V_H replacement in rearranged immunoglobulin genes

Examples suggesting that all or part of the V<sub>H</sub> segment of a rearranged V<sub>H</sub>DJ<sub>H</sub> may be replaced by all or part of another V<sub>H</sub> have been appearing since the 1980s. Evidence has been presented of two rather different types of replacement. One of these has gained acceptance and has now been clearly demonstrated to occur. The other, proposed more recently, has not yet gained general acceptance because the same effect can be produced by polymerase chain reaction artefact. We review both types of replacement including a critical examination of evidence for the latter. The first type involves RAG proteins and recombination signal sequences (RSS) and occurs in immature B cells. The second was also thought to be brought about by RAG proteins and RSS. However, it has been reported in hypermutating cells which are not thought to express RAG proteins but in which activation-induced cytidine deaminase (AID) has recently been shown to initiate homologous recombination. Re-examination of the published sequences reveals AID target sites in V<sub>H</sub>-V<sub>H</sub> junction regions and examples that resemble gene conversion

The CEACAM1 expression is decreased in the liver of severely obese patients with or without diabetes

<p>Abstract</p> <p>Background</p> <p>Type 2 diabetes is mainly caused by insulin resistance. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is an important candidate for causing insulin resistance.</p> <p>Methods</p> <p>The CEACAM1 expression was evaluated immunohistochemically in the liver tissues of 99 severely obese or non-obese subjects with or without diabetes. The CEACAM1 expression was classified into two categories: a normal expression or a decreased expression.</p> <p>Results</p> <p>The CEACAM1 expression was markedly decreased in the hepatocytes with macrovesicular steatosis. A decreased CEACAM1 expression was noted in 29 (29%) of 99 cases. The incidence of a decreased CEACAM1 expression was significantly higher in high grade fatty liver as well as severe obesity with or without diabetes (p < 0.05). The incidence of a decreased CEACAM1 expression was not different between the diabetic and non-diabetic groups.</p> <p>Conclusions</p> <p>This data supports that a decreased CEACAM1 expression is related to obesity and a fatty liver.</p

Mental rotation task of hands: differential influence number of rotational axes

Various studies on the hand laterality judgment task, using complex sets of stimuli, have shown that the judgments during this task are dependent on bodily constraints. More specific, these studies showed that reaction times are dependent on the participant’s posture or differ for hand pictures rotated away or toward the mid-sagittal plane (i.e., lateral or medial rotation, respectively). These findings point to the use of a cognitive embodied process referred to as motor imagery. We hypothesize that the number of axes of rotation of the displayed stimuli during the task is a critical factor for showing engagement in a mental rotation task, with an increased number of rotational axes leading to a facilitation of motor imagery. To test this hypothesis, we used a hand laterality judgment paradigm in which we manipulated the difficulty of the task via the manipulation of the number of rotational axes of the shown stimuli. Our results showed increased influence of bodily constraints for increasing number of axes of rotation. More specifically, for the stimulus set containing stimuli rotated over a single axis, no influence of biomechanical constraints was present. The stimulus sets containing stimuli rotated over more than one axes of rotation did induce the use of motor imagery, as a clear influence of bodily constraints on the reaction times was found. These findings extend and refine previous findings on motor imagery as our results show that engagement in motor imagery critically depends on the used number of axes of rotation of the stimulus set

Genomic profiling identifies common HPV-associated chromosomal alterations in squamous cell carcinomas of cervix and head and neck

<p>Abstract</p> <p>Background</p> <p>It is well known that a persistent infection with high-risk human papillomavirus (hrHPV) is causally involved in the development of squamous cell carcinomas of the uterine cervix (CxSCCs) and a subset of SCCs of the head and neck (HNSCCs). The latter differ from hrHPV-negative HNSCCs at the clinical and molecular level.</p> <p>Methods</p> <p>To determine whether hrHPV-associated SCCs arising from different organs have specific chromosomal alterations in common, we compared genome-wide chromosomal profiles of 10 CxSCCs (all hrHPV-positive) with 12 hrHPV-positive HNSCCs and 30 hrHPV-negative HNSCCs. Potential organ-specific alterations and alterations shared by SCCs in general were investigated as well.</p> <p>Results</p> <p>Unsupervised hierarchical clustering resulted in one mainly hrHPV-positive and one mainly hrHPV-negative cluster. Interestingly, loss at 13q and gain at 20q were frequent in HPV-positive carcinomas of both origins, but uncommon in hrHPV-negative HNSCCs, indicating that these alterations are associated with hrHPV-mediated carcinogenesis. Within the group of hrHPV-positive carcinomas, HNSCCs more frequently showed gains of multiple regions at 8q whereas CxSCCs more often showed loss at 17p. Finally, gains at 3q24-29 and losses at 11q22.3-25 were frequent (>50%) in all sample groups.</p> <p>Conclusion</p> <p>In this study hrHPV-specific, organ-specific, and pan-SCC chromosomal alterations were identified. The existence of hrHPV-specific alterations in SCCs of different anatomical origin, suggests that these alterations are crucial for hrHPV-mediated carcinogenesis.</p

Triage of high-risk HPV-positive women in population-based screening by miRNA expression analysis in cervical scrapes; a feasibility study

Background: Primary testing for high-risk HPV (hrHPV) is increasingly implemented in cervical cancer screening programs. Many hrHPV-positive women, however, harbor clinically irrelevant infections, demanding additional disease markers to prevent over-referral and over-treatment. Most promising biomarkers reflect molecular events relevant to the disease process that can be measured objectively in small amounts of clinical material, such as miRNAs. We previously identified eight miRNAs with altered expression in cervical precancer and cancer due to either methylation-mediated silencing or chromosomal alterations. In this study, we evaluated the clinical value of these eight miRNAs on cervical scrapes to triage hrHPV-positive women in cervical screening. Results: Expression levels of the eight candidate miRNAs in cervical tissue samples (n =

Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas.

BACKGROUND: Nonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas. METHODS: Quantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples. RESULTS: Increased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (p < 0.01). Combining both adenoma types, a positive trend between APC mutation and both WIF-1 and DKK3 methylation was observed (p < 0.05). CONCLUSIONS: Methylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations

Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas

BACKGROUND: Nonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas. METHODS: Quantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples. RESULTS: Increased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (p < 0.01). Combining both adenoma types, a positive trend between APC mutation and both WIF-1 and DKK3 methylation was observed (p < 0.05). CONCLUSIONS: Methylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations

Counting on the mental number line to make a move: sensorimotor ('pen') control and numerical processing

Mathematics is often conducted with a writing implement. But is there a relationship between numerical processing and sensorimotor ‘pen’ control? We asked participants to move a stylus so it crossed an unmarked line at a location specified by a symbolic number (1–9), where number colour indicated whether the line ran left–right (‘normal’) or vice versa (‘reversed’). The task could be simplified through the use of a ‘mental number line’ (MNL). Many modern societies use number lines in mathematical education and the brain’s representation of number appears to follow a culturally determined spatial organisation (so better task performance is associated with this culturally normal orientation—the MNL effect). Participants (counter-balanced) completed two consistent blocks of trials, ‘normal’ and ‘reversed’, followed by a mixed block where line direction varied randomly. Experiment 1 established that the MNL effect was robust, and showed that the cognitive load associated with reversing the MNL not only affected response selection but also the actual movement execution (indexed by duration) within the mixed trials. Experiment 2 showed that an individual’s motor abilities predicted performance in the difficult (mixed) condition but not the easier blocks. These results suggest that numerical processing is not isolated from motor capabilities—a finding with applied consequences

Lessons from bright-spots for advancing knowledge exchange at the interface of marine science and policy

Evidence-informed decision-making is in increasing demand given growing pressures on marine environments. A way to facilitate this is by knowledge exchange among marine scientists and decision-makers. While many barriers are reported in the literature, there are also examples whereby research has successfully informed marine decision-making (i.e., 'bright-spots'). Here, we identify and analyze 25 bright-spots from a wide range of marine fields, contexts, and locations to provide insights into how to improve knowledge exchange at the interface of marine science and policy. Through qualitative surveys we investigate what initiated the bright-spots, their goals, and approaches to knowledge exchange. We also seek to identify what outcomes/impacts have been achieved, the enablers of success, and what lessons can be learnt to guide future knowledge exchange efforts. Results show that a diversity of approaches were used for knowledge exchange, from consultative engagement to genuine knowledge co-production. We show that diverse successes at the interface of marine science and policy are achievable and include impacts on policy, people, and governance. Such successes were enabled by factors related to the actors, processes, support, context, and timing. For example, the importance of involving diverse actors and managing positive relationships is a key lesson for success. However, enabling routine success will require: 1) transforming the ways in which we train scientists to include a greater focus on interpersonal skills, 2) institutionalizing and supporting knowledge exchange activities in organizational agendas, 3) conceptualizing and implementing broader research impact metrics, and 4) transforming funding mechanisms to focus on need-based interventions, impact planning, and an acknowledgement of the required time and effort that underpin knowledge exchange activities