BACKGROUND & AIMS: :Li-Fraumeni syndrome (LFS) is an autosomal-dominant cancer predisposition syndrome of which the majority is caused by TP53 germline mutations and is characterised by different tumour types occurring at relatively young age. Recently, it was shown that a single-nucleotide polymorphism (SNP) in the MDM2 gene, SNP309 (T>G variation), was associated with accelerated tumour formation in LFS patients who carry a TP53 germline mutation. To confirm this finding in different populations, we screened 25 Dutch and 11 Finnish TP53 mutation carriers for the presence of the SNP309 G allele in the MDM2 gene. Additionally, we investigated whether the SNP309 G allele plays a role in 72 Dutch TP53-negative LFS and LFS-related patients. In the TP53 germline mutation carriers, a significant difference was seen in the mean age of tumour onset for the SNP309 G allele group, that is, 29.7 years as compared to the SNP309 homozygous T group 45.5 years (P=0.005). In patients of LFS and LFS-related TP53-negative families, no difference was seen in the mean age of tumour onset. However, this TP53-negative group did show a significantly higher percentage of SNP309 homozygotes (G/G) compared to the general population (P=0.02). In conclusion, TP53 germline mutation carriers who have an SNP309 G allele have an earlier onset of tumour formation. The higher prevalence of MDM2 SNP309 homozygous G/G carriers in the TP53-negative group suggests that this allele contributes to cancer susceptibility in LFS and LFS-related families.

背景与目标： : Li-Fraumeni综合征 (LFS) 是一种常染色体显性癌症易感性综合征，其中大多数是由TP53种系突变引起的，其特征是在相对年轻的时候发生的不同肿瘤类型。最近，研究表明，MDM2基因SNP309 (T>G变异) 中的单核苷酸多态性 (SNP) 与携带TP53种系突变的LFS患者的肿瘤加速形成有关。为了在不同人群中证实这一发现，我们筛选了25个荷兰和11个芬兰TP53突变携带者，以寻找MDM2基因中snp309g等位基因的存在。此外，我们调查了SNP309 G等位基因是否在72名荷兰TP53-negative LFS和LFS相关患者中起作用。在TP53种系突变携带者中，与SNP309纯合T组相比，SNP309 G等位基因组的平均肿瘤发病年龄存在显着差异，即29.7岁 (P = 0.005)。在LFS和LFS相关TP53-negative家族的患者中，肿瘤平均发病年龄没有差异。然而，与普通人群相比，该TP53-negative组确实显示出明显更高的SNP309纯合子百分比 (G/G) (P = 0.02)。总之，具有snp309g等位基因的TP53种系突变携带者的肿瘤形成较早。TP53-negative组中MDM2 SNP309纯合G/G携带者的患病率较高，这表明该等位基因有助于LFS和LFS相关家庭的癌症易感性。

BACKGROUND & AIMS: OBJECTIVES:A broad range of phenytoin doses is used in clinical practice, with the final 'maintenance' dose normally determined by trial and error. A common functional polymorphism in the SCN1A gene (one of the genes encoding the drug target) has been previously associated with maximum dose of phenytoin used clinically, and also maximum dose of carbamazepine, another antiepileptic drug with the same drug target. METHODS:We have related variation at the SCN1A IVS5-91 G>A polymorphism to maximum dose and to maintenance dose of phenytoin in 168 patients with epilepsy treated with phenytoin. We also related genotype to phenytoin serum levels at maximum dose and at maintenance dose of phenytoin. We genotyped the polymorphism using an Applied Biosystems Taqman assay. RESULTS:The polymorphism is associated with phenytoin serum concentration at maintenance dose (P=0.03). In a reduced cohort of 71 patients receiving phenytoin monotherapy this association is also significant (P=0.03). Neither association remains significant after Bonferroni correction for multiple testing. CONCLUSIONS:These results are not a replication of the original study. They do, however, support the hypothesis that this polymorphism influences the clinical use of phenytoin. They also demonstrate the utility of using multiple phenotypes in pharmacogenetics studies, particularly when attempting to separate pharmacokinetic and pharmacodynamic effects. As the SCN1A polymorphism affects phenytoin pharmacodynamics, it is particularly useful to obtain data on serum levels in addition to dose because association of a pharmacodynamic variant may be stronger with serum levels than dose as the serum level may eliminate or reduce pharmacokinetic variability.

背景与目标：

BACKGROUND & AIMS: :We examined the extent of variation of the 3' region of the circumsporozoite gene among Plasmodium falciparum isolates through amplification of a selected DNA fragment followed by DNA sequencing. A total of 32 isolates were analyzed, of which 24 were from Amazon endemic areas in Brazil and 8 from widely separated geographical regions in the world. Among Brazilian isolates only 2 variants were detected: 19 displayed the same sequence of strain 7G8 whereas the 4 remaining isolates differed from the 7G8 strain at five nucleotide positions which also led to amino acid changes. Variation was restricted to one of the T-helper epitopes while the sequence identified as a cytotoxic T cell epitope was conserved in all Brazilian isolates. P. falciparum samples from other geographical regions in the world showed sequences distinct from those of Brazilian isolates. However, some constancy could be observed within that variation. For instance, the most frequent nucleotide substitutions, from A and C at nucleotide positions 1015 and 1024, were the same in all isolates.

背景与目标： : 我们通过扩增选定的DNA片段，然后进行DNA测序，检查了恶性疟原虫分离株中环子孢子基因3' 区域的变异程度。共分析了32个分离株，其中24个来自巴西的亚马逊流行地区，8个来自世界上广泛分离的地理区域。在巴西分离株中，仅检测到2个变体: 19个显示了相同的7G8菌株序列，而其余4个分离株在五个核苷酸位置与7G8菌株不同，这也导致了氨基酸变化。变异仅限于T辅助表位之一，而在所有巴西分离株中，被鉴定为细胞毒性T细胞表位的序列都是保守的。来自世界其他地理区域的恶性疟原虫样品显示出与巴西分离株不同的序列。但是，在该变化中可以观察到一些恒定性。例如，在所有分离物中，来自核苷酸位置1015和1024处的A和C的最频繁的核苷酸取代是相同的。

BACKGROUND & AIMS: OBJECTIVE:To investigate phenotypic consequences of renin gene polymorphism between Lyon hypertensive (LH) and normotensive (LN) rats because previously we demonstrated cosegregation of the LH allele with increased blood pressure in a cross of LH with LN rats.

DESIGN:Two studies were conducted. Study 1 used a cohort of male F2 rats from a LH x LN cross. Eighty-two rats homozygous for the hypertensive (HH) renin gene allele were compared with 82 rats homozygous for the normotensive (NN) allele. Urinary steroid excretion was measured in 24 h urine samples collected from rats aged 6 weeks. The direct aortic blood pressure was recorded in 30-week-old rats and, after they had been killed, their kidney renin concentration (KRC) was measured. In study 2, renin, angiotensinogen and angiotensin converting enzyme plasma concentrations and renin messenger RNA (mRNA) levels were measured in renal and extra-renal tissues from 6- and 25-week-old LH and LN parental and HH and NN F2 male rats.

METHODS:Urinary steroids and plasma components of the renin-angiotensin system (RAS) were measured using specific radioimmunoassays. mRNA levels were quantified by northern blotting.

RESULTS:In study 1, HH F2 rats had a higher blood pressure (151.5 +/- 8.2 versus 146.0 +/- 7.4 mmHg, P < 0.001) and a lower KRC (514 +/- 203 versus 666 +/- 304 micrograms A1/h per g cortex, P < 0.01) than did NN rats aged 30 weeks. In covariate analysis the decrease in KRC in HH rats was attributable to their increased blood pressure rather than to the renin genotype. The renin genotype of rats aged 6 weeks was not associated with a change in the urinary excretion of aldosterone, desoxycorticosterone, corticosterone or 18-hydroxy desoxycorticosterone. In study 2, we found no difference either in plasma levels of RAS components or in renal or extrarenal renin mRNA levels either between parental LH and LN rats or between HH and NN F2 rats apart from a higher plasma renin concentration in LH rats aged 6 weeks. Renal, but not extra-renal, renin mRNA levels declined with age.

CONCLUSIONS:We found no evidence of a renin genotype-dependent phenotypic difference in the RAS that could account for the effect of the renin locus on blood pressure in Lyon rats. Our findings suggest that the effect of the locus on blood pressure might be due to an as yet unidentified gene linked to renin.

背景与目标： 目标 : 为了研究里昂高血压 (LH) 和正常血压 (LN) 大鼠之间肾素基因多态性的表型后果，因为以前我们证明了LH等位基因与LN大鼠杂交中血压升高的共分离。
设计 : 进行了两项研究。研究1使用了来自LH x LN杂交的雄性F2大鼠队列。将82只高血压 (HH) 肾素基因等位基因纯合的大鼠与82只正常血压 (NN) 等位基因纯合的大鼠进行了比较。在从6周龄大鼠收集的24小时尿液样本中测量了尿类固醇排泄。在30周龄的大鼠中记录了直接的主动脉血压，并在杀死它们后测量了它们的肾脏肾素浓度 (KRC)。在研究2中，肾素，在6周和25周龄的LH和LN亲本以及HH和NN F2雄性大鼠的肾和肾外组织中测量了血管紧张素原和血管紧张素转换酶的血浆浓度以及肾素信使RNA (mRNA) 水平。
方法 : 使用特定的放射免疫测定法测量肾素-血管紧张素系统 (RAS) 的尿类固醇和血浆成分。通过northern印迹法定量mRNA水平。
结果 : 在研究1中，HH F2大鼠的血压较高 (151.5/- 8.2与146.0/- 7.4 mmHg，P <0.001) 和低于30周龄NN大鼠的KRC (514 +/- 203对666 +/- 304微克A1/h/g皮质，P <0.01)。在协变量分析中，HH大鼠的KRC降低归因于其血压升高，而不是肾素基因型。6周龄大鼠的肾素基因型与醛固酮，脱氧皮质酮，皮质酮或18-羟基脱氧皮质酮的尿排泄变化无关。在研究2中，我们发现父母LH和LN大鼠之间或HH和NN F2大鼠之间的RAS成分血浆水平或肾脏或肾外肾素mRNA水平没有差异，除了LH大鼠中较高的血浆肾素浓度外6周。肾素mRNA水平随着年龄的增长而下降，但肾素mRNA水平却没有下降。
结论 : 我们没有发现RAS中肾素基因型依赖性表型差异的证据，可以解释肾素基因座对里昂大鼠血压的影响。我们的发现表明，该基因座对血压的影响可能是由于与肾素相关的尚未鉴定的基因所致。

BACKGROUND & AIMS: :The human multidrug resistance gene (MDR1) encodes for P-glycoprotein (P-gp) which is a transmembrane transporter protein that acts as an efflux pump for a number of lypophilic compounds. It plays a protective role for cells against DNA damage. The wobble C3435T polymorphism at exon 26 has been associated with different expression levels and activity. Differences in allele frequency of the C3435T polymorphism have been demonstrated between distinct ethnic groups. In our study we examined these polymorphisms in 433 healthy individuals. From these, 229 were Central American mestizos from Nicaragua (n = 117) and El Salvador (n = 112) to be compared with a group of 204 North Spaniards, with the aim of detecting potential genotypic differences between these populations. The genotypes were determined by PCR-RFLP. The frequencies of the C allele were very similar among Central Americans (0.53) and Spaniards (0.52), which is consistent with the ethnic origin of Central American individuals (Amerindians and European Caucasians). In comparison to other previously studied populations, the C allele frequency in Central Americans was significantly lower than that found in African populations and higher than that observed in the Indian and Southwest Asian populations. These data may be relevant for dose recommendation of P-gp substrate drugs and also for studies of allele disease association in the Central American population.

背景与目标： : 人类多药耐药基因 (MDR1) 编码P-糖蛋白 (P-gp)，P-糖蛋白是一种跨膜转运蛋白，可作为许多嗜酸性化合物的外排泵。它对细胞免受DNA损伤起保护作用。外显子26的摆动C3435T多态性与不同的表达水平和活性有关。已在不同种族之间证明了C3435T多态性的等位基因频率差异。在我们的研究中，我们在433健康个体中检查了这些多态性。从这些229中，将尼加拉瓜 (n = 117) 和萨尔瓦多 (n = 112) 的中美洲混血儿与一组204的北西班牙人进行比较，目的是检测这些人群之间的潜在基因型差异。通过pcr-rflp确定基因型。C等位基因的频率在中美洲 (0.53) 和西班牙人 (0.52) 之间非常相似，这与中美洲个体 (美洲印第安人和欧洲高加索人) 的种族起源一致。与其他先前研究的人群相比，中美洲人的C等位基因频率明显低于非洲人群，高于印度和西南亚人群。这些数据可能与P-gp底物药物的剂量推荐有关，也与中美洲人群的等位基因疾病关联研究有关。

BACKGROUND & AIMS: :The clinical heterogeneity of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with trisomy 8 as the sole abnormality may result from cytogenetically undetectable genetic changes. The purpose of this study was to identify hidden genomic aberrations not detected by metaphase cytogenetics (MC) using high-resolution single nucleotide polymorphism array (SNP-A)-based karyotyping in AML/MDS patients with a sole trisomy 8. The study group included 8 patients (3 AML and 5 MDS) and array-based karyotyping was done using whole-genome SNP-A (SNP 6.0 and SNP 2.7M). By SNP-A, additional genomic aberrations not detected by MC were identified in 2 patients: 1 AML patient exhibited a copy-neutral loss of heterozygosity (CN-LOH) of 3q21.1-q29 and 11q13.1-q25 and the other patient with MDS (refractory cytopenia with unilineage dysplasia) had CN-LOH of 2p25.3-p15. In particular, the latter patient progressed to AML 18 months after the diagnosis. In 3 patients, aberrations in addition to trisomy 8 were not identified by SNP-A. In the remaining 3 patients, SNP-A could not detect trisomy 8, while trisomy 8 was found in 25-67% of metaphase cells by MC. This study suggests that additional genomic aberrations may in fact be present even in cases of trisomy 8 as sole abnormality by MC, and SNP-A could be a useful karyotyping tool to identify hidden aberrations such as CN-LOH.

背景与目标： : 以8三体为唯一异常的急性髓性白血病 (AML) 或骨髓增生异常综合征 (MDS) 患者的临床异质性可能是由于细胞遗传学上无法检测到的遗传变化所致。这项研究的目的是使用高分辨率的基于单核苷酸多态性阵列 (snp-a) 的核型分析来鉴定中期细胞遗传学 (MC) 未检测到的隐藏的基因组畸变。研究组包括8例患者 (3例AML和5例MDS)，使用全基因组SNP-A (SNP 6.0和SNP 2.7M) 进行基于阵列的核型分析。通过SNP-A，在2例患者中发现了MC未检测到的其他基因组畸变: 1例AML患者表现出3q21.1-q29和11q13.1-q25的拷贝中性杂合性缺失 (cn-loh)，另一例MDS患者 (难治性血细胞减少症伴单膜发育不良) 的cn-loh为2p25.3-p15。特别是，后者在诊断后18个月进展为AML。在3例患者中，SNP-A未发现除8三体外的畸变。在其余3例患者中，SNP-A不能检测到8三体，而MC在25-67% 的中期细胞中发现8三体。这项研究表明，即使在MC唯一异常的8三体病例中，实际上也可能存在其他基因组畸变，SNP-A可能是识别隐藏畸变 (例如CN-LOH) 的有用核型分析工具。

BACKGROUND & AIMS: OBJECTIVE:The aim of the study was to explore the possible role of the 5-HT2A -1438G/A polymorphism in the susceptibility to anorexia nervosa (AN) in the Chinese Han population. METHODS:The -1438G/A polymorphism of 249 female AN patients, 228 matched healthy controls, and 198 trios was genotyped using SNaP shot assay. Psychopathological traits of eating-disordered behaviors in AN subjects were examined using the Chinese version of the Eating Disorder Examination Questionnaire. RESULTS:Neither the case-control analysis nor the transmission disequilibrium test revealed significant associations between the -1438G/A polymorphism and AN (P > .05). However, AA homozygote patients with AN had lower weight and shape concern scores of the EDE-Q6.0 than those of GA heterozygotes (P < .05). DISCUSSION:Our findings suggested that female AN patients with 5-HT2A -1438AA genotype may be characterized by less severe eating-disordered psychopathological traits in the Chinese Han population.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:The IDH1 gene, which encodes isocitrate dehydrogenase 1, is frequently mutated in gliomas and acute myeloid leukemia. The single-nucleotide polymorphism (SNP) (reference SNP no. rs11554137:C>T) located on IDH1 codon 105 has been associated with a poor outcome in patients with acute myeloid leukemia but has not been investigated in patients with gliomas. METHODS:The IDH1 codon 105 SNP was genotyped first in a series of 952 patients with grade 2 through 4 gliomas and was correlated with outcomes and tumor genomic profile. Then, it was genotyped in 2 validations sets of 306 patients with glioblastoma (GBM) and 591 patients with glioma. RESULTS:The minor allele codon 105 glycine (GGT) SNP (IDH1(105GGT) ) was identified in 98 of 952 patients (10.3%) and was not associated with the codon 132 (IDH1(132) ) mutation. Patients who had GMB with the IDH1(105GGT) variant had a poorer outcome than patients without the variant (median overall survival [OS], 10.7 months vs 15.5 months; P = .001; median progression-free survival [PFS], 6.4 months vs 8.5 months; P = .003). The prognostic impact was confirmed in an independent validation set of 306 GBMs from the same center (median PFS, 6.8 months vs 9.7 months; P = .006; median OS, 13.9 months vs 18.8 months; P = .0187). In the second validation cohort (591 grade 2-4 gliomas), a significant association was observed between IDH1(105GGT) and an adverse prognosis for the overall series and for patients with World Health Organization grade 3 gliomas, but the difference did not reach significance in patients with GBM. CONCLUSIONS:Taken together, the current data strongly suggested an association between the SNP rs11554137:C>T polymorphism and adverse outcomes in patients with malignant glioma. A single-nucleotide polymorphism (SNP) located on codon 105 of the isocitrate dehydrogenase 1 (IDH1) gene (reference SNP rs11554137) is analyzed in 3 independent series of patients with gliomas. The SNP rs11554137 is independent of the occurrence of somatic mutation on IDH1 codon 132, but, per se, has a prognostic impact in malignant gliomas.

背景与目标：

BACKGROUND & AIMS: :HepG2 and Huh7 cell lines are frequently used as models to study viral hepatitis and hepatocellular carcinoma. However, they exhibit significantly different capacities in their ability to support hepatitis B virus (HBV) replication. To investigate the basis for this, transcription factor-binding motifs at the HBV core promoter (HBVCP) were tested in luciferase reporter constructs to identify the possible role of host factors. Among the transcription factors screened: PARP1, SP1, HNF4α, HNF3, hB1F and HNF1, deletion of the PARP1 binding motif abrogated transcriptional activity at the HBVCP in HepG2 but not Huh7 cells. Sequencing of the PARP1 gene revealed that HepG2 cells carried an Ala762 allele which has low ADP-ribosylation activity, which was shown to have increased PARP1 binding affinity to its cognate motif thus resulting in higher transcriptional activity. PARP1 inhibitors that are being developed as broad cancer therapeutics also target PARP1 ADP-ribosylation enzymatic function. Four PARP1 inhibitors: PJ-34, ABT888, AZD2281 and AG014699 were tested for their effect on HBV replication. All four small molecules effectively enhanced HBV replication in vitro, confirming the role of PARP1 in HBV replication and that alteration of ADP-ribosylation by mutation or drugs can affect HBV replication. Our data demonstrate that natural polymorphisms in the host affecting proteins such as PARP1 can have a significant effect on HBV replication. Hence, patients who are infected with HBV and are on clinical trials involving PARP1 inhibitors may be at risk from unintended side-effects such as exacerbation of HBV replication.

背景与目标： : HepG2和Huh7细胞系经常用作研究病毒性肝炎和肝细胞癌的模型。然而，它们在支持乙型肝炎病毒 (HBV) 复制的能力方面表现出明显不同的能力。为了研究这一点的基础，在荧光素酶报告构建体中测试了HBV核心启动子 (HBVCP) 的转录因子结合基序，以确定宿主因子的可能作用。在筛选的转录因子中: PARP1，SP1，HNF4α，HNF3，hB1F和HNF1，PARP1结合基序的缺失消除了HepG2中HBVCP的转录活性，而不是Huh7细胞。PARP1基因的测序表明，HepG2细胞携带Ala762等位基因，该等位基因具有较低的ADP-核糖基化活性，这被证明具有增加的PARP1与其同源基序的结合亲和力，从而导致更高的转录活性。作为广泛的癌症治疗药物正在开发的PARP1抑制剂也针对PARP1 ADP-核糖基化酶功能。测试了四种PARP1抑制剂: PJ-34，ABT888，AZD2281和AG014699对HBV复制的影响。所有四个小分子在体外有效地增强了HBV复制，证实了PARP1在HBV复制中的作用，并且通过突变或药物改变ADP-核糖基化可以影响HBV复制。我们的数据表明，宿主中影响蛋白 (如PARP1) 的自然多态性对HBV复制有显著影响。因此，感染HBV并正在进行涉及PARP1抑制剂的临床试验的患者可能会受到意外副作用 (例如HBV复制恶化) 的风险。

BACKGROUND & AIMS: :Several genetic polymorphisms in metabolic activation or detoxification enzymes have been associated with susceptibility to therapy-related leukemia and myelodysplastic leukemia (TRLIMDS). We analyzed gene polymorphisms of NAD(P)H:quinone oxidoreductase (NQOl), glutathione S-tranferase (GST)-MI and -TI, and CYP3A4, the enzymes of which are capable of metabolizing anticancer drugs, in 58 patients with TRL/MDS and in 411 patients with de novo acute myeloid leukemia (AML). Homozygous Ser/Ser genotype of NQOl at codon 187, causing loss of function, was more frequent in the patients with TRLIMDS (14 of 58, 24.1%; OR = 2.62) than in those with de novo AML (64 of 411, 15.6%), and control (16 of 150, 10.6%; P = 0.002). Allelic frequencies of NQOJ were different between TRL/ MDS and de novo AML (P = 0.01). In GST-MJ and -Ti, the incidence of homologous deletion was similar among the three groups. The polymorphism of the 5' promoter region of CYP3A4 was not found in persons of Japanese ethnicity. These results suggest that the NQOJ polymorphism is significantly associated with the genetic risk of TRLIMDS.

背景与目标： : 代谢激活或解毒酶中的几种遗传多态性与治疗相关的白血病和骨髓增生异常性白血病 (TRLIMDS) 的易感性有关。我们分析了NAD(P)H: 醌氧化还原酶 (NQOl)，谷胱甘肽S-转移酶 (GST)-MI和-TI和CYP3A4的基因多态性，这些酶能够代谢抗癌药物，58例TRL/MDS患者和411例从头急性髓细胞白血病 (AML) 患者。NQOl密码子187的纯合Ser/Ser基因型导致功能丧失，TRLIMDS患者 (58例中的14例，24.1% 例; OR = 2.62例) 比从头AML患者 (411例中的64例，15.6% 例) 和对照组 (150例中的16例，10.6% 例) 更常见; P = 0.002)。在TRL/ MDS和从头AML之间，NQOJ的等位基因频率不同 (P = 0.01)。在GST-MJ和-Ti中，三组之间同源缺失的发生率相似。在日本人中未发现CYP3A4的5' 启动子区域的多态性。这些结果表明，NQOJ多态性与trimds的遗传风险显着相关。

BACKGROUND & AIMS: :The toll-like receptor 2 (TLR2) has gained importance as a major mammalian receptor for lipoproteins derived from the cell wall of a variety of bacteria, such as Borrelia burgdorferi, Treponema pallidum, and Mycoplasma fermentans. We were interested in identifying mutations in the TLR2 gene that might prove to be associated with altered susceptibility to septic shock. We performed a mutation screen of the TLR2 gene using single-stranded conformational polymorphism in 110 normal, healthy study subjects and detected an Arg753Gln mutation in three individuals. No other missense mutations were detected in the TLR2 open reading frame. Functional studies demonstrate that the Arg753Gln polymorphism, in comparison to the wild-type TLR2 gene, is significantly less responsive to bacterial peptides derived from B. burgdorferi and T. pallidum. In a septic shock population, the Arg753Gln TLR2 polymorphism occurred in 2 out of 91 septic patients. More importantly, both of the subjects with the TLR2 Arg753Gln polymorphism had staphylococcal infections. These findings suggest that a mutation in the TLR2 gene may predispose individuals to life-threatening bacterial infections.

背景与目标： : toll样受体2 (TLR2) 已成为哺乳动物主要的脂蛋白受体，其衍生自多种细菌的细胞壁，例如伯氏疏螺旋体，梅毒螺旋体和发酵支原体。我们对鉴定TLR2基因突变感兴趣，这些突变可能被证明与败血性休克易感性的改变有关。我们在110名正常，健康的研究对象中使用单链构象多态性对TLR2基因进行了突变筛选，并在三个个体中检测到Arg753Gln突变。在TLR2开放阅读框中未检测到其他错义突变。功能研究表明，与野生型TLR2基因相比，Arg753Gln多态性对源自B. burgdorferi和T. pallidum的细菌肽的反应明显降低。在败血性休克人群中，91例败血症患者中有2例发生了Arg753Gln TLR2多态性。更重要的是，具有TLR2 Arg753Gln多态性的两个受试者均患有葡萄球菌感染。这些发现表明，TLR2基因的突变可能使个体容易受到威胁生命的细菌感染。

BACKGROUND & AIMS: :A small cryptic Lactobacillus helveticus plasmid, pLBL4, was able to reveal restriction fragment length polymorphism in different bacterial species including Lactobacillus species, Bacillus species, and Escherichia coli when used as a DNA probe. The observed polymorphism was a result of the combined hybridization of several microsatellite sequences. The 6-bp sequence (TTGTTT) was repeated 12 times, seven of which were concentrated within the region between 1791 and 1997 bp of the plasmid sequence. The polymorphic patterns generated with pLBL4 differed from those obtained with M13 DNA in the larger number of bands observed. The results presented here open the possibility of using pLBL4 as a new broad-spectrum polymorphic DNA probe for fingerprint analysis.

背景与目标： : 当用作DNA探针时，一个小的隐秘螺旋乳杆菌质粒pLBL4能够揭示不同细菌物种 (包括乳杆菌物种，芽孢杆菌物种和大肠杆菌) 中的限制性片段长度多态性。观察到的多态性是几个微卫星序列联合杂交的结果。将6-bp序列 (TTGTTT) 重复12次，其中7次集中在质粒序列的1791至1997 bp之间的区域内。在观察到的大量条带中，pLBL4生成的多态性模式与M13 DNA获得的多态性模式不同。此处介绍的结果为使用pLBL4作为新的广谱多态性DNA探针进行指纹分析提供了可能性。

BACKGROUND & AIMS: :Background: The association of the fetal MTHFR A1298C (rs1801131) polymorphism and neural tube defects (NTDs) susceptibility has been widely demonstrated, but the results remain inconclusive. Thus, we performed a meta-analysis to investigate the association between fetal MTHFR A1298C polymorphism and NTDs risk.Methods: An electronic search of PubMed, web of science, SciELO, CNKI database for studies on the fetal MTHFR A1298C polymorphism and NTDs risk was performed up to March 30, 2020.Results: A total of 22 case-control studies with 3,224 fetuses with NTDs and 3,295 controls were selected. Overall, pooled data showed that the fetal MTHFR A1298C polymorphism was not significantly associated with risk an increased risk of NTDs in the global population. When stratified analysis by ethnicity, country of origin and NTDs type, still no statistically significant association was found.Conclusions: Our pooled data emerged no evidence for significant association between fetal MTHFR A1298C polymorphism and NTDs risk.

背景与目标： 背景: 胎儿MTHFR A1298C (rs1801131) 多态性与神经管缺陷 (NTDs) 易感性的关联已被广泛证明，但结果尚无定论。因此，我们进行了荟萃分析，以调查胎儿MTHFR A1298C多态性与NTDs风险之间的关系。方法: 对PubMed，web of science，SciELO，CNKI数据库进行了2020年3月30日的胎儿MTHFR A1298C多态性与NTDs风险研究。结果: 总共选择了22例病例对照研究，其中3,224例具有NTDs的胎儿和3,295例对照。总体而言，汇总数据显示，胎儿MTHFR A1298C多态性与全球人群中NTDs风险增加的风险没有显着相关性。当按种族，原籍国和NTDs类型进行分层分析时，仍然没有发现统计学上的显着关联。结论: 我们的汇总数据没有证据表明胎儿MTHFR A1298C多态性与NTDs风险之间存在显着关联。

BACKGROUND & AIMS: OBJECTIVE:Mild traumatic brain injuries (mTBIs) have frequently been associated with the emergence and persistence of depressive symptoms. However, the factors which contribute to the increased risk for depression after these head injuries remain unclear. Accordingly, we examined the relationship between frequency of self-reported mTBIs and current symptoms of depression and the mediating role of rumination and cognitive flexibility. We also examined whether these relations were moderated by sex differences and the presence of the Val66Met polymorphism in a gene coding for brain-derived neurotrophic factor (BDNF). DESIGN:Retrospective, cross-sectional. SETTING:Carleton University. PARTICIPANTS:Two hundred nineteen Carleton University undergraduate students. MAIN OUTCOME MEASURES:Cognitive flexibility as assessed by the Wisconsin Card Sorting Task (WCST); subtypes of rumination (Ruminative Response Scale; Treynor, Gonzalez, and Nolen-Hoeksema, 2003); depressive symptoms (Beck Depression Inventory; Beck, Ward, and Mendelson, 1961). RESULTS:Greater frequency of self-reported mTBIs was associated with more frequent depressive rumination among women, but not men, which was accompanied by elevated current depressive symptoms. In addition, among Met allele carriers of the BDNF polymorphism, but not those who were Val homozygotes, greater frequency of mTBIs was related to higher levels of brooding, which was accompanied by heightened depressive symptoms. Brain-derived neurotrophic factor genotype also moderated the relationship between self-reported mTBIs and cognitive flexibility in that more frequent mTBIs were associated with more perseverative errors on the WCST among Met carriers, but not Val homozygotes. CONCLUSIONS:The present findings raise the possibility that the evolution of depression after mTBIs may be dependant on a BDNF polymorphism and sex differences.

背景与目标：

BACKGROUND & AIMS: :TLR4 polymorphisms such as Asp299Gly and Thr399Ile related to Gram-negative sepsis have been reported to result in significantly blunted responsiveness to LPS. Our study group previously screened other TLR4 polymorphic variants by checking the NF-κB activation in comparison to wild type (WT) TLR4 in human embryonic kidney 293T cells. In this study, we found that the Lys694Arg (K694R) polymorphism reduced the activation of NF-κB, and the production of downstream inflammatory factors IL-1, TNF-α and IL-6, representing the K694R polymorphism, led to blunted responsiveness to LPS. Then, we examined the influence of the K694R polymorphism on total and cell-surface TLR4 expression by Western blotting and flow cytometry, respectively, but observed no differences between the K694R polymorphism and WT TLR4. We also used co-immunoprecipitation to determine the interaction of the K694R polymorphism and WT TLR4 with their co-receptor myeloid differentiation factor 2 (MD2) and their downstream signal adaptor MyD88. We found that K694R reduced the recruitment of MyD88 in TLR4 signalling but had no impact on the interaction with MD2.

背景与目标： : 据报道，与革兰氏阴性脓毒症相关的TLR4多态性 (如Asp299Gly和Thr399Ile) 导致对LPS的反应性明显减弱。我们的研究小组先前通过检查人胚肾293T细胞中与野生型 (WT) TLR4相比的NF-κ b活化来筛选其他TLR4多态性变体。在这项研究中，我们发现Lys694Arg (K694R) 多态性降低了NF-κ b的活化，并且代表K694R多态性的下游炎症因子IL-1，TNF-α 和IL-6的产生导致对LPS的反应性减弱。然后，我们分别通过蛋白质印迹和流式细胞术检查了K694R多态性对总TLR4和细胞表面TLR4表达的影响，但在K694R多态性和WT TLR4之间没有观察到差异。我们还使用共免疫沉淀来确定K694R多态性和WT TLR4与其共受体髓样分化因子2 (MD2) 及其下游信号衔接子myd88的相互作用。我们发现K694R减少了TLR4信号传导中MyD88的募集，但对与md2的相互作用没有影响。