Dectin-3-targeted antifungal liposomes efficiently bind and kill diverse fungal pathogens.

DectiSomes are anti-infective drug-loaded liposomes targeted to pathogenic cells by pathogen receptors including the Dectins. We have previously used C-type lectin (CTL) pathogen receptors Dectin-1, Dectin-2, and DC-SIGN to target DectiSomes to the extracellular oligoglycans surrounding diverse pathogenic fungi and kill them. Dectin-3 (also known as MCL, CLEC4D) is a CTL pathogen receptor whose known cognate ligands are partly distinct from other CTLs. We expressed and purified a truncated Dectin-3 polypeptide (DEC3) comprised of its carbohydrate recognition domain and stalk region. We prepared amphotericin B (AmB)-loaded pegylated liposomes (AmB-LLs) and coated them with this isoform of Dectin-3 (DEC3-AmB-LLs), and we prepared control liposomes coated with bovine serum albumin (BSA-AmB-LLs). DEC3-AmB-LLs bound to the exopolysaccharide matrices of Candida albicans, Rhizopus delemar (formerly known as R. oryzae), and Cryptococcus neoformans from one to several orders of magnitude more strongly than untargeted AmB-LLs or BSA-AmB-LLs. The data from our quantitative fluorescent binding assays were standardized using a CellProfiler program, AreaPipe, that was developed for this purpose. Consistent with enhanced binding, DEC3-AmB-LLs inhibited and/or killed C. albicans and R. delemar more efficiently than control liposomes and significantly reduced the effective dose of AmB. In conclusion, Dectin-3 targeting has the potential to advance our goal of building pan-antifungal DectiSomes.

Droperidol undermining gastroparesis symptoms (DRUGS) in the emergency department.

BACKGROUND/PURPOSE: Gastroparesis is a syndrome of delayed gastric emptying without obstruction. There are high rates of Emergency Department (ED) visits due to gastroparesis, and this chronic disease is difficult to treat which often leads to hospital admissions. This study aimed to evaluate the impact droperidol administration has on opioid therapy, symptom relief, co-administration of antiemetic and prokinetic medications, disposition, cost, and length of stay (LOS) of patients presenting to the ED. RESULTS: A total of 431 patients were identified and 233 met the inclusion criteria. Droperidol administration reduced the number of patients requiring opioid therapy (108/233 [46%] vs 139/233 [60%], P-value 0.0040), reduced patient-reported pain scales by 4 points, and reduced antiemetic therapy requirement (140/233 [60%] vs 169/233 [73%], P-value 0.0045). No differences were found in terms of ED LOS (Median 6 h [IQR 4-8] vs 5 h [IQR 4-9], P-value 0.3638), hospital LOS (Median 6 h [IQR 4-30 vs 7 h [IQR 4-40], P-value 0.8888), hospital admission rates (67/233 [29%] vs 71/233 [31%], P-value 0.6101), ED cost to the facility (Median $1462 [IQR $1114 - $1986] vs $1481 [IQR $1034 - $2235], P-value 0.0943), or hospital cost (Median $4412 [IQR $2359 - $9826] vs $4672 [IQR $2075 - $9911], P-value 0.3136). CONCLUSION: In patients with gastroparesis presenting to the ED, droperidol reduced opioid use, improved pain control, and decreased antiemetic use without any differences in MME per dose, length of stay, hospital admission rate, or cost.

Behavioral and social drivers of COVID-19 vaccination initiation in the US: a longitudinal study March─ October 2021.

Many studies have examined behavioral and social drivers of COVID-19 vaccination initiation, but few have examined these drivers longitudinally. We sought to identify the drivers of COVID-19 vaccination initiation using the Behavioral and Social Drivers of Vaccination (BeSD) Framework. Participants were a nationally-representative sample of 1,563 US adults who had not received a COVID-19 vaccine by baseline. Participants took surveys online at baseline (spring 2021) and follow-up (fall 2021). The surveys assessed variables from BeSD Framework domains (i.e., thinking and feeling, social processes, and practical issues), COVID-19 vaccination initiation, and demographics at baseline and follow-up. Between baseline and follow-up, 65% of respondents reported initiating COVID-19 vaccination. Vaccination intent increased from baseline to follow-up (p < .01). Higher vaccine confidence, more positive social norms towards vaccination, and receiving vaccine recommendations at baseline predicted subsequent COVID-19 vaccine initiation (all p < .01). Among factors assessed at follow-up, social responsibility and vaccine requirements had the greatest associations with vaccine initiation (all p < .01). Baseline vaccine confidence, social norms, and vaccination recommendations were associated with subsequent vaccine initiation, all of which could be useful targets for behavioral interventions. Furthermore, interventions that highlight social responsibility to vaccinate or promote vaccination requirements could also be beneficial.

IMITATION SWITCH is required for normal chromatin structure and gene repression in PRC2 target domains.

Polycomb Group (PcG) proteins are part of an epigenetic cell memory system that plays essential roles in multicellular development, stem cell biology, X chromosome inactivation, and cancer. In animals, plants, and many fungi, Polycomb Repressive Complex 2 (PRC2) catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to assemble transcriptionally repressed facultative heterochromatin. PRC2 is structurally and functionally conserved in the model fungus Neurospora crassa, and recent work in this organism has generated insights into PRC2 control and function. To identify components of the facultative heterochromatin pathway, we performed a targeted screen of Neurospora deletion strains lacking individual ATP-dependent chromatin remodeling enzymes. We found the Neurospora homolog of IMITATION SWITCH (ISW) is critical for normal transcriptional repression, nucleosome organization, and establishment of typical histone methylation patterns in facultative heterochromatin domains. We also found that stable interaction between PRC2 and chromatin depends on ISW. A functional ISW ATPase domain is required for gene repression and normal H3K27 methylation. ISW homologs interact with accessory proteins to form multiple complexes with distinct functions. Using proteomics and molecular approaches, we identified three distinct Neurospora ISW-containing complexes. A triple mutant lacking three ISW accessory factors and disrupting multiple ISW complexes led to widespread up-regulation of PRC2 target genes and altered H3K27 methylation patterns, similar to an ISW-deficient strain. Taken together, our data show that ISW is a key component of the facultative heterochromatin pathway in Neurospora, and that distinct ISW complexes perform an apparently overlapping role to regulate chromatin structure and gene repression at PRC2 target domains.

A machine learning one-class logistic regression model to predict stemness for single cell transcriptomics and spatial omics.

Cell annotation is a crucial methodological component to interpreting single cell and spatial omics data. These approaches were developed for single cell analysis but are often biased, manually curated and yet unproven in spatial omics. Here we apply a stemness model for assessing oncogenic states to single cell and spatial omic cancer datasets. This one-class logistic regression machine learning algorithm is used to extract transcriptomic features from non-transformed stem cells to identify dedifferentiated cell states in tumors. We found this method identifies single cell states in metastatic tumor cell populations without the requirement of cell annotation. This machine learning model identified stem-like cell populations not identified in single cell or spatial transcriptomic analysis using existing methods. For the first time, we demonstrate the application of a ML tool across five emerging spatial transcriptomic and proteomic technologies to identify oncogenic stem-like cell types in the tumor microenvironment.

Aiming for a bull's-eye: Targeting antifungals to fungi with dectin-decorated liposomes.

Globally, there are several million individuals with life-threatening invasive fungal diseases such as candidiasis, aspergillosis, cryptococcosis, Pneumocystis pneumonia (PCP), and mucormycosis. The mortality rate for these diseases generally exceeds 40%. Annual medical costs to treat these invasive fungal diseases in the United States exceed several billion dollars. In addition to AIDS patients, the risks of invasive mycoses are increasingly found in immune-impaired individuals or in immunosuppressed patients following stem cell or organ transplant or implantation of medical devices. Current antifungal drug therapies are not meeting the challenge, because (1) at safe doses, they do not provide sufficient fungal clearance to prevent reemergence of infection; (2) most become toxic with extended use; (3) drug-resistant fungal isolates are emerging; and (4) only one new class of antifungal drugs has been approved for clinical use in the last 2 decades. DectiSomes represent a novel design of drug delivery to drastically increase drug efficacy. Antifungals packaged in liposomes are targeted specifically to where the pathogen is, through binding to the fungal cell walls or exopolysaccharide matrices using the carbohydrate recognition domains of pathogen receptors. Relative to untargeted liposomal drug, DectiSomes show order of magnitude increases in the binding to and killing of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in vitro and similarly improved efficacy in mouse models of pulmonary aspergillosis. DectiSomes have the potential to usher in a new antifungal drug treatment paradigm.

Gene co-expression reveals the modularity and integration of C4 and CAM in Portulaca.

C4 photosynthesis and Crassulacean acid metabolism (CAM) have been considered as largely independent adaptations despite sharing key biochemical modules. Portulaca is a geographically widespread clade of over 100 annual and perennial angiosperm species that primarily use C4 but facultatively exhibit CAM when drought stressed, a photosynthetic system known as C4 + CAM. It has been hypothesized that C4 + CAM is rare because of pleiotropic constraints, but these have not been deeply explored. We generated a chromosome-level genome assembly of Portulaca amilis and sampled mRNA from P. amilis and Portulaca oleracea during CAM induction. Gene co-expression network analyses identified C4 and CAM gene modules shared and unique to both Portulaca species. A conserved CAM module linked phosphoenolpyruvate carboxylase to starch turnover during the day-night transition and was enriched in circadian clock regulatory motifs in the P. amilis genome. Preservation of this co-expression module regardless of water status suggests that Portulaca constitutively operate a weak CAM cycle that is transcriptionally and posttranscriptionally upregulated during drought. C4 and CAM mostly used mutually exclusive genes for primary carbon fixation, and it is likely that nocturnal CAM malate stores are shuttled into diurnal C4 decarboxylation pathways, but we found evidence that metabolite cycling may occur at low levels. C4 likely evolved in Portulaca through co-option of redundant genes and integration of the diurnal portion of CAM. Thus, the ancestral CAM system did not strongly constrain C4 evolution because photosynthetic gene networks are not co-regulated for both daytime and nighttime functions.

Explaining demographic differences in COVID-19 vaccination stage in the United States - April-May 2021.

COVID-19 vaccine coverage in the US has marked demographic and geographical disparities, but few explanations exist for them. Our paper aimed to identify behavioral and social drivers that explain these vaccination disparities. Participants were a national probability sample of 3562 American adults, recruited from the Ipsos KnowledgePanel. Participants completed an online survey in spring 2021, when COVD-19 vaccination was available for higher-risk groups but not yet available to all US adults. The survey assessed COVID-19 vaccination stage (intentions and vaccine uptake), constructs from the Increasing Vaccination Model (IVM) domains (thinking and feeling, social processes, and direct behavior change), self-reported exposure to COVID-19 vaccine information, and demographic characteristics. Analyses used multiple imputation to address item nonresponse and linear regressions to conduct mediation analyses. Higher COVID-19 vaccination stage was strongly associated with older age, liberal political ideology, and higher income in adjusted analyses (all p < .001). Vaccination stage was more modestly associated with urbanicity, white race, and Hispanic ethnicity (all p < .05). Some key mediators that explained more than one-third of demographic differences in vaccination stage were perceived vaccine effectiveness, social norms, and recommendations from family and friends across most demographic characteristics (all p < .05). Other mediators included safety concerns, trust, altruism, provider recommendation, and information seeking. Access to vaccination, barriers to vaccination, and self-efficacy explained few demographic differences. One of the most reliable explanations for demographic differences in COVID-19 vaccination stage is social processes, including social norms, recommendations, and altruism. Interventions to promote COVID-19 vaccination should address social processes and other domains in the IVM.

DNA Methylation: Shared and Divergent Features across Eukaryotes.

Chemical modification of nucleotide bases in DNA provides one mechanism for conveying information in addition to the genetic code. 5-methylcytosine (5mC) represents the most common chemically modified base in eukaryotic genomes. Sometimes referred to simply as DNA methylation, in eukaryotes 5mC is most prevalent at CpG dinucleotides and is frequently associated with transcriptional repression of transposable elements. However, 5mC levels and distributions are variable across phylogenies, and emerging evidence suggests that the functions of DNA methylation may be more diverse and complex than was previously appreciated. We summarize the current understanding of DNA methylation profiles and functions in different eukaryotic lineages.

DectiSomes: Glycan Targeting of Liposomal Drugs Improves the Treatment of Disseminated Candidiasis.

Candida albicans causes life-threatening disseminated candidiasis. Individuals at greatest risk have weakened immune systems. An outer cell wall, exopolysaccharide matrix, and biofilm rich in oligoglucans and oligomannans help Candida spp. evade host defenses. Even after antifungal treatment, the 1-year mortality rate exceeds 25%. Undoubtedly, there is room to improve drug performance. The mammalian C-type lectin pathogen receptors Dectin-1 and Dectin-2 bind to fungal oligoglucans and oligomannans, respectively. We previously coated amphotericin B-loaded liposomes, AmB-LLs, pegylated analogs of AmBisome, with the ligand binding domains of these two Dectins. DectiSomes, DEC1-AmB-LLs and DEC2-AmB-LLs, showed two distinct patterns of binding to the exopolysaccharide matrix surrounding C. albicans hyphae grown in vitro. Here we showed that DectiSomes were preferentially associated with fungal colonies in the kidneys. In a neutropenic mouse model of candidiasis, DEC1-AmB-LLs and DEC2-AmB-LLs delivering only one dose of 0.2 mg/kg AmB reduced the kidney fungal burden several fold relative to AmB-LLs. DEC1-AmB-LLs and DEC2-AmB-LLs increased the percent of surviving mice 2.5-fold and 8.3-fold, respectively, relative to AmB-LLs. Dectin-2 targeting of anidulafungin loaded liposomes, DEC2-AFG-LLs, and of commercial AmBisome, DEC2-AmBisome, reduced fungal burden in the kidneys several fold over their untargeted counterparts. The data herein suggest that targeting of a variety of antifungal drugs to fungal glycans may achieve lower safer effective doses and improve drug efficacy against a variety of invasive fungal infections.

Emergent and urgent ventral hernia repair: comparing recurrence rates amongst procedures utilizing mesh versus no mesh.

BACKGROUND: The decision for emergent and urgent ventral hernia repair (VHR) is driven by acute symptomatology, concern for incarceration and strangulation, and perforation. Although mesh has been established to reduce hernia recurrences, the potential for mesh complications may impact the decision for utilization in emergent repairs. This study evaluates hernia repair outcomes in the emergent setting with/without mesh. METHODS: An IRB-approved review of NSQIP and retrospective chart review data of emergent/urgent VHRs performed between 2013 and 2017 was conducted at a single academic institution. Six-month postoperative emergency department and surgery clinic visits, hospital readmissions, and hernia recurrences were recorded. Patients were grouped based on mesh utilization. Perioperative and outcome variables were compared using Chi-square, Fisher's exact, and t-tests. RESULTS: Among 94 patients, 41 (44%) received mesh; 53 (56%) did not. Synthetic mesh was used in 27 cases (65.9%); bioresorbable or biologic mesh was used in 14 cases (34.1%). ASA class (p = 0.016) was higher in the no-mesh group, as were emergent vs. urgent cases (p ≤ 0.001). Preoperative SIRS/Sepsis, COPD, and diabetes were increased in the no-mesh group. Hernia recurrence was significantly higher in the no-mesh group vs. the mesh group (24.5% vs. 7.3%, p = 0.03). No difference was found in wound complications between groups. ED visits occurred almost twice as often in the mesh group (42% vs. 23%, p = 0.071). Postoperative surgery clinic visits were more frequent among the mesh group (> 1 visit 61% vs. 24%, p = 0.004). CONCLUSIONS: Mesh-based hernia repairs in the urgent/emergent patient population are performed in fewer than half of patients in our tertiary care referral center. Repairs without mesh were associated with over a three-fold increase in recurrence without a difference in the risk of infectious complications. Efforts to understand the rationale for suture-based repair compared to mesh repair are needed to reduce hernia recurrences in the emergent population.

A REVIEW OF LAWSUITS RELATED TO POINT-OF-CARE EMERGENCY ULTRASOUND APPLICATIONS.

BACKGROUND: Previous investigators have assessed United States Case Law to evaluate the medicolegal risk surrounding point-of-care ultrasound applications. These studies have suggested that nonperformance is the primary source of an allegation of medical malpractice. OBJECTIVES: The objective of this study is to update the literature regarding medical malpractice cases involving ultrasound applications that could be used at the point of care, and assess the risk conveyed to advanced practice providers and by application of emerging applications of ultrasound. METHODS: Authors reviewed the Westlaw database for medical malpractice cases involving point-of-care ultrasound applications between December 2012 and January 2021. Cases were included if there was an allegation of misconduct by an emergency provider and if an ultrasound included in the American College of Emergency Physicians investigators core, extended, emerging, or adjunct applications was discussed to any degree. Investigators independently reviewed the cases for inclusion. Authors abstracted the case information, type of ultrasound performed, and the specific allegation of misconduct. RESULTS: Nineteen cases met inclusion criteria. Seven cases involved core applications of emergency ultrasound and 13 involved extended, emerging, or adjunct applications. One case was included in both categories as it included elements of both core and extended applications. The most common primary allegation was failure to perform an ultrasound. No cases clearly alleged misinterpretation of a point-of-care ultrasound. CONCLUSION: As previous studies have suggested, nonperformance of ultrasound seems to convey the greatest medicolegal risk. Extended, emerging, or adjunct applications of ultrasound may convey a slightly higher risk.

The Chromatin Remodeler HELLS: A New Regulator in DNA Repair, Genome Maintenance, and Cancer.

Robust, tightly regulated DNA repair is critical to maintaining genome stability and preventing cancer. Eukaryotic DNA is packaged into chromatin, which has a profound, yet incompletely understood, regulatory influence on DNA repair and genome stability. The chromatin remodeler HELLS (helicase, lymphoid specific) has emerged as an important epigenetic regulator of DNA repair, genome stability, and multiple cancer-associated pathways. HELLS belongs to a subfamily of the conserved SNF2 ATP-dependent chromatin-remodeling complexes, which use energy from ATP hydrolysis to alter nucleosome structure and packaging of chromatin during the processes of DNA replication, transcription, and repair. The mouse homologue, LSH (lymphoid-specific helicase), plays an important role in the maintenance of heterochromatin and genome-wide DNA methylation, and is crucial in embryonic development, gametogenesis, and maturation of the immune system. Human HELLS is abundantly expressed in highly proliferating cells of the lymphoid tissue, skin, germ cells, and embryonic stem cells. Mutations in HELLS cause the human immunodeficiency syndrome ICF (Immunodeficiency, Centromeric instability, Facial anomalies). HELLS has been implicated in many types of cancer, including retinoblastoma, colorectal cancer, hepatocellular carcinoma, and glioblastoma. Here, we review and summarize accumulating evidence highlighting important roles for HELLS in DNA repair, genome maintenance, and key pathways relevant to cancer development, progression, and treatment.

Chromatin accessibility profiling in Neurospora crassa reveals molecular features associated with accessible and inaccessible chromatin.

BACKGROUND: Regulation of chromatin accessibility and transcription are tightly coordinated processes. Studies in yeast and higher eukaryotes have described accessible chromatin regions, but little work has been done in filamentous fungi. RESULTS: Here we present a genome-scale characterization of accessible chromatin regions in Neurospora crassa, which revealed characteristic molecular features of accessible and inaccessible chromatin. We present experimental evidence of inaccessibility within heterochromatin regions in Neurospora, and we examine features of both accessible and inaccessible chromatin, including the presence of histone modifications, types of transcription, transcription factor binding, and relative nucleosome turnover rates. Chromatin accessibility is not strictly correlated with expression level. Accessible chromatin regions in the model filamentous fungus Neurospora are characterized the presence of H3K27 acetylation and commonly associated with pervasive non-coding transcription. Conversely, methylation of H3 lysine-36 catalyzed by ASH1 is correlated with inaccessible chromatin within promoter regions. CONCLUSIONS: In N. crassa, H3K27 acetylation is the most predictive histone modification for open chromatin. Conversely, our data show that H3K36 methylation is a key marker of inaccessible chromatin in gene-rich regions of the genome. Our data are consistent with an expanded role for H3K36 methylation in intergenic regions of filamentous fungi compared to the model yeasts, S. cerevisiae and S. pombe, which lack homologs of the ASH1 methyltransferase.

Ultrasound-Assisted Diagnosis of Embolic Cerebrovascular Accident From Left Atrial Myxoma in the Emergency Department.

BACKGROUND: Acute-onset, unilateral weakness is an alarming presentation due to the possibility of a cerebrovascular accident. When considering cerebrovascular accidents in patients younger than 35 years, emergency physicians should evaluate embolic sources. CASE REPORT: A 28-year-old man with no reported past medical history presented to the Emergency Department with a complaint of acute-onset left-sided hemiparesis and facial droop that started a day prior to arrival. He was stable, had unilateral weakness, hyperreflexia, and slightly slurred speech. He reported no sensory deficits. A computed tomography scan of the head demonstrated areas of ischemia. Patient demographics suggested an embolic source, so point-of-care-ultrasound (POCUS) was performed by emergency practitioners, leading to the discovery of a large, mobile, left atrial mass. After admission and confirmatory imaging, the mass was surgically removed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In young, otherwise healthy individuals, heart masses should be considered as a cause of unexplained stroke-like symptoms. POCUS can identify these masses and expedite care.

Polycomb Group Systems in Fungi: New Models for Understanding Polycomb Repressive Complex 2.

Polycomb group (PcG) proteins form multiple complexes that direct assembly of transcriptionally repressed chromatin, an essential process for multicellular development. Recent studies in plants and animals have uncovered surprising complexity in the form of multiple, variant PcG complexes governed by an extensive regulatory network. PcG proteins are absent from major yeast models, but recent research revealed minimal PcG systems in several well-studied fungi. In both animals and fungi, PcG complexes are responsive to local chromatin structure, but important aspects of PcG regulation remain unknown. Moreover, how PcG complexes repress transcription is poorly understood. The emergence of new fungal models to study PcG proteins is an important development that will accelerate understanding of this important chromatin regulation pathway.

The LSH/DDM1 Homolog MUS-30 Is Required for Genome Stability, but Not for DNA Methylation in Neurospora crassa.

LSH/DDM1 enzymes are required for DNA methylation in higher eukaryotes and have poorly defined roles in genome maintenance in yeast, plants, and animals. The filamentous fungus Neurospora crassa is a tractable system that encodes a single LSH/DDM1 homolog (NCU06306). We report that the Neurospora LSH/DDM1 enzyme is encoded by mutagen sensitive-30 (mus-30), a locus identified in a genetic screen over 25 years ago. We show that MUS-30-deficient cells have normal DNA methylation, but are hypersensitive to DNA damaging agents. MUS-30 is a nuclear protein, consistent with its predicted role as a chromatin remodeling enzyme, and levels of MUS-30 are increased following DNA damage. MUS-30 co-purifies with Neurospora WDR76, a homolog of yeast Changed Mutation Rate-1 and mammalian WD40 repeat domain 76. Deletion of wdr76 rescued DNA damage-hypersensitivity of Δmus-30 strains, demonstrating that the MUS-30-WDR76 interaction is functionally important. DNA damage-sensitivity of Δmus-30 is partially suppressed by deletion of methyl adenine glycosylase-1, a component of the base excision repair machinery (BER); however, the rate of BER is not affected in Δmus-30 strains. We found that MUS-30-deficient cells are not defective for DSB repair, and we observed a negative genetic interaction between Δmus-30 and Δmei-3, the Neurospora RAD51 homolog required for homologous recombination. Together, our findings suggest that MUS-30, an LSH/DDM1 homolog, is required to prevent DNA damage arising from toxic base excision repair intermediates. Overall, our study provides important new information about the functions of the LSH/DDM1 family of enzymes.

KdmB, a Jumonji Histone H3 Demethylase, Regulates Genome-Wide H3K4 Trimethylation and Is Required for Normal Induction of Secondary Metabolism in Aspergillus nidulans.

Histone posttranslational modifications (HPTMs) are involved in chromatin-based regulation of fungal secondary metabolite biosynthesis (SMB) in which the corresponding genes-usually physically linked in co-regulated clusters-are silenced under optimal physiological conditions (nutrient-rich) but are activated when nutrients are limiting. The exact molecular mechanisms by which HPTMs influence silencing and activation, however, are still to be better understood. Here we show by a combined approach of quantitative mass spectrometry (LC-MS/MS), genome-wide chromatin immunoprecipitation (ChIP-seq) and transcriptional network analysis (RNA-seq) that the core regions of silent A. nidulans SM clusters generally carry low levels of all tested chromatin modifications and that heterochromatic marks flank most of these SM clusters. During secondary metabolism, histone marks typically associated with transcriptional activity such as H3 trimethylated at lysine-4 (H3K4me3) are established in some, but not all gene clusters even upon full activation. KdmB, a Jarid1-family histone H3 lysine demethylase predicted to comprise a BRIGHT domain, a zinc-finger and two PHD domains in addition to the catalytic Jumonji domain, targets and demethylates H3K4me3 in vivo and mediates transcriptional downregulation. Deletion of kdmB leads to increased transcription of about ~1750 genes across nutrient-rich (primary metabolism) and nutrient-limiting (secondary metabolism) conditions. Unexpectedly, an equally high number of genes exhibited reduced expression in the kdmB deletion strain and notably, this group was significantly enriched for genes with known or predicted functions in secondary metabolite biosynthesis. Taken together, this study extends our general knowledge about multi-domain KDM5 histone demethylases and provides new details on the chromatin-level regulation of fungal secondary metabolite production.

Ultrasound-Assisted Diagnosis of Optic Neuritis in the Emergency Department: A Case Report.

BACKGROUND: Optic neuritis is a common cause of subacute unilateral vision loss, occurring in 1-5 per 100,000 persons per year. It is more common in Caucasians, women, and those from countries with northern latitudes. Those aged 20-49 years are at greatest risk. The condition arises due to inflammation of the optic nerve. Inflammation may occur due to systemic inflammatory disorders, most commonly multiple sclerosis. CASE REPORT: A 21-year-old African-American male presented to our emergency department with a complaint of painful unilateral vision loss. On examination he was found to have a relative afferent pupillary defect and red desaturation. A bedside ultrasound suggested pseudopapilledema suggestive of optic neuritis. He was admitted to Neurology for confirmation of and treatment for optic neuritis. Magnetic resonance imaging confirmed optic neuritis. The patient was treated with i.v. steroids and discharged after improvement in visual function. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Optic neuritis is a clinical diagnosis. The subtle historical components and examination findings make it a diagnostic challenge for the busy emergency physician. Early diagnosis may improve visual outcomes. Discovery of pseudopapilledema on bedside ultrasound may be seen in optic neuritis, and is another finding that emergency physicians may assess for in patient presenting with unilateral vision loss.