Stable variants of sperm aneuploidy among healthy men show associations between germinal and somatic aneuploidy

Repeated semen specimens from healthy men were analyzed by sperm fluorescence in situ hybridization (FISH), to identify men who consistently produced elevated frequencies of aneuploid sperm and to determine whether men who were identified as stable variants of sperm aneuploidy also exhibited higher frequencies of aneuploidy in their peripheral blood lymphocytes. Seven semen specimens were provided by each of 15 men over a 2-year period and were evaluated by the X-Y-8 multicolor sperm FISH method (i.e., approximately 1,050,000 sperm were analyzed from 105 specimens). Three men were identified as stable aneuploidy variants producing significantly higher frequencies of XY, disomy X, disomy Y, disomy 8, and/or diploid sperm over time. In addition, one man and three men were identified as sperm-morphology and sperm-motility variants, respectively. Strong correlations were found between the frequencies of sperm with autosomal and sex-chromosome aneuploidies and between the two types of meiosis II diploidy; but not between sperm aneuploidy and semen quality. A significant association was found between the frequencies of sex-chromosome aneuploidies in sperm and lymphocytes in a subset of 10 men (r2=0.67, P=.004), especially between XY sperm and sex-chromosome aneuploidy in lymphocytes (r2=0.70, P=.003). These findings suggest that certain apparently healthy men can produce significantly higher frequencies of both aneuploid sperm and lymphocytes. Serious long-term somatic and reproductive health consequences may include increased risks of aneuploidy-related somatic diseases and of having children with paternally transmitted aneuploidies, such as Klinefelter, Turner, triple-X, and XYY syndromes.     

CD24 and APC Genetic Polymorphisms in Pancreatic Cancers as Potential Biomarkers for Clinical Outcome

Background

There are no validated biomarkers that correlate with the prognosis of pancreatic ductal adenocarcinoma (PDA). The CD24 and adenomatous polyposis coli (APC) genes are important in the malignant transformation of gastrointestinal cells. This study examined APC and CD24 genetic polymorphisms and their possible impact on survival of patients with PDA.

Methods

Clinical and pathological data as well as blood samples for extracting DNA were obtained for 73 patients with PDA. Real-time PCR assessed genetic variants of APC (I1307K and E1317Q), and four different single nucleotide polymorphisms (SNPs) in the CD24 gene: C170T (rs52812045), TG1527del (rs3838646), A1626G (rs1058881) and A1056G (rs1058818).

Results

The median age at diagnosis was 64 (41–90) years. Thirty-one patients (42.5%) were operable, 16 (22%) had locally advanced disease and 26 (35.5%) had disseminated metastatic cancer. The malignancy-related mortality rate was 84%. Median survival was 14 months (11.25–16.74). Survival was similar for wild-type (WT), heterozygous and homozygous variants of the APC or CD24 genes. The three most frequent CD24 SNP combinations were: heterozygote for A1626G and WT for the rest of the alleles (14% of patients), heterozygote for C170T, A1626G, A1056G and WT for the rest (14% of patients), and heterozygote for C170T, A1056G and WT for the rest (10% of patients). All patients were APC WT. The first two groups were significantly younger at diagnosis than the third group.

Conclusions

Specific polymorphisms in the APC and CD24 genes may play a role in pancreatic cancer development. Correlation with survival requires a larger cohort.     

Potential feedback between coral presence and farmerfish collective behavior promotes coral recovery

Stable between‐group differences in collective behavior have been documented in a variety of social taxa. Here we evaluate the effects of such variation, often termed collective or colony‐level personality, on coral recovery in a tropical marine farmerfish system. Groups of the farmerfish Stegastes nigricans cultivate and defend gardens of palatable algae on coral reefs in the Indo‐Pacific. These gardens can promote the recruitment, growth, and survival of corals by providing a refuge from coral predation. Here we experimentally evaluate whether the collective response of farmerfish colonies is correlated across intruder feeding guilds – herbivores, corallivores and egg‐eating predators. Further, we evaluate if overall colony responsiveness or situation‐specific responsiveness (i.e. towards herbivores, corallivores, or egg‐eaters in particular) best predicts the growth of outplanted corals. Finally, we experimentally manipulated communities within S. nigricans gardens, adding either macroalgae or large colonies of coral, to assess if farmerfish behavior changes in response to the communities they occupy. Between‐group differences in collective responsiveness were repeatable across intruder guilds. Despite this consistency, responsiveness towards corallivores (porcupinefish and ornate butterflyfish) was a better predictor of outplanted coral growth than responsiveness towards herbivores or egg‐eaters. Adding large corals to farmerfish gardens increased farmerfish attacks towards intruders, pointing to possible positive feedback loops between their aggression towards intruders and the presence of corals whose growth they facilitate. These data provide evidence that among‐group behavioral variation could strongly influence the ecological properties of whole communities.     

WNT5A signaling affects pituitary gland shape

Wnt signaling is important in organogenesis, and aberrant signaling in mature cells is associated with tumorigenesis. Several members of the Wnt family of signaling molecules are expressed in the developing pituitary gland. Wnt5a is expressed in the neuroectoderm that induces pituitary gland development and has been proposed to influence pituitary cell specification. We discovered that mice deficient in Wnt5a display abnormal morphology in the dorsal part of the developing pituitary. The expression of downstream effectors of the canonical Wnt pathway is not altered, and expression of genes in other signaling pathways such as Shh, Fgf8, Fgf10 and Fgfr2b is intact. Prop1 and Hesx1 are also important for normal shape of the pituitary primordium, but their expression is unaltered in the Wnt5a mutants. Specification of the hormone-producing cell types of the mature anterior pituitary gland occurs appropriately. This study suggests that the primary role of Wnt5a in the developing pituitary gland is in establishment of the shape of the gland.     

Mitochondria at the Crossroad of Apoptotic Cell Death

In the past few years, it has become widely appreciated that apoptotic cell death generallyinvolves activation of a family of proteases, the caspases, which undermine the integrity ofthe cell by cleavage of critical intracellular substrates. Caspases, which are synthesized asinactive zymogens, are themselves caspase substrates and this cleavage leads to their activation.Hence, the potential exists for cascades of caspases leading to cell death. However, it has beenrecently recognized that another, perhaps more prominent route to caspase activation, involvesthe mitochondria. Upon receipt of apoptotic stimuli, either externally or internally generated,cells initiate signaling pathways which converge upon the mitochondria to promote release ofcytochrome C to the cytoplasm; cytochrome c, thus released, acts as a potent cofactor incaspase activation. Even cell surface death receptors such as Fas, which can trigger directcaspase activation (and potentially a caspase cascade), appear to utilize mitochondria as partof an amplification mechanism; it has been recently demonstrated that activated caspases cancleave key substrates to trigger mitochondrial release of cytochrome c, thereby inducing furthercaspase activation and amplifying the apoptotic signal. Therefore, mitochondria play a centralrole in apoptotic cell death, serving as a repository for cytochrome c.     

Profiling of oligolignols reveals monolignol coupling conditions in lignifying poplar xylem

Lignin is an aromatic heteropolymer, abundantly present in the walls of secondary thickened cells. Although much research has been devoted to the structure and composition of the polymer to obtain insight into lignin polymerization, the low-molecular weight oligolignol fraction has escaped a detailed characterization. This fraction, in contrast to the rather inaccessible polymer, is a simple and accessible model that reveals details about the coupling of monolignols, an issue that has raised considerable controversy over the past years. We have profiled the methanol-soluble oligolignol fraction of poplar (Populus spp.) xylem, a tissue with extensive lignification. Using liquid chromatography-mass spectrometry, chemical synthesis, and nuclear magnetic resonance, we have elucidated the structures of 38 compounds, most of which were dimers, trimers, and tetramers derived from coniferyl alcohol, sinapyl alcohol, their aldehyde analogs, or vanillin. All structures support the recently challenged random chemical coupling hypothesis for lignin polymerization. Importantly, the structures of two oligomers, each containing a gamma-p-hydroxybenzoylated syringyl unit, strongly suggest that sinapyl p-hydroxybenzoate is an authentic precursor for lignin polymerization in poplar.     

Regulation of primary spinal neuron lineages after deletion of a major progenitor

Vertebrate embryos are able to reconstitute the body plan when early blastomeres are deleted, but it is not known whether this is accomplished by cells local to the lesion or by a readjustment of the entire pattern of the embryo. We distinguished between these two possibilities by studying which embryonic cells change primary spinal neuronal fates after deletion of a major spinal cord progenitor. After ablation of the V1.2 blastomere of the 16-cell Xenopus embryo, the spinal cord contained normal numbers of Rohon-Beard neurons and primary motoneurons, indicating that the remaining blastomeres numerically reconstituted these populations. Using lineage-tracing techniques we revealed a global response: 10 out of the 15 remaining blastomeres significantly changed the number of one or both neuronal types they produced. This widespread response indicates that position in the early embryo plays an important role in regulating the production of primary spinal neurons. However, not all cells are influenced solely by position; a vegetal cell transplanted into the position of the deleted V1.2 did not take on the neuronal fate of its new position. Thus, restitution of pattern relies on a combination of positional cues and intrinsic fate restrictions.     

Variation of mechanical properties with amino acid content in the silk of Nephila clavipes

In this paper, we explore the impact of dietary deprivation, where spiders are provided diets missing one or more of the amino acids, on the properties of the spider dragline silk spun after one month on the diet. Cohorts of female N. clavipes spiders were selected for diets deprived of alanine (Ala) and glycine (Gly), arginine (Arg), leucine (Leu), or tyrosine (Tyr), and their silk was harvested twice weekly during the one-month course of the diet. Significant mechanical differences are observed after as little as 6 days on the diet. Utilizing conventional tensile testing methods, single fibers were strained to break so as to study the influence of diet on the stress/strain properties. Diets deprived of Ala and Gly appear to most directly impact the load-bearing foundation of dragline silk. Diets deprived of Arg, Tyr, and possibly Leu reduce the strength of the silk, and diets missing Tyr and Leu reduce the strain-to-failure. Observations obtained from ESEM photos of the fracture interfaces after tensile testing illustrate the fracture mechanics of spider silk. Both solid-state NMR and amino acid analysis of the digested protein suggest, however, that the relationship between diet and amino acid incorporation into the silk fiber is not straightforward.     

Human antiglobulin response to foreign antibodies: therapeutic benefit?

Immunotherapies for cancer offer attractive alternatives to conventional therapies although human anti-globulin antibody (HAGA) against the antibody (Ab) administered to the patient can be an obstacle to repeated treatment. Monoclonal antibodies (mAb), whether foreign or human in origin, have been used safely in patients for two decades. Adverse events have not proven to be significant clinical obstacles, although alterations of pharmacokinetic behavior of subsequently administered Ab can lead to less effective therapy. Not only is HAGA safe, but it can be associated with beneficial immunity in patients. Studies have shown that some patients have unexpectedly prolonged survival associated with HAGA. In our own non-Hodgkin's lymphoma (NHL) patients treated with mouse Lym-1 anti-lymphoma mAb, a high human anti-mouse Ab (HAMA) titer was associated with increased survival. The possible mechanisms linking HAMA responses to survival are likely related to Ab generated against the idiotopes of the administered Ab. An induced immune cascade in these patients, including anti-idiotypic Ab (Ab2) and cytotoxic Ab1' or Ab3 probably contributed to survival. In summary, HAGA should not a priori preclude the therapeutic use of Ab for cancer.