The adenoma-carcinoma sequence in the colorectum--early appearance of a hierarchy of small intestinal mucin antigen (SIMA) epitopes and correlation with malignant potential.

The colorectal adenoma-carcinoma sequence was examined in relation to the ectopic expression of the oncofoetal Small Intestinal Mucin Antigen (SIMA), to the development of morphologic changes in the adenoma and perineoplastic mucosa and to indices of malignant potential. Four anti-SIMA MAbs, which define a novel hierarchy of SIMA epitopes in the normal small intestine and adjacent to colorectal cancers, were used in a retrospective immunohistochemical study of Familial Adenomatous Polyposis (FAP, n = 183) and non-familial (n = 44) adenomas. Inappropriate expression of SIMA epitopes was first detected in mucosa adjacent to minute microadenomas larger than three glands, and with increase in size, in increasing amounts within adenomas themselves, but not with microadenomas smaller than three glands or regions of flat mucosa free of adenomas. SIMA epitope expressed in mucosa adjacent to adenomas preceded changes in perineoplastic morphology, which progressed with adenoma growth to resemble transitional mucosa (TM) adjacent to cancers. Thus, the onset of both SIMA expression and morphological changes in TM were consistent with reactive rather than pre-existing field change phenomena. The previously reported hierarchy of four SIMA epitopes (5C5, 3D4, 4D3, 6C5) was also consistently observed in the adenoma-carcinoma sequence, and applied to (i) the order of epitope detection, (ii) the number of positive adenomas and (iii) extent of staining; (iv) the height in the crypt and (v) distance from the adenoma to which epitopes were expressed in perineoplastic mucosa. These observations are consistent with a progression of changes in mucin composition with adenoma development. The percentage of positive adenomas and reactivity scores for each anti-SIMA MAb correlated with increasing adenoma size, degree of dysplasia and growth pattern. SIMA expression appears to predate the earliest reported oncogene and tumour suppressor gene changes, was persistent and increased throughout adenoma development. SIMA epitopes are thus markers of very early neoplastic change, whose expression correlates with malignant potential and may contribute to the accumulation of changes necessary for tumourigenesis

Aberrant expression of intestinal mucin antigens associated with colorectal carcinoma defined by a panel of monoclonal antibodies.

Small intestine mucin antigen (SIMA) is an oncofoetal antigen for the colon and is distinct from the normal large intestinal mucin antigen (LIMA). In the present study, a panel of anti-SIMA and anti-LIMA monoclonal antibodies (MAb) was used to charaterise altered mucin expression in colorectal adenocarcinomas, by immunohistochemistry and quantitative immunoassays of tissue extracts. These results are compared with CEA expression and correlated with various clinicopathological indices. All mucin MAb reacted with a high proportion of the 100 colon cancers of every stage, histological type (including non-mucinous cancers), differentiation, site, or size. Inappropriate SIMA production was detected by either anti-SIMA MAb 4D3 or 4A1, even in 85% of early stage cancers. MAb 4D3 reacted with a higher proportion of cancers of smaller size and better differentiation. At the subcellular level, both anti-SIMA MAb showed reactivity typical of normal mucin, i.e., goblet cell and extracellular mucin. The normal colonic antigen, LIMA, was also detectable in the majority of cases, but quantitatively overproduced in some cases and reduced in others. However, in contrast to SIMA, LIMA was detected in predominantly undifferentiated cancer cells but not in goblet cells. Heterogeneity of MAb reactivity between cases and complementarity within each cancer was frequently observed. Mucin reactive with at least one of the MAb was detected in all of the CEA-negative cancers. A high rate of inappropriate SIMA expression was also detected in the perineoplastic transitional mucosa (88%, c.f. CEA, 35%) and adjacent, morphologically normal mucosa (80% c.f. CEA, 24%), indicating biochemical changes similar to the cancer. This panel of anti-mucin MAb demonstrated altered mucin glycoprotein metabolism associated with the development and progression of most colorectal cancers, which emphasises their utility as indicators of neoplastic change in the colon, and their superiority to CEA

Manifesting Unobtainable Secrets: Threshold Elliptic Curve Key Generation using Nested Shamir Secret Sharing

We present a mechanism to manifest unobtainable secrets using a nested Shamir secret sharing scheme to create public/private key pairs for elliptic curves. A threshold secret sharing scheme can be used as a decentralised trust mechanism with applications in identity validation, message decryption, and agreement empowerment. Decentralising trust means that there is no single point vulnerability which could enable compromise of a system. Our primary interest is in twisted Edwards curves as used in EdDSA, and the related Diffie-Hellman key-exchange algorithms. The key generation is also decentralised, so can be used as a decentralised secret RNG suitable for use in other algorithms. The algorithms presented could be used to fill a ``[TBS]'' in the draft IETF specification ``Threshold modes in elliptic curves'' published in 2020 and updated in 2022

MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2- and TLR4-mediated NF-kappaB proinflammatory responses

Toll/interleukin-1 (TIR)receptor-containing adapters are critical in orchestrating the different signal transduction pathways following Toll-like receptor (TLR) activation. MyD88 adapter-like (Mal), also termed TIRAP, is involved in bridging MyD88 to the receptor complex for TLR-2 and TLR4 signaling in response to bacterial infection. We have previously reported an interaction between Mal and tumor necrosis factor receptor-associated factor 6 (TRAF6) via a TRAF6-binding motif, the disruption of which inhibited TLR-mediated NF-kappaB-luciferase reporter activity. Given the recent report of intracellular TRAM localization promoting sequential signaling in TLR4 responses, we further characterized Mal interaction with TRAF6, the cellular localization, and the outcomes of disrupting this association on TLR inflammatory responses. We found that Mal and TRAF6 directly interact in response to TLR2 and TLR4 stimulation, although membrane localization is not necessary to facilitate interaction. Critically, reconstitution of murine Mal-deficient macrophages with MalE190A, containing a mutation within the TRAF6-binding motif, fails to reconstitute the proinflammatory response to TLR2 and TLR4 ligands compared with wild type Mal. Furthermore, Mal interaction with TRAF6 mediates Ser phosphorylation of the p65 subunit of NF-kappaB and thus controls transcriptional activation but not nuclear translocation of NF-kappaB. This study characterizes the novel role for Mal in facilitating the direct recruitment of TRAF6 to the plasma membrane, which is necessary for TLR2- and TLR4-induced transactivation of NF-kappaB and regulation of the subsequent pro-inflammatory response

Measurement of the Positive Muon Lifetime and Determination of the Fermi Constant to Part-per-Million Precision

We report a measurement of the positive muon lifetime to a precision of 1.0 parts per million (ppm); it is the most precise particle lifetime ever measured. The experiment used a time-structured, low-energy muon beam and a segmented plastic scintillator array to record more than 2 x 10^{12} decays. Two different stopping target configurations were employed in independent data-taking periods. The combined results give tau_{mu^+}(MuLan) = 2196980.3(2.2) ps, more than 15 times as precise as any previous experiment. The muon lifetime gives the most precise value for the Fermi constant: G_F(MuLan) = 1.1663788 (7) x 10^-5 GeV^-2 (0.6 ppm). It is also used to extract the mu^-p singlet capture rate, which determines the proton's weak induced pseudoscalar coupling g_P.Comment: Accepted for publication in Phys. Rev. Let

Asymptomatic Thoracic Kidney

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66641/2/10.1177_000992286900800510.pd

Sensitive Search for a Permanent Muon Electric Dipole Moment

We are proposing a new method to carry out a dedicated search for a permanent electric dipole moment (EDM) of the muon with a sensitivity at a level of 10^{-24} e cm. The experimental design exploits the strong motional electric field sensed by relativistic particles in a magnetic storage ring. As a key feature, a novel technique has been invented in which the g-2 precession is compensated with radial electric field. This technique will benefit greatly when the intense muon sources advocated by the developers of the muon storage rings and the muon colliders become available.Comment: 16 pages, 3 figures. Submitted for publication in Proceedings of the International Workshop on High Intensity Muon Sources (HIMUS99), KEK, Japan, December 1-4 199

Improved Measurement of the Positive Muon Lifetime and Determination of the Fermi Constant

The mean life of the positive muon has been measured to a precision of 11 ppm using a low-energy, pulsed muon beam stopped in a ferromagnetic target, which was surrounded by a scintillator detector array. The result, tau_mu = 2.197013(24) us, is in excellent agreement with the previous world average. The new world average tau_mu = 2.197019(21) us determines the Fermi constant G_F = 1.166371(6) x 10^-5 GeV^-2 (5 ppm). Additionally, the precision measurement of the positive muon lifetime is needed to determine the nucleon pseudoscalar coupling g_P.Comment: As published version (PRL, July 2007

Physics at a Fermilab Proton Driver

This report documents the physics case for building a 2 MW, 8 GeV superconducting linac proton driver at Fermilab.Comment: 52 pages, 15 figure

Eyewitness metamemory predicts identification performance in biased and unbiased line‐ups

Purpose Distinguishing accurate from inaccurate identifications is a challenging issue in the criminal justice system, especially for biased police line-ups. That is because biased line-ups undermine the diagnostic value of accuracy post-dictors such as confidence and decision time. Here, we aimed to test general and eyewitness-specific self-ratings of memory capacity as potential estimators of identification performance that are unaffected by line-up bias. Methods Participants (N = 744) completed a metamemory assessment consisting of the Multifactorial Metamemory Questionnaire and the Eyewitness Metamemory Scale and took part in a standard eyewitness paradigm. Following the presentation of a mock-crime video, they viewed either biased or unbiased line-ups. Results Self-ratings of discontentment with eyewitness memory ability were indicative of identification accuracy for both biased and unbiased line-ups. Participants who scored low on eyewitness metamemory factors also displayed a stronger confidence-accuracy calibration than those who scored high. Conclusions These results suggest a promising role for self-ratings of memory capacity in the evaluation of eyewitness identifications, while also advancing theory on self-assessments for different memory systems