Resolving the life cycle alters expected impacts of climate change Levy, Ofir; Buckley, Lauren B.; Keitt, Timothy H. ...
Proceedings - Royal Society. Biological sciences/Proceedings - Royal Society. Biological Sciences,
08/2015, Letnik:
282, Številka:
1813
Journal Article
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Recent models predict contrasting impacts of climate change on tropical and temperate species, but these models ignore how environmental stress and organismal tolerance change during the life cycle. ...For example, geographical ranges and extinction risks have been inferred from thermal constraints on activity during the adult stage. Yet, most animals pass through a sessile embryonic stage before reaching adulthood, making them more susceptible to warming climates than current models would suggest. By projecting microclimates at high spatio-temporal resolution and measuring thermal tolerances of embryos, we developed a life cycle model of population dynamics for North American lizards. Our analyses show that previous models dramatically underestimate the demographic impacts of climate change. A predicted loss of fitness in 2% of the USA by 2100 became 35% when considering embryonic performance in response to hourly fluctuations in soil temperature. Most lethal events would have been overlooked if we had ignored thermal stress during embryonic development or had averaged temperatures over time. Therefore, accurate forecasts require detailed knowledge of environmental conditions and thermal tolerances throughout the life cycle.
Pegaspargase (PEG-ASP) has largely replaced native
asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for ...allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome.
PEG-ASP was administered to 598 patients in St Jude's Total XVI study. Results were compared with Total XV study (ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti-PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti-polyethylene glycol (PEG) and anti-L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics.
Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 13.5% of 598) than in the Total XV study with L-ASP (169 41.2% of 410;
= 1.4 × 10
). For Total XVI, anti-PEG, not anti-L-ASP, was the predominant component of anti-PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions (
= 2.4 × 10
), which is consistent with an immunosuppressant contribution of IT. Anti-PEG-ASP was associated with accelerated drug clearance (
= 5.0 × 10
). Failure of rechallenge after initial reactions was associated with anti-PEG-ASP (
= .0078) and was predicted by the occurrence of angioedema with first reaction (
= .01).
Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.
T-cell immunotherapy that takes advantage of Epstein-Barr virus (EBV)–stimulated immunity has the potential to fill an important niche in targeted therapy for EBV-related cancers. To address ...questions of long-term efficacy, safety, and practicality, we studied 114 patients who had received infusions of EBV-specific cytotoxic T lymphocytes (CTLs) at 3 different centers to prevent or treat EBV+ lymphoproliferative disease (LPD) arising after hematopoietic stem cell transplantation. Toxicity was minimal, consisting mainly of localized swelling at sites of responsive disease. None of the 101 patients who received CTL prophylaxis developed EBV+ LPD, whereas 11 of 13 patients treated with CTLs for biopsy-proven or probable LPD achieved sustained complete remissions. The gene-marking component of this study enabled us to demonstrate the persistence of functional CTLs for up to 9 years. A preliminary analysis indicated that a patient-specific CTL line can be manufactured, tested, and infused for $6095, a cost that compares favorably with other modalities used in the treatment of LPD. We conclude that the CTL lines described here provide safe and effective prophylaxis or treatment for lymphoproliferative disease in transplantation recipients, and the manufacturing methodology is robust and can be transferred readily from one institution to another without loss of reproducibility. The current trial was registered at www.clinicaltrials.gov as #NCT00058812.
Defining the structural and functional changes in the nervous system underlying learning and memory represents a major challenge for modern neuroscience. Although changes in neuronal activity ...following memory formation have been studied B. F. Grewe et al.,
543, 670-675 (2017); M. T. Rogan, U. V. Stäubli, J. E. LeDoux,
390, 604-607 (1997), the underlying structural changes at the synapse level remain poorly understood. Here, we capture synaptic changes in the midlarval zebrafish brain that occur during associative memory formation by imaging excitatory synapses labeled with recombinant probes using selective plane illumination microscopy. Imaging the same subjects before and after classical conditioning at single-synapse resolution provides an unbiased mapping of synaptic changes accompanying memory formation. In control animals and animals that failed to learn the task, there were no significant changes in the spatial patterns of synapses in the pallium, which contains the equivalent of the mammalian amygdala and is essential for associative learning in teleost fish M. Portavella, J. P. Vargas, B. Torres, C. Salas,
57, 397-399 (2002). In zebrafish that formed memories, we saw a dramatic increase in the number of synapses in the ventrolateral pallium, which contains neurons active during memory formation and retrieval. Concurrently, synapse loss predominated in the dorsomedial pallium. Surprisingly, we did not observe significant changes in the intensity of synaptic labeling, a proxy for synaptic strength, with memory formation in any region of the pallium. Our results suggest that memory formation due to classical conditioning is associated with reciprocal changes in synapse numbers in the pallium.
The expression patterns of the transcription factor FOXP2 in the developing mammalian forebrain have been described, and some studies have tested the role of this protein in the development and ...function of specific forebrain circuits by diverse methods and in multiple species. Clinically, mutations in
are associated with severe developmental speech disturbances, and molecular studies indicate that impairment of
may lead to dysregulation of genes involved in forebrain histogenesis. Here, anatomical and molecular phenotypes of the cortical neuron populations that express FOXP2 were characterized in mice. Additionally,
was removed from the developing mouse cortex at different prenatal ages using two Cre-recombinase driver lines. Detailed molecular and circuit analyses were undertaken to identify potential disruptions of development. Surprisingly, the results demonstrate that
function is not required for many functions that it has been proposed to regulate, and therefore plays a more limited role in cortical development than previously thought.
Background
Artificial intelligence (AI)-driven software has been developed and become commercially available within the past few years for the detection of intracranial hemorrhage (ICH) and chronic ...cerebral microbleeds (CMBs). However, there is currently no systematic review that summarizes all of these tools or provides pooled estimates of their performance.
Methods
In this PROSPERO-registered, PRISMA compliant systematic review, we sought to compile and review all MEDLINE and EMBASE published studies that have developed and/or tested AI algorithms for ICH detection on non-contrast CT scans (NCCTs) or MRI scans and CMBs detection on MRI scans.
Results
In total, 40 studies described AI algorithms for ICH detection in NCCTs/MRIs and 19 for CMBs detection in MRIs. The overall sensitivity, specificity, and accuracy were 92.06%, 93.54%, and 93.46%, respectively, for ICH detection and 91.6%, 93.9%, and 92.7% for CMBs detection. Some of the challenges encountered in the development of these algorithms include the laborious work of creating large, labeled and balanced datasets, the volumetric nature of the imaging examinations, the fine tuning of the algorithms, and the reduction in false positives.
Conclusions
Numerous AI-driven software tools have been developed over the last decade. On average, they are characterized by high performance and expert-level accuracy for the diagnosis of ICH and CMBs. As a result, implementing these tools in clinical practice may improve workflow and act as a failsafe for the detection of such lesions.
Registration-URL
https://www.crd.york.ac.uk/prospero/
Unique Identifier: CRD42021246848.
Methotrexate clearance can influence the cure of and toxicity in children with acute lymphoblastic leukemia (ALL). We estimated methotrexate plasma clearance for 1279 patients with ALL treated with ...methotrexate (24-hour infusion of a 1 g/m2 dose or 4-hour infusion of a 2 g/m2 dose) on the Children's Oncology Group P9904 and P9905 protocols. Methotrexate clearance was lower in older children (P = 7 × 10−7), girls (P = 2.7 × 10−4), and those who received a delayed-intensification phase (P = .0022). A genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in the organic anion transporter gene SLCO1B1 (P = 2.1 × 10−11). This replicates findings using different schedules of high-dose methotrexate in St Jude ALL treatment protocols; a combined meta-analysis yields a P value of 5.7 × 10−19 for the association of methotrexate clearance with SLCO1B1 SNP rs4149056. Validation of this variant with 5 different treatment regimens of methotrexate solidifies the robustness of this pharmacogenomic determinant of methotrexate clearance. This study is registered at http://www.clinicaltrials.gov as NCT00005585 and NCT00005596.
•A genome-wide study of the association of over 5 million SNPs with methotrexate clearance in 1279 patients treated with HDMTX in multicenter COG trials 9904 and 9905.•We replicated the finding that inherited variations in SLCO1B1 are the most important genetic variations influencing methotrexate clearance.
The thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are ...poorly understood, and delayed repair is common after cytoreductive therapies. Here, we demonstrate a trigger of thymic regeneration, centered on detecting the loss of dying thymocytes that are abundant during steady-state T cell development. Specifically, apoptotic thymocytes suppressed production of the regenerative factors IL-23 and BMP4 via TAM receptor signaling and activation of the Rho-GTPase Rac1, the intracellular pattern recognition receptor NOD2, and micro-RNA-29c. However, after damage, when profound thymocyte depletion occurs, this TAM-Rac1-NOD2-miR29c pathway is attenuated, increasing production of IL-23 and BMP4. Notably, pharmacological inhibition of Rac1-GTPase enhanced thymic function after acute damage. These findings identify a complex trigger of tissue regeneration and offer a regenerative strategy for restoring immune competence in patients whose thymic function has been compromised.
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•NOD2 suppresses the production of the key thymic regenerative factors BMP4 and IL-23•Detection of apoptotic thymocytes by TAM receptors mediates NOD2-dependent suppression•Depletion of thymocytes after acute damage attenuates detection of apoptotic cells•Inhibition of Rac1 promotes thymus repair and T cell reconstitution after damage
Delayed lymphopenia is a common feature of many cancer therapies that is predicated on poor regeneration of thymic function. Kinsella et al. identify a trigger of endogenous thymic repair, centered on the detection of apoptotic thymocytes, that can be exploited to improve T cell regeneration after immune-depleting therapies.
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