPLE POPULATION: Participants included were diagnosed with moderate-to-severe obstructive sleep apnea (OSA) and became noncompliant to prescribed APAP. Thirteen participants with a mean age of 61.6 years were recruited for this study. MATERIALS AND METHODS: All participants were given a MAD to use with their APAP. Parameters measured included APAP pressure, AHI, mask leak reported via ResMed AirViewTM software, and self-reported daytime sleepiness (Epworth Sleepiness Scale [ESS]). A paired two-sample for mean t-test was performed to determine significance. RESULTS: The mean difference of pre- and postintervention APAP compliance was 23.1%, which was statistically significant (p = 0.015). The mean APAP air pressures were unchanged. The difference between pre- and postintervention mean ESS scores was 1.4 and was statistically significant (p = 0.027). The mean difference between pre- and postintervention AHI values and mask leak showed no significant difference. CONCLUSION: This study showed that combination of APAP-MAD therapy, for patients with moderate-to-severe OSA who were noncompliant to APAP use, significantly increased compliance with APAP therapy, and significantly decreased the daytime sleepiness of participants.

To teach or not to teach: making the transition from dental practice to dental faculty.

The authors, with more than forty years of combined private practice experience, discuss professional satisfaction in the private practice setting. A change to an academic career may provide job satisfaction and revitalize a dental career, while simultaneously satisfying the need for faculty in our dental schools.