A plasmid locus associated with Klebsiella clinical infections encodes a microbiome-dependent gut fitness factor

Klebsiella pneumoniae (Kp) is an important cause of healthcare-associated infections, which increases patient morbidity, mortality, and hospitalization costs. Gut colonization by Kp is consistently associated with subsequent Kp disease, and patients are predominantly infected with their colonizing strain. Our previous comparative genomics study, between disease-causing and asymptomatically colonizing Kp isolates, identified a plasmid-encoded tellurite (TeO₃^-2)-resistance (ter) operon as strongly associated with infection. However, TeO₃^-2 is extremely rare and toxic to humans. Thus, we used a multidisciplinary approach to determine the biological link between ter and Kp infection. First, we used a genomic and bioinformatic approach to extensively characterize Kp plasmids encoding the ter locus. These plasmids displayed substantial variation in plasmid incompatibility type and gene content. Moreover, the ter operon was genetically independent of other plasmid-encoded virulence and antibiotic resistance loci, both in our original patient cohort and in a large set (n = 88) of publicly available ter operon-encoding Kp plasmids, indicating that the ter operon is likely playing a direct, but yet undescribed role in Kp disease. Next, we employed multiple mouse models of infection and colonization to show that 1) the ter operon is dispensable during bacteremia, 2) the ter operon enhances fitness in the gut, 3) this phenotype is dependent on the colony of origin of mice, and 4) antibiotic disruption of the gut microbiota eliminates the requirement for ter. Furthermore, using 16S rRNA gene sequencing, we show that the ter operon enhances Kp fitness in the gut in the presence of specific indigenous microbiota, including those predicted to produce short chain fatty acids. Finally, administration of exogenous short-chain fatty acids in our mouse model of colonization was sufficient to reduce fitness of a ter mutant. These findings indicate that the ter operon, strongly associated with human infection, encodes factors that resist stress induced by the indigenous gut microbiota during colonization. This work represents a substantial advancement in our molecular understanding of Kp pathogenesis and gut colonization, directly relevant to Kp disease in healthcare settings.     

JAK2 Tyrosine Kinase Phosphorylates and Is Negatively Regulated by Centrosomal Protein Ninein

JAK2 is a cytoplasmic tyrosine kinase critical for cytokine signaling. In this study, we have identified a novel centrosome-associated complex containing ninein and JAK2. We have found that active JAK2 localizes around the mother centrioles, where it partly colocalizes with ninein, a protein involved in microtubule (MT) nucleation and anchoring. We demonstrated that JAK2 is an important regulator of centrosome function. Depletion of JAK2 or use of JAK2-null cells causes defects in MT anchoring and increased numbers of cells with mitotic defects; however, MT nucleation is unaffected. We showed that JAK2 directly phosphorylates the N terminus of ninein while the C terminus of ninein inhibits JAK2 kinase activity in vitro. Overexpressed wild-type (WT) or C-terminal (amino acids 1179 to 1931) ninein inhibits JAK2. This ninein-dependent inhibition of JAK2 significantly decreases prolactin- and interferon gamma (IFN-γ)-induced tyrosyl phosphorylation of STAT1 and STAT5. Downregulation of ninein enhances JAK2 activation. These results indicate that JAK2 is a novel member of centrosome-associated complex and that this localization regulates both centrosomal function and JAK2 kinase activity, thus controlling cytokine-activated molecular pathways.     

Patterns and drivers for wetland connections in the Prairie Pothole Region,United States

Ecosystem function in rivers, lakes and coastal waters depends on the functioning of upstream aquatic ecosystems, necessitating an improved understanding of watershed-scale interactions including variable surface-water flows between wetlands and streams. As surface water in the Prairie Pothole Region expands in wet years, surface-water connections occur between many depressional wetlands and streams. Minimal research has explored the spatial patterns and drivers for the abundance of these connections, despite their potential to inform resource management and regulatory programs including the U.S. Clean Water Act. In this study, wetlands were identified that did not intersect the stream network, but were shown with Landsat images (1990–2011) to become merged with the stream network as surface water expanded. Wetlands were found to spill into or consolidate with other wetlands within both small (2–10 wetlands) and large (>100 wetlands) wetland clusters, eventually intersecting a stream channel, most often via a riparian wetland. These surface-water connections occurred over a wide range of wetland distances from streams (averaging 90–1400 m in different ecoregions). Differences in the spatial abundance of wetlands that show a variable surface-water connection to a stream were best explained by smaller wetland-to-wetland distances, greater wetland abundance, and maximum surface-water extent. This analysis demonstrated that wetland arrangement and surface water expansion are important mechanisms for depressional wetlands to connect to streams and provides a first step to understanding the frequency and abundance of these surface-water connections across the Prairie Pothole Region.     

Viral parkinsonism

Parkinson's disease is a debilitating neurological disorder that affects 1–2% of the adult population over 55 years of age. For the vast majority of cases, the etiology of this disorder is unknown, although it is generally accepted that there is a genetic susceptibility to any number of environmental agents. One such agent may be viruses. It has been shown that numerous viruses can enter the nervous system, i.e. they are neurotropic, and induce a number of encephalopathies. One of the secondary consequences of these encephalopathies can be parkinsonism, that is both transient as well as permanent. One of the most highlighted and controversial cases of viral parkinsonism is that which followed the 1918 influenza outbreak and the subsequent induction of von Economo's encephalopathy. In this review, we discuss the neurological sequelae of infection by influenza virus as well as that of other viruses known to induce parkinsonism including Coxsackie, Japanese encephalitis B, St. Louis, West Nile and HIV viruses.     

Meta-Analysis of Relationships between Human Offtake,Total Mortality and Population Dynamics of Gray Wolves (Canis lupus)

Following the growth and geographic expansion of wolf (Canis lupus) populations reintroduced to Yellowstone National Park and central Idaho in 1995–1996, Rocky Mountain wolves were removed from the endangered species list in May 2009. Idaho and Montana immediately established hunting seasons with quotas equaling 20% of the regional wolf population. Combining hunting with predator control, 37.1% of Montana and Idaho wolves were killed in the year of delisting. Hunting and predator control are well-established methods to broaden societal acceptance of large carnivores, but it is unprecedented for a species to move so rapidly from protection under the Endangered Species Act to heavy direct harvest, and it is important to use all available data to assess the likely consequences of these changes in policy. For wolves, it is widely argued that human offtake has little effect on total mortality rates, so that a harvest of 28–50% per year can be sustained. Using previously published data from 21 North American wolf populations, we related total annual mortality and population growth to annual human offtake. Contrary to current conventional wisdom, there was a strong association between human offtake and total mortality rates across North American wolf populations. Human offtake was associated with a strongly additive or super-additive increase in total mortality. Population growth declined as human offtake increased, even at low rates of offtake. Finally, wolf populations declined with harvests substantially lower than the thresholds identified in current state and federal policies. These results should help to inform management of Rocky Mountain wolves.     

Robustness of close‐kin mark–recapture estimators to dispersal limitation and spatially varying sampling probabilities

1. Close‐kin mark–recapture (CKMR) is a method for estimating abundance and vital rates from kinship relationships observed in genetic samples. CKMR inference only requires animals to be sampled once (e.g., lethally), potentially widening the scope of population‐level inference relative to traditional monitoring programs.
2. One assumption of CKMR is that, conditional on individual covariates like age, all animals have an equal probability of being sampled. However, if genetic data are collected opportunistically (e.g., via hunters or fishers), there is potential for spatial variation in sampling probability that can bias CKMR estimators, particularly when genetically related individuals stay in close proximity.
3. We used individual‐based simulation to investigate consequences of dispersal limitation and spatially biased sampling on performance of naive (nonspatial) CKMR estimators of abundance, fecundity, and adult survival. Population dynamics approximated that of a long‐lived mammal species subject to lethal sampling.
4. Naive CKMR abundance estimators were relatively unbiased when dispersal was unconstrained (i.e., complete mixing) or when sampling was random or subject to moderate levels of spatial variation. When dispersal was limited, extreme variation in spatial sampling probabilities negatively biased abundance estimates. Reproductive schedules and survival were well estimated, except for survival when adults could emigrate out of the sampled area. Incomplete mixing was readily detected using Kolmogorov–Smirnov tests.
5. Although CKMR appears promising for estimating abundance and vital rates with opportunistically collected genetic data, care is needed when dispersal limitation is coupled with spatially biased sampling. Fortunately, incomplete mixing is easily detected with adequate sample sizes. In principle, it is possible to devise and fit spatially explicit CKMR models to avoid bias under dispersal limitation, but development of such models necessitates additional complexity (and possibly additional data). We suggest using simulation studies to examine potential bias and precision of proposed modeling approaches prior to implementing a CKMR program.