Stringent Tests of Lorentz Invariance Violation from LHAASO Observations of GRB 221009A.

On 9 October 2022, the Large High Altitude Air Shower Observatory (LHAASO) reported the observation of the very early TeV afterglow of the brightest-of-all-time gamma-ray burst 221009A, recording the highest photon statistics in the TeV band ever obtained from a gamma-ray burst. We use this unique observation to place stringent constraints on the energy dependence of the speed of light in vacuum, a manifestation of Lorentz invariance violation (LIV) predicted by some quantum gravity (QG) theories. Our results show that the 95% confidence level lower limits on the QG energy scales are E_{QG,1}>10 times the Planck energy E_{Pl} for the linear LIV effect, and E_{QG,2}>6×10^{-8}E_{Pl} for the quadratic LIV effect. Our limits on the quadratic LIV case improve previous best bounds by factors of 5-7.

Constraints on Ultraheavy Dark Matter Properties from Dwarf Spheroidal Galaxies with LHAASO Observations.

In this Letter we try to search for signals generated by ultraheavy dark matter at the Large High Altitude Air Shower Observatory (LHAASO) data. We look for possible γ rays by dark matter annihilation or decay from 16 dwarf spheroidal galaxies in the field of view of the LHAASO. Dwarf spheroidal galaxies are among the most promising targets for indirect detection of dark matter that have low fluxes of astrophysical γ-ray background while having large amount of dark matter. By analyzing more than 700 days of observational data at LHAASO, no significant dark matter signal from 1 TeV to 1 EeV is detected. Accordingly we derive the most stringent constraints on the ultraheavy dark matter annihilation cross section up to EeV. The constraints on the lifetime of dark matter in decay mode are also derived.

Measurements of All-Particle Energy Spectrum and Mean Logarithmic Mass of Cosmic Rays from 0.3 to 30 PeV with LHAASO-KM2A.

We present the measurements of all-particle energy spectrum and mean logarithmic mass of cosmic rays in the energy range of 0.3-30 PeV using data collected from LHAASO-KM2A between September 2021 and December 2022, which is based on a nearly composition-independent energy reconstruction method, achieving unprecedented accuracy. Our analysis reveals the position of the knee at 3.67±0.05±0.15 PeV. Below the knee, the spectral index is found to be -2.7413±0.0004±0.0050, while above the knee, it is -3.128±0.005±0.027, with the sharpness of the transition measured with a statistical error of 2%. The mean logarithmic mass of cosmic rays is almost heavier than helium in the whole measured energy range. It decreases from 1.7 at 0.3 PeV to 1.3 at 3 PeV, representing a 24% decline following a power law with an index of -0.1200±0.0003±0.0341. This is equivalent to an increase in abundance of light components. Above the knee, the mean logarithmic mass exhibits a power law trend towards heavier components, which is reversal to the behavior observed in the all-particle energy spectrum. Additionally, the knee position and the change in power-law index are approximately the same. These findings suggest that the knee observed in the all-particle spectrum corresponds to the knee of the light component, rather than the medium-heavy components.

Measurement of Ultra-High-Energy Diffuse Gamma-Ray Emission of the Galactic Plane from 10 TeV to 1 PeV with LHAASO-KM2A.

The diffuse Galactic γ-ray emission, mainly produced via interactions between cosmic rays and the interstellar medium and/or radiation field, is a very important probe of the distribution, propagation, and interaction of cosmic rays in the Milky Way. In this Letter, we report the measurements of diffuse γ rays from the Galactic plane between 10 TeV and 1 PeV energies, with the square kilometer array of the Large High Altitude Air Shower Observatory (LHAASO). Diffuse emissions from the inner (15°10 TeV). The energy spectrum in the inner Galaxy regions can be described by a power-law function with an index of -2.99±0.04, which is different from the curved spectrum as expected from hadronic interactions between locally measured cosmic rays and the line-of-sight integrated gas content. Furthermore, the measured flux is higher by a factor of ∼3 than the prediction. A similar spectrum with an index of -2.99±0.07 is found in the outer Galaxy region, and the absolute flux for 10≲E≲60 TeV is again higher than the prediction for hadronic cosmic ray interactions. The latitude distributions of the diffuse emission are consistent with the gas distribution, while the longitude distributions show clear deviation from the gas distribution. The LHAASO measurements imply that either additional emission sources exist or cosmic ray intensities have spatial variations.

Inflammatory factors mediated the effect of air pollution on ischemic stroke: a two-step, mediation Mendelian randomization study.

OBJECTIVE: Numerous investigations have indicated a correlation between air pollution (AP) and an elevated ischemic stroke (IS) likelihood. The existing literature does not provide a consensus about the possible link between AP and IS. A two-sample Mendelian randomization (MR) analysis was utilized to systematically measure the causal link between AP and ischemic stroke. Furthermore, the mediating impact of inflammatory factors was also performed by a two-step MR. MATERIALS AND METHODS: A two-sample MR analysis was utilized to examine the AP impact on the incidence of IS. Additionally, a two-step MR approach was carried out to account for possible mediating variables. The indirect impact was determined by employing the product approach, which included multiplying the AP impact on inflammatory factors by the inflammatory factors' impacts on IS. The MR effect was identified through inverse variance-weighted (IVW) meta-analysis of each Wald Ratio. Additionally, complementary studies were conducted using the weighted median and MR-egger approaches. RESULTS: The IVW method with random effects showed that the per unit increase in genetically predicted PM2.5 was linked to the 0.362-fold elevated ischemic stroke risk (OR: 1.362, 95% CI: 1.032-1.796, p=0.029). Furthermore, the IVM technique, incorporating random effects, demonstrated that the per unit increase in genetically predicted PM2.5 was related to an elevated Interleukin (IL)-1ß risk (OR: 1.529, 95% CI: 1.191-1.963, p=0.001), IL-6 (OR: 1.498, 95% CI: 1.094-2.052, p=0.012) and IL-17 (OR: 1.478, 95% CI: 1.021-2.139, p=0.038). IL-1ß, IL-6, and IL-17 modulated the PM2.5 impact on ischemic stroke, while the proportion mediated by them was 59.5%. CONCLUSIONS: A positive correlation between genetically predicted PM2.5 levels and elevated ischemic stroke risk is mediated by IL-1ß, IL-6, and IL-17.

Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis.

The T cell response to the 65-kD mycobacterial heat-shock protein (Bhsp65) has been implicated in the pathogenesis of autoimmune arthritis. Adjuvant arthritis (AA) induced in the Lewis rat (RT-1(l)) by injection of Mycobacterium tuberculosis serves as an experimental model for human rheumatoid arthritis (RA). However, the immunological basis of regulation of acute AA, or of susceptibility/resistance to AA is not known. We have defined the specificity of the proliferative T cell responses to Bhsp65 during the course of AA in the Lewis rat. During the early phase of the disease (6-9 d after onset of AA), Lewis rats raised T cell responses to many determinants within Bhsp65, spread throughout the molecule. Importantly, in the late phase of the disease (8-10 wk after onset of AA), there was evidence for diversification of the T cell responses toward Bhsp65 carboxy-terminal determinants (BCTD) (namely, 417-431, 441-455, 465-479, 513-527, and 521-535). Moreover, arthritic rats in the late phase of AA also raised vigorous T cell responses to those carboxy-terminal determinants within self(rat) hsp65 (Rhsp65) that correspond in position to the above BCTD. These results suggest that the observed diversification is possibly triggered in vivo by induction of self(Rhsp65)-reactive T cells. Interestingly, another strain of rat, the Wistar Kyoto (WKY/NHsd) rat (RT-1(l)), with the same major histocompatibility complex class II molecules as the Lewis rat, was found to be resistant to AA. In WKY rats, vigorous responses to the BCTD, to which the Lewis rat responded only in the late phase of AA, were observed very early, 10 d after injection of M. tuberculosis, Strikingly, pretreatment with the peptides comprising the set of BCTD, but not its amino-terminal determinants, provided significant protection to naive Lewis rats from subsequent induction of AA. Thus, T cell responses to the BCTD are involved in regulating inflammatory arthritis in the Lewis rat and in conferring resistance to AA in the WKY rat. These results have important implications in understanding the pathogenesis of RA and in devising new immunotherapeutic strategies for this disease.

Brown-Séquard syndrome due to penetrating injury by an iron fence point.

STUDY DESIGN: Case report. OBJECTIVES: To present an unusual type of penetrating objects causing Brown-Séquard syndrome (BSS) and its clinical character. SETTING: Department of Orthopaedic Surgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, PR China. METHODS: A 54-year-old man fell from a height of 4 m onto an iron fence, and a sharp iron fence point penetrated the right side of his back. He developed left-sided BSS. Both X-ray film and computed tomography scanning of the thoracic spine showed a right vertebral plate of Th5 fracture and metal fragments inclining through the posterior and left lateral of the spinal canal. Emergency decompressive laminectomy and removal of the foreign metal piece were performed. No improvement in neurological function was observed 10 days after surgery, and thus hyperbaric oxygen treatment was initiated twice a day for the next 1 month. RESULTS: Forty days after surgery, his bladder function returned to normal. The motor deficit had regressed and he could walk without assistance 70 days after the operation. One year later, his lower extremity functions recovered almost completely, except for slight numbness on the right side. CONCLUSION: As far as we know, on the basis of existing literature, the injury mechanism to BSS by a sharp iron fence point has not been reported so far. The satisfactory recovery after injury may in part be attributed to timely surgery and continuing hyperbaric oxygen treatment.

Base of skull recurrences after treatment of salivary gland cancer with perineural invasion reduced by postoperative radiotherapy.

OBJECTIVES: To determine the effect of postoperative radiation therapy for salivary gland carcinomas in the presence of microscopic perineural invasion. DESIGN AND SETTING: Retrospective review at an academic tertiary center. PARTICIPANTS: One hundred and forty patients with pathological evidence of perineural invasion at the time of initial surgery for salivary gland carcinomas were analysed. Sixteen patients (11%) had major (named) nerve involvement. Ninety-four patients (67%) received postoperative radiation therapy to the primary site, and the portal films of 65 of these patients were available for review. MAIN OUTCOME MEASURES: The incidence of skull base recurrences among patients treated by surgery with or without postoperative radiation therapy. RESULTS: Ten patients experienced skull base recurrences. T4 disease and the omission of postoperative radiation therapy were identified as significant predictors of skull base recurrence. Postoperative radiation therapy reduced the actuarial probability of skull base recurrence from 15% to 5% (P = 0.03). The crude rates of skull base recurrence were 6% (2/35) and 10% (3/30), respectively, for patients whose skull base were and were not confirmed to be encompassed in the irradiation field. The 5-year overall survival for patients who experienced a skull base recurrence was 19% compared to 91% for those who did not (P < 0.001). CONCLUSION: The use of postoperative radiation therapy significantly reduced the incidence of skull base recurrence among salivary gland carcinoma patients with perineural invasion.

[Correlation between(Pro) renin receptor levels and gender and disease severity in patients with obstructive sleep apnea syndrome].

Objective:The aim of this study is to investigate the relationship between the level of (pro) renin(P)RR in obstructive sleep apnea syndrome (OSA) patients, and the gender and disease severity of the disease.b>Method:From March 2010 to March 2018, eighty OSA patients who were treated and diagnosed in our hospital were selected as subjects. Another 20 healthy subjects were selected as the control group.Plasma soluble (pro) renin receptor ï¼»s(P)RRï¼½ levels and clinical parameters were measured in healthy subjects and OSA patients with different sex and disease severity. Result:The plasma s(P)RR concentrations were significantly higher in OSA patients than that in control group. In all patients, plasma s(P)RR concentrations increased with increasing disease levels and showed the same trend between men and women. In addition,in all patients, plasma s(P)RR concentrations were significantly positively correlated with waist-to-hip ratio, HbA1c, AHI, and oxygen desaturation index. There was a significant negative correlation between saturation (MSpO2) and minimum oxygen saturation (minSpO2) (P<0.05).In female subjects,plasma s(P)RR concentrations were significantly positively correlated with waist-to-hip ratio and AHI,but significantly negatively correlated with eGFR (P<0.05).In male subjects,plasma s(P)RR concentration was significantly positively correlated with waist-to-hip ratio,HbA1c,renin level,AHI and oxygen desaturation index, but negatively correlated with eGFR, MSpO2 and minSpO2 (P<0.05). Plasma s(P)RR concentrations were significantly reduced after treatment with nasal continuous positive airway pressure ventilator. In addition, ESS,AHI,MSpO2,minSpO2,and oxygen desaturation index were all significantly improved (P<0.05).Conclusion: Plasma s(P)RR levels in OSA patients are significantly positively correlated with the severity of the disease and can directly reflect the severity of the disease. In addition, the patient with higher waist-to-hip ratio and HbA1c, and lower eGFR can effect plasma s(P)RR levels, and may lead to OSA aggravation.

[Analysis of infants with moderate to severe laryngomalacia].

Objective:To investigate the clinical features and the treatment of moderate-severe laryngeallacia, and the application of CO2laser supraglotation in laryngeallacia.Method:Collecting the clinical data of 18 infants with moderate-to-severe laryngeallacia diagnosed in our hospital,10 cases were moderate. Eight cases were severe children; according to the classification of laryngeallacia, most of them were mixed type, including 2 cases of type Ⅱ, 3 cases of type Ⅲ, 5 cases of typeⅠ + type Ⅱ, 7 cases of typeⅡ+ type Ⅲ, and 1 case of typeⅠ+ typeⅡ + type Ⅲ. Among them, 8 patients underwent CO2laser supraglotation,10 patients underwent conservative treatment.The children underwent surgery to evaluate the improvement of laryngeal wheezing, respiration, body weight, and Diet situation. All children were followed up for 12 months.Result:Eight cases with severe laryngeallacia receving CO2laser supraglotation had rapid improvement after surgery, including laryngeal wheezing, dyspnea, and cough symptoms. They were completely cured 3 months after surgery; None of the 10 cases of moderate children were cured in 3 months, 2 cases of laryngeal wheezing and dyspnea basically disappeared in 6 months, 7 cases improved, 1 case was in the plateau stage; Despnea in 8 cases of children basically disappeared 12 months later and 2 cases with mild throat wheezing, continuing conservative treatment; The weight changes, diet and respiration were closely monitored in all 18 children. The weight of the 5 children after surgery in the 3, 6 and 12 months were significantly higher than that in the untreated children. The difference was statistically significant (P<0.05).Conclusion: Electronic laryngoscope should be taked when children are suspected of laryngeal asthma, which could help diagnose moderate-severe laryngeallacia. Follow-up should be done closely. CO2laser supraglottic surgery for severe laryngeallacia, can relieve dyspnea, throat wheezing, eating difficulties and gain weight. The surgical is safety with very slight trauma and less complications, which is worth promoting; for moderate laryngeal softening, close follow-up is recommended, most of which can be treated conservatively. If there is a change in the condition, surgery should be considered.

URG4-silencing suppresses cell proliferation in nasopharyngeal carcinoma through induction of apoptosis.

OBJECTIVE: To investigate the expression and function of up-regulator of gene-4 (URG4) in nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Fresh NPC tumor tissue samples with paired adjacent normal nasopharyngeal tissues samples of 9 NPC patients were collected from NPC curative resection surgery. NPC cell lines (CNE1, CNE2 and HONE1) were cultured. Lentivirus-mediated URG4-specific short hairpin RNA (shRNA) stable transfection was done. The effect of URG4 on CNE4 and HONE1 cells viability was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). The plate-colony-formation assay was performed. Apoptosis analysis was done by flow cytometry. The expression levels of protein and RNA were detected by Western blotting and quantitative polymerase chain reaction (qPCR). RESULTS: We determined the expression of URG4/URGCP in NPC tissues and cell lines using qPCR analysis and found it was significantly upregulated in NPC. After that, stable URG4-silencing NPC cells were constructed by transfection with lentivirus-mediated shRNA. Functionally analyses indicated that knockdown of URG4 significantly impaired cell viability and colony formation ability, as confirmed by MTT and colony formation assays. Furthermore, URG4-silencing NPC cells showed more cells in the stage of early and late apoptosis compared with controls by flow cytometry assay. Western blot analysis further confirmed that knockdown of URG4 enhanced the expression of cleaved caspase-3, cleaved PARP and Bax, while decreased the expression of Bcl-2 and survivin. CONCLUSIONS: URG4/URGCP might play an essential role in NPC cell growth and proliferation and its silencing might be as a potential therapeutic target for NPC.

Metformin promotes differentiation of human bone marrow derived mesenchymal stem cells into osteoblast via GSK3ß inhibition.

OBJECTIVE: Metformin, a common and first-line drug for diabetes mellitus, is widely used in the world. Recently, many studies have documented that osteogenesis could be mediated by metformin. However, the specific mechanism by which metformin affects osteogenesis has not been clearly identified. Therefore, the aim of this study is to evaluate the role of GSK3ß in metformin-induced osteogenic differentiation of mesenchymal stem cells (MSCs). MATERIALS AND METHODS: Osteoblast-marker genes, including Col-1, OCN, and RUNX2, were measured by RT-PCR in differentiated MSCs treated with Metformin. Osteogenic differentiation viability was measured by Alkaline phosphatase (ALP) assays and Alizarin Red Staining. The expression of GSK3ß, ß-catenin and AMPK were measured by Western blotting in MSCs treated with metformin. RESULTS: We found that metformin at 100 µM significantly promoted osteogenic differentiation of human mesenchymal stem cells (hBMSCs). Next, we showed that GSK3ß and Wnt signaling pathway are involved in metformin-induced osteogenic differentiation of hBMSCs. Furthermore, osteogenic differentiation of hBMSCs induced by metformin could be eliminated by inhibiting phosphorylation of GSK3ß. CONCLUSIONS: The data suggested that metformin promoted the osteoblast differentiation of MSCs by, at least partly, inhibiting GSK3ß activity. Additionally, we also found that AMPK plays an essential role in the inhibition of GSK3ß by metformin.

MRI-guided radiotherapy for head and neck cancer: initial clinical experience.

PURPOSE: To report a single-institutional experience with the use of magnetic resonance imaging (MRI)-guided radiotherapy for cancers of the head and neck. MATERIALS AND METHODS: Between October 2014 and October 2016, 18 patients with newly diagnosed cancers of the head and neck were prospectively enrolled on an institutional registry trial investigating the feasibility and efficacy of external-beam radiotherapy delivered using on-board MRI. All patients had biopsy-proven evidence of malignancy, measurable disease, and the ability to provide consent. None had previously received any treatment. Median dose was 70 Gy (range 54-70 Gy). MRI scans were obtained as part of an image-guided registration protocol for alignment prior to and during each treatment. Concurrent chemotherapy was administered to 14 patients (78%). Patient-reported outcomes were assessed using the University of Washington quality of life instrument. RESULTS: Seventeen of 18 patients completed the planned intensity-modulated radiotherapy (IMRT) treatment of which 15 (83%) had a complete response and 2 (11%) had a partial response based on initial post-therapy positron emission tomography (PET) at 3 months. The 1-year estimates of progression-free survival, overall survival, and local-regional control were 95, 96, and 95%, respectively. There were no treatment-related fatalities. The incidence of grade 3+ acute toxicity was 44%. The proportion of patients rating their health-related quality of life as "very good" or "outstanding" at 6 months and 1 year after completion of radiation therapy was 60 and 70%, respectively. CONCLUSIONS: MRI-guided radiotherapy achieves clinical outcomes comparable to contemporary series reporting on IMRT for head and neck cancer.

Aggregation between xanthan and nonyphenyloxypropyl beta-hydroxyltrimethylammonium bromide in aqueous solution: MesoDyn simulation and binding isotherm measurement.

The aggregation behavior of nonyphenyloxypropyl beta-hydroxyltrimethylammonium bromide (C9phNBr) and xanthan (XC) in aqueous solution was investigated by MesoDyn density functional simulation and binding isotherm measurement. The process of aggregate formation and the aggregate morphology are reported. The formation of aggregates includes three stages and the morphology of XC-C9phNBr aggregates is rodlike or ellipsoidal. The effects of temperature and XC concentration on the aggregation are analyzed. Results indicate that the formation of aggregates is an exothermic process, and their formation becomes more difficult and the formation rate decreases with increasing temperature. The formation of aggregates is also related to XC concentration, and it becomes much more difficult when the concentration of XC is higher than 20 vol %. The simulation results agree with binding isotherms of C9phNBr to XC obtained via the potentiometric titration method, which shows a typical cooperative binding between C9phNBr and XC.

Role of antibody-independent complement activation in rejection of porcine bone marrow cells in mice.

BACKGROUND: Although complement activation has been shown to be important in the rejection of solid organs in some xenogeneic species combinations, its role in the rejection of xenogeneic marrow engraftment is unknown. METHODS: The effect of complement depletion with cobra venom factor on porcine bone marrow cell (BMC) engraftment was examined in 3 Gy-irradiated C.B-17 severe combined immunodeficiency mice receiving 10(8) pig BMC. RESULTS: At 26 days after transplantation, the percentages of swine class I+, myeloid, and CD2+ cells in marrow, spleen, and peripheral blood, and the numbers of porcine myeloid progenitor cells in marrow, were increased in cobra venom factor-treated recipients compared with simultaneous control recipients. Consistent with the in vivo results, preheating serum (56 degrees C for 30 min) reduced the inhibitory effect of severe combined immunodeficiency mouse serum on the proliferation of pig BMC in vitro. CONCLUSION: Murine complement is capable of resisting xenogeneic hematopoietic engraftment through an antibody-independent mechanism.

Porcine stem cell engraftment and seeding of murine thymus with class II+ cells in mice expressing porcine cytokines: toward tolerance induction across discordant xenogeneic barriers.

BACKGROUND: Mixed hematopoietic chimerism is a reliable means of tolerance induction, but its utility has not been demonstrated in discordant xenogeneic combinations because of the difficulty in achieving lasting hematopoietic engraftment. Miniature swine are likely to be suitable organ donors for humans. To evaluate the ability of mixed chimerism to induce swine-specific tolerance in widely disparate xenogeneic recipients, this study aimed to achieve long-lasting chimerism in a pig to mouse combination. METHODS: Immunodeficient transgenic mice were developed by crossing transgenic founders carrying porcine interleukin-3, granulocyte macrophage-colony stimulating factor, and stem cell factor genes with severe combined immunodeficient mice or non-obese diabetic/severe combined immunodeficient mice. Swine bone marrow transplantation was performed in these mice, and porcine chimerism was followed for 20 weeks. RESULTS: Whereas swine cells became undetectable in all non-Tg littermates by 7 weeks, high levels of porcine hematopoietic chimerism, including the presence of porcine class II+ cells in the host thymus were maintained in Tg mice for >20 weeks. Colony-forming assays revealed the presence of large numbers of swine hematopoietic progenitor cells in the marrow of these mice at 20 weeks after bone marrow transplantation. CONCLUSIONS: These transgenic mice demonstrate for the first time that spontaneous migration of marrow donor antigen-presenting cells to an intact recipient thymus can occur and that porcine stem cells can persist in this highly disparate species combination. These data therefore support the feasibility of the eventual goal of tolerance induction by mixed chimerism in discordant xenogeneic combinations.

Misrejoining of double-strand breaks after X irradiation: relating moderate to very high doses by a Markov model.

Misrejoining of double-strand breaks (DSBs) detected with pulsed-field gel electrophoresis (PFGE) after X irradiation of human cells at very high doses (80-160 Gy) is related to dose-response relationships for chromosome aberrations at moderate doses (1-5 Gy) by the Sax-Markov binary eurejoining/misrejoining (SMBE) model. The SMBE model applies Sax's breakage-and-reunion hypothesis to a subset of DSBs active in binary misrejoining and in binary eurejoining (accidental restitution). The model is numerically consistent with both data on chromosome aberrations and the data obtained by PFGE if proximity effects (restrictions on the range of interactions of DSB free ends) are present. Proximity effects are modeled by partitioning the cell's nucleus into approximately 400 interaction sites, with two active DSB free ends capable of rejoining only if they were produced within the same site. Neglecting one-track action, the SMBE model predicts a quadratic-linear dose-response relationship for DSB misrejoining after exposure to low-LET radiation; i.e., there is a quadratic response at moderate doses which becomes linear as the dose becomes large, rather than vice versa. The linear region results because at very high doses almost all of the active DSB free ends misrejoin rather than eurejoin.

Intra-arm and interarm chromosome intrachanges: tools for probing the geometry and dynamics of chromatin.

Many chromosome-type, exchange-type chromosomal aberrations produced by radiation are intrachanges, i.e. involve only one chromosome. It is assumed such intrachanges are formed by illegitimate reunion of two double-strand breaks (DSBs) on the chromosome. The yield of intra-arm intrachanges (acentric rings or paracentric inversions) relative to that of interarm intrachanges (centric rings or pericentric inversions) is larger than would occur if production and illegitimate reunion of DSBs were spatially random. The excess of intra-arm intrachanges is presumably due to proximity effects for illegitimate reunions, i.e. enhancement of the intrachange probability when two DSBs are formed close to one another. Radiation track structure may also play a role. Using a polymer description for "large-scale" chromatin geometry (>2 Mb), and using two alternate (rapid or slow motion) models for the way that DSBs move after they are produced, theoretical estimates are given for size distributions of intrachanges at low or high linear energy transfer (LET). The ratio of intra-arm to interarm intrachanges is derived from the size distribution and compared with data from the literature on centric rings, inversions, interstitial deletions and excess acentric fragments. Proximity effects enhance yields of intra-arm relative to interarm intrachanges at least severalfold and perhaps as much as 10-fold compared to expectations based on spatial randomness. We argue that further measurements of intra-arm and interarm intrachanges would be informative about large-scale chromatin structure and chromosome motion. Because inversions are more frequent than estimates of randomness would indicate, and are transmissible to daughter cells, their size distribution could also help characterize past exposure to high-LET radiation.

Computer simulation of data on chromosome aberrations produced by X rays or alpha particles and detected by fluorescence in situ hybridization.

With fluorescence in situ hybridization (FISH), many different categories of chromosome aberrations can be recognized-dicentrics, translocations, rings and various complex aberrations such as insertions or three-way interchanges. Relative frequencies for the various aberration categories indicate mechanisms of radiation-induced damage and reflect radiation quality. Data obtained with FISH support a proximity version of the classic random breakage-and-reunion model for the formation of aberrations. A Monte Carlo computer implementation of the model, called the CAS (chromosome aberration simulator), is generalized here to high linear energy transfer (LET) and compared to published data for human cells irradiated with X rays or 238Pu alpha particles. For each kind of radiation, the CAS has two adjustable parameters: the number of interaction sites per cell nucleus and the number of reactive double-strand breaks (DSBs) per gray. Aberration frequencies for various painted chromosomes, of varying lengths, and for 11 different categories of simple or complex aberrations were simulated and compared to the data. The optimal number of interaction sites was found to be approximately 13 for X irradiation and approximately 25 for alpha-particle irradiation. The relative biological effectiveness (RBE) of alpha particles for the induction of reactive DSBs (which are a minority of all DSBs) was found to be approximately 4. The two-parameter CAS model adequately matches data for many different categories of aberrations. It can use data obtained with FISH for any one painting pattern to predict results for any other kind of painting pattern or whole-genome staining, and to estimate a suggested overall numerical damage indicator for chromosome aberration studies, the total misrejoining number.

Current and future applications of immunological attenuation via pegylation of cells and tissue.

Prevention of immunological rejection of transplanted tissues is of crucial importance in transplantation medicine. Current procedures primarily use pharmacological agents such as cyclosporin, which, while effective, must be typically administered for the life of the individual. Furthermore, the drug-induced global immunosuppression of the patient predisposes the individual to infection and enhances their risk of developing certain forms of cancer. Hence, additional methods are needed to both enhance tissue engraftment and diminish the adverse effects of current immunosuppressive therapy. Studies from blood transfusion (i.e. a specialised form of cellular transplantation) suggest that covalent modification of cells and tissues with methoxypoly(ethylene glycol) [mPEG] can significantly diminish rejection episodes and may further enhance the induction of tolerance to donor tissues. The mechanisms underlying mPEG-mediated immunocamouflage are the loss of antigen recognition, impaired cell-cell interaction, and an inability of endogenous antibodies (e.g. immunoglobulin G) to effectively recognise and bind foreign epitopes. As a consequence of the global camouflage imparted by mPEG, the weak co-stimulation of alloreactive T cells may subsequently induce apoptosis, thus leading to tolerance. Initial studies on the transplantation of pegylated isogeneic rat pancreatic islets demonstrates that mPEG-derivatisation does not impair in vivo cellular signalling and function. Thus, in contrast to the pharmacological inhibition of the recipient's immune response, the mPEG-mediated immunocamouflage directly addresses the inherent antigenicity and immunogenicity of the donor tissue itself while leaving the recipient a fully competent immune system.