Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.     

Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA)

Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.     

Telophase behavior of extranuclear chromatin and its bearing on telophase changes in chromosomes

Zusammenfassung Extranukleares Chromatin, in der Form azentrischer Fragmente oder Teile ungebrochener Chromosomen, welche aus der Kernregion von Heuschreken-Neuroblasten herausragen, unterliegt nicht gleichzeitig mit dem intranuklearen Chromatin den telophasischen Veränderungen. Der oder die für die Telophaseveranderungen vor allem verantwortlichen Faktoren scheinen in der Kernregion der Zelle lokalisiert zu sein. Es werden Belege dafür gegeben, dass die Chromosomen während der Telophase sich bedeutend vergrössern, und es wird die Ansicht vertreten, dass im Spindelmaterial, zum Teil wenigstens, die für die Schwellung der Chromosomen verantwortliche Substanz zu sehen ist.

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Work performed for Atomic Energy Commission under Contract No. W-7405-eng-26.     

Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin

Nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of four genes mutated in NPHP subtypes 1-4 (refs. 4-9) has linked the pathogenesis of NPHP to ciliary functions. Ten percent of affected individuals have retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome (SLSN). Here we identify, by positional cloning, mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Hence, we examined the interaction of nephrocystin-5 with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. We show that nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Our studies emphasize the central role of ciliary dysfunction in the pathogenesis of SLSN.     

The effect of abdominal wounding on the rate of tissue regeneration

Zusammenfassung Verwundung induziert Regeneration in entfernten Stellen bei männlichen und weiblichen Kaninchcn. Dies gilt für frühe Regenerationsstadien bei männlichen Tieren, während bei Weibchen die Regenerationswirkung mindestens 49 Tage anhält. Es wird vermutet, dass es sich um hormonale Einwirkungen infolge Stress handelt.     

Effects of anoxia on excitability,refractoriness, and contractility in isolated rabbit atria

Zusammenfassung An der isolierten Kaninchenherzvorkammer verursacht Sauerstoffmangel Verminderung der diastolischen Erregbarkeit, Verlängerung der refraktären Phase sowie Herabsetzung der Kontraktionsfähigkeit. Herzmuskelflimmern wurde während dieser Anoxie nicht beobachtet. Sauerstoffzufuhr führte zu einer vollständigen Aufhebung der Anoxieauswirkung auf die absolute Refraktärperiode, zu einer teilweisen Aufhebung dieser Auswirkungen auf die Dauer der refraktären Gesamtpause, die diastolische Erregbarkeit und das Kontraktionsvermögen.     

Antigonadotrophic effect of melatonin in male lizards (Callisaurus draconoides)

Summary Results of a preliminary experiment indicate that injections of melatonin elicit testicular regression in male lizards having maximally recrudesced gonads at the outset of study.Supported by grants from the National Science Foundation (No. BMS74-04861), the American Philosophical Society (Penrose Fund), and the Biomedical Research program at Colorado State University.