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string | predicted_class
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TMZ, on the other hand, was tested to be non-inferior to RT in elderly patients with a methylated MGMT-promotor in the NOA-08-Trial: The efficacy of RT did not depend on the MGMT-status of the treated high grade gliomas. Also this trial did not test radiochemotherapy in elderly patients . This gap recently was closed by prospective data from an international phase III trial. By comparing hypofractionated RT with concomitant TMZ followed by up to 6 adjuvant cycles of TMZ, the authors demonstrated a significant advantage accompanied by a tolerable toxicity profile also for elderly patients treated with the combined regimen, independently from age and using a very inclusive paradigm .
|
review
| 99.56 |
While the current evidence strongly supports the role of loco-regional treatments in elderly patients, too, population based studies demonstrate a positive correlation between age and the treatment by best supportive care only, hinting to a possible under-treatment of elderly patients . Hence, there must be a difference between aged frail, almost palliative patients and extremely fit and active elderly, which arguments against age only as a decision making tool.
|
review
| 99.7 |
In the present article, we report on our experience in treating elderly patients with RT and RChT and confirm that a combined modality treatment with radiochemotherapy with TMZ results in a longer survival, independently from the age but dependent from the performance status of the patients.
|
study
| 58.84 |
Patients with primary GBM, aged 65 years or older, starting their first course of RT between 01/2009 and 12/2015, were extracted from the prospective patient’s registry of the local department for radiation oncology at the Technical University of Munich (TUM), Germany. For all patients, treatment decisions were consented within an interdisciplinary tumor board specialised for neuro-oncologic tumors. The median age of the 62 patients was 69.6 years (range 65.1-85.6 years). Since molecular marker evaluation became a standard for all patients only recently, this information was not available for all patients: IDH mutation status was available in 32 cases (51.6%) and was negative for all of these patients. MGMT methylation was tested in 37 cases (59.6%) with 15 cases of methylated MGMT promotor (40.1%) (Table 1).Table 1Patient characteristicsCharacteristicsRT (n = 27)RChT (n = 35)Age – years Median69.670.469.3 Range65.1–85.665.8–85.665.1–78.8Sex – no. (%) Male32 (51.6)9 (33.3)23 (65.7) Female30 (48.4)18 (66.6)12 (34.3)ECOG-Score – no. (%) 0909 (25.7) 1288 (29.6)20 (57.1) 21813 (48.1)5 (14.3) 366 (22.2)0 Missing101 (2.9)Extent of surgery – no. (%) Biopsy only7 (11.3)5 (18.5)2 (5.7) Subtotal resection34 (54.8)17 (68.0)17 (48.6) Gross total resection21 (33.9)5 (18.5)16 (45.7)MGMT-promotor Methylated – no.15411 Non-methylated – no.221012 Missing – no.251312Time from Surgery to RT (d) Median28.52928 Range12–6112–5814–61RT regimen (total/ single; Gy) 42/312120 40.05/2.67880 60/2 or 59.4/1.834331 other844Salvage Treatment – no.23320 Radiotherapy14014 Chemotherapy15114 Surgery14212
|
study
| 99.94 |
All patients were diagnosed with operation and histological examination. In 7 cases (11.3%) patients received biopsy only; subtotal resection was performed in 34 cases (54.8%) and gross total resection could be achieved in 21 cases (33.9%). Resection status as well as evidence for postoperative ischemia was evaluated by a post-operative MRI within 48 hours after surgery. The median performance status at the onset of RT was ECOG 1 (0–3). RT was administered using 3D-conformal or intensity modulated RT in all cases and was planned with post-operative MRI, a planning MRI one week before RT and contrast enhanced planning CT with a slice thickness of 2–3 mm. The clinical target volume (CTV) consisted of the sum of the resection cavity as well as all contrast enhancing areas plus a 2 cm margin and Fluid attenuated inversion recovery (FLAIR)- or T2-hyperintense areas, plus a 1 cm margin. A margin of 5 mm was added for the Planning Target Volume (PTV). Single doses ranged from 1.8 to 3.0 Gy, total doses from 40.05 to 60.0 Gy, mean 52Gy. All patients received 5 fractions per week.
|
study
| 68.6 |
If chemotherapy was administered, patients received 75 mg temozolomide (TMZ) / m2 daily during radiotherapy. Adjuvant treatment was started 4 weeks after the end of RT and consisted of 150 to 200 mg/ m2/d of TMZ in 5 of 28 days. 6 cycles of chemotherapy were planned.
|
other
| 99.9 |
All patients were included into a strict follow-up regimen, with a first clinical visit and a first imaging study 4 weeks after RT. Clinical follow up as well as MRI-studies were repeated every 3 months. The median follow up at our institution was 6.0 months (range 0–41 months).
|
clinical case
| 99.9 |
We retrospectively reviewed all imaging data and reports from our patients for the extent of the resection, the evidence of post-operative ischemia, defined by hyperintense area in diffusion weighted images (DWI, b1000) with hypointensities within spatially matched apparent diffusion coefficient (ADC) maps, and for the pattern of recurrence. We defined gross total resection (GTR) as resection of at least 99% of the contrast enhancing tumor. Subtotal resection was defined as evidence of contrast enhancing tumor after resection while resection of less than 20% of the tumor mass were defined as biopsy. Progression was defined according to the RANO-HGG criteria .
|
study
| 99.8 |
Analysis was done by SPSS v. 18. Overall as well as progression free survival were analysed with the Kaplan-Meier-method. Differences between the survival of two groups were analysed using the log-rank test (univariate statistics). Univariate cox regression analysis was used to compare categorical variables. Overall survival was defined as time from surgery to death. Progression free survival was defined as time from the start of radiotherapy to the evidence of progression according to the RANO-HGG-criteria or to death. If patients were alive at the time of our analysis (01.12.2016), survival times were censored to the date of the last follow up visit.
|
study
| 99.94 |
The median overall survival of our cohort was 10.9 months (range 3.0 to 43.3; Fig. 1a). The median progression free survival was 5.7 months (range 1.2-31.7; Fig. 1b). Local recurrence occurred in 25 cases, local and distant in 10 cases and distant recurrence occurred in 4 cases. Clinical progression occurred in 7 cases, in two of these cases an MRI could not describe a specific focus. For the 5 patients remaining, MRI was not performed as the patients were not deemed to be able to undergo a salvage treatment. 12 patients died without clinical or imaging evidence for progression. At the time of our analysis, 12 patients were still alive, 1 of these patients without evidence for progression after the initial treatment, one further patient was loss of follow up.Fig. 1Kaplan Meier estimates of a overall survival and b progression free survival
|
study
| 99.25 |
Concomitant radiochemotherapy (RChT) was given to 35 patients. The median age of patients receiving a combined treatment was 69.3 years (65.1-78.8). A better ECOG was significantly associated with the initiation of adjuvant chemotherapy (p <0.001) as well as with the decision for a combined modality treatment (p <0.001). Patients receiving combined treatment generally were in a good performance status (median ECOG of 1; 0–2). All these patients received a standard fractionation regimen with single doses from 1.8 to 2.0 Gy up to a median dose of 60.0 Gy. MGMT promotor methylation was examined in 23 cases and was positive in 11 of these cases (47.8%). 1 to 9 cycles of adjuvant chemotherapy with temozolomide were given to the majority of these patients (26 of 35 patients; median No. of cycles 6) and were tolerated well. In 3 cases decision against adjuvant treatment was due to a poor performance status. Also in 3 cases, early progression occurred after RChT; one patient underwent salvage treatment, two patients were included into a best supportive care program. Two patients with severe infection during RChT decided against further chemotherapy. One patient underwent revision surgery for symptomatic radionecrosis, therefore adjuvant chemotherapy started with a delay of 3 months and the patient was not included into the adjuvant ChT group.
|
clinical case
| 51.66 |
Twenty-seven patients were treated with RT only. The median age of this cohort was 70.4 years (65.8–85.6). The performance status was worse in this cohort with a median ECOG of 2 (1–3) and less patients received a gross total resection. Patients with mono-RT were more likely to be treated with a hypofractionated schedule with either 2.67 or 3.0 single dose up to a dose of 40.05 or 42 Gy. 2 patients received an adjuvant TMZ based chemotherapy (one patient decided against concomitant RChT, the other patient received hypofractionated treatment with 3 Gy single dose and actively decided to receive further adjuvant treatment). MGMT promotor methylation status was available for 14 patients with positive result in 4 of these cases (28.5%). For the two patients which underwent adjuvant ChT, no MGMT methylation status was available.
|
study
| 99.75 |
Twenty-three patients received some kind of salvage treatment. In more detail, 14 patients underwent re-irradiation, 15 patients received ChT for recurrent disease and 14 patients underwent surgery for recurrent disease. Patients treated for their recurrent disease had a significantly longer survival compared to patients who underwent best supportive care (BSC) at progression of their disease (mOS 8.8 vs. 22.3 months, p < 0.001).
|
study
| 85.8 |
Treatment with chemotherapy as part of the initial treatment was the most powerful discriminator for a longer survival, with a median OS of 20.5 vs. 7.8 months (patients with vs. without adjuvant CHT; p < 0.001) and 18.7 vs. 7.9 months (patients with RCHT vs. patients with mono-RT; p = 0.002) (Fig. 2). Furthermore, ECOG (p = 0.008), MGMT (p = 0.03) and the extent of resection (p = 0.014) were significant predictors for a longer OS. Younger age (median 69.6 years, p = 0.216) and a shorter interval between surgery and the onset of RT (median 28 days, p = 0.82) were not associated with longer survival (Fig. 3). Postoperative ischemia was not significantly (p = 0.052) influencing overall survival, however, this might be a matter of numbers. All results from Cox regression analysis are summarized in Table 2.Fig. 2Survival stratified for Radiochemotherapy (a), adjuvant Chemotherapy (b), and e treatment (39 patients with imaging-defined recurrent GBM) (c) Fig. 3Overall survival of elderly patients stratified by Age (a), ECOG (b), Extent of Resection (c) and MGMT (d) Table 2Cox regression analysisCox regressionHR95% CI p Age (older vs. younger than 69.6 years)1.440.81–2.540.216ECOG ( 2–3 vs. 0–1)2.351.28–4.340.008MGMT (negative vs. positive)a 2.631.04–6.660.03Extent of resection ( GTR vs. STR & Biopsy )0.470.25–0.8760.014Ischemia (ischemia vs. no ischemia)b 1.940.98–3.820.059Time from surgery to RTx (earlier vs. later than 28 days)1.070.61–1.890.816Adjuvant CHT vs. No Adjuvant CHT0.240.13–0.47<0.001RCHT vs. RT0.380.21–0.690.002Treatment for recurrent disease (Treatment vs. BSC)c 0.060.02–0.17<0.001 aonly patients with measured MGMT methylation; bonly patients with postoperative imaging including DWI b1000 and ADC; conly patients with recurrence diagnosed by imaging
|
study
| 99.94 |
Importantly, age was not significantly related to a worse ECOG (p = 0.11; Chi-square test), but it was related to the initiation of radiochemotherapy (p = 0.001; Chi-square test) and the prescription of an adjuvant chemotherapy (p = 0.005; Chi-square test). Furthermore, we asked whether the subgroup patients with an ECOG of 1 or 2 would benefit from RChT or not. The median OS of ECOG 1 patients was 7 and 16.3 months with RT and RChT, respectively (Fig. 4a). The difference was not significant (p = 0.174), however, this is most likely due to the low patient number of this subgroup. In comparison to this, the median OS of patients with an ECOG of 2 was 6.2 and 7.2 with RT and RChT (Fig. 4b). Also this difference was not significant (p = 0.774).Fig. 4Kaplan Meier estimares for patients undergoing RT and RChT. In patients with ECOG 1 (a), median OS 7 vs. 16.3 months. In patients with ECOG 2 (b), median OS was 6.2 vs. 7.2
|
study
| 99.94 |
GBM almost always leads to the loss of independence by increasingly developing disabilities throughout the course of disease; the loss of independence is mostly due to progression of the disease . RT, chemotherapy as well as combined modality treatments have shown to prolong the progression free survival and to increase the OS, too [2, 15, 16]. Based on reports about increased toxicities of either of these treatments in elderly patients, mono-therapeutic regimens have emerged [2, 10, 11]. All of these aim on minimizing the burden by the treatment, and, all of them have demonstrated mOS between 6.4 and 9.6 months in elderly people [2, 10]. Inclusion criteria of these trials were mostly based on age (65 years or older) and a modest to good performance status (Karnofsky Performance Score (KPS) of at least 60% or ECOG of 2 or less).
|
review
| 99.9 |
The median age of the NOA-08 trial, a trial comparing chemotherapy to RT in elderly patients, was 71 vs. 72 years, the median OS was 8.6 for TMZ and 9.4 months for RT, p = 0.033. The trial also analysed the impact of MGMT promotor methylation and described the predictive value for MGMT for the efficacy of TMZ. Similar results were reported from the Nordic Trial, which furthermore reported a small but significant positive effect of either TMZ or hypofractionated RT to a standard fractionated RT . The trial included patients with an age of 60 years or older, the difference described above was more pronounced within the group of patients older than 70 years. Rao et al. randomized patients with a minimum age of 60 years and a mean age of 72.4 and 71 years to receive either a 6 week normofractionated or a 3 week hypofractionated regimen. Both groups had a median KPS of 70%. The trial was closed earlier due to high similarity between the two arms. The trial demonstrated equal efficacy of both dosing schemes, with a median OS of 5.1 and 5.6 months. Notably, Gross Total Resection (GTR) was achieved in only 4.2 and 14.6% of the cases, almost 40% received biopsy only . A mono-institutional report from Ontario, Canada, reported about hypofractionated RT with and without concurrent TMZ. GTR was achieved in one third of the patients. The median survival was superior for the mono-RT group (6.9 vs. 9.3 months), yet the difference was not significant. Similar to our results, also elderly patients had a significant benefit from salvage therapies (5.7 vs. 13.3 months) . Already in 2008, Combs et al. demonstrated the efficacy and safety of RChT for patients older than 65 years. This cohort had a median survival of 11 months, a subgroup with gross total resection had a median survival of 18 months . Only recently, results from the randomized phase III EORTC 26062–22061 / TROG 08.02-Trial were presented by Perry and colleagues. 562 patients were randomized between a hypofractionated RT up to 40.05 Gy alone or in combination with concurrent TMZ. In opposite to the retrospective data from Cao et al., this trial showed a significant advantage for the combined modality treatment (7.6 vs 9.3 months). Importantly, also patients with non-methylated MGMT-promotor benefited from concurrent radiochemotherapy . Unfortunately, the article did not report whether also patients with ECOG 2 did profit from the combined modality treatment. In our cohort, albeit not significant, patients with an ECOG 1 did profit more than patients with ECOG 2. In our view, the radiotherapy treatment regimen could be an important reason for this difference. Hypofractionated radiotherapy was shown to be equally effective in elderly and frail patients not eligible to standard fractionated treatment [10, 11, 17], but concerns about the long term safety have been raised . On the other hand, nether safety nor efficiency of hypofractionated and standard-fractionated RChT have been compared directly. Taken that in hypofractionated treatments the concomitant chemotherapy time it cut in half, medically fit patients (ECOG 0 and 1) treated according to the Perry-Study can be considered to be under risk of being undertreated. A standard fractionated RChT therefore should be deemed to be the standard of care for elderly patients with a good performance status. This concepts has been published previously, stressing the necessity of proactive treatment in medically fit patients above age 65 years .
|
review
| 99.8 |
We also analysed the survival of patients after diagnosis for objective progressive disease. Patients which were treated for recurrent GBM, either by surgery, re-irradiation or chemotherapy, did have a longer survival compared to patients receiving best supportive care (BSC) in this situation. Prospective trials comparing BSC and re-irradiation or any other salvage-strategy in elderly patients are scarce; only one article analysed this topic and concluded, that salvage treatment for recurrent GBM could be beneficial . This comparison as well as our analysis are influenced by a selection bias, as patients with a better performance score are more likely to undergo a salvage treatment than patients with a poor OS. Concerning re-irradiation, an interval of less than 6 months between the first course of radiotherapy and progressive disease is usually believed as to short to undergo re-irradiation. As RChT can result in progression free survival of more than 6 months in elderly patients, especially when MGMT promotor hypermethylation is present , re-irradiation could become more frequent. Further studies, especially on the safety and efficacy of re-irradiation, are therefore highly recommended.
|
review
| 86.94 |
Our data underline the role of an intensive early treatment as well as of salvage treatments for older patients. Especially patients treated with standard-fractionated RChT as well as adjuvant chemotherapy had a median OS that was similar to younger patients. This is in-line with the conclusion from a SEER-based analysis from 2015 . Reasons for this might be the good physical status of patients within this cohort as well as the high amount of patients with methylated MGMT promotors. As the performance score but not age significantly related to the treatment decision and to the outcome, monotherapy should only be considered for patients older than >70 years and presenting with a lower performance score. This algorithm is also in line with the resent guidelines for the treatment of GBM from the American Society of Clinical Oncology (ASCO) . Notably, when reviewing earlier studies or studies from other geographic areas, the huge geographic differences of life expectancies have to be taken into account. Exemplarily, the life expectancy within the western world approximately increases every 20 years by 5 years, currently reaching an average life expectancy of 80 years, compared to an average life expectancy of 66 years in India.
|
study
| 99.7 |
Combination of RT and chemotherapy in elderly patients, independently of fractionation, has a good efficacy also in elderly patients and should be considered even in higher age but with taking the performance status into account. Therefore, treatment decision should be made based not only on age in order to prevent undertreatment in elderly patients.
|
other
| 99.94 |
If resource allocation and policy for the reduction of the burden of health problems are to be effective, the burden posed by injuries needs to be carefully evaluated. The disability-adjusted life-year (DALY), as used in the Global Burden of Disease (GBD) 1990, 2010 and 2013 studies,1,2 is based on both premature mortality – i.e. years of life lost – and years lived with disability (YLD).3,4 The assignment of disability weights, to represent the decrease in health associated with specific diseases or injuries, is a fundamental step in the estimation of YLD.3,5 Different approaches to estimating disability weights3 can lead to substantially different estimates of DALYs and YLD.6,7
|
review
| 99.3 |
In panel-based studies of health burden, a lay description –a vignette – is used to represent the health impact of the condition of interest on a hypothetical affected individual. Health professionals or representatives of the general population then give the health status of that affected individual a score, or panel-based disability weight, that ranges between zero – representing no disability or perfect health – and one – representing disability equivalent to death.3,5 The limitations of such a panel-based approach include the uncertain generalizability of the resultant weights to different geographical and socioeconomic contexts, the difficulty of developing vignettes to represent complex and varied health impacts and the limited focus on the time-course of any disability.4,5
|
review
| 51.94 |
In an alternative to the panel-based approach, self-reported data collected directly from affected individuals, using multi-attribute utility instruments – such as the EQ-5D standardized measures of health status – can be used to derive case-based disability weights.3 An individual’s responses to a standardized set of questions can be used to determine that individual’s generic health state and then the health states of all respondents having a particular health problem can be used to assign a disability weight to that problem. It has been suggested that such case-based disability weights should be used to quantify injury burdens.8–10 Two studies based on injury cohorts led to case-based weights that were larger than corresponding panel-based estimates, but both studies were limited by small sample sizes.6,7 The GBD 2013 study incorporated case-based weights for some injury groups but was hampered by the limited availability of case-reported data.11 As an adjunct or alternative to the use of panel-based weights in burden of disease studies, we used pooled patient-reported data, from six longitudinal injury-outcome studies, to create case-based weights for individual injury diagnosis codes and established nature-of-injury classifications.
|
study
| 99.94 |
Our investigation was based on the Validating and Improving Injury Burden Estimates Study (Injury-VIBES) cohort, which consists of participants’ data from six longitudinal studies in five countries (Table 1).19 The main aim of the Injury-VIBES study is to improve the measurement of non-fatal injury burden through analysis of pooled, de-identified, patient-level data. Our investigation was approved by Monash University’s Human Research Ethics Committee.
|
study
| 100.0 |
ACC: Accident Compensation Corporation; AIS, Abbreviated injury scale; DIPS: Dutch Injury Patient Survey; ICU: intensive care unit; ISS: injury severity score; NSCOT: National Study on Costs and Outcomes of Trauma; POIS: Prospective Outcomes of Injury Study; VOTOR: Victorian Orthopaedic Trauma Outcomes Registry; VSTR: Victorian State Trauma Registry; UKBOIS: United Kingdom Burden of Injury Study.
|
other
| 99.94 |
We investigated persons with injury aged at least 18 years who were included in two Australian registries – that is, the Victorian State Trauma Registry16,17 and the Victorian Orthopaedic Trauma Outcomes Registry15 –in the United Kingdom Burden of Injury Study in the United Kingdom of Great Britain and Northern Ireland,18 the Prospective Outcomes of Injury Study in New Zealand,14 the National Study on Costs and Outcomes of Trauma in the United States of America13 and the Dutch Injury Patient Survey in the Netherlands.12
|
study
| 99.94 |
When possible, weights were initially calculated for each of the four-character principal diagnosis codes listed in the 10th revision of the International statistical classification of diseases and related health problems (ICD-10)20 and then mapped to each of the 47 injury groups used in the GBD 2013 study,11 each of the 39 EUROCOST classification groups21 and each of the European Injury Data Base groupings.22 The ICD-10 codes for the cases from the USA were derived from the ICD-9 codes used in the data set. The Dutch data set only categorized injuries into the European Injury Data Base groupings. Although we could recategorize the Dutch patients into the injury groups used in the GBD 2013 study, we could not use the data from these patients to estimate weights for individual ICD-10 diagnosis codes.
|
study
| 100.0 |
In general, the patients’ responses to the questions in the three-level EQ-5D questionnaire were used to estimate disability weights. The questionnaire is designed to record a respondent’s self-reported health status in terms of five topics: (i) anxiety/depression; (ii) mobility; (iii) pain/discomfort; (iv) self-care; and (v) usual activities. For each of these topics, a respondent is asked if they have no problems, some problems or extreme problems.23 The three-level EQ-5D questionnaire was used for the Australian cases from 2009 onwards and for all the injury cases included in the participating British, Dutch and New Zealand data sets. For all the other cases we considered, the recorded responses to the questions in the 12-item Short Form Health Survey24 had to be translated into EQ-5D responses.24 EQ-5D responses are used to calculate a preference score for each respondent. Such scores can range from −0.59 to 1.00. Negative values and values of zero and one indicate, respectively, respondents who have health states that are worse than death or equivalent to death and respondents who are in perfect health.1 Disability weights were calculated at three time points – that is at three, six and 12 months post-injury – by subtracting the EQ-5D preference scores for respondents with a particular health problem from the age- and sex-specific norms.23
|
study
| 100.0 |
The average EQ-5D differences at each time point were multiplied by a factor corresponding to the length of the period over which the disability weight applied and then these weighted disability averages were summed to provide an annualized or time-averaged disability weight. Thus, the calculated averages at three, six and 12 months were multiplied by 3/12, 3/12 and 6/12, respectively, with the resulting three weighted disability averages then summed together to produce a single disability weight. The nine-month outcomes from the Dutch data set were included in the 12-month estimates. Weights calculated at 12 months post-injury – hereafter called 12-month weights – were assumed to represent both the degree of residual disability at 12 months and the expected lifelong disability.12,25
|
study
| 100.0 |
We compared our new disability weights with the one-year Integration of European Injury Statistics weights21 and the long-term weights – for treated cases when weights for treated and untreated cases were given separately – of the GBD 2013 study.11 The former represent injured cases admitted to hospital while the latter represent cases who warrant “some form of health care in a system with full access to health care”.1,21 We calculated new disability weights separately for cases admitted to hospital and for other cases who only presented at emergency departments. Disability weights and corresponding 95% confidence intervals (CI) were calculated for each category that covered at least 30 cases.
|
study
| 100.0 |
Across the six data sets and three different time points we investigated, there were 29 770 injury cases with at least one EQ-5D score – 9003, 20 929 and 24 894 responses were recorded at three, six and 12 months post-injury, respectively. The mean age of the respondents was 51 years, most of them were male and almost a third of them had had road traffic injuries. The proportion of the cases from each data set that had been admitted to hospital ranged from 25% to 100% (Table 2). To save space, we have not reported weights for European Injury Data Base groupings but these are available from the corresponding author.
|
study
| 100.0 |
DIPS: Dutch Injury Patient Survey; NSCOT: National Study on Costs and Outcomes of Trauma; POIS: Prospective Outcomes of Injury Study; SD: standard deviation; VOTOR: Victorian Orthopaedic Trauma Outcomes Registry; VSTR: Victorian State Trauma Registry; UKBOIS: United Kingdom Burden of Injury Study.
|
other
| 99.94 |
There were insufficient case numbers to calculate new disability weights for admitted cases in 14 of the 40 nature-of-injury categories used in the GBD 2013 study (Table 3). Annualized new weights for the admitted cases sustaining one of the 26 other categories were relatively high for spinal cord injury, femoral fracture, hip fracture, pelvic fracture and lower airway burns, and relatively low for radius/ulna fractures, wrist/hand fractures and superficial injuries. For 22 injury categories, the annualized and 12-month new weights were higher –1.1-fold to 22.2-fold higher – than the corresponding GBD 2013 weights (Table 3). However, the new weights for hospitalized cases of severe traumatic brain injury and spinal cord lesion at neck level were lower than the corresponding GBD 2013 weights (Table 3).
|
study
| 100.0 |
Long-term outcome data for injury cases not admitted to hospital were only available for 16 of the nature-of-injury categories used in the GBD 2013 study (Table 4). The new disability weights for such cases were much lower than the corresponding weights for the admitted cases and several were near zero – indicating that long-term disability is unlikely to occur (Table 4).
|
study
| 100.0 |
Annualized new disability weights were calculated for admitted cases sustaining injuries in 31 EUROCOST groups (Table 5). These new weights were lower than the corresponding Integration of European Injury Statistics weights for all but three groups – facial fractures, open facial wounds and spinal cord injuries (Table 5) – and higher than the corresponding new weights for cases not admitted to hospital, several of which were close to – or less than – zero (Table 6).
|
study
| 100.0 |
Within the data sets we investigated, there were at least 30 cases admitted to hospital for each of 80 ICD-10 codes (Table 7; available at: http://www.who.int/bulletin/volumes/94/10/16-172155) and at least 30 cases who only presented in an emergency department for each of 16 ICD-10 codes (Table 8; available at: http://www.who.int/bulletin/volumes/94/10/16-172155). The new weights for most intracranial injuries were similar but those for skull fracture codes and concussion were relatively low. The new disability weights for individual ICD-10 codes indicated wide variation in fracture-related disability within body regions. For example, the new weight for lateral malleolus fractures was substantially lower than the new weights for other fractures in the knee or lower leg (Table 7; available at: http://www.who.int/bulletin/volumes/94/10/16-172155).
|
study
| 99.94 |
We found differences between our new weights, which were based entirely on case-reported outcomes, and the corresponding GBD 2013 weights, which were based on a combination of panel-based and case-outcome studies. It could be argued that our new weights are not directly comparable with the GBD 2013 weights, due to distinctly different approaches to weight generation, although either set of weights could be used to derive population-based measures of injury burden. The GBD studies primarily relied on the responses of a public panel or panel of experts when faced with a standardized set of brief descriptors. Our new weights are entirely based on case-reported outcomes from cohort studies in high-income countries. The GBD studies, our study and other epidemiological studies designed to generate disability weights have generally not explicitly considered the extent to which factors such as socioeconomic status, access to high-quality care, environmental barriers or resilience, adaptation and the coping strategies of injured individuals can influence the lived experience of injury-related disability.
|
study
| 99.94 |
One argument for the preferential use of panel-based weights is the potential for individuals with chronic conditions to adapt and underestimate disease burden.26 In general, however, our new weights – like the case-based Integration of European Injury Statistics weights – were substantially higher than the largely panel-based GBD 2013 weights. This difference was especially marked for the more common categories of injury such as fractures and dislocations. In a previous study, estimates of injury burden based on data collected from the general public were generally found to be lower than those estimated from the experiences of the injured, particularly for categories of injury that are generally perceived to be less severe, such as sprains and fractures.6 However, those living with spinal cord injury reported less disability than that predicted by the general public.6 The general public’s overestimation of the burden of disability resulting from some severe injuries may reflect the limitations of the vignette to convey the variability in disability within injuries adequately. This could explain why our new weights for severe traumatic brain injury and spinal cord lesion at neck level are substantially lower than the corresponding GBD 2013 weights. A perceived benefit of the case-based approach is the capacity to evaluate variation in disability within an injury group.
|
study
| 99.94 |
An argument for favouring estimates of disease burdens based on the perceptions of the general public over those based on the responses of the diseased has been that people living with a disease may have difficulty in placing their experiences in the context of other diseases.26–28 Our new weights were based on the measurement of case-reported outcomes using validated multi-attribute utility instruments. Such instruments use population preferences to create norms for health states rather than for specific conditions. Their use helps to place the experience of people living with injury into a wide context. Our new weights reflect the deviation of actual patient function from population-based norms.
|
study
| 99.94 |
The panel-based approach requires a brief lay description of what living with a particular condition is like for a typical case. The description of a typical injury case is difficult because of the potential variation in the severity of the injury and in the injury’s impact on the injured person’s life. In the GBD 2013 study, the lay description of a spinal cord lesion below neck level, as used in the GBD 2010 study, was revised to include “and no urine and bowel control”. This revision led to a sixfold increase in the corresponding disability weight – from 0.047 to 0.296.11 In the case-based approach, the problems associated with the variable scope and specificity of lay descriptions are avoided.
|
study
| 99.94 |
The results of our analysis indicated that all categories of injury treated via hospital admission – and most categories of injury treated only in emergency departments – were associated with persistent measurable disability. They also provided evidence of long-term disability for several injury groups where specific long-term weights were not provided by the GBD 2013 study. Similarly, where the GBD 2013 study provided long-term weights only for so-called untreated cases – for example for cases of fracture of the femur, radius or ulna – the corresponding new weights were relatively high, even though the new weights were based on cases recruited directly from health-care services in high-income countries that presumably, had access to relatively well resourced treatment.
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Many EUROCOST and GBD injury groups combine several types of injury. The combination of several conditions into a single group – for which a single weight is estimated – is not problematic if the outcomes of the combined conditions are similar. Injuries of a single nature from a single body region, such as fractures within the shoulder, are often bundled together in this manner. However, our new disability weights for individual ICD-10 diagnosis codes (Table 7 and Table 8; available at: http://www.who.int/bulletin/volumes/94/10/16-172155) indicate considerable heterogeneity in disability experienced by patients with fractures in the same body region or even the same bone. For example, the new weights indicate that clavicle fractures have a much lower disability weight than fractures of the humerus or scapula and that fractures of the distal radius are less disabling than fractures of the proximal radius.
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| 99.94 |
A major strength of our analysis was the large sample size – from multiple studies and health jurisdictions – which allowed weights to be estimated, for most commonly used injury classifications, for both hospital admissions and cases who were only treated in emergency departments. However, our analysis did have several limitations. The accuracy of the coding of injury diagnoses cannot be guaranteed, especially for cases attending emergency departments – whose injuries may not have been be recorded by a trained coder. Disability weights for some categories of injury were based on relatively small numbers of cases. We therefore provided 95% confidence intervals to indicate the precision of each weight estimate. Inconsistencies and errors in documentation from the GBD 2013 study11 sometimes made it difficult to map ICD-10 codes to the relevant GBD 2013 injury group. The six data sets we employed differed in terms of follow-up rates and availability of EQ-5D data for each time point post-injury. Responder bias may have affected the British and Dutch data sets, which showed higher losses to follow-up than the other data sets. For some data sets, there was no collection of EQ-5D scores and we needed to estimate such scores from the responses to questions in the 12-item Short Form Health Survey.
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For consistency and comparability, we mapped the principal diagnosis of each case to the EUROCOST and GBD 2013 injury groups. We did not take into account additional injury diagnoses even though disability at 12 months post-injury is known to increase with the number of injuries affecting the patient.29 Future evaluation of injury weights should consider multiple injuries. Our method ignored recovery within three months and the data sets we used predominantly included cases of falls and road trauma. Penetrating injuries were underrepresented.
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| 99.94 |
Our weights were also calculated using data from adult cases only. While the GBD studies do cover all age groups, the vignettes used in these studies have not accounted for differences between children and adults and the GBD weights have simply been assumed to be applicable to all ages. It is plausible that there are differences in the recovery trajectories of children and adults, although the magnitude of these differences is not yet known. Like the GBD 2013 weights, our new weights do not explicitly consider the presence of comorbidity. However, the new weights are calculated from responses to a multi-attribute utility instrument that included age-specific population preferences – and age is a partial proxy for comorbidity.
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Our new weights were based entirely on data collected in high-income countries and it remains unclear if they could and should be applied to cases in low- and middle-income countries. Finally, we considered any disability reported 12 months post-injury as persistent. While some studies on injuries have shown little or no improvement after more than 12 months,12,25 others have shown such late improvement as well as nonlinear recovery trajectories.30,31
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| 99.94 |
In conclusion, new case-based disability weights have been estimated for individual injury-related ICD-10 diagnosis codes and commonly used injury groups. In general, these weights were higher than the corresponding largely panel-based weights that have been estimated previously. Long-term disability was evident in all categories of injuries admitted to hospital. The findings indicate that injury is often a chronic disorder and burden of disease estimates should reflect this. The impact of applying the new disability weights to DALY calculations will depend on the injury incidence profile of the population studied. A similar case-based approach could be used to determine disability weights for other conditions.
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| 99.94 |
Quantum annealing is a quantum computing paradigm with the aim to solve generic optimization problems1234, where the cost function corresponds to the energy of an infinite-range Ising spin glass5. Finding the optimal solution of the problem is thus equivalent to determining the ground state of the spin glass. In quantum annealing, this task is accomplished by adiabatic passage of a system of N spins in the instantaneous ground state of a Hamiltonian (denoted logical spin model) of the form
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| 99.7 |
Here are Pauli spin operators, and time-dependent scheduling functions and deform from a trivial initial Hamiltonian with and transverse local fields , into the spin glass Hamiltonian with , where the optimization problem is encoded in local fields and infinite–range interactions 5.
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Current quantum annealing implementations6 focus on the adiabatic preparation of classical states with thermally assisted adiabatic quantum protocols. Here, we propose a setup for coherent annealing with the aim to open an experimental route to adiabatic and non-adiabatic protocols. For example, non-adiabatic and fully coherent sweeps allow for counter-diabatic protocols7 with the potential to improve scaling laws in quantum annealing considerably, as well as the recently introduced hybrid annealing method8. While thermally assisted annealing is suitable to prepare classical ground states or mixtures, a fully coherent annealer can also be used to prepare quantum superpositions from Hamiltonians with degenerate ground states9. A coherent protocol with non-stoquastic10 driver terms opens a promising route to highly efficient protocols for optimization problems11.
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| 99.94 |
A major challenge in implementing equation (1) is posed by the required individually programmable long–range interactions , which is in contradiction to polynomially decaying interactions in cold atoms and molecule setups. Adopting the LHZ architecture12, the infinite-range spin glass is translated to a lattice spin model, where new physical spins represent the relative orientation of two logical spins of equation (1). If two logical spins are aligned in parallel, that is, or , then the corresponding physical spin is in state , while if the logical spins are aligned anti-parallel, that is, or , then the physical spin is in state . The major advantage of this approach is that the interaction energy of a pair of logical spins can now be implemented with a local field acting on a single physical spin.
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with new schedule functions At, Bt and Ct, and transverse fields ai. Physical spins are arranged on a square lattice (see blue spheres in Fig. 1), where the index i labels the entries of the matrix . The number of physical spins K equals the number of connections in the original model, which is quadratically larger than in the original problem, for example, K=N(N−1)/2 for all-to-all connected graphs. This enlarged state space contains states, where collections of physical spins encode conflicting relative orientations of the logical spins. These states can be locally identified and energetically penalized by four-body constraints H□ at each plaquette □ of the square lattice, such that at the end of the sweep plaquettes either contain all an even12, or all an odd13 number of spins in the state, thus realising an even or odd parity representation of equation (2). This ensures that the final ground state of the LHZ Hamiltonian (2) corresponds to the final ground state of the logical Hamiltonian (1), and thus to the optimal solution of the optimization problem. Importantly, the optimization problem is now encoded in local fields , corresponding to single-particle energy shifts. We show that the above model for a programmable quantum annealer can be emulated in an atomic Rydberg setup, which builds on the remarkable recent advances towards realizing complex spin models with cold atoms in lattices interacting via designed Rydberg–Rydberg interactions1415161718.
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The key challenge of implementing is resolved with Rydberg atoms by combining the odd parity representation13 of equation (2) with enhanced Rydberg–Rydberg dressing19 schemes in a two-species mixture2021. In the odd parity representation, the sum of the four spins at each plaquette is either 2 or −2. We introduce a single ancilla qubit at each plaquette, which can compensate the two associated energies and make odd parity plaquette states degenerate ground states of the constraint Hamiltonian , with stabilizer operators , and energy gap . This allows to implement the four-body gauge constraints via appropriately designed two-body Ising interactions between physical and ancilla qubits.
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| 99.9 |
where α and β are relative interaction strengths compared to spin interactions along the plaquette edge. The energy spectrum E□ of a single plaquette Hamiltonian is shown in Fig. 2(b), as a function of the parameters α and β. Importantly, there exists a parameter regime 0<2−β<α<2+β with 0<β<1, where the odd parity states are degenerate and have a lower energy than the even parity states. As the precise value of the gap in Fig. 2 is not relevant, as long as it exceeds all other energy scales, is quite robust against small variations in interaction strengths, and the parameters α, β need not be fine-tuned.
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In the Rydberg quantum annealer illustrated in Fig. 1, qubits are encoded in two long-lived hyperfine ground states , of 87Rb and , of 133Cs, representing physical and ancilla spins, respectively. These states are trapped in a deep optical or magnetic square lattice with unity filling and frozen motion2223. Consecutive loading schemes of rubidium and caesium have been successfully demonstrated21, which could be combined with the recent remarkable progress in trapping atoms in almost arbitrary 2D geometries using optical tweezers2223. Alternatively, it was suggested20 that rubidium and caesium atoms are trapped in the same optical lattice created by counter-propagating laser beams with wavelength λL≈820 nm. This particular wavelength is blue detuned for Cs atoms, which will be trapped at the intensity minima, but red detuned for Rb atoms, which will be trapped at the intensity maxima. Thus the atoms are trapped in an alternating pattern, as illustrated in Fig. 1.
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In particular, we choose the and hyperfine states of the 52S1/2 ground state manifold of 87Rb and the and hyperfine states of the 62S1/2 ground state manifold of 133Cs. The first term of equation (2) can be realized with a coherent driving field of amplitude ai coupling the and states for both physical and ancilla atoms, written in a rotating frame. The second term is obtained using single-particle AC-Stark shifts from off-resonant laser coupling of the spin state to low-lying states using a digital micro-mirror device24. The strenght of these fields can be easily varied as a function of time, thus implementing the sweep coefficients At and Bt in equation (2).
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To implement the two-body interactions of equation (3) we turn to the technique of Rydberg dressing25262728, where off-resonant laser light weakly admixes some Rydberg character into the ground state levels , leading to an effective interaction between them. For large laser detunings, the Rydberg dressing acts as a perturbation and the dressed levels predominantly retain their ground state character and remain trapped29. Interactions between two spins i and j arise, as spatially dependent light shifts and of the dressed pair states and , respectively. These pair states are coupled via two photon excitations to doubly excited Rydberg states. Because of multipole–multipole interactions, the energies of the doubly excited Rydberg states vary strongly as a function of the relative position Rij of the atoms, and can exceed typical laser detunings and coupling strengths even at micrometre distances. This strongly affects the light shifts of the dressed pair ground states, thus endowing them with an effective interaction.
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Here, we propose to couple the and states of Rb and Cs using single photon transitions to the mJ=−1/2 magnetic sublevels of Rydberg P states16173031323334, with laser light that is linearly polarized along the z axis and thus retains the symmetry of the lattice geometry. Figure 3 shows the Rydberg pair energies in the presence of multipole interactions, in the vicinity of (a) the and (b) the Rydberg states of 87Rb and (c) the mixed Rydberg states. The pair potentials are obtained from an exact diagonalization calculation (Supplementary Note 2), including interactions up to quadrupole–quadrupole and dipole–octupole couplings. In the regime of strong interactions, the Rydberg states are mixed by the multipole couplings, and each energy level corresponds to a superposition of Rydberg states with a variety of quantum numbers. The blue colouring in Fig. 3 represents the overlap with the laser targeted mJ=−1/2 states, and is therefore indicative of the effective coupling strength to the pair ground states. Although there are many energy levels in the regime of interest, we see that at distances >0.5 μm only a handful of potential curves is significantly coupled by the dressing laser, while the vast majority of states (grey curves) is only coupled with negligible strengths.
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The particular Rydberg P pair states shown in Fig. 3(a–c) feature pronounced potential wells which enable an enhanced Rydberg dressing scheme19. For this purpose, we tune the (two-photon) detuning of the dressing laser such that, in the rotating frame, the energy of the ground pair states (green line in Fig. 3(a,b) for , and yellow line in panel (c)) is close to a potential minimum. This gives rise to pronounced light shifts of the pair ground states at the point of closest approach, as shown in Fig. 3(d), while at the same time producing negligible light shifts elsewhere. The particular Rydberg states in Fig. 3(a–c) are chosen such that the dressed ground state potentials and plotted in Fig. 3(d) show peaks at distances , aL and , commensurate with a square lattice geometry with aL=0.89 μm. Accidental crossings of the doubly excited Rydberg levels with the pair ground state energy give rise to resonances in the dressed state level shifts, but these either occur at distances which are not present in the lattice geometry, or they are of negligible width on behalf of a vanishing laser coupling strength to the crossing states.
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apart from additional single-particle corrections to the local fields. The height of the two peaks of at aL and for Rb-Rb (green line in Fig. 3(d)) and of at for Rb–Cs (yellow line in Fig. 3(d)) can be tuned by varying the Rabi frequencies and detunings of the dressing laser. In particular, we choose Rabi frequencies Ω1=Ω2=2π × 35 MHz, ΩC=2π × 30 MHz and detunings Δ1=−2π × 618 MHz, Δ2=−2π × 373 MHz and ΔC=2π × 175 MHz which leads to light-shifts of for Rb–Rb and for Rb–Cs (Supplementary Note 2). We note that an external magnetic field and small vertical offset of the Cs atoms are used to obtain the final interaction strengths and precisely align the potential extrema with plaquette distances (Supplementary Note 2).
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All interactions between atoms (spins and ancillas) that are not part of a common plaquette are at least two orders of magnitude smaller than the interactions within a plaquette. This allows us to restrict the sum in equation (4) to pairs of atoms belonging to the same plaquette, thus realizing of equation (3) for the optimal parameters α=2 and β=1. For the above system parameters, we obtain a final energy gap Δ□=−2π × 20 kHz. Note that the energy gap is negative, which can be easily accounted for by a sign change of all local fields and making the annealer adiabatically follow the maximum energy state, instead of the minimum.
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| 99.94 |
Because of the finite lifetime of the Rydberg states, the dressed ground state interactions come at a cost of an effective decoherence rate 1/τ0 for each qubit. However, as there is only a small Rydberg component admixed, the effective decay rate is also only a correspondingly small fraction of the bare Rydberg decay rate. Ultimately, the figure of merit for fully coherent operation of the quantum annealer is the ratio of the attained interaction strength versus the effective decay rate. In the enhanced dressing scheme this ratio becomes particularly favourable and is of the order of for the system parameters above (Supplementary Note 2).
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| 99.94 |
Using the above potentials we demonstrate numerically the feasibility of the Rydberg annealer for the minimal instance (Fig. 1) with eight qubits and three ancillas. Figure 4 depicts the time dependent spectrum in reduced units for an instance of Hamiltonian equation (2) for random . The sweep functions At, Bt and Ct are simple linear functions. Note, that the efficiency can be considerably increased by adopting non-linear sweep functions. In Fig. 4 all energies are given relative to the ground state energy. The pronounced minimal gap is an order of magnitude smaller than the gap in the final state. Figure 4(b) shows the histogram of the success probability , defined as the overlap of the final state with the ground state , averaged over Nr=40 random instances for different sweep times far below the decoherence times τ<τ0/K. For the fastest switching time the average success probability is 75% and approaches unity for slower sweeps.
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The proposed implementation of a quantum annealer with ultracold Rydberg atoms in optical lattices provides a platform for adiabatic quantum computing, featuring a highly controllable environment to explore the many-body adiabatic passage, the role of entanglement and effects of decoherence during the annealing sweep. The large lifetimes of Rydberg dressed atoms enable coherent quantum annealing as an alternative to the current paradigm of quantum enhanced thermal annealing35. We anticipate that due to the coherent evolution the number of spins in future experiments can readily be extended well beyond the minimal example presented here, by using shorter annealing cycles with many repetitions36, or by employing counter-diabatic driving schemes that could greatly increase the attained fidelities7. Finally, our proposal allows to realize atomic quantum simulators of arbitrary infinite-range Ising spin glass models (see, for example, references in ref. 37), and the combination of multi-color Rydberg-dressed interactions with two-species mixtures has applications in realizing lattice gauge theories beyond the present example38.
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In general, female lepidopteran moths use species-specific sex pheromones to lure the conspecific males for successful mating and subsequent reproduction. Lepidopteran sex pheromones are de novo synthesized in the pheromone glands (PGs) from acetyl-CoA through fatty acid biosynthesis followed by desaturation, chain-shortening, fatty acyl reduction and carbonyl carbon modification1. The biosynthesis and release of sex pheromones in moths were first proposed to be controlled by a neuroendocrine factor2. This was late confirmed in Helicoverpa zea in which a neuropeptide, named pheromone biosynthesis activating neuropeptide (PBAN), was found to regulate the biosynthesis and release of sex pheromone3. PBAN regulates either fatty acyl reduction step or prior to fatty acid biosynthesis (likely acetyl coenzyme A carboxylase) dependent on the moth species45.
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| 99.7 |
Bombykol is the first sex pheromone discovered and identified from the PGs of the silkworm moth Bombyx mori, located between the eighth and ninth segments of the ovipositor tip of females, which produce and release bombykol, (E, Z)-10, 12-hexadecadien-1-ol, as a major component of sex pheromones upon adult emergence6. Similar to other moths, B. mori synthesizes and releases bombykol under the regulation of PBAN. The actions of PBAN in B. mori have been well investigated and a series of associated genes involved in this process have been identified and characterized in detail5. Bombykol is synthesized in PG cells from acetyl-CoA via the fatty acid biosynthesis pathway. The biosynthetic fatty acid is converted into bombykol via the action of PG-specific desaturase 1 (pgdesat1) and PG-specific fatty-acyl reductase. Knockdown of the genes encoding pgdesat1 and PG-specific fatty-acyl reductase reduces bombykol production. This finding indicates that these two genes serve important functions in bombykol biosynthesis78. Before adult emergence, PG cells rapidly produce numerous bombykol precursors, lipid droplets (LDs) in the form of triacylglycerols (TAGs) stored in cytoplasm. A diacylglycerol acyltransferase 2 gene encoding for a speed-limiting enzyme of TAG biosynthesis was previously identified in B. mori PGs. RNAi knockdown of this gene significantly decreases bombykol production, suggesting that diacylglycerol acyltransferase 2 plays an important role in storage of TAGs, bombykol precursors9. After adult emergence, PBAN stimulates the lipolysis and subsequent reduction of LD TAGs to generate final bombykol10. Our previous study confirmed the high expression of seven lipase genes in PG cells through digital gene expression profiling. RNAi knockdown of four of the seven lipase genes individually leads to reduced bombykol production, suggesting that these four lipase genes are involved in the lipolysis process of TAGs1112. A similar function of PBAN induced movement of the stored pheromone precursor fatty acids in B. mori is also found in Manduca sexta13.
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The lipolysis of TAGs was also studied in impressive detail in B. mori. PBAN activates the calcium influx upon binding to its receptor (i.e. a G-protein coupled receptor)14. Ca2+/calmodulin-dependent protein kinase II (BmCaMKII), activated by PBAN-mediated calcium influx, phosphorylates lipid storage droplet protein-1 (Lsd-1), a homologue of perilipin in mammalians. The phosphorylation of Lsd-1 facilitates and promotes the release of the lipase activator complex to activate TAG lipase for the generation of bombykol precursors10. In addition, several key proteins involved in B. mori sex pheromone biosynthesis were identified, such as fatty acid transport protein, which facilitates the uptake of extracellular long-chain fatty acids across the plasma membrane15, Acyl-CoA binding proteins (ACBPs), which protect fatty acyl-CoA esters from hydrolysis and ensure enough fatty acid precursors for bombykol biosynthesis, stromal interaction molecule I (STIMl) and store-operated channel protein (Orail: including OrailA and OrailB), which are essential components of the signal transduction cascade regulating bombykol production516. Despite previous efforts, the essential components involved in biosynthesis of bombykol precursor and activation of lipases for TAG lipolysis have yet to be identified. In the present study, quantitative proteomics, molecular biology and behavior analysis were combined to investigate the molecular mechanism regarding the synthesis of sex pheromone precursor. The results showed that glycerol-3-phosphate O-acyltransferase (GPAT) is required for TAG biosynthesis and subsequent bombykol production in B. mori, thus, providing insights into the PBAN-regulated pheromone biosynthesis in B. mori.
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In B. mori, PG is formed at 72 h before emergence (−72 h), begins to produce sex pheromone at emergence (0 h) and maintains to release sex pheromone until 72 h after emergence (72 h). Thus these 3 time points (−72 h, 0 h and 72 h) in B. mori development were chosen for proteomic analysis. iTRAQ-based quantitative proteomic analysis was performed to determine the differentially expressed proteins at the different time points of PG development in B. mori. A total of 10117 peptides matched to 1523 proteins with scores higher than 1.3 (confidence level of 95%) and FDRs lower than 0.01.
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| 100.0 |
Proteins were considered differentially expressed when they showed a 1.2-fold change at the p < 0.05 level in the different samples (0 h PG vs. −72 h PG, 72 h PG vs. 0 h PG and 72 h PG vs. −72 h PG). A total of 612 proteins were differentially expressed between the 0 h PG and −72 h PG samples (Fig. 1, Table S1), with 276 up-regulated and 336 down-regulated proteins. Further GO classification analysis of these proteins was performed. For biological processes, 24%, 19% and 10% of the differentially expressed proteins were correlated with metabolic processes, cellular processes and developmental processes respectively. For molecular function, 44% and 40% of the differentially expressed proteins were associated with binding and catalytic activity respectively. For cellular components, 43% and 27% were related to cells and organelles, respectively (Fig. 2).
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| 100.0 |
Comparative analysis of the 72 h and −72 h PG samples revealed that 863 proteins were significantly expressed with 396 up-regulated proteins and 467 down-regulated proteins (Fig. 1, and Table S1). Further GO classification analysis of these proteins was performed. For biological processes, 26%, 20% and 10% of the differentially expressed proteins were correlated with metabolic processes, cellular processes and developmental processes, respectively. For molecular functions, 46% and 41% of the differentially expressed proteins were associated with catalytic and binding activities, respectively. For cellular components, 43% and 26% of the differentially expressed proteins were related to cells and organelles, respectively (Fig. 2).
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| 100.0 |
A total of 137 proteins showed significant changes between the 72 and 0 h PG samples, with 80 up-regulated and 57 down-regulated proteins (Fig.1, and Table S1). Further GO classification analysis of these proteins was performed. For molecular functions, 43% and 39% of the differentially expressed proteins were associated with binding and catalytic activities, respectively. For cellular components, 38% and 21% of the differentially expressed proteins were related to cells and macromolecular matrix, respectively (Fig. 2).
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| 100.0 |
A series of sex pheromone biosynthesis-associated proteins were highly expressed in 0 h and 72 h PG samples, which are crucial for the biosynthesis and release of sex pheromones (Table 1). These proteins include fatty acid transport protein, acyl CoA desaturase, acyl-CoA binding protein, fatty-acyl reductase, perilipin, Orai1 alternative splice form A, calcineurin A and acyl carrier protein. These proteins indicated the biosynthesis and release of sex pheromones in PGs and further confirmed the reliability of quantitative proteomic analysis. qPCR results manifested that the expression levels of these proteins (Fig. 3A) were consistent with their transcript levels (Fig. 3B).
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| 100.0 |
Proteomic analysis identified a polypeptide sequence, VIMEEIGPR, encoded by GPAT gene (Fig. 4A). Since GPAT catalyzes the first step of TAG biosynthesis pathway by KEGG analysis, thus GPAT was chosen to be the target gene for further study. The protein expression profile based on proteomics revealed that GPAT was highly expressed in the 0 h and 72 h PG samples, compared with the expressed level of GPAT at −72 h PG samples (Fig. 4B). Further qPCR results manifested that GPAT was highly expressed in the 0 h and 72 h PG samples, compared with the expressed level of GPAT at −72 h PG samples (Fig. 4C).
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| 100.0 |
The dsRNA corresponding to two regions of GPAT (GPAT-F1 and GPAT-F2) was synthesized to elucidate the function of GPAT (Fig. 5A). When 15 μg dsRNA of GPAT was injected into female pupa 48 h before eclosion, the mRNA level of GPAT in PGs significant decreased 48 h after injection, compared with that in pupa injected with control EGFP dsRNA (Fig. 5B). GPAT-F1 dsRNA had higher interference efficiency than GPAT-F2 dsRNA.
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| 100.0 |
Bombykol precursors are stored in the form of TAGs within cytoplasmic LDs. The LDs release the bombykol precursor fatty acid in response to the external PBAN signal. The PGs were stained with Nile Red to monitor the LD dynamics after the successful suppression of GPAT transcript by RNAi. Nile Red staining revealed that PBAN treatment significantly reduced the fluorescence brightness, indicating reduced LD production. The female PGs injected with GPAT dsRNA substantially accumulated fewer LDs compared with the control females injected with EGFP dsRNA (Fig. 5C). Further TAG content analysis manifested that the female PGs injected with GPAT dsRNA synthesized fewer TAGs compared with the control females injected with EGFP dsRNA (Fig. 5D). These results suggested that GPAT significantly affected the biosynthesis of TAGs and LDs. In addition, GPAT-F1 dsRNA had stronger inhibitory effect than GPAT-F2 dsRNA. These results were in agreement with the findings of RNAi efficiency.
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| 100.0 |
After the successful reduction of GPAT mRNAs and TAG content by RNAi, the effect of GPAT dsRNA on subsequent PBAN-induced bombykol production was determined using GC/MS. RNAi significantly reduced bombykol production by approximate 50% (Fig. 5E). GPAT-F1 dsRNA had stronger suppression effect than GPAT-F2 dsRNA. This result was consistent with the results of RNAi efficiency and cytoplasmic LD dynamics.
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| 100.0 |
The effect of RNAi knockdown of GPAT mRNAs on female ability to attract males was analyzed by using Y-tube olfactometer (Fig. 6A). The results showed that the GPAT knockdown significantly reduced female's ability to attract males when tested against EGFP control (GPAT-F1:EGFP = 28:72; GPAT-F2:EGFP = 33:67) (Fig. 6B), similar results were also found in the reciprocal experiments of Y-tube left and right portions (data not shown).
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| 100.0 |
In most moths, the biosynthesis and release of sex pheromone are precisely regulated by PBAN. The PBAN signal transduction in B. mori has been elucidated in impressive detail for complete genomics information of B. mori. A series of genes responsible for sex pheromone biosynthesis and release have been well documented. Nonetheless, as a model species, the detail molecular mechanisms of B. mori sex pheromone biosynthesis are not fully elucidated. In this study, iTRAQ-based proteomics was employed to study the developmental expression profile of PGs, the targeted tissues of PBAN. The results revealed a series of differentially expressed proteins during PG development. These differentially expressed proteins, including fatty acid transport protein, acyl CoA desaturase, acyl-CoA binding protein, fatty-acyl reductase, perilipin, Orai1 alternative splice form A, calcineurin A and acyl carrier protein, were involved in the developmental regulation of sex pheromone biosynthesis and release. They served as marker proteins for the biosynthesis and release of sex pheromones, as being confirmed in B. mori. The proteomics results were consistent with the previous results, in which the transcripts of these proteins were richly expressed at key stages of sex pheromone biosynthesis57810151617.
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| 100.0 |
In B. mori PGs, LDs rapidly accumulated before adult emergence. These LDs contain various TAGs which provide the precursor fatty acids and are released for sex pheromone production in response to PBAN. The LDs fluctuate in both size and number in accordance with the fluctuation of PBAN release and bombykol amount18. These fluctuations in LD and bombykol amount could be prevented by decapitation and preceded by PBAN injection. The amount of TAGs also significantly decreased after PBAN application. These results clearly demonstrated that PBAN stimulated the lipolysis by activating lipases which hydrolyze TAGs for the release of bombykol precursor. LSD-1 was found to play an important role in TAG lipolysis associated with bombykol production in B. mori. PBAN-mediated calcium influx led to the activation of a series of components, including CaMKII, which activates LSD-1 phosophorylation. The activated LSD-1 then resulted in activation of the associated lipases. RNA Seq studies found that seven lipases were highly expressed in B. mori PGs at key stages of sex pheromone biosynthesis. RNAi-mediated knockdown confirmed that four of seven lipases are involved in TAG lipolysis11.
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| 100.0 |
Since TAGs are the bombykol precursors, they play import roles in sex pheromone biosynthesis and release. However TAG biosynthesis and storage are rarely investigated. Our previous study revealed that diacylglycerol acyltransferase 2 (DGAT) catalyses the final step in TAG biosynthesis, RNAi knockdown of DGAT causes a substantial decrease in sex pheromone production9. However TAG biosynthesis consists of two pathways, namely the monoacylglycerol (MAG) pathway and glycerol phosphate pathway (GAP). The MAG and GAP pathways share a common final step which is controlled by DGAT. The results of proteomics show an increase in GPAT protein level at key stage of sex pheromone biosynthesis. GPAT catalyses the first step in TAG biosynthesis via GAP, namely the conversion of glycerol 3-phosphate and acyl-CoA into 1-acylglycerol-3- phosphate. GPAT has the lowest enzyme specific activity in this pathway, thus it has been considered to be a speed-limiting enzyme for TAG biosynthesis via GAP19. Four GPAT isoforms have been identified in mammalian animals. GPAT1 and GPAT2 are mitochondrial isoforms, and GPAT3 and GPAT4 are ER membrane isoforms20. The present iTRAQ-based proteomics identified a GPAT homologue in B. mori (BmGPAT) (Table 1). The homologue was highly expressed in the 0 and 72 h PG samples at the translational levels (Fig. 4B), this finding was consistent with the transcript profile of BmGPAT (Fig. 4C). Sequence analysis indicated that the amino sequence encoded by BmGPAT showed 31% identity with that of human GPAT1, suggesting that the BmGPAT identified in PGs was a GPAT1 isoform (data not shown).
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study
| 100.0 |
In mammalian animals, the expression level of GPAT1 is the highest in liver and adipose tissues. GPAT activity has closely associated with the events which require de nove TAG biosynthesis. Thus the GPAT1 transcript increases by >20-fold in mouse liver once refed with a high-carbohydrate diet after starvation. By contrast, starvation for 48 h significantly reduces GPAT1 activity in rat liver and adipose tissues. This result indicates that GPAT1 is involved in TAG biosynthesis19. Mice with GPAT1 deficiency have reduced hepatic TAG, plasma TAG and VLDL–TAG secretion21. Even after feeding with high-fat diet, mice with GPAT1 deficiency have lower plasma and liver TAG and DAG contents than wild-type mice22. Correspondingly, the liver-directed overexpression of GPAT in mouse significantly increases hepatic TAG and DAG contents by 12- and 7-fold, respectively23. These results completely elucidated the function of GPAT in TAG biosynthesis. In the present study, expression analysis of BmGPAT in PGs revealed that BmGPAT was predominantly expressed during adult stages. The RNAi-mediated knockdown of the BmGPAT gene significantly reduced PG TAG contents (Fig. 5C; Fig. 5D), bombykol production (Fig. 5E) and female ability to attract males (Fig. 6B). This result suggested that BmGPAT play an import role in TAG biosynthesis, bombykol production and subsequent mating behavior in B. mori.
|
study
| 100.0 |
Our previous study identified a DGAT gene which regulates the biosynthesis of bombykol precursor, TAG9. The present study went further to demonstrate the role of GPAT, an upstream component of DGAT, in bombykol biosynthesis. Combined both findings, we conclude that bombykol precursor are synthesized and stored in the cytoplasm in the form of TAGs via the GAP pathway. Once stimulated by PBAN, the corresponding lipases promote TAG lipolysis and release the bombykol precursors for final sex pheromone biosynthesis (Fig. 7). In animals GPAT1 is regulated by sterol regulatory element-binding protein-l, insulin signal, etc. BmGPAT has been proved to be an important component for sex pheromone precursor biosynthesis. However the corresponding regulatory mechanism of BmGPAT in PGs remains elusive and requires further studies.
|
study
| 100.0 |
The PBAN of B. mori was synthesized by Sangon Biotech (Shanghai) Co., Ltd. The sex pheromone component, Bombykol, was obtained from Shogo Matsumoto (RIKEN, Advanced Science Institute, Japan) and used as the internal standard for gas chromatography/mass spectrometry (GC/MS).
|
other
| 99.9 |
PGs were dissected at −72 h, 0 h and 72 h. Each sample includes at least 300 PGs. The collected samples were completely homogenized with a STD buffer(4% SDS, 1 mM DTT, 150 mM Tris-HCl pH 8.0), heated at 100°C for 5 min and then cooled to room temperature. The supernatants were transferred to new tubes and the corresponding protein concentration was determined using the Bicinchoninic acid (BCA) assay protocol (Bio-Rad, Berkeley, CA).
|
study
| 99.94 |
Protein digestion was carried out following the protocol described by Wisniewski et al24 and the resulting peptide mixture was labeled using the 8-plex iTRAQ reagent according to the manufacturer's instructions (Applied Biosystems). Briefly, a total 200 μg protein/sample prepared in 30 μL STD buffer was diluted in 200 μL of UA buffer (800 mM urea, 150 mM Tris-HCI pH 8.0). Detergent, DTT and other low-molecular-weight components were removed using UA buffer by repeated ultrafiltration using Microcon 30 (30 kD MW cutoff). Then 100 μL of UA buffer (contain 50 mM iodoacetamide) was added to each filtrate, followed by 20 min incubation in the dark. After 10 min of centrifugation under the above conditions, the filters were washed three times with 100 μL UA buffer. Then, 100 μL of DS buffer (50 mM triethylammonium bicarbonate, pH 8.5) was added to the filters and centrifuged twice at 14000 g, each for 10 min. Finally 2 μg trypsin (Promega) in 40 μL of DS buffer was added to each filtrate and incubated overnight at 37°C. The resulting peptides were harvested by centrifugation. The peptide content was measured by UV light spectral density at 280 nm using an extinction coefficient of l.1 in 0.l% (g/L) solution which was calculated based on the frequency of tryptophan and tyrosine.
|
study
| 100.0 |
iTRAQ labelling was performed following the manufacturer's instructions (Applied Biosystems). One hundred microgram peptide for each sample was labelled with iTRAQ regent. The −72 h PG sample (100 μg) were labelled with reagents 113 and 114. The 0 h PG samples were labelled with reagents 115, 116 and 117. The 72 h PG samples were labelled with reagents 118, 119 and 121. The labeling reaction was performed at room temperature for 1 h, then pooled and dried by vacuum centrifugation.
|
study
| 78.75 |
The iTRAQ-labeled peptides were fractionated by SCX chromatography using the AKTA Purifier system (GE Healthcare). In brief, the peptide mixture was reconstituted with 2 mL buffer A (10 mM KH2P04 in 25% of acetonitrile, pH 3.0), loaded into a polysulphoethyl 4.6 mm × 100 mm column (5 μm, 200 Å, PolyLC Inc, Maryland, USA.) and then eluted at a flow rate of 1 mL/min with a gradient of 0%–10% buffer B (10 mM KH2P04 pH 3.0, 500 mM KCl and 25% acetonitrile) for 2 min, 10% to 20% buffer B for 25 min followed by 20% to 45% buffer B for 5 min and 50% to 100% buffer B for 5 min. The UV absorbance at 214 nm was monitored when the fractions were collected. The fractions were collected every minute (about 30 fractions), combined in 10 pools and then desalted on C18 Cartridges [Empore SPE Cartridges C18 (standard density), 7 mm inner diameter, 3 mL volumes, Sigma]. Each fraction was concentrated by vacuum centrifugation and reconstituted in 40 μL of 0.1% formic acid for liquid chromatography-tandem mass spectrometry (LC-MS/MS).
|
study
| 99.94 |
Three technical replicates with respect to a Q Exactive mass spectrometer coupled to Easy nLC (Proxeon Biosystems, now Thermo Fisher Scientific) were set for better coverage of the target proteome with reliable statistical consistency. A 10 μL aliquot of each fraction was injected for nanoLC-MS/MS analysis. 5 μg of the peptide mixture was loaded into a the C18-reversed phase column (Zorbax 300SB-C18 peptide traps, Agilent Technologies, Wilmington, DE, 150 mm × 75 μm) packed with RP-C18 5 μm resin equilibrated for 20 min in buffer A (0.1% formic acid in water). The separation of peptide mixtures was performed with a linear gradient of buffer B (80% acetonitrile and 0.l% formic acid) at 250 nL/min rate controlled by IntelliFlow technology over 140 min. the gradient included 4% to 28% (v/v) for 110 min, 28% to 40% (v/v) for 20 min, 40% to 90% (v/v) for 5 min and 90% (v/v) for 5 min.
|
study
| 99.94 |
MS data acquisition was performed using the 10 most abundant precursor ions from the survey scan within the 300 m/z to 1800 m/z mass range for high-energy collisional dissociation (HCD) fragmentation. The target value was determined on the basis of predictive Automatic Gain Control (pAGC). Dynamic exclusion for selected precursor ions was set at 60 s. The resolution was set as follows: 70,000 at m/z 200 for MS scan and 17,500 at m/z 200 for HCD spectra. The normalized collision energy was 30 eV and the under fill ratio was defined as 0.1%. This ratio specifies the minimum percentage of the target value likely to be reached at the maximum fill time. The instrument was operated in peptide recognition mode enabled.
|
study
| 99.9 |
The protein identification and iTRAQ quantification were carried out as previously described using a MASCOT engine (Matrix Science, London, UK; version 2.2) embedded into Proteome Discoverer 1.3 (Thermo Electron, San Jose, CA.)25. Briefly, the database search was performed against the lepidopteran (Uniprot)database. The corresponding parameters were set as follows: Peptide mass tolerance = 20 ppm, MS/MS tolerance = 0.1 Da, Enzyme = Trypsin, Missed cleavage = 2, Fixed modification: Carbamidomethyl (C), iTRAQ 8plex(K), iTRAQ8plex(N-term), Variable modification:Oxidation(M), thorough search effort and detected protein threshold(False discovery rate, FDR) < 0.01. The ProGroup algorithm in the software was used to eliminate redundancy from the grouping of identified proteins.
|
study
| 99.94 |
The metabolic pathways of the identified proteins were analyzed according to the KEGG pathway database (http://www.genome.jp/kegg/pathway.html). Gene Ontology (GO) analyses (http://www.geneontology.org) were conducted according to a previously reported method26. For the differential protein expression, GO functional enrichment and KEGG pathway analyses were performed using the Cytoscape software version 2.6.2 (http://www.cytoscape.org/).
|
study
| 99.94 |
Total RNA was extracted from the harvested PG samples (n = 40) at different time points in B. mori development using Trizol reagent (Invitrogen, Carlsbad, CA) following the manufacturer's instructions. RNA concentration was further determined by spectrophotometer. Prior to first-strand cDNA synthesis, the purified RNA was treated with DNase for excluding genomic DNA contamination. First-strand cDNA synthesized from the total RNA (1 μg) of each PG sample using the PrimeScript RT reagent kit with gDNA Eraser (TaKaRa) was used as the template for qPCR. The primers for qPCR analysis are listed in Table S2. Since the ribosomal protein 49 (rp49) gene is the most stable in B. mori and has been widely used as a reference gene27, thus rp49 was chosen as a reference gene for normalization in our experiments. The efficiencies (E) of corresponding primers used in qPCR were calculated according to the equation: E = (10[−1/slope]−1) × 10028. qPCR was carried out using SYBR Green Supermix (TaKaRa) on an Applied Biosystems 7500 Fast Real-time PCR system (ABI, Carlsbad, CA, USA) according to the manufacturer's instructions. The thermal cycle conditions for qPCR were 95°C for 4 min, followed by 40 cycles of 95°C for 15 s and 60°C for 20 s. The specificity of the SYBR green PCR signal was further confirmed using agarose gel electrophoresis and melting curve analysis. The mRNA expression was quantified using the comparative Cross Threshold method (CT, the PCR cycle number that crosses the signal threshold)29. The CT of the rp49 gene was subtracted from the CT of the target gene to obtain ΔCT. The normalized fold changes of the target gene mRNA expression were expressed as 2−ΔΔCT, where ΔΔCT is equal to ΔCT treated sample −ΔCT control.
|
study
| 100.0 |
dsRNA was synthesized using the MEGAscript RNAi kit (Ambion) according to the manufacturer's instructions. The templates for dsRNA were prepared as previously described using gene-specific primers containing T7 polymerase sites911. All the primer sets are listed in Table S2. PCR was carried out as follows at 94°C for 3 min, 35 cycles of 94°C for 1 min, 59°C for 1 min, 72°C for 1 min, and a final elongation at 72°C for 10 min. The purified PCR product was used as template for in vitro dsRNA synthesis. The template DNA and single-stranded RNA were removed by DNase and RNase treatments followed by dsRNA purification using MEGAclearTM columns (Ambion). The synthesized dsRNA was then eluted in diethyl pyrocarbonate-treated nuclease-free water and the corresponding concentrations were measured using a biophotometer (Eppendorf). The dsRNA of enhanced green fluorescent protein (EGFP) was used as the negative control.
|
study
| 99.94 |
Fifteen micrograms of GPAT dsRNA was injected into the abdominal intersegment membrane of female pupae at 48 h before adult elcosion. The female pupae were maintained for 48 h until emergence under normal conditions. The newly emerged females were decapitated, maintained for 24 h and then injected with 10 pmol PBAN. The PGs were collected 90 min after the injection and then dissolved in hexane. Control females were injected with dsRNA of EGFP.
|
study
| 99.94 |
Bombykol accumulation was measured by GC/MS (Trace GC Ultra Trace DSQ; MS-Thermo Scientific DSQ II) equipped with a 30 m capillary column (RTX-5SILMS, Restek, 0.25 mm diameter). Each sample containing a pooled hexane extract from 12 or more B. mori PGs was subjected to GC/MS analysis.
|
study
| 99.94 |
The PG samples were collected after dsRNA and PBAN treatments above mention, fixed with 4% formalin (dissolve in phosphate buffered saline), and then stained with Nile Red (Molecular probes, Eugene, OR) as previously described30. Fluorescence microscopy was performed with an Olympus BX-60 system. Nile Red images were captured and processed using Photoshop CS. Relative fluorescence brightness was determined by Quantity One soft (Bio-Rad). Corresponding results were compared using ANOVA and Tukey's test.
|
study
| 99.94 |
Fifteen micrograms of GPAT dsRNA was injected into the female pupae at 48 h before adult elcosion. The female pupae were maintained for 48 h until emergence under normal conditions. PGs were collected and rinsed in PBS. The lipid were extracted by using chloroform: methanol (v:v, 2:1) and then were used for TAG determination using a TAG assay kit (Rong Sheng Biotech Co., Ltd, Shanghai, China) following a previously described method31. Control females were injected with dsRNA of EGFP. Corresponding results were compared using ANOVA and Tukey's test.
|
study
| 100.0 |
Female ability to attract males after RNAi knockdown of GPAT was analyzed by using a Y-tube olfactometer with 5 cm internal diameter and 15 cm long arms, set at a 450 angles and 15 cm basal stem. 15 ug of dsRNA (GPAT or EGFP) was injected into the abdominal intersegment membrane of female pupae at 48 h before adult elcosion. Two treatments of newly emerged females were placed at two arms of Y-tube respectively. Newly emerged males were tested in the following olfactometer bioassays: 1) the female injected with GPAT-F1 dsRNA vs the female injected with EGFP dsRNA, 2) the female injected with GPAT-F2 dsRNA vs the female injected with EGFP dsRNA. For each of bioassays, 100 newly-emerged males were tested. The frequency of male making choice was recorded. A Yates corrected Chi-square test was used to determine differences between the frequencies of male choosing different female treatments (RNAi knockdown of GPAT or EGFP control).
|
study
| 100.0 |
Prion diseases are rare fatal neurodegenerative diseases of humans and animals which are transmissible by exposure to diseased tissues via ingestion, injection or transplantation. These diseases are often characterized by spongiform degeneration or vacuolation of gray matter, astrogliosis and microgliosis, and deposition of a partially proteinase K-resistant disease-associated form of the normal host prion protein (PrP) [5, 24]. The disease-related PrP, known as PrP scrapie (PrPSc), is generated by a seeded conversion mechanism where small aggregates of PrPSc bind normal PrP and mediate its conversion to PrPSc .
|
review
| 99.2 |
A similar prion-like seeded polymerization mechanism appears to be responsible for the formation of protein aggregates involving α-synuclein, Aβ and tau in Parkinson’s disease, Alzheimer’s disease, and tauopathies [13, 48]. These findings have increased interest in prion diseases, and there is hope that there might be a crossover in potential therapies for prion diseases and prion-like diseases.
|
review
| 99.8 |
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