Showing papers by "University of New Mexico published in 2009"

Introducing mothur: Open-Source, Platform-Independent, Community-Supported Software for Describing and Comparing Microbial Communities

Abstract: mothur aims to be a comprehensive software package that allows users to use a single piece of software to analyze community sequence data. It builds upon previous tools to provide a flexible and powerful software package for analyzing sequencing data. As a case study, we used mothur to trim, screen, and align sequences; calculate distances; assign sequences to operational taxonomic units; and describe the alpha and beta diversity of eight marine samples previously characterized by pyrosequencing of 16S rRNA gene fragments. This analysis of more than 222,000 sequences was completed in less than 2 h with a laptop computer.

Power-Law Distributions in Empirical Data

Abstract: Power-law distributions occur in many situations of scientific interest and have significant consequences for our understanding of natural and man-made phenomena. Unfortunately, the detection and characterization of power laws is complicated by the large fluctuations that occur in the tail of the distribution—the part of the distribution representing large but rare events—and by the difficulty of identifying the range over which power-law behavior holds. Commonly used methods for analyzing power-law data, such as least-squares fitting, can produce substantially inaccurate estimates of parameters for power-law distributions, and even in cases where such methods return accurate answers they are still unsatisfactory because they give no indication of whether the data obey a power law at all. Here we present a principled statistical framework for discerning and quantifying power-law behavior in empirical data. Our approach combines maximum-likelihood fitting methods with goodness-of-fit tests based on the Kolmogorov-Smirnov (KS) statistic and likelihood ratios. We evaluate the effectiveness of the approach with tests on synthetic data and give critical comparisons to previous approaches. We also apply the proposed methods to twenty-four real-world data sets from a range of different disciplines, each of which has been conjectured to follow a power-law distribution. In some cases we find these conjectures to be consistent with the data, while in others the power law is ruled out.

Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

Abstract: Methods We randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. Results The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P = 0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P = 0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group. Conclusions Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications, with the exception of progression of albuminuria (P = 0.01). (ClinicalTrials.gov number, NCT00032487.)

Toward a Theory of Motivational Interviewing

Abstract: The widely disseminated clinical method of motivational interviewing (MI) arose through a convergence of science and practice. Beyond a large base of clinical trials, advances have been made toward "looking under the hood" of MI to understand the underlying mechanisms by which it affects behavior change. Such specification of outcome-relevant aspects of practice is vital to theory development and can inform both treatment delivery and clinical training. An emergent theory of MI is proposed that emphasizes two specific active components: a relational component focused on empathy and the interpersonal spirit of MI, and a technical component involving the differential evocation and reinforcement of client change talk. A resulting causal chain model links therapist training, therapist and client responses during treatment sessions, and posttreatment outcomes.

The rising prevalence of chronic low back pain.

Abstract: Background National or state-level estimates on trends in the prevalence of chronic low back pain (LBP) are lacking. The objective of this study was to determine whether the prevalence of chronic LBP and the demographic, health-related, and health care–seeking characteristics of individuals with the condition have changed over the last 14 years. Methods A cross-sectional, telephone survey of a representative sample of North Carolina households was conducted in 1992 and repeated in 2006. A total of 4437 households were contacted in 1992 and 5357 households in 2006 to identify noninstitutionalized adults 21 years or older with chronic (>3 months), impairing LBP or neck pain that limits daily activities. These individuals were interviewed in more detail about their health and health care seeking. Results The prevalence of chronic, impairing LBP rose significantly over the 14-year interval, from 3.9% (95% confidence interval [CI], 3.4%-4.4%) in 1992 to 10.2% (95% CI, 9.3%-11.0%) in 2006. Increases were seen for all adult age strata, in men and women, and in white and black races. Symptom severity and general health were similar for both years. The proportion of individuals who sought care from a health care provider in the past year increased from 73.1% (95% CI, 65.2%-79.8%) to 84.0% (95% CI, 80.8%-86.8%), while the mean number of visits to all health care providers were similar (19.5 [1992] vs 19.4 [2006]). Conclusions The prevalence of chronic, impairing LBP has risen significantly in North Carolina, with continuing high levels of disability and health care use. A substantial portion of the rise in LBP care costs over the past 2 decades may be related to this rising prevalence.

Pathological and protective roles of glia in chronic pain

Abstract: Glia have emerged as key contributors to pathological and chronic pain mechanisms. On activation, both astrocytes and microglia respond to and release a number of signalling molecules, which have protective and/or pathological functions. Here we review the current understanding of the contribution of glia to pathological pain and neuroprotection, and how the protective, anti-inflammatory actions of glia are being harnessed to develop new drug targets for neuropathic pain control. Given the prevalence of chronic pain and the partial efficacy of current drugs, which exclusively target neuronal mechanisms, new strategies to manipulate neuron–glia interactions in pain processing hold considerable promise.

Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.

Abstract: Background Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. Methods We studied a cohort of 221 children with high-risk B-cell–progenitor ALL with the use of single-nucleotide–polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1–positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell–progenitor ALL. Results More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients...

Outcomes Following Endovascular vs Open Repair of Abdominal Aortic Aneurysm: A Randomized Trial

Abstract: Context Limited data are available to assess whether endovascular repair of abdominal aortic aneurysm (AAA) improves short-term outcomes compared with traditional open repair. Objective To compare postoperative outcomes up to 2 years after endovascular or open repair of AAA in a planned interim report of a 9-year trial. Design, Setting, and Patients A randomized, multicenter clinical trial of 881 veterans (aged ≥49 years) from 42 Veterans Affairs Medical Centers with eligible AAA who were candidates for both elective endovascular repair and open repair of AAA. The trial is ongoing and this report describes the period between October 15, 2002, and October 15, 2008. Intervention Elective endovascular (n = 444) or open (n = 437) repair of AAA. Main Outcome Measures Procedure failure, secondary therapeutic procedures, length of stay, quality of life, erectile dysfunction, major morbidity, and mortality. Results Mean follow-up was 1.8 years. Perioperative mortality (30 days or inpatient) was lower for endovascular repair (0.5% vs 3.0%; P = .004), but there was no significant difference in mortality at 2 years (7.0% vs 9.8%, P = .13). Patients in the endovascular repair group had reduced median procedure time (2.9 vs 3.7 hours), blood loss (200 vs 1000 mL), transfusion requirement (0 vs 1.0 units), duration of mechanical ventilation (3.6 vs 5.0 hours), hospital stay (3 vs 7 days), and intensive care unit stay (1 vs 4 days), but required substantial exposure to fluoroscopy and contrast. There were no differences between the 2 groups in major morbidity, procedure failure, secondary therapeutic procedures, aneurysm-related hospitalizations, health-related quality of life, or erectile function. Conclusions In this report of short-term outcomes after elective AAA repair, perioperative mortality was low for both procedures and lower for endovascular than open repair. The early advantage of endovascular repair was not offset by increased morbidity or mortality in the first 2 years after repair. Longer-term outcome data are needed to fully assess the relative merits of the 2 procedures. Trial Registration clinicaltrials.gov Identifier: NCT00094575

Ecoenzymatic stoichiometry of microbial organic nutrient acquisition in soil and sediment

Abstract: Biota can be described in terms of elemental composition, expressed as an atomic ratio of carbon:nitrogen:phosphorus (refs 1-3). The elemental stoichiometry of microoorganisms is fundamental for understanding the production dynamics and biogeochemical cycles of ecosystems because microbial biomass is the trophic base of detrital food webs. Here we show that heterotrophic microbial communities of diverse composition from terrestrial soils and freshwater sediments share a common functional stoichiometry in relation to organic nutrient acquisition. The activities of four enzymes that catalyse the hydrolysis of assimilable products from the principal environmental sources of C, N and P show similar scaling relationships over several orders of magnitude, with a mean ratio for C:N:P activities near 1:1:1 in all habitats. We suggest that these ecoenzymatic ratios reflect the equilibria between the elemental composition of microbial biomass and detrital organic matter and the efficiencies of microbial nutrient assimilation and growth. Because ecoenzymatic activities intersect the stoichiometric and metabolic theories of ecology, they provide a functional measure of the threshold at which control of community metabolism shifts from nutrient to energy flow.

Prevalence and epidemiologic characteristics of FASD from various research methods with an emphasis on recent in-school studies

Abstract: Researching the epidemiology and estimating the prevalence of fetal alcohol syndrome (FAS) and other fetal alcohol spectrum disorders (FASD) for mainstream populations anywhere in the world has presented a challenge to researchers. Three major approaches have been used in the past: surveillance and record review systems, clinic-based studies, and active case ascertainment methods. The literature on each of these methods is reviewed citing the strengths, weaknesses, prevalence results, and other practical considerations for each method. Previous conclusions about the prevalence of FAS and total FASD in the United States (US) population are summarized. Active approaches which provide clinical outreach, recruitment, and diagnostic services in specific populations have been demonstrated to produce the highest prevalence estimates. We then describe and review studies utilizing in-school screening and diagnosis, a special type of active case ascertainment. Selected results from a number of in-school studies in South Africa, Italy, and the US are highlighted. The particular focus of the review is on the nature of the data produced from in-school methods and the specific prevalence rates of FAS and total FASD which have emanated from them. We conclude that FAS and other FASD are more prevalent in school populations, and therefore the general population, than previously estimated. We believe that the prevalence of FAS in typical, mixed-racial, and mixed-socioeconomic populations of the US is at least 2 to 7 per 1,000. Regarding all levels of FASD, we estimate that the current prevalence of FASD in populations of younger school children may be as high as 2-5% in the US and some Western European countries.

Ten Things that Motivational Interviewing Is Not

Abstract: Background: In the 26 years since it was first introduced in this journal, motivational interviewing (MI) has become confused with various other ideas and approaches, owing in part to its rapid international diffusion. Methods: Based on confusions that have arisen in publications and presentations regarding MI, the authors compiled a list of 10 concepts and procedures with which MI should not be addled. Results: This article discusses 10 things that MI is not: (1) the transtheoretical model of change; (2) a way of tricking people into doing what you want them to do; (3) a technique; (4) decisional balance; (5) assessment feedback; (6) cognitive-behavior therapy; (7) client-centered therapy; (8) easy to learn; (9) practice as usual; and (10) a panacea. Conclusion: Clarity about what does (and does not) constitute MI promotes quality assurance in scientific research, clinical practice, and training.

Microbes, mating, and morality: individual differences in three functional domains of disgust.

Abstract: What is the function of disgust? Whereas traditional models have suggested that disgust serves to protect the self or neutralize reminders of our animal nature, an evolutionary perspective suggests that disgust functions to solve 3 qualitatively different adaptive problems related to pathogen avoidance, mate choice, and social interaction. The authors investigated this 3-domain model of disgust across 4 studies and examined how sensitivity to these functional domains relates to individual differences in other psychological constructs. Consistent with their predictions, factor analyses demonstrated that disgust sensitivity partitions into domains related to pathogens, sexuality, and morality. Further, sensitivity to the 3 domains showed predictable differentiation based on sex, perceived vulnerability to disease, psychopathic tendencies, and Big 5 personality traits. In exploring these 3 domains of disgust, the authors introduce a new measure of disgust sensitivity. Appreciation of the functional heterogeneity of disgust has important implications for research on individual differences in disgust sensitivity, emotion, clinical impairments, and neuroscience.

Language Is a Complex Adaptive System: Position Paper

Abstract: Language has a fundamentally social function. Processes of human interaction along with domain-general cognitive processes shape the structure and knowledge of language. Recent research in the cognitive sciences has demonstrated that patterns of use strongly affect how language is acquired, is used, and changes. These processes are not independent of one another but are facets of the same complex adaptive system (CAS). Language as a CAS involves the following key features: The system consists of multiple agents (the speakers in the speech community) interacting with one another. The system is adaptive; that is, speakers’ behavior is based on their past interactions, and current and past interactions together feed forward into future behavior. A speaker's behavior is the consequence of competing factors ranging from perceptual constraints to social motivations. The structures of language emerge from interrelated patterns of experience, social interaction, and cognitive mechanisms. The CAS approach reveals commonalities in many areas of language research, including first and second language acquisition, historical linguistics, psycholinguistics, language evolution, and computational modeling.

Automatically finding patches using genetic programming

Abstract: Automatic program repair has been a longstanding goal in software engineering, yet debugging remains a largely manual process. We introduce a fully automated method for locating and repairing bugs in software. The approach works on off-the-shelf legacy applications and does not require formal specifications, program annotations or special coding practices. Once a program fault is discovered, an extended form of genetic programming is used to evolve program variants until one is found that both retains required functionality and also avoids the defect in question. Standard test cases are used to exercise the fault and to encode program requirements. After a successful repair has been discovered, it is minimized using structural differencing algorithms and delta debugging. We describe the proposed method and report experimental results demonstrating that it can successfully repair ten different C programs totaling 63,000 lines in under 200 seconds, on average.

Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop.

Abstract: Background: At the Third International Workshop on Asymptomatic Primary Hyperparathyroidism (PHPT) in May 2008, recent data on the disease were reviewed. We present the results of a literature review on issues arising from the clinical presentation and natural history of PHPT. Methods: Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was reviewed, and the questions of the International Task Force were addressed by the Consensus Panel. Conclusions: 1) Data on the extent and nature of cardiovascular involvement in those with mild disease are too limited to provide a complete picture. 2) Patients with mild PHPT have neuropsychological complaints. Although some symptoms may improve with surgery, available data remain inconsistent on their precise nature and reversibility. 3) Surgery leads to long-term gains in spine, hip, and radius bone mineral density (BMD). Because some patients have early disease progression and others lose BMD after ...

The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness.

Abstract: Objectives Poor adherence to medication treatment can have devastating consequences for patients with mental illness. The goal of this project was to develop recommendations for addressing adherence problems to improve patient outcomes. Methods The editors identified important topics and questions concerning medication adherence problems in serious mental illness that are not fully addressed in the literature. A survey was developed containing 39 questions (521 options) asking about defining nonadherence, extent of adherence problems in schizophrenia and bipolar disorder, risk factors for nonadherence, assessment methods, and interventions for specific types of adherence problems. The survey was completed by 41 (85%) of the 48 experts to whom it was sent. Results of the literature review and survey were used to develop recommendations for assessing and improving adherence in patients with serious mental illness. Results ASSESSING ADHERENCE: The experts endorsed percentage of medication not taken as the preferred method of defining adherence, with 80% or more of medication taken endorsed as an appropriate cut-off for adherence in bipolar disorder and schizophrenia. Although self- and physician report are the most common methods used to assess adherence in clinical settings, they are often inaccurate and may underestimate nonadherence. The experts recommend that, if possible, clinicians also use more objective measures (e.g., pill counts, pharmacy records, and, when appropriate, serum levels such as are used for lithium). Use of a validated self-report scale may help improve accuracy. Scope of the problem The majority of the experts believed the average patient with schizophrenia or bipolar disorder in their practices takes only 51%-70% of prescribed medication. FACTORS ASSOCIATED WITH NONADHERENCE: The experts endorsed poor insight and lack of illness awareness, distress associated with specific side effects or a general fear of side effects, inadequate efficacy with persistent symptoms, and believing medications are no longer needed as the most important factors leading to adherence problems in schizophrenia and bipolar disorder. The experts considered weight gain a side effect that is very likely to lead to adherence problems in patients with schizophrenia and bipolar disorder; sedation was considered a more important contributor to adherence problems in bipolar disorder than schizophrenia. The experts rated persistent positive or negative symptoms in schizophrenia and persistent grandiosity and manic symptoms in bipolar disorder as the most important symptomatic contributors to adherence problems in these illnesses. Interventions It is important to identify the specific factors that may be contributing to a patient's adherence problems in order to customize interventions to target those problems. Multiple problems may be involved, requiring a combination of interventions. Conclusions Adherence problems are complex and multidetermined. The experts recommended customized interventions focused on the underlying causes.

The Impact of Quadrivalent Human Papillomavirus (HPV; Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine on Infection and Disease Due to Oncogenic Nonvaccine HPV Types in Generally HPV-Naive Women Aged 16–26 Years

Abstract: Background. Human papillomavirus (HPV)-6/11/16/18 vaccine reduces the risk of HPV-6/11/16/18-related cervical intraepithelial neoplasia (CIN) 1-3 or adenocarcinoma in situ (AIS). Here, its impact on CIN1-3/AIS associated with nonvaccine oncogenic HPV types was evaluated. Methods. We enrolled 17,622 women aged 16-26 years. All underwent cervicovaginal sampling and Pap testing at regular intervals for up to 4 years. HPV genotying was performed for biopsy samples, and histological diagnoses were determined by a pathology panel. Analyses were conducted among subjects who were negative for 14 HPV types on day 1. Prespecified analyses included infection of >= 6 months' duration and CIN1-3/AIS due to the 2 and 5 most common HPV types in cervical cancer after HPV types 16 and 18, as well as all tested nonvaccine types. Results. Vaccination reduced the incidence of HPV-31/45 infection by 40.3% (95% confidence interval [CI], 13.9% to 59.0%) and of CIN1-3/AIS by 43.6% (95% CI, 12.9% to 64.1%), respectively. The reduction in HPV-31/33/45/52/58 infection and CIN1-3/AIS was 25.0% (95% CI, 5.0% to 40.9%) and 29.2% (95% CI, 8.3% to 45.5%), respectively. Efficacy for CIN2-3/AIS associated with the 10 nonvaccine HPV types was 32.5% (95% CI, 6.0% to 51.9%). Reductions were most notable for HPV-31. Conclusions. HPV-6/11/16/18 vaccine reduced the risk of CIN2-3/AIS associated with nonvaccine types responsible for similar to 20% of cervical cancers. The clinical benefit of cross-protection is not expected to be fully additive to the efficacy already observed against HPV-6/11/16/18-related disease, because women may have >1 CIN lesion, each associated with a different HPV type. (Less)

Genome, transcriptome, and secretome analysis of wood decay fungus Postia placenta supports unique mechanisms of lignocellulose conversion

Abstract: Brown-rot fungi such as Postia placenta are common inhabitants of forest ecosystems and are also largely responsible for the destructive decay of wooden structures. Rapid depolymerization of cellulose is a distinguishing feature of brown-rot, but the biochemical mechanisms and underlying genetics are poorly understood. Systematic examination of the P. placenta genome, transcriptome, and secretome revealed unique extracellular enzyme systems, including an unusual repertoire of extracellular glycoside hydrolases. Genes encoding exocellobiohydrolases and cellulose-binding domains, typical of cellulolytic microbes, are absent in this efficient cellulose-degrading fungus. When P. placenta was grown in medium containing cellulose as sole carbon source, transcripts corresponding to many hemicellulases and to a single putative β-1–4 endoglucanase were expressed at high levels relative to glucose-grown cultures. These transcript profiles were confirmed by direct identification of peptides by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Also up-regulated during growth on cellulose medium were putative iron reductases, quinone reductase, and structurally divergent oxidases potentially involved in extracellular generation of Fe(II) and H2O2. These observations are consistent with a biodegradative role for Fenton chemistry in which Fe(II) and H2O2 react to form hydroxyl radicals, highly reactive oxidants capable of depolymerizing cellulose. The P. placenta genome resources provide unparalleled opportunities for investigating such unusual mechanisms of cellulose conversion. More broadly, the genome offers insight into the diversification of lignocellulose degrading mechanisms in fungi. Comparisons with the closely related white-rot fungus Phanerochaete chrysosporium support an evolutionary shift from white-rot to brown-rot during which the capacity for efficient depolymerization of lignin was lost.

Pathogenesis of chytridiomycosis, a cause of catastrophic amphibian declines.

Abstract: The pathogen Batrachochytrium dendrobatidis (Bd), which causes the skin disease chytridiomycosis, is one of the few highly virulent fungi in vertebrates and has been implicated in worldwide amphibian declines. However, the mechanism by which Bd causes death has not been determined. We show that Bd infection is associated with pathophysiological changes that lead to mortality in green tree frogs (Litoria caerulea). In diseased individuals, electrolyte transport across the epidermis was inhibited by >50%, plasma sodium and potassium concentrations were respectively reduced by ~20% and ~50%, and asystolic cardiac arrest resulted in death. Because the skin is critical in maintaining amphibian homeostasis, disruption to cutaneous function may be the mechanism by which Bd produces morbidity and mortality across a wide range of phylogenetically distant amphibian taxa.

How Many Bootstrap Replicates Are Necessary

Abstract: Phylogenetic Bootstrapping (BS) is a standard technique for inferring confidence values on phylogenetic trees that is based on reconstructing many trees from minor variations of the input data, trees called replicates. BS is used with all phylogenetic reconstruction approaches, but we focus here on the most popular, Maximum Likelihood (ML). Because ML inference is so computationally demanding, it has proved too expensive to date to assess the impact of the number of replicates used in BS on the quality of the support values. For the same reason, a rather small number (typically 100) of BS replicates are computed in real-world studies. Stamatakis et al. recently introduced a BS algorithm that is 1---2 orders of magnitude faster than previous techniques, while yielding qualitatively comparable support values, making an experimental study possible. In this paper, we propose stopping criteria , that is, thresholds computed at runtime to determine when enough replicates have been generated, and report on the first large-scale experimental study to assess the effect of the number of replicates on the quality of support values, including the performance of our proposed criteria. We run our tests on 17 diverse real-world DNA, single-gene as well as multi-gene, datasets, that include between 125 and 2,554 sequences. We find that our stopping criteria typically stop computations after 100---500 replicates (although the most conservative criterion may continue for several thousand replicates) while producing support values that correlate at better than 99.5% with the reference values on the best ML trees. Significantly, we also find that the stopping criteria can recommend very different numbers of replicates for different datasets of comparable sizes. Our results are thus two-fold: (i) they give the first experimental assessment of the effect of the number of BS replicates on the quality of support values returned through bootstrapping; and (ii) they validate our proposals for stopping criteria. Practitioners will no longer have to enter a guess nor worry about the quality of support values; moreover, with most counts of replicates in the 100---500 range, robust BS under ML inference becomes computationally practical for most datasets. The complete test suite is available at http://lcbb.epfl.ch/BS.tar.bz2 and BS with our stopping criteria is included in RAxML 7.1.0.

JAK mutations in high-risk childhood acute lymphoblastic leukemia.

Abstract: Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosome-positive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases JAK1 (n = 3), JAK2 (n = 16), and JAK3 (n = 1) in 20 (10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P = 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL.

Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia.

Abstract: Aneuploidy and translocations are hallmarks of B-progenitor acute lymphoblastic leukemia (ALL), but many individuals with this cancer lack recurring chromosomal alterations. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. We identified the P2RY8-CRLF2 fusion in 7% of individuals with B-progenitor ALL and 53% of individuals with ALL associated with Down syndrome. CRLF2 alteration was associated with activating JAK mutations, and expression of human P2RY8-CRLF2 together with mutated mouse Jak2 resulted in constitutive Jak-Stat activation and cytokine-independent growth of Ba/F3 cells overexpressing interleukin-7 receptor alpha. Our findings indicate that these two genetic lesions together contribute to leukemogenesis in B-progenitor ALL.

Matrix Metalloproteinases and Their Multiple Roles in Neurodegenerative Diseases

Abstract: Summary Matrix metalloproteinases (MMPs) and proteins containing a disintegrin and metalloproteinase domain (ADAM) are important in neuroinflammation, and recent studies have linked their actions to neurodegenerative disorders. MMPs act as cell-surface sheddases and can affect cell signalling initiated by growth factors or death receptors. Four tissue inhibitors of metalloproteinases (TIMPs) regulate metalloproteinase activity. These proteases increase the permeability of the blood–brain barrier, which can cause oedema, haemorrhage, and cell death. MMPs also participate in tissue repair by promoting angiogenesis and neurogenesis. In vascular cognitive impairment, MMPs change permeability of the blood–brain barrier and might contribute to white matter damage. MMPs and ADAMs might contribute to the formation and degradation of amyloid proteins in Alzheimer's disease and cause death of dopaminergic neurons in Parkinson's disease. In this Review, by examining the effects of neuroinflammation, we try to understand the role that MMPs might have in neurodegenerative diseases. Therapeutic strategies that use inhibitors of MMPs could represent potential novel treatments for neurological diseases.

Tree die-off in response to global change-type drought: mortality insights from a decade of plant water potential measurements.

Abstract: Global climate change is projected to produce warmer, longer, and more frequent droughts, referred to here as “global change-type droughts”, which have the potential to trigger widespread tree die-off. However, drought-induced tree mortality cannot be predicted with confidence, because long-term field observations of plant water stress prior to, and culminating in, mortality are rare, precluding the development and testing of mechanisms. Here, we document plant water stress in two widely distributed, co-occurring species, pinon pine (Pinus edulis) and juniper (Juniperus monosperma), over more than a decade, leading up to regional-scale die-off of pinon pine trees in response to global change-related drought. Pinon leaf water potentials remained substantially below their zero carbon assimilation point for at least 10 months prior to dying, in contrast to those of juniper, which rarely dropped below their zero-assimilation point. These data suggest that pinon mortality was driven by protracted water stress,...