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Abstract Background Blue mold is a globally important and economically impactful postharvest disease of apples caused by multiple Penicillium spp. There are currently four postharvest fungicides registered for blue mold control, and some isolates have developed resistance manifesting in decay on fungicide-treated fruit during storage. To date, mechanisms of fungicide resistance have not been explored in this fungus using a transcriptomic approach. Results We have conducted a comparative transcriptomic study by exposing naturally-occurring difenoconazole (DIF) resistant (G10) and sensitive (P11) blue mold isolates to technical grade difenoconazole, an azole fungicide in the commercial postharvest product Academy (Syngenta Crop Protection, LLC). Dynamic changes in gene expression patterns were observed encompassing candidates involved in active efflux and transcriptional regulators between the resistant and sensitive isolates. Unlike other systems, 3 isoforms of cytochrome P450 monoxygenase (CYP51A-C) were discovered and expressed in both sensitive and resistant strains upon difenoconazole treatment. Active efflux pumps were coordinately regulated in the resistant isolate and were shown to mediate the global resistance response as their inhibition reversed the difenoconazole-resistant phenotype in vitro. Conclusions Our data support the observation that global transcriptional changes modulate difenoconazole resistance in Penicillium spp. While the dogma of CYP51 overexpression is supported in the resistant isolate, our studies shed light on additional new mechanisms of difenoconazole resistance on a global scale in Penicillium spp. These new findings broaden our fundamental understanding of azole fungicide resistance in fungi, which has identified multiple genetic targets, that can be used for the detection, management, and abatement of difenoconazole-resistant blue mold isolates during long-term storage of apples.

The necroptotic cell death pathway involves signaling through pseudokinases. Here the authors define the structural determinants of species specificity in necroptosis signaling mediated by the essential necroptotic effector pseudokinase, Mixed Lineage Kinase Domain-Like (MLKL).

Blue mold, caused by Penicillium spp., is an impactful postharvest disease resulting in significant economic losses due to reduced pome fruit quality and mycotoxin contamination. Using two Penicillium species with different levels of aggressiveness, transcriptomics were implemented in order to identify genes expressed during apple fruit decay and loci expressed in ungerminated conidia. Total RNA was isolated from ungerminated conidia and decayed apple fruit infected with P. expansum R19 or P. polonicum RS1. There were 2442 differentially expressed genes (DEGs) between the R19 and RS1 in apple. Comparisons within species between apple and conidia revealed 4404 DEGs for R19 and 2935 for RS1, respectively. Gene ontology (GO) analysis revealed differential regulation in fungal transport and metabolism genes during decay, suggesting a flux in nutrient acquisition and detoxification strategies. In R19, the oxidoreductase GO category comprised 20% of all DEG groups in apple verses conidia. Ungerminated conidia from both species showed DEGs encoding the glyoxylate shunt and beta-oxidation, specifying the earliest metabolic requirements for germination. This is the first study to identify pre-loaded transcripts in conidia from blue mold fungi, reveal unique genes between species expressed during apple decay, and show the expression dynamics of known fungal virulence factors. These findings will enable development of targeted approaches for blue mold abatement strategies.

Studies in both humans and model organisms suggest that the microbiome may play a significant role in host health, including digestion and immune function. Microbiota can offer protection from exogenous pathogens through colonization resistance, but microbial dysbiosis in the gastrointestinal tract can decrease resistance and is associated with pathogenesis. Little is known about the effects of potential pathogens, such as Salmonella, on the microbiome in wildlife, which are known to play an important role in disease transmission to humans. Culturing techniques have traditionally been used to detect pathogens, but recent studies have utilized high throughput sequencing of the 16S rRNA gene to characterize host-associated microbial communities (i.e., the microbiome) and to detect specific bacteria. Building upon this work, we evaluated the utility of high throughput 16S rRNA gene sequencing for potential bacterial pathogen detection in barn swallows (Hirundo rustica) and used these data to explore relationships between potential pathogens and microbiota. To accomplish this, we first compared the detection of Salmonella spp. in swallows using 16S rRNA data with standard culture techniques. Second, we examined the prevalence of Salmonella using 16S rRNA data and examined the relationship between Salmonella-presence or -absence and individual host factors. Lastly, we evaluated host-associated bacterial diversity and community composition in Salmonella-present vs. -absent birds. Out of 108 samples, we detected Salmonella in six (5.6%) samples based on culture, 25 (23.1%) samples with unrarefied 16S rRNA gene sequencing data, and three (2.8%) samples with both techniques. We found that sex, migratory status, and weight were correlated with Salmonella presence in swallows. In addition, bacterial community composition and diversity differed between birds based on Salmonella status. This study highlights the value of 16S rRNA gene sequencing data for monitoring pathogens in wild birds and investigating the ecology of host microbe-pathogen relationships, data which are important for prediction and mitigation of disease spillover into domestic animals and humans.

Familiarity with the landscape increases foraging efficiency and safety. Thus, when animals are confronted with a novel environment, either by natural dispersal or translocation, establishing a home range becomes a priority. While the search for a home range carries a cost of functioning in an unfamiliar environment, ceasing the search carries a cost of missed opportunities. Thus, when to establish a home range is essentially a weighted sum of a two-criteria cost-minimization problem. The process is predominantly heuristic, where the animal must decide how to study the environment and, consequently, when to stop searching and establish a home range in a manner that will reduce the cost and maximize or at least satisfice its fitness. These issues fall within the framework of optimal stopping theory. In this paper we review stopping theory and three stopping rules relevant to home range establishment: the best-of-n rule, the threshold rule, and the comparative Bayes rule. We then describe how these rules can be distinguished from movement data, hypothesize when each rule should be practiced, and speculate what and how environmental factors and animal attributes affect the stopping time. We provide a set of stopping-theory-related predictions that are testable within the context of translocation projects and discuss some management implications.

SARS-Cov-2 escape mutations (EM) have been detected and are spreading. Vaccines may need adjustment to respond to these or future mutations. We designed a population level model integrating both waning immunity and EM. We also designed a set of criteria for elaborating and fitting this model to cross-neutralization and other data with a goal of minimizing vaccine decision errors. We formulated four related models. These differ regarding which strains can drift to escape immunity in the host when that immunity was elicited by different strains. Across changing waning and escape mutation parameter values, these model variations led to patterns where: 1) EM are rare in the first epidemic, 2) rebound outbreaks after the first outbreak are accelerated by increasing waning and by increasing drifting, 3) the long term endemic level of infection is determined mostly by waning rates with small effects of the drifting parameter, 4) EM caused loss of vaccine effectiveness, and under some conditions: vaccines induced EM that caused higher levels of infection with vaccines than without them. The differences and similarities across the four models suggest paths for developing models specifying the epitopes where EM act. This model provides a base on which to construct epitope specific evolutionary models using new high-throughput assay data from population samples to guide vaccine decisions.

Spin-1/2^{119}Sn nuclei in a silicon semiconductor could make excellent qubits. Nuclear spins in silicon are known to have long coherence times. Tin is isoelectronic with silicon, so we expect that electrons can easily shuttle from one Sn atom to another to propagate quantum information via a hyperfine interaction that we predict, from all-electron linearized augmented plane-wave density-functional-theory calculations, to be roughly 10 times larger than that of intrinsic ^{29}Si. A hyperfine-induced electron-nuclear controlled-phase (e-n-CPhase) gate operation, generated (up to local rotations) by merely holding an electron at a sweet spot of maximum hyperfine strength for a specific duration of time, is predicted to be exceptionally resilient to charge or voltage noise. Diabatic spin flips are suppressed with a modest magnetic field (>15mT for

Natural killer (NK) cells are essential for early protection against virus infection and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia-inducible factor-1α (HIF1α) is a feature of mouse NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF1α-deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF1αKO NK cells; however, their numbers were significantly reduced. Loss of HIF1α did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found that HIF1α-deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF1α-deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF1α-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.

Modern humans and Neanderthals coexisted in the Levant for tens of thousands of years before modern humans spread and replaced Neanderthals. Here, Greenbaum et al. develop a model showing that transmission of disease and genes can explain the maintenance and then collapse of this contact zone.

Abstract Background Although there is growing evidence that stepped models of care are useful for providing appropriate, person centered care, there are very few studies applied to personality disorders. A brief, four session, psychological treatment intervention for personality disorder within a whole of service stepped care model was evaluated. The intervention stepped between acute emergency crisis mental health services and longer-term outpatient treatments. Methods Study 1 used service utilization data from 191 individuals referred to the brief intervention at a single community health site in a metropolitan health service. Proportions of individuals retained across the intervention and the referral pathways accessed following the intervention were examined. Study 2 examined 67 individuals referred to the brief intervention across 4 different sites in metropolitan health services. A range of measures of symptoms and quality of life were administered at the first and last session of the intervention. Effect sizes were calculated to examine mean changes across the course of the intervention. Results Study 1 found that 84.29% of individuals referred to the intervention attended at least 1 session, 60.21% attended 2 sessions or more and 41.89% attended 3 or more sessions. 13.61% of the sample required their care to be “stepped up” within the service, whereas 29.31% were referred to other treatment providers following referral to the intervention. Study 2 found a significant reduction in borderline personality disorder symptom severity and distress following the intervention, and an increase in quality of life. The largest reduction was found for suicidal ideation (d = 1.01). Conclusions Brief psychological intervention was a useful step between acute services and longer-term treatments in this stepped model of care for personality disorder. Suicide risk and symptom severity reduced and quality of life improved, with only a small proportion of individuals requiring ongoing support from the health service following the intervention.

Abstract Background Understanding rhino movement behavior, especially their recursive movements, holds significant promise for enhancing rhino conservation efforts, and protecting their habitats and the biodiversity they support. Here we investigate the daily, biweekly, and seasonal recursion behavior of rhinos, to aid conservation applications and increase our foundational knowledge about these important ecosystem engineers. Methods Using relocation data from 59 rhinos across northern Namibia and 8 years of sampling efforts, we investigated patterns in 24-h displacement at dawn, dusk, midday, and midnight to examine movement behaviors at an intermediate scale and across daily behavioral modes of foraging and resting. To understand recursion patterns across animals’ short and long-term ranges, we built T-LoCoH time use grids to estimate recursive movement by each individual. Comparing these grids to contemporaneous MODIS imagery, we investigated productivity’s influence on short-term space use and recursion. Finally, we investigated patterns of recursion within a year’s home range, measuring the time to return to the most intensively used patches. Results Twenty four-hour displacements at dawn were frequently smaller than 24-h displacements at dusk or at midday and midnight resting periods. Recursion analyses demonstrated that short-term recursion was most common in areas of median rather than maximum NDVI values. Investigated across a full year, recursion analysis showed rhinos most frequently returned to areas within 8–21 days, though visits were also seen separated by months likely suggesting seasonality in range use. Conclusions Our results indicate that rhinos may frequently stay within the same area of their home ranges for days at a time, and possibly return to the same general area days in a row especially during morning foraging bouts. Recursion across larger time scales is also evident, and likely a contributing mechanism for maintaining open landscapes and browsing lawns of the savanna.

Abstract Background Hydroxycinnamoyl-spermine conjugates (HCSpm) are a class of hydroxycinnamic acid amides (HCAAs), which not only are instrumental in plant development and stress response, but also benefit human health. However, HCSpm are not commonly produced in plants, and the mechanism of their biosynthesis remains unclear. In previous investigations of phenolics in Solanum fruits related to eggplant (Solanum melongena L.), we discovered that Solanum richardii, an African wild relative of eggplant, was rich in HCSpms in fruits. Results The putative spermine hydroxycinnamoyl transferase (HT) SpmHT was isolated from S. richardii and eggplant. SrSpmHT expression was high in flowers and fruit, and was associated with HCSpm accumulation in S. richardii; however, SpmHT was hardly detected in eggplant cultivars and other wild relatives. Recombinant SpmHT exclusively selected spermine as the acyl acceptor substrate, while showing donor substrate preference in the following order: caffeoyl-CoA, feruloyl-CoA, and p-coumaroyl-CoA. Molecular docking revealed that substrate binding pockets of SpmHT could properly accommodate spermine but not the shorter, more common spermidine. Conclusion SrSpmHT is a novel spermine hydroxycinnamoyl transferase that uses Spm exclusively as the acyl acceptor substrate to produce HCSpms. Our findings shed light on the HCSpm biosynthetic pathway that may allow an increase of health beneficial metabolites in Solanum crops via methods such as introgression or engineering HCAA metabolism.

Epidemiological models are dominated by compartmental models, of which SIR formulations are the most commonly used. These formulations can be continuous or discrete (in either the state-variable values or time), deterministic or stochastic, or spatially homogeneous or heterogeneous, the latter often embracing a network formulation. Here we review the continuous and discrete deterministic and discrete stochastic formulations of the SIR dynamical systems models, and we outline how they can be easily and rapidly constructed using Numerus Model Builder, a graphically-driven coding platform. We also demonstrate how to extend these models to a metapopulation setting using NMB network and mapping tools. Keywords: SIR, SEIR models, Stochastic simulation, Dynamic networks, Compartmental models

Purpose: To identify molecular features that distinguish individuals with shared clinical features of granulomatous uveitis. Design: Cross-sectional observational study. Participants: Four eyes from patients with active granulomatous uveitis. Methods: We performed single-cell RNA sequencing with antigen-receptor sequence analysis to obtain an unbiased gene expression survey of ocular immune cells and to identify clonally expanded lymphocytes. Main Outcomes Measures: For each inflamed eye, we measured the proportion of distinct immune cell types, the amount of B- or T-cell clonal expansion, and the transcriptional profile of T and B cells. Results: Each individual showed robust clonal expansion arising from a single T- or B-cell lineage, suggesting distinct, antigen-driven pathogenic processes in each patient. This variability in clonal expansion was mirrored by individual variability in CD4 T-cell populations, whereas ocular CD8 T cells and B cells were more similar transcriptionally among patients. Finally, ocular B cells displayed evidence of class switching and plasmablast differentiation within the ocular microenvironment, providing additional support for antigen-driven immune responses in granulomatous uveitis. Conclusions: Collectively, our study identified both conserved and individualized features of granulomatous uveitis, illuminating parallel pathophysiologic mechanisms and suggesting that future personalized therapeutic approaches may be warranted.

Mycotoxins are a prevalent problem for stored fruits, grains, and vegetables. Alternariol, aflatoxin, and patulin, produced by Alternaria spp., Aspergillus spp., and Penicillium spp., are the major mycotoxins that negatively affect human and animal health and reduce fruit and produce quality. Control strategies for these toxins are varied, but one method that is increasing in interest is through host microbiome manipulation, mirroring a biocontrol approach. While the majority of mycotoxins and other secondary metabolites (SM) produced by fungi impact host–fungal interactions, there is also an interplay between the various organisms within the host microbiome. In addition to SMs, these interactions involve compounds such as signaling molecules, plant defense and growth hormones, and metabolites produced by both the plants and microbial community. Therefore, studies to understand the impact of the various toxins impacting the beneficial and harmful microorganisms that reside within the microbiome is warranted, and could lead to identification of safe analogs for antimicrobial activity to reduce fruit decay. Additionally, exploring the composition of the microbial carposphere of host plants is likely to shed light on developing a microbial consortium to maintain quality during storage and abate mycotoxin contamination.

A change of an aspartic acid to asparagine of Taq (Thermus aquaticus) DNA polymerase is a gain of function mutation that supports faster PCR: the extension times for PCR amplification can be 2–3 times shorter. Surprising results from negative controls led to the discovery of strand-displacement ability and reverse transcriptase activity of Taq D732N DNA polymerase. We demonstrate that the mutant enzyme can, by itself, catalyze RT-PCR, and RT-LAMP assays. Residue 732 is on the surface of the enzyme, not near the active site.

The organic anion transporter Adenosine triphosphate binding cassette subfamily C member 1 (ABCC1), also known as MRP1, has been demonstrated in murine models of Alzheimer's disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood–brain barrier to the periphery, and that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that its overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the amyloid precursor protein (APP), likely via indirect modulation of alpha-, beta- and gamma-secretase activity.

A high genetic load can negatively affect population viability and increase susceptibility to diseases and other environmental stressors. Prior microsatellite studies of two African buffalo (Syncerus caffer) populations in South Africa indicated substantial genome-wide genetic load due to high-frequency occurrence of deleterious alleles. The occurrence of these alleles, which negatively affect male body condition and bovine tuberculosis resistance, throughout most of the buffalo’s range were evaluated in this study. Using available microsatellite data (2–17 microsatellite loci) for 1676 animals from 34 localities (from 25°S to 5°N), we uncovered continent-wide frequency clines of microsatellite alleles associated with the aforementioned male traits. Frequencies decreased over a south-to-north latitude range (average per-locus Pearson r = -0.22). The frequency clines coincided with a multilocus-heterozygosity cline (adjusted R2 = 0.84), showing up to a 16% decrease in southern Africa compared to East Africa. Furthermore, continent-wide linkage disequilibrium (LD) at five linked locus pairs was detected, characterized by a high fraction of positive interlocus associations (0.66, 95% CI: 0.53, 0.77) between male-deleterious-trait-associated alleles. Our findings suggest continent-wide and genome-wide selection of male-deleterious alleles driven by an earlier observed sex-chromosomal meiotic drive system, resulting in frequency clines, reduced heterozygosity due to hitchhiking effects and extensive LD due to male-deleterious alleles co-occurring in haplotypes. The selection pressures involved must be high to prevent destruction of allele-frequency clines and haplotypes by LD decay. Since most buffalo populations are stable, these results indicate that natural mammal populations, depending on their genetic background, can withstand a high genetic load.

A patient at risk of harboring prostate cancer with a history of ulcerative colitis surgically managed with total colectomy (including the distal rectum and anal canal) underwent CT-planned transperineal prostate biopsy with fluoroscopic guidance. We describe the planning and intraoperative technique to obtain prostate biopsy cores.

Selection for a promiscuous enzyme activity provides substantial opportunity for competition between endogenous and newly-encountered substrates to influence the evolutionary trajectory, an aspect that is often overlooked in laboratory directed evolution studies. We selected the Escherichia coli nitro/quinone reductase NfsA for chloramphenicol detoxification by simultaneously randomising eight active-site residues and interrogating ~250,000,000 reconfigured variants. Analysis of every possible intermediate of the two best chloramphenicol reductases revealed complex epistatic interactions. In both cases, improved chloramphenicol detoxification was only observed after an R225 substitution that largely eliminated activity with endogenous quinones. Error-prone PCR mutagenesis reinforced the importance of R225 substitutions, found in 100% of selected variants. This strong activity trade-off demonstrates that endogenous cellular metabolites hold considerable potential to shape evolutionary outcomes. Unselected prodrug-converting activities were mostly unaffected, emphasising the importance of negative selection to effect enzyme specialisation, and offering an application for the evolved genes as dual-purpose selectable/counter-selectable markers.

Environmentally mediated indirect pathogen transmission is linked to host movement and foraging in areas where pathogens are maintained in the environment. In the case of anthrax, spores of the causative bacterium Bacillus anthracis are released into the environment following host death and create locally infectious zones (LIZs) around carcass sites; by grazing at LIZs, herbivores are potentially exposed to spores. Here, we used camera traps to assess how ungulate species use carcass sites in southwestern Montana and evaluated how these behaviours may promote indirect anthrax transmission, thus providing, to our knowledge, the first detailed documentation and study of the fine-scale mechanisms underlying foraging-based disease transmission in this ecosystem. We found that carcasses at LIZs significantly increased aboveground biomass of vegetation and concentrations of sodium and phosphorus, potentially making these sites more appealing to grazers. Host behavioural responses to LIZs varied depending on species, sex, season and carcass age; but, overall, our results demonstrated that carcasses or carcass sites serve as an attractant to herbivores in this system. Attraction to LIZs probably represents an increased risk of exposure to B. anthracis and, consequently, increased anthrax transmission rates. Accordingly, continued anthrax surveillance and control strategies are critical in this system.

Summary: Major histocompatibility complex class I (MHC-I)-restricted immune responses are largely attributed to cytotoxic T lymphocytes (CTLs). However, natural killer (NK) cells, as predicted by the missing-self hypothesis, have opposing requirements for MHC-I, suggesting that they may also demonstrate MHC-I-restricted effects. In mice, the Ly49 inhibitory receptors prevent NK cell killing of missing-self targets in effector responses, and they have a proposed second function in licensing or educating NK cells via self-MHC-I in vivo. Here we show MHC-I-restricted control of murine cytomegalovirus (MCMV) infection in vivo that is NK cell dependent. Using mice lacking specific Ly49 receptors, we show that control of MCMV requires inhibitory Ly49 receptors and an inhibitory signaling motif and the capacity for MCMV to downregulate MHC-I. Taken together, these data provide definitive evidence that the inhibitory receptors are required for missing-self rejection and are relevant to MHC-I-restricted NK cell control of a viral infection in vivo.

Recognition of DNA viruses, such as cytomegaloviruses (CMVs), through pattern-recognition receptor (PRR) pathways involving MyD88 or STING constitute a first-line defense against infections mainly through production of type I interferon (IFN-I). However, the role of these pathways in different tissues is incompletely understood, an issue particularly relevant to the CMVs which have broad tissue tropisms. Herein, we contrasted anti-viral effects of MyD88 versus STING in distinct cell types that are infected with murine CMV (MCMV). Bone marrow chimeras revealed STING-mediated MCMV control in hematological cells, similar to MyD88. However, unlike MyD88, STING also contributed to viral control in non-hematological, stromal cells. Infected splenic stromal cells produced IFN-I in a cGAS-STING-dependent and MyD88-independent manner, while we confirmed plasmacytoid dendritic cell IFN-I had inverse requirements. MCMV-induced natural killer cytotoxicity was dependent on MyD88 and STING. Thus, MyD88 and STING contribute to MCMV control in distinct cell types that initiate downstream immune responses.

[This corrects the article DOI: 10.1371/journal.pone.0093102.].

Abstract Background Continued exploration of the performance of the recently proposed cross-validation-based approach for delimiting home ranges using the Time Local Convex Hull (T-LoCoH) method has revealed a number of issues with the original formulation. Main text Here we replace the ad hoc cross-validation score with a new formulation based on the total log probability of out-of-sample predictions. To obtain these probabilities, we interpret the normalized LoCoH hulls as a probability density. The application of the approach described here results in optimal parameter sets that differ dramatically from those selected using the original formulation. The derived metrics of home range size, mean revisitation rate, and mean duration of visit are also altered using the corrected formulation. Conclusion Despite these differences, we encourage the use of the cross-validation-based approach, as it provides a unifying framework governed by the statistical properties of the home ranges rather than subjective selections by the user.

Abstract Background Paleozoic holocephalian tooth plates are rarely found articulated in their original positions. When they are found isolated, it is difficult to associate the small, anterior tooth plates with the larger, more posterior ones. Tooth plates are presumed to have evolved from fusion of tooth files. However, there is little fossil evidence for this hypothesis. Results We report a tooth plate having nearly perfect bilateral symmetry from the Mississippian (Chesterian Stage) Bangor Limestone of Franklin County, Alabama, USA. The high degree of symmetry suggests that it may have occupied a symphyseal or parasymphyseal position. The tooth plate resembles Deltodopsis? bialveatus St. John and Worthen, 1883, but differs in having a sharp ridge with multiple cusps arranged along the occlusal surface of the presumed labiolingual axis, rather than a relatively smooth occlusal surface. The multicusped shape is suggestive of a fused tooth file. The middle to latest Chesterian (Serpukhovian) age is determined by conodonts found in the same bed. Conclusion The new tooth plate is interpreted as an anterior tooth plate of a chondrichthyan fish. It is referred to Arcuodus multicuspidatus Itano and Lambert, gen. et sp. nov. Deltodopsis? bialveatus is also referred to Arcuodus.

As the performance of silicon-based qubits has improved, there has been increasing focus on developing designs that are compatible with industrial processes. Here, Jock et al. exploit spin-orbit coupling to demonstrate full, all-electrical control of a metal-oxide-semiconductor electron spin qubit.

Erlang differential equation models of epidemic processes provide more realistic disease-class transition dynamics from susceptible (S) to exposed (E) to infectious (I) and removed (R) categories than the ubiquitous SEIR model. The latter is itself is at one end of the spectrum of Erlang SE $ _m $ I $ _n $ R models with $ m\ge 1 $ concatenated E compartments and $ n \ge 1 $ concatenated I compartments. Discrete-time models, however, are computationally much simpler to simulate and fit to epidemic outbreak data than continuous-time differential equations, and are also much more readily extended to include demographic and other types of stochasticity. Here we formulate discrete-time deterministic analogs of the Erlang models, and their stochastic extension, based on a time-to-go distributional principle. Depending on which distributions are used (e.g. discretized Erlang, Gamma, Beta, or Uniform distributions), we demonstrate that our formulation represents both a discretization of Erlang epidemic models and generalizations thereof. We consider the challenges of fitting SE $ _m $ I $ _n $ R models and our discrete-time analog to data (the recent outbreak of Ebola in Liberia). We demonstrate that the latter performs much better than the former; although confining fits to strict SEIR formulations reduces the numerical challenges, but sacrifices best-fit likelihood scores by at least 7%.

Blue mold, caused by Penicillium spp., is one of the most economically important postharvest diseases of pome fruits, globally. Pome fruits, in particular apple, is the most widely grown pome fruit in Serbia, and the distribution of Penicillium spp. responsible for postharvest decay is unknown. A two-year survey was conducted in 2014 and 2015, where four pome fruits (apple, pear, quince, and medlar) with blue mold symptoms were collected from 20 storage locations throughout Serbia. Detailed morphological characterization, analysis of virulence in three apple cultivars, and multilocus phylogeny revealed three main Penicillium spp. in order of abundance: P. expansum, P. crustosum, and P. solitum. Interestingly, P. expansum split into two distinct clades with strong statistical support that coincided with several morphological observations. Findings from this study are significant and showed previously undocumented diversity in blue mold fungi responsible for postharvest decay including the first finding of P. crustosum, and P. solitum as postharvest pathogens of quince and P. crustosum of medlar fruit in the world, and P. expansum of quince in Serbia. Data from this study provide timely information regarding phenotypic, morphological and genotypic plasticity in P. expansum that will impact the design of species-specific detection tools and guide the development of blue mold management strategies.

Blue mold of apple is caused by several different Penicillium species, among which P. expansum and P. solitum are the most frequently isolated. P. expansum is the most aggressive species, and P. solitum is very weak when infecting apple fruit during storage. In this study, we report complete genomic analyses of three different Penicillium species: P. expansum R21 and P. crustosum NJ1, isolated from stored apple fruit; and P. maximae 113, isolated in 2013 from a flooded home in New Jersey, USA, in the aftermath of Hurricane Sandy. Patulin and citrinin gene cluster analyses explained the lack of patulin production in NJ1 compared to R21 and lack of citrinin production in all three strains. A Drosophila bioassay demonstrated that volatiles emitted by P. solitum SA and P. polonicum RS1 were more toxic than those from P. expansum and P. crustosum strains (R27, R11, R21, G10, and R19). The toxicity was hypothesized to be related to production of eight-carbon oxylipins. Putative lipoxygenase genes were identified in P. expansum and P. maximae strains, but not in P. crustosum. Our data will provide a better understanding of Penicillium spp. complex secondary metabolic capabilities, especially concerning the genetic bases of mycotoxins and toxic VOCs.

Purpose : To evaluate the impact of supplemental external beam radiation therapy (EBRT) prior to permanent prostate brachytherapy on long term urinary, bowel, and erectile function. Material and methods : Patient administered urinary, bowel, and erectile quality of life (QoL) instrument were obtained prior to treatment and following brachytherapy. The study population was comprised of the 457 patients who were alive as of June 2016, had been randomized to two markedly different supplemental EBRT dose regimens and a third arm without supplemental EBRT, and had completed the June 2016 QoL survey. The need for urinary or bowel surgical intervention was prospectively recorded during routine follow-up. Multiple parameters were evaluated for effect on outcomes. Results : The urinary catheter was removed on day 0 in 92.1% of patients and 0.4% required a post-implant transurethral prostatic resection (TURP). On average, the International Prostate Symptom Score (IPSS) normalized at week 14. The 10-year rate of urethral strictures was 5.3%. No significant differences were discerned between baseline and post-implant rectal function assessment score (RFAS), and no patient developed a rectal ulcer or fistula. The 10-year potency preservation rate was 50.3%. Supplemental EBRT did not affect urinary, bowel, or erectile function. Urethral strictures were most closely related to bulbomembranous urethral brachytherapy doses, post-implant rectal function to pre-implant hemorroidal bleeding, and RFAS and erectile function to pre-brachytherapy international index of erectile function and age. Conclusions : Supplemental EBRT did not significantly effect catheter dependency, IPSS resolution, urethral stricture rate, the need for post-implant TURP, bowel, or erectile function. Careful attention to brachytherapy dose distributions appears to be most important in minimizing post-brachytherapy morbidity.

Abstract Background With decreasing costs of GPS telemetry devices, data repositories of animal movement paths are increasing almost exponentially in size. A series of complex statistical tools have been developed in conjunction with this increase in data. Each of these methods offers certain improvements over previously proposed methods, but each has certain assumptions or shortcomings that make its general application difficult. In the case of the recently developed Time Local Convex Hull (T-LoCoH) method, the subjectivity in parameter selection serves as one of the primary impediments to its more widespread use. While there are certain advantages to the flexibility it offers for question-driven research, the lack of an objective approach for parameter selection may prevent some users from exploring the benefits of the method. Methods Here we present a cross-validation-based approach for selecting parameter values to optimize the T-LoCoH algorithm. We demonstrate the utility of the approach using a case study from the Etosha National Park anthrax system. Results Utilizing the proposed algorithm, rather than the guidelines in the T-LoCoH documentation, results in significantly different values for derived site fidelity metrics. Conclusions Due to its basis in principles of cross-validation, the application of this method offers a more objective approach than the relatively subjective guidelines set forth in the T-LoCoH documentation and enables a more accurate basis for the comparison of home ranges among individuals and species, as well as among studies.

Purpose: To evaluate prostate-cancer specific mortality (PCSM) in a cohort of high-risk patients treated with a permanent prostate brachytherapy approach, stratified by pre-treatment PSA. Material and methods : 448 high-risk patients (NCCN criteria) underwent permanent prostate brachytherapy. High risk patients were stratified by pre-treatment PSA (≤ 10.0, 10.1-20, and > 20 ng/ml). Biochemical failure (BF), prostate cancer-specific mortality (PCSM), distant failure (DM), and overall mortality (OM) were assessed as a function of prognostic group. Multiple clinical, treatment, and dosimetric parameters were evaluated for impact on outcome. Results : The 10-year OM, BF, and PCSM for the entire cohort were 28.5%, 13.3%, and 4.9%, respectively. At 10 years, PCSM was 2.5%, 10.7%, and 4.5% in the PSA ≤ 10, 10.1-20, and > 20 ng/ml groups, respectively. No statistically significant differences in BF or overall survival (OS) were noted when stratified by pre-treatment PSA. DF was the most common in the 10.1-20 ng/ml cohort (8.6% at 10 years). In multivariate analysis, PCSM was most closely related to percent positive biopsies (p = 0.001) and tobacco (p = 0.042). Conclusions : High-risk prostate cancer treated with permanent prostate brachytherapy and supplemental external beam radiotherapy resulted in excellent long-term biochemical control and PCSM. Overall, PCSM was low in all cohorts but highest in the intermediate PSA group (10.1-20 ng/ml).