FAM72A antagonizes UNG2 to promote mutagenic repair during antibody maturation.

Activation-induced cytidine deaminase (AID) catalyses the deamination of deoxycytidines to deoxyuracils within immunoglobulin genes to induce somatic hypermutation and class-switch recombination1,2. AID-generated deoxyuracils are recognized and processed by subverted base-excision and mismatch repair pathways that ensure a mutagenic outcome in B cells3-6. However, why these DNA repair pathways do not accurately repair AID-induced lesions remains unknown. Here, using a genome-wide CRISPR screen, we show that FAM72A is a major determinant for the error-prone processing of deoxyuracils. Fam72a-deficient CH12F3-2 B cells and primary B cells from Fam72a-/- mice exhibit reduced class-switch recombination and somatic hypermutation frequencies at immunoglobulin and Bcl6 genes, and reduced genome-wide deoxyuracils. The somatic hypermutation spectrum in B cells from Fam72a-/- mice is opposite to that observed in mice deficient in uracil DNA glycosylase 2 (UNG2)7, which suggests that UNG2 is hyperactive in FAM72A-deficient cells. Indeed, FAM72A binds to UNG2, resulting in reduced levels of UNG2 protein in the G1 phase of the cell cycle, coinciding with peak AID activity. FAM72A therefore causes U·G mispairs to persist into S phase, leading to error-prone processing by mismatch repair. By disabling the DNA repair pathways that normally efficiently remove deoxyuracils from DNA, FAM72A enables AID to exert its full effects on antibody maturation. This work has implications in cancer, as the overexpression of FAM72A that is observed in many cancers8 could promote mutagenesis.

Reproductive Outcomes of Patients Undergoing Uterine Artery Embolization for Uterine Fibroids: Proceedings from The Dr. James B. Spies Summit for Uterine Fibroid Research- a Society of Interventional Radiology Foundation Research Consensus Panel.

Reproductive outcomes after uterine artery embolization (UAE) for the treatment of uterine fibroids are challenging to study, leaving several unanswered questions surrounding the future fertility of patients undergoing the procedure. Subject matter experts from Interventional Radiology, Diagnostic Radiology, Obstetrics & Gynecology, and Reproductive Medicine participated in a Society of Interventional Radiology Foundation Research Consensus Panel to discuss and prioritize critical research topics focusing on fertility and reproductive outcomes in patients undergoing UAE for symptomatic uterine fibroids. After presentations and discussion of research ideas, the panelists prioritized the following topics for further investigation: 1) a prospective study of factors that influence implantation and gene expression in patients undergoing UAE or myomectomy over 1 year, 2) refinement of a classification system for uterine fibroids that can allow for more focused study design, which may include burden of fibroid disease, and 3) conjoint analysis/discrete choice experiments to better characterize those patients for whom fertility preservation is a high priority.

Use of n-Butyl-2-Cyanoacrylate for Fallopian Tube Embolization via Selective Catheterization in a Rabbit Model: Feasibility Study for Potential Nonsurgical Sterilization.

PURPOSE: To determine whether fallopian tube embolization with n-butyl-2-cyanoacrylate (nBCA) administered via a microcatheter in a rabbit model was technically feasible and resulted in short-term tubal occlusion. MATERIALS AND METHODS: In 10 female New Zealand white rabbits, the 2 cervices were cannulated using a 5-F catheter and hydrophilic guide wire transvaginally. Salpingography confirmed tubal patency bilaterally. A 2.4-F microcatheter was advanced to the distal fallopian tube, and nBCA/ethiodized oil was administered as the microcatheter was withdrawn to fill the length of the tube. A metallic coil was deployed prior to nBCA administration in half of the fallopian tubes. Rabbits were evaluated for tubal occlusion with salpingography at 1 month, followed by euthanasia and histopathologic analysis. Inflammation and fibrosis were graded from 0 (normal) to 3 (severe). RESULTS: Fallopian tube embolization was technically successful in 17 (85%) of 20 fallopian tubes. Thirteen (76%) of 17 embolized fallopian tubes were occluded at 1 month on salpingography (nBCA only, 7/9; nBCA and coil, 6/8). On histopathologic analysis, direct or indirect evidence of occlusion was observed in 14 (82%) of 17 fallopian tubes. Mild or early fibrosis was observed in 65% of the tubes. The mean inflammation and fibrosis scores for the embolized tubes were 0.62 and 0.94, respectively. CONCLUSIONS: This pilot study demonstrated that embolization of rabbit fallopian tubes using nBCA administered via a microcatheter is technically feasible and results in occlusion of most fallopian tubes in the short term with minimal inflammation. Investigation of efficacy in preventing pregnancy over the long term is warranted.

Added Value of Cone-Beam CT to Identify Arterial Supply during Genicular Artery Embolization for Knee Osteoarthritis.

PURPOSE: To evaluate if the addition of cone-beam computed tomography (CT) to digital subtraction angiography (DSA) improves the identification of the genicular arteries during genicular artery embolization (GAE) for knee pain secondary to osteoarthritis (OA). MATERIALS AND METHODS: This single-center study retrospectively analyzed 222 patients who underwent GAE for painful knee OA between May 2018 and April 2022. Intraprocedural cone-beam CT and DSA images were reviewed independently by 2 sets of interventional radiologists. DSA was performed for all patients. Technically adequate cone-beam CT was available for 205 patients (92.3%). The presence of the genicular arteries identified by cone-beam CT and DSA was compared using Φ coefficients. Embolization targets identified by both cone-beam CT and DSA were evaluated against those identified by DSA alone. RESULTS: Genicular arteries with the highest concordance between cone-beam CT and DSA were the inferior lateral (196 vs 198; Φ = 0.3530; P < .0001), superior lateral (197 vs 200; Φ = 0.3060; P < .0001), and superior medial genicular (186 vs 161; Φ = 0.2836; P < .0001) arteries. Cone-beam CT demonstrated higher rates of detection of the inferior medial (195 vs 178; Φ = 0.04573; P = .5150) and median genicular arteries (200 vs 192; Φ = 0.04573; P = .5150). Meanwhile, genicular arteries less frequently identified by cone-beam CT were the descending genicular (197 vs 200; Φ = -0.03186; P = .6502), superior patellar (175 vs 184; Φ = 0.1332; P = .0569), and recurrent anterior tibial (156 vs 186; Φ = 0.01809; P = .7969) arteries. Cone-beam CT in combination with DSA identified 13.4% (372 vs 328) more targets compared to DSA alone. CONCLUSIONS: Based on the results of the current study, cone-beam CT serves as a valuable adjunct for visualizing the genicular arteries during GAE, and together with DSA, it identifies more potential embolization targets.

Mycobacterium vaccae NCTC 11659, a Soil-Derived Bacterium with Stress Resilience Properties, Modulates the Proinflammatory Effects of LPS in Macrophages.

Inflammatory conditions, including allergic asthma and conditions in which chronic low-grade inflammation is a risk factor, such as stress-related psychiatric disorders, are prevalent and are a significant cause of disability worldwide. Novel approaches for the prevention and treatment of these disorders are needed. One approach is the use of immunoregulatory microorganisms, such as Mycobacterium vaccae NCTC 11659, which have anti-inflammatory, immunoregulatory, and stress-resilience properties. However, little is known about how M. vaccae NCTC 11659 affects specific immune cell targets, including monocytes, which can traffic to peripheral organs and the central nervous system and differentiate into monocyte-derived macrophages that, in turn, can drive inflammation and neuroinflammation. In this study, we investigated the effects of M. vaccae NCTC 11659 and subsequent lipopolysaccharide (LPS) challenge on gene expression in human monocyte-derived macrophages. THP-1 monocytes were differentiated into macrophages, exposed to M. vaccae NCTC 11659 (0, 10, 30, 100, 300 µg/mL), then, 24 h later, challenged with LPS (0, 0.5, 2.5, 250 ng/mL), and assessed for gene expression 24 h following challenge with LPS. Exposure to M. vaccae NCTC 11659 prior to challenge with higher concentrations of LPS (250 ng/mL) polarized human monocyte-derived macrophages with decreased IL12A, IL12B, and IL23A expression relative to IL10 and TGFB1 mRNA expression. These data identify human monocyte-derived macrophages as a direct target of M. vaccae NCTC 11659 and support the development of M. vaccae NCTC 11659 as a potential intervention to prevent stress-induced inflammation and neuroinflammation implicated in the etiology and pathophysiology of inflammatory conditions and stress-related psychiatric disorders.

Social needs and health-related quality of life among hematologic cancer survivors.

OBJECTIVES: Recent studies have examined social needs (social determinants of health) among cancer survivors, but studies have not specifically focused on patients with leukemia or lymphoma. We examined food insecurity and other social needs among hematologic cancer survivors, including individuals who had completed primary therapy for leukemia, lymphoma, or multiple myeloma. A particular focus of the study was on the relationship between social needs and health-related quality of life. METHODS: We conducted a postal survey of a multiethnic cohort of hematologic cancer survivors who reside in Augusta, GA, or the surrounding area and who had been treated at the Georgia Cancer Center. RESULTS: A total of 53 patients with a history of hematologic cancer (leukemia, lymphoma, or multiple myeloma) completed the survey (10.6% response rate). The mean age was 62.6 years. The participants were diverse according to annual household income and employment status. About two-thirds were white and almost one-third were African American. Five of 52 participants (9.6%) experienced food insecurity. Patients with food insecurity had poorer HRQOL compared with those who were food secure (63.3 vs. 87.33, p = 0.0308). A similar pattern was seen for those who had difficulty paying utility bills, those who had housing insecurity, and those who had to go without health care because of a lack of transportation. Overall, there was a statistically significant inverse association between HRQOL and number of social needs (p = 0.004). CONCLUSION: When caring for cancer survivors, social needs such as food insecurity and housing insecurity are important considerations for oncologists and primary care providers, especially when caring for patients with lower socioeconomic status and racial/ethnic minorities.

Visualization of uracils created by APOBEC3A using UdgX shows colocalization with RPA at stalled replication forks.

The AID/APOBEC enzymes deaminate cytosines in single-stranded DNA (ssDNA) and play key roles in innate and adaptive immunity. The resulting uracils cause mutations and strand breaks that inactivate viruses and diversify antibody repertoire. Mutational evidence suggests that two members of this family, APOBEC3A (A3A) and APOBEC3B, deaminate cytosines in the lagging-strand template during replication. To obtain direct evidence for the presence of these uracils, we engineered a protein that covalently links to DNA at uracils, UdgX, for mammalian expression and immunohistochemistry. We show that UdgX strongly prefers uracils in ssDNA over those in U•G or U:A pairs, and localizes to nuclei in a dispersed form. When A3A is expressed in these cells, UdgX tends to form foci. The treatment of cells with cisplatin, which blocks replication, causes a significant increase in UdgX foci. Furthermore, this protein- and hence the uracils created by A3A- colocalize with replication protein A (RPA), but not with A3A. Using purified proteins, we confirm that RPA inhibits A3A by binding ssDNA, but despite its overexpression following cisplatin treatment, RPA is unable to fully protect ssDNA created by cisplatin adducts. This suggests that cisplatin treatment of cells expressing APOBEC3A should cause accumulation of APOBEC signature mutations.

Ultrasound-Guided Chemical Component Separation with Botulinum Toxin A prior to Surgical Hernia Repair.

US-guided chemical component separation (CCS) of the abdominal musculature using botulinum toxin A can facilitate the surgical repair of large or complex hernias. Eight patients (2 women and 6 men with median age of 54 years [range, 34-78 years]) underwent preoperative US-guided CCS with hydrodissection before planned surgical repair of large or complex ventral (n = 4), inguinal (n = 2), and flank (n = 2) hernias by 2 interventional radiologists. Technical success rate of US-guided CCS procedures was 100%, and all patients achieved surgical closure a mean 34.1 days (range, 14-48 days) after US-guided CCS.

Genome-wide mapping of regions preferentially targeted by the human DNA-cytosine deaminase APOBEC3A using uracil-DNA pulldown and sequencing.

Activation-induced deaminase (AID) and apolipoprotein B mRNA-editing enzyme catalytic subunit (APOBEC) enzymes convert cytosines to uracils, creating signature mutations that have been used to predict sites targeted by these enzymes. Mutation-based targeting maps are distorted by the error-prone or error-free repair of these uracils and by selection pressures. To directly map uracils created by AID/APOBEC enzymes, here we used uracil-DNA glycosylase and an alkoxyamine to covalently tag and sequence uracil-containing DNA fragments (UPD-Seq). We applied this technique to the genome of repair-defective, APOBEC3A-expressing bacterial cells and created a uracilation genome map, i.e. uracilome. The peak uracilated regions were in the 5'-ends of genes and operons mainly containing tRNA genes and a few protein-coding genes. We validated these findings through deep sequencing of pulldown regions and whole-genome sequencing of independent clones. The peaks were not correlated with high transcription rates or stable RNA:DNA hybrid formation. We defined the uracilation index (UI) as the frequency of occurrence of TT in UPD-Seq reads at different original TC dinucleotides. Genome-wide UI calculation confirmed that APOBEC3A modifies cytosines in the lagging-strand template during replication and in short hairpin loops. APOBEC3A's preference for tRNA genes was observed previously in yeast, and an analysis of human tumor sequences revealed that in tumors with a high percentage of APOBEC3 signature mutations, the frequency of tRNA gene mutations was much higher than in the rest of the genome. These results identify multiple causes underlying selection of cytosines by APOBEC3A for deamination, and demonstrate the utility of UPD-Seq.

Photoactivatable Glycolipid Probes for Identifying Mycolate-Protein Interactions in Live Mycobacteria.

Mycobacteria have a distinctive glycolipid-rich outer membrane, the mycomembrane, which is a critical target for tuberculosis drug development. However, proteins that associate with the mycomembrane, or that are involved in its metabolism and host interactions, are not well-characterized. To facilitate the study of mycomembrane-related proteins, we developed photoactivatable trehalose monomycolate analogues that metabolically incorporate into the mycomembrane in live mycobacteria, enabling in vivo photo-cross-linking and click-chemistry-mediated analysis of mycolate-interacting proteins. When deployed in Mycobacterium smegmatis with quantitative proteomics, this strategy enriched over 100 proteins, including the mycomembrane porin (MspA), several proteins with known mycomembrane synthesis or remodeling functions (CmrA, MmpL3, Ag85, Tdmh), and numerous candidate mycolate-interacting proteins. Our approach is highly versatile, as it (i) enlists click chemistry for flexible protein functionalization; (ii) in principle can be applied to any mycobacterial species to identify endogenous bacterial proteins or host proteins that interact with mycolates; and (iii) can potentially be expanded to investigate protein interactions with other mycobacterial lipids. This tool is expected to help elucidate fundamental physiological and pathological processes related to the mycomembrane and may reveal novel diagnostic and therapeutic targets.

Superior Hypogastric Nerve Block for Pain Control after Uterine Artery Embolization: Effect of Addition of Steroids on Analgesia.

Superior hypogastric nerve block (SHNB) decreases pain and use of narcotic pain medication following uterine artery embolization (UAE). The purpose of this retrospective study was to evaluate the effect of the addition of a corticosteroid (triamcinolone) to SHNB on analgesia following UAE. Records of 16 patients were reviewed for when pain occurred or acutely worsened after the procedure. No major complications were identified. Patients reported that pain began or worsened an average of 33.8 hours after the procedure, when their average pain increased from 0.6/10 to 5.9/10 (P < .001). This suggests that addition of triamcinolone to SHNB could result in prolonged analgesia following UAE.

Survivorship issues in older breast cancer survivors.

PURPOSE: Almost half of breast cancer survivors are aged ≥ 65 years and the proportion is likely to increase due to the aging of the population. The objectives of this article were to review studies of health outcomes among older breast cancer survivors ≥ 65 years to identify gaps in the published literature and offer suggestions for future research. METHODS: The present review is based upon bibliographic searches in PubMed and CINAHL and relevant search terms. Articles published in English from January 1, 1970 through October 1, 2018 were identified using the following MeSH search terms and Boolean algebra commands. RESULTS: This review has revealed that older breast cancer survivors cope with health issues related to cancer treatment and the aging process, including comorbidities, osteoporosis, symptoms, physical functioning, cognitive functioning, nutrition, and physical activity. CONCLUSIONS: Additional research is needed to examine therapeutic interventions to address the health conditions older breast cancer survivors are coping with. Particular focus of further research should be on the nutritional status and physical activity levels of older breast cancer survivors. Individualized nutrition plans and tailored physical activity programs for older survivors are needed that meet people where they are and that form habits.

Predictors of Prostatic Artery Embolization Technical Outcomes: Patient and Procedural Factors.

PURPOSE: To identify technical factors that significantly change prostatic artery embolization (PAE) technical outcomes and to derive and test technical outcome predictive models. MATERIALS AND METHODS: Retrospective analysis of PAEs performed by 2 operators (OPs) was performed: OP1, between April 2014 and May 2017 (n = 150); OP2, between February 2017 and December 2017 (n = 67). Multivariate analysis with mixed-effects modeling was used to test significance and derive predictive models. Mean difference was used to analyze prediction accuracy. RESULTS: Moderate versus none subjective iliac tortuosity grade (SITG) and the presence of internal iliac atherosclerosis (PIIAA) versus none were associated with the following respective technical outcome increases: procedure time (PT): 43% (P < .01), 16% (P < .01); fluoroscopy time (FT): 47% (P < .01), 25% (P < .01); contrast volume (CV): 25.6 mL (P < .001), 13.7 mL (P = .01); and dose area product (DAP) 52% (P < .01), 20% (P = 0.03). Prostatic artery origin left obturator versus left superior vesical was associated with a 24% (P = .01) DAP decrease. For every 1 cc that prostate volume increased, CV decreased on average by 0.1 mL (P = .05). For every 1-cm decrease in patient height and 1-kg increase in weight, DAP increased on average by 0.02% (P < .01) for each. Unilateral versus bilateral versus 3-vessel embolization resulted in a 16.3-mL CV decrease on average for each additional vessel embolized (P = .03). The mean absolute differences between predicted and measured technical outcome values were: PT: 16 minutes, FT: 7 minutes, CV: 25 mL, and DAP: 44 Gy·cm2. CONCLUSIONS: In this study, higher SITGs and PIIAA most likely contributed to higher technical outcomes when controlling for the 2 OPs.

Concordance between self-report and medical records of preventive healthcare delivery among a sample of disadvantaged patients from four aboriginal community controlled health services.

BACKGROUND: This cross-sectional study aimed to explore, among a sample of patients attending one of four Aboriginal Health Services (ACCHSs), the degree of concordance between self-report and medical records for whether screening for key healthcare items had ever been undertaken, or had been undertaken within the recommended timeframe. METHODS: Across the four ACCHSs, a convenience sample of 109 patients was recruited. Patients completed a self-report computer survey assessing when they last had preventive care items undertaken at the service. ACCHS staff completed a medical record audit for matching items. The degree of concordance (i.e. the percentage of cases in which self-reports matched responses from the medical record) was calculated. RESULTS: Concordance was relatively high for items including assessment of Body Mass Index and blood pressure, but was substantially lower for items including assessment of waist circumference, alcohol intake, physical activity, and diet. CONCLUSIONS: Reliance on either patient self-report or medical record data for assessing the level of preventive care service delivery by ACCHSs requires caution. Efforts to improve documentation of some preventive care delivery in medical records are needed. These findings are likely to also apply to patients in other general practice settings.

Can a continuous quality improvement program create culturally safe emergency departments for Aboriginal people in Australia? A multiple baseline study.

BACKGROUND: Providing culturally safe health care can contribute to improved health among Aboriginal people. However, little is known about how to make hospitals culturally safe for Aboriginal people. This study assessed the impact of an emergency department (ED)-based continuous quality improvement program on: the accuracy of recording of Aboriginal status in ED information systems; incomplete ED visits among Aboriginal patients; and the cultural appropriateness of ED systems and environments. METHODS: Between 2012 and 2014, the Aboriginal Identification in Hospitals Quality Improvement Program (AIHQIP) was implemented in eight EDs in NSW, Australia. A multiple baseline design and analysis of linked administrative data were used to assess program impact on the proportion of Aboriginal patients correctly identified as Aboriginal in ED information systems and incomplete ED visits in Aboriginal patients. Key informant interviews and document review were used to explore organisational changes. RESULTS: In all EDs combined, the AIHQIP was not associated with a reduction in incomplete ED visits in Aboriginal people, nor did it influence the proportion of ED visits made by Aboriginal people that had an accurate recording of Aboriginal status. However, in two EDs it was associated with an increase in the trend of accurate recording of Aboriginality from baseline to the intervention period (odds ratio (OR) 1.31, p < 0.001 in ED 4 and OR 1.15, p = 0.020 in ED 5). In other words, the accuracy of recording of Aboriginality increased from 61.4 to 70% in ED 4 and from 72.6 to 73.9% in ED 5. If the program were not implemented, only a marginal increase would have occurred in ED 4 (from 61.4 to 64%) and, in ED 5, the accuracy of reporting would have decreased (from 72.6 to 71.1%). Organisational changes were achieved across EDs, including modifications to waiting areas and improved processes for identifying Aboriginal patients and managing incomplete visits. CONCLUSIONS: The AIHQIP did not have an overall effect on the accuracy of recording of Aboriginal status or on levels of incomplete ED visits in Aboriginal patients. However, important organisational changes were achieved. Further research investigating the effectiveness of interventions to improve Aboriginal cultural safety is warranted.

How are evidence generation partnerships between researchers and policy-makers enacted in practice? A qualitative interview study.

BACKGROUND: Evidence generation partnerships between researchers and policy-makers are a potential method for producing more relevant research with greater potential to impact on policy and practice. Little is known about how such partnerships are enacted in practice, however, or how to increase their effectiveness. We aimed to determine why researchers and policy-makers choose to work together, how they work together, which partnership models are most common, and what the key (1) relationship-based and (2) practical components of successful research partnerships are. METHODS: Semi-structured qualitative interviews were conducted with 18 key informants largely based in New South Wales, Australia, who were (1) researchers experienced in working in partnership with policy in health or health-related areas or (2) policy and programme developers and health system decision-makers experienced in working in partnership with researchers. Data was analysed thematically by two researchers. RESULTS: Researcher-initiated and policy agency-initiated evidence generation partnerships were common. While policy-initiated partnerships were thought to be the most likely to result in impact, researcher-initiated projects were considered important in advancing the science and were favoured by researchers due to greater perceived opportunities to achieve key academic career metrics. Participants acknowledged that levels of collaboration varied widely in research/policy partnerships from minimal to co-production. Co-production was considered a worthy goal by all, conferring a range of benefits, but one that was difficult to achieve in practice. Some participants asserted that the increased time and resources required for effective co-production meant it was best suited to evaluation and implementation projects where the tacit, experiential knowledge of policy-makers provided critical nuance to underpin study design, implementation and analysis. Partnerships that were mutually considered to have produced the desired outcomes were seen to be underpinned by a range of both relationship-based (such as shared aims and goals and trust) and practical factors (such as sound governance and processes). CONCLUSIONS: Our findings highlight the important role of policy-makers in New South Wales in ensuring the relevance of research. There is still much to understand about how to initiate and sustain successful research/policy partnerships, particularly at the highly collaborative end.

Interprofessional Education Among Occupational Therapy Programs: Faculty Perceptions of Challenges and Opportunities.

OBJECTIVE: We investigated occupational therapy faculty beliefs about and perceptions of interprofessional education (IPE) and to identify differences in faculty positions on IPE between programs affiliated with an on-campus academic health care center (AHC) and programs not affiliated with an on-campus AHC. METHOD: Online surveys were distributed by email to 1,466 faculty at programs accredited by the Accreditation Council for Occupational Therapy Education. The results were described using descriptive statistics and cross-tabulations. RESULTS: Faculty responses supported the need for IPE. Ethics was ranked as the most important IPE competency among both the AHC and the non-AHC groups. IPE was more commonly included in the curriculum of programs with an on-campus AHC than in the curriculum of those without an AHC. CONCLUSION: The majority of occupational therapy faculty supported the need for IPE; however, many reported limitations with faculty or time constraints as barriers to IPE.

The APC/C activator FZR1 is essential for meiotic prophase I in mice.

Fizzy-related 1 (FZR1) is an activator of the Anaphase promoting complex/cyclosome (APC/C) and an important regulator of the mitotic cell division cycle. Using a germ-cell-specific conditional knockout model we examined its role in entry into meiosis and early meiotic events in both sexes. Loss of APC/C(FZR1) activity in the male germline led to both a mitotic and a meiotic testicular defect resulting in infertility due to the absence of mature spermatozoa. Spermatogonia in the prepubertal testes of such mice had abnormal proliferation and delayed entry into meiosis. Although early recombination events were initiated, male germ cells failed to progress beyond zygotene and underwent apoptosis. Loss of APC/C(FZR1) activity was associated with raised cyclin B1 levels, suggesting that CDK1 may trigger apoptosis. By contrast, female FZR1Δ mice were subfertile, with premature onset of ovarian failure by 5 months of age. Germ cell loss occurred embryonically in the ovary, around the time of the zygotene-pachytene transition, similar to that observed in males. In addition, the transition of primordial follicles into the growing follicle pool in the neonatal ovary was abnormal, such that the primordial follicles were prematurely depleted. We conclude that APC/C(FZR1) is an essential regulator of spermatogonial proliferation and early meiotic prophase I in both male and female germ cells and is therefore important in establishing the reproductive health of adult male and female mammals.