CD80 on skin stem cells promotes local expansion of regulatory T cells upon injury to orchestrate repair within an inflammatory environment.

Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune-modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored.

Ras drives malignancy through stem cell crosstalk with the microenvironment.

Squamous cell carcinomas are triggered by marked elevation of RAS-MAPK signalling and progression from benign papilloma to invasive malignancy1-4. At tumour-stromal interfaces, a subset of tumour-initiating progenitors, the cancer stem cells, obtain increased resistance to chemotherapy and immunotherapy along this pathway5,6. The distribution and changes in cancer stem cells during progression from a benign state to invasive squamous cell carcinoma remain unclear. Here we show in mice that, after oncogenic RAS activation, cancer stem cells rewire their gene expression program and trigger self-propelling, aberrant signalling crosstalk with their tissue microenvironment that drives their malignant progression. The non-genetic, dynamic cascade of intercellular exchanges involves downstream pathways that are often mutated in advanced metastatic squamous cell carcinomas with high mutational burden7. Coupling our clonal skin HRASG12V mouse model with single-cell transcriptomics, chromatin landscaping, lentiviral reporters and lineage tracing, we show that aberrant crosstalk between cancer stem cells and their microenvironment triggers angiogenesis and TGFß signalling, creating conditions that are conducive for hijacking leptin and leptin receptor signalling, which in turn launches downstream phosphoinositide 3-kinase (PI3K)-AKT-mTOR signalling during the benign-to-malignant transition. By functionally examining each step in this pathway, we reveal how dynamic temporal crosstalk with the microenvironment orchestrated by the stem cells profoundly fuels this path to malignancy. These insights suggest broad implications for cancer therapeutics.

BMP signaling: at the gate between activated melanocyte stem cells and differentiation.

Through recurrent bouts synchronous with the hair cycle, quiescent melanocyte stem cells (McSCs) become activated to generate proliferative progeny that differentiate into pigment-producing melanocytes. The signaling factors orchestrating these events remain incompletely understood. Here, we use single-cell RNA sequencing with comparative gene expression analysis to elucidate the transcriptional dynamics of McSCs through quiescence, activation, and melanocyte maturation. Unearthing converging signs of increased WNT and BMP signaling along this progression, we endeavored to understand how these pathways are integrated. Employing conditional lineage-specific genetic ablation studies in mice, we found that loss of BMP signaling in the lineage leads to hair graying due to a block in melanocyte maturation. We show that interestingly, BMP signaling functions downstream from activated McSCs and maintains WNT effector, transcription factor LEF1. Employing pseudotime analysis, genetics, and chromatin landscaping, we show that following WNT-mediated activation of McSCs, BMP and WNT pathways collaborate to trigger the commitment of proliferative progeny by fueling LEF1- and MITF-dependent differentiation. Our findings shed light upon the signaling interplay and timing of cues that orchestrate melanocyte lineage progression in the hair follicle and underscore a key role for BMP signaling in driving complete differentiation.

Lymphatic Mapping and Sentinel Node Biopsy in High-Grade Uterine Cancers.

PURPOSE OF REVIEW: Sentinel lymph node (SLN) mapping has been adopted as an acceptable method of lymph node evaluation in the surgical staging for low-grade endometrial cancer. In this review, we analyze the literature on the utility of SLN mapping in high-grade endometrial cancer. RECENT FINDINGS: SLN mapping in high-grade endometrial cancer demonstrates similar high detection rates and diagnostic accuracy as seen in low-grade endometrial cancers. However, obtaining sufficient operator experience (at least 30 cases) and following SLN mapping algorithm continues to be essential to preserving diagnostic accuracy. Although limited in retrospective study design and short-term follow-up, current studies have not demonstrated inferior survival outcomes of SLN mapping compared to traditional lymphadenectomy. SLN mapping is an acceptable and accurate method of lymph node evaluation in high-grade endometrial cancer. Future prospective studies are needed to evaluate long-term oncologic outcomes between SLN mapping and systematic lymphadenectomy in this patient population.

Sentinel lymph node biopsy in high-grade endometrial cancer: a systematic review and meta-analysis of performance characteristics.

OBJECTIVE: A sentinel lymph node biopsy is widely accepted as the standard of care for surgical staging in low-grade endometrial cancer, but its value in high-grade endometrial cancer remains controversial. The aim of this systematic review and meta-analysis was to evaluate the performance characteristics of sentinel lymph node biopsy in patients with endometrial cancer with high-grade histology (registered in the International Prospective Register of Systematic Reviews with identifying number CRD42020160280). DATA SOURCES: We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Embase databases all through the OvidSP platform. The search was performed between January 1, 2000, and January 26, 2021. ClinicalTrials.gov was searched to identify ongoing registered clinical trials. STUDY ELIGIBILITY CRITERIA: We included prospective cohort studies in which sentinel lymph node biopsy were evaluated in clinical stage I patients with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, undifferentiated or dedifferentiated, and high-grade not otherwise specified) with a cervical injection of indocyanine green for sentinel lymph node detection and at least a bilateral pelvic lymphadenectomy as a reference standard. If the data were not reported specifically for patients with high-grade histology, the authors were contacted for aggregate data. METHODS: We pooled the detection rates and measures of diagnostic accuracy using a generalized linear mixed-effects model with a logit and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. RESULTS: We identified 16 eligible studies of which the authors for 9 of the studies provided data on 429 patients with high-grade endometrial cancer specifically. The study-level median age was 66 years (range, 44-82.5 years) and the study-level median body mass index was 28.6 kg/m2 (range, 19.4-43.7 kg/m2). The pooled detection rates were 91% per patient (95% confidence interval, 85%-95%; I2=59%) and 64% bilaterally (95% confidence interval, 53%-73%; I2=69%). The overall node positivity rate was 26% (95% confidence interval, 19%-34%; I2=44%). Of the 87 patients with positive node results, a sentinel lymph node biopsy correctly identified 80, yielding a pooled sensitivity of 92% per patient (95% confidence interval, 84%-96%; I2=0%), a false negative rate of 8% (95% confidence interval, 4%-16%; I2=0%), and a negative predictive value of 97% (95% confidence interval, 95%-99%; I2=0%). CONCLUSION: Sentinel lymph node biopsy accurately detect lymph node metastases in patients with high-grade endometrial cancer with a false negative rate comparable with that observed in low-grade endometrial cancer, melanoma, vulvar cancer, and breast cancer. These findings suggest that sentinel lymph node biopsy can replace complete lymphadenectomies as the standard of care for surgical staging in patients with high-grade endometrial cancer.

Fertility considerations prior to conservative management of gynecologic cancers.

Fertility-sparing management of early-stage gynecologic cancers is becoming more prevalent as increasing evidence demonstrates acceptable oncologic and reproductive outcomes in appropriately selected patients. However, in the absence of randomized controlled trials, most of the commonly used treatment algorithms are based only on observational studies. As women are increasingly postponing childbearing, the need for evidence-based guidance on the optimal selection of appropriate candidates for fertility-sparing therapies is paramount. It is imperative to seriously consider the fertility potential of a given individual prior to making major oncologic treatment decisions that may deviate from the accepted standard of care. It is a disservice to patients to undergo a fertility-sparing procedure in hopes of ultimately achieving a live birth, only to determine later they have poor baseline fertility potential or other substantial barriers to conception including excess financial toxicity. Many women with oncologic diagnoses are of advanced maternal age and their obstetric and neonatal risks must be considered. In the era of advanced assisted reproductive technologies, patients should be provided realistic expectations regarding success rates while understanding the potential oncologic perils. A multidisciplinary approach to the conservative treatment of early-stage gynecologic cancers with early referral to reproductive specialists as well as maternal-fetal medicine specialists is warranted. In this review, we discuss the recommended fertility evaluation for patients with newly diagnosed, early-stage gynecologic cancers who are considering fertility-sparing management.

The utilization of CTA in management of gastrointestinal bleeding in a tertiary care center ED. Are we using it enough?

BACKGROUND: Gastrointestinal (GI) bleeding is a common patient presentation to the Emergency Department (ED) and the source can be difficult to diagnose. PROCEDURE: Computed tomography angiography (CTA) is a new but validated modality with high sensitivity and specificity for diagnosis and treatment of GI bleeds, especially in differentiating arterial from venous bleeding. With high reported validity of CTA, some studies have suggested its ability to better triage patients in the ED and impact ED workflow and resource utilization. We evaluated the use of CTA use an academic tertiary care center ED for GI bleeding. FINDINGS: Retrospective chart review of 1493 patient (2012-2015), one - way ANOVA, and one-tail t-test, found CTA is used significantly less (0.7%) compared to classical endoscopy (75.7%, p < .001), video capsule endoscopy (VCE)(4.8%, p < .001), tagged red blood cell scintigraphy(4.4%, p < .001), and traditional catheter-directed angiography(2.88%, p < .001). In our subset of 11 CTA cases, we found mean time (in hours) to CTA was faster than mean time to endoscopy, 31:47 [95% CI: -7:50-71:24] and 42:44 [95% CI: 18:27-67:01] respectively. The difference in means between time to CTA and time to endoscopy did not achieve statistical significance, 12:57 h [95% CI -18:51-44:45; p = .40]. CONCLUSION: We concluded that in light of its validation against these other diagnostic modalities, CTA may be underutilized in the care of patients with GI bleeding and should be studied further to study its impact on early risk stratification, treatment, and resource utilization.

Indigenous community participation in resource development decision-making: Practitioner perceptions of legal and voluntary arrangements.

Indigenous nations worldwide are working with and lobbying private and public resource developers to ensure meaningful engagement in decisions tied to resource development in their territories. The diversity of approaches for engagement can be framed along a continuum, with voluntary practices at one end and legal responsibilities at the other. Given this continuum, the roles and responsibilities of various actors involved have become blurred, which leads to poor practice. In an effort to bring clarity, the aim of this research was to understand the distinctions between voluntary practices and legal responsibilities among key actors, identify how key actors understood their different roles and responsibilities, and explain the implications of these differences. In partnership with a First Nation and a public power utility in Northern Saskatchewan, Canada, we employed semi-structured interviews and group workshops with Indigenous, industry, and government actors who participate in environmental management and resource development decisions. We found that actors had distinct motivations for interacting with one another, that perceptions of voluntary practices and legal responsibilities aligned among some participants but not among others, and that participants were indeed confused about their roles and responsibilities in relation to legal requirements and voluntary engagement activities. Furthermore, we learned that clarifying the intended roles of those involved in resource development decisions would be insufficient for improving practice. This is because improved clarity may not address underlying mistrust of government by Indigenous people, or may not be possible where rights and interests are intertwined under a broad conception of Indigenous rights. Findings also suggest the need for government and industry to work with Indigenous nations as self-determining entities, rather than imposing unilateral processes upon them. Consequently, more serious scrutiny, understanding and action is needed by government and industry when employing and assessing voluntary actions and legal measures for Indigenous inclusion in resource development decision-making processes.

Drift, dissipation and risk to wildlife following targeted herbicide applications on boreal transmission rights-of-way.

Herbicide use on boreal transmission line rights-of-way has been relatively limited compared to more temperate regions and therefore challenges exist in estimating and communicating the associated risks. Herbicides directly enter the ecosystem through deposition on vegetation and soils and can be a vector of contamination to browsing herbivores. Triclopyr drift and foliage concentrations were quantified following basal bark (Garlon RTU) and low-volume foliar (Garlon XRT) field treatments to aspen (Populus tremuloides) saplings and willow (Salix bebbiana) shrubs, respectively. Greater drift concentrations localized at the stem base were observed following basal bark treatments. Conversely, concentrations in foliage following the low-volume foliar treatment (DT50 = 5.7 days and DT90 = 34.6 days) were much higher than following basal bark treatment, which also required two days to translocate into the leaves. However, dissipation was rapid from both application methods and triclopyr in foliage was less than 20 µg g-1 a year following application. A risk assessment revealed an acceptable level of risk for acute toxicity to wildlife browsing on contaminated leaves from the residues detected in this study; however, an unacceptable level of risk for chronic toxicity to long-term browsing moose. Site-specific data regarding browsing behaviour on herbicide treated rights-of-ways and species-specific reference values are needed to improve confidence in the tier-two risk assessment. Basal bark application is ideal when stem density is lower and toxic effects for herbivores is of concern and low-volume foliar applications are best suited in areas with higher stem density when off-target herbicide deposition is less acceptable.

Implementation of a sentinel lymph node mapping algorithm for endometrial cancer: surgical outcomes and hospital charges.

INTRODUCTION: The purpose of this study was to compare operative times, surgical outcomes, resource utilization, and hospital charges before and after the implementation of a sentinel lymph node (SLN) mapping algorithm in endometrial cancer. METHODS: All patients with clinical stage I endometrial cancer were identified pre- (2012) and post- (2017) implementation of the SLN algorithm. Clinical data were summarized and compared between groups. Total hospital charges incurred on the day of surgery were extracted from the hospital financial system for each patient and all charges were adjusted to 2017 US dollars. RESULTS: A total of 203 patients were included: 71 patients in 2012 and 130 patients in 2017. There was no difference in median age, body mass index, or stage. In 2012, 35/71 patients (49.3%) underwent a lymphadenectomy. In 2017, SLN mapping was attempted in 120/130 patients (92.3%) and at least one SLN was identified in 110/120 (91.7%). Median estimated blood loss was similar between groups (100 mL vs 75 mL, p=0.081). There was a significant decrease in both median operative time (210 vs 171 min, p=0.007) and utilization of intraoperative frozen section (63.4% vs 14.6%, p<0.0001). No significant differences were noted in intraoperative (p=1.00) or 30 day postoperative complication rates (p=0.30). The median total hospital charges decreased by 2.73% in 2017 as compared with 2012 (p=0.96). DISCUSSION: Implementation of an SLN mapping algorithm for high- and low-risk endometrial cancer resulted in a decrease in both operative time and intraoperative frozen section utilization with no change in surgical morbidity. While hospital charges did not significantly change, further studies are warranted to assess the true cost of SLN mapping.

Modulation of apoptotic response by LAR family phosphatases-cIAP1 signaling during urinary tract morphogenesis.

The elimination of unwanted cells by apoptosis is necessary for tissue morphogenesis. However, the cellular control of morphogenetic apoptosis is poorly understood, notably the modulation of cell sensitivity to apoptotic stimuli. Ureter maturation, the process by which the ureter is displaced to the bladder wall, represents an exquisite example of morphogenetic apoptosis, requiring the receptor protein tyrosine phosphatases (RPTPs): LAR and RPTPσ. Here we show that LAR-RPTPs act through cellular inhibitor of apoptosis protein 1 (cIAP1) to modulate caspase 3,7-mediated ureter maturation. Pharmacologic or genetic inactivation of cIAP1 reverts the apoptotic deficit of LAR-RPTP-deficient embryos. Moreover, Birc2 (cIAP1) inactivation generates excessive apoptosis leading to vesicoureteral reflux in newborns, which underscores the importance of apoptotic modulation during urinary tract morphogenesis. We finally demonstrate that LAR-RPTP deficiency increases cIAP1 stability during apoptotic cell death. Together these results identify a mode of cIAP1 regulation playing a critical role in the cellular response to apoptotic pathway activation in the embryo.

The Aftermath and the Aftermyth: Learning From Memoirists Who Experienced Sexual Assault While at University.

There is an abundance of research on the health consequences of sexual assault during university, but less attention has been paid to how sexual assault also shapes women's everyday lives. To develop an understanding of the everyday aftermath of sexual assault, we used narrative inquiry to analyze how women textually represent everyday living after sexual assault during university within four memoirs. Memoirists discussed their lives as significantly changed and worked to repair their lives after sexual assault by engaging in a range of everyday activities. Although no single behavioral response was described, some memoirists were perceived as deviant if they engaged in behaviors that contradicted prevailing cultural myths and expectations about how one should behave after sexual assault. We need to create room for women to engage in personal, idiosyncratic responses if we are to challenge restrictive standards for doing in the aftermath of sexual assault during university.

Preoperative PET/CT does not accurately detect extrauterine disease in patients with newly diagnosed high-risk endometrial cancer: A prospective study.

BACKGROUND: The identification of extrauterine disease is critical to the management of patients with high-risk endometrial cancer. The purpose of the current study was to determine the accuracy of preoperative positron emission tomography (PET)/computed tomography (CT) in the detection of extrauterine disease. METHODS: Women with high-risk endometrial cancer were enrolled prospectively and underwent preoperative PET/CT followed by surgery, including sentinel lymph node biopsy and lymphadenectomy. Primary tumor factors on PET/CT were correlated with lymph node pathology. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the detection of lymphadenopathy and peritoneal disease by PET/CT. RESULTS: A total of 112 patients were enrolled and underwent PET/CT between April 2013 and May 2016, 108 of whom were evaluable. On PET/CT, 21 patients (19.4%) were found to have extrauterine disease, 18 (17%) had positive lymph nodes, and 8 (7%) had peritoneal disease. A total of 108 patients underwent surgery, 103 of whom (95%) underwent lymphadenectomy. The sensitivity of PET/CT to detect positive lymph nodes was 45.8%, with a specificity of 91.1%, positive predictive value of 61.1%, and negative predictive value of 84.7%. The false-negative rate was 54.2%. There was no difference in primary tumor characteristics on imaging noted between patients with positive and negative lymph nodes. The sensitivity of PET/CT to detect peritoneal disease was 37.5%, with a specificity of 97.8%, positive predictive value of 75%, and negative predictive value of 90.0%. The false-negative rate was 62.5%. CONCLUSIONS: Preoperative PET/CT did not reliably predict the presence of extrauterine disease in women with high-risk endometrial cancer. Given the high false-negative rates, PET/CT should not be used in the preoperative treatment planning of these patients.

A Point Mutation in p190A RhoGAP Affects Ciliogenesis and Leads to Glomerulocystic Kidney Defects.

Rho family GTPases act as molecular switches regulating actin cytoskeleton dynamics. Attenuation of their signaling capacity is provided by GTPase-activating proteins (GAPs), including p190A, that promote the intrinsic GTPase activity of Rho proteins. In the current study we have performed a small-scale ENU mutagenesis screen and identified a novel loss of function allele of the p190A gene Arhgap35, which introduces a Leu1396 to Gln substitution in the GAP domain. This results in decreased GAP activity for the prototypical Rho-family members, RhoA and Rac1, likely due to disrupted ordering of the Rho binding surface. Consequently, Arhgap35-deficient animals exhibit hypoplastic and glomerulocystic kidneys. Investigation into the cystic phenotype shows that p190A is required for appropriate primary cilium formation in renal nephrons. P190A specifically localizes to the base of the cilia to permit axoneme elongation, which requires a functional GAP domain. Pharmacological manipulations further reveal that inhibition of either Rho kinase (ROCK) or F-actin polymerization is able to rescue the ciliogenesis defects observed upon loss of p190A activity. We propose a model in which p190A acts as a modulator of Rho GTPases in a localized area around the cilia to permit the dynamic actin rearrangement required for cilia elongation. Together, our results establish an unexpected link between Rho GTPase regulation, ciliogenesis and glomerulocystic kidney disease.

Linking Herbicide Dissipation to Soil Ecological Risk along Transmission Rights-of-Way in the Yukon Territory, Canada.

In the Yukon Territory, transmission rights-of-way (ROWs) are managed using brushing and mowing techniques alone. When cut, target species such as Michx. and spp. grow rapidly shortening maintenance cycles. Long-term vegetation control may be improved by integrating herbicide application. However, prior to implementation, the dissipation and toxicity of herbicides in northern latitudes needed to be assessed. The dissipation of Garlon XRT (triclopyr) and Arsenal Powerline (imazapyr) in soils was assessed at five ROW locations representative of the main ecoregion types where ROWs occur within the Yukon Territory. Soils from four sites were collected at 1, 30, and 365 d after treatment to determine persistence of herbicides for each of three application methods (backpack spraying, cut stump, and point injection). Increased sampling intervals were added to better determine the dissipation rate of each herbicide in Yukon Territory soils. Soil dissipation data were linked to a series of standardized toxicity tests, including three soil invertebrates (, , and ). Additionally, the dissipation of both herbicides from the target species L. was assessed at one site. Herbicide residues persisted in soils for longer than 365 d after treatment and longer than 30 d after treatment in . However, concentrations were below the concentration that would affect 25% of the invertebrate species tested. Weight of evidence and toxic exposure ratios were used to characterize the risks associated with herbicide application in northern latitudes and provided both qualitative and quantitative means to communicate the results to the public.

New Developments in Minimally Invasive Gynecologic Oncology Surgery.

Minimally invasive surgery continues to transform the field of gynecologic oncology and has now become the standard of care for many early-stage malignancies. The proven benefits of minimally invasive surgery are driving the rapid introduction and dissemination of novel technologies and the increasing ability to perform even the most complex procedures less invasively. In this article, we will review the current literature on traditional multiport laparoscopy, robotic-assisted laparoscopy, laparoendoscopic single-site surgery as well as robotic-assisted laparoendoscopic single-site surgery, with a specific focus on their role in the treatment of gynecologic malignancies.

Application Method and Biochar Type Affect Petroleum Hydrocarbon Degradation in Northern Landfarms.

To integrate biochar as a practical and successful remedial amendment at northern landfarms, components of its formulation and application must be optimized for site-specific environmental conditions. Different biochar amendments were applied to petroleum hydrocarbon (PHC)-contaminated soil at two northern field sites (Iqaluit and Whitehorse) and in a laboratory study at -5°C to determine the effects of application method (injection or incorporation) and biochar type (wood, fishmeal, bonemeal, and/or compost) on PHC degradation and associated soil properties. Incorporation decreased F2 (equivalent C-C) and F3 (equivalent C-C) PHC concentrations in soil after 31 d, whereas injection did not decrease PHC concentrations until Day 334. Bonemeal-derived biochar selectively stimulated F3-PHC degradation in frozen soil over 90 d under controlled laboratory conditions. In the field, there was little difference in PHC degradation between biochar types and the fertilizer control. Incorporation also increased NO availability, and in field trials, all biochars increased NO availability relative to the fertilizer control, whereas the effects of biochars on NH and PO were variable. Aromatic functional gene abundance was enhanced when treatments were incorporated, compared with when injected. In field trials, 6% Zakus wood plus fertilizer inhibited aliphatic and aromatic gene abundance. Liquid water content increased in incorporated treatments, specifically those amended with fishmeal biochar. Incorporation was the most successful application method for these northern soils, and although biochar amendments are not clearly effective in reducing PHC concentrations, there is evidence to suggest it can beneficially influence soil properties and PHC degradation under specific environmental conditions.

Herbicide Toxicity Testing with Non-Target Boreal Plants: The Sensitivity of Achillea millefolium L. and Chamerion angustifolium L. to Triclopyr and Imazapyr.

Terrestrial plant toxicity tests were conducted to determine the sensitivity of two boreal plants, yarrow (Achillea millefolium L.) and fireweed (Chamerion angustifolium L.), to the herbicides imazapyr and triclopyr. Both plants are common non-target species on northern powerline rights-of-way where the impacts of proposed herbicide applications are of concern. In the vegetative vigour test, triclopyr foliar spray caused extensive damage to A. millefolium at <50% of the maximum field application rate (inhibition concentration (IC)50 = 1443.8 g a.i. ha-1) and was lethal to C. angustifolium at the lowest dose tested (1210.9 g a.i. ha-1). Both species demonstrated extremely high sensitivity to imazapyr foliar spray: IC50s = 8.29 g a.i. ha-1 and 4.82 g a.i. ha-1 (<1.5% of the maximum field rate). The seedling emergence and seedling growth tests were conducted in the organic horizon of five boreal soils. Few differences in herbicide bioavailability between soils were detected. Triclopyr limited growth of A. millefolium, C. angustifolium and standard test species Calamagrostis canadensis at low levels (most IC50 estimates between 2-20 µg g-1). For imazapyr, IC50 estimates could not be calculated as there was >75% inhibition of endpoints at the lowest doses of ~2 µg g-1. A foliar application of triclopyr or imazapyr for woody species control would likely cause significant damage to boreal non-target plants. The high sensitivity of both species to herbicide residues in soil indicates long term impacts are dependent on herbicide degradation rates in northern conditions. A. millefolium performed well and is recommended for use in toxicity testing relevant to boreal regions.

Coordinated cell behaviours in early urogenital system morphogenesis.

The elaboration of functional kidneys during embryonic development proceeds in a stepwise manner, starting with the formation of the embryonic pro- and mesonephros, followed by the induction and growth of the final metanephric kidney. These early stages of urinary tract development are critical for the embryo as a failure in pro/mesonephros morphogenesis leads to major developmental defects, often incompatible with life. The formation of the pro/mesonephros and its central component the nephric duct, is also interesting as it offers a relatively simple system to study cell biological behaviours underlying tissue morphogenesis. This system is especially well adapted to study the questions of cell lineage specification, epithelial integrity and plasticity, tissue interactions, collective cell migration/guidance and programmed cell death. In this review, we establish the link between these cell behaviours, their molecular regulators and early genitourinary tract development.

Inactivation of LAR family phosphatase genes Ptprs and Ptprf causes craniofacial malformations resembling Pierre-Robin sequence.

Leukocyte antigen related (LAR) family receptor protein tyrosine phosphatases (RPTPs) regulate the fine balance between tyrosine phosphorylation and dephosphorylation that is crucial for cell signaling during development and tissue homeostasis. Here we show that LAR RPTPs are required for normal development of the mandibular and maxillary regions. Approximately half of the mouse embryos lacking both Ptprs (RPTPσ) and Ptprf (LAR) exhibit micrognathia (small lower jaw), cleft palate and microglossia/glossoptosis (small and deep tongue), a phenotype closely resembling Pierre-Robin sequence in humans. We show that jaw bone and cartilage patterning occurs aberrantly in LAR family phosphatase-deficient embryos and that the mandibular arch harbors a marked decrease in cell proliferation. Analysis of signal transduction in embryonic tissues and mouse embryonic fibroblast cultures identifies an increase in Bmp-Smad signaling and an abrogation of canonical Wnt signaling associated with loss of the LAR family phosphatases. A reactivation of ß-catenin signaling by chemical inhibition of GSK3ß successfully resensitizes LAR family phosphatase-deficient cells to Wnt induction, indicating that RPTPs are necessary for normal Wnt/ß-catenin pathway activation. Together these results identify LAR RPTPs as important regulators of craniofacial morphogenesis and provide insight into the etiology of Pierre-Robin sequence.