Genetic variations of antioxidant genes and their association with male infertility in Vietnamese men.

BACKGROUND: Antioxidant genes, such as superoxide dismutase (SOD), catalase (CAT), and nitric oxide synthase (NOS), play critical roles in spermatogenesis and sperm functions. Polymorphisms of antioxidant genes have been shown to be strongly associated with sperm quality which affects male fertility. METHODS: To investigate the association of antioxidant gene polymorphisms to male infertility in Vietnamese men, in this case-control study, using Sanger sequencing, we genotyped four variants SOD1:7958G>A, SOD2:c.47T>C, CAT:-262C>T, and NOS3:-786C>T. RESULTS AND CONCLUSIONS: We identified SOD1:7958GA genotype and NOS3:-786CT genotype in the infertility group were significantly higher than in the control with OR = 2.191 (95% CI: 1.226-3.915, p = 0.004) and OR = 3.135 (95% CI: 1.591-6.180, p < 0.001), respectively. We also detected that the frequency of the SOD2:c.47TC genotype was significantly higher in the male infertility group than in fertile men (OR = 1.941, 95% CI: 1.063-3.595, p = 0.029). Gene-gene interactions between the SNPs of SOD1, SOD2, and CAT might increase the risk of male infertility patients. In particular, patients carrying the SOD1:GA+AA, SOD2:TC+CC, and CAT:CT/TT genotype pattern have an increased risk of male infertility (OR = 7.614, p = 0.007). To our knowledge, this is the first study to evaluate the association between the SOD1:7958G>A polymorphism and male infertility. Further studies with larger sample sizes and more genes are needed to better assess the association between variants of antioxidant genes and male infertility.

Glycan modulation and sulfoengineering of anti-HIV-1 monoclonal antibody PG9 in plants.

Broadly neutralizing anti-HIV-1 monoclonal antibodies, such as PG9, and its derivative RSH hold great promise in AIDS therapy and prevention. An important feature related to the exceptional efficacy of PG9 and RSH is the presence of sulfated tyrosine residues in their antigen-binding regions. To maximize antibody functionalities, we have now produced glycan-optimized, fucose-free versions of PG9 and RSH in Nicotiana benthamiana. Both antibodies were efficiently sulfated in planta on coexpression of an engineered human tyrosylprotein sulfotransferase, resulting in antigen-binding and virus neutralization activities equivalent to PG9 synthesized by mammalian cells ((CHO)PG9). Based on the controlled production of both sulfated and nonsulfated variants in plants, we could unequivocally prove that tyrosine sulfation is critical for the potency of PG9 and RSH. Moreover, the fucose-free antibodies generated in N. benthamiana are capable of inducing antibody-dependent cellular cytotoxicity, an activity not observed for (CHO)PG9. Thus, tailoring of the antigen-binding site combined with glycan modulation and sulfoengineering yielded plant-produced anti-HIV-1 antibodies with effector functions superior to PG9 made in CHO cells.

A Novel Frameshift Microdeletion of the TEX12 Gene Caused Infertility in Two Brothers with Nonobstructive Azoospermia.

Male infertility is a growing health problem, which affects approximately 7% of the global male population. Nonobstructive azoospermia (NOA) is one of the most severe forms of male infertility caused by genetic defects, including chromosome structural abnormalities, Y chromosome microdeletions, or single-gene alterations. However, the etiology of up to 40% of NOA cases is unidentified. By whole-exome sequencing, we detected a homozygous 5-bp-deletion variant in exon 4 of the TEX12 gene (c.196-200del, p.L66fs, NM_031275.4) in two brothers with NOA of a nonconsanguineous Vietnamese family. This deletion variant of 5 nucleotides (ATTAG) results in a premature stop codon in exon 4 and truncation of the C-terminal. Segregation analysis by Sanger sequencing confirmed that the deletion variant was inherited in an autosomal recessive pattern. The 1st and 3rd infertile sons were homozygous for the deletion, whereas the 2nd fertile son and both parents were heterozygous. The new deletion mutation identified in TEX12 gene caused loss of function of TEX12 gene. The loss of TEX12 function has already caused infertility in male mice. Therefore, we concluded that the loss of TEX12 function may cause infertility in men. To our knowledge, this is the first case reported so far indicating disruption of human TEX12, which leads to infertility in men.

An integrated approach for investigating the correlation between floods and river morphology: A case study of the Saalach River, Germany.

Man-made structures in the Saalach River have changed the hydromorphological characteristics of the river regime. In some river reaches, the Saalach has lost the high morphological versatility and high variation in sediment transport characteristic of a mountain river. Among the negative effects, an extreme flow discharge in combination with riverbed variation could be one of the possible causes of flood disasters along the river. For example, the heavy and long lasting rainfall in June 2013 led to a peak discharge of 1100 m3/s, which was slightly above the 100-year flood return period, inundating a nearby city. However, the influence of the man-made structures on this flood event in this reach is unclear. In this study an integrative hydromorphological model is applied to evaluate this impact by a comparison with a standard clear water model with fixed bed. Moreover, a comparative analysis of a three-and two-dimensional flow model is performed to assess the models suitability representing the flow in this river stretch. The integrative model concept is based on the software TELEMAC-MASCARET, in an enhanced version for better representing graded sediment transport in rivers. In contrast to our integrative model, the standard clear water model with fixed bed overestimates the water elevations as it cannot take the significant changes in morphology into account. Results demonstrate that our proposed model more accurately represents the inundation in the floodplain and could thus be used to provide more reliable predictions to decision-makers for improved flood protection strategy.

A plant-expressed conjugate vaccine breaks CD4(+) tolerance and induces potent immunity against metastatic Her2(+) breast cancer.

Passive antibody therapy for cancer is an effective but costly treatment modality. Induction of therapeutically potent anticancer antibodies by active vaccination is an attractive alternative but has proven challenging in cancer due to tolerogenic pressure in patients. Here, we used the clinically relevant cancer target Her2, known to be susceptible to targeting by antibody therapy, to demonstrate how potent antibody can be induced by vaccination. A novel 44kD Her2 protein fragment was generated and found to be highly effective at inducing anti-Her2 antibody including trastuzumab-like reactivities. In the tolerant and spontaneous BALB-neuT mouse model of metastatic breast cancer this Her2-targeting vaccine was only effective if the fragment was conjugated to a foreign immunogenic carrier; Fragment C of tetanus toxin. Only the conjugate vaccine induced high affinity anti-Her2 antibody of multiple isotypes and suppressed tumor development. The magnitude of CD4(+) T-cell help and breadth of cytokines secreted by the CD4(+) T helper (Th) cells induced to the foreign antigen was critical. We used a highly efficient plant-based bio-manufacturing process for protein antigens, magnICON, for vaccine expression, to underpin feasibility of future clinical testing. Hence, our novel Her2-targeting conjugate vaccine combines preclinical efficacy with clinical deliverability, thus setting the scene for therapeutic testing.

Discovery of a novel class of highly conserved vaccine antigens using genomic scale antigenic fingerprinting of pneumococcus with human antibodies.

Pneumococcus is one of the most important human pathogens that causes life-threatening invasive diseases, especially at the extremities of age. Capsular polysaccharides (CPSs) are known to induce protective antibodies; however, it is not feasible to develop CPS-based vaccines that cover all of the 90 disease-causing serotypes. We applied a genomic approach and described the antibody repertoire for pneumococcal proteins using display libraries expressing 15-150 amino acid fragments of the pathogen's proteome. Serum antibodies of exposed, but not infected, individuals and convalescing patients identified the ANTIGENome of pneumococcus consisting of approximately 140 antigens, many of them surface exposed. Based on several in vitro assays, 18 novel candidates were preselected for animal studies, and 4 of them showed significant protection against lethal sepsis. Two lead vaccine candidates, protein required for cell wall separation of group B streptococcus (PcsB) and serine/threonine protein kinase (StkP), were found to be exceptionally conserved among clinical isolates (>99.5% identity) and cross-protective against four different serotypes in lethal sepsis and pneumonia models, and have important nonredundant functions in bacterial multiplication based on gene deletion studies. We describe for the first time opsonophagocytic killing activity for pneumococcal protein antigens. A vaccine containing PcsB and StkP is intended for the prevention of infections caused by all serotypes of pneumococcus in the elderly and in children.