Elaborating Transition Interface Sampling Methods

We review two recently developed efficient methods for calculating rate constants of processes dominated by rare events in high-dimensional complex systems. The first is transition interface sampling (TIS), based on the measurement of effective fluxes through hypersurfaces in phase space. TIS improves efficiency with respect to standard transition path sampling (TPS) rate constant techniques, because it allows a variable path length and is less sensitive to recrossings. The second method is the partial path version of TIS. Developed for diffusive processes, it exploits the loss of long time correlation. We discuss the relation between the new techniques and the standard reactive flux methods in detail. Path sampling algorithms can suffer from ergodicity problems, and we introduce several new techniques to alleviate these problems, notably path swapping, stochastic configurational bias Monte Carlo shooting moves and order-parameter free path sampling. In addition, we give algorithms to calculate other interesting properties from path ensembles besides rate constants, such as activation energies and reaction mechanisms.Comment: 36 pages, 5 figure

Racial Differences in Treatments and Toxicity in Non-Small Cell Lung Cancer Patients Treated with Thoracic Radiation Therapy

Background: Racial disparities are of particular concern for lung cancer patients given historical differences in surgery rates for African-American lung cancer patients that resulted in lower overall survival and higher recurrence rates compared with rates in White patients. Objectives: The overall objective of this study was to examine racial differences in thoracic radiation therapy (RT) treatments and toxicities in a large cohort of patients from a multi-institutional consortium database of non-small cell lung cancer (NSCLC) patients. Methods: A large multi-institutional statewide prospectively collected patient-level database of locally advanced (stage II or III) NSCLC patients who received thoracic RT from March 2012 to November 2019 was analyzed to assess the associations between race and treatment and toxicity variables. Race (White or African-American) was defined by patient self-report or if not available then by the electronic medical record system classification. Race categories other than White or African-American comprised a small minority of patients and were excluded from this analysis. Patient-reported toxicity was determined by validated tools including the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Provider-reported toxicity was determined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Uni-variable and multi-variable regression models were then fitted to assess relationships between primary outcomes by race and indicators of high-quality treatment and secondary analysis of symptoms. Spearman rank correlation coefficients were calculated between provider reported toxicity and similar patient reported outcomes for each race category. Results: A total of 1441 patients from 24 institutions with mean age of 68 years (range 38-94) were evaluated; 226 patients were African-American, of whom 61% were treated at three facilities. Race was not significantly associated with RT treatment approach, use of concurrent chemotherapy, or the dose to the planning target volume (PTV) or organs at risk including the heart and lungs. However, there was increased patient-reported general pain in African-American patients (compared with White patients) at several time points including pre-RT (22% (vs 15%), P=0.02) and at the end of RT (30% (vs 17%), P=0.001). African-American patients were significantly less likely to have provider-reported grade 2+ radiation pneumonitis (odds ratio (OR) 0.36, P=0.03), despite similar levels of patient-reported respiratory toxicities such as cough and shortness of breath and even after controlling for known patient and treatment-related factors. Correlation coefficients between provider- and patient-reported toxicities were generally similar across race categories. Conclusions: In this large multi-institutional observational study, we reassuringly found no evidence of differences in radiation treatment or chemotherapy approaches by race, in contrast to historical differences by race in surgical care that led to worse survival and outcomes in minority race patients. However, we did unexpectedly find that African-American race was associated with lower odds of provider-reported grade 2+ radiation pneumonitis despite similar patient-reported toxicities of shortness of breath and cough. There are several possibilities for this finding including that pneumonitis is a multifactorial diagnosis that relies on clinical as well as radiologic information and clinical information alone may be insufficient. The Spearman correlation analysis also revealed stronger correlations between patient- and provider-reported toxicities in White patients compared with African-American patients, particularly for trouble swallowing/esophagitis. These findings together for pneumonitis and esophagitis discouragingly suggest possible under-recognition of symptoms in black patients. Further investigation is now warranted to better understand how these findings impact the care of racially diverse lung cancer patients

Rescue of Historical Materials in Awaji atHanshin-Awaji Earthquake

Purpose: In peptide receptor radionuclide therapy (PRRT), the bone marrow (BM) is one of the dose-limiting organs. The accepted dose limit for BM is 2 Gy, adopted from 131I treatment. We investigated the incidence and duration of haematological toxicity and its risk factors in patients treated with PRRT with 177Lu-DOTA0-Tyr3-octreotate (177Lu-DOTATATE). Also, absorbed BM dose estimates were evaluated and compared with the accepted 2 Gy dose limit. Methods: The incidence and duration of grade 3 or 4 haematological toxicity (according to CTCAE v3.0) and risk factors were analysed. Mean BM dose per unit (gigabecquerels) of administered radioactivity was calculated and the correlations between doses to the BM and haematological risk factors were determined. Results: Haematological toxicity (grade 3/4) occurred in 34 (11 %) of 320 patients. In 15 of the 34 patients, this lasted more than 6 months or blood transfusions were required. Risk factors significantly associated with haematological toxicity were: poor renal function, white blood cell (WBC) count <4.0 × 109/l, age over 70 years, extensive tumour mass and high tumour uptake on the OctreoScan. Previous chemotherapy was not associated. The mean BM dose per administered activity in 23 evaluable patients was 67 ± 7 mGy/GBq, resulting in a mean BM dose of 2 Gy in patients who received four cycles of 7.4 GBq 177Lu-DOTATATE. Significant correlations between (cumulative) BM dose and platelet and WBC counts were found in a selected group of patients. Conclusion: The incidence of subacute haematological toxicity after PRRT with 177Lu-DOTATATE is acceptable (11 %). Patients with impaired renal function, low WBC count, extensive tumour mass, high tumour uptake on the OctreoScan and/or advanced age are more likely to develop grade 3/4 haematological toxicity. The BM dose limit of 2 Gy, adopted from 131I, seems not to be valid for PRRT with 177Lu-DOTATATE

Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid a-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5' UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient

Novel GAA Variants and Mosaicism in Pompe Disease Identified by Extended Analyses of Patients with an Incomplete DNA Diagnosis

Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5′ UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient

Fine mapping of Restorer-of-fertility in pepper (Capsicum annuum L.) identified a candidate gene encoding a pentatricopeptide repeat (PPR)-containing protein

Key message Using fine mapping techniques, the genomic region co-segregating with Restorer-of-fertility (Rf) in pepper was delimited to a region of 821 kb in length. A PPR gene in this region, CaPPR6, was identified as a strong candidate for Rf based on expression pattern and characteristics of encoding sequence. Abstract Cytoplasmic-genic male sterility (CGMS) has been used for the efficient production of hybrid seeds in peppers (Capsicum annuum L.). Although the mitochondrial candidate genes that might be responsible for cytoplasmic male sterility (CMS) have been identified, the nuclear Restorer-of-fertility (Rf) gene has not been isolated. To identify the genomic region co-segregating with Rf in pepper, we performed fine mapping using an Rf-segregating population consisting of 1068 F2 individuals, based on BSA-AFLP and a comparative mapping approach. Through six cycles of chromosome walking, the co-segregating region harboring the Rf locus was delimited to be within 821 kb of sequence. Prediction of expressed genes in this region based on transcription analysis revealed four candidate genes. Among these, CaPPR6 encodes a pentatricopeptide repeat (PPR) protein with PPR motifs that are repeated 14 times. Characterization of the CaPPR6 protein sequence, based on alignment with other homologs, showed that CaPPR6 is a typical Rf-like (RFL) gene reported to have undergone diversifying selection during evolution. A marker developed from a sequence near CaPPR6 showed a higher prediction rate of the Rf phenotype than those of previously developed markers when applied to a panel of breeding lines of diverse origin. These results suggest that CaPPR6 is a strong candidate for the Rf gene in pepper.OAIID:RECH_ACHV_DSTSH_NO:T201625308RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A076900CITE_RATE:3.9FILENAME:TAG(2016) Fine mapping of Rf in pepper.pdfDEPT_NM:식물생산과학부EMAIL:[email protected]_YN:YFILEURL:https://srnd.snu.ac.kr/eXrepEIR/fws/file/8c5822f8-5600-4a60-a386-0529e2f49934/linkCONFIRM:

Aging, microglia and cytoskeletal regulation are key factors in the pathological evolution of the APP23 mouse model for Alzheimer's disease

Aging is the key risk factor for Alzheimer's disease (AD). In addition, the amyloid-beta (A beta) peptide is considered a critical neurotoxic agent in AD pathology. However, the connection between these factors is unclear. We aimed to provide an extensive characterization of the gene expression profiles of the amyloidosis APP23 model for AD and control mice and to evaluate the effect of aging on these profiles. We also correlated our findings to changes in soluble A beta-levels and other pathological and symptomatic features of the model. We observed a clear biphasic expression profile. The first phase displayed a maturation profile, which resembled features found in young carriers of familial AD mutations. The second phase reflected aging processes and showed similarities to the progression of human AD pathology. During this phase, the model displayed a clear upregulation of microglial activation and lysosomal pathways and downregulation of neuron differentiation and axon guidance pathways. Interestingly, the changes in expression were all correlated to aging in general, but appeared more extensive/accelerated in APP23 mice. (C) 2016 Elsevier B.V. All rights reserved

Coping with stress: a pilot study of a self-help stress management intervention for patients with epileptic or psychogenic non-epileptic seizures

Purpose: Many patients with epilepsy or psychogenic non-epileptic seizures (PNES) experience high levels of stress. Although psychological interventions have been developed for seizure disorders, few patients can currently access them. We aimed to assess the acceptability and feasibility of a self-help intervention targeting stress in patients with seizures, and to provide preliminary evidence for its effectiveness. Method: Patients were recruited from outpatient neurology clinics and randomised to an immediate intervention group (n=39), who received the intervention at baseline, or a delayed intervention group (n=43), who received the intervention one month post-baseline. Participants completed self-report questionnaires measuring stress (SSSI), anxiety (GAD-7), depression (NDDI-E), quality of life (EQ-5D), seizure severity and frequency (LSSS-3) at baseline, and at one- and two-month follow-up. Participants also provided telephone feedback. The intervention consisted of a self-help stress management workbook based on an integrative stress model framework. Results: Although the rate of participants failing to return follow-up information at two months was approximately 50%, those who completed the trial found the intervention acceptable; with the majority rating it as helpful (63.6%) and that they would recommend it to others with seizures (88.1%). A significant reduction in self-reported stress (p = 0.01) with a medium effect size (dz = 0.51) was observed one-month post-intervention. There were no significant changes in any other measures. Conclusion: The intervention was perceived to be acceptable, safe and helpful by participants. It could be a useful complementary treatment option for reducing stress experienced by patients living with seizure disorders. Further evaluation in a larger trial is warranted

Effect of starch-based biomaterials on the in vitro proliferation and viability of osteoblast-like cells

The cytotoxicity of starch-based polymers was investigated using different methodologies. Poly-L-lactic acid (PLLA) was used as a control for comparison purposes. Extracts of four different starch-based blends (corn starch and ethylene vinyl alcohol (SEVA-C), corn starch and cellulose acetate (SCA), corn starch and polycaprolactone (SPCL) and starch and poly-lactic acid (SPLA70) were prepared in culture medium and their toxicity was analysed. Osteoblast-like cells (SaOs-2) were incubated with the extracts and cell viability was assessed using the MTT test and a lactate dehydrogenase (LDH) assay. In addition DNA and total protein were quantified in order to evaluate cell proliferation. Cells were also cultured in direct contact with the polymers for 3 and 7 days and observed in light and scanning electron microscopy (SEM). LDH and DNA quantification revealed to be the most sensitive tests to assess respectively cell viability and cell proliferation after incubation with starch-based materials and PLLA. SCA was the starch blend with higher cytotoxicity index although similar to PLLA polymer. Cell adhesion tests confirmed the worst performance of the blend of starch with cellulose acetate but also showed that SPCL does not perform as well as it could be expected. All the other materials were shown to present a comparable behaviour in terms of cell adhesion showing slight differences in morphology that seem to disappear for longer culture times. The results of this study suggest that not only the extract of the materials but also their three-dimensional form has to be biologically tested in order to analyse material-associated parameters that are not possible to consider within the degradation extract. In this study, the majority of the starch-based biomaterials presented very promising results in terms of cytotoxicity, comparable to the currently used biodegradable PLLA which might lead the biocompatibility evaluation of those novel biomaterials to other studies.Fundação para a Ciência e a Tecnologia (FCT