Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.

A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer.

We examined the coding sequence of 518 protein kinases, approximately 1.3 Mb of DNA per sample, in 25 breast cancers. In many tumors, we detected no somatic mutations. But a few had numerous somatic mutations with distinctive patterns indicative of either a mutator phenotype or a past exposure.

An experiment with three studies of physiological connectedness amongst twins and its possible relationship to attachment.

Fourteen pairs of twins were selected on the basis of their high scores on The Exceptional Experiences Questionnaire (EEQ), which documents the frequency and intensity of telepathic and synchronistic experiences amongst twins. The twins alternated in the role of sender in which they were exposed to a surprise or shock stimulus and in the role of receiver in which their electrodermal activity (EDA) was monitored. Sender and receiver were placed in laboratory rooms at remote ends of a building separated by distance and barriers ensuring sensory isolation. Twins in the role of sender were presented with a series of surprise or shock stimuli during the period randomly selected for presentation. This was one out of the 8 periods occurring in the block of 5 min. Within the selected period, the actual presentation lasted 30 s and occurred at approximately the midpoint of the period. The stimulus presentation in this block of 5 min was repeated 5 times making thereby a 25-minute session for each twin belonging to the sender-receiver pair. During this session, the other twin in the role of receiver, had been equipped with electrodes recording EDA and otherwise advised to relax during the session. The task for the judge in the studies was to use the electrophysiological data from the non-shocked twin to identify the exact periods when the stimuli had been exposed to the sending twin. The EDA from 91 useable presentations were displayed and analysed for the purpose of locating any peak EDA response in each of the possible eight periods corresponding to the stimuli exposure times. Correct identifications would thus occur by chance one in eight times. The attempts at these identifications were carried out by GB, a researcher experienced at EDA interpretation but blind as to the periods that had been chosen for the stimulus exposure. The findings from the three experimental studies showed there were 18 correct identifications out of the total 91 stimulus exposures (MCE = 11.4), which reached statistical significance on a one-tailed t-test (p = 0.043), and with a binomial test (p = .03, one-tailed). However, only one of the three studies reached significance, in this case at the same level as the collective results (p = 0.043, one-tailed). Two explanations for this are the observed variability in the task-performances of the pairs of twins and in the differences in the sources of the twins for each of the studies. The results of a questionnaire entitled 'Experiences in Close Relationships' (ECR), adapted for twin relationships to assess their degree of attachment, indicated that those twins with many "correct identifications of epochs from the EDA" were not significantly different from the others on this measure of attachment. However, it should be noted that the twins here according to the ECR all had close emotional relationships to each other, thereby giving too little variation to adequately test the hypotheses concerning the role of attachment. The data provides justification for carrying out further studies using this methodology and furthermore that pairs of twins should be used with greater variation in attachment measures. The results are briefly discussed in the context of recent findings concerning the neuropsychology of experiences of synchronicity.

Lung cancer: intragenic ERBB2 kinase mutations in tumours.

The protein-kinase family is the most frequently mutated gene family found in human cancer and faulty kinase enzymes are being investigated as promising targets for the design of antitumour therapies. We have sequenced the gene encoding the transmembrane protein tyrosine kinase ERBB2 (also known as HER2 or Neu) from 120 primary lung tumours and identified 4% that have mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. ERBB2 inhibitors, which have so far proved to be ineffective in treating lung cancer, should now be clinically re-evaluated in the specific subset of patients with lung cancer whose tumours carry ERBB2 mutations.

Effects of active silicon uptake by rice on 29Si fractionation in various plant parts.

Rice (Oryza sativa L.) accumulates large amounts of silicon which improves its growth and health due to enhanced resistance to biotic and abiotic stresses. Silicon uptake and loading to xylem in rice are predominantly active processes performed by transporters encoded by the recently identified genes Lsi1 (Si influx transporter gene) and Lsi2 (Si efflux transporter gene). Silicon deposition in rice during translocation to upper plant tissues is known to discriminate against the heavier isotopes (29)Si and (30)Si, resulting in isotope fractionation within the plant. We analyzed straw and husk samples of rice mutants defective in Lsi1, Lsi2 or both for silicon content and delta(29)Si using isotope ratio mass spectrometry (IRMS) and compared these results with those for the corresponding wild-type varieties (WT). The silicon content was higher in husk than in straw. All the mutant rice lines showed clearly lower silicon content than the WT lines (4-23% Si of WT). The delta(29)Si was lower in straw and husk for the uptake defective mutant (lsi1) than for WT, albeit delta(29)Si was 0.3 per thousand higher in husk than in straw in both lines. The effect of defective efflux (lsi2) differed for straw and husk with higher delta(29)Si in straw, but lower delta(29)Si in husk while WT showed similar delta(29)Si in both fractions. These initial results show the potential of Si isotopes to enlighten the influence of active uptake on translocation and deposition processes in the plant.

20,000 years of societal vulnerability and adaptation to climate change in southwest Asia.

The Fertile Crescent, its hilly flanks and surrounding drylands has been a critical region for studying how climate has influenced societal change, and this review focuses on the region over the last 20,000 years. The complex social, economic, and environmental landscapes in the region today are not new phenomena and understanding their interactions requires a nuanced, multidisciplinary understanding of the past. This review builds on a history of collaboration between the social and natural palaeoscience disciplines. We provide a multidisciplinary, multiscalar perspective on the relevance of past climate, environmental, and archaeological research in assessing present day vulnerabilities and risks for the populations of southwest Asia. We discuss the complexity of palaeoclimatic data interpretation, particularly in relation to hydrology, and provide an overview of key time periods of palaeoclimatic interest. We discuss the critical role that vegetation plays in the human-climate-environment nexus and discuss the implications of the available palaeoclimate and archaeological data, and their interpretation, for palaeonarratives of the region, both climatically and socially. We also provide an overview of how modelling can improve our understanding of past climate impacts and associated change in risk to societies. We conclude by looking to future work, and identify themes of "scale" and "seasonality" as still requiring further focus. We suggest that by appreciating a given locale's place in the regional hydroscape, be it an archaeological site or palaeoenvironmental archive, more robust links to climate can be made where appropriate and interpretations drawn will demand the resolution of factors acting across multiple scales. This article is categorized under:Human Water > Water as Imagined and RepresentedScience of Water > Water and Environmental ChangeWater and Life > Nature of Freshwater Ecosystems.

A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy.

Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers.

Somatic mutations of the protein kinase gene family in human lung cancer.

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of approximately 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.

Mutation analysis of 24 known cancer genes in the NCI-60 cell line set.

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 genes for homozygous deletions. One hundred thirty-seven oncogenic mutations were identified in 14 (APC, BRAF, CDKN2, CTNNB1, HRAS, KRAS, NRAS, SMAD4, PIK3CA, PTEN, RB1, STK11, TP53, and VHL) of the 24 genes. All lines have at least one mutation among the cancer genes examined, with most lines (73%) having more than one. Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCI-60 cell lines for molecularly targeted screens.

Recurrent KRAS codon 146 mutations in human colorectal cancer.

An activating point mutation in codon 12 of the HRAS gene was the first somatic point mutation identified in a human cancer and established the role of somatic mutations as the common driver of oncogenesis. Since then, there have been over 11,000 mutations in the three RAS (HRAS, KRAS and NRAS) genes in codons 12, 13 and 61 reported in the literature. We report here the identification of recurrent somatic missense mutations at alanine 146, a highly conserved residue in the guanine nucleotide binding domain. In two independent series of colorectal cancers from Hong Kong and the United States we detected KRAS A146 mutations in 7/126 and 2/94 cases, respectively, giving a combined frequency of 4%. We also detected KRAS A146 mutations in 2/40 (5%) colorectal cell lines, including the NCI-60 colorectal cancer line HCC2998. Codon 146 mutations thus are likely to make an equal or greater contribution to colorectal cancer than codon 61 mutations (4.2% in our combined series, 1% in the literature). Lung adenocarcinomas and large cell carcinomas did not show codon 146 mutations. We did, however, identify a KRAS A146 mutation in the ML-2 acute myeloid leukemia cell line and an NRAS A146 mutation in the NALM-6 B-cell acute lymphoblastic leukemia line, suggesting that the contribution of codon 146 mutations is not entirely restricted to colorectal cancers or to KRAS.

The forensic analysis of soils and sediment taken from the cast of a footprint.

The routine production of a cast of a shoe-print taken in soil provides information other than shoe size and gait. Material adhering to the surface of the cast represents the preservation of the moment of footprint impression. The analysis of the interface between the cast and soil is therefore a potentially lucrative source of information for forensic reconstruction. These principles are demonstrated with reference to a murder case which took place in the English Midlands. The cast of a footprint provided evidence of a two-way transfer of material between the sole of a boot and the soil of a recently ploughed field. Lumps of soil, which had dried on a boot, were deposited on the field as the footprints were made. Pollen analysis of these lumps of soil indicated that the perpetrator of the imprint had been standing recently in a nearby stream. Fibre analysis together with physical and chemical characteristics of the soil suggested a provenance for contamination of this mud prior to deposition of the footprint. Carbon/nitrogen ratios of the water taken from the cast showed that distilled water had been used thus excluding the possibility of contamination of the boot-soil interface. It was possible to reconstruct three phases of previous activity of the wearer of the boot prior to leaving the footprint in the field after the murder had taken place. This analysis shows the power of integrating different independent techniques in the analysis of hitherto unrecognised forensic materials.

The role of forensic geoscience in wildlife crime detection.

The increase in both automation and precision in the analysis of geological materials has had significant impact upon forensic investigations in the last 10 years. There is however, a fundamental philosophical difference between forensic and geological enquiry. This paper presents the results of forensic geoscientific investigations of three cases of wildlife crime. Two cases involve the analysis of soils recovered after incidents of illegal badger baiting in the United Kingdom. The third case involves the illegal importation of Eleonora's Falcon (Falco eleonorae) into the United Kingdom from the Mediterranean. All three cases utilise the analysis of soils by a variety of physical, chemical and biological techniques. These involve mineral and grain size analyses, cation and anion compositions, pH, organic content and pollen analysis. The independent analysis undertaken by specialists in each of these three main fields conclude firstly, that there is a significant similarity between sediments taken at the crime site at both badger setts and with sediments recovered from various spades, shovels and clothing belonging to suspects and secondly, that the soils analysed associated with the removal of the falcon eggs in the Mediterranean contained characteristics similar in many respects to the soils of the breeding areas of F. eleonorae on the cliffs of Mallorca. The use of these independent techniques in wildlife crime detection has great potential given the ubiquitous nature of soils and sediments found in association with wildlife sites.

Heart rate changes accompanying jaw movement Pavlovian conditioning in rabbits: concomitant blood pressure adjustments and effects of peripheral autonomic blockade.

Two experiments were conducted to ascertain the cardiovascular accompaniments of differential Pavlovian jaw movement (JM) conditioning. The first examined the blood pressure (BP) changes that accompany the tachycardiac conditioned responses (CRs) associated with JM conditioning. The BP response in all instances consisted of a depressor response that was greater to the reinforced CS+ than CS-, although the magnitude of the CR was quite small. The second experiment determined the effects of peripheral autonomic antagonists on the cardiac accelerations associated with JM conditioning. It was found that the peripheral vagal antagonist methyl scopolamine completely abolished responses to both CS+ and CS-, whereas atenolol, a beta adrenergic antagonist, augmented the response, compared to saline control injections. The JM responses were also affected by the autonomic blockades, with minimal responding occurring in the scopolamine group but slightly more JM CRs in the atenolol group, compared to saline control animals. These results suggest that the major cardiovascular response to an appetitive stimulus, which evokes JM conditioning, consists of cardiac accelerations with the BP depressor responses playing a minimal, if any, role. Moreover, these conditioned cardiac increases appear to be due solely to the release of vagal inhibition.

A prospective, multicenter pilot study investigating the utility of flat detector derived parenchymal blood volume maps to estimate cerebral blood volume in stroke patients.

PURPOSE: Newer flat panel angiographic detector (FD) systems have the capability to generate parenchymal blood volume (PBV) maps. The ability to generate these maps in the angiographic suite has the potential to markedly expedite the triage and treatment of patients with acute ischemic stroke. The present study compares FP-PBV maps with cerebral blood volume (CBV) maps derived using standard dynamic CT perfusion (CTP) in a population of patients with stroke. METHODS: 56 patients with cerebrovascular ischemic disease at two participating institutions prospectively underwent both standard dynamic CTP imaging followed by FD-PBV imaging (syngo Neuro PBV IR; Siemens, Erlangen, Germany) under a protocol approved by both institutional review boards. The feasibility of the FD system to generate PBV maps was assessed. The radiation doses for both studies were compared. The sensitivity and specificity of the PBV technique to detect (1) any blood volume deficit and (2) a blood volume deficit greater than one-third of a vascular territory, were defined using standard dynamic CTP CBV maps as the gold standard. RESULTS: Of the 56 patients imaged, PBV maps were technically adequate in 42 (75%). The 14 inadequate studies were not interpretable secondary to patient motion/positioning (n=4), an injection issue (n=2), or another reason (n=8). The average dose for FD-PBV was 219 mGy (median 208) versus 204 mGy (median 201) for CT-CBV. On CT-CBV maps 26 of 42 had a CBV deficit (61.9%) and 15 (35.7%) had a deficit that accounted for greater than one-third of a vascular territory. FD-PBV maps were 100% sensitive and 81.3% specific to detect any CBV deficit and 100% sensitive and 62.9% specific to detect any CBV deficit of greater than one-third of a territory. CONCLUSIONS: PBV maps can be generated using FP systems. The average radiation dose is similar to a standard CTP examination. PBV maps have a high sensitivity for detecting CBV deficits defined by conventional CTP. PBV maps often overestimate the size of CBV deficits. We hypothesize that the FP protocol initiates PBV imaging prior to complete saturation of the blood volume in areas perfused via indirect pathways (ie, leptomeningeal collaterals), resulting in an overestimation of CBV deficits, particularly in the setting of large vessel occlusion.

Further possible physiological connectedness between identical twins: the London study.

Four pairs of monozygotic twins were tested for synchronous responses that occurred in the physiological data of one twin during the period when the other twin was exposed to shock and surprise stimuli. Each of the five stimuli was presented in random order, producing five blocks of trial periods within each 25-minute session per twin. There were eight possible trial periods within each block. The choice of the trial periods, that is, the exact time placement of the shock stimuli within the blocks, was determined randomly. Data from six sessions with the four pairs of twins were used by the same polygraph expert who was successful in a previous study in identifying these trial periods. In accordance with the previously determined protocol for the experiment, six of these trials were passed on, leaving 24 trial blocks for which assessments were made as to which period the stimulus had occurred. Six of these gave hits, whereas three hits were expected by chance and four of these six correct placements were made by one of the pairs of twins. The data provide further justification for a major study in this area using the outlined methodology with selected pairs of twins.

Beyond the Levant: first evidence of a pre-pottery Neolithic incursion into the Nefud Desert, Saudi Arabia.

Pre-Pottery Neolithic assemblages are best known from the fertile areas of the Mediterranean Levant. The archaeological site of Jebel Qattar 101 (JQ-101), at Jubbah in the southern part of the Nefud Desert of northern Saudi Arabia, contains a large collection of stone tools, adjacent to an Early Holocene palaeolake. The stone tool assemblage contains lithic types, including El-Khiam and Helwan projectile points, which are similar to those recorded in Pre-Pottery Neolithic A and Pre-Pottery Neolithic B assemblages in the Fertile Crescent. Jebel Qattar lies ∼500 kilometres outside the previously identified geographic range of Pre-Pottery Neolithic cultures. Technological analysis of the typologically diagnostic Jebel Qattar 101 projectile points indicates a unique strategy to manufacture the final forms, thereby raising the possibility of either direct migration of Levantine groups or the acculturation of mobile communities in Arabia. The discovery of the Early Holocene site of Jebel Qattar suggests that our view of the geographic distribution and character of Pre-Pottery Neolithic cultures may be in need of revision.

Entangled in the womb? A pilot study on the possible physiological connectedness between identical twins with different embryonic backgrounds.

OBJECTIVE: Studies of synchronous physiological responses to startle stimuli between monozygotic twins and other paired subjects have suffered from methodological flaws such as post-hoc specifications of "connectedness" criteria. The mechanisms that affect any such connectedness are unknown. With the logistic and financial support of a television company, we conducted a methodological pilot study with predefined objective hit criteria in which we used four pairs of twins with frequent experiences of connectedness. METHODS: While one twin was exposed during a 12-minute period to five randomly presented mild shock or surprise stimuli, the electrodermal activity, blood pressure, breathing, and bodily movements were simultaneously recorded in the second twin. An authorized polygraph expert who was blind to the stimulus exposure times examined the data for deviations from normal physiological patterns during relaxation and delivered precisely timed estimates of such deviations. "Hits" (indications of connectedness) were objectively defined as an estimate lying within a 15-second "hit window." RESULTS: Overall results were nonsignificant, P > .7. However, for one pair of twins, the polygraph expert identified 10 deviating patterns, of which three were hits were P < .03. This data set was sent to a second, independent expert, who blindly identified the same three hits, pointing to only eight patterns, P < .0003. DISCUSSION: We argue that the applied methodology for "hit" identification is objective and recommendable. Speculatively, because the "successful" pair of twins was reported to be monochorionic-monoamnionic (as embryos, they shared the same placenta and the same bag of water), embryonic history might be further investigated as a potential factor for connectedness between monozygotic twins.

Independent association between obstructive sleep apnea and noncalcified coronary plaque demonstrated by noninvasive coronary computed tomography angiography.

BACKGROUND: Coronary artery atherosclerosis has been associated with obstructive sleep apnea (OSA). However, the type and severity of plaque formation have not been characterized. This study evaluated the association of coronary noncalcified plaques and severity of stenosis in patients with OSA. METHODS: This study was a retrospective analysis of 81 patients, 49 with OSA and 32 without OSA, who had undergone multidetector-row helical computed tomography scanning. The board-certified radiologist was blinded to the diagnosis of OSA and reviewed the scans for plaque characterization, severity of stenosis, and number of vessels involved. RESULTS: Of the 81 patients reviewed, the mean apnea-hypopnea index in the OSA group was 42.2 vs 7.5 in the non-OSA group. The groups did not significantly differ in the distribution of comorbid conditions. We found that among the patients with OSA, 63% had noncalcified/mixed plaques, as opposed to 16% in the non-OSA group (P < 0.0001), with unadjusted odds ratio of 9.3 (3.0, 28.4). After adjustment for other risk factors such as age, sex, race, hypercholesterolemia, and history of smoking, the association remained strong, with an odds ratio of 7.0 (1.9, 26.5; P < 0.05). CONCLUSIONS: Our study finds that the frequency of noncalcified/mixed plaques is much higher in patients with OSA than in non-OSA patients. Patients with OSA also have more severe stenosis and a higher number of vessels involved. This study adds to a growing body of data regarding our understanding of the association of OSA and atherosclerosis.