Control of meiotic crossover interference by a proteolytic chaperone network.

Meiosis is a specialized eukaryotic division that produces genetically diverse gametes for sexual reproduction. During meiosis, homologous chromosomes pair and undergo reciprocal exchanges, called crossovers, which recombine genetic variation. Meiotic crossovers are stringently controlled with at least one obligate exchange forming per chromosome pair, while closely spaced crossovers are inhibited by interference. In Arabidopsis, crossover positions can be explained by a diffusion-mediated coarsening model, in which large, approximately evenly spaced foci of the pro-crossover E3 ligase HEI10 grow at the expense of smaller, closely spaced clusters. However, the mechanisms that control HEI10 dynamics during meiosis remain unclear. Here, through a forward genetic screen in Arabidopsis, we identified high crossover rate3 (hcr3), a dominant-negative mutant that reduces crossover interference and increases crossovers genome-wide. HCR3 encodes J3, a co-chaperone related to HSP40, which acts to target protein aggregates and biomolecular condensates to the disassembly chaperone HSP70, thereby promoting proteasomal degradation. Consistently, we show that a network of HCR3 and HSP70 chaperones facilitates proteolysis of HEI10, thereby regulating interference and the recombination landscape. These results reveal a new role for the HSP40/J3-HSP70 chaperones in regulating chromosome-wide dynamics of recombination via control of HEI10 proteolysis.

Arabidopsis HEAT SHOCK FACTOR BINDING PROTEIN is required to limit meiotic crossovers and HEI10 transcription.

The number of meiotic crossovers is tightly controlled and most depend on pro-crossover ZMM proteins, such as the E3 ligase HEI10. Despite the importance of HEI10 dosage for crossover formation, how HEI10 transcription is controlled remains unexplored. In a forward genetic screen using a fluorescent crossover reporter in Arabidopsis thaliana, we identify heat shock factor binding protein (HSBP) as a repressor of HEI10 transcription and crossover numbers. Using genome-wide crossover mapping and cytogenetics, we show that hsbp mutations or meiotic HSBP knockdowns increase ZMM-dependent crossovers toward the telomeres, mirroring the effects of HEI10 overexpression. Through RNA sequencing, DNA methylome, and chromatin immunoprecipitation analysis, we reveal that HSBP is required to repress HEI10 transcription by binding with heat shock factors (HSFs) at the HEI10 promoter and maintaining DNA methylation over the HEI10 5' untranslated region. Our findings provide insights into how the temperature response regulator HSBP restricts meiotic HEI10 transcription and crossover number by attenuating HSF activity.

HIGH CROSSOVER RATE1 encodes PROTEIN PHOSPHATASE X1 and restricts meiotic crossovers in Arabidopsis.

Meiotic crossovers are tightly restricted in most eukaryotes, despite an excess of initiating DNA double-strand breaks. The majority of plant crossovers are dependent on class I interfering repair, with a minority formed via the class II pathway. Class II repair is limited by anti-recombination pathways; however, similar pathways repressing class I crossovers have not been identified. Here, we performed a forward genetic screen in Arabidopsis using fluorescent crossover reporters to identify mutants with increased or decreased recombination frequency. We identified HIGH CROSSOVER RATE1 (HCR1) as repressing crossovers and encoding PROTEIN PHOSPHATASE X1. Genome-wide analysis showed that hcr1 crossovers are increased in the distal chromosome arms. MLH1 foci significantly increase in hcr1 and crossover interference decreases, demonstrating an effect on class I repair. Consistently, yeast two-hybrid and in planta assays show interaction between HCR1 and class I proteins, including HEI10, PTD, MSH5 and MLH1. We propose that HCR1 plays a major role in opposition to pro-recombination kinases to restrict crossovers in Arabidopsis.

DeepTetrad: high-throughput image analysis of meiotic tetrads by deep learning in Arabidopsis thaliana.

Meiotic crossovers facilitate chromosome segregation and create new combinations of alleles in gametes. Crossover frequency varies along chromosomes and crossover interference limits the coincidence of closely spaced crossovers. Crossovers can be measured by observing the inheritance of linked transgenes expressing different colors of fluorescent protein in Arabidopsis pollen tetrads. Here we establish DeepTetrad, a deep learning-based image recognition package for pollen tetrad analysis that enables high-throughput measurements of crossover frequency and interference in individual plants. DeepTetrad will accelerate the genetic dissection of mechanisms that control meiotic recombination.

An association of urinary sodium-potassium ratio with insulin resistance among Korean adults.

BACKGROUND/OBJECTIVES: This study was conducted to investigate the effects of sodium-potassium ratio on insulin resistance and sensitivity in Korean adults. SUBJECTS/METHODS: Subjects were 3,722 adults (1,632 men and 2,090 women) aged 40-69 years participating in the Korean genome and epidemiology study_Ansan and Ansung study. Insulin resistance was assessed using homeostasis model assessment of insulin resistance (HoMA-IR) and fasting insulin, and insulin sensitivity was assessed by using the quantitative insulin sensitivity check index (QUICKI). The 24-h urinary sodium and potassium excretion were estimated from spot urinary samples using the Tanaka formula. The generalized linear model was applied to determine the association between urinary sodium-potassium ratio and insulin resistance. RESULTS: HoMA-IR (P-value = 0.029, P-trend = 0.008) and fasting insulin (P-value = 0.017, P-trend = 0.005) levels were positively associated with 24-h estimated urinary sodium-potassium ratio in the multivariable model. QUICKI was inversely associated with 24-h estimated urinary sodium-potassium ratio in all models (P-value = 0.0002, P-trend < 0.0001 in the multivariate model). CONCLUSION: The present study suggests that high sodium-potassium ratio is related to high insulin resistance and low insulin sensitivity. Decreasing sodium intake and increasing potassium intake are important for maintaining insulin sensitivity. Further studies are needed to confirm these findings in longitudinal studies.

Associations of serum levels of vitamins A, C, and E with the risk of cognitive impairment among elderly Koreans.

BACKGROUND/OBJECTIVES: Korea is quickly becoming an aged society. Dementia is also becoming a vital public health problem in Korea. Cognitive impairment as a pre-stage of dementia shares most risk factors for dementia. The aim of the present study was to determine associations of serum levels of vitamins A, C, and E with the risk of cognitive impairment among elderly Koreans. SUBJECTS/METHODS: In this cross-sectional study, a total of 230 participants aged 60-79 years from Yangpyeong cohort were included. Cognitive function was assessed by the Korean version of the Mini-Mental State Examination for Dementia Screening. The logistic multivariable regression model was applied to determine the effect of serum vitamins A, C, and E on the risk of cognitive impairment. RESULTS: There was no significant association between the risk of cognitive impairment and serum levels of vitamin A and vitamin C. There was a significant odd ratio when the second tertile group of beta-gamma tocopherol level was compared to the first tertile group [odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.14-0.98, P for trend = 0.051]. In subgroup analyses, there were significant negative associations between beta-gamma tocopherol level and the risk of cognitive impairment in men (OR = 0.17, 95% CI = 0.03-0.87, P for trend = 0.028), non-drinkers or former drinkers (OR = 0.13, 95% CI = 0.02-0.66, P for trend = 0.025), and non-smokers or former smokers (OR = 0.27, 95% CI = 0.09-0.82, P for trend = 0.017). CONCLUSION: Serum beta-gamma tocopherol levels tended to be inversely associated with the risk of cognitive impairment. Further prospective large-scaled studies are needed to examine this association.

Circulating folate levels and colorectal adenoma: a case-control study and a meta-analysis.

BACKGROUND/OBJECTIVES: The relationship between folate and colorectal neoplasia remains controversial. We examined the association between serum folate concentrations and colorectal adenomas in a case-control study of Korean adults and conducted a meta-analysis. SUBJECTS/METHODS: Our case-control study included 113 pairs of case and control who underwent colonoscopy and provided blood samples. We used multivariable conditional logistic regression models to obtain the odds ratios and 95% confidence interval (CIs). For meta-analysis, we identified the relevant studies by searching the PubMed database up to February 2017, included our case-control study and combined the study-specific relative risks (RRs) using a random-effects model. RESULTS: In this case-control study, we included 58 men and 55 women with colorectal adenomas and sex and fasting status matched the controls. We did not find any significant association between the serum folate levels and colorectal adenomas in either men or women. For meta-analysis, a total of eleven studies were included in our analysis and classified into two groups; polyp clearance group (PC) for the studies that included participants who underwent endoscopies and had their polyps removed at baseline; and no polyp clearance group (NPC) for the studies that included participants whose histories of endoscopies were unknown or who underwent their first endoscopies. Four PC (1,311 cases and 1,672 non-cases) and eight NPC studies (3,501 cases and 11,347 non-cases) were included. The combined RRs (95% CIs) comparing the bottom with the top categories of circulating folate levels were 1.07 (0.97-1.18) for the NPC group but 1.45 (1.16-1.74) for the PC group. CONCLUSIONS: Low circulating folate levels were associated with new adenoma formation.

Interaction between Single Nucleotide Polymorphism and Urinary Sodium, Potassium, and Sodium-Potassium Ratio on the Risk of Hypertension in Korean Adults.

Hypertension is a complex disease explained with diverse factors including environmental factors and genetic factors. The objectives of this study were to determine the interaction effects between gene variants and 24 h estimated urinary sodium and potassium excretion and sodium-potassium excretion ratios on the risk of hypertension. A total of 8839 participants were included in the genome-wide association study (GWAS) to find genetic factors associated with hypertension. Tanaka and Kawasaki formulas were applied to estimate 24 h urinary sodium and potassium excretion. A total of 4414 participants were included in interaction analyses to identify the interaction effects of gene variants according to 24 h estimated urinary factors on the risk of hypertension. CSK rs1378942 and CSK-MIR4513 rs3784789 were significantly modified by urinary sodium-potassium excretion ratio. In addition, MKLN rs1643270 with urinary potassium excretion, LOC101929750 rs7554672 with urinary sodium and potassium excretion, and TENM4 rs10466739 with urinary sodium-potassium excretion ratio showed significant interaction effects. The present study results indicated that the mutant alleles of CSK rs1378942 and CSK-MIR4513 rs3784789 had the strongest protective effects against hypertension in the middle group of 24 h estimated urinary sodium-potassium excretion ratio. Further studies are needed to replicate these analyses in other populations.

Ultrasonographic findings of the various diseases presenting as calf pain.

There are various causes of calf pain. The differential diagnoses affecting the lower leg include cystic lesions, trauma-related lesions, infection or inflammation, vascular lesions, neoplasms, and miscellaneous entities. Ultrasound (US) provide detailed anatomical information of the calf structures, and it offers the ability to confirm, other calf abnormalities, particularly when deep vein thrombosis (DVT) is ruled out. The purpose of this article is to review the causes of a painful calf presenting as DVT and incidental findings found as part of the work-up of DVT, and to provide a broad overview of US findings and clinical features of these pathologies.

Alcohol intake, smoking, and colorectal adenoma.

BACKGROUND: Colorectal cancer is the third most common cancer in Korea. Because colorectal adenoma is a precursor lesion of colorectal cancer, primary prevention of colorectal adenomas may be important for reducing morbidity and mortality from the disease. The aim of this study is to examine the association of alcohol consumption and cigarette smoking in relation with colorectal adenoma in a cross-sectional study of Korean adults. METHODS: A total of 366 participants who underwent colonoscopy were included (113 cases and 255 controls) in this study. Information on alcohol intake and cigarette smoking was collected from structured questionnaires. The odds ratio (ORs) and 95% confidence intervals (CIs) were calculated using the multivariate logistic regression models. RESULTS: Alcohol intake was associated with a higher prevalence of colorectal adenoma in men; compared to non-drinkers, ORs (95% CIs) were 11.49 (2.55-51.89) for 10-20 g/day of alcohol intake and 14.15 (3.31-60.59) for â 20 g/day of alcohol intake (P for trend = 0.003). There was a weaker association of alcohol intake for women than men; however, there was a suggestive increase in the prevalence of colorectal cancer in women. Cigarette smoking was not associated with colorectal adenoma, but we cannot rule out the possibility that this was due to low statistical power. CONCLUSION: Our study provides evidence to suggest that alcohol intake may contribute to colorectal adenoma in the Korean population. Our study results demonstrate that a larger epidemiologic study is needed.

Periductal mastitis mimicking breast cancer in a male breast.

Periductal mastitis in a male patient rarely has been reported in the English literature. Herein, we now present a rare case of periductal mastitis mimicking breast cancer, both clinically and radiologically, in a 37-year-old man. Mammogram and sonogram showed a mass with irregular shape, spiculated margin and a nipple retraction, mimicking a male breast cancer. Radiologic and pathologic correlation is provided.

Imaging findings of intravascular papillary endothelial hyperplasia presenting in extremities: correlation with pathological findings.

OBJECTIVE: To describe magnetic resonance imaging (MRI) and ultrasound (US) findings of intravascular papillary endothelial hyperplasia (IPEH) arising in extremities. MATERIALS AND METHODS: Six patients with IPEH confirmed by surgical resection were reviewed retrospectively. Before resection, 3 patients underwent both MRI and US and 3 patients underwent only MRI. Two radiologists retrospectively reviewed MR/US imaging results and correlated them with pathological features. RESULTS: The 6 IPEHs were diagnosed as 4 mixed forms and 2 pure forms. The pre-existing pathology of four mixed forms was intramuscular or intermuscular hemangioma. By MRI, the mixed form of IPEH (n = 4) revealed iso- to slightly high signal intensity containing nodule-like foci of high signal intensity on T1-weighted images (T1WI) and high signal intensity-containing nodule-like foci of low signal intensity on T2-weighted images (T2WI). The pure form of IPEH (n = 2) showed homogeneous iso- signal intensity on T1WI and high and low signal intensity containing nodule-like foci of low signal intensity on T2WI. On gadolinium-enhanced fat-suppressed T1WI, 50% of cases (n = 3: mixed forms) revealed peripheral, septal, and central enhancement. The other IPEHs (n = 3: 1 mixed and 2 pure forms) showed peripheral and septal enhancement or only peripheral enhancement. By US, two mixed forms of IPEH showed well-defined hypoechoic masses containing hyperechoic septa and central portion with vascularities. One pure form of IPEH was a homogeneous hypoechoic mass with septal and peripheral vascularities on color Doppler imaging. The foci of high signal intensity on T1WI, foci of low signal intensity on T2WI, and non-enhancing portions on MRI and the hypoechoic portion on US were histopathologically correlated with thrombi and the peripheral/septal or central enhancing areas on MRI, hyperechoic septa and the central portion on US, and septal/central or peripheral vascularities on color Doppler imaging corresponded to hypertrophic papillary epithelium and a fibrovascular core. CONCLUSIONS: Even though imaging findings of the pure form of IPEH are rather nonspecific, the mixed form of IPEH should be considered a possible diagnosis when a well-defined mass with T2 hyperintense signal containing nodule-like foci of low signal intensity, T1 iso- to slightly hyperintense signal containing nodule-like foci of high signal intensity, and peripheral/septal or central enhancement on MRI is seen in extremities, along with the US finding of a hypoechoic mass containing hyperechoic septa with vascularities.

Crisscross-configured dual stent placement for trisectoral drainage in patients with advanced biliary hilar malignancies.

PURPOSE: To evaluate technical success and clinical efficacy of crisscross-configured dual biliary stent implantation in patients with a biliary hilar tumor extending beyond the segmental ducts. MATERIALS AND METHODS: Between January 2002 and December 2006, two metallic stents were placed crossing each other in a hepatic hilum in 42 patients. One stent was placed between one right sectoral duct and the left hepatic duct and the other was placed between another right sectoral duct and the common bile duct. The patients ranged in age from 36 to 83 years (mean, 63.3 y) and included 26 men and 16 women. Technical success, clinical success, complications, and long-term results were analyzed by retrospective review. RESULTS: Stent placement was performed through two right accesses (n = 30), one right and one left access (n = 3), or two right accesses and one left access (n = 6). Successful "trisectoral" drainage was obtained with two stents in 41 patients (98%). In one case of initial technical failure, an additional stent was needed to connect the two previously placed stents. Clinical success was obtained in 34 of the remaining 36 patients (92%). No procedure-related major complication was observed. The median primary stent patency time was 187 days and the median patient survival time was 247 days. CONCLUSIONS: Crisscross-configured dual stent implantation is a feasible, safe, and effective method to maximize hepatic drainage with a minimal number of stents in patients with advanced biliary hilar malignancy.