The maternal protein NLRP5 stabilizes UHRF1 in the cytoplasm: implication for the pathogenesis of multilocus imprinting disturbance.

We have recently discovered that the so-called subcortical maternal complex (SCMC) proteins composing of cytoplasmic lattices are destabilized in Uhrf1 knockout murine fully grown oocytes (FGOs). Here we report that human UHRF1 interacts with human NLRP5 and OOEP, which are core components of the SCMC. Moreover, NLRP5 and OOEP interact with DPPA3, which is an essential factor for exporting UHRF1 from the nucleus to the cytoplasm in oocytes. We identify that NLRP5, not OOEP, stabilizes UHRF1 protein in the cytoplasm utilizing specifically engineered cell lines mimicking UHRF1 status in oocytes and preimplantation embryos. Further, UHRF1 is destabilized both in the cytoplasm and nucleus of Nlrp5 knockout murine FGOs. Since pathogenic variants of the SCMC components frequently cause multilocus imprinting disturbance and UHRF1 is essential for maintaining CpG methylation of imprinting control regions during preimplantation development, our results suggest possible pathogenesis behind the disease, which has been a long-standing mystery.

DPPA3 facilitates genome-wide DNA demethylation in mouse primordial germ cells.

BACKGROUND: Genome-wide DNA demethylation occurs in mammalian primordial germ cells (PGCs) as part of the epigenetic reprogramming important for gametogenesis and resetting the epigenetic information for totipotency. Dppa3 (also known as Stella or Pgc7) is highly expressed in mouse PGCs and oocytes and encodes a factor essential for female fertility. It prevents excessive DNA methylation in oocytes and ensures proper gene expression in preimplantation embryos: however, its role in PGCs is largely unexplored. In the present study, we investigated whether or not DPPA3 has an impact on CG methylation/demethylation in mouse PGCs. RESULTS: We show that DPPA3 plays a role in genome-wide demethylation in PGCs even before sex differentiation. Dppa3 knockout female PGCs show aberrant hypermethylation, most predominantly at H3K9me3-marked retrotransposons, which persists up to the fully-grown oocyte stage. DPPA3 works downstream of PRDM14, a master regulator of epigenetic reprogramming in embryonic stem cells and PGCs, and independently of TET1, an enzyme that hydroxylates 5-methylcytosine. CONCLUSIONS: The results suggest that DPPA3 facilitates DNA demethylation through a replication-coupled passive mechanism in PGCs. Our study identifies DPPA3 as a novel epigenetic reprogramming factor in mouse PGCs.

Combined and differential roles of ADD domains of DNMT3A and DNMT3L on DNA methylation landscapes in mouse germ cells.

DNA methyltransferase 3A (DNMT3A) and its catalytically inactive cofactor DNA methyltransferase 3-Like (DNMT3L) proteins form functional heterotetramers to deposit DNA methylation in mammalian germ cells. While both proteins have an ATRX-DNMT3-DNMT3L (ADD) domain that recognizes histone H3 tail unmethylated at lysine-4 (H3K4me0), the combined and differential roles of the domains in the two proteins have not been fully defined in vivo. Here we investigate DNA methylation landscapes in female and male germ cells derived from mice with loss-of-function amino acid substitutions in the ADD domains of DNMT3A and/or DNMT3L. Mutations in either the DNMT3A-ADD or the DNMT3L-ADD domain moderately decrease global CG methylation levels, but to different degrees, in both germ cells. Furthermore, when the ADD domains of both DNMT3A and DNMT3L lose their functions, the CG methylation levels are much more reduced, especially in oocytes, comparable to the impact of the Dnmt3a/3L knockout. In contrast, aberrant accumulation of non-CG methylation occurs at thousands of genomic regions in the double mutant oocytes and spermatozoa. These results highlight the critical role of the ADD-H3K4me0 binding in proper CG and non-CG methylation in germ cells and the various impacts of the ADD domains of the two proteins.

Detection of newly synthesized RNA reveals transcriptional reprogramming during ZGA and a role of Obox3 in totipotency acquisition.

Zygotic genome activation (ZGA) after fertilization enables the maternal-to-zygotic transition. However, the global view of ZGA, particularly at initiation, is incompletely understood. Here, we develop a method to capture and sequence newly synthesized RNA in early mouse embryos, providing a view of transcriptional reprogramming during ZGA. Our data demonstrate that major ZGA gene activation begins earlier than previously thought. Furthermore, we identify a set of genes activated during minor ZGA, the promoters of which show enrichment of the Obox factor motif, and find that Obox3 or Obox5 overexpression in mouse embryonic stem cells activates ZGA genes. Notably, the expression of Obox factors is severely impaired in somatic cell nuclear transfer (SCNT) embryos, and restoration of Obox3 expression corrects the ZGA profile and greatly improves SCNT embryo development. Hence, our study reveals dynamic transcriptional reprogramming during ZGA and underscores the crucial role of Obox3 in facilitating totipotency acquisition.

H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation.

Histone H3 lysine 4 mono-methylation (H3K4me1) marks poised or active enhancers. KMT2C (MLL3) and KMT2D (MLL4) catalyze H3K4me1, but their histone methyltransferase activities are largely dispensable for transcription during early embryogenesis in mammals. To better understand the role of H3K4me1 in enhancer function, we analyze dynamic enhancer-promoter (E-P) interactions and gene expression during neural differentiation of the mouse embryonic stem cells. We found that KMT2C/D catalytic activities were only required for H3K4me1 and E-P contacts at a subset of candidate enhancers, induced upon neural differentiation. By contrast, a majority of enhancers retained H3K4me1 in KMT2C/D catalytic mutant cells. Surprisingly, H3K4me1 signals at these KMT2C/D-independent sites were reduced after acute depletion of KMT2B, resulting in aggravated transcriptional defects. Our observations therefore implicate KMT2B in the catalysis of H3K4me1 at enhancers and provide additional support for an active role of H3K4me1 in enhancer-promoter interactions and transcription in mammalian cells.

The 2024 Noto Peninsula Earthquake and the Strategy of Medical Assistance from the Tohoku University Hospital.

A moment magnitude (Mw) 7.5 earthquake (the Global IDentifire (GLIDE) number: # Q-2024-000001-JPN) struck the Noto Peninsula of Ishikawa Prefecture on 1 January 2024 at 16:10 (Japan Standard Time). The reversed fault, 150 km in length and subducting beneath the peninsula, resulted in maximum seismic intensity 7 shaking, triggered the tsunami, destroyed over 43 thousand buildings, and disrupted roads and lifelines. The disaster claimed 236 deaths, including 15 indirect disaster deaths as of Jan. 28, 2024. There were Disaster Base Hospitals (DBHs) in the region, which survived structurally but suffered from impaired functions and the surge of medical needs of affected people. The disaster medical system of Japan immediately responded and coordinated the hundreds of emergency medical teams (EMTs), i.e., the Japan Disaster Medical Assistance Team (DMAT), from all over the country. Tohoku University Hospital, which had the experience of the 2011 Great East Japan Earthquake (GEJE), joined the coordinated response, dispatching a chain of DMATs, which helped the medical and public health coordination in Wajima City. The medical and public health needs included injuries, non-communicable diseases, infectious diseases, mental health issues, and maternal and child health issues, which were similar in the affected communities in GEJE. Although the actual damage far exceeded expectations, the structural retrofitting and business continuity plans of DBHs and the coordinated response of the national disaster medical system enhanced the effectiveness of medical and public health response.

Spatiotemporal DNA methylation dynamics shape megabase-scale methylome landscapes.

DNA methylation is an essential epigenetic mechanism that regulates cellular reprogramming and development. Studies using whole-genome bisulfite sequencing have revealed distinct DNA methylome landscapes in human and mouse cells and tissues. However, the factors responsible for the differences in megabase-scale methylome patterns between cell types remain poorly understood. By analyzing publicly available 258 human and 301 mouse whole-genome bisulfite sequencing datasets, we reveal that genomic regions rich in guanine and cytosine, when located near the nuclear center, are highly susceptible to both global DNA demethylation and methylation events during embryonic and germline reprogramming. Furthermore, we found that regions that generate partially methylated domains during global DNA methylation are more likely to resist global DNA demethylation, contain high levels of adenine and thymine, and are adjacent to the nuclear lamina. The spatial properties of genomic regions, influenced by their guanine-cytosine content, are likely to affect the accessibility of molecules involved in DNA (de)methylation. These properties shape megabase-scale DNA methylation patterns and change as cells differentiate, leading to the emergence of different megabase-scale methylome patterns across cell types.

Serial assessment of computed tomography angiography for pulmonary and systemic arteries using a reduced contrast agent dose for the diagnosis of systemic artery-to-pulmonary artery shunts.

PURPOSE: To evaluate the diagnostic performance and feasibility of a modified computed tomography (CT) scan protocol, we performed a serial assessment of the computed tomography angiography for pulmonary artery (CTA-P) and systemic artery (CTA-S) (CTA-PS) using a reduced contrast agent dose to diagnose systemic artery-to-pulmonary artery shunts (SPSs). MATERIALS AND METHODS: Twenty-five patients who underwent multiphase contrast-enhanced chest CT and conventional chest angiography were included. Three image sets (CTA-P, CTA-S, and CTA-PS) were evaluated by two board-certified radiologists. The visualization of the CT image findings associated with SPSs, such as filling defects and enhancement in the pulmonary arteries, was evaluated using a 5-point scale. RESULTS: The diagnostic performance (sensitivity, specificity, and accuracy) of CT imaging findings associated with SPSs in CTA-P and CTA-PS were as follows: CTA-P, 57.1%, 87.5%, and 62.0%; CTA-PS, 81.0%, 100.0%, and 84.0%. CT findings associated with SPSs in CTA-P were significantly sensitive to the CTA-PS protocol. There were no significant differences between the CTA-S and CTA-PS protocols. The area under the curve (AUC) of the CT imaging findings associated with SPSs in the CTA-P and CTA-PS groups was 0.835 and 0.911, respectively (P = 0.191). The AUC of the CT imaging findings associated with SPSs in CTA-S and CTA-PS were 0.891 and 0.926, respectively (P = 0.373). CONCLUSION: CTA-PS using a reduced contrast agent dose protocol could improve the overall diagnostic confidence of SPSs, owing to better visualization of CT imaging findings associated with SPSs compared to individual assessments of CTA-P or CTA-S. Therefore, CTA-PS can be used as an alternative preembolization evaluation modality to conventional angiography in patients with hemoptysis suspected of having SPSs.

Is non-synesthetes' B Blue? Grapheme-color association improves non-synesthetes' detection in visual search.

Grapheme-color synesthesia is expected to provide a clue to solving the "binding problem" of visual features. Synesthetic research uses non-synesthetes as a control group and shows that synesthetes perform better with synesthetic color congruency, while non-synesthetes' performances do not. However, non-synesthetes also have certain grapheme-color associations. Therefore, this study examined whether non-synesthetes' grapheme-color associations improve their performance in a visual search task. The results indicated that non-synesthetes were significantly faster at detecting congruent targets with their grapheme-color associations, such as red for "A," blue for "B," and yellow for "C." However, the effect was not found in relation to numerical characters. This study has implications for future neuroscience and consciousness research regarding grapheme-color synesthesia.

The DNMT3A ADD domain is required for efficient de novo DNA methylation and maternal imprinting in mouse oocytes.

Establishment of a proper DNA methylation landscape in mammalian oocytes is important for maternal imprinting and embryonic development. De novo DNA methylation in oocytes is mediated by the DNA methyltransferase DNMT3A, which has an ATRX-DNMT3-DNMT3L (ADD) domain that interacts with histone H3 tail unmethylated at lysine-4 (H3K4me0). The domain normally blocks the methyltransferase domain via intramolecular interaction and binding to histone H3K4me0 releases the autoinhibition. However, H3K4me0 is widespread in chromatin and the role of the ADD-histone interaction has not been studied in vivo. We herein show that amino-acid substitutions in the ADD domain of mouse DNMT3A cause dwarfism. Oocytes derived from homozygous females show mosaic loss of CG methylation and almost complete loss of non-CG methylation. Embryos derived from such oocytes die in mid-to-late gestation, with stochastic and often all-or-none-type CG-methylation loss at imprinting control regions and misexpression of the linked genes. The stochastic loss is a two-step process, with loss occurring in cleavage-stage embryos and regaining occurring after implantation. These results highlight an important role for the ADD domain in efficient, and likely processive, de novo CG methylation and pose a model for stochastic inheritance of epigenetic perturbations in germ cells to the next generation.

Dynamic nucleosome remodeling mediated by YY1 underlies early mouse development.

Nucleosome positioning can alter the accessibility of DNA-binding proteins to their cognate DNA elements, and thus its precise control is essential for cell identity and function. Mammalian preimplantation embryos undergo temporal changes in gene expression and cell potency, suggesting the involvement of dynamic epigenetic control during this developmental phase. However, the dynamics of nucleosome organization during early development are poorly understood. In this study, using a low-input MNase-seq method, we show that nucleosome positioning is globally obscure in zygotes but becomes well defined during subsequent development. Down-regulation of the chromatin assembly in embryonic stem cells can partially reverse nucleosome organization into a zygote-like pattern, suggesting a possible link between the chromatin assembly pathway and fuzzy nucleosomes in zygotes. We also reveal that YY1, a zinc finger-containing transcription factor expressed upon zygotic genome activation, regulates the de novo formation of well-positioned nucleosome arrays at the regulatory elements through identifying YY1-binding sites in eight-cell embryos. The YY1-binding regions acquire H3K27ac enrichment around the eight-cell and morula stages, and YY1 depletion impairs the morula-to-blastocyst transition. Thus, our study delineates the remodeling of nucleosome organization and its underlying mechanism during early mouse development.

Combined resistant dextrin and low-dose Mg oxide administration increases short-chain fatty acid and lactic acid production by gut microbiota.

The consumption of resistant dextrin improves constipation, while its fermentation and degradation by the intestinal microbiota produce short-chain fatty acids (SCFA) and lactic acid, which have beneficial effects on host metabolism and immunity. Mg oxide (MgO) is an important mineral that is used to treat constipation. Therefore, resistant dextrin and MgO are often administered together to improve constipation. However, limited information is available regarding the effect of this combination on SCFA and lactic acid production. Crl:CD1(ICR) mice were fed a Mg-free diet with 5% resistant dextrin, followed by oral administration of MgO. We collected the cecum contents and measured SCFA and lactic acid levels. Additionally, the human subjects received resistant dextrin and Mg supplements as part of their habitual diet. The results of this study demonstrate that intestinal microbiota cannot promote SCFA and lactic acid production in the absence of Mg. In a mouse model, low doses of MgO promoted the production of SCFA and lactic acid, whereas high doses decreased their production. In humans, the combined consumption of resistant dextrin and Mg supplements increased the production of SCFA and lactic acid. The production of SCFA and lactic acid from dietary fiber may be augmented by the presence of MgO.

Effects of Additional Granola in Children's Breakfast on Nutritional Balance, Sleep and Defecation: An Open-Label Randomized Cross-Over Trial.

The contribution of breakfast to daily nutrient intake is low, particularly among children, at only about 20%, and it is difficult to determine whether children are receiving adequate nutrients at breakfast. Although alterations in breakfast content are considered to affect lifestyle habits such as sleep and defecation, there have been few intervention studies in children. The relationship between nutritional balance, dietary intake, and lifestyle habits in children remains unclear. We conducted an intervention study on elementary school children's breakfasts and observed the effects of improving the nutritional balance of breakfast on sleep parameters and defecation status. An intervention study was conducted with 26 elementary school students in Tokyo. The study design was an open-label randomized cross-over trial. Subjects consumed their usual breakfast during the control period and a granola snack containing soy protein in addition to their usual breakfast during the intervention period. Questionnaires regarding breakfast, sleep, and bowel movements were administered during each period. Based on the answers to these questionnaires, we compared the nutritional sufficiency of macronutrients, vitamins, and minerals (29 in total), as well as changes in sleep parameters and defecation status. The additional consumption of granola snacks increased the breakfast intake of 15 nutrients. The changes were particularly significant for iron, vitamin B1, vitamin D, and dietary fiber. During the intervention, sleep duration was decreased and wake-up time became earlier. In terms of defecation, the intervention did not change stool characteristics, but the frequency of defecations per week increased on average by 1.2 per week. These results suggest that the nutritional balance and the amount of breakfast are linked to sleep and defecation and that improving breakfast content can lead to lifestyle improvements in children.

Evacuation at Home Delayed the First Medical Intervention in Minamisanriku Town after the 2011 Great East Japan Earthquake.

INTRODUCTION: In Japan, evacuation at home is expected to increase in the future as a post-disaster evacuation type due to the pandemic, aging, and diverse disabilities of the population. However, more disaster-related indirect deaths occurred in homes than in evacuation centers after the 2011 Great East Japan Earthquake (GEJE). The health risks faced by evacuees at home have not been adequately discussed. STUDY OBJECTIVE: This study aimed to clarify the gap in disaster health management for evacuees at home compared to the evacuees at the evacuation centers in Minamisanriku Town, which lost all health care facilities after the 2011 GEJE. METHODS: This was a retrospective cross-sectional and quasi-experimental study based on the anonymized disaster medical records (DMRs) of patients from March 11 through April 10, 2011, that compared the evacuation-at-home and evacuation-center groups focusing on the day of the first medical intervention after the onset. Multivariable Cox regression analysis and propensity score (PS)-matching analysis were performed to identify the risk factors and causal relationship between the evacuation type and the delay of medical intervention. RESULTS: Of the 2,838 eligible patients, 460 and 2,378 were in the evacuation-at-home and evacuation-center groups, respectively. In the month after the onset, the evacuation-at-home group had significantly lower rates of respiratory and mental health diseases than the evacuation-center group. However, the mean time to the first medical intervention was significantly delayed in the evacuation-at-home group (19.3 [SD = 6.1] days) compared to that in the evacuation-center group (14.1 [SD = 6.3] days); P <.001). In the multivariable Cox regression analysis, the hazard ratio (HR) of delayed medical intervention for evacuation-at-home was 2.31 with a 95% confident interval of 2.07-2.59. The PS-matching analysis of the adjusted 459 patients in each group confirmed that evacuation at home was significantly associated with delays in the first medical intervention (P <.001). CONCLUSION: This study suggested, for the first time, the causal relationship between evacuation at home and delay in the first medical intervention by PS-matching analysis. Although evacuation at home had several advantages in reducing the frequencies of some diseases, the delay in medical intervention could exacerbate the symptoms and be a cause of indirect death. As more evacuees are likely to remain in their homes in the future, this study recommends earlier surveillance and health care provision to the home evacuees.

UHRF1 is essential for proper cytoplasmic architecture and function of mouse oocytes and derived embryos.

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a protein essential for the maintenance of DNA methylation in somatic cells. However, UHRF1 is predominantly localized in the cytoplasm of mouse oocytes and preimplantation embryos, where it may play a role unrelated to the nuclear function. We herein report that oocyte-specific Uhrf1 KO results in impaired chromosome segregation, abnormal cleavage division, and preimplantation lethality of derived embryos. Our nuclear transfer experiment showed that the phenotype is attributable to cytoplasmic rather than nuclear defects of the zygotes. A proteomic analysis of KO oocytes revealed the down-regulation of proteins associated with microtubules including tubulins, which occurred independently of transcriptomic changes. Intriguingly, cytoplasmic lattices were disorganized, and mitochondria, endoplasmic reticulum, and components of the subcortical maternal complex were mislocalized. Thus, maternal UHRF1 regulates the proper cytoplasmic architecture and function of oocytes and preimplantation embryos, likely through a mechanism unrelated to DNA methylation.

Effect of circadian clock and claudin regulations on inulin-induced calcium absorption in the mouse intestinal tract.

Dietary calcium supplementation has been shown to be an effective adjunct therapy in an inflammatory bowel disease model. Soluble dietary fiber reduces intestinal pH and is known to enhance calcium absorption. Although many circadian clock regulations of nutrient absorption in the intestinal tract have been reported, the effects of clock regulation on calcium absorption have yet to be understood. In this study, we investigated the timing of efficient calcium intake by measuring urinary calcium excretion in mice. The diurnal variations in channel-forming tight junctions (claudins) were detected in both the jejunum and ileum. Following 2 days of feeding with a Ca2+-free diet, Ca2+-containing diets with or without soluble fiber (inulin) were fed at specific timings, and urine was subsequently examined every 4 hr. There was an evident increase in urinary calcium concentration when the inulin diet was fed at the beginning of the resting period. The Claudin 2 (Cldn2) expression level also showed a significant day-night change, which seemed to be a mechanism for the increased calcium excretion after inulin intake. This diurnal rhythm and enhanced Cldn2 expression were abolished by disruption of the suprachiasmatic nucleus, the central clock in the hypothalamus. This study suggests that intestinal calcium absorption might be modulated by the circadian clock and that the intake of inulin is more effective at the beginning of the resting period in mice.

Mid-Point of the Active Phase Is Better to Achieve the Natriuretic Effect of Acute Salt Load in Mice.

Excess sodium intake and insufficient potassium intake are a prominent global issue because of their influence on high blood pressure. Supplementation of potassium induces kaliuresis and natriuresis, which partially explains its antihypertensive effect. Balancing of minerals takes place in the kidney and is controlled by the circadian clock; in fact, various renal functions exhibit circadian rhythms. In our previous research, higher intake of potassium at lunch time was negatively associated with blood pressure, suggesting the importance of timing for sodium and potassium intake. However, the effects of intake timing on urinary excretion remain unclear. In this study, we investigated the effect of 24 h urinary sodium and potassium excretion after acute sodium and potassium load with different timings in mice. Compared to other timings, the middle of the active phase resulted in higher urinary sodium and potassium excretion. In Clock mutant mice, in which the circadian clock is genetically disrupted, urinary excretion differences from intake timings were not observed. Restricted feeding during the inactive phase reversed the excretion timing difference, suggesting that a feeding-induced signal may cause this timing difference. Our results indicate that salt intake timing is important for urinary sodium and potassium excretion and provide new perspectives regarding hypertension prevention.

Novel compound heterozygous mutations in UHRF1 are associated with atypical immunodeficiency, centromeric instability and facial anomalies syndrome with distinctive genome-wide DNA hypomethylation.

Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is in most cases caused by mutations in either DNA methyltransferase (DNMT)3B, zinc finger and BTB domain containing 24, cell division cycle associated 7 or helicase lymphoid-specific. However, the causative genes of a few ICF patients remain unknown. We, herein, identified ubiquitin-like with plant homeodomain and really interesting new gene finger domains 1 (UHRF1) as a novel causative gene of one such patient with atypical symptoms. This patient is a compound heterozygote for two previously unreported mutations in UHRF1: c.886C > T (p.R296W) and c.1852C > T (p.R618X). The R618X mutation plausibly caused nonsense-mediated decay, while the R296W mutation changed the higher order structure of UHRF1, which is indispensable for the maintenance of CG methylation along with DNMT1. Genome-wide methylation analysis revealed that the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes. Structural and biochemical analyses revealed that the R296W mutation disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1 and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and proliferating cell nuclear antigen -associated factor 15 (PAF15). We confirmed that the R296W mutation causes hypomethylation at pericentromeric repeats by generating the HEK293 cell lines that mimic the patient's UHRF1 molecular context. Since proper interactions of the UHRF1 with LIG1, PAF15 and histone H3 are essential for the maintenance of CG methylation, the mutation could disturb the maintenance process. Evidence for the importance of the UHRF1 conformation for CG methylation in humans is, herein, provided for the first time and deepens our understanding of its role in regulation of CG methylation.

Health Emergency and Disaster Risk Management Workforce Development Strategies: Delphi Consensus Study.

INTRODUCTION: Health workforce development is essential for achieving the goals of an effective health system, as well as establishing national Health Emergency and Disaster Risk Management (Health EDRM). STUDY OBJECTIVE: The objective of this Delphi consensus study was to identify strategic recommendations for strengthening the workforce for Health EDRM in low- and middle-income countries (LMIC) and high-income countries (HIC). METHODS: A total of 31 international experts were asked to rate the level of importance (one being strongly unimportant to seven being strongly important) for 46 statements that contain recommendations for strengthening the workforce for Health EDRM. The experts were divided into a LMIC group and an HIC group. There were three rounds of rating, and statements that did not reach consensus (SD ≥ 1.0) proceeded to the next round for further ranking. RESULTS: In total, 44 statements from the LMIC group and 34 statements from the HIC group attained consensus and achieved high mean scores for importance (higher than five out of seven). The components of the World Health Organization (WHO) Health EDRM Framework with the highest number of recommendations were "Human Resources" (n = 15), "Planning and Coordination" (n = 7), and "Community Capacities for Health EDRM" (n = 6) in the LMIC group. "Policies, Strategies, and Legislation" (n = 7) and "Human Resources" (n = 7) were the components with the most recommendations for the HIC group. CONCLUSION: The expert panel provided a comprehensive list of important and actionable strategic recommendations on workforce development for Health EDRM.

The UHRF protein family in epigenetics, development, and carcinogenesis.

The UHRF protein family consists of multidomain regulatory proteins that sense modification status of DNA and/or proteins and catalyze the ubiquitylation of target proteins. Through their functional domains, they interact with other molecules and serve as a hub for regulatory networks of several important biological processes, including maintenance of DNA methylation and DNA damage repair. The UHRF family is conserved in vertebrates and plants but is missing from fungi and many nonvertebrate animals. Mammals commonly have UHRF1 and UHRF2, but, despite their high structural similarity, the two paralogues appear to have distinct functions. Furthermore, UHRF1 and UHRF2 show different expression patterns and different outcomes in gene knockout experiments. In this review, we summarize the current knowledge on the molecular function of the UHRF family in various biological pathways and discuss their roles in epigenetics, development, gametogenesis, and carcinogenesis, with a focus on the mammalian UHRF proteins.