Biallelic mutations in IRF8 impair human NK cell maturation and function

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8–/–, but not Irf8+/–, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense

Gaze following in an asocial reptile (Eublepharis macularius)

Gaze following is the ability to utilise information from another's gaze. It is most often seen in a social context or as a reflexive response to interesting external stimuli. Social species can potentially reveal utilisable knowledge about another's future intentions by attending to the target of their gaze. However, in even more fundamental situations, being sensitive to another's gaze can also be useful such as when it can facilitate greater foraging efficiency or lead to earlier predator detection. While gaze sensitivity has been shown to be prevalent in a number of social species, little is currently known about the potential for gaze following in asocial species. The current study investigated whether an asocial reptile, the leopard gecko (Eublepharis macularius), could reliably use the visual indicators of attention to follow the gaze of a conspecific around a barrier. We operated three trial conditions and found subjects (N = 6) responded significantly more to the conspecific demonstrator looking up at a laser stimulus projected onto an occluder during the experimental condition compared to either of two control conditions. The study's findings point toward growing evidence for gaze-following ability in reptiles, who are typically categorised as asocial. Furthermore, our findings support developing comparative social cognition research showing the origins of gaze following and other cognitive behaviours that may be more widely distributed across taxonomic groups than hitherto thought

Scratch lottery tickets are a poor incentive to respond to mailed questionnaires

BACKGROUND: It has been demonstrated that the enclosure of money with a mailed questionnaire increases the response rate significantly. We evaluated scratch lottery tickets as an alternative to cash. METHODS: 1500 randomly selected Norwegians between the ages of 40 and 65 years were sent a short questionnaire. 250 received one lottery scratch ticket worth 20 Norwegian kroner (approximately 3 US$) together with the questionnaire, 250 received two scratch tickets, and 250 were promised two scratch tickets if they replied within one week. A fourth group of 250 persons received a 50 kroner banknote with the questionnaire. The remaining 500 letters served as controls. RESULTS: The overall response rate after 6 weeks was 77%. Logistic regression analysis showed that only the 50 kroner group had a response rate that was statistically significantly higher than the controls (p < 0.0001). It was also significantly higher than that in any of the other incentive groups (p < 0.0001, p < 0.004 and p < 0.0001 respectively). Female sex (p < 0.001) and age (p < 0.002) increased the response rate significantly. CONCLUSION: It is possible that the recipients scratched their cards before completing the questionnaire, and that it was a disincentive for the majority that they did not win anything. Lottery scratch tickets are no substitute for cash as an incentive to respond to a questionnaire

Novel Prognostic and Therapeutic Targets for Oral Squamous Cell Carcinoma

In oral squamous cell carcinoma (OSCC), metastasis to lymph nodes is associated with a 50% reduction in 5-year survival. To identify a metastatic gene set based on DNA copy number abnormalities (CNAs) of differentially expressed genes, we compared DNA and RNA of OSCC cells laser-microdissected from non-metastatic primary tumors (n = 17) with those from lymph node metastases (n = 20), using Affymetrix 250K Nsp single-nucleotide polymorphism (SNP) arrays and U133 Plus 2.0 arrays, respectively. With a false discovery rate (FDR)<5%, 1988 transcripts were found to be differentially expressed between primary and metastatic OSCC. Of these, 114 were found to have a significant correlation between DNA copy number and gene expression (FDR<0.01). Among these 114 correlated transcripts, the corresponding genomic regions of each of 95 transcripts had CNAs differences between primary and metastatic OSCC (FDR<0.01). Using an independent dataset of 133 patients, multivariable analysis showed that the OSCC-specific and overall mortality hazards ratio (HR) for patients carrying the 95-transcript signature were 4.75 (95% CI: 2.03-11.11) and 3.45 (95% CI: 1.84-6.50), respectively. To determine the degree by which these genes impact cell survival, we compared the growth of five OSCC cell lines before and after knockdown of over-amplified transcripts via a high-throughput siRNA-mediated screen. The expression-knockdown of 18 of the 26 genes tested showed a growth suppression ≥ 30% in at least one cell line (P<0.01). In particular, cell lines derived from late-stage OSCC were more sensitive to the knockdown of G3BP1 than cell lines derived from early-stage OSCC, and the growth suppression was likely caused by increase in apoptosis. Further investigation is warranted to examine the biological role of these genes in OSCC progression and their therapeutic potentials

Assessment of Virally Vectored Autoimmunity as a Biocontrol Strategy for Cane Toads

BACKGROUND: The cane toad, Bufo (Chaunus) marinus, is one of the most notorious vertebrate pests introduced into Australia over the last 200 years and, so far, efforts to identify a naturally occurring B. marinus-specific pathogen for use as a biological control agent have been unsuccessful. We explored an alternative approach that entailed genetically modifying a pathogen with broad host specificity so that it no longer caused disease, but carried a gene to disrupt the cane toad life cycle in a species specific manner. METHODOLOGY/PRINCIPAL FINDINGS: The adult beta globin gene was selected as the model gene for proof of concept of autoimmunity as a biocontrol method for cane toads. A previous report showed injection of bullfrog tadpoles with adult beta globin resulted in an alteration in the form of beta globin expressed in metamorphs as well as reduced survival. In B. marinus we established for the first time that the switch from tadpole to adult globin exists. The effect of injecting B. marinus tadpoles with purified recombinant adult globin protein was then assessed using behavioural (swim speed in tadpoles and jump length in metamorphs), developmental (time to metamorphosis, weight and length at various developmental stages, protein profile of adult globin) and genetic (adult globin mRNA levels) measures. However, we were unable to detect any differences between treated and control animals. Further, globin delivery using Bohle iridovirus, an Australian ranavirus isolate belonging to the Iridovirus family, did not reduce the survival of metamorphs or alter the form of beta globin expressed in metamorphs. CONCLUSIONS/SIGNIFICANCE: While we were able to show for the first time that the switch from tadpole to adult globin does occur in B. marinus, we were not able to induce autoimmunity and disrupt metamorphosis. The short development time of B. marinus tadpoles may preclude this approach

The Lesser Known Challenge of Climate Change: Thermal Variance and Sex-Reversal in Vertebrates with Temperature-Dependent Sex Determination

Climate change is expected to disrupt biological systems. Particularly susceptible are species with temperature-dependent sex determination (TSD), as in many reptiles. While the potentially devastating effect of rising mean temperatures on sex ratios in TSD species is appreciated, the consequences of increased thermal variance predicted to accompany climate change remain obscure. Surprisingly, no study has tested if the effect of thermal variance around high-temperatures (which are particularly relevant given climate change predictions) has the same or opposite effects as around lower temperatures. Here we show that sex ratios of the painted turtle (Chrysemys picta) were reversed as fluctuations increased around low and high unisexual mean-temperatures. Unexpectedly, the developmental and sexual responses around female-producing temperatures were decoupled in a more complex manner than around male-producing values. Our novel observations are not fully explained by existing ecological models of development and sex determination, and provide strong evidence that thermal fluctuations are critical for shaping the biological outcomes of climate change

Clustering of cancer among families of cases with Hodgkin Lymphoma (HL), Multiple Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), Soft Tissue Sarcoma (STS) and control subjects

<p>Abstract</p> <p>Background</p> <p>A positive family history of chronic diseases including cancer can be used as an index of genetic and shared environmental influences. The tumours studied have several putative risk factors in common including occupational exposure to certain pesticides and a positive family history of cancer.</p> <p>Methods</p> <p>We conducted population-based studies of Hodgkin lymphoma (HL), Multiple Myeloma (MM), non-Hodgkin's Lymphoma (NHL), and Soft Tissue Sarcoma (STS) among male incident case and control subjects in six Canadian provinces. The postal questionnaire was used to collect personal demographic data, a medical history, a lifetime occupational history, smoking pattern, and the information on family history of cancer. The family history of cancer was restricted to first degree relatives and included relationship to the index subjects and the types of tumours diagnosed among relatives. The information was collected on 1528 cases (HL (n = 316), MM (n = 342), NHL (n = 513), STS (n = 357)) and 1506 age ± 2 years and province of residence matched control subjects. Conditional logistic regression analyses adjusted for the matching variables were conducted.</p> <p>Results</p> <p>We found that most families were cancer free, and a minority included two or more affected relatives. HL [(OR_adj(95% CI) <b>1.79 (1.33, 2.42)]</b>, MM <b>(1.38(1.07, 1.78))</b>, NHL <b>(1.43 (1.15, 1.77)</b>), and STS cases <b>(1.30(1.00, 1.68)) </b>had higher incidence of cancer if any first degree relative was affected with cancer compared to control families. Constructing mutually exclusive categories combining "family history of cancer" (yes, no) and "pesticide exposure ≥10 hours per year" (yes, no) indicated that a positive family history was important for HL <b>(2.25(1.61, 3.15))</b>, and for the combination of the two exposures increased risk for MM <b>(1.69(1.14,2.51))</b>. Also, a positive family history of cancer both with <b>(1.72 (1.21, 2.45)) </b>and without pesticide exposure <b>(1.43(1.12, 1.83)) </b>increased risk of NHL.</p> <p>Conclusion</p> <p>HL, MM, NHL, and STS cases had higher incidence of cancer if any first degree relative affected with cancer compared to control families. A positive family history of cancer and/or shared environmental exposure to agricultural chemicals play an important role in the development of cancer.</p

Choline transporter gene variation is associated with attention-deficit hyperactivity disorder

The neurotransmitter acetylcholine (ACh) plays a critical role in brain circuits mediating motor control, attention, learning and memory. Cholinergic dysfunction is associated with multiple brain disorders including Alzheimer’s Disease, addiction, schizophrenia and Attention-Deficit Hyperactivity Disorder (ADHD). The presynaptic choline transporter (CHT, SLC5A7) is the major, rate-limiting determinant of ACh production in the brain and periphery and is consequently upregulated during tasks that require sustained attention. Given the contribution of central cholinergic circuits to the control of movement and attention, we hypothesized that functional CHT gene variants might impact risk for ADHD. We performed a case-control study, followed by family-based association tests on a separate cohort, of two purportedly functional CHT polymorphisms (coding variant Ile89Val (rs1013940) and a genomic SNP 3’ of the CHT gene (rs333229), affording both a replication sample and opportunities to reduce potential population stratification biases. Initial genotyping of pediatric ADHD subjects for two purportedly functional CHT alleles revealed a 2–3 fold elevation of the Val89 allele (n = 100; P = 0.02) relative to healthy controls, as well as a significant decrease of the 3’SNP minor allele in Caucasian male subjects (n = 60; P = 0.004). In family based association tests, we found significant overtransmission of the Val89 variant to children with a Combined subtype diagnosis (OR = 3.16; P = 0.01), with an increased Odds Ratio for a haplotype comprising both minor alleles. These studies show evidence of cholinergic deficits in ADHD, particularly for subjects with the Combined subtype, and, if replicated, may encourage further consideration of cholinergic agonist therapy in the disorder