Anthropogenic and Natural Disturbance Differentially Affect Sagebrush Bird Habitat Use

North American sagebrush (Artemisia spp.)-obligate birds are experiencing steep population declines due in part to increased disturbance, mainly human-caused, across their range. At the eastern edge of the sagebrush steppe, this issue may potentially be exacerbated because of natural disturbance by black-tailed prairie dogs (Cynomys ludovicianus). Our goal was to compare local and landscape models of habitat use by greater sage-grouse (Centrocercus urophasianus), Brewer's sparrow (Spizella breweri), and sage thrasher (Oreoscoptes montanus) with models including effects of natural (i.e., prairie dog) and anthropogenic disturbance. We used a combination of field data collection, and state and national datasets for the Thunder Basin National Grassland, eastern Wyoming, USA, to understand the factors that influence lek attendance by sage-grouse and habitat use by 2 passerines in this system. For all 3 species, models including big sagebrush (Artemisia tridentata) cover at local and landscape scales were the most competitive among univariate models, supporting the paradigm that sagebrush is key for these species. Models including anthropogenic disturbance (well density, road density) explained more variation than models of prairie dog disturbance alone for 2 of the 3 species, but long-term disturbance by prairie dogs did reduce abundance of Brewer's sparrows. Although long-term prairie dog disturbance has the potential to reduce sagebrush cover for sagebrush-obligate birds, such events are likely rare because outbreaks of plague (Yersina pestis) and lethal control on borders with private land reduce prairie dog disturbance. Conversely, anthropogenic disturbance is slated to increase in this system, suggesting potentially accelerated declines for sagebrush birds into the future. © 2020 The Wildlife Society.     

Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC

Elotuzumab is a monoclonal antibody in development for multiple myeloma (MM) that targets CS1, a cell surface glycoprotein expressed on MM cells. In preclinical models, elotuzumab exerts anti-MM efficacy via natural killer (NK)-cell-mediated antibody-dependent cellular cytotoxicity (ADCC). CS1 is also expressed at lower levels on NK cells where it acts as an activating receptor. We hypothesized that elotuzumab may have additional mechanisms of action via ligation of CS1 on NK cells that complement ADCC activity. Herein, we show that elotuzumab appears to induce activation of NK cells by binding to NK cell CS1 which promotes cytotoxicity against CS1(+) MM cells but not against autologous CS1(+) NK cells. Elotuzumab may also promote CS1–CS1 interactions between NK cells and CS1(+) target cells to enhance cytotoxicity in a manner independent of ADCC. NK cell activation appears dependent on differential expression of the signaling intermediary EAT-2 which is present in NK cells but absent in primary, human MM cells. Taken together, these data suggest elotuzumab may enhance NK cell function directly and confer anti-MM efficacy by means beyond ADCC alone.     

Maternal coding variants in complement receptor 1 and spontaneous idiopathic preterm birth

Preterm birth (PTB) is a major global public health concern. However, little is known about the pathophysiology of spontaneous idiopathic PTB. We tested the hypothesis that rare variants in families would target specific genes and pathways that contribute to PTB risk in the general population. Whole-exome sequencing was performed on 10 PTB mothers from densely affected families including two mother–daughter pairs. We identified novel variants shared between the two mother–daughter pairs when compared to a 1000 Genomes Project background exome file and investigated these genes for pathway aggregation using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Genes in enriched pathways were then surveyed in the other six PTB exomes and tested for association in a larger number of nuclear families. The KEGG complement and coagulation cascade was one of the most enriched pathways in our two mother–daughter pairs. When the six genes found in this pathway (CFH, CR1, F13B, F5, CR2, and C4BPA) were examined for novel missense variants, half of all the exomes harbored at least one. Association analysis of variants in these six gene regions in nuclear families from Finland (237 cases and 328 controls) found statistically significant associations after multiple test corrections in three CR1 SNPs; the strongest in an exonic missense SNP, rs6691117, p value = 6.91e?5, OR = 1.71. Our results demonstrate the importance of the complement and coagulation cascades in the pathophysiology of PTB, and suggest potential screening and intervention approaches to prevent prematurity that target this pathway.     

The effects of predator removal on mallard production and population change in northeastern North Dakota

In 1994, Delta Waterfowl Foundation began trapping mammalian meso-predators in North Dakota during the breeding season in an attempt to increase waterfowl nest success and enhance recruitment into the fall flight and subsequent breeding population. Multiple studies on these sites demonstrated that removing predators results in near doubling of nest success, which previous simulation modeling suggests is the most influential vital rate influencing the population growth rate of mid-continent mallards (Anas platyrhynchos). We present an assessment of the impact of predator removal on mallard production using population models. We conducted this study on 9 township-sized (93.2 km²) sites (4–8 sites annually per vital rate) in northeastern North Dakota from 2006–2008. Trappers removed mammalian meso-predators on 5 sites and the other 4 served as unmanaged reference sites. To estimate recruitment, we used derived estimates and process variance of pair numbers, hen success (nest survival corrected for renesting), initial brood size, pre-fledging survival, and post-fledging survival, along with previously published estimates of breeding propensity and adult female survival rates. Trapped sites had greater hen success (H = 0.69, = 0.03) than reference sites (H = 0.53, = 0.06), but similar indicated breeding pairs, initial brood size, and pre-fledging survival. We estimated that females on trapped sites added 140 more mallards of both sexes to the fall flight than females on reference sites, at an approximate cost of $74.29 per incremental mallard. Additionally, trapping predators provided a marginal increase (0.04) in finite population growth. We found that predator removal targeted at mammalian nest predators did not produce as many incremental mallards as previously thought and may not be a viable strategy for increasing mallard productivity under conditions similar to those observed during this study. We conducted a sensitivity analysis and determined that pre-fledging survival was the most influential factor regulating mallard population growth. Although hen success increased as a result of trapping, duckling survival became a limiting factor. We suggest that waterfowl managers assess multiple vital rates to determine the likelihood that management actions focused on a single parameter, such as nest success, will yield desired population level effects. © 2012 The Wildlife Society.     

Wildlife conservation planning under the United States Forest Service's 2012 planning rule

In 2012, the United States Forest Service (USFS) promulgated new planning regulations in accordance with the National Forest Management Act (NFMA). These regulations represent the most significant change in federal forest policy in decades and have sweeping implications for wildlife populations. We provide a brief overview of the history of the NFMA planning regulations and their wildlife provisions and review the current science on planning for effective wildlife conservation at the landscape scale. We then discuss the approach to wildlife conservation planning in the 2012 rule and compare it to alternatives that were not selected and previous iterations of the planning rule. The new planning rule is of concern because of its highly discretionary nature and the inconsistency between its intent on the one hand and operational requirements on the other. Therefore, we recommend that the USFS include in the Directives for implementing the rule commitments to directly monitor populations of selected species of conservation concern and focal species and to maintain the viability of both categories of species. Additional guidance must be included to ensure the effective selection of species of conservation concern and focal species, and these categories should overlap when possible. If the USFS determines that the planning unit is not inherently capable of maintaining viable populations of a species, this finding should be made available for scientific review and public comment, and in such cases the USFS should commit to doing nothing that would further impair the viability of such species. In cases where extrinsic factors decrease the viability of species, the USFS has an increased, not lessened, responsibility to protect those species. Monitoring plans must include trigger points that will initiate a review of management actions, and plans must include provisions to ensure monitoring takes place as planned. If wildlife provisions in forest plans are implemented so that they are enforceable and ensure consistency between intent and operational requirements, this will help to prevent the need for additional listings under the Endangered Species Act and facilitate delisting. Although the discretionary nature of the wildlife provisions in the planning rule gives cause for concern, forward-thinking USFS officials have the opportunity under the 2012 rule to create a robust and effective framework for wildlife conservation planning. © 2013 The Wildlife Society.     

Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids

Chronic hepatitis B virus (HBV) infection, a serious public health problem leading to cirrhosis and hepatocellular carcinoma, is currently treated with either pegylated alpha interferon (pegIFN-α) or one of the five nucleos(t)ide analogue viral DNA polymerase inhibitors. However, neither pegIFN-α nor nucleos(t)ide analogues are capable of reliably curing the viral infection. In order to develop novel antiviral drugs against HBV, we established a cell-based screening assay by using an immortalized mouse hepatocyte-derived stable cell line supporting a high level of HBV replication in a tetracycline-inducible manner. Screening of a library consisting of 26,900 small molecules led to the discovery of a series of sulfamoylbenzamide (SBA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA. Structure-activity relationship studies have thus far identified a group of fluorine-substituted SBAs with submicromolar antiviral activity against HBV in human hepatoma cells. Mechanistic analyses reveal that the compounds dose dependently inhibit the formation of pregenomic RNA (pgRNA)-containing nucleocapsids of HBV but not other animal hepadnaviruses, such as woodchuck hepatitis virus (WHV) and duck hepatitis B virus (DHBV). Moreover, heterologous genetic complementation studies of capsid protein, DNA polymerase, and pgRNA between HBV and WHV suggest that HBV capsid protein confers sensitivity to the SBAs. In summary, SBAs represent a novel chemical entity with superior activity and a unique antiviral mechanism and are thus warranted for further development as novel antiviral therapeutics for the treatment of chronic hepatitis B.     

A TRPC1 Protein-dependent Pathway Regulates Osteoclast Formation and Function

Ca²⁺ signaling is essential for bone homeostasis and skeletal development. Here, we show that the transient receptor potential canonical 1 (TRPC1) channel and the inhibitor of MyoD family, I-mfa, function antagonistically in the regulation of osteoclastogenesis. I-mfa null mice have an osteopenic phenotype characterized by increased osteoclast numbers and surface, which are normalized in mice lacking both Trpc1 and I-mfa. In vitro differentiation of pre-osteoclasts derived from I-mfa-deficient mice leads to an increased number of mature osteoclasts and higher bone resorption per osteoclast. These parameters return to normal levels in osteoclasts derived from double mutant mice. Consistently, whole cell currents activated in response to the depletion of intracellular Ca²⁺ stores are larger in pre-osteoclasts derived from I-mfa knock-out mice compared with currents in wild type mice and normalized in cells derived from double mutant mice, suggesting a cell-autonomous effect of I-mfa on TRPC1 in these cells. A new splice variant of TRPC1 (TRPC1ϵ) was identified in early pre-osteoclasts. Heterologous expression of TRPC1ϵ in HEK293 cells revealed that it is unique among all known TRPC1 isoforms in its ability to amplify the activity of the Ca²⁺ release-activated Ca²⁺ (CRAC) channel, mediating store-operated currents. TRPC1ϵ physically interacts with Orai1, the pore-forming subunit of the CRAC channel, and I-mfa is recruited to the TRPC1ϵ-Orai1 complex through TRPC1ϵ suppressing CRAC channel activity. We propose that the positive and negative modulation of the CRAC channel by TRPC1ϵ and I-mfa, respectively, fine-tunes the dynamic range of the CRAC channel regulating osteoclastogenesis.