Myeloid-derived suppressor cells are associated with disease progression and decreased overall survival in advanced-stage melanoma patients

Myeloid-derived suppressor cells are increased in the peripheral blood of advanced-stage cancer patients; however, no studies have shown a correlation of these immunosuppressive cells with clinical outcomes in melanoma patients. We characterized the frequency and suppressive function of multiple subsets of myeloid-derived suppressor cells in the peripheral blood of 34 patients with Stage IV melanoma, 20 patients with Stage I melanoma, and 15 healthy donors. The frequency of CD14⁺ MDSCs (Lin^? CD11b⁺ HLA-DR^? CD14⁺ CD33⁺) and CD14^? MDSCs (Lin^? CD11b⁺ HLA-DR^? CD14^? CD33⁺) was increased in the peripheral blood of Stage IV melanoma patients relative to healthy donors. The frequency of CD14⁺ and CD14^? MDSCs correlated with each other and with the increased frequency of regulatory T cells, but not with classically defined monocytes. CD14^? MDSCs isolated from the peripheral blood of Stage IV melanoma patients suppressed T cell activation more than those isolated from healthy donors, and the frequency of these cells correlated with disease progression and decreased overall survival. Our study provides the first evidence that the frequency of CD14^? MDSCs negatively correlates with clinical outcomes in advanced-stage melanoma patients. These data indicate that suppressive MDSCs should be considered as targets for future immunotherapies.     

Reduced Apparent Photorespiration by the C(3)-C(4) Intermediate Species, Moricandia arvensis and Panicum milioides

The CO₂/O₂ specificity factor of sucrose gradient purified ribulose 1,5-bisphosphate carboxylase/oxygenase from the C₃-C₄ intermediate plants Moricandia arvensis (79 ± 1) and Panicum milioides (89 ± 2) was similar to the respective values of the enzyme from the closely related C₃ species, Moricandia foetida (80 ± 5) and Panicum laxum (86 ± 2). Thus, the kinetic properties of this bifunctional enzyme do not explain the reduced rates of photorespiration exhibited by either of these intermediate species.     

Origin of a substantial fraction of human regulatory sequences from transposable elements

Transposable elements (TEs) are abundant in mammalian genomes and have potentially contributed to their hosts' evolution by providing novel regulatory or coding sequences. We surveyed different classes of regulatory region in the human genome to assess systematically the potential contribution of TEs to gene regulation. Almost 25% of the analyzed promoter regions contain TE-derived sequences, including many experimentally characterized cis-regulatory elements. Scaffold/matrix attachment regions (S/MARs) and locus control regions (LCRs) that are involved in the simultaneous regulation of multiple genes also contain numerous TE-derived sequences. Thus, TEs have probably contributed substantially to the evolution of both gene-specific and global patterns of human gene regulation.     

Comparison of growth limits of Listeria monocytogenes in milk,broth and cheese

Aim: To determine growth initiation differences of Listeria monocytogenes between a cheesemaking context, milk and tryptic soy broth (TSB). Methods and Results: A laboratory‐scale cheese was made with a mix of two strains of L. monocytogenes at four initial pH values, five water activity (a_w) values and two contamination levels at 30°C. Counts of L. monocytogenes were determined at time 0 and after 8 h of cheese manufacture. Milk and TSB at the same pH and a_w conditions were inoculated with the L. monocytogenes mix in multi‐well plates. Growth was determined by plating each well onto Agosti & Ottaviani Listeria Agar after 8 h of incubation at 30°C. Each condition was repeated six times, and growth initiation probability was modelled with logistic regression models. Growth initiation boundaries were obtained for each matrix type. The results showed that the growth limits were matrix dependent. In the three matrix types, a_w was the most important factor affecting the probability of growth initiation. Contamination level affected growth TSB and cheesemaking conditions. Conclusions: The interface wideness and position in cheese, milk and TSB were dissimilar, indicating that the use of models evaluated in TSB or milk could not be used to predict the behaviour of L. monocytogenes under cheesemaking conditions. Significance and Impact of the Study: Predictive models generated in liquid media are not necessarily adaptable to solid food, and the generation of real food models is necessary.     

Metal migration and subunit swapping in ALS-linked SOD1: Zn2+ transfer between mutant and wild-type occurs faster than the rate of heterodimerization

The heterodimerization of WT Cu, Zn superoxide dismutase-1 (SOD1), and mutant SOD1 might be a critical step in the pathogenesis of SOD1-linked amyotrophic lateral sclerosis (ALS). Rates and free energies of heterodimerization (ΔG_Het) between WT and ALS-mutant SOD1 in mismatched metalation states—where one subunit is metalated and the other is not—have been difficult to obtain. Consequently, the hypothesis that under-metalated SOD1 might trigger misfolding of metalated SOD1 by “stealing” metal ions remains untested. This study used capillary zone electrophoresis and mass spectrometry to track heterodimerization and metal transfer between WT SOD1, ALS-variant SOD1 (E100K, E100G, D90A), and triply deamidated SOD1 (modeled with N26D/N131D/N139D substitutions). We determined that rates of subunit exchange between apo dimers and metalated dimers—expressed as time to reach 30% heterodimer—ranged from t_30% = 67.75 ± 9.08 to 338.53 ± 26.95 min; free energies of heterodimerization ranged from ΔG_Het = -1.21 ± 0.31 to -3.06 ± 0.12 kJ/mol. Rates and ΔG_Het values of partially metalated heterodimers were more similar to those of fully metalated heterodimers than apo heterodimers, and largely independent of which subunit (mutant or WT) was metal-replete or metal-free. Mass spectrometry and capillary electrophoresis demonstrated that mutant or WT 4Zn-SOD1 could transfer up to two equivalents of Zn²⁺ to mutant or WT apo-SOD1 (at rates faster than the rate of heterodimerization). This result suggests that zinc-replete SOD1 can function as a chaperone to deliver Zn²⁺ to apo-SOD1, and that WT apo-SOD1 might increase the toxicity of mutant SOD1 by stealing its Zn²⁺.     

Application of machine learning to identify predators of stocked fish in Lake Ontario: using acoustic telemetry predation tags to inform management

Understanding predator–prey interactions and food web dynamics is important for ecosystem-based management in aquatic environments, as they experience increasing rates of human-induced changes, such as the addition and removal of fishes. To quantify the post-stocking survival and predation of a prey fish in Lake Ontario, 48 bloater Coregonus hoyi were tagged with acoustic telemetry predation tags and were tracked on an array of 105 acoustic receivers from November 2018 to June 2019. Putative predators of tagged bloater were identified by comparing movement patterns of six species of salmonids (i.e., predators) in Lake Ontario with the post-predated movements of bloater (i.e., prey) using a random forests algorithm, a type of supervised machine learning. A total of 25 bloater (53% of all detected) were consumed by predators on average (± S.D. ) 3.1 ± 2.1 days after release. Post-predation detections of predators occurred for an average (± S.D. ) of 78.9 ± 76.9 days, providing sufficient detection data to classify movement patterns. Tagged lake trout Salvelinus namaycush provided the most reliable classification from behavioural predictor variables (89% success rate) and was identified as the main consumer of bloater (consumed 50%). Movement networks between predicted and tagged lake trout were significantly correlated over a 6 month period, supporting the classification of lake trout as a common bloater predator. This study demonstrated the ability of supervised learning techniques to provide greater insight into the fate of stocked fishes and predator–prey dynamics, and this technique is widely applicable to inform future stocking and other management efforts.