Single-cell epigenomics reveals mechanisms of human cortical development.

During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes in the gene regulatory landscape1. In the developing brain, cell fate specification and topographic identity are important for defining cell identity2 and confer selective vulnerabilities to neurodevelopmental disorders3. Here, to identify cell-type-specific chromatin accessibility patterns in the developing human brain, we used a single-cell assay for transposase accessibility by sequencing (scATAC-seq) in primary tissue samples from the human forebrain. We applied unbiased analyses to identify genomic loci that undergo extensive cell-type- and brain-region-specific changes in accessibility during neurogenesis, and an integrative analysis to predict cell-type-specific candidate regulatory elements. We found that cerebral organoids recapitulate most putative cell-type-specific enhancer accessibility patterns but lack many cell-type-specific open chromatin regions that are found in vivo. Systematic comparison of chromatin accessibility across brain regions revealed unexpected diversity among neural progenitor cells in the cerebral cortex and implicated retinoic acid signalling in the specification of neuronal lineage identity in the prefrontal cortex. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.

Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders.

Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance (P < 3.64e-7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense (n = 41) or truncating (n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden (DDX3X, MECP2, WDR45, and HDAC8). This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.

Identification of vulnerable carotid plaque with CT-based radiomics nomogram.

AIM: To develop and validate a radiomics nomogram for identifying high-risk carotid plaques on computed tomography (CT) angiography (CTA). MATERIALS AND METHODS: A total of 280 patients with symptomatic (n=131) and asymptomatic (n=139) carotid plaques were divided into a training set (n=135), validation set (n=58), and external test set (n=87). Radiomic features were extracted from CTA images. A radiomics model was constructed based on selected features and a radiomics score (rad-score) was calculated. A clinical factor model was constructed by demographics and CT findings. A radiomics nomogram combining independent clinical factors and the rad-score was constructed. The diagnostic performance of three models was evaluated and validated by region of characteristic curves. RESULTS: Calcification and maximum plaque thickness were the independent clinical factors. Twenty-four features were used to build the radiomics signature. In the validation set, the nomogram (area under the curve [AUC], 0.977; 95% CI, 0.899-0.999) performed better (p=0.017 and p=0.031) than the clinical factor model (AUC, 0.862; 95% CI, 0.746-0.938) and radiomics signature (AUC, 0.944; 95% CI, 0.850-0.987). In external test set, the nomogram (AUC, 0.952; 95% CI, 0.884-0.987) and radiomics signature (AUC, 0.932; 95% CI, 0.857-0.975) showed better discrimination capability (p=0.002 and p=0.037) than clinical factor model (AUC, 0.818; 95% CI, 0.721-0.892). CONCLUSION: The CT-based nomogram showed satisfactory performance in identification of high-risk plaques in carotid arteries, and it may serve as a potential non-invasive tool to identify carotid plaque vulnerability and risk stratification.

Genus-Wide Characterization of Bumblebee Genomes Provides Insights into Their Evolution and Variation in Ecological and Behavioral Traits.

Bumblebees are a diverse group of globally important pollinators in natural ecosystems and for agricultural food production. With both eusocial and solitary life-cycle phases, and some social parasite species, they are especially interesting models to understand social evolution, behavior, and ecology. Reports of many species in decline point to pathogen transmission, habitat loss, pesticide usage, and global climate change, as interconnected causes. These threats to bumblebee diversity make our reliance on a handful of well-studied species for agricultural pollination particularly precarious. To broadly sample bumblebee genomic and phenotypic diversity, we de novo sequenced and assembled the genomes of 17 species, representing all 15 subgenera, producing the first genus-wide quantification of genetic and genomic variation potentially underlying key ecological and behavioral traits. The species phylogeny resolves subgenera relationships, whereas incomplete lineage sorting likely drives high levels of gene tree discordance. Five chromosome-level assemblies show a stable 18-chromosome karyotype, with major rearrangements creating 25 chromosomes in social parasites. Differential transposable element activity drives changes in genome sizes, with putative domestications of repetitive sequences influencing gene coding and regulatory potential. Dynamically evolving gene families and signatures of positive selection point to genus-wide variation in processes linked to foraging, diet and metabolism, immunity and detoxification, as well as adaptations for life at high altitudes. Our study reveals how bumblebee genes and genomes have evolved across the Bombus phylogeny and identifies variations potentially linked to key ecological and behavioral traits of these important pollinators.

[IgG4-related diseases of retroperitoneum in urinary and male reproductive system: a clinicopathological analysis of eleven cases].

Objective: To analyze the clinicopathological features of IgG4-related diseases (RD) of retroperitoneum and the urinary and male reproductive system (IgG4-RUMR). Methods: A total of 11 IgG4-RUMR cases from January 2013 to March 2021 were retrospectively collected at Peking University Third Hospital and Shandong Provincial Hospital affiliated to Shandong First Medical University. The clinicopathologic features, laboratory and imaging findings were analyzed and scored according to the 2019 ACR/EULAR classification criteria for IgG4-RD. Results: The 11 patients (male:female is 9∶2; mean age 59 years, range from 44 to 83 years) were initially admitted to the Deparment of Urology/Kidney Transplantation (10 cases) and the Department of Oncology (1 case). All patients had urogenital disorders or imaging abnormalities. Three of the 11 patients had a history of IgG4-RD such as lacrimal gland engorgement, salivary gland engorgement and IgG4-associated pancreatitis. Abnormal retroperitoneal soft tissue and hydronephrosis were found in eight cases, while epididymal and spermatic cord masses were found in one case, simple renal mass in one case, and"benign prostatic hyperplasia"in one case. In the 10 patients tested for serum IgG4, the serum IgG4 level was 0.8-14.4 g/L. Histologically, all cases showed significant lymphoplasmacytic infiltration and storiform fibrosis, and some were accompanied by obliterative phlebitis. The number of IgG4 positive plasma cells was 12-155 per high-power field, and the IgG4/IgG ratio was 15%-77%. According to the 2019 ACR/EULAR IgG4-RD classification standard 11 cases scored 20-48 points, all of which met the diagnostic criteria of IgG4-RUMR. Therapeutically, the patient with a simple renal mass underwent partial nephrectomy. The patient with prostate lesion underwent transurethral resection of prostate and was initially diagnosed as nonspecific chronic prostatitis. Later, the patient was admitted again because of salivary gland swelling, and the pathologic diagnosis was amended. The patient with epididymal and spermatic cord masses participated in a clinical trial about retroperitoneal fibrosis. The remaining eight patients received symptomatic treatment such as adhesiolysis and stent placement. All the patients were subsequently treated with glucocorticoid/immunosuppressant and symptoms relieved. Conclusions: IgG4-RUMR is uncommon. In clinical practice, information from clinical, serologic, radiologic and pathologic evaluations must be integrated. IgG4-RUMR should be considered in the differential diagnosis of urinary and male reproductive diseases. The 2019 ACR/EULAR classification criteria for IgG4-RD, while relatively complex, are objective and practical in the diagnosis of IgG4-RUMR.

Single-dose oral anti-arrhythmic drugs for cardioversion of recent-onset atrial fibrillation: a systematic review and network meta-analysis of randomized controlled trials.

AIMS: Single oral dose anti-arrhythmic drugs (AADs) are used to cardiovert recent-onset atrial fibrillation (AF); however, the optimal agent is uncertain. METHODS: We performed a systematic review and network meta-analysis of randomized trials testing single oral dose AADs vs. any comparator to cardiovert AF <7 days duration. We searched MEDLINE, Embase, and CENTRAL to April 2020. The primary outcome was successful cardioversion at timepoint nearest 8 h after administration. RESULTS: From 12 712 citations, 22 trials (2320 patients) were included. Thirteen trials included patients with some degree of heart failure; 19 included patients with some degree of ischaemic heart disease vs. placebo or rate-control (32% success) at 8 h, flecainide [73%, network odds ratio (OR) 7.6, 95% credible interval (CrI) 4.4-14.0], propafenone (70%, OR 4.6, CrI 2.9-7.3), and pilsicainide (59%, OR 10.0, CrI 1.8-69.0), but not amiodarone (28%, OR 1.0, CrI 0.4-2.8) were superior. Flecainide (OR 7.5, CrI 2.6-24.0) and propafenone (OR 4.5, CrI 1.6-13.0) were superior to amiodarone; propafenone vs. flecainide did not statistically differ (OR 0.6, CrI 0.3-1.1). At longest follow-up, amiodarone was superior to placebo (OR 11.0, CrI 3.2-41.0), flecainide vs. amiodarone (OR 0.79, CrI 0.19-3.1), and propafenone vs. amiodarone (OR 0.36, CrI 0.092-1.4) were not statistically different, and flecainide was superior to propafenone (OR 2.2, CrI 1.1-4.8). Atrial and ventricular tachyarrhythmias, bradyarrhythmias, and hypotension were rare with PO AADs. CONCLUSION: Single oral dose Class 1C AADs are effective and safe for cardioversion of recent-onset AF. Flecainide may be superior to propafenone. Amiodarone is a slower acting alternative.

Pediatric Quality of Life Inventory (PedsQL) 3.2 Diabetes Module for youth with Type 2 diabetes: reliability and validity.

AIM: To test the measurement properties of the revised and updated Pediatric Quality of Life Inventory (PedsQL) 3.2 Diabetes Module originally developed in Type 1 diabetes in youth with Type 2 diabetes. METHODS: The PedsQL 3.2 Diabetes Module and PedsQL Generic Core Scales were administered in a field test study to 100 young people aged 9-25 years with Type 2 diabetes. Factor analysis was conducted to determine the factor structure of the items. RESULTS: The 15-item Diabetes Symptoms Summary Score and 12-item Type 2-specific Diabetes Management Summary Score were empirically derived through factor analysis. The Diabetes Symptoms and Type 2-specific Diabetes Management Summary Scores showed acceptable to excellent reliability across the age groups tested (α = 0.85-0.94). The Diabetes Symptoms and Type 2-specific Diabetes Management Summary Scores evidenced construct validity through large effect size correlations with the Generic Core Scales Total Scale Score (r = 0.67 and 0.57, respectively). HbA1c was correlated with the Diabetes Symptoms and Type 2-specific Diabetes Management Summary Scores (r = -0.13 and -0.22). Minimal clinically important difference (MCID) scores were 5.91 and 7.39 for the Diabetes Symptoms and Type 2-specific Diabetes Management Summary Scores. CONCLUSIONS: The PedsQL 3.2 Diabetes Module Diabetes Symptoms Summary Score and Type 2-specific Diabetes Management Summary Score exhibited satisfactory measurement properties for use as youth self-reported diabetes symptoms and diabetes management outcomes for clinical research and clinical practice for young people with Type 2 diabetes.

Monitoring Taiwanese bovine arboviruses and non-arboviruses using a vector-based approach.

In current sampling approaches, there exists a divergence between the surveillance of arthropod-borne and that of non-arthropod-borne viruses. It is commonly held that the collection of vector specimens applies only to arbovirus surveillance and that the surveillance of non-arboviruses must rely on traditional methods that involve the sampling of blood, faeces or saliva, or other examinations. The vector-based approach is a sampling method that has the ability to survey both arboviruses and non-arboviruses by distinguishing engorged vector specimens from entire vector samples. Accordingly, five arboviruses and three non-arboviruses were detected in a study using a vector-based approach conducted during 2012-2015. Hence, this report provides the first description of the Taiwanese vector species for the bovine arboviruses detected. The present investigations demonstrate that the vector-based approach applies not only to the surveillance of arboviruses, but also has potential as a possible tool for monitoring non-arboviruses on livestock farms in the future.

[The prevalence and etiology of anemia in urban community dwelling elderly population in Beijing].

OBJECTIVE: To estimate the prevalence of anemia in urban community dwelling elderly population. METHODS: This study was a cross-sectional survey of prevalence of anemia in randomly selected community dwelling residents aged over 65 years in Beijing. Anemia was defined as hemoglobin concentration less than 130 g/L in men and 120 g/L in women. RESULTS: The hemoglobin concentration was (135.65±14.48) g/L in total of 1 947 eligible participants and was much higher in men than in women [(142.56±15.56) g/L vs (130.95±11.53) g/L, P<0.001]. There were 288 (14.8%) patients with anemia, including 16.3%(129/789) in men and 13.7%(159/1 158) in women. The prevalence of anemia increased significantly with age, which was 7.6% in 65-69 years, 10.8% in 70-74 years, 18.8% in 75-79 years and 24.1% over 80 years (P<0.001). Two hundred and seventy-nine (96.9%) subjects were mild anemia, 8 (2.8%) moderate, only 1 subject (0.3%) severe. Unexplained anemia was predominant, which accounted for 63.2%. Only 16.7% people were diagnosed as nutritional anemia, renal anemia 5.2%, anemia of chronic disease (ACD) 12.2%. There were 2.4% people with overlapped renal anemia and ACD. Compared with non-anemic subjects, more subjects with unexplained anemia represented macrocytosis (7.1% vs 3.2%, P=0.007). CONCLUSIONS: Anemia is a common health problem in urban community dwelling elderly population. Most subjects have anemia with unknown origin. Further investigation is needed to explore the mechanism and related factors of elderly anemia.

Suppression of autoimmunity by CD5(+) IL-10-producing B cells in lupus-prone mice.

Systemic lupus erythematosus is a complex autoimmune disorder characterized by the production of pathogenic anti-nuclear antibodies. Previous work from our laboratory has shown that the introgression of a New Zealand Black-derived chromosome 4 interval onto a lupus-prone background suppresses the disease. Interestingly, the same genetic interval promoted the expansion of both Natural Killer T- and CD5(+) B cells in suppressed mice. In this study, we show that ablation of NKT cells with a CD1d knockout had no impact on either the suppression of lupus or the expansion of CD5(+) B cells. On the other hand, suppressed mice had an expanded population of IL-10-producing B cells that predominantly localized to the CD5(+)CD1d(low) compartment. The expansion of CD5(+) B cells negatively correlated with the frequency of pro-inflammatory IL-17 A-producing T-cells and kidney damage. Adoptive transfer with a single injection of total B cells with an enriched CD5(+) compartment reduced the frequency of memory/activated, IFNγ-producing, and IL-17 A-producing CD4 T-cells but did not significantly reduce autoantibody levels. Taken together, these data suggest that the expansion of CD5(+) IL-10-producing B cells and not NKT cells protects against lupus in these mice, by limiting the expansion of pro-inflammatory IL-17 A- and IFNγ-producing CD4 T-cells.

Arterial flow regulator enables transplantation and growth of human fetal kidneys in rats.

Here we introduce a novel method of transplanting human fetal kidneys into adult rats. To overcome the technical challenges of fetal-to-adult organ transplantation, we devised an arterial flow regulator (AFR), consisting of a volume adjustable saline-filled cuff, which enables low-pressure human fetal kidneys to be transplanted into high-pressure adult rat hosts. By incrementally withdrawing saline from the AFR over time, blood flow entering the human fetal kidney was gradually increased until full blood flow was restored 30 days after transplantation. Human fetal kidneys were shown to dramatically increase in size and function. Moreover, rats which had all native renal mass removed 30 days after successful transplantation of the human fetal kidney were shown to have a mean survival time of 122 days compared to 3 days for control rats that underwent bilateral nephrectomy without a prior human fetal kidney transplant. These in vivo human fetal kidney models may serve as powerful platforms for drug testing and discovery.

Agronomically important thrips: development of species-specific primers in multiplex PCR and microarray assay using internal transcribed spacer 1 (ITS1) sequences for identification.

Thrips, the sole vector of plant Tospovirus, are major pests of many agricultural crops throughout the world. Molecular approaches have been applied in recent decades to identify these minute and morphologically difficult to distinguish insects. In this study, sequences of internal transcribed spacer 1 (ITS1) region of 15 agronomically important thrips, including several virus transmission species, have been analyzed in order to design species-specific primers for multiplex PCR and probes for microarray assay. That the ITS1 sequence distances within species were smaller than those among species suggests that the ITS1 fragment can be used for thrips species identification. The specificity and stability of these primers, combined with universal paired primers, were tested and verified in multiplex PCR. Using these specific primers as probes, microarray assay showed that PCR products of all thrips species hybridized consistently to their corresponding probes, though some signals were weak. We have demonstrated that multiplex PCR using specific primers based on ITS1 sequences is a simple, reliable, and cost-effective diagnostic tool for thrips species identification. Moreover, the DNA microarray assay is expected to extend into a reliable high-throughput screening tool for the vast numbers of thrips.

Vertical habitat shift of viviparous and oviparous deep-sea cusk eels revealed by otolith microstructure and stable-isotope composition.

Otolith stable-oxygen-isotope composition and microstructure were analysed in order to investigate the vertical habitat shift of deep-sea cusk eels (Ophidiiformes). Otolith δ18 O profiles suggested that both viviparous blind cusk eels and oviparous cusk eels experienced a pelagic larval stage and then settled to the deep-sea floor over a vertical distance that ranged among individuals from 200 to >1000 m. This result shows that the larvae of viviparous Barathronus maculatus undertake an ontogenetic vertical migration after a period of larval drift that may facilitate their wide distribution on the sea floor.

Determination of fourteen sunscreen agents in cosmetics using high-performance liquid chromatography.

OBJECTIVE: Commercial sunscreens consist of various compounds ranging from inorganic mineral pigments to organic chemical absorbents to achieve the required degree of protection against sunlight. However, the UV radiation screening ingredients have side effects. In this study, therefore, to ensure compliance with the maximum permissible chemical concentrations in sunscreen cosmetic products, a simultaneous and improved determination method for sunscreen chemicals was assessed. METHODS: Waters 2690 separations module HPLC system equipped with a Waters 486 tunable absorbance detector (UV-visible detector) has been employed and optimized to detect 14 compounds. For the separation, a Waters C18 column (5 µm, 4.6 mm i.d. 150 mm) and 1% of 0.1 M phosphoric acid in ethanol (solvent A) and in distilled water (solvent B) as mobile phases were used. RESULTS: The correlation coefficients of 14 standard mixture solutions exceeded 0.9993 in the range 2.5-200 µg mL(-1). The intra- and interday recovery and precision (relative standard deviation) of the method were 90.91-109.98% and within 10%, respectively, indicating that the developed method could provide reliable, precise and reproducible data. The detection limit was determined to be 0.01-1.99 µg mL(-1), and the quantization limit was determined to be 0.02-6.02 µg mL(-1), which were relatively lower than previous studies. CONCLUSION: This method was highly optimized in terms of selectivity, reproducibility and efficiency for the detection of 14 compounds. The validation data indicated that the improved method was quite suitable for their quantitative analysis of commercial product samples. Therefore, this method was applied to the determination of 14 compounds in commercial sunscreen cosmetic products. We verified that the amounts of sunscreen ingredients in the five currently sold sunscreens were >0.5% and within the designated limit, which means those could produce the safe and desired sunscreen effects on the skin. The present method could be applied to effectively monitor the process management and quality control of the cosmetics that are sold in the market.

Completely abdominal intersphincteric resection for lower rectal cancer: feasibility and comparison of robot-assisted and open surgery.

BACKGROUND: Most previous studies of intersphincteric resection (ISR) adopted a two-stage procedure involving abdominal and transanal approaches. We performed completely abdominal ISR via open and a robot-assisted (RA) approaches as treatments for lower rectal cancer (LRC). The RA approach might enable deep dissection and facilitate ISR in patients with restrictive pelvic anatomy. METHODS: A consecutive cohort of 222 LRC patients who underwent completely abdominal ISR (RA ISR, n = 108; open ISR, n = 114) was enrolled prospectively, and their short-term outcomes were evaluated. RESULTS: In a multivariate analysis, ISR was performed more frequently in the RA than in the open group (82.6 vs. 67.9 %, p = 0.008). The number of harvested lymph nodes was >12 in both groups. A positive distal resection margin was not observed in either group, and a positive circumferential resection margin was found in one patient in the RA group. Overall morbidity did not differ between the groups. Moderate to severe sexual dysfunction occurred 2.7-fold more frequently in the open group (p = 0.023) among male patients ≤65 years. Mean Wexner's fecal incontinence scores at postoperative months 6 and 12 were greater in the open group than in the RA group (p < 0.05). CONCLUSIONS: Completely abdominal ISR may be feasible in the treatment of LRC, based on a short-term study. Furthermore, RA ISR had equivalent oncological outcomes and slightly improved functional recovery relative to open ISR.

Development of Species-Specific Primers for Agronomical Thrips and Multiplex Assay for Quarantine Identification of Western Flower Thrips.

While morphological identification of thrips species has been difficult because of their minute size and a lack of easily recognizable characteristics, molecular identification based on the development of specific molecular markers can be easily and reliably carried out. Among the known molecular markers, the nuclear internal transcribed spacer (ITS) exhibits distinguishable variations among thrips species. In this study, sequences of ITS2 region of 10 agriculturally important thrips were established to design species-specific primers for polymerase chain reaction (PCR). ITS2 sequence variations within these species were far less than those among species, indicating the suitability of this marker for species-specific primers design. These primers, though with one or two sporadically variable positions, showed a good efficacy within species. The specificity of these primers, examined on thrips species belonging to 15 genera, proved satisfactory. Furthermore, a multiplex PCR was used successfully for identifying Frankliniella occidentalis (Pergande), an insect pest monitored for quarantine purpose, and three additional thrips also commonly found in imported agricultural products and field samples, i.e., Thrips tabaci Lindeman, Thrips hawaiiensis (Morgan), and Frankliniella intonsa (Trybom). This study has demonstrated that specific primers and multiplex PCR based on ITS2 are reliable, convenient, and diagnostic tool to discriminate thrips species of quarantine and agricultural importance.

Thalamocortical organoids enable in vitro modeling of 22q11.2 microdeletion associated with neuropsychiatric disorders.

Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of FOXP2. Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletion mediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, we identify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpression on thalamic axon overgrowth. Together, our study suggests that early steps in thalamic development are dysregulated in a model of genetic risk for schizophrenia and contribute to neural phenotypes in 22q11.2 deletion syndrome.

Identification of a lupus-susceptibility locus leading to impaired clearance of apoptotic debris on New Zealand Black chromosome 13.

Systemic lupus erythematosus is a chronic multi-organ autoimmune disease marked mainly by the production of anti-nuclear antibodies. Nuclear antigens become accessible to the immune system following apoptosis and defective clearance of apoptotic debris has been shown in several knockout mouse models to promote lupus. However, genetic loci associated with defective clearance are not well defined in spontaneously arising lupus models. We previously showed that introgression of the chromosome 13 interval from lupus-prone New Zealand Black (NZB) mice onto a non-autoimmune B6 genetic background (B6.NZBc13) recapitulated many of the NZB autoimmune phenotypes. Here, we show that B6.NZBc13 mice have impaired clearance of apoptotic debris by peritoneal and tingible-body macrophages and have narrowed down the chromosomal interval of this defect using subcongenic mice with truncated NZB chromosome 13 intervals. This chromosomal region (81-94 Mb) is sufficient to produce polyclonal B- and T-cell activation, and expansion of dendritic cells. To fully recapitulate the autoimmune phenotypes seen in B6.NZBc13 mice, at least one additional locus located in the centromeric portion of the interval is required. Thus, we have identified a novel lupus susceptibility locus on NZB chromosome 13 that is associated with impaired clearance of apoptotic debris.