Tag Archives: diprenorphine

The maturation of human erythroblasts from adult

The maturation of human erythroblasts from adult CD34+ hematopoietic stem/progenitor diprenorphine (HSPCs) can be assessed by serially tracing the expression of erythroid lineage markers. These markers for adult-type erythroblasts\’ developmental process are widely used to recognize hPSC-derived erythroblasts, along with analysis of their functional properties. However, there is no detailed information about how erythroid cells originate from hPSC-derived progenitors and which phenotypes they share during the early developmental stages, hindering the elucidation of step-by-step mechanisms that control human early erythropoiesis from hPSCs.
Phenotypically, adult-type hematopoietic stem cell (HSC)-derived erythroblasts mature by losing CD34 and then gaining glycophorin A (GPA; also known as CD235a) on their surface. CD36 co-expresses with GPA when cells are committed to erythroid lineage. Expression of CD36 is then gradually downregulated during the terminal maturation stage on enucleated red blood cells (RBCs) (Okumura et al., 1992; Neildez-Nguyen et al., 2002; Fajtova et al., 2013; Li et al., 2014). However, in this study we demonstrated that the expression process of CD34, GPA, and CD36 on hPSC/AGM-S3 co-culture-derived early erythroblasts was distinct. These hPSC-derived early erythroblasts were generated from endothelium precursors, underwent maturation by losing mesodermal and endothelial properties, and gradually gained definitive erythropoietic potential. Our results suggest that a unique pathway for early definitive erythropoiesis from hPSCs is phenotypically different from that of adult HSPC-derived definitive erythropoiesis.

Results

Discussion
Human early erythropoiesis has been primarily studied using adult models with definitive hematopoiesis. Through subtle investigations, several laboratories reported that the regulatory pathway of definitive erythropoiesis development from adult HSPCs can be serially tracked by the expression of erythroid lineage surface markers, particularly CD34, GPA, CD71, and CD36 (Freyssinier et al., 1999; Gregory and Eaves, 1978). However, this may not be applicable to definitive erythropoiesis of hPSCs (Giarratana et al., 2011; Lu et al., 2008). In the present study, we investigated hPSC-derived early definitive erythroblasts during their development defined by expression of GPA, CD34, and CD36 (Figure 7). A unique cell population of GPA+CD34lowCD36− is firstly generated by day 5 of H1/AGM-S3 co-culture. Then, by losing CD34 expression, they developed and matured sequentially to G+34−36−, G+34−36low/+ and then G+34−36− erythroblasts with a gradual upregulation of β-globin. It is reported that before CD34+cells occur, GPA is firstly expressed on KDR+CD34−CD144− (abbreviated as G+K+34−144−) mesodermal cells (Sturgeon et al., 2014; Vodyanik et al., 2006), which could generate exclusively primitive hematopoiesis. However, the GPA+CD34low36− cells generated in H1/AGM-S3 co-culture are different from those early mesodermal cells. Since CD34 is known as an important marker of endothelial/hematopoietic cells, according to our data GPA+CD34low36− cells in day-7 co-culture are endowed with endothelial features while a small portion of them have already shared definitive erythroid potential. More than one-quarter of them express CD71 and even 1.7% ± 0.2% have already expressed adult-type β-globin. Consequently, the GPA+CD34low36− (G+34low36−) cells in day-10 co-culture showed an enhanced generation of erythroblasts (hemoglobin-positive cells >60%). When purified by cell sorting, these day-10 co-culture-derived GPA+CD34low cells can further proliferate and generate definitive erythroblasts with very high levels of β-globin (>95%), proving their definitive erythroid potential.
Accumulated data in our laboratory suggest that, by co-culture with AGM-S3, the hPSC-derived early erythroblasts may originate from definitive endothelium precursors that differ from adult-type HSC-derived erythroblasts. Human adult-type HSPCs enriched in hCB or peripheral blood (hPB) are phenotypically CD34+CD45+, while committed erythroid cells expressing GPA appear only after CD34 disappears. There is no co-expression of GPA and CD34 stage throughout the developmental process of adult-type HSC-derived erythroblasts. Clearly, the G+34low36− early precursors derived from our H1/AGM-S3 co-culture are CD45 negative, showing their lack of HSPC or myeloid source.

Meanwhile to our knowledge this is the

Meanwhile, to our knowledge, this is the first report of B-cell function gene diprenorphine profile in a large cohort of Chinese DLBCL patients treated with R-CHOP. Presenting with similar incidence as Western population, B-cell function gene mutations were closely related to DLBCL progression, particularly those involved in TLRs and TNFR pathways, resulting in aberrant activation of NF-κB cascade and resistance to immunochemotherapy in DLBCL (Davis et al., 2010). Clinical trials simply targeting NF-κB have been attempted recent years in patients but most of the results were disappointing (Offner et al., 2015; Leonard et al., 2016). Here we provided evidence that, among mutations involving NF-κB activation, the BCRs pathway, rather than the TLRs and TNFR pathway, was inhibited by rituximab, in consistence with previous basic study (Kheirallah et al., 2010). Thus, the presence of BCR/NF-κB mutations may be more precise in guiding the response to rituximab and referred as a major consideration on rituximab consolidation. As for the TLRs and TNFR related gene mutations, they reflected poor therapeutic response and represented actionable targets for new therapeutic approaches like the BTK inhibitor ibrutinib (Wilson et al., 2015) and IRAK1/4 inhibitor for MYD88 (Li et al., 2015), as well as proteasome inhibitors bortezomib and carfilzomib for TNFAIP3 (Shembade et al., 2010).

Funding
This study was supported, in part, by research funding from the National Natural Science Foundation of China (81325003, 81520108003, 81670716 and 81201863), the Shanghai Commission of Science and Technology (14430723400, 14140903100 and 16JC1405800), Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206 and 20152208), Multi-center clinical research project by Shanghai Jiao Tong University School of Medicine (DLY201601), SMC-Chen Xing Scholars Program, Chang Jiang Scholars Program, Collaborative Innovation Center of Systems Biomedicine and the Samuel Waxman Cancer Research Foundation.

Authorship

Disclosures

Introduction
Esophageal cancer is the fourth most common cancer in China, with a total of 477,900 new cases and 375,000 deaths projected to occur in 2015, and it is more common in males than in females (Chen et al., 2016). The two major histological types of esophageal cancer, viz. esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), which are distinct entities affected by diverse risk profiles, are now experiencing a global epidemiologic shift in recent decades (Brown and Devesa, 2002; Alexandre et al., 2014; Rustgi and El-Serag, 2014). Remarkably, compared with the most prevalent EAC in the U.S. and many Western countries, ESCC is the dominant histological type in China, and accounts for over 90% of esophageal cancer cases (Torre et al., 2015; Arnold et al., 2015). Despite recent substantial advances in clinical diagnostic and therapeutic tools (Sawayama et al., 2014; Messager et al., 2017), esophageal cancer exhibits an extremely poor prognosis with the 5-year survival rate of around 20% in China, mainly because it grows aggressively and is often diagnosed at an advanced stage (Zeng et al., 2015; Tseng et al., 2015; Klein and Stoecklein, 2009). One of the practical choices to improve overall survival is the identification of easy-to-obtain markers with prognostic significance for esophageal cancer by formulating more targeted and effective management strategies for high risk patients, such as metabolic profiling markers (Yakoub et al., 2010).
Large population-based studies have revealed that some metabolic factors such as obesity and diabetes are significant risk predictors for esophageal cancer, whereas the associated risk directions were not uniformly reported (Rustgi and El-Serag, 2014; Lindkvist et al., 2014; Lin et al., 2015; Alexandre et al., 2014). As for metabolic syndrome, several prospective studies have failed to identify its significant prediction for ESCC risk (Lin et al., 2015; Lindkvist et al., 2014). However, the prognostic prediction of metabolic risk factors has been reported only sparingly for esophageal cancer, except for a retrospective report by Wen et al. on the prognosis of preoperative metabolic syndrome among 596 patients with esophageal cancer (Wen et al., 2016). To our great surprise, they observed that the concomitance of metabolic syndrome before surgery was associated with better overall survival and tumor differentiation (Wen et al., 2016). This observation is somewhat counterintuitive based on what is known about the established relationship between metabolic syndrome and cancer risk (Esposito et al., 2012). Hence, a large prospective study is urgently needed to update our knowledge about the impact of metabolic syndrome on esophageal cancer prognosis. As an initial step toward meeting this need, we elicited a subset of data on esophageal cancer from the Fujian prospective investigation of cancer (FIESTA) study, and assessed the preoperative prediction of metabolic syndrome and its single components for esophageal cancer mortality.

Although many studies addressed students and green

Although many studies addressed students and green space, few considered the school context. High school students spend at least 8000h during their adolescence in schools (Rutter et al., 1979). Therefore, the education diprenorphine could benefit from more studies of perceived restorativeness of school greenness and the relationship between high school greenness and students’ stress, mental and physical health, and quality of life (Matsuoka, 2010; Chawla et al., 2014). In addition, although the ART is well examined with adults, the application of ART to young people\’s environments remains understudied (Bagot et al., 2015). Hence, we know very little about how the presence of high school greenness is associated with students’ perceived restoration. Students are an extremely important population, at a time in their improvement when their academic performance will set them on a life-course. In this respect, the main purpose of this study was to determine the association between perceived restorativeness of high school greenness and students’ perceived restoration. The secondary aim of this study was to explore the relationship between high school greenness and students’ stress, mental and physical health, and quality of life. Based on the ART (Kaplan and Kaplan, 1989), the Psycho-evolutionary Theory (Ulrich, 1983), and previous studies (Bagot, 2004; Corraliza et al., 2012; Kelz et al., 2015; Bagot et al., 2015), the following hypotheses are proposed:

Methods

Results

Discussion
This study examined the associations between the perceived restorativeness of high school greenness and students’ perceived restoration and health. Findings show that the perceived restorativeness (being away, fascination, coherence, and compatibility) is predicted by the green space present in the high school campus (H1 is accepted), which is consistent with prior research with children (Bagot, 2004; Corraliza et al., 2012; Bagot et al., 2015). On the other hand, students’ level of stress, mental health, physical health, and quality of life were not correlated with naturalness of school greenness (H2 is rejected), which is unexpected when considering the previous studies with children (Wells and Evans, 2003; Chawla et al., 2014; Kelz et al., 2015).
In terms of covariates, stratified analyses show that boys’ perceived restoration was positively associated with perceived restorativeness (i.e. being away, fascination, and compatibility) of school greenness. Boys also reported better levels of stress, than girls, which is consistent with previous studies of Bagot (2004) and Bagot et al. (2015), but different than the other prior studies of Faber Taylor et al. (2002). In addition, younger students reported better physical health and quality of life than older students, which is parallel with prior studies (Bagot, 2004; Collado and Corraliza, 2012; Bagot et al., 2015), while older students reported stronger perceived being away, fascination, and compatibility than younger students, which is not parallel with previous studies (Bagot, 2004; Collado and Corraliza, 2012; Bagot et al., 2015). Regarding the boarder students, results reveal that being away, fascination, and compatibility of school greenness are negatively perceived by boarder students, whereas commuter students perceive more being away, fascination, and compatibility from school greenness. In terms of health, findings showed there is no differences between boarder and commuter students. Some of the results are expected and parallel with the previous studies, whereas some are unexpected and different. Several points that explain the differences between this study and the previous studies are highlighted.
First of all, although previous studies of children indicated that view of and access to green space is associated with health (i.e. physical and psychological) benefits (Grahn, 1996; Wells and Evans, 2003; Chawla et al., 2014; Kelz et al., 2015), some philosophical approaches have argued the need for engagement with beauty of green space (Wei Zhang et al., 2014). Studies showed that perceiving the beauty of green space is associated with well-being (DeNeve and Cooper, 1998; Zhang and Howell, 2011), and those who perceive the beauty of green space well, reported better life satisfaction and gratitude (Diessner et al., 2008). In addition, Collado and Corraliza (2012) points out that the potential restoration of the school playground depends on the amount of nature perceived in the school playground. Therefore, one of the reasons why high school students’ health was not associated with school greenness may be due to students’ preferences and perceptions as seen in Table 4 that only one of students’ perceived restorations (i.e. coherence) correlated with health indicators. It seems students did not perceive the school greenness positively for their health. That is why students’ health indicators may not have correlated with high school greenness. Additionally, Matsuoka (2010) indicated that not all types of green space are associated with benefits for students. It seems students’ perception and preferences for certain type and quality of green space in school could be related to the likelihood that glycoproteins provides health benefits for students. In future studies, it is worth investigating what features and characteristics of green space are correlated with student health most.

br Discussion We detected Baylisascaris ova

Discussion
We detected Baylisascaris ova in the diprenorphine of domestic dogs across a wide geographic range within the US. The prevalence was low, but confirms that dogs are shedding Baylisascaris ova into the domestic environment, which may put people or other animals at risk of exposure. These results highlight the importance of testing, treatment, and preventive use. The Companion Animal Parasite Council (CAPC) recommends testing dogs for intestinal parasites at least four times during their first year and then at least two times per year afterwards (www.capcvet.org). Puppies should be given anthelmintics, many of which are efficacious for treating intestinal Baylisascaris infections, and treatment should be repeated until regular broad-spectrum parasite control begins, and adult dogs should receive year-round broad-spectrum parasite control (www.capcvet.org) (Bauer and Gey, 1995; Bowman et al., 2005). Many anthelmintics are proven efficacious against intestinal B. procyonis in raccoons, including fenbendazole, pyrantel pamoate, ivermectin, and moxidectin; milbemycin oxime has also been proven efficacious in naturally- and experimentally-infected dogs (Bowman et al., 2005; Kazacos, 2016).
The data used in this study were obtained from veterinary reference laboratories so the reason of testing is unknown (routine exam or due to illness). These data are biased towards dogs taken to veterinarians for care and the prevalence of Baylisascaris spp. ova is thus expected to be higher in dogs that do not get veterinary care regularly. A more accurate prevalence would be obtained by testing unowned/feral dogs, shelter dogs, or dogs owned by individuals who do not seek routine or any veterinary care. For example, the prevalence of Toxocara canis in shelter dogs in the US was significantly higher than prevalence in owned dogs tested at Banfield veterinary hospitals or by IDEXX reference laboratories (Blagburn et al., 1996; Lucio-Forster et al., 2016; Mohamed et al., 2009). Our prevalence was much lower than the only previous systematic survey of dogs for B. procyonis where 2 of 555 (0.36%) dogs were positive, but it is unknown if the difference was related to sampling strategy or if transmission is very common on Prince Edward Island, Canada (Conboy et al., 2010). Additionally, Baylisascaris spp. and Toxocara spp. eggs are morphologically similar, so it is possible that some infections were misidentified. Although it is impossible to determine how often this occurred, we believe that it is more likely for individuals to miss Baylisascaris infections due to perceptions that it is rare or absent in dogs. However, personnel at IDEXX Laboratories, Inc. reference laboratories have comprehensive technician training, thus test results may be more accurate compared to fecal exams conducted in veterinary offices where technician training may not be as standardized.
Positive dogs were detected in 35 states and Washington D.C. and prevalence was greater in the Northeast and Midwest compared to the South, Central, or Western regions. This corresponds with regions where the prevalence of B. procyonis is highest in raccoons (Sapp et al., 2016). Among these 35 states, 9 represent new state records for Baylisascaris (Alaska, Connecticut, Delaware, Maine, Montana, North Dakota, New Hampshire, Rhode Island, South Carolina); however, it is possible that some of these cases were acquired during travel to endemic states. Also, most of these positive dogs are presumed to be passing B. procyonis ova, but some dogs could be passing other species of Baylisascaris such as B. columnaris, a common parasite of skunks, or B. transfuga, a parasite of bears (especially the single positive dog in Alaska as raccoons are absent in Fairbanks).
A limitation of testing a single fecal sample is that actual infection status is unknown (i.e. true infection with adult parasites versus spurious “infections” of eggs passing through the digestive tract after coprophagy). A low percentage (15%) of the Baylisascaris-positive dogs also were passing Eimeria spp. ooycsts and/or Moniezia spp. ova and because these are not parasites of dogs, these positives could have been due to coprophagy (Nijsse et al., 2014). It is also possible that other genera of parasites detected were also acquired due to coprophagy. However, even if these spurious parasites are detected, this does not rule out patent infection with Baylisascaris spp. Testing a fecal sample acquired after a dog has been prevented from coprophagy activity can confirm if the dog is infected with Baylisascaris; however, our study design precluded subsequent sampling. Also, the development status of the eggs may also assist if coprophagy is suspected; if larvated eggs are detected on fecal exam of fresh feces, this would indicate coprophagy as Baylisascaris spp. eggs require at least 10–14days in the environment to develop. A client could be asked if a dog had an opportunity to engage in coprophagy in the past 2–3days; however, even owners who indicate there was no opportunity had dogs passing spurious parasites (Nijsse et al., 2014). Regardless, our data indicate that Baylisascaris spp. ova are being passed in the feces of these owned dogs which means they represent a public health risk even if they are obtaining the parasites by ingesting raccoon feces. In addition, ingesting raccoon feces is a transmission route for a dog to obtain an intestinal infection. This may be of importance to puppies, because experimental infections with various Baylisascaris spp. species suggest that young definitive hosts are much more susceptible to infections by the egg ingestion route (versus older animals, which are more likely to become infected by ingesting larvae in paratenic host tissues) (Kazacos, 2016).

br Our study demonstrated that the

Our study demonstrated that the average excursions of the bilateral diprenorphine during tidal breathing (right: 11.0 mm, 95% CI 10.4 to 11.6 mm; left: 14.9 mm, 95% CI 14.2 to 15.5 mm) were numerically less than those during forced breathing in previous studies using other modalities 2; 7 ;  8. Using fluoroscopy, Alexander reported that the average right excursion was 27.5 mm and the average left excursion was 31.5 mm during forced breathing in the standing position in 127 patients (2). Using ultrasound, Harris et al. reported that the average right diaphragm excursion was 48 mm during forced breathing in the supine position in 53 healthy adults (7). Using MR fluoroscopy, Gierada et al. reported that the average right excursion was 44 mm and the average left excursion was 42 mm during forced breathing in the supine position in 10 healthy volunteers (8). The difference in diaphragmatic excursion during tidal breathing versus forced breathing is unsurprising.

Our study showed that the excursion and peak motion speed of the left diaphragm are significantly greater and faster than those of the right. With regard to the excursion, the results of our study are consistent with those of previous reports using fluoroscopy in a standing position 2 ;  3. However, in the previous studies evaluating diaphragmatic motion in the supine position, the asymmetric diaphragmatic motion was not mentioned 7 ;  8. The asymmetric excursion of the bilateral diaphragm may be more apparent in the standing position, but may not be detectable or may disappear in the supine position. Although we cannot explain the reason for the asymmetry in diaphragmatic motion, we speculate that the presence of the liver may limit the excursion of the right diaphragm. Regarding the motion speed, to the best of our knowledge this study is the first to evaluate it. The faster motion speed of the left diaphragm compared to that of the right diaphragm would be related to the greater excursion of the left diaphragm.

We found that higher BMI and higher tidal volume were independently associated with the increased excursions of the bilateral diaphragm by both univariate and multivariate analyses, although the strength of these associations was weak. We cannot explain the exact reason for the correlation between BMI and the excursion of the diaphragm. However, a previous study showed that BMI is associated with peak oxygen consumption (23), and the increased oxygen consumption in an obese participant may affect diaphragmatic movement. Another possible reason is that lower thoracic compliance due to higher BMI may cause increased movement of the diaphragm for compensation. Regarding the correlation between tidal volume and excursion of the diaphragm, given that diaphragmatic muscle serves as the most important respiratory muscle, the result is to be expected. Considering our results, the excursion evaluated by dynamic X-ray phrenicography could potentially predict tidal volume.

Our study has several limitations. First, we included only 172 volunteers, and additional studies on larger participant populations are required to confirm these preliminary findings. Second, we evaluated only the motion of the highest point of the diaphragms for the sake of simplicity, and three-dimensional motion of the diaphragm could not be completely reflected in our results. However, we believe that this simple method would be practical and more easily applicable in a clinical setting.

Conclusions

The time-resolved quantitative analysis of the diaphragms with dynamic X-ray phrenicography is feasible. The average excursions of the diaphragms are 11.0 mm (right) and 14.9 mm (left) during tidal breathing in a standing position in our health screening center cohort. The diaphragmatic motion of the left is significantly larger and faster than that of the right. Higher tidal volume and BMI are associated with increased excursions of the bilateral diaphragm.

diprenorphine The reason for this discrepancy

The reason for this discrepancy is not obvious. One possible reason is that snow depth has been grossly overestimated. This seems unlikely; snow depths in midwinter in the Sierra Nevada are normally many meters and there are no data to indicate that these sites experience anomalously low snow cover of the magnitude required to explain the discrepancy. The sites needing correction for snow shielding are in valley bottoms where windblown snow tends to collect, rather than on wind-deflated ridge tops. Another possible reason is that calculations for topographic shielding have significantly underestimated the shielding correction for the sloping surfaces (i.e., that the shielding coefficients should be smaller). However, for the samples without snow-cover issues, the topographic shielding correction greatly reduces the coefficient of variation of the sample concentrations and this seems quite unlikely if it diprenorphine is seriously in error. Furthermore, the topographic shielding calculation has a strong physical basis (Nishiizumi et al., 1989 ; Gosse and Phillips, 2001). The discrepancy may point to a smaller effect from snow shielding than is calculated from the standard mass shielding calculation, such as that given in Gosse and Phillips (2001). However, the recent numerical simulations by Zweck et al. (2013) and the cosmic-ray flux data under snow by Delunel et al. (2014), both discussed in Section 5, point in the opposite direction: shielding by snow is about 40% more effective than by silicate rock (i.e., an effective attenuation coefficient of 109 g cm?2, or more, for snow compared to 153 g cm?2 for quartz). In summary, we have no ready explanation and this puzzling discrepancy points to a need for further investigation of snow-cover effects.
The 36Cl samples associated with the Tioga 4 advance show small site-to-site biases (+2 to ?4 percent, compared to average individual sample age uncertainties of 7–13 percent). These could easily be explained by small errors in the estimation of the snow-cover correction that vary systematically from site to site.
The 36Cl samples from the Recess Peak advance, in contrast, show site age biases of ?10 and ?15 percent that are significantly larger than the average age uncertainties of 9 percent. Whether this can plausibly be attributed to error in the snow correction is equivocal. Four of the seven total Recess Peak samples were assigned small snow shielding values (0.96–0.99) because they were from tall boulders that were in positions where snow was thought to be rapidly blown off their tops. This may have resulted in underestimation of the snow-shielding coefficient. (Note in this regard that only three boulders were sampled at the Baboon Lakes site; the large number of 36Cl analyses reported were performed on different mineralogical fractions of these three boulders.) One piece of evidence possibly favoring this hypothesis is that if the oldest age from each of the three sample groups (upper Bishop Creek 36Cl, Baboon Lakes 10Be, Baboon Lakes 36Cl) is averaged, the mean is 13.5 ± 0.2 ka, in very good agreement with the independent age of 13.3 ± 0.25 ka. However, arguing against this hypothesis, the “old” 10Be and 36Cl ages at the Baboon Lakes come from different boulders, and the old age is not replicated on the other mineralogical fractions.
Another argument against snow as the entire explanation for the underestimation of the Recess Peak ages is that the magnitude of the postulated snow cover seems to be too large to be reasonable. Snow normally persists from January through June (California Department of Water Resources (2012)). Averaging the significant snow cover over six months and assuming a standard production attenuation coefficient of 150 g cm?2 and an annual average reduction of the production rate by 14.9% would require approximately 50 g cm?2 snow cover during the six snow months, or about 2 m of snow. This is about double the average monthly snow accumulation on flat surfaces in this area during this part of the year (California Department of Water Resources (2012)). Given that the boulders are in general 1–2 m tall and are from areas exposed to removal of snow cover by wind, this degree of snow cover does not seem feasible. Even assuming the boulders carried as much snow as flat surfaces, a reduction of age by only about 7% would be justified under the traditional approach.
However, the results of Delunel et al. (2014) render this inference less certain. Application of their snow-shielding algorithm implies that an average winter snow depth of 10 g cm?2, equivalent to about 40 cm depth of snow, would reduce the annual production rate by about 15%. This much winter snow cover cannot be ruled out.
In summary, errors in, or inadequate models for, snow-cover estimation clearly played a role in the spread of the legacy 10Be data, and are a plausible explanation for the site-to-site biases of the Tioga 4 36Cl ages distributions. Whether snow-cover effects explain the mean age discrepancy of the Recess Peak ages is equivocal. Application of the Delunel et al. (2014) results indicates that a reduction of the average annual production rate by ~15% may be consistent with realistic snow accumulations. Under the traditional approach, the snow depths are inadequate to explain the production-rate reduction. Furthermore, even assuming that the Delunel et al. (2014) results are applicable, this still leaves open the question of why the traditional approach apparently successfully corrected the Tioga 4 samples, which are from very similar boulders as the Recess Peak one, but did not do so for the Recess Peak samples. This suggests that snow cover is not the entire explanation for the systematic underestimation of the Recess Peak ages.