Discovery and structure–activity relationships of small molecules that block the human immunoglobulin G–human neonatal Fc receptor (hIgG–hFcRn) protein–protein interaction

The neonatal Fc receptor, FcRn, prolongs the half-life of IgG in the serum and represents a potential therapeutic target for the treatment of autoimmune disease. Small molecules that block the protein–protein interactions of human IgG–human FcRn may lower pathogenic autoantibodies and provide effective treatment. A novel class of quinoxalines has been discovered as antagonists of the IgG:FcRn protein–protein interaction through optimization of a hit derived from a virtual ligand-based screen.     

Thermal sensitivity of scope for activity in Pagothenia borchgrevinki, a cryopelagic Antarctic nototheniid fish

The thermal sensitivity of scope for activity was studied in the Antarctic nototheniid fish Pagothenia borchgrevinki. The scope for activity of P. borchgrevinki at 0°C was 189 mg O₂ kg⁻¹ h⁻¹ (factorial scope 6.8) which is similar to that of temperate and tropical species at their environmental temperatures, providing no evidence for metabolic cold adaptation of maximum activity. The scope for activity increased to a maximum value of 266 mg O₂ kg⁻¹ h⁻¹ (factorial scope 8.3) at 3°C and then decreased from 3 to 6°C. The thermal sensitivity of critical swimming speed was also investigated and followed a similar pattern to aerobic scope for activity, suggesting oxygen limitation of aerobic performance. Oxygen consumption rates and ventilation frequencies were monitored for 24 h after the swimming challenge and the recovery of both parameters to resting levels was rapid and independent of temperature.     

Depressed cytotoxic T-cell responses in previously treated Hodgkin's and non-Hodgkin's lymphoma patients

Summary Peripheral blood lymphocytes from 62 previously treated Hodgkin's and non-Hodgkin's lymphoma patients were tested for their ability to generate cytotoxic T lymphocytes in response to stimulation with allogeneic cells in mixed leukocyte culture. In most patients, including some in long-term unmaintained remission, extremely low cytotoxic responses were generated. To test whether these patients have circulating cells that suppress autologous lymphocytes from responding to alloantigens, patients' responding cells were passaged over columns of sepharose beads conjugated with histamine-rabbit serum albumin (Hist-RSA). This procedure has been shown to remove mouse suppressor cells and Concanavalin A(ConA)-induced human suppressor cells. Passage of patients' cells, prior to allogeneic stimulation, over columns of sepharose beads conjugated with Hist-RSA but not over control RSA columns, resulted in the isolation of lymphocytes that generated increased cytotoxic responses to alloantigens in 18 of 22 patients with initially low cytotoxic responses. These results suggest that the impaired ability of treated Hodgkin's and non-Hodgkin's lymphoma patients' lymphocytes to differentiate into cytotoxic T lymphocytes is at least in part due to the presence of circulating suppressor cells that bear histamine receptors.Scholar of the Leukemia Society of America     

Lack of adequate seed supply is a major bottleneck for effective ecosystem restoration in Chile: friendly amendment to Bannister et al. (2018)

We argue that the need for a quality seed supply chain is a major bottleneck for the restoration of Chile's native ecosystems, thus supplementing the list of bottlenecks proposed by Bannister et al. in 2018. Specifically, there is a need for defining seed transfer zones, developing standards and capacities for properly collecting and storing seeds, reducing information gaps on seed physiology and longevity, and implementing an efficient seed supply chain with certification of seed origin and quality. Without such capacities, countries are unlikely to meet their restoration commitments. Although we focus on bottlenecks in Chile, the issues we raise are relevant to other countries and thus the global agenda for ecological restoration.     

Evaluation of quenching methods for metabolite recovery in photoautotrophic Synechococcus sp. PCC 7002

The first step of many metabolomics studies is quenching, a technique vital for rapidly halting metabolism and ensuring that the metabolite profile remains unchanging during sample processing. The most widely used approach is to plunge the sample into prechilled cold methanol; however, this led to significant metabolite loss in Synecheococcus sp. PCC 7002. Here we describe our analysis of the impacts of cold methanol quenching on the model marine cyanobacterium Synechococcus sp. PCC 7002, as well as our brief investigation of alternative quenching methods. We tested several methods including cold methanol, cold saline, and two filtration approaches. Targeted central metabolites were extracted and metabolomic profiles were generated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results indicate that cold methanol quenching induces dramatic metabolite leakage in Synechococcus, resulting in a majority of central metabolites being lost prior to extraction. Alternatively, usage of a chilled saline quenching solution mitigates metabolite leakage and improves sample recovery without sacrificing rapid quenching of cellular metabolism. Finally, we illustrate that metabolite leakage can be assessed, and subsequently accounted for, in order to determine absolute metabolite pool sizes; however, our results show that metabolite leakage is inconsistent across various metabolite pools and therefore must be determined for each individually measured metabolite.     

Eco-evolutionary consequences of habitat warming and fragmentation in communities

Eco-evolutionary dynamics can mediate species and community responses to habitat warming and fragmentation, two of the largest threats to biodiversity and ecosystems. The eco-evolutionary consequences of warming and fragmentation are typically studied independently, hindering our understanding of their simultaneous impacts. Here, we provide a new perspective rooted in trade-offs among traits for understanding their eco-evolutionary consequences. On the one hand, temperature influences traits related to metabolism, such as resource acquisition and activity levels. Such traits are also likely to have trade-offs with other energetically costly traits, like antipredator defences or dispersal. On the other hand, fragmentation can influence a variety of traits (e.g. dispersal) through its effects on the spatial environment experienced by individuals, as well as properties of populations, such as genetic structure. The combined effects of warming and fragmentation on communities should thus reflect their collective impact on traits of individuals and populations, as well as trade-offs at multiple trophic levels, leading to unexpected dynamics when effects are not additive and when evolutionary responses modulate them. Here, we provide a road map to navigate this complexity. First, we review single-species responses to warming and fragmentation. Second, we focus on consumer–resource interactions, considering how eco-evolutionary dynamics can arise in response to warming, fragmentation, and their interaction. Third, we illustrate our perspective with several example scenarios in which trait trade-offs could result in significant eco-evolutionary dynamics. Specifically, we consider the possible eco-evolutionary consequences of (i) evolution in thermal performance of a species involved in a consumer–resource interaction, (ii) ecological or evolutionary changes to encounter and attack rates of consumers, and (iii) changes to top consumer body size in tri-trophic food chains. In these scenarios, we present a number of novel, sometimes counter-intuitive, potential outcomes. Some of these expectations contrast with those solely based on ecological dynamics, for example, evolutionary responses in unexpected directions for resource species or unanticipated population declines in top consumers. Finally, we identify several unanswered questions about the conditions most likely to yield strong eco-evolutionary dynamics, how better to incorporate the role of trade-offs among traits, and the role of eco-evolutionary dynamics in governing responses to warming in fragmented communities.     

Increased Respiratory Disease Mortality at a Microwave Popcorn Production Facility with Worker Risk of Bronchiolitis Obliterans

Background

Bronchiolitis obliterans, an irreversible lung disease, was first associated with inhalation of butter flavorings (diacetyl) in workers at a microwave popcorn company. Excess rates of lung-function abnormalities were related to cumulative diacetyl exposure. Because information on potential excess mortality would support development of permissible exposure limits for diacetyl, we investigated respiratory-associated mortality during 2000–2011 among current and former workers at this company who had exposure to flavorings and participated in cross-sectional surveys conducted between 2000–2003.

Methods

We ascertained workers'' vital status through a Social Security Administration search. Causes of death were abstracted from death certificates. Because bronchiolitis obliterans is not coded in the International Classification of Disease 10^th revision (ICD-10), we identified respiratory mortality decedents with ICD-10 codes J40–J44 which encompass bronchitis (J40), simple and mucopurulent chronic bronchitis (J41), unspecified chronic bronchitis (J42), emphysema (J43), and other chronic obstructive pulmonary disease (COPD) (J44). We calculated expected number of deaths and standardized mortality ratios (SMRs) with 95% confidence intervals (CI) to determine if workers exposed to diacetyl experienced greater respiratory mortality than expected.

Results

We identified 15 deaths among 511 workers. Based on U.S. population estimates, 17.39 deaths were expected among these workers (SMR = 0.86; CI:0.48-1.42). Causes of death were available for 14 decedents. Four deaths among production and flavor mixing workers were documented to have a multiple cause of ‘other COPD’ (J44), while 0.98 ‘other COPD’-associated deaths were expected (SMR = 4.10; CI:1.12–10.49). Three of the 4 ‘other COPD’-associated deaths occurred among former workers and workers employed before the company implemented interventions reducing diacetyl exposure in 2001.

Conclusion

Workers at the microwave popcorn company experienced normal rates of all-cause mortality but higher rates of COPD-associated mortality, especially workers employed before the company reduced diacetyl exposure. The demonstrated excess in COPD-associated mortality suggests continued efforts to lower flavoring exposure are prudent.