Temporal metabonomic modeling of l-arginine-induced exocrine pancreatitis

The time-related metabolic responses to l-arginine (ARG)-induced exocrine pancreatic toxicity were investigated using single ip doses of 1,000 and 4,000 mg/kg body weight over a 7 day experimental period in male Sprague-Dawley rats. Sequential timed urine and plasma samples were analyzed using high resolution (1)H NMR spectroscopy together with complementary clinical chemistry and histopathology analyses. Principal components analysis (PCA) and orthogonal projection on latent structures discriminant analysis (O-PLS-DA) were utilized to analyze the (1)H NMR data and to extract and identify candidate biomarkers and to construct metabolic trajectories post ARG administration. Low doses of ARG resulted in virtually no histopathological damage and distinct reversible metabolic response trajectories. High doses of ARG caused pancreatic acinar degeneration and necrosis and characteristic metabolic trajectory profiles with several distinct phases. The initial trajectory phase (0-8 h) involved changes in the urea cycle and transamination indicating a homeostatic response to detoxify excess ammonia generated from ARG catabolism. By 48 h, there was a notable enhancement of the excretion of the gut microbial metabolites, phenylacetylglycine (PAG), 4-cresol-glucuronide and 4-cresol-sulfate, suggesting that compromised pancreatic function impacts on the activity of the gut microbiota giving potential rise to a novel class of surrogate extragenomic biomarkers of pancreatic injury. The implied compromise of microbiotal function may also contribute to secondary hepatic and pancreatic toxic responses. We show here for the first time the value of metabonomic studies in investigating metabolic disruption due to experimental pancreatitis. The variety of observed systemic responses suggests that this approach may be of general value in the assessment of other animal models or human pancreatitis.     

Virus-induced gene silencing is an effective tool for assaying gene function in the basal eudicot species Papaver somniferum (opium poppy)

Virus-induced gene silencing (VIGS) is an attractive method for assaying gene function in species that are resistant to conventional genetic approaches. However, VIGS has been shown to be effective in only a few, closely related plant species. Tobacco rattle virus (TRV), a bipartite RNA virus, has a wide host range and so in principle could serve as an efficient vector for VIGS in a diverse array of plant species. Here we show that a vector based on TRV sequences is effective at silencing the endogenous phytoene desaturase (PapsPDS) gene in Papaver somniferum (opium poppy). We show that this vector does not compromise the growth or reproduction of poppy and the plants did not display viral symptoms. The silencing of PapsPDS resulted in a significant reduction in PapsPDS mRNA and a concomitant photobleached phenotype. The ability to rapidly assay gene function in P. somniferum will be valuable in manipulation of the opiate pathway in this pharmaceutically important species. We suggest that our vacuum infiltration method used to deliver TRV-based vectors into poppy is a promising approach for expanding VIGS to diverse angiosperm species in which traditional delivery methods fail to induce VIGS. Furthermore, these studies demonstrate the utility of TRV-VIGS for probing gene function in a basal eudicot species that is phylogenetically distant from model plant species.     

Post-intervention epidemiology of STH in Bangladesh: Data to sustain the gains

In 2008, Bangladesh initiated Preventive Chemotherapy (PCT) for school-age children (SAC) through bi-annual school-based mass drug administration (MDA) to control Soil-Transmitted Helminth (STH) infections. In 2016, the Ministry of Health and Family Welfare’s Program on Lymphatic Filariasis Elimination and STH (ELFSTH) initiated district-level community impact assessments with Children Without Worms (CWW) using standardized, population-based sampling to measure the post-intervention STH burden across all ages (≥ 1 yr) for the three STH species. The Integrated Community-based Survey for Program Monitoring (ICSPM) was developed by CWW and was used to survey 12 districts in Bangladesh from 2017–2020. We excluded the first two district data as piloting caused some sampling errors and combined the individual demographic and parasite-specific characteristics from the subsequent 10 districts, linking them with the laboratory data for collective analysis. Our analysis identified district-specific epidemiologic findings, important for program decisions. Of the 17,874 enrolled individuals, our results are based on 10,824 (61.0%) stool samples. Overall, the prevalence of any STH species was substantially reduced to 14% from 79.8% in 2005. The impact was similar across all ages. STH prevalence was 14% in 10 districts collectively, but remained high in four districts, despite their high reported PCT coverage in previous years. Among all, Bhola district was unique because it was the only district with high T.trichuris prevalence. Bangladesh successfully lowered STH prevalence across all ages despite targeting SAC only. Data from the survey indicate a significant number of adults and pre-school age children (PSAC) were self-deworming with purchased pills. This may account for the flat impact curve across all ages. Overall prevalence varied across surveyed districts, with persistent high transmission in the northeastern districts and a district in the central flood zone, indicating possible service and ecological factors. Discrepancies in the impact between districts highlight the need for district-level data to evaluate program implementation after consistent high PCT coverage.     

Chronic kidney disease delays VLDL-apoB-100 particle catabolism: potential role of apolipoprotein C-III

To determine the relative contribution of obesity and/or insulin resistance (IR) in the development of dyslipidemia in chronic kidney disease (CKD), we investigated the transport of apolipoprotein (apo) B-100 in nonobese, nondiabetic, nonnephrotic CKD subjects and healthy controls (HC). We determined total VLDL, VLDL₁, VLDL₂, intermediate density lipoprotein (IDL), and LDL-apoB-100 using intravenous D3-leucine, GC-MS, and multicompartmental modeling. Plasma apoC-III and apoB-48 were immunoassayed. In this case control study, we report higher plasma triglyceride, IDL-, VLDL-, VLDL₁-, and VLDL₂-apoB-100 concentrations in CKD compared with HC (P < 0.05). This was associated with decreased fractional catabolic rates [FCRs (pools/day)] [IDL:CKD 3.4 (1.6) vs. HC 5.0 (3.2), P < 0.0001; VLDL:CKD 4.8 (5.2) vs. HC 7.8 (4.8), P = 0.038; VLDL₁:CKD 10.1 (8.5) vs. HC 29.5 (45.1), P = 0.007; VLDL₂:CKD 5.4 (4.6) vs. HC 10.4 (3.4), P = 0.001] with no difference in production rates. Plasma apoC-III and apoB-48 were significantly higher in CKD (P < 0.001) and both correlated with impaired FCRs of VLDL, VLDL₁, and VLDL₂ apoB-100 (P < 0.05). In CKD, apoC-III concentration was the only independent predictor of clearance defects in VLDL and its subfractions. Moderate CKD in the absence of central adiposity and IR is associated with mild hypertriglyceridemia due to delayed catabolism of triglyceride rich lipoproteins, IDL, and VLDL, without changes in production rate. Altered apoC-III metabolism may contribute to dyslipidemia in CKD, and this requires further investigation.     

An investigation of dominance in phytoplankton using the PROTECH model

1. Using a model (PROTECH-C) that simulates the simultaneous daily growth of eight phytoplankton species, the following hypotheses were tested: (i) for each given set of simulated conditions, the species with the most appropriate trait, as predicted by a functional group classification, should dominate the community; (ii) with removal of this dominant species, the next best-adapted species should dominate and should be from the same, or a close, functional group where available; (iii) a reduction in the inoculum size of the initially dominant species will not prevent its eventual dominance of the community.
2. For clearer insight into the mechanisms underlying these community processes, a functional group classification based upon species morphology has been used to produce a matrix analogous to Grime's CSR (C, competitor; S, stress tolerator; R, ruderal) paradigm. The effects upon this phytoplankton community of temperature, grazing, limiting light and nutrients over a simulated year were recorded.
3. The results supported all three hypotheses. It was found that, for a given selective constraint, functional traits provided excellent predictors of the dominant types. Also, under conditions of resource competition, the number of functional groups represented decreased. Competition was greatest within functional groups where niche overlap was high, but one species was always clearly the strongest competitor, i.e. its superiority over its nearest functional competitor was regularly expressed even when the difference in inoculum size was great (1000-fold). These conclusions emphasized the power that trait selection can have in the shaping of communities.     

DEVELOPMENT OF TASSEL SEED 2 INFLORESCENCES IN MAIZE

The normal pattern of maize floral development of staminate florets on the terminal inflorescence (tassel) and pistillate florets on the lateral inflorescences (ears) is disrupted by the recessive mutation tassel seed 2. Tassel seed 2 mutant plants develop pistillate florets instead of staminate florets in the tassel. In addition, the ears of tassel seed 2 plants display irregular rowing of kernels due to the development of the normally suppressed lower floret of each spikelet. The morphology of tassel and ear florets of the recessive maize mutant tassel seed 2 has been compared to those of wild-type maize through development. We have identified the earliest stages at which morphological signs of sex differentiation are evident. We find that sex determination occurs during the same stage on tassel and ear development. Early postsex determination morphology of florets in wild-type ears and in tassel seed 2 tassels and ears is identical.     

CYP78A5 encodes a cytochrome P450 that marks the shoot apical meristem boundary in Arabidopsis

The normal development of shoot structures depends on controlling the growth, proliferation and differentiation of cells derived from the shoot apical meristem. We have identified the CYP78A5 gene encoding a putative cytochrome P450 monooxygenase that is the first member of the CYP78 family from Arabidopsis. This gene is strongly expressed in the peripheral regions of the vegetative and reproductive shoot apical meristems, defining a boundary between the central meristematic zone and the developing organ primordia. In addition, CYP78A5 shows a dynamic pattern of expression during floral development. Overexpression of CYP78A5 affects multiple cell types, causing twisting and kinking of the stem and defects in floral development. To define the relationship of CYP78A5 to genes controlling meristem function, we examined CYP78A5 expression in plants mutant for SHOOT MERISTEMLESS, ZWILLE and ARGONAUTE, and have found that CYP78A5 expression is altered in these mutant backgrounds. We propose that CYP78A5 has a role in regulating directional growth in the peripheral region of the shoot apical meristem in response to cues established by genes regulating meristem function.     

Interactions Between tassel seed Genes and Other Sex Determining Genes in Maize (Article was originally published in Developmental Genetics 15:155–171.)

Erin E. Irish, Jane A. Langdale, and Timothy Nelson. Interactions Between tassel seed Genes and Other Sex Determining Genes in Maize (Article was originally published in Developmental Genetics 15:155–171.) An incorrect version of Table 2 was printed in the above article. The corrected version is shown below.     

Impact of cancer surgery slowdowns on patient survival during the COVID-19 pandemic: a microsimulation modelling study

Background:With the declaration of the global pandemic, surgical slowdowns were instituted to conserve health care resources for anticipated surges in patients with COVID-19. The long-term implications on survival of these slowdowns for patients with cancer in Canada is unknown.Methods:We constructed a microsimulation model based on real-world population data on cancer care from Ontario, Canada, from 2019 and 2020. Our model estimated wait times for cancer surgery over a 6-month period during the pandemic by simulating a slowdown in operating room capacity (60% operating room resources in month 1, 70% in month 2, 85% in months 3–6), as compared with simulated prepandemic conditions with 100% resources. We used incremental differences in simulated wait times to model survival using per-day hazard ratios for risk of death. Primary outcomes included life-years lost per patient and per cancer population. We conducted scenario analyses to evaluate alternative, hypothetical scenarios of different levels of surgical slowdowns on risk of death.Results:The simulated model population comprised 22 799 patients waiting for cancer surgery before the pandemic and 20 177 patients during the pandemic. Mean wait time to surgery prepandemic was 25 days and during the pandemic was 32 days. Excess wait time led to 0.01–0.07 life-years lost per patient across cancer sites, translating to 843 (95% credible interval 646–950) life-years lost among patients with cancer in Ontario.Interpretation:Pandemic-related slowdowns of cancer surgeries were projected to result in decreased long-term survival for many patients with cancer. Measures to preserve surgical resources and health care capacity for affected patients are critical to mitigate unintended consequences.

Declaration of the global COVID-19 pandemic led to the implementation of several clinical and policy-related measures to mitigate risk to vulnerable populations and conserve health care resources. Literature from early waves of the pandemic characterized patients with cancer as a vulnerable population.^1,2 Moreover, cancer surgery can be highly resource intensive, which could strain the health care system’s ability to respond to the pandemic. Accordingly, in March 2020, the Ontario government recommended reducing the number of cancer surgeries, along with other elective surgeries performed in the province. These measures were aimed at reducing both patient morbidity and use of health care resources, primarily by decreasing routine postoperative admissions to wards and intensive care units, in anticipation of a potential surge of patients with COVID-19.³Although necessary, this initial strategy resulted in a backlog of cancer surgeries, and some patients faced longer wait times to surgical treatment.⁴ Given clear evidence showing that longer surgical wait times can increase cancer-related risk of death, there is concern for the unintended consequences of the surgical slowdowns during the COVID-19 pandemic.^5–8 International data have projected the negative impact on long-term survival associated with potential delays to cancer diagnosis or surgery across various cancer types.^9–11 Recognizing the global differences in level of infection, response to the COVID-19 pandemic and cancer survival rates, country-specific data are required to understand local consequences and better guide future responses to times of resource constraint. As such, the objective of the current study was to evaluate the long-term implications of pandemic–related cancer surgery slowdowns on cancer survival in Ontario, Canada.