Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis.

OBJECTIVES: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV). METHODS: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation. RESULTS: Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. INTERPRETATION: CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21-33.

An In-Depth Evaluation of Powdery Mildew Hosts Reveals One of the World's Most Common and Widespread Groups of Fungal Plant Pathogens.

Powdery mildews are highly destructive fungal plant pathogens that have a significant economic impact on both agricultural and ecological systems worldwide. The intricate relationship between powdery mildews and their host plants has led to cospeciation. In this study, we conducted an extensive evaluation of powdery mildew hosts to provide an updated understanding of the host ranges and distributions of these fungi. The "United States National Fungus Collections Fungus-Host Dataset" is the primary source of information for our analyses. The analysis of the dataset demonstrated the worldwide prevalence of powdery mildews; the data contained over 72,000 reports of powdery mildews, representing ∼8.7% of all host-fungal records. We have updated the taxonomy and nomenclature of powdery mildews. In total, powdery mildews infect ∼10,125 host taxa belonging to 205 families of flowering plants, which accounts for 1,970 genera in 200 countries across six continents. Furthermore, we estimate that powdery mildews infect approximately 2.9% of described angiosperm species. Our study underscores the need for regular updates on powdery mildew host information due to the continuously evolving taxonomy and the discovery of new host taxa. Since 1986, we estimate an additional 1,866 host taxa, 353 genera, and 36 families have been reported. Additionally, the identification of powdery mildew hosts provides valuable insights into the coevolutionary dynamics between the fungi and their plant hosts. Overall, this updated list provides valuable insights into the taxonomy and geographic distribution of powdery mildew species, which builds upon the previous work of Amano in 1986. Discerning the geographic spread and host range of economically significant plant pathogens is vital for biosecurity measures and identifying the origins and expansion of potentially harmful pathogens.

Genetic time traveling: sequencing old herbarium specimens, including the oldest herbarium specimen sequenced from kingdom Fungi, reveals the population structure of an agriculturally significant rust.

Sequencing herbarium specimens can be instrumental in answering ecological, evolutionary, and taxonomic inquiries. We developed a protocol for sequencing herbarium specimens of rust fungi (Pucciniales) and proceeded to sequence specimens ranging from 4 to 211 yr old from five different genera. We then obtained sequences from an economically important biological control agent, Puccinia suaveolens, to highlight the potential of sequencing herbarium specimens in an ecological sense and to evaluate the following hypotheses: (1) The population structure of a plant pathogen changes over time, and (2) introduced pathogens are more diverse in their native range. Our efforts resulted in sequences from 87 herbarium specimens that revealed a high level of diversity with a population structure that exhibited spatial-temporal patterns. The specimens sequenced from Europe showed more diversity than the ones from North America, uncovering an invasion pattern likely related to its European native host in North America. Additionally, to the best of our knowledge, the specimen from France collected in c. 1811 is the oldest herbarium specimen sequenced from kingdom Fungi. In conclusion, sequencing old herbarium specimens is an important tool that can be extrapolated to better understand plant-microbe evolution and to evaluate old type specimens to solidify the taxonomy of plant pathogenic fungi.

More than a Virulence Factor: Patulin Is a Non-Host-Specific Toxin that Inhibits Postharvest Phytopathogens and Requires Efflux for Penicillium Tolerance.

Mycotoxin contamination is a leading cause of food spoilage and waste on a global scale. Patulin, a mycotoxin produced by Penicillium spp. during postharvest pome fruit decay, causes acute and chronic effects in humans, withstands pasteurization, and is not eliminated by fermentation. While much is known about the impact of patulin on human health, there are significant knowledge gaps concerning the effect of patulin during postharvest fruit-pathogen interactions. Application of patulin on six apple cultivars reproduced some blue mold symptoms that were cultivar-independent and dose-dependent. Identical symptoms were also observed in pear and mandarin orange. Six Penicillium isolates exposed to exogenous patulin exhibited delayed germination after 24 h, yet all produced viable colonies in 7 days. However, four common postharvest phytopathogenic fungi were completely inhibited by patulin during conidial germination and growth, suggesting the toxin is important for Penicillium to dominate the postharvest niche. Using clorgyline, a broad-spectrum efflux pump inhibitor, we demonstrated that efflux plays a role in Penicillium auto-resistance to patulin during conidial germination. The work presented here contributes new knowledge of patulin auto-resistance, its mode of action, and inhibitory role in fungal-fungal interactions. Our findings provide a solid foundation to develop toxin and decay mitigation approaches.

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

An Analysis of Postharvest Fungal Pathogens Reveals Temporal-Spatial and Host-Pathogen Associations with Fungicide Resistance-Related Mutations.

Fungicides are the primary tools to control a wide range of postharvest fungal pathogens. Fungicide resistance is a widespread problem that has reduced the efficacy of fungicides. Resistance to FRAC-1 (Fungicide Resistance Action Committee-1) chemistries is associated with mutations in amino acid position 198 in the ß-tubulin gene. In our study, we conducted a meta-analysis of ß-tubulin sequences to infer temporal, spatial, plant host, and pathogen genus patterns of fungicide resistance in postharvest fungal pathogens. In total, data were acquired from 2,647 specimens from 12 genera of fungal phytopathogens residing in 53 countries on >200 hosts collected between 1926 and 2020. The specimens containing a position 198 mutation were globally distributed in a variety of pathosystems. Analyses showed that there are associations among the mutation and the year an isolate was collected, the pathogen genus, the pathogen host, and the collection region. Interestingly, fungicide-resistant ß-tubulin genotypes have been in a decline since their peak between 2005 and 2009. FRAC-1 fungicide usage data followed a similar pattern in that applications have been in a decline since their peak between 1997 and 2003. The data show that, with the reduction of selection pressure, FRAC-1 fungicide resistance in fungal populations will decline within 5 to 10 years. Based on this line of evidence, we contend that a ß-tubulin position 198 mutation has uncharacterized fitness cost(s) on fungi in nature. The compiled dataset can inform end users on the regions and hosts that are most prone to contain resistant pathogens and assist decisions concerning fungicide resistance management strategies.

Evolution of Disease Severity and Susceptibility in the Asteraceae to the Powdery Mildew Golovinomyces latisporus: Major Phylogenetic Structure Coupled With Highly Variable Disease Severity at Fine Scales.

Pathogen host range and pathogen severity are dependent on interactions with their hosts and are hypothesized to have evolved as products of a coevolutionary arms race. An understanding of the factors that affect host range and pathogen severity is especially crucial in introduced pathogens that infect evolutionarily naïve hosts and cause substantial damage to ecosystems. Powdery mildews are detrimental pathogens found worldwide in managed and natural systems. Golovinomyces latisporus is a powdery mildew species that is especially damaging to plants within Asteraceae and to plants within the genus Helianthus in particular. In this study, we evaluated 126 species within Asteraceae to measure the role of host plant morphophysiological traits and evolutionary history on susceptibility to G. latisporus and disease severity. We observed phylogenetic signal in both susceptibility and severity within and among major clades of the Asteraceae. In general, there was a major phylogenetic structure of host severity to G. latisporus; however, there was some fine-scale phylogenetic variability. Phylogenetic statistical methods showed that chlorophyll content, biomass, stomatal index, and trichome density were not associated with disease severity, thus providing evidence that phylogenetic structure, rather than observed plant morphophysiological traits, is the most reliable predictor of pathogen severity. This work sheds light on the role that evolutionary history plays in plant susceptibility and severity to disease and underscores the relative unimportance of commonly assessed host plant traits in powdery mildew severity.

First report of blue mold caused by Penicillium polonicum on apple in the United States.

Apples (Malus domestica, Rosaceae) are one of the most widely grown and economically valuable fruits worldwide. In Hood River County, Oregon in 1991 decayed apples exhibiting blue mold signs and symptoms were collected and spores from the causal agent of the disease were isolated. The decayed area of the infected apples was brown colored with soft, decayed tissue, which had bluish-green colored spores on the fruit surface. The whole genome of this isolate was sequenced (GenBank number: JYNM00000000) and it was originally identified as Penicillium solitum strain RS1 (Yu et al. 2016). Subsequent genome-wide species-level investigations showed higher homology to P. polonicum. Therefore, we taxonomically and phylogenetically reevaluated the fungus in question. Colonies were analyzed growing on potato dextrose agar (PDA), Czapek yeast autolysate agar (CYA) and malt extract agar (MEA) at 25°C. Colonies on PDA were blue-green and growth was moderately deep and raised at the center with low margins. Colonies on CYA were blue-green. The range of the colony diameter after 7 days at 25ºC was 24-27 mm on CYA and 20-25 mm on MEA. Colony reverse color on CYA was yellow-brown and on MEA was cream. Conidiophores were terverticillate. Stipes were septate with smooth walls and measured 62-250 × 3-5 µm, x̄ = 111.1 × 3.8 µm with 1-4 branches per stipe. Branches measured 8-25 × 2-6 µm, x̄ = 4.9 × 16.3 µm with 2-4 metulae per branch. Metulae measured 7-14 × 2-5 µm, x̄ = 10.1 × 3.6 µm with 1-3 phialides per metulae. Phialides were flask shaped and measured 5-11 × 2-5 µm, x̄ = 7.5 × 3.4 µm. Conidia were globose to subglobose, borne in columns measuring 2.2-5.4 × 2.1-5.3 µm, x̄ = 3.6 × 3.4 µm. Morphologically, the fungal strain RS1 matched the description of Penicillium polonicum K. Zaleski from Bashir et al. (2017), Duduk et al. (2014) and Frisvad and Sampson (2004) with some minor differences. The ITS, TUB and RpB2 sequences of the strain RS1 were extracted from GenBank accession number JYNM00000000. The sequences were then submitted for nucleotide BLAST (NCBI) analysis in GenBank and evaluated. The ITS sequence aligned 100% with the type specimen (CBS 222.28) of P. polonicum (GenBank number: NR_103687). The TUB sequence aligned over 99% with P. polonicum (GenBank numbers: MK450898, MK450935, MK450899). The RpB2 sequences aligned 99.9% or higher with multiple P. polonicum specimens deposited in CBS and CMV (GenBank numbers: MK450847, MK450846, JN985414 and JN985415). Koch's postulates were conducted. Ten apples were wounded with the point of a 16-penny nail, and 10ul of a conidial suspension adjusted to 106 conidia-distilled water/tween solution was added to the wound. Ten separate apples served as a control that were wounded and 10ul of sterile Tween treated water was used to simulate inoculation. None of the control apples developed signs or symptoms of the disease. The inoculated apples all developed typical blue mold symptoms. The fungus was reisolated from the fruit and deemed to be morphologically identical to those of the original RS1, P. polonicum isolate. To the best of our knowledge this is the first report of blue mold caused by P. polonicum in the USA on apples (Farr and Rossman 2021). This information is important for the apple industry for which blue mold is a major problem.

Characterizing the ribosomal tandem repeat and its utility as a DNA barcode in lichen-forming fungi.

BACKGROUND: Regions within the nuclear ribosomal operon are a major tool for inferring evolutionary relationships and investigating diversity in fungi. In spite of the prevalent use of ribosomal markers in fungal research, central features of nuclear ribosomal DNA (nrDNA) evolution are poorly characterized for fungi in general, including lichenized fungi. The internal transcribed spacer (ITS) region of the nrDNA has been adopted as the primary DNA barcode identification marker for fungi. However, little is known about intragenomic variation in the nrDNA in symbiotic fungi. In order to better understand evolution of nrDNA and the utility of the ITS region for barcode identification of lichen-forming fungal species, we generated nearly complete nuclear ribosomal operon sequences from nine species in the Rhizoplaca melanophthalma species complex using short reads from high-throughput sequencing. RESULTS: We estimated copy numbers for the nrDNA operon, ranging from nine to 48 copies for members of this complex, and found low levels of intragenomic variation in the standard barcode region (ITS). Monophyly of currently described species in this complex was supported in phylogenetic inferences based on the ITS, 28S, intergenic spacer region, and some intronic regions, independently; however, a phylogenetic inference based on the 18S provided much lower resolution. Phylogenetic analysis of concatenated ITS and intergenic spacer sequence data generated from 496 specimens collected worldwide revealed previously unrecognized lineages in the nrDNA phylogeny. CONCLUSIONS: The results from our study support the general assumption that the ITS region of the nrDNA is an effective barcoding marker for fungi. For the R. melanophthalma group, the limited amount of potential intragenomic variability in the ITS region did not correspond to fixed diagnostic nucleotide position characters separating taxa within this species complex. Previously unrecognized lineages inferred from ITS sequence data may represent undescribed species-level lineages or reflect uncharacterized aspects of nrDNA evolution in the R. melanophthalma species complex.

Meningoencephalitis due to Spotted Fever Rickettsioses, Including Rocky Mountain Spotted Fever.

BACKGROUND: The spotted fever rickettsioses (SFR), including Rocky Mountain spotted fever, are tick-borne infections with frequent neurologic involvement. High morbidity and mortality make early recognition and empiric treatment critical. Most literature on SFR meningoencephalitis predates widespread magnetic resonance imaging (MRI) utilization. To better understand the contemporary presentation and outcomes of this disease, we analyzed clinical and radiographic features of patients with SFR meningoencephalitis. METHODS: Patients were identified through hospital laboratory-based surveillance or through the Tennessee Unexplained Encephalitis Study. Cases meeting inclusion criteria underwent medical records review and, when available, independent review of the neuroimaging. RESULTS: Nineteen cases (11 children, 8 adults) met criteria for SFR meningoencephalitis. Rash was significantly more common in children than adults (100% vs 50%, respectively), but other clinical features were similar between the 2 groups. Cerebrospinal fluid pleocytosis and protein elevation were each seen in 87.5% of cases, and hypoglycorrhachia was present in 18.8% of cases. The "starry sky" sign (multifocal, punctate diffusion restricting or T2 hyperintense lesions) was seen on MRI in all children, but no adults. Ninety percent of patients required intensive care unit admission and 39% were intubated. Outcomes were similar between adults and children, with only 46% making a complete recovery by the time of discharge. CONCLUSIONS: SFR meningoencephalitis is a life-threatening infection. The clinical presentation varies between adults and children based on the presence of rash and brain MRI findings. The starry sky sign was ubiquitous in children and should prompt consideration of empiric treatment for SFR when present.

Multi-locus phylogeny and taxonomy of an unresolved, heterogeneous species complex within the genus Golovinomyces (Ascomycota, Erysiphales), including G. ambrosiae, G. circumfusus and G. spadiceus.

BACKGROUND: Previous phylogenetic analyses of species within the genus Golovinomyces (Ascomycota, Erysiphales), based on ITS and 28S rDNA sequence data, revealed a co-evolutionary relationship between powdery mildew species and hosts of certain tribes of the plant family Asteraceae. Golovinomyces growing on host plants belonging to the Heliantheae formed a single lineage, comprised of a morphologically differentiated complex of species, which included G. ambrosiae, G. circumfusus, and G. spadiceus. However, the lineage also encompassed sequences retrieved from Golovinomyces specimens on other Asteraceae tribes as well as other plant families, suggesting the involvement of a plurivorous species. A multilocus phylogenetic examination of this complex, using ITS, 28S, IGS (intergenic spacer), TUB2 (beta-tubulin), and CHS1 (chitin synthase I) sequence data was carried out to clarify the discrepancies between ITS and 28S rDNA sequence data and morphological differences. Furthermore, the circumscription of species and their host ranges were emended. RESULTS: The phylogenetic and morphological analyses conducted in this study revealed three distinct species named, viz., (1) G. ambrosiae emend. (including G. spadiceus), a plurivorous species that occurs on a multitude of hosts including, Ambrosia spp., multiple species of the Heliantheae and plant species of other tribes of Asteraceae including the Asian species of Eupatorium; (2) G. latisporus comb. nov. (≡ Oidium latisporum), the closely related, but morphologically distinct species confined to hosts of the Heliantheae genera Helianthus, Zinnia, and most likely Rudbeckia; and (3) G. circumfusus confined to Eupatorium cannabinum in Europe. CONCLUSIONS: The present results provide strong evidence that the combination of multi-locus phylogeny and morphological analysis is an effective way to identify species in the genus Golovinomyces.

Sequencing Herbarium Specimens of a Common Detrimental Plant Disease (Powdery Mildew).

Powdery mildew (Erysiphaceae) is a detrimental plant disease that occurs on a variety of economically important crops. Powdery mildew consists of over 873 species of fungal pathogens that affect over 10,000 plant species. Genetic identification of powdery mildew is accomplished using the internal transcribed spacer (ITS) and large subunit (LSU) regions of the nuclear ribosomal RNA gene cluster. The ITS and LSU regions of powdery mildews can be useful in ecological, epidemiological, phylogenetic, and taxonomic investigations. However, sequencing these regions is not without its challenges. For example, powdery mildew sequences are often contaminated with plant and/or fungal DNA. Also, there tends to be a limited amount and older specimens' DNA can fragment over time. The success of sequencing powdery mildew often depends on the primers used for running polymerase chain reaction (PCR). The primers need to be broad enough that they match the majority of powdery mildew DNA yet specific enough that they do not align with other organisms. A review of the taxonomy and phylogeny of the powdery mildews is presented with an emphasis on sequencing the ITS + LSU genomic regions. Additionally, we introduce a new nested primer protocol for sequencing powdery mildew herbarium samples that includes six new powdery mildew-specific primers. The new sequencing protocol presented allows specimens up to 130 years old to be sequenced consistently. Sequencing herbarium specimens can be extremely useful for addressing many ecological, epidemiological, phylogenetic, and taxonomic problems in multiple plant pathogenic systems including the powdery mildews.

Emergency Evaluation and Management of Encephalitis and Myelitis in Adults.

Infection of the central nervous system is often a life-threatening emergency. In many cases, the clinician faces an unknown pathogen and must rely upon clinical acumen and a thorough, systematic diagnostic investigation to establish a diagnosis and initiate appropriate treatment. Because patients typically present with a syndrome, such as temporal lobe encephalitis, rather than a known pathogen (e.g., herpes simplex virus 1 encephalitis), we describe diagnostic considerations in the context of their neuroanatomic tropisms and patterns of disease. This paradigm reflects the challenges clinicians face; however, tropisms are not absolute, patterns of disease are not specific, and this approach does not obviate the need for empirical treatment while a systematic diagnostic investigation is underway. Specific treatment is available for many infectious agents, including bacterial, fungal, and parasitic pathogens, as well as the herpesviruses. In cases with no specific treatment, clinicians must strive to establish the diagnosis (and thereby spare unneeded treatment), anticipate and recognize complications and pitfalls, and initiate appropriate supportive care, all of which are best achieved with a well-prepared multidisciplinary team.

An Overview of Autoimmune and Paraneoplastic Encephalitides.

The understanding of the manifestations, mechanisms, and management of autoimmune encephalitis has expanded dramatically in recent decades. Immune-mediated encephalitides are comparable in incidence and prevalence to infectious etiologies, and are associated with significant morbidity, especially when there is a delay in recognition and treatment. As such, clinicians from many specialties must develop a functional understanding of these disorders. Herein we provide an overview of the autoimmune and paraneoplastic encephalitides, including those associated with either intracellular or cell surface/synaptic neuronal autoantibodies. After briefly reviewing the current understanding of the pathobiology of autoimmune encephalitis, we combine a neuroanatomical approach with specific antibody syndromes to provide the reader with a clinically relevant review of these disorders. The clinical manifestations, diagnosis, and management of autoimmune encephalitis are reviewed, with an emphasis on clinical relevance. We also introduce updates in the field, including autoimmune encephalitis associated with novel cancer immunotherapies, infectious triggers of autoimmune encephalitis, and autoimmune encephalitis with demyelinating overlap syndromes.

Powdery mildew of Chrysanthemum × morifolium: phylogeny and taxonomy in the context of Golovinomyces species on Asteraceae hosts.

The taxonomic history of the common powdery mildew of Chrysanthemum × morifolium (chrysanthemum, florist's daisy), originally described in Germany as Oidium chrysanthemi, is discussed. The position of O. chrysanthemi was investigated on the basis of morphological traits and molecular phylogenetic analyses. Based on the results of this study, this species, which is closely related to Golovinomyces artemisae, was reassessed and reallocated to Golovinomyces. The phylogenetic analysis and taxonomic reassessment of the chrysanthemum powdery mildew is supplemented by a morphological description, a summary of its worldwide distribution data, and a brief discussion of the introduction of this fungus to North America. G. chrysanthemi differs from true G. artemisiae in that it has much longer conidiophores, is not constricted at the base, and has much larger and most importantly longer conidia. The close affinity of Golovinomyces to Artemisia and Chrysanthemum species signifies a coevolutionary event between the powdery mildews concerned and their host species in the subtribe Artemisiinae (Asteraceae tribe Anthemideae). This conclusion is fully supported by the current phylogeny and taxonomy of the host plant genera and the coevolution that occurred with the host and pathogen. The following powdery mildew species, which are associated with hosts belonging to the tribe Anthemideae of the Asteraceae, are epitypified: Alphitomorpha depressa ß artemisiae (≡ Alphitomorpha artemisiae), Erysiphe artemisiae, and Oidium chrysanthemi. Erysiphe macrocarpa is neotypified. Their sequences were retrieved from the epitype collections and have been added to the phylogenetic tree. Golovinomyces orontii, an additional powdery mildew species on Chrysanthemum ×morifolium, is reported. This species is rarely found as a spontaneous infection and was obtained from inoculation experiments.

Dose-Dependent Therapeutic Distinction between Active and Passive Targeting Revealed Using Transferrin-Coated PGMA Nanoparticles.

The paradigm of using nanoparticle-based formulations for drug delivery relies on their enhanced passive accumulation in the tumor interstitium. Nanoparticles with active targeting capabilities attempt to further enhance specific delivery of drugs to the tumors via interaction with overexpressed cellular receptors. Consequently, it is widely accepted that drug delivery using actively targeted nanoparticles maximizes the therapeutic benefit and minimizes the off-target effects. However, the process of nanoparticle mediated active targeting initially relies on their passive accumulation in tumors. In this article, it is demonstrated that these two tumor-targeted drug delivery mechanisms are interrelated and dosage dependent. It is reported that at lower doses, actively targeted nanoparticles have distinctly higher efficacy in tumor inhibition than their passively targeted counterparts. However, the enhanced permeability and retention effect of the tumor tissue becomes the dominant factor influencing the efficacy of both passively and actively targeted nanoparticles when they are administered at higher doses. Importantly, it is demonstrated that dosage is a pivotal parameter that needs to be taken into account in the assessment of nanoparticle mediated targeted drug delivery.

The Inflammatory Form of Cerebral Amyloid Angiopathy or "Cerebral Amyloid Angiopathy-Related Inflammation" (CAARI).

Cerebral amyloid angiopathy-related inflammation (CAARI) is a recently recognized syndrome of reversible encephalopathy seen in a subset of patients with cerebral amyloid angiopathy (CAA). CAA is a disorder of the elderly in which amyloid peptides are deposited in the walls of cerebral arteries, leading to microhemorrhages, macrohemorrhages, and eventually dementia. In a few cases, the amyloid deposition is accompanied by inflammation or edema. The clinical syndrome of CAARI is distinguished by subacute neurobehavioral symptoms, headaches, seizures, and stroke-like signs, contrasting the acute intracranial hemorrhage typically seen in CAA. Magnetic resonance imaging findings may be symmetric or asymmetric and involve patchy or confluent T2 hyperintense lesions in the cortex and subcortical white matter. Recent diagnostic criteria have been proposed which help distinguish CAARI from alternative diagnoses. Improvement has been reported in most cases with immunosuppression, although a few cases have had recurrent symptoms. Here, we review the clinical and radiologic features of CAARI and compare these with CAA.

Phylogeny and taxonomy of the genera of Erysiphaceae, part 5: Erysiphe (the "Microsphaera lineage" part 1).

In this contribution, we offer the fifth installment of a series focusing on the phylogeny and taxonomy of powdery mildews. This paper is the second segment evaluating the genus Erysiphe. The first treatment of Erysiphe focused on phylogenetically basal species in the "Uncinula lineage." This research presents a phylogenetic-taxonomic assessment of species that form the group previously referred to as the "Microsphaera lineage." Given the size of the group, we split the treatment of this lineage of Erysiphe species into two parts based on their phylogenetic placement. Phylogenetic trees based on ITS+28S data are supplemented by sequences of additional markers (CAM, GADPH, GS, RPB2, and TUB). Included in the analysis of the Microsphaera lineage is the "Erysiphe aquilegiae complex" (group, clade, cluster), which encompasses sequences obtained from an assemblage of Erysiphe species with insufficient resolution in rDNA analyses. Attempts have been made to resolve this group at the species level by applying a multilocus approach. A detailed discussion of the "Erysiphe aquilegiae complex" is provided. Sequences are provided for the first time for several species, particularly North American species, such as Erysiphe aggregata, E. erineophila, E. parnassiae, and E. semitosta. Ex-type sequences for Microsphaera benzoin and M. magnusii have been retrieved. Alphitomorpha penicillata, Microsphaera vanbruntiana, and M. symphoricarpi are epitypified with ex-epitype sequences. The new species Erysiphe alnicola, E. deutziana, E. cornigena, E. lentaginis, and E. sambucina are described, the new combinations E. lauracearum, E. passiflorae, and E. sambucicola are introduced, and the new name E. santali is proposed.