Medical Research Council (UKRI)

Background and Aims In the past decade, unmanned aerial systems (UASs), commonly known as drones, have found applications not only in military and agriculture but also in the transportation of medical supplies. Purpose The present study was conducted to assess the practicality of utilizing drones as a mode for the delivery of vaccines to combat the challenges. Study Design An exploratory study. Methodology Due to the COVID‐19 pandemic restrictions and paucity of availability of rules and regulations related to drones in India in 2021, this study was conducted as a exploratory study for which number of regulatory approvals are obtained and it involves five drone missions within the premises of the Indian Institute of Technology (IIT), Kanpur, India on a confined airstrip of 3 km² to transport simulated vaccine vials using a multi‐rotor top‐load UAS in the normal weather conditions in daylight where dummy vaccine vials (COVID‐19) were packed with cool packs to maintain the temperature. Study was conducted to explore feasibility to carry vaccines through drones and any environmental impact on the vaccine vials while its transportation. Results The drones demonstrated a maximum flight endurance of 31 min while carrying a payload of up to 4.5 Kg, covering an aerial distance of 17 km at an average speed ranging at 12 m per second. Notably, the vaccine carrier box was able to maintain a recommended temperature of 3°C–4°C throughout the transportation process, and there is no impact of vibration on the physical integrity and leakage of the vaccine vials during flight. Conclusions These findings signify the potential for the drone‐based medical supply deliveries across confined and controlled environment conditions. This study provides the insights that there is no environmental impact such as humidity, temperature, wind etc on the drone and no impact on vibrations on the physical integrity and leakage of the dummy vaccine vials. There were few regulatory barriers that required special approvals from concerned authorities. The study was not designed to assess for cost‐effectiveness, also it was conducted in defined geography so all sorties were VLOS. Study has various limitations such as using simulated vaccine vials, regulatory barriers, operational barriers etc. Conducting the study in a controlled environment at IIT Kanpur limits generalizability. In spite of these limitations this study provides valuable insights and may explore a diverse environment that can help in strengthening health services especially in difficult terrains.

DNA topology is a direct consequence of the double helical nature of DNA and is defined by how the two complementary DNA strands are intertwined. Virtually every reaction involving DNA is influenced by DNA topology or has topological effects. It is therefore of fundamental importance to understand how this phenomenon is controlled in living cells. DNA topoisomerases are the key actors dedicated to the regulation of DNA topology in cells from all domains of life. While significant progress has been made in the last two decades in understanding how these enzymes operate in vivo in Bacteria and Eukaryotes, studies in Archaea have been lagging behind. This review article aims to summarize what is currently known about DNA topology regulation by DNA topoisomerases in main archaeal model organisms. These model archaea exhibit markedly different lifestyles, genome organization and topoisomerase content, thus highlighting the diversity and the complexity of DNA topology regulation mechanisms and their evolution in this domain of life. The recent development of functional genomic assays supported by next‐generation sequencing now allows to delve deeper into this timely and exciting, yet still understudied topic.

PI3Kα, consisting of the p110α isoform of the catalytic subunit of PI 3-kinase (encoded by PIK3CA) and the p85α regulatory subunit (encoded by PI3KR1) is activated by growth factor receptors. The identification of common oncogenic mutations in PIK3CA has driven the development of many inhibitors that bind to the ATP-binding site in the p110α subunit. Upon activation, PI3Kα undergoes conformational changes that promote its membrane interaction and catalytic activity, yet the effects of ATP-site directed inhibitors on the PI3Kα membrane interaction are unknown. Using FRET and Biolayer Interferometry assays, we show that a class of ATP-site directed inhibitors represented by GSK2126458 block the growth factor activated PI3KαWT membrane interaction, an activity dependent on the ligand forming specific ATP-site interactions. The membrane interaction for hot spot oncogenic mutations that bypass normal p85α regulatory mechanisms was insensitive to GSK2126458, while GSK2126458 could regulate mutations found outside of these hot spot regions. Our data show that the effect of GSK126458 on the membrane interaction requires the enzyme to revert from its growth factor activated state to a basal state. We find that an ATP substrate analogue can increase the wild type PI3Kα membrane interaction, uncovering a substrate based regulatory event that can be mimicked by different inhibitor chemotypes. Our findings, together with the discovery of small molecule allosteric activators of PI3Kα illustrate that PI3Kα membrane interactions can be modulated by factors related to ligand binding both within the ATP site and at allosteric sites.

Background Documentation of research outcomes using impact case studies (ICS) is increasingly required to demonstrate the wider societal benefits of research. However, there is limited evidence of the best way to communicate research outcomes using ICS, especially when highlighting research impact that is not part of a research assessment programme. This study aims, for the first time, to analyse expectations, and methods of communicating impact from medical research across a varied set of stakeholders relevant to the Medical Research Council (MRC). Methods Impact narratives about outcomes and impact from MRC research were evaluated using an online survey and in depth semi-structured interviews. Participants were recruited from internal MRC databases and included early career and senior management academics as well as representatives from industry, healthcare, charities, and the government. Informed consent was gained prior to data collection and the study was approved by the university’s research ethics committee. Qualitative and quantitative analysis determined stakeholder preferences for ICS content, language and presentation as well as capturing themes and perspectives on the concept of research impact. Results 193 participants responded to the online survey exploring definitions of impact and methods of communicating medical research outcomes. The work uncovered expectations of improved health and wellbeing as well as knowledge generation via publications and citations. In depth interviews with sixteen participants demonstrated preferences for clear, easy to read content that focused on facts and evidence and avoided both academic and hyperbolic language. Emergent themes from this work revealed that ICS need to quickly capture imagination and grab attention, while the views and expectations are quite different to press releases and are audience specific. Conclusions The content of ICS often focuses on non-academic impacts; however this work highlighted that evidence of academic impacts were outcomes highly valued by stakeholders relevant to the MRC. This work examined a new typology of ICS attributes, which emphasised that the language and presentation of impact narratives can influence the perception of research outcomes, providing useful information for individuals and organisations using ICS to showcase their research. It also shows that if ICS attempt to communicate challenges and issues around achieving impact from research, they may be more credible and useful to their intended audience.

Background Carbamazepine is an anticonvulsant drug which is monitored in patients due to toxic side effects. At Manchester University NHS Foundation Trust (MFT), carbamazepine is measured using Roche’s Kinetic Interaction of Microparticles in Solution (KIMS) method on the c 702 platform. The assay has an upper limit of linearity of 20 mg/L. Samples with concentrations above this limit should be identified and manually diluted. However, a poor EQA return from UK NEQAS for Tox and TDM Distribution 456 has highlighted an issue with the Roche KIMS assay. Sample A of the distribution had a carbamazepine concentration of 36 mg/L but was underreported by several Roche users. This indicated that the assay was not consistently identifying high concentration samples which required a dilution. Method In this investigation, fresh frozen plasma was spiked with carbamazepine concentrations ranging from 15 to 40 mg/L. The spiked samples and EQA material were analysed at two clinical laboratories using the Roche KIMS assay. Results Samples spiked with concentrations 20–30 mg/L were not consistently identified for dilution by the analyser. This was observed at both hospital sites. Spike samples and EQA with concentrations >30 mg/L were correctly identified at both sites. Conclusion The manual dilution policy has been changed at MFT, so all samples with a carbamazepine level ≥15 mg/L will be manually diluted. The problem was reported to Roche who are investigating the issue further. We would suggest that other laboratories look at validating their dilution protocols.

BACKGROUND Biochemical hyperandrogenism is a hallmark and diagnostic feature of polycystic ovary syndrome (PCOS). However, the most accurate androgen measurement for assessing biochemical hyperandrogenism in PCOS diagnosis remains uncertain. OBJECTIVE AND RATIONALE This systematic review aimed to assess different androgen measures [including total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI), androstenedione (A4), dehydroepiandrosterone sulfate (DHEAS), and dihydrotestosterone (DHT)] for accuracy in diagnosing biochemical hyperandrogenism in women with PCOS, to inform the 2023 International PCOS Evidence-based Guidelines. SEARCH METHODS To update evidence from the 2018 International PCOS Guidelines, a systematic search from 3 July 2017 to 23 June 2023 was conducted across Medline (Ovid), CINAHL, all EBM, EMBASE, and PsycInfo for articles evaluating androgens in the diagnosis of biochemical hyperandrogenism. The revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess the risk of bias and applicability. A diagnostic test accuracy meta-analysis was performed using STATA 18 software. Summary sensitivity and specificity were calculated with 95% CIs using the bivariate model, while the hierarchical summary receiver operating characteristics (ROC) model was used to produce a summary ROC curve. OUTCOMES Of 23 studies reviewed, 18 were included in the meta-analysis, with data from 2857 participants (1650 with PCOS and 1207 controls). For diagnosing biochemical hyperandrogenism in PCOS, the pooled sensitivity, specificity, and AUC with 95% CI were for TT: 0.74 (0.63–0.82), 0.86 (0.77–0.91), and 0.87 (0.84–0.90); cFT: 0.89 (0.69–0.96), 0.83 (0.79–0.86), and 0.85 (0.81–0.88); FAI: 0.78 (0.70–0.83), 0.85 (0.76–0.90), and 0.87 (0.84–0.90); A4: 0.75 (0.60–0.86), 0.71 (0.51–0.85), and 0.80 (0.76–0.83); and DHEAS: 0.75 (0.61–0.85), 0.67 (0.48–0.81), and 0.77 (0.73–0.81), respectively. In subgroup analyses, liquid chromatography with tandem mass spectrometry (LC-MS/MS) had superior sensitivity for measuring cFT, FAI, A4, and DHEAS, and superior specificity for measuring TT, cFT, and FAI, compared to the direct immunoassay method. WIDER IMPLICATIONS Our results directly informed the 2023 International PCOS Guideline recommendations to use TT and FT as the first-line laboratory tests to assess biochemical hyperandrogenism in the diagnosis of PCOS. cFT should be assessed by equilibrium dialysis or ammonium sulfate precipitation, or calculated using FAI. If TT or cFT are not elevated, A4 and DHEAS could also be considered, noting their poorer specificity. Laboratories should utilize LC-MS/MS for androgen measurement given its high accuracy. Future studies should focus on establishing optimal normative cut-off values in large, unselected, and ethnically diverse cohorts of women. REGISTRATION NUMBER The review protocol was prepublished in the 2023 PCOS Guideline Technical Report (https://www.monash.edu/__data/assets/pdf_file/0010/3379591/TechnicalReport-2023.pdf).

Inhibition of S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice, but the underlying mechanisms are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory senescence-associated secretory phenotype (SASP). Cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology, but the specific role of S6K1 has not been determined. Here we show that S6K1 deletion does not reduce senescence but ameliorates inflammation in aged mouse livers. Using human and mouse models of senescence, we demonstrate that reduced inflammation is a liver-intrinsic effect associated with S6K deletion. Specifically, we show that S6K1 deletion results in reduced IRF3 activation; impaired production of cytokines, such as IL1β; and reduced immune infiltration. Using either liver-specific or myeloid-specific S6K knockout mice, we also demonstrate that reduced immune infiltration and clearance of senescent cells is a hepatocyte-intrinsic phenomenon. Overall, deletion of S6K reduces inflammation in the liver, suggesting that suppression of the inflammatory SASP by loss of S6K could underlie the beneficial effects of inhibiting this pathway on healthspan and lifespan.

Biobanks have become an integral part of health and bioscience research. However, the ultra-low temperature (ULT) storage methods that biobanks employ [ULT freezers and liquid nitrogen (LN2)] are associated with carbon emissions that contribute to anthropogenic climate change. This paper aims to provide a ‘Roadmap’ for reducing carbon emissions associated with ULT storage in biobanking. The Roadmap offers recommendations associated with nine areas of ULT storage practice: four relating to ULT freezers, three associated with LN2 storage, and two generalised discussions regarding biosample management and centralisation. For each practice, we describe (a) the best approaches to mitigate carbon emissions, (b) explore barriers associated with hindering their implementation, and (c) make a series of recommendations that can help biobank stakeholders overcome these barriers. The recommendations were the output of a one year, UK-based, multidisciplinary research project that involved a quantitative Carbon Footprinting Assessment of the emissions associated with 1 year of ULT storage (for both freezers and LN2) at four different case study sites; as well as two follow up stakeholder workshops to qualitatively explore UK biobank stakeholder perceptions, views, and experiences on how to consider such assessments within the broader social, political, financial, technical, and cultural contexts of biobanking.

Objectives 7α-Hydroxy-4-cholesten-3-one (C4) is the common intermediary of both primary bile acids. C4 is recommended by the British Society of Gastroenterology for the investigation of bile acid diarrhoea (BAD) in patients with chronic diarrhoea. This project aimed to develop and validate an assay to quantitate C4 in serum and assess the stability of C4 in unseparated blood. Methods Accuracy was underpinned by calibrating to quantitative nuclear magnetic resonance analysis. C4 was analysed in a 96-well plate format with a deuterated C4 internal standard and liquid-liquid extraction. Validation followed the 2018 Food and Drug Administration guidelines. To assess C4 stability, healthy volunteers (n=12) donated 8 fasted samples each. Samples were incubated at 20 °C for up to 72 h and retrieved, centrifuged, aliquoted and frozen for storage at different time points prior to C4 analysis. Results The C4 method demonstrated excellent analytical performance and passed all validation criteria. The method was found to be accurate, precise, free from matrix effects and interference. After 72 h of delayed sample separation, C4 concentration gradually declined by up to 14 % from baseline. However, the change was not significant for up to 12 h. Conclusions We present a robust method of analysing serum C4, offering a convenient alternative to ⁷⁵ SeHCAT for BAD investigation. C4 was found to decline in unseparated blood over time; however, after 12 h the mean change was <5 % from baseline. Our results suggest C4 is suitable for collection from both primary and secondary care prior to gastroenterology referral.

Triple-negative breast cancer (TNBC) poses a significant global health challenge due to its highly aggressive nature and invasive characteristics. Dysregulation of the Hippo pathway, a key regulator of various biological processes, is observed in TNBC, and its inhibition holds promise for impeding cancer growth. This in-silico analysis investigates the role of Transcriptional Enhanced Associate Domain 4 (TEAD4) in TNBC and its interaction with Yes Associated Protein (YAP) in cancer progression. Our results demonstrate that TEAD4 upregulation is linked to poor prognosis in TNBC, emphasizing its critical role in the disease. Moreover, we identify CID44521006, an analog of Flufenamic acid, as a potential therapeutic compound capable of disrupting the TEAD4-YAP interaction by binding to the YAP-binding domain of TEAD4. These findings underscore the significance of TEAD4 in TNBC and propose CID44521006 as a promising candidate for therapeutic intervention. The study contributes valuable insights to advance treatment options for TNBC, offering a potential avenue for the development of targeted therapies against this aggressive form of breast cancer. Graphical Abstract

Background Respiratory viral illnesses among children are a prominent cause of morbidity and mortality in the developing world. The aim of this study is to understand the seasonal pattern and surge of respiratory viruses among the Nicobarese tribe. Methods Respiratory specimens were collected from both ARI and SARI cases attended the BJR district hospital in Car Nicobar Island, India, between 2021 and 2022. Respiratory viruses were identified from the specimens by using the qRT-PCR assay. Meteorological parameters were collected and evaluated using Microsoft Excel and SPSS 21. The significant association between the surge of respiratory viruses and each climatic parameter was evaluated. Results In this hospital-based cross-sectional study, 471 ILI cases were enrolled, and 209 of these were positive for respiratory viral infections. Of these respiratory virus infections, 201 (96.2%) were infected with a single respiratory virus infection, and 8 (3.8%) had mixed viral infections. Fever, cough, and chills were the most common symptoms of respiratory illness among this indigenous population. There was a significant link between respiratory viruses and influenza-like illness in children (below 5 years and 6 to 15 years). Conclusion This prevalence study revealed that viral respiratory infections were more common in children than adults. Among these respiratory viruses, respiratory syncytial virus A (RSV) and influenza B virus were predominantly reported among tribal children up to age five years. In the year 2021, these viruses were recorded frequently during the winter season. Climate factors such as high humidity, high precipitation, moderate temperature, and moderate rainfall are found to be correlated with respiratory viral infections. This study implicates important information for preventing a further outbreak of respiratory viral infections in Car Nicobar Island.

523 Background: The incidence of breast cancer (BC) among young patients is increasing. Historically, young age itself has been recognised as a poor prognostic factor for BC. However, there is limited evidence regarding the impact of age at diagnosis and on survival outcomesaccording to tumor subtype. Methods: We collected individual patient (pt)-level data from newly diagnosed stage I to III BC pts participating in 5 randomized clinical trials conducted by Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) study groups. Patients were categorized into the following age groups based on their age at BC diagnosis: ≤40, 41-50, 51-60, 61-70, >70 years (yr). Multivariable Cox proportional hazards models were used to assess the relationship between age and breast cancer–free interval (BCFI) and breast cancer specific survival (BCSS). Results: 8,338 pts with stage I to III BC were included in the study: 778 (9%) aged ≤40 years, 1629 (20%) 41-50 years, 2,595 (31%) 51-60 years, 2,435 (29%) 61-70 years, and 901 (11%) >70 years. Compared to older, young pts were more likely to have ductal tumors as histology, larger than 2 cm, with nodal involvement, G3 and triple negative or HER2 positive subtypes (p<0.001). With a median follow-up of 9.0 years (IQR 5.5-14.4), 2,161 BCFI and 927 BCSS events were observed in the overall population. Pts ≤40 years at diagnosis had greater risk of reporting BC event (adjusted hazard ratio (adjHR) for BCFI 1.27, 95% CI 0.93-1.74) compared to pts aged 51-60 years (reference group), while pts 41-50 years had a lower risk (adjHR 0.74, 95%CI 0.55-0.99). Pts aged ≤40 years presented some evidence of a lower risk of BCSS events (adjHR 0.80, 95%CI 0.50-1.26) compared to pts aged 51-60 years, while pts aged 41-50 years had the lowest risk (adjHR 0.50, 95%CI 0.32-0.78). There was evidence of interaction between age and tumor subtype, nodal status both for BCFI and BCSS. A significant increase in risk of BC events was observed among pts ≤40 years with hormone-receptor positive/HER2 negative tumors (HR 1.70 for BCFI) and among ≤40 years with node negative tumors (HR for BCFI 2.43). Conclusions: The prognostic significance of young age at diagnosis may vary depending on tumor subtypes and nodal status, indicating poorer outcomes for young pts with hormone-receptor positive/HER2 negative and node negative tumors.

Aldo‐keto reductase 1C3 (AKR1C3) is a key enzyme in the activation of both classic and 11‐oxygenated androgens. In adipose tissue, AKR1C3 is co‐expressed with 11β‐hydroxysteroid dehydrogenase type 1 (HSD11B1), which catalyzes not only the local activation of glucocorticoids but also the inactivation of 11‐oxygenated androgens, and thus has the potential to counteract AKR1C3. Using a combination of in vitro assays and in silico modeling we show that HSD11B1 attenuates the biosynthesis of the potent 11‐oxygenated androgen, 11‐ketotestosterone (11KT), by AKR1C3. Employing ex vivo incubations of human female adipose tissue samples we show that inhibition of HSD11B1 results in the increased peripheral biosynthesis of 11KT. Moreover, circulating 11KT increased 2–3 fold in individuals with type 2 diabetes after receiving the selective oral HSD11B1 inhibitor AZD4017 for 35 days, thus confirming that HSD11B1 inhibition results in systemic increases in 11KT concentrations. Our findings show that HSD11B1 protects against excess 11KT production by adipose tissue, a finding of particular significance when considering the evidence for adverse metabolic effects of androgens in women. Therefore, when targeting glucocorticoid activation by HSD11B1 inhibitor treatment in women, the consequently increased generation of 11KT may offset beneficial effects of decreased glucocorticoid activation.

PURPOSE We sought to evaluate the prognostic impact of prostate-specific antigen (PSA) at 6 months after completion of radiotherapy (RT) in patients treated with RT alone, RT plus short-term (st; 3-6 months), and RT plus long-term (lt; 24-36 months) androgen-deprivation therapy (ADT). PATIENTS AND METHODS Individual patient data were obtained from 16 randomized trials evaluating RT ± ADT for localized prostate cancer (PCa) between 1987 and 2011. The lowest PSA recorded within 6 months after RT completion was identified and categorized as < or ≥0.1 ng/mL. The primary outcomes were metastasis-free survival (MFS), PCa-specific mortality (PCSM), and overall survival (OS), from 12 months after random assignment. RESULTS Ninety-eight percent (n = 2,339/2,376) of patients allocated to RT alone, 84% (n = 4,756/5,658) allocated to RT + stADT, and 77% (n = 1,258/1,626) allocated to RT + ltADT had PSA ≥0.1 ng/mL within 6 months after completing RT. PSA ≥0.1 ng/mL was associated with lower MFS and OS and higher PCSM among patients allocated to RT ± ADT (RT – MFS: hazard ratio [HR], 2.24 [95% CI, 1.21 to 4.16]; PCSM: subdistribution hazard ratio [sHR], 1.82 [0.51 to 6.49]; OS: HR, 1.72 [0.97 to 3.05]; RT + stADT – MFS: HR, 1.27 [1.12 to 1.44]; PCSM: sHR, 2.10 [1.52 to 2.92]; OS: HR, 1.26 [1.11 to 1.44]; RT + ltADT – MFS: HR, 1.58 [1.27 to 1.96]; PCSM: sHR, 1.97 [1.11 to 3.49]; OS: HR, 1.59 [1.27 to 1.99]). Five-year MFS rates among patients allocated to RT, RT + stADT, and RT + ltADT were 91% versus 79%, 83% versus 76%, and 87% versus 74%, respectively, based on PSA < or ≥0.1 ng/mL. CONCLUSION PSA ≥0.1 ng/mL within 6 months after RT completion was prognostic for lt outcomes in patients treated with RT ± ADT for localized PCa. This can be used to counsel patients treated with RT ± ADT and in guiding clinical trial design evaluating novel systemic therapies with RT + ADT as well as (de)intensification strategies.

Peer review is an important part of the scientific process, but traditional peer review at journals is coming under increased scrutiny for its inefficiency and lack of transparency. As preprints become more widely used and accepted, they raise the possibility of rethinking the peer-review process. Preprints are enabling new forms of peer review that have the potential to be more thorough, inclusive, and collegial than traditional journal peer review, and to thus fundamentally shift the culture of peer review toward constructive collaboration. In this Consensus View, we make a call to action to stakeholders in the community to accelerate the growing momentum of preprint sharing and provide recommendations to empower researchers to provide open and constructive peer review for preprints.

Background Human papillomavirus (HPV) is associated with cervical cancer and cervical dysplasia worldwide. Data on HPV prevalence in a region is important because it serves as a predictor of the likelihood of the population in that particular region acquiring cervical cancer. Moreover, with the availability of effective vaccines, the public health system must be aware of the preponderance of HPV to implement the vaccine. The present study was designed to understand the prevalence of HPV and associated factors among the women of South Andaman Island. Methods A cross-sectional study was conducted among married women of reproductive age (18–59 years) from South Andaman District from 2018 to 2022. Cervical scrapes were collected from participants after obtaining informed written consent for HPV molecular testing (HPV DNA) such as PCR assay. Demographic data was collected using a standard questionnaire and statistical analyses were performed to determine the associated factors. Results The study showed prevalence of HPV as 5.9%(95% CI: 3.9–7.9) and prevalence of HR-HPV16 was 4.1% (95% CI 2.6 – 5.5) and HR-HPV18 prevalence was 1.8(95% CI: 0.6–3). The independent factors associated the HPV positivity were age above 55 years, menopause, post-menopausal bleeding, blood-stained vaginal discharge and loss of weight. Age was associated with all HPV infections among the South Andaman women. Conclusions HPV 16 was reported as the predominant high risk HPV type circulating among women of South Andaman. Cervical cancer and precancerous lesions were significantly associated with HPV positivity and High risk HPV 16. Based on the knowledge of the risk factors associated with HPV, implementation of stronger public health awareness and prophylactic HPV vaccination is crucial among the women of this remote island.

Genome regulation in eukaryotes revolves around the nucleosome, the fundamental building block of eukaryotic chromatin. Its constituent parts, the four core histones (H3, H4, H2A, H2B), are universal to eukaryotes. Yet despite its exceptional conservation and central role in orchestrating transcription, repair, and other DNA-templated processes, the origins and early evolution of the nucleosome remain opaque. Histone-fold proteins are also found in archaea, but the nucleosome we know—a hetero-octameric complex composed of histones with long, disordered tails—is a hallmark of eukaryotes. What were the properties of the earliest nucleosomes? Did ancestral histones inevitably assemble into nucleosomes? When and why did the four core histones evolve? This review will look at the evolution of the eukaryotic nucleosome from the vantage point of archaea, focusing on the key evolutionary transitions required to build a modern nucleosome. We will highlight recent work on the closest archaeal relatives of eukaryotes, the Asgardarchaea, and discuss what their histones can and cannot tell us about the early evolution of eukaryotic chromatin. We will also discuss how viruses have become an unexpected source of information about the evolutionary path toward the nucleosome. Finally, we highlight the properties of early nucleosomes as an area where new tools and data promise tangible progress in the not-too-distant future.