Gamma passing rates of daily EPID transit images correlate to PTV coverage for breast cancer IMRT treatment plans.

PURPOSE: The use of the transit image obtained with the electronic portal-imaging device (EPID) is becoming an extended method to perform in-vivo dosimetry. The transit images acquired during each fraction can be compared with a predicted image, if available, or with a baseline image, usually the obtained in the first fraction. This work aims to study the dosimetric impact of the failing fractions and to evaluate the appropriateness of using a baseline image in breast plans. MATERIAL AND METHODS: Twenty breast patients treated in a Halcyon were retrospectively selected. For each patient and fraction, the treatment plan was calculated over the daily CBCT image. For each fraction, the differences respect to the treatment plan values of OARs and PTV dosimetric parameters were analyzed: ΔDmean , ΔD95%, ΔD98%, ΔD2%, ΔV36Gy, ΔV38.5Gy, and ΔV43.5Gy. Daily fractions were ranked according to the differences found in the dosimetric parameters between the treatment plan and the daily CBCT to establish the best fraction. The daily transit images acquired in every fraction were compared to the first fraction using the global gamma index with the Portal Dosimetry tool. The comparison was repeated using the best fraction image as a baseline. We assessed the correlation of the dosimetric differences obtained from the CBCT images-based treatment plans with the gamma index passing rates obtained using first fraction and best fraction as baseline. RESULTS: Average values of -11.6% [-21.4%, -3.3%] and -3.2% [-1.0%, -10.3%] for the ∆PTVD98% and ∆PTVD95% per every 10% decrease in the passing rate were found, respectively. When using the best fraction as baseline patients were detected with failing fractions that were not detected with the first fraction as baseline. CONCLUSION: The gamma passing rates of daily transit images correlate with the coverage loss parameters in breast IMRT plans. Using first fraction image as baseline can lead to the non-detectability of failing fractions.

Farmers Experiencing Potato Seed Degeneration Respond but Do Not Adjust Their Seed Replacement Strategies in Ecuador.

In Ecuador, farmers poorly adopt practices to manage potato seed degeneration. This could be related to the deficient understanding of the farmers' capacity to experience seed degeneration and respond to it. We contribute to this understanding by answering: How do farmers experience seed degeneration?; What practices do farmers implement when their seed is degenerated?; and Is experiencing degeneration the pivotal factor determining how farmers replace their seed regardless their income? We analysed data collected in Ecuador through farmers' focus group discussions, farmers' surveys and interviews, and the Ecuadorian employment status survey. We found that approximately half of the farmers experienced degeneration. Farmers experienced it through low yields, change in seed appearance, crop weakening, and seed physiological problems. When farmers experienced degeneration, they replaced their seed, sought for technical advice, applied more agricultural inputs, or grew other crops. Income was an important trigger for farmers to change their seed replacement practices.

The Effectiveness of Common Cannabis Products for Treatment of Nausea.

GOALS: We measure for the first time how a wide range of cannabis products affect nausea intensity in actual time. BACKGROUND: Even though the Cannabis plant has been used to treat nausea for millennia, few studies have measured real-time effects of common and commercially available cannabis-based products. STUDY: Using the Releaf App, 886 people completed 2220 cannabis self-administration sessions intended to treat nausea between June 6, 2016 and July 8, 2019. They recorded the characteristics of self-administered cannabis products and baseline symptom intensity levels before tracking real-time changes in the intensity of their nausea. RESULTS: By 1 hour postconsumption, 96.4% of people had experienced symptom relief with an average symptom intensity reduction of -3.85 points on a 0 to 10 visual analog scale (SD=2.45, d=1.85, P<0.001). Symptom relief was statistically significant at 5 minutes and increased with time. Among product characteristics, flower and concentrates yielded the strongest, yet similar results; products labeled as Cannabis indica underperformed those labeled as Cannabis sativa or hybrid; and joints were associated with greater symptom relief than pipes or vaporizers. In sessions using flower, higher tetrahydrocannbinol and lower cannabidiol were generally associated with greater symptom relief (eg, within 5 min). CONCLUSIONS: The findings suggest that the vast majority of patients self-selecting into cannabis use for treatment of nausea likely experience relief within a relative short duration of time, but the level of antiemetic effect varies with the characteristics of the cannabis products consumed in vivo. Future research should focus on longer term symptom relief, including nausea-free intervals and dosing frequency; the risks of consumption of medical cannabis, especially among high-risk populations, such as pregnant women and children; and potential interactions between cannabis, conventional antiemetics, other medications, food, tobacco, alcohol, and street drugs among specific patient populations.

Classification of Depression Through Resting-State Electroencephalogram as a Novel Practice in Psychiatry: Review.

BACKGROUND: Machine learning applications in health care have increased considerably in the recent past, and this review focuses on an important application in psychiatry related to the detection of depression. Since the advent of computational psychiatry, research based on functional magnetic resonance imaging has yielded remarkable results, but these tools tend to be too expensive for everyday clinical use. OBJECTIVE: This review focuses on an affordable data-driven approach based on electroencephalographic recordings. Web-based applications via public or private cloud-based platforms would be a logical next step. We aim to compare several different approaches to the detection of depression from electroencephalographic recordings using various features and machine learning models. METHODS: To detect depression, we reviewed published detection studies based on resting-state electroencephalogram with final machine learning, and to predict therapy outcomes, we reviewed a set of interventional studies using some form of stimulation in their methodology. RESULTS: We reviewed 14 detection studies and 12 interventional studies published between 2008 and 2019. As direct comparison was not possible due to the large diversity of theoretical approaches and methods used, we compared them based on the steps in analysis and accuracies yielded. In addition, we compared possible drawbacks in terms of sample size, feature extraction, feature selection, classification, internal and external validation, and possible unwarranted optimism and reproducibility. In addition, we suggested desirable practices to avoid misinterpretation of results and optimism. CONCLUSIONS: This review shows the need for larger data sets and more systematic procedures to improve the use of the solution for clinical diagnostics. Therefore, regulation of the pipeline and standard requirements for methodology used should become mandatory to increase the reliability and accuracy of the complete methodology for it to be translated to modern psychiatry.

Catalytic Dehydrogenative Stannylation of C(sp)-H Bonds Involving Cooperative Sn-H Bond Activation of Hydrostannanes.

The catalytic generation of a stannylium-ion-like tin electrophile by heterolytic cleavage of the Sn-H bond in hydrostannanes at the Ru-S bond of Ohki-Tatsumi complexes is reported. Reacting these activated hydrostannanes with terminal acetylenes does not lead to hydrostannylation of the C-C triple bond but to dehydrogenative stannylation of the alkyne terminus. The scope of this rare direct C(sp)-H bond stannylation with hydrostannanes is broad, and a mechanism involving a ß-tin-stabilized vinyl cation likely having a bridged structure is presented.

Lymphoid Gene Upregulation on Circulating Progenitors Participates in Their T-Lineage Commitment.

Extrathymic T cell precursors can be detected in many tissues and represent an immediately competent population for rapid T cell reconstitution in the event of immunodeficiencies. Blood T cell progenitors have been detected, but their source in the bone marrow (BM) remains unclear. Prospective purification of BM-resident and circulating progenitors, together with RT-PCR single-cell analysis, was used to evaluate and compare multipotent progenitors (MPPs) and common lymphoid progenitors (CLPs). Molecular analysis of circulating progenitors in comparison with BM-resident progenitors revealed that CCR9(+) progenitors are more abundant in the blood than CCR7(+) progenitors. Second, although Flt3(-) CLPs are less common in the BM, they are abundant in the blood and have reduced Cd25(+)-expressing cells and downregulated c-Kit and IL-7Rα intensities. Third, in contrast, stage 3 MPP (MPP3) cells, the unique circulating MPP subset, have upregulated Il7r, Gata3, and Notch1 in comparison with BM-resident counterparts. Evaluation of the populations' respective abilities to generate splenic T cell precursors (Lin(-)Thy1.2(+)CD25(+)IL7Rα(+)) after grafting recipient nude mice revealed that MPP3 cells were the most effective subset (relative to CLPs). Although several lymphoid genes are expressed by MPP3 cells and Flt3(-) CLPs, the latter only give rise to B cells in the spleen, and Notch1 expression level is not modulated in the blood, as for MPP3 cells. We conclude that CLPs have reached the point where they cannot be a Notch1 target, a limiting condition on the path to T cell engagement.

Honey Bee Colonies Remote Monitoring System.

Bees are very important for terrestrial ecosystems and, above all, for the subsistence of many crops, due to their ability to pollinate flowers. Currently, the honey bee populations are decreasing due to colony collapse disorder (CCD). The reasons for CCD are not fully known, and as a result, it is essential to obtain all possible information on the environmental conditions surrounding the beehives. On the other hand, it is important to carry out such information gathering as non-intrusively as possible to avoid modifying the bees' work conditions and to obtain more reliable data. We designed a wireless-sensor networks meet these requirements. We designed a remote monitoring system (called WBee) based on a hierarchical three-level model formed by the wireless node, a local data server, and a cloud data server. WBee is a low-cost, fully scalable, easily deployable system with regard to the number and types of sensors and the number of hives and their geographical distribution. WBee saves the data in each of the levels if there are failures in communication. In addition, the nodes include a backup battery, which allows for further data acquisition and storage in the event of a power outage. Unlike other systems that monitor a single point of a hive, the system we present monitors and stores the temperature and relative humidity of the beehive in three different spots. Additionally, the hive is continuously weighed on a weighing scale. Real-time weight measurement is an innovation in wireless beehive-monitoring systems. We designed an adaptation board to facilitate the connection of the sensors to the node. Through the Internet, researchers and beekeepers can access the cloud data server to find out the condition of their hives in real time.

Inhibition of type I interferon signalling prevents TLR ligand-mediated proteinuria.

The mechanisms by which inflammation or autoimmunity causes proteinuric kidney disease remain elusive. Yet proteinuria is a hallmark and a prognostic indicator of kidney disease, and also an independent risk factor for cardiovascular morbidity and mortality. Podocytes are an integral component of the kidney filtration barrier and podocyte injury leads to proteinuria. Here we show that podocytes, which receive signals from the vascular space including circulating antigens, constitutively express TLR1­6 and TLR8. We find that podocytes can respond to TLR ligands including staphylococcal enterotoxin B (SEB), poly I:C, or lipopolysaccharide (LPS) with pro-inflammatory cytokine release and activation of type I interferon (IFN) signalling. This in turn stimulates podocyte B7-1 expression and actin remodelling in vitro and transient proteinuria in vivo. Importantly, the treatment of mice with a type I IFN receptor-blocking antibody (Ab) prevents LPS-induced proteinuria. These results significantly extend our understanding of podocyte response to immune stimuli and reveal a novel mechanism for infection- or inflammation-induced transient proteinuria. Dysregulation or aberrant activation of this response may result in persistent proteinuria and progressive glomerular disease. In summary, the inhibition of glomerular type I IFN signalling with anti-IFN Abs may be a novel therapy for proteinuric kidney diseases.

Control of Listeria monocytogenes contamination in an Iberian pork processing plant and selection of benzalkonium chloride-resistant strains.

The aims of this study were to characterize the different strains of Listeria monocytogenes collected at an Iberian pork processing plant and to investigate whether their specific characteristics were associated with prolonged survival in the plant. Using pulsed-field gel electrophoresis (PFGE), 29 PFGE types were previously identified during a three-year period. Eight of these PFGE types persisted in the plant during that period. In the present study, a subset of 29 PFGE type strains, which represented the 29 different PFGE types, was further characterized by assessing the potential virulence, and using motility, surface attachment, and antimicrobial susceptibility tests. After changing the disinfection procedures in the plant, the isolation rate of L. monocytogenes decreased, and only four of the 29 PFGE types, including three of the eight persistent PFGE types, were found the following year. These four "surviving" PFGE types included three from PCR serogroup IIa that were characterized by their low virulence mutations and low-level resistance to benzalkonium chloride (BAC). Furthermore, these PFGE types comprised the only BAC-resistant isolates found in the study, and they appear to have been selected due to the control of Listeria contamination. The resistance to increased sublethal concentrations of disinfectants may lead to prolonged survival of L. monocytogenes in food plants.

Antibiotic susceptibility in benzalkonium chloride-resistant and -susceptible Listeria monocytogenes strains.

This study aimed to investigate whether Listeria monocytogenes strains with resistance to a commonly used biocide display any cross-resistance to antibiotics. Using pulsed-field gel electrophoresis (PFGE), 29 different PFGE types were previously identified in an Iberian pig abattoir and processing plant. Only three PFGE types were resistant to benzalkonium chloride (BAC), but they represented a significant proportion of the PFGE types surviving in the plant after 4 years. In the present study, a subset of 29 strains, representing the 29 different PFGE types, underwent antibiotic susceptibility testing. Antibiotic susceptibility was assessed by Etest, utilizing 12 commonly prescribed antibiotics. All of the 29 strains were susceptible to all of the antibiotics tested. The study revealed that this group of different PFGE types of L. monocytogenes, including those resistant to BAC, possesses uniform sensitivity to antibiotics.

[Terrestrial flora of Malpelo Island, Colombia, Eastern Tropical Pacific]. / Flora terrestre de la isla Malpelo (Colombia), Pacífico Oriental Tropical.

Malpelo Island is located 380km off the mainland continental coast of Colombia, in the Pacific Ocean. Several geological, ecological, and zoological studies, both marine and terrestrial, have been conducted in this island. Despite some marginal comments on some publications, no single specific survey has been devoted to botany so far. In order to make a floristic inventory of the terrestrial flora of this island, three field trips were made in 2010 to collect vascular plants, mosses, and lichens, as well as data on their distribution within the island. We collected and identified 25 species of lichens, two species of vascular plants and one moss. Lichens were the most diverse group found, including records of four new genera (Endocarpon, Fuscidea, Lecanographa and Verrucaria) and 13 new species for Colombia. The high lichen richness on Malpelo might be explained by their efficient form of asexual reproduction (soredia and isidia), that may have facilitated their transport to the island by migrating birds or wind. Once on the island, it is possible that lichens persist by being chemically protected against herbivores. The great number of new generic and species records for Colombia is explained by the low number of studies in saxicolous lichens conducted so far in the country, particularly on coastal areas and remote islands. Only two species of vascular plants were collected, a grass, Paspalum sp., and a fern, Pityrogramma calomelanos, and both of them correspond to new determinations for Malpelo. A moss species previously reported but with no positive identification was collected and identified as Octoblepharum albidum. Other species previously reported, for example, some species of shrubs, were not observed. The low number of vascular plants is probably due to a combination of soil conditions and herbivory by land crabs. This study is the first complete inventory of the flora of Malpelo and is a starting and reference point for future comparisons among islands in the Eastern

Cannabis as a shareable commodity in a social discounting task.

Cannabis use and cannabis use disorder diagnoses continue to increase in United States college-aged students as more states legalize recreational cannabis. Previous studies have attempted to associate cannabis use with delay discount rates, which involves participants making choices for smaller sooner versus larger later hypothetical rewards. More smaller sooner choices result in higher discount rates and suggest increased impulsivity. Delay discounting studies have shown a significant, but small effect size with people who use cannabis more likely to choose the smaller sooner rewards, relative to people who do not use cannabis. The present study tested whether students with different experience using cannabis (people who currently use cannabis, people who formerly used cannabis, or people who never used cannabis) would be sensitive to sharing a proportion of hypothetical marijuana with another individual at a given social distance, as a putative measure for cannabis value. Results from two separate data sets showed that students classified as current cannabis users were significantly less likely to share a proportion of hypothetical marijuana across a range of social distances, relative to students that self-reported never using cannabis. Students classified as either former or current users were not statistically different. These results were consistent with previous delay discounting results and showed a medium effect size (η² ≥ 0.10) for each data set, both separately and when combined. These results indicate that social distance is a meaningful variable that can be used in a modified discounting task to assess differential cannabis value in a student population who are increasingly susceptible to cannabis use disorder. These results may have future clinical implications. Social discount rates for cannabis may be able to differentiate individuals who will continue recreational use versus individuals that may develop cannabis dependence problems. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The relationship between discrimination, alcohol use severity, and PTSD symptoms among Latinx heavy drinkers.

INTRODUCTION: Discrimination is linked to alcohol use severity among Latinx adults, who also show high prevalence rates of PTSD compared to non-Latinx adults. We know little about whether PTSD symptoms affects the relationship between discrimination and alcohol use severity. We hypothesized that the association between discrimination and alcohol use severity might differ by level of PTSD symptom severity. METHODS: This is a secondary cross-sectional analysis of data collected at baseline from a completed randomized clinical trial testing the relative efficacy of a culturally adapted motivational interview designed to address discrimination and drinking behavior against an unadapted motivational interview for Latinx adults. Eligible participants screened positive for the NIAAA Single Alcohol Screening Question for heavy drinking days, identified as Latinx, and were 18-65 years old. We assessed the Everyday Discrimination Scale, Primary Care PC-PTSD screener, Alcohol Use Disorder Identification Test, and the Short Acculturation Scale for Hispanics. The study analyzed the main and interactive effects of discrimination and PTSD symptoms on alcohol use severity, while controlling for age, sex, household income, and acculturation. RESULTS: After controlling for covariates in model 2, the interaction of discrimination and PTSD symptoms was significantly related to alcohol use severity. Simple slopes analysis indicated that discrimination was positively related to alcohol use severity among those with high (1 SD above the mean) but not low (1 SD below the mean) levels of PTSD symptoms. CONCLUSIONS: Evidence suggests that the experiences of discrimination were associated with alcohol use severity among those who reported more PTSD symptoms. Specifically, discrimination may have a stronger effect on alcohol use severity among Latinx adults who report more PTSD symptoms. Screening Latinx adults for heavy drinking days, discrimination, and PTSD symptoms is clinically important. Culturally adapted alcohol interventions that target discrimination may be particularly effective for Latinx individuals with more PTSD symptoms.

Effects of 700 and 3500 MHz 5G radiofrequency exposure on developing zebrafish embryos.

Telecommunications industries are rapidly deploying the fifth generation (5G) spectrum and there is public concern about the safety and health impacts of this type of Radio Frequency Radiation (RFR), in part because of the lack of comparable scientific evidence. In this study we have used a validated commercially available setting producing a uniform field to expose zebrafish embryos (ZFe) to unmodulated 700 and 3500 MHz frequencies. We have combined a battery of toxicity, developmental and behavioral assays to further explore potential RFR effects. Our neurobehavioral profiles include a tail coiling assay, a light/dark activity assay, two thigmotaxis anxiety assays (auditory and visual stimuli), and a startle response - habituation assay in response to auditory stimuli. ZFe were exposed for 1 and 4 h during the blastula period of development and endpoints evaluated up to 120 hours post fertilization (hpf). Our results show no effects on mortality, hatching or body length. However, we have demonstrated specific organ morphological effects, and behavioral effects in activity, anxiety-like behavior, and habituation that lasted in larvae exposed during the early embryonic period. A decrease in acetylcholinesterase activity was also observed and could explain some of the observed behavioral alterations. Interestingly, effects were more pronounced in ZFe exposed to the 700 MHz frequency, and especially for the 4 h exposure period. In addition, we have demonstrated that our exposure setup is robust, flexible with regard to frequency and power testing, and highly comparable. Future work will include exposure of ZFe to 5G modulated signals for different time periods to better understand the potential health effects of novel 5G RFR.

Seroprevalence status of vaccine-preventable diseases in migrants living in shelter centers in Barcelona, Spain.

INTRODUCTION: Almost 281 million people were living in a foreign country in 2022, and more than 100 million were displaced because of war conflicts and human right violations. Vaccination coverage of infectious diseases in migrants from some disadvantaged settings could be lower than reception countries populations, consequently seroprevalence studies and better access to vaccination could contribute to reducing these differences. METHODS: A descriptive retrospective cross-sectional study was conducted including migrants, living ≤5 years in the reception country and ≥16 years old, who requested a medical exam between January 1st, 2020 and January 31st, 2021. Seroprevalence assessment was performed, and vaccination was offered to those individuals without immunity to hepatitis B, hepatitis A, varicella, measles, mumps, and rubella. RESULTS: A total of 315 migrants were attended during the study period. Immunity protection at arrival was 252/296 (85.1%) for measles, 274/295 (92.9%) for rubella, 257/296 (86.8%) for mumps, 264/295 (89.5%) for varicella, 267/313 (85.3%) for hepatitis A, and 104/300 (34.6%) for hepatitis B. The final immunity protection after full vaccination schedules was 278/296 (93.9%) for measles, 287/295 (97.3%) for rubella, 274/296 (92.6%) for mumps, 276/295 (93.6%) for varicella, 280/313 (89.5%) for hepatitis A, and 139/300 (46.3%) for hepatitis B. CONCLUSIONS: The vaccination intervention has increased immunity rates for the studied diseases in the attended migrants in our center, however, such interventions should be maintained to reach local population immunization levels. Moreover, the collaboration between shelter and reference specialized health centers is fundamental to implement such vaccination programs.

Case report: Efficacy of immunotherapy as conversion therapy in dMMR/MSI-H colorectal cancer: a case series and review of the literature.

Immunotherapy has demonstrated a role in the therapeutic landscape of a small subset of patients with colorectal carcinoma (CRC) that harbor a microsatellite instability (MSI-H) status due to a deficient DNA mismatch repair (dMMR) system. The remarkable responses to immune checkpoint inhibitors (ICIs) are now being tested in the neoadjuvant setting in localized CRC, where the dMMR/MSI-H status can be found in up to 15% of patients, with remarkable results obtained in NICHE2 and 3 trials, among others. This case series aims to report our experience at a tertiary center and provide a comprehensive analysis of the possible questions and challenges to overcome if ICIs were established as standard of care in a neoadjuvant setting, as well as the potential role they may have as conversion therapy not only in locoregional advanced CRC but also in oligometastatic disease.

Characterization of Polylepis tarapacana Life Forms in the Highest-Elevation Altiplano in South America: Influence of the Topography, Climate and Human Uses.

In the upper vegetation limit of the Andes, trees change to shrub forms or other life forms, such as low scrubs. The diversity of life forms decreases with elevation; tree life forms generally decrease, and communities of shrubs and herbs increase in the Andean highlands. Most of treeline populations in the northwestern Argentina Altiplano are monospecific stands of Polylepis tarapacana, a cold-tolerant evergreen species that is able to withstand harsh climatic conditions under different life forms. There are no studies for P. tarapacana that analyze life forms across environmental and human impact gradients relating them with environmental factors. This study aims to determine the influence of topographic, climatic, geographic and proxies to human uses on the occurrence of life forms in P. tarapacana trees. We worked with 70 plots, and a new proposal of tree life form classification was presented for P. tarapacana (arborescent, dwarf trees, shrubs and brousse tigrée). We describe the forest biometry of each life form and evaluate the frequency of these life forms in relation to the environmental factors and human uses. The results show a consistency in the changes in the different life forms across the studied environmental gradients, where the main changes were related to elevation, slope and temperature.

Impact of nutritional and educational support on home enteral nutrition.

BACKGROUND: Home Enteral Nutrition (HEN) is used to prevent or correct malnutrition in outpatients. Due to the complexity of this process, the indication, follow-up, and results of an educational program of HEN patients was evaluated. METHODS: A prospective, observational, real-life, multicenter study was performed in 21 Spanish Hospital. Patients receiving HEN by nasogastric tube or ostomy were included. The following variables were collected: age, gender, HEN indication, type of formula, nutritional requirements, laboratory variables, complications, and quality standards of the educational program. To calculate the energy and protein requirements, the FAO/WHO/UNU formula was used considering the adjusted weight of the patients. All data were analyzed using SPSS.24. RESULTS: 414 patients were included. Most conditions diagnosed were neurodegenerative diseases (64.8%). 100 (25.3%) were diabetic. The mean weight was 59.3 ± 10.4 kg and BMI 22.6 ± 3.2. Moderate protein-calorie malnutrition was predominant at baseline (46.4%). Improvement in nutritional status at six months was recorded in more than 75% of patients (p < 0.05). Tolerance problems, diarrhea and abdominal distension fell between the 3- and 6-month visits (p < 0.05). Patients who received intermittent EN had fewer tolerance-related effects (OR 0.042; 95% CI 0.006-0.279) and less diarrhoea (OR 0.042; 95% CI 0.006-0.279). At the baseline and 6-month visits, compliance with the educational measures proposed by the prescriber was ≥ 99%. CONCLUSION: The nutritional assessment to prescribe individualized HEN to each patient, together with educational measures and training in the proper use of this treatment for both patients and trainers, improves nutritional status and reduces the onset of adverse events.

Structural basis of histone H2A lysine 119 deubiquitination by Polycomb Repressive Deubiquitinase BAP1/ASXL1.

The maintenance of gene expression patterns during metazoan development is achieved by the actions of Polycomb group (PcG) complexes. An essential modification marking silenced genes is monoubiquitination of histone H2A lysine 119 (H2AK119Ub) deposited by the E3 ubiquitin ligase activity of the non-canonical Polycomb Repressive Complex 1. The Polycomb Repressive Deubiquitinase (PR-DUB) complex cleaves monoubiquitin from histone H2A lysine 119 (H2AK119Ub) to restrict focal H2AK119Ub at Polycomb target sites and to protect active genes from aberrant silencing. BAP1 and ASXL1, subunits that form active PR-DUB, are among the most frequently mutated epigenetic factors in human cancers, underscoring their biological importance. How PR-DUB achieves specificity for H2AK119Ub to regulate Polycomb silencing is unknown, and the mechanisms of most of the mutations in BAP1 and ASXL1 found in cancer have not been established. Here we determine a cryo-EM structure of human BAP1 bound to the ASXL1 DEUBAD domain in complex with a H2AK119Ub nucleosome. Our structural, biochemical, and cellular data reveal the molecular interactions of BAP1 and ASXL1 with histones and DNA that are critical for remodeling the nucleosome and thus establishing specificity for H2AK119Ub. These results further provide a molecular explanation for how >50 mutations in BAP1 and ASXL1 found in cancer can dysregulate H2AK119Ub deubiquitination, providing new insight into understanding cancer etiology. One Sentence Summary: We reveal the molecular mechanism of nucleosomal H2AK119Ub deubiquitination by human BAP1/ASXL1.

Structural basis of histone H2A lysine 119 deubiquitination by Polycomb repressive deubiquitinase BAP1/ASXL1.

Histone H2A lysine 119 (H2AK119Ub) is monoubiquitinated by Polycomb repressive complex 1 and deubiquitinated by Polycomb repressive deubiquitinase complex (PR-DUB). PR-DUB cleaves H2AK119Ub to restrict focal H2AK119Ub at Polycomb target sites and to protect active genes from aberrant silencing. The PR-DUB subunits (BAP1 and ASXL1) are among the most frequently mutated epigenetic factors in human cancers. How PR-DUB establishes specificity for H2AK119Ub over other nucleosomal ubiquitination sites and how disease-associated mutations of the enzyme affect activity are unclear. Here, we determine a cryo-EM structure of human BAP1 and the ASXL1 DEUBAD in complex with a H2AK119Ub nucleosome. Our structural, biochemical, and cellular data reveal the molecular interactions of BAP1 and ASXL1 with histones and DNA that are critical for restructuring the nucleosome and thus establishing specificity for H2AK119Ub. These results further provide a molecular explanation for how >50 mutations in BAP1 and ASXL1 found in cancer can dysregulate H2AK119Ub deubiquitination, providing insight into understanding cancer etiology.