[Comparison of follow-up treatment regimens for colorectal cancer liver metastases without objective response to neoadjuvant chemotherapy: direct surgery or surgery after second-line chemotherapy].

Objective: To compare the effect of direct surgery or surgery after second-line chemotherapy for colorectal cancer patients with liver metastases who did not achieve objective remission after neoadjuvant chemotherapy. Methods: A retrospective case cohort study was used. The clinical and pathological data of 107 patients with colorectal cancer liver metastases who did not achieve objective response to neoadjuvant chemotherapy at Department of Hepatobiliary Surgery,Cancer Hospital,Chinese Academy of Medical Sciences from December 2008 to December 2016 were retrospectively collected. There were 71 males and 36 females, median age was 57 years (range: 28 to 79 years). According to the different treatment regimens after neoadjuvant chemotherapy,107 cases were divided into a direct surgery group (direct group,n=65) and an operation after receiving second-line chemotherapy group (second-line group,n=42). The propensity score matching(PSM) of the Logistic regression model was used to match the bilobar distribution of liver metastases and the number of first-line chemotherapy cycles in the two groups of patients. The caliper value was set to 0.10 and the matching ratio was 1∶2. T test, Mann-Whitney U test, χ2 test or Fisher's exat test was used to analyzed the data between the tuo groups, respectively. Survival analysis design was used to investigate the difference in prognosis between the two groups of patients. Results: The follow-up time(M(IQR)) was 56.3(34.3) months (range: 2.1 to 95.0 months),and all patients were followed up. After PSM,there were 28 cases in the direct group and 42 cases in the second-line group, there were no significant differences in whether R0 resection was feasible,blood loss,blood transfusion,postoperative complications and postoperative hospital stay between the two groups (all P>0.05). The 1,3,and 5-year progression-free survival(PFS) rates of the direct group were 40.0%,16.5%,and 11.0%,and the 1,3,and 5-year overall survival(OS) rates were 98.5%,61.2%,and 41.4%,respectively, the second-line group 1,3,5 years PFS rates were 35.7%,14.3%,14.3%,1,3,5-year OS rate were 95.2%,55.1%,44.4%,respectively. The median PFS time of the direct group and the second-line group was 8.5 months and 7.5 months,respectively,and the difference was not statistically significant (P=0.826). The median OS time of the direct group and the second-line group were 33.8 months and 46.9 months,respectively. The difference was not statistically significant(P=0.646).The median PFS time of the direct group and second-line chemotherapy complete remission and partial remission group(CR/PR group) was 10.2 months and 9.1 months,respectively,and the difference was not statistically significant(P=0.669). The median OS time of the direct group and the second-line CR/PR group was 51.0 months and 46.9 months,respectively,and the difference was not statistically significant(P=0.427). The results of survival analysis suggested that major liver resection was an independent prognosis factor for PFS (HR=1.809,95%CI: 1.067 to 3.067,P=0.028) and OS(HR=2.751,95%CI: 1.317 to 5.747,P=0.007). Second-line chemotherapy was not an independent prognostic factor for PFS (HR=0.945, 95%CI:0.570 to 1.567,P=0.828) and OS (HR=0.866,95%CI: 0.468 to 1.602,P=0.646). Conclusions: There is no significant difference in the short-term outcome and long-term prognosis between direct surgery patients and second-line chemotherapy followed by surgery. Second-line chemotherapy is not an independent prognostic factor for colorectal cancer liver metastases patients who fail to achieve objective response after neoadjuvant chemotherapy.

[A comparative study of total laparoscopic and laparoscopic-assisted simultaneous resection for colorectal cancer liver metastasis].

Objective: To compare the safety and outcome between total laparoscopic and laparoscopy-assisted synchronous resection for colorectal cancer patients with liver metastases. Methods: The data of patients who underwent total laparoscopic or laparoscopy-assisted simultaneous resection of primary colorectal cancer and liver metastases in our hospital between December 2008 and December 2016 were collected and analyzed. The total laparoscopic surgery patients were matched 1∶2 to the laparoscopy-assisted surgery patients based on the propensity score. 22 patients were classified in the total laparoscopic group and 44 patients were classified in the laparoscopy-assisted group. The intraoperative conditions and postoperative outcomes of the two groups were compared. Results: There was no difference in the preoperative baseline data between the two groups (P>0.05). The median operative time were 317.50 and 267.50 minutes in the total laparoscopic group and the laparoscopy-assisted group, respectively, and the median intraoperative blood loss were 100 and 200 ml, both with no statistically significant differences (P>0.05). There were 1 case of intraoperative blood transfusion in the total laparoscopic group and 5 cases in the laparoscopy-assisted group, with no statistically significant difference (P=0.650). The median postoperative hospital stay in the two groups were 11.0 and 10.0 days, the median postoperative defecation time were 4.0 and 4.0 days and postoperative complication rates were 13.6% and 20.5%, and none of these differences were statistically significant (P>0.05). However, no Clavien-DindoⅡ level and above complications occurred in total laparoscopic group. The median disease-free survival (DFS) were 15.0 and 15.7 months in the total laparoscopic group and the laparoscopy-assisted group, the overall survival (OS) were 25.9 and 37.6 months, respectively, with no statistically significant differences (P>0.05). Conclusion: Laparoscopy-assisted approaches are similar, so the appropriate approach should be chosen according to the clinical condition and surgeon's experience.

Identification and analysis of the jnk1 gene in polyploid hybrids of red crucian carp (Carassius auratus red var.) and common carp (Cyprinus carpio L.).

c-Jun N-terminal kinase (JNK) is an important member of the mitogen-activated protein kinase superfamily. The allotetraploid crucian carp is a product of distant hybridization of female red crucian carp with male common carp. It is the first natural case of an allotetraploid with stable genetic characters, including fertility of both female and male animals. In this study, 2 jnk1 cDNAs (including jnk1a and jnk1b) have been cloned from the polyploid crucian carp system, consisting of the allotetraploid crucian carp, the triploid crucian carp, and their original parents (red crucian and common carp). We show that jnk1a and jnk1b represent 2 splice forms arising from the jnk1 gene. On the basis of the genetic structure of jnk1a gene in the polyploid crucian carp system, we demonstrated that the allotetraploid crucian carp is phylogenetically closer to its paternal parent (common carp) than to its maternal parent. We further show a similarity between the triploid crucian carp and its original female parent (red crucian carp). Comparisons of genetic structures indicated that the jnk1b genes of allotetraploid and triploid crucian carp are more similar to those of the original paternal parent rather than the original female parent (red crucian carp). RT-PCR analysis indicated that both the jnk1a and jnk1b genes are widely expressed in fish embryos and in the adult organs, displaying distinct features of embryonic-stage and organ specificity in the polyploid crucian carp system.

First Report of Leaf Spot Disease Caused by Exserohilum rostratum on Pineapple in Hainan Province, China.

Pineapple (Ananas comosus (L.) Merr.) is an important perennial monocotyledonous plant that serves as an important fruit crop globally and is also produced in the Hainan Province of China where production in 2009 was 296,600 t. In July 2009, atypical symptoms of a leaf spot disease were observed on mature pineapple leaves in Chengmai County; approximately 15% of plants propagated from suckers became symptomatic after 150 to 300 days, eventually causing a 3 to 10% yield loss. In the initial infection stage, grayish white-to-yellowish white spots emerged on the leaf surfaces that ranged from 1.0 to 2.4 × 0.3 to 0.7 cm; black specks were not always present in the spots. Leaf spots also had distinctive light brown-to-reddish brown banding pattern on the edges. Several spots would often merge to form large lesions, 6.5 to 15.4 × 2.5 to 5.6 cm, covering more than 67% of the leaf surface, which can lead to death of the plant. Infected pineapple leaves collected from an orchard of Chengmai County were surface sterilized (75% ethanol for 30 s, 0.1% HgCl2 for 2 min, and rinsed three times in sterile distilled water). Leaf pieces were placed on potato dextrose agar medium and then incubated at 25°C. The emerging fungal colonies were grayish white to brown. Similar strains were obtained from Qionghai City and Wanning City subsequently. Two isolates, ITF0706-1 and ITF0706-2, were used in confirmation of the identity of the pathogen and in pathogenicity tests. Colonies were fast growing (more than 15 mm per day at 25 to 30°C) with dense aerial mycelia. Conidia were fusiform, pyriform to oval or cylindrical, olive brown to dark brown, 3 to 10 septate (typically 5 to 8), 33.2 to 102.5 × 9.0 to 21.3 µm, with a strongly protruding hilum bulged from the basal cell, which were similar to the Type A conidia described by Lin et al. (3). The strains were subjected to PCR amplification of the internal transcribed spacer (ITS)1-5.8S-ITS2 regions with universal primer pair ITS1/ITS4. The ITS sequence comparisons (GenBank Accession Nos. JN711431 and JN711432) shared between 99.60 and 99.83% identity with the isolate CATAS-ER01 (GenBank Accession No. GQ169762). According to morphological and molecular analysis, the two strains were identified as Exserohilum rostratum (Drechs.) Leonard & Suggs. Pathogenicity experiments were conducted five times and carried out by spraying a conidial suspension (105 CFU/ml) on newly matured leaves of healthy pineapple plants; plants sprayed with sterile water served as the negative control. Plants were incubated in the growth chamber at 20 to 25°C. Symptoms of leaf spot developed on test plants 7 days after inoculation while the control plants remained asymptomatic. Koch's postulates were fulfilled with the reisolation of the two fungal strains. Currently, E. rostratum is one of the most common pathogens on Bromeliads in Florida (2) and has been reported on Zea mays (4), Musa paradisiacal (3), and Calathea picturata (1) in China, but to our knowledge, this is the first report of leaf spot disease caused by E. rostratum on pineapple in Hainan Province of P.R. China. References: (1) L. L. Chern et al. Plant Dis. 95:1033, 2011. (2) R. M. Leahy. Plant Pathol. Circ. No. 393. Florida Department of Agriculture and Consumer Services Division of Plant Industry, 1999. (3) S. H. Lin et al. Australas. Plant Pathol. 40:246, 2011. (4) J. N. Tsai et al. Plant Pathol. Bull. 10:181, 2001.

[Prediction of trends for fine-scale spread of Oncomelania hupensis in Shanghai Municipality based on supervised machine learning models].

OBJECTIVE: To predict the trends for fine-scale spread of Oncomelania hupensis based on supervised machine learning models in Shanghai Municipality, so as to provide insights into precision O. hupensis snail control. METHODS: Based on 2016 O. hupensis snail survey data in Shanghai Municipality and climatic, geographical, vegetation and socioeconomic data relating to O. hupensis snail distribution, seven supervised machine learning models were created to predict the risk of snail spread in Shanghai, including decision tree, random forest, generalized boosted model, support vector machine, naive Bayes, k-nearest neighbor and C5.0. The performance of seven models for predicting snail spread was evaluated with the area under the receiver operating characteristic curve (AUC), F1-score and accuracy, and optimal models were selected to identify the environmental variables affecting snail spread and predict the areas at risk of snail spread in Shanghai Municipality. RESULTS: Seven supervised machine learning models were successfully created to predict the risk of snail spread in Shanghai Municipality, and random forest (AUC = 0.901, F1-score = 0.840, ACC = 0.797) and generalized boosted model (AUC= 0.889, F1-score = 0.869, ACC = 0.835) showed higher predictive performance than other models. Random forest analysis showed that the three most important climatic variables contributing to snail spread in Shanghai included aridity (11.87%), ≥ 0 °C annual accumulated temperature (10.19%), moisture index (10.18%) and average annual precipitation (9.86%), the two most important vegetation variables included the vegetation index of the first quarter (8.30%) and vegetation index of the second quarter (7.69%). Snails were more likely to spread at aridity of < 0.87, ≥ 0 °C annual accumulated temperature of 5 550 to 5 675 °C, moisture index of > 39% and average annual precipitation of > 1 180 mm, and with the vegetation index of the first quarter of > 0.4 and the vegetation index of the first quarter of > 0.6. According to the water resource developments and township administrative maps, the areas at risk of snail spread were mainly predicted in 10 townships/subdistricts, covering the Xipian, Dongpian and Tainan sections of southern Shanghai. CONCLUSIONS: Supervised machine learning models are effective to predict the risk of fine-scale O. hupensis snail spread and identify the environmental determinants relating to snail spread. The areas at risk of O. hupensis snail spread are mainly located in southwestern Songjiang District, northwestern Jinshan District and southeastern Qingpu District of Shanghai Municipality.

[Prevalence of mountain-zoonotic type visceral leishmaniasis in Yangquan City of Shanxi Province from 2015 to 2020].

OBJECTIVE: To investigate the prevalence of mountain-type zoonotic visceral leishmaniasis (MT-ZVL) in Yangquan City, Shanxi Province from 2015 to 2020, so as to provide the scientific evidence for formulating the MT-ZVL control strategy. METHODS: The epidemiological data pertaining to MT-ZVL cases in Yangquan City from 2015 to 2020 were collected and descriptively analyzed. A Joinpoint regression model was created to analyze the trend in the MT-ZVL incidence in Yangquan City from 2015 to 2020 using annual percent change (APC). The sandflies surveillance data and the prevalence of Leishmania infections in dogs were collected in Yangquan City in 2020, and the regional distribution of sandflies density and sero-prevalence of Leishmania infections in dogs were calculated. In addition, the associations of sandflies density and sero-prevalence of Leishmania infections in dogs with the incidence of human MT-ZVL were examined using the linear correlation analysis. RESULTS: A total of 162 MT-ZVL cases were reported in Yangquan City, Shanxi Province from 2015 to 2020, with annual mean incidence of 1.9/105, and there were 4, 7, 16, 27, 33 cases and 75 cases with MT-ZVL reported from 2015 to 2020, appearing a tendency towards a rapid rise (APC = 72.79%, t = 11.10, P < 0.01). MT-ZVL cases were reported across the five counties (districts) of Yangquan City, and the cases predominantly occurred in Jiaoqu District (35.2%, 57/162) and Pingding County (33.3%, 54/162). MT-ZVL cases were predominantly detected in residents at ages of 15 years and older (71.6%, 116/162) and at ages of 0 to 2 years (22.2%, 36/162), with farmers (37.4%, 61/162) and diaspora children (24.5%, 40/162) as predominant occupations. The mean density of Phlebotomus chinensis was 6.3 sandflies per trap per night in Yangquan City from during the period from May to September, 2020, with the highest density observed in Jiaoqu District (12.6 sandflies per trap per night) and the lowest in Yuxian County (1.1 sandflies per trap per night), and there was a region-specific mean density of Ph. chinensis in Yangquan City (H = 17.282, P < 0.01). The sero-prevalence of serum anti-Leishmania antibody was 7.4% (2 996/40 573) in domestic dogs in Yangquan City, with the highest sero-prevalence seen in Jiaoqu District (16.6%, 1 444/8 677), and the lowest in Yuxian County (2.3%, 266/11 501), and there was a region-specific sero-prevalence rate of anti-Leishmania antibody in domestic dogs in Yangquan City (χ2 = 1 753.74, P < 0.01). The sero-prevalence of anti-Leishmania antibody was significantly higher in stray dogs (20.0%, 159/794) than in domestic dogs (χ2 = 176.63, P < 0.01). In addition, there were significant associations among the sandflies density, sero-prevalence of anti-Leishmania antibody in domestic dogs and the incidence of human MT-ZVL (r = 0.832 to 0.870, all P values < 0.05). CONCLUSIONS: The prevalence of MT-ZVL appeared a tendency towards a rapid rise in Yangquan City from 2015 to 2020, and systematic interventions are urgently needed for MT-ZVL control.

Prognostic value of neutrophil-lymphocyte ratio in critically ill patients with cancer: a propensity score matching study.

BACKGROUND: Neutrophil-lymphocyte ratio (NLR) has shown a good prognostic value in many different type of malignancies. The purpose of this study was to investigate the relationship between NLR and the outcome of critically ill patients with cancer. METHODS: We performed a single-institution, retrospective study of 1317 adult critically ill patients with cancer and determined the optimal cut-off for NLR by X-tile software. Propensity score matching (PSM) and inverse probabilities of treatment weighting (IPTW) were performed to control confounders. Cox proportional hazards model was used to evaluate the relationship between NLR and 28-day, 6-month and 1-year all-cause mortality. Kaplan-Meier method, subgroup analysis, and receiver operating characteristics (ROC) analysis were applied to assess the prognostic value of NLR. RESULTS: The cut-off value for NLR was 17.6. Cox proportional hazards model demonstrated that high NLR (> 17.6) was independently associated with 28-day, 6-month and 1-year all-cause mortality with hazard ratio (HR) of 1.58 (1.29, 1.94), 1.51 (1.28, 1.77) and 1.45 (1.25, 1.69), respectively. The results were consistent with survival analyses (p < 0.001, log-rank test). The ROC analyses showed that the discrimination abilities of NLR were better than other blood-based biomarkers. CONCLUSION: NLR is a promising prognostic indicator of survival in unselected critical ill patients with cancer.

The E-cadherin gene polymorphism 160C->A and cancer risk: A HuGE review and meta-analysis of 26 case-control studies.

A single nucleotide polymorphism, - 160C-->A, has been identified in the promoter region of the E-cadherin gene and has been shown to alter its transcriptional activity. To assess susceptibility of -160A allele carriers to seven types of cancers, the authors conducted a comprehensive meta-analysis, up to November 2006, of 26 case-control studies comprising 7,042 cases and 7,011 controls. Pooled odds ratios and 95% confidence intervals were calculated by using the random-effects model. Publication bias, subgroup, and sensitivity analyses were also performed, which showed that -160A allele carriers, compared with noncarriers, had about a 17-19% increased risk of several invasive/metastatic tumors. Analyses of various types of cancers revealed that, in Europeans, the -160AA homozygote was associated with an increased risk of urothelial cancer, carriers of -160A were at increased risk of lung and prostate cancers, and carriers of -160A with gastric cancer were found to suffer a significantly increased risk, whereas their Asian counterparts seemed to be tolerant. No evidence was found that the -160A allele predisposed its carriers to breast, colorectal, or esophageal cancers. These findings indicate that -160A of the E-cadherin gene is emerging as a low-penetrance tumor susceptibility allele for the development of gastric, lung, prostate, and urothelial cancers.

SFP genotyping from affymetrix arrays is robust but largely detects cis-acting expression regulators.

The recent development of Affymetrix chips designed from assembled EST sequences has spawned considerable interest in identifying single-feature polymorphisms (SFPs) from transcriptome data. SFPs are valuable genetic markers that potentially offer a physical link to the structural genes themselves. However, most current SFP prediction methodologies were developed for sequenced species although SFPs are particularly valuable for species with complex and unsequenced genomes. To establish the sensitivity and specificity of prediction, we explored four methods for identifying SFPs from experiments involving two tissues in two commercial barleys and their doubled-haploid progeny. The methods were compared in terms of numbers of SFPs predicted and their ability to identify known sequence polymorphisms in the features, to confirm existing SNP genotypes and to match existing maps and individual haplotypes. We identified >4000 separate SFPs that accurately predicted the SNP genotype of >98% of the doubled-haploid (DH) lines. They were highly enriched for features containing sequence polymorphisms but all methods uniformly identified a majority of SFPs ( approximately 64%) in features for which there was no sequence polymorphism while 5% mapped to different locations, indicating that "SFPs" mainly represent polymorphism in cis-acting regulators. All methods are efficient and robust at predicting markers for gene mapping.

Genetic dissection of ethanol tolerance in the budding yeast Saccharomyces cerevisiae.

Uncovering genetic control of variation in ethanol tolerance in natural populations of yeast Saccharomyces cerevisiae is essential for understanding the evolution of fermentation, the dominant lifestyle of the species, and for improving efficiency of selection for strains with high ethanol tolerance, a character of great economic value for the brewing and biofuel industries. To date, as many as 251 genes have been predicted to be involved in influencing this character. Candidacy of these genes was determined from a tested phenotypic effect following gene knockout, from an induced change in gene function under an ethanol stress condition, or by mutagenesis. This article represents the first genomics approach for dissecting genetic variation in ethanol tolerance between two yeast strains with a highly divergent trait phenotype. We developed a simple but reliable experimental protocol for scoring the phenotype and a set of STR/SNP markers evenly covering the whole genome. We created a mapping population comprising 319 segregants from crossing the parental strains. On the basis of the data sets, we find that the tolerance trait has a high heritability and that additive genetic variance dominates genetic variation of the trait. Segregation at five QTL detected has explained approximately 50% of phenotypic variation; in particular, the major QTL mapped on yeast chromosome 9 has accounted for a quarter of the phenotypic variation. We integrated the QTL analysis with the predicted candidacy of ethanol resistance genes and found that only a few of these candidates fall in the QTL regions.

Promoter-hypermethylation associated defective expression of E-cadherin in primary non-small cell lung cancer.

Hypermethylation of CpG islands is well known as a major inactivation mechanism of tumor suppressor genes. E-cadherin (E-cad) as a tumor invasion suppressor has been reported in several invasive and metastatic carcinomas. However, its significance in carcinogenesis of primary non-small cell lung cancer (NSCLC) is not well documented. This study was designed to assess the significance with 95 pairs of carefully collected NSCLC tumors and corresponding nonmalignant tissue samples. We carried out PCR-SSCP (single-strand conformation polymorphism) and PCR-RFLP (restriction fragment length polymorphism) screening for DNA variants, bisulfite conversion-specific MSP for methylation analysis, reverse transcription (RT)-PCR for mRNA and immunohistochemistry (IHC) for protein expression assays. To investigate effect of promoter-hypermethylation on E-cad expression, we also did demethylation experiment in six cell lines. First, we found that the -160A carriers (a single nucleotide polymorphism (SNP) in the promoter region of E-cad) had an increased risk for lung cancer development when compared to DNA from healthy volunteers (OR (odds ratio)=2.81; 95% CI (confidence interval), 1.36-5.86). Methylation of E-cad occurred with a significantly higher frequency in tumors than corresponding normal peritumoral tissues (P<10(-5)). Reduced expression of E-cad was detected as a distinct molecular feature of tumors in comparison to corresponding counterparts. Moreover, the methylation alteration was detected more frequently in low-differentiated tumors than in well-differentiated ones. Defective expression of E-cad in methylated cell lines was markedly recovered after treated with 5-Aza-dC (5-aza-2'-deoxycytidine). Thus, promoter-hypermethylation of E-cad is significantly associated with its defective expression and tumor differentiation, and the demethylating observation proposes a therapeutic strategy to reverse the tumor's malignancy by restoring normal expression of E-cad.

Constructing genetic linkage maps under a tetrasomic model.

An international consortium has launched the whole-genome sequencing of potato, the fourth most important food crop in the world. Construction of genetic linkage maps is an inevitable step for taking advantage of the genome projects for the development of novel cultivars in the autotetraploid crop species. However, linkage analysis in autopolyploids, the kernel of linkage map construction, is theoretically challenging and methodologically unavailable in the current literature. We present here a theoretical analysis and a statistical method for tetrasomic linkage analysis with dominant and/or codominant molecular markers. The analysis reveals some essential properties of the tetrasomic model. The method accounts properly for double reduction and incomplete information of marker phenotype in regard to the corresponding phenotype in estimating the coefficients of double reduction and recombination frequency and in testing their significance by using the marker phenotype data. Computer simulation was developed to validate the analysis and the method and a case study with 201 AFLP and SSR markers scored on 228 full-sib individuals of autotetraploid potato is used to illustrate the utility of the method in map construction in autotetraploid species.

Modeling population genetic data in autotetraploid species.

Allozyme and PCR-based molecular markers have been widely used to investigate genetic diversity and population genetic structure in autotetraploid species. However, an empirical but inaccurate approach was often used to infer marker genotype from the pattern and intensity of gel bands. Obviously, this introduces serious errors in prediction of the marker genotypes and severely biases the data analysis. This article developed a theoretical model to characterize genetic segregation of alleles at genetic marker loci in autotetraploid populations and a novel likelihood-based method to estimate the model parameters. The model properly accounts for segregation complexities due to multiple alleles and double reduction at autotetrasomic loci in natural populations, and the method takes appropriate account of incomplete marker phenotype information with respect to genotype due to multiple-dosage allele segregation at marker loci in tetraploids. The theoretical analyses were validated by making use of a computer simulation study and their utility is demonstrated by analyzing microsatellite marker data collected from two populations of sycamore maple (Acer pseudoplatanus L.), an economically important autotetraploid tree species. Numerical analyses based on simulation data indicate that the model parameters can be adequately estimated and double reduction is detected with good power using reasonable sample size.

SUMOylation in Neurological Diseases.

Since the discovery of SUMOs (small ubiquitin-like modifiers) over 20 years ago, sumoylation has recently emerged as an important posttranslational modification involved in almost all aspects of cellular physiology. In neurons, sumoylation dynamically modulates protein function and consequently plays an important role in neuronal maturation, synapse formation and plasticity. Thus, the dysfunction of sumoylation pathway is associated with many different neurological disorders. Hundreds of different proteins implicated in the pathogenesis of neurological disorders are SUMO-modified, indicating the importance of sumoylation involved in the neurological diseases. In this review, we summarize the growing findings on protein sumoylation in neuronal function and dysfunction. It is essential to have a thorough understanding on the mechanism how sumoylation contributes to neurological diseases in developing efficient therapy for these diseases.

Sumoylation in Lens Differentiation and Pathogenesis.

Sumoylation, a post-translational modification discovered over a decade ago, turns out to be a very important regulatory mechanism mediating multiple cellular processes. Recent studies from our laboratory and others also revealed that it plays a crucial role in regulating both differentiation and pathogenesis of the ocular lens. This review will summarize these progresses.

Molecular Cloning and Developmental Expression Patterns of the Striatin Gene Encoding A Member of the Regulatory Subunits for the Protein Serine/Threonine Phosphatase-2A in Fish.

PURPOSE: The protein phosphatase-2A (PP-2A) is one of the most important serine/threonine phosphatases in eukaryotes. The holoenzyme of PP-2A consists of three subunits: a scaffold A subunit, a catalytic C subunit and a regulatory B subunit. While both A and C subunits are coded by two different genes, the B subunits exist in 26 or more isoforms which are encoded by at least 15 different genes. Previous studies have shown that besides regulating specific PP-2A activity, various B subunits may have other functions. To explore the possible roles of the regulatory subunits of PP-2A in vertebrate development, we have cloned the gene encoding goldfish striatin, a member of the B'" family regulatory subunits for PP-2A, and determined their tissue-specific and temporal expression patterns. METHODS: The cDNA cloning was conducted with RT-PCR-based RACE. The mRNA expression levels for the goldfish striatin were analyzed with RT-PCR. The expression levels of the striatin protein from goldfish were determined with Western blot analysis. The semi-quantitation of the mRNA and protein expression levels was conducted with the software of U-scanning. RESULTS: Our study revealed that the full length cDNA for striatin consists of 2965 bp coding for a deduced protein of 769 amino acids, which bears a very high level of amino acid sequence identity with the homolog protein from other species. The striatin mRNA is highly expressed in the kidney, to a less degree in brain, fin, muscle, liver, ovary and gill, and the lowest in testis and heart. Similar pattern of protein expression is detected in the above 9 tissues. During the development of goldfish, the striatin mRNA maintains a relatively high level at the 2-cell, multiple cell and blastula stages. Then, it drops down substantially at gastrula stage and fluctuates around this level in the next 8 different stages. At the protein level, the striatin maintained higher level from 2-cell to gastrula stages, then decreased at neurula and optic vesicle stages, and gradually increased again to peak at eye pigmentation stage, then slightly decreased in the next few stages of development. CONCLUSIONS: Our results suggest that the striatin may play an important role in regulating goldfish development and adult tissue homeostasis. While the former function may or may not occur through PP- 2A functions, the later function appears to occur via PP-2A activity.

The Male Abnormal Gene Family 21 (Mab21) Members Regulate Eye Development.

The male abnormal gene family contains 3 members, named mab21l1, mab21l2 and mab21l3. Since their first discovery in C. elegans, homologues of mab21l1 and mab21l2 have been found in Drosophila, Zebrafish, Xenopus, chicken, mouse and human. A number of studies have revealed that mab21 gene family members, mab21l1 and mab21l2, play important roles in regulating eye development. Here, we review the functions of the mab genes in regulating ocular development.

Estimating linkage disequilibrium between a polymorphic marker locus and a trait locus in natural populations.

Positional cloning of gene(s) underlying a complex trait requires a high-resolution linkage map between the trait locus and genetic marker loci. Recent research has shown that this may be achieved through appropriately modeling and screening linkage disequilibrium between the candidate marker locus and the major trait locus. A quantitative genetics model was developed in the present study to estimate the coefficient of linkage disequilibrium between a polymorphic genetic marker locus and a locus underlying a quantitative trait as well as the relevant genetic parameters using the sample from randomly mating populations. Asymptotic covariances of the maximum-likelihood estimates of the parameters were formulated. Convergence of the EM-based statistical algorithm for calculating the maximum-likelihood estimates was confirmed and its utility to analyze practical data was exploited by use of extensive Monte-Carlo simulations. Appropriateness of calculating the asymptotic covariance matrix in the present model was investigated for three different approaches. Numerical analyses based on simulation data indicated that accurate estimation of the genetic parameters may be achieved if a sample size of 500 is used and if segregation at the trait locus explains not less than a quarter of phenotypic variation of the trait, but the study reveals difficulties in predicting the asymptotic variances of these maximum-likelihood estimates. A comparison was made between the statistical powers of the maximum-likelihood analysis and the previously proposed regression analysis for detecting the disequilibrium.

Modeling linkage disequilibrium between a polymorphic marker locus and a locus affecting complex dichotomous traits in natural populations.

Linkage disequilibrium is an important topic in evolutionary and population genetics. An issue yet to be settled is the theory required to extend the linkage disequilibrium analysis to complex traits. In this study, we present theoretical analysis and methods for detecting or estimating linkage disequilibrium (LD) between a polymorphic marker locus and any one of the loci affecting a complex dichotomous trait on the basis of samples randomly or selectively collected from natural populations. Statistical properties of these methods were investigated and their powers were compared analytically or by use of Monte Carlo simulations. The results show that the disequilibrium may be detected with a power of 80% by using phenotypic records and marker genotype when both the trait and marker variants are common (30%) and the LD is relatively high (40-100% of the theoretical maximum). The maximum-likelihood approach provides accurate estimates of the model parameters as well as detection of linkage disequilibrium. The likelihood method is preferred for its higher power and reliability in parameter estimation. The approaches developed in this article are also compared to those for analyzing a continuously distributed quantitative trait. It is shown that a larger sample size is required for the dichotomous trait model to obtain the same level of power in detecting linkage disequilibrium as the continuous trait analysis. Potential use of these estimates in mapping the trait locus is also discussed.

A population genetics model of marker-assisted selection.

A deterministic two-loci model was developed to predict genetic response to marker-assisted selection (MAS) in one generation and in multiple generations. Formulas were derived to relate linkage disequilibrium in a population to the proportion of additive genetic variance used by MAS, and in turn to an extra improvement in genetic response over phenotypic selection. Predictions of the response were compared to those predicted by using an infinite-loci model and the factors affecting efficiency of MAS were examined. Theoretical analyses of the present study revealed the nonlinearity between the selection intensity and genetic response in MAS. In addition to the heritability of the trait and the proportion of the marker-associated genetic variance, the frequencies of the selectively favorable alleles at the two loci, one marker and one quantitative trait locus, were found to play an important role in determining both the short- and long-term efficiencies of MAS. The evolution of linkage disequilibrium and thus the genetic response over several generations were predicted theoretically and examined by simulation. MAS dissipated the disequilibrium more quickly than drift alone. In some cases studied, the rate of dissipation was as large as that to be expected in the circumstance where the true recombination fraction was increased by three times and selection was absent.