Despite the importance of consumers in structuring communities, and the widespread assumption that consumption is strongest at low latitudes, empirical tests for global scale patterns in the ...magnitude of consumer impacts are limited. In marine systems, the long tradition of experimentally excluding herbivores in their natural environments allows consumer impacts to be quantified on global scales using consistent methodology. We present a quantitative synthesis of 613 marine herbivore exclusion experiments to test the influence of consumer traits, producer traits and the environment on the strength of herbivore impacts on benthic producers. Across the globe, marine herbivores profoundly reduced producer abundance (by 68% on average), with strongest effects in rocky intertidal habitats and the weakest effects on habitats dominated by vascular plants. Unexpectedly, we found little or no influence of latitude or mean annual water temperature. Instead, herbivore impacts differed most consistently among producer taxonomic and morphological groups. Our results show that grazing impacts on plant abundance are better predicted by producer traits than by large‐scale variation in habitat or mean temperature, and that there is a previously unrecognised degree of phylogenetic conservatism in producer susceptibility to consumption.
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 approximately 20% and approximately 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.
Eliciting doses (EDs) (eg, ED01 or ED05 values, which are the amounts of allergen expected to cause objective symptoms in 1% and 5% of the population with an allergy, respectively) are increasingly ...being used to inform allergen labeling and clinical management. These values are generated from food challenge, but the frequency of anaphylaxis in response to these low levels of allergen exposure and their reproducibility are unknown.
Our aim was to determine (1) the rate of anaphylaxis in response to low-level peanut exposure and (2) the reproducibility of reaction thresholds (and anaphylaxis) at food challenge.
We conducted a systematic review and individual participant data meta-analysis of studies that reported at least 50 individuals with peanut allergy reacting to peanut at double-blind, placebo-controlled food challenge (DBPCFC) and were published between January 2010 and September 2020. Risk of bias was assessed by using National Institute for Clinical Excellence methodologic checklists.
A total of 19 studies were included (covering a total of 3151 participants, 534 of whom subsequently underwent further peanut challenge). At individual participant data meta-analysis, 4.5% (95% CI, 1.9% to 10.1%) of individuals reacted to 5 mg or less of peanut protein with anaphylaxis (moderate heterogeneity I2 = 57%). Intraindividual thresholds varied by up to 3 logs, although this variation was limited to a half-log change in 71.2% (95% CI, 56.2% to 82.6%) of individuals. In all, 2.4% (95% CI, 1.1% to 5.0%) of patients initially tolerated 5 mg of peanut protein but then reacted to this dose at subsequent challenge (low heterogeneity I2 = 16%); none developed anaphylaxis.
Around 5% of individuals reacting to an ED01 or ED05 level of exposure to peanut might develop anaphylaxis in response to that dose. This equates to 1 and 6 anaphylaxis events per 2500 patients exposed to an ED01 or ED05 dose, respectively, in the broader population of individuals with peanut allergy.
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The nucleus accumbens shell is a critical node in reward circuitry, encoding environments associated with reward. Long-range inputs from the ventral hippocampus (ventral subiculum) to the nucleus ...accumbens shell have been identified, yet their precise molecular phenotype remains to be determined. Here we used retrograde tracing to identify the ventral subiculum as the brain region with the densest glutamatergic (VGluT1–
Slc17a7
) input to the shell. We then used circuit-directed translating ribosome affinity purification to examine the molecular characteristics of distinct glutamatergic (VGluT1, VGluT2–
Slc17a6
) ventral subiculum to nucleus accumbens shell projections. We immunoprecipitated translating ribosomes from this population of projection neurons and analysed molecular connectomic information using RNA sequencing. We found differential gene enrichment across both glutamatergic projection neuron subtypes. In VGluT1 projections, we found enrichment of
Pfkl
, a gene involved in glucose metabolism. In VGluT2 projections, we found a depletion of
Sparcl1
and
Dlg1
, genes known to play a role in depression- and addiction-related behaviours. These findings highlight potential glutamatergic neuronal-projection-specific differences in ventral subiculum to nucleus accumbens shell projections. Together these data advance our understanding of the phenotype of a defined brain circuit.
As genome sequencing becomes better integrated into scientific research, government policy, and personalized medicine, the primary challenge for researchers is shifting from generating raw data to ...analyzing these vast datasets. Although much work has been done to reduce compute times using various configurations of traditional CPU computing infrastructures, Graphics Processing Units (GPUs) offer opportunities to accelerate genomic workflows by orders of magnitude. Here we benchmark one GPU-accelerated software suite called NVIDIA Parabricks on Amazon Web Services (AWS), Google Cloud Platform (GCP), and an NVIDIA DGX cluster. We benchmarked six variant calling pipelines, including two germline callers (HaplotypeCaller and DeepVariant) and four somatic callers (Mutect2, Muse, LoFreq, SomaticSniper).
We achieved up to 65 × acceleration with germline variant callers, bringing HaplotypeCaller runtimes down from 36 h to 33 min on AWS, 35 min on GCP, and 24 min on the NVIDIA DGX. Somatic callers exhibited more variation between the number of GPUs and computing platforms. On cloud platforms, GPU-accelerated germline callers resulted in cost savings compared with CPU runs, whereas some somatic callers were more expensive than CPU runs because their GPU acceleration was not sufficient to overcome the increased GPU cost.
Germline variant callers scaled well with the number of GPUs across platforms, whereas somatic variant callers exhibited more variation in the number of GPUs with the fastest runtimes, suggesting that, at least with the version of Parabricks used here, these workflows are less GPU optimized and require benchmarking on the platform of choice before being deployed at production scales. Our study demonstrates that GPUs can be used to greatly accelerate genomic workflows, thus bringing closer to grasp urgent societal advances in the areas of biosurveillance and personalized medicine.
In this review, we examine senescent cells and the overlap between the direct biological impact of senescence and the indirect impact senescence has
via
its effects on other cell types, particularly ...the macrophage. The canonical roles of macrophages in cell clearance and in other physiological functions are discussed with reference to their functions in diseases of the kidney and other organs. We also explore the translational potential of different approaches based around the macrophage in future interventions to target senescent cells, with the goal of preventing or reversing pathologies driven or contributed to in part by senescent cell load
in vivo.
The presence of inflammation is a key hallmark of cancer and, plays an important role in disease progression and survival in colorectal cancer (CRC). Calprotectin detected in the faeces is a ...sensitive measure of colonic inflammation. The role of FC as a diagnostic test that may categorise patients by risk of neoplasia is poorly defined. This systematic review and meta-analysis aims to characterise the relationship between elevations of FC and colorectal neoplasia.
A systematic review was performed using the keywords (MESH terms) and a statistical and meta-analysis was performed.
A total of 35 studies are included in this review. CRC patients are more likely than controls to have an elevated FC OR 5.19, 95% CI 3.12-8.62, p < 0.001 with a heterogeneity (I
= 27%). No tumour characteristics significantly correlated with FC, only stage of CRC shows signs that it may potentially correlate with FC.
FC levels are significantly higher in CRC, with high sensitivity. Its low specificity prevents it from being used to diagnose or screen for CRC.
Accumulating evidence demonstrates important roles for natural killer (NK) cells in controlling multiple myeloma (MM). A prospective flow cytometry-based analysis of NK cells in the blood and bone ...marrow (BM) of MM patient subgroups was performed (smoldering (SMM), newly diagnosed (ND), relapsed/refractory, (RR) and post-stem cell transplantation (pSCT)). Assessments included the biomarker expression and function of NK cells, correlations between the expression of receptors on NK cells with their ligands on myeloma cells, and comparisons between MM patient subgroups and healthy controls. The most striking differences from healthy controls were found in RR and pSCT patients, in which NK cells were less mature and expressed reduced levels of the activating receptors DNAM-1, NKG2D, and CD16. These differences were more pronounced in the BM than in blood, including upregulation of the therapeutic targets TIM3, TIGIT, ICOS, and GITR. Their expression suggests NK cells became exhausted upon chronic encounters with the tumor. A high expression of SLAMF7 on blood NK cells correlated with shorter progression-free survival. This correlation was particularly evident in ND patients, including on mature CD56
NK cells in the BM. Thus, our NK cell analysis identified possible therapeutic targets in MM and a biomarker with prognostic potential for disease progression.
Purpose
Patients with early breast cancer and coexistent comorbidities generally experience worse prognosis which may be in part related to inferior treatment. Randomised data on chemotherapy use and ...tolerance in comorbid patients are limited. We aimed to review the available literature regarding the use of chemotherapy in such patients.
Methods
A systematic search of databases was performed for English-language articles evaluating the impact of comorbidity on chemotherapy use for early breast cancer. Comorbidity was assessed as a specific condition, summary count or index. Outcomes of interest were receipt of chemotherapy, change in chemotherapy delivery and occurrence of toxicity.
Results
Sixty studies met inclusion criteria for systematic review. Thirty-three studies evaluated receipt of chemotherapy, with 19 reporting reduced treatment, particularly with higher levels of comorbidity. Meta-analysis of 10 eligible studies returned odds ratios (OR’s) of 0.88 95% confidence interval (CI) 0.80–0.96 and 0.63 (95% CI 0.49–0.80) for receipt of chemotherapy by patients with comorbidity scores of 1 and ≥2, respectively, compared with no comorbidity. Comorbidity had a generally adverse impact on the quality of chemotherapy delivery, although outcomes were heterogeneous. Toxicity was greater in patients with comorbidity, with 10 out of 13 studies reporting greater odds of toxicity or hospitalisation during chemotherapy. Meta-analysis of three studies addressing chemotherapy-associated hospitalisation produced OR’s of 1.42 (95% CI 1.20–1.67) and 2.23 (95% CI 1.46–3.39) for comorbidity scores of 1 and ≥2, respectively.
Conclusions
Compared with their non-comorbid counterparts, comorbid patients with early breast cancer receive less quality adjuvant chemotherapy and experience greater toxicity.
Acute myeloid leukaemia (AML) is distinguished by the generation of dysfunctional leukaemic blasts, and patients characteristically suffer from fatal infections and anaemia due to insufficient normal ...myelo-erythropoiesis. Direct physical crowding of bone marrow (BM) by accumulating leukaemic cells does not fully account for this haematopoietic failure. Here, analyses from AML patients were applied to both in vitro co-culture platforms and in vivo xenograft modelling, revealing that human AML disease specifically disrupts the adipocytic niche in BM. Leukaemic suppression of BM adipocytes led to imbalanced regulation of endogenous haematopoietic stem and progenitor cells, resulting in impaired myelo-erythroid maturation. In vivo administration of PPARγ agonists induced BM adipogenesis, which rescued healthy haematopoietic maturation while repressing leukaemic growth. Our study identifies a previously unappreciated axis between BM adipogenesis and normal myelo-erythroid maturation that is therapeutically accessible to improve symptoms of BM failure in AML via non-cell autonomous targeting of the niche.
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