The suppression of experimental allergic encephalomyelitis in Lewis rats by treatment with myelin basic protein-cell conjugates

Pretreatment of Lewis rats with guinea pig (GP) myelin basic protein (MBP) coupled to syngeneic spleen leukocytes (SL) suppressed the subsequent induction of experimental allegic encephalomyelitis (EAE) with GP-MBP in Freund's complete adjuvant. The degree of suppression correlated positively with the amount of antigen coupled to the SL. GP-MBP coupled to syngeneic red blood cells (RBC) also resulted in suppression of EAE and the extent of the suppression was related to the dose of cells. These regimens of pretreatment also resulted in a decrease in the in vitro lymphocyte proliferative response to GP-MBP and in the extent of perivascular cuffing in the spinal cord. No decrease in the anti-MBP antibody response was detected in rats pretreated with either GP-MBP-SL or GP-MBP-RBC conjugates. Transfer of lymph node cells from rats pretreated with GP-MBP-RBC resulted in a decrease in disease severity in recipients. It is concluded that prior administration of MBP-cell conjugates is an effective way of suppressing the symptoms of EAE.     

Quail and rain in semiarid rangelands: Does management matter?

Rainfall is a strong driver of quail populations on southwestern rangelands and can account for a large portion (~70–95%) of the variability in regional quail production and abundance. Landowners have attempted to moderate these boom-and-bust fluctuations via management; however, presently it is unknown whether management can increase or stabilize quail populations in semiarid environments or whether rainfall remains as influential at small spatial extents. Our objectives were to evaluate the efficacy of management at mitigating the effects of rainfall on northern bobwhite (Colinus virginianus) populations on semiarid rangelands and to quantify the influence of rainfall on bobwhite density at smaller spatial extents. We conducted a study to evaluate these objectives during 2014–2020 in the Rio Grande Plains (n = 11 sites; 1,100‒6,500 ha) and Rolling Plains (n = 4 sites; 1,900‒4,000 ha) of Texas, USA. We estimated bobwhite density during late autumn (Dec‒Jan) on all sites using helicopter surveys within a distance-sampling framework. We also obtained site-level seasonal rainfall (Apr‒Aug) and quantified management intensity via landowner surveys and a scoring rubric to categorize sites into 3 classes (low, medium, and high management intensity). Bobwhite populations during this study experienced a boom-bust cycle in both the Rio Grande Plains and Rolling Plains, with mean bobwhite density fluctuating considerably (0.57‒2.96 bobwhites/ha and 0.02‒2.88 bobwhites/ha, respectively). In the Rio Grande Plains, mean bobwhite density significantly increased from low to high management intensity in 2015 (1.12 ± 0.17 bobwhites/ha vs. 2.87 ± 0.39 bobwhites/ha, respectively), 2016 (1.06 ± 0.20 bobwhites/ha vs. 2.96 ± 0.36 bobwhites/ha, respectively), 2017 (0.73 ± 0.16 bobwhites/ha vs. 1.91 ± 0.32 bobwhites/ha, respectively), and 2019 (0.42 ± 0.14 bobwhites/ha vs. 1.01 ± 0.26 bobwhites/ha, respectively; P < 0.05). In addition, rainfall at the site level accounted for a low amount of the variation in bobwhite density (r² = 0.09; P < 0.01). Similarly, in the Rolling Plains, mean bobwhite density significantly increased from low to high management intensity in 2015 (1.30 ± 0.27 bobwhites/ha vs. 2.20 ± 0.29 bobwhites/ha, respectively) and 2016 (1.26 ± 0.26 bobwhites/ha vs. 2.88 ± 0.34 bobwhites/ha, respectively; P < 0.05). Rainfall at the site level also accounted for a low amount of the variation in bobwhite density (r² < 0.02; P = 0.82). Our findings suggest that management can increase bobwhite density beyond that of less-managed properties but does not completely eliminate inter-annual fluctuations in semiarid environments. In addition, rainfall appears to exert less of an influence on bobwhite density at a site level (e.g., 2,000 ha) than has been documented at a regional level (e.g., ≥8 million ha).     

The role of molecular modelling and simulation in the discovery and deployment of metal-organic frameworks for gas storage and separation*

ABSTRACT

Metal-organic frameworks (MOFs) are highly tuneable, extended-network, crystalline, nanoporous materials with applications in gas storage, separations, and sensing. We review how molecular models and simulations of gas adsorption in MOFs have informed the discovery of performant MOFs for methane, hydrogen, and oxygen storage, xenon, carbon dioxide, and chemical warfare agent capture, and xylene enrichment. Particularly, we highlight how large, open databases of MOF crystal structures, post-processed to enable molecular simulations, are a platform for computational materials discovery. We discuss how to orient research efforts to routinise the computational discovery of MOFs for adsorption-based engineering applications.     

Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation

The body's surfaces form the interface with the external environment, protecting the host. These epithelial barriers are also colonized by a controlled diversity of microorganisms, disturbances of which can give rise to disease. Specialized intraepithelial lymphocytes (IELs), which reside at these sites, are important as a first line of defense as well as in epithelial barrier organization and wound repair. We show here that the aryl hydrocarbon receptor (AhR) is a crucial regulator in maintaining IEL numbers in both the skin and the intestine. In the intestine, AhR deficiency or the lack of AhR ligands compromises the maintenance of IELs and the control of the microbial load and composition, resulting in heightened immune activation and increased vulnerability to epithelial damage. AhR activity can be regulated by dietary components, such as those present in cruciferous vegetables, providing a mechanistic link between dietary compounds, the intestinal immune system, and the microbiota.     

A critical role for autophagy in pancreatic cancer

Autophagy is a regulated catabolic process that leads to the lysosomal degradation of damaged proteins, organelles and other macromolecules, with subsequent recycling of bioenergetic intermediates. The role of autophagy in cancer is undoubtedly complex and likely dependent on tumor type and on the cellular and developmental context. While it has been well demonstrated that autophagy may function as a tumor suppressor, there is mounting evidence that autophagy may have pro-tumorigenic roles, e.g., promoting therapeutic resistance as well as survival under stresses such as hypoxia and nutrient deprivation. These two, seemingly disparate functions can be reconciled by a possible temporal role of autophagy during tumor development, initially suppressing tumor initiation yet supporting tumor growth at later stages.     

Inhibition of non-homologous end joining repair impairs pancreatic cancer growth and enhances radiation response

Pancreatic ductal adenocarcinoma (PDAC) is amongst the deadliest of human cancers, due to its late diagnosis as well as its intense resistance to currently available therapeutics. To identify mechanisms as to why PDAC are refractory to DNA damaging cytoxic chemotherapy and radiation, we performed a global interrogation of the DNA damage response of PDAC. We find that PDAC cells generally harbor high levels of spontaneous DNA damage. Inhibition of Non-Homologous End Joining (NHEJ) repair either pharmacologically or by RNAi resulted in a further accumulation of DNA damage, inhibition of growth, and ultimately apoptosis even in the absence of exogenous DNA damaging agents. In response to radiation, PDAC cells rely on the NHEJ pathway to rapidly repair DNA double strand breaks. Mechanistically, when NHEJ is inhibited there is a compensatory increase in Homologous Recombination (HR). Despite this upregulation of HR, DNA damage persists and cells are significantly more sensitive to radiation. Together, these findings support the incorporation of NHEJ inhibition into PDAC therapeutic approaches, either alone, or in combination with DNA damaging therapies such as radiation.     

Cellular survival in rat vein-to-artery grafts

Microsurgical models of vein-to-artery graft surgery have been developed in rats as a means of assessing vein graft adaptation and neo-intimal hyperplasia. Neo-intimal hyperplasia in these grafts is often attributed, at least in part, to an adaptive response by venous smooth muscle cells to the increased intraluminal pressure of the arterial pressure. However, considerable evidence suggests complete or near-complete cellular replacement in these grafts. A series of experiments were undertaken in which male vein or artery grafts were placed into either allogeneic female nude rat hosts or into syngeneic WKy female hosts as a means of determining donor cell survival. Grafts were removed at postsurgery week 2 or week 6 and the fate of the donor male cells assessed by PCR amplification of the testis-determining gene Sry. The Sry gene was undetectable in 2-week male to female vein grafts. When left for 6 weeks, donor cells were detectable in vein grafts only after multiple 50-cycle PCR analyses. Minimal donor cell survival was not due to an allograft response, as donor male cells were readily detectable in WKy male to female nude rat artery-to-artery grafts. These data were not nude rat specific, as poor donor cell survival was also evidenced in syngeneic male to female vein-to-artery grafts. In conclusion, we demonstrate only marginal survival of donor cells in rat vein-to-artery grafts. Neo-intimal hyperplasia in these grafts was not a consequence of donor venous smooth muscle cell proliferation.     

Lyn Delivers Bacteria to Lysosomes for Eradication through TLR2-Initiated Autophagy Related Phagocytosis

Extracellular bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, have been reported to induce autophagy; however, the role and machinery of infection-induced autophagy remain elusive. We show that the pleiotropic Src kinase Lyn mediates phagocytosis and autophagosome maturation in alveolar macrophages (AM), which facilitates eventual bacterial eradication. We report that Lyn is required for bacterial infection-induced recruitment of autophagic components to pathogen-containing phagosomes. When we blocked autophagy with 3-methyladenine (3-MA) or by depleting Lyn, we observed less phagocytosis and subsequent bacterial clearance by AM. Both morphological and biological evidence demonstrated that Lyn delivered bacteria to lysosomes through xenophagy. TLR2 initiated the phagocytic process and activated Lyn following infection. Cytoskeletal trafficking proteins, such as Rab5 and Rab7, critically facilitated early phagosome formation, autophagosome maturation, and eventual autophagy-mediated bacterial degradation. These findings reveal that Lyn, TLR2 and Rab modulate autophagy related phagocytosis and augment bactericidal activity, which may offer insight into novel therapeutic strategies to control lung infection.