SON is an essential RNA splicing factor promoting ErbB2 and ErbB3 expression in breast cancer.

BACKGROUND: In breast cancer, ErbB receptors play a critical role, and overcoming drug resistance remains a major challenge in the clinic. However, intricate regulatory mechanisms of ErbB family genes are poorly understood. Here, we demonstrate SON as an ErbB-regulatory splicing factor and a novel therapeutic target for ErbB-positive breast cancer. METHODS: SON and ErbB expression analyses using public database, patient tissue microarray, and cell lines were performed. SON knockdown assessed its impact on cell proliferation, apoptosis, kinase phosphorylation, RNA splicing, and in vivo tumour growth. RNA immunoprecipitation was performed to measure SON binding. RESULTS: SON is highly expressed in ErbB2-positive breast cancer patient samples, inversely correlating with patient survival. SON knockdown induced intron retention in selective splice sites within ErbB2 and ErbB3 transcripts, impairing effective RNA splicing and reducing protein expression. SON disruption suppressed downstream kinase signalling of ErbB2/3, including the Akt, p38, and JNK pathways, with increased vulnerability in ErbB2-positive breast cancer cells compared to ErbB2-negative cells. SON silencing in ErbB2-positive breast cancer xenografts led to tumour regression in vivo. CONCLUSION: We identified SON as a novel RNA splicing factor that plays a critical role in regulating ErbB2/3 expression, suggesting SON is an ideal therapeutic target in ErbB2-positive breast cancers.

Unfilled prescriptions: Surveying patients' experiences with buprenorphine treatment in Massachusetts before and during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: We explored potential challenges to accessing office-based opioid treatment (OBOT) with buprenorphine during the COVID-19 pandemic. METHODS: Using Facebook advertisements, we recruited a sample of N = 72 participants and conducted four repeated-measures analysis of variance comparing ratings of participants' abilities to access aspects of OBOT treatment. RESULTS: Participants reported increased difficulty filling buprenorphine prescriptions during the pandemic than before, p = .011, partial η2 = 0.092, and this was correlated with past month opioid use, r = .236, p = .042. DISCUSSION, CONCLUSIONS, AND SCIENTIFIC SIGNIFICANCE: This is the first investigation to report unfilled prescriptions during the pandemic and an association with opioid use. Unfilled prescriptions may contribute to relapse and partially explain increased overdose deaths during COVID-19.

Liposome Formulation for Tumor-Targeted Drug Delivery Using Radiation Therapy.

Targeted delivery of drugs or other therapeutic agents through internal or external triggers has been used to control and accelerate the release from liposomal carriers in a number of studies, but relatively few utilize energy of therapeutic X-rays as a trigger. We have synthesized liposomes that are triggered by ionizing radiation (RTLs) to release their therapeutic payload. These liposomes are composed of natural egg phosphatidylethanolamine (PE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-disteroyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG-2000), and the mean size of the RTL was in the range of 114 to 133 nm, as measured by nanoparticle tracking analysis (NTA). The trigger mechanism is the organic halogen, chloral hydrate, which is known to generate free protons upon exposure to ionizing radiation. Once protons are liberated, a drop in internal pH of the liposome promotes destabilization of the lipid bilayer and escape of the liposomal contents. In proof of principle studies, we assessed RTL radiation-release of fluorescent tracers upon exposure to a low pH extracellular environment or exposure to X-ray irradiation. Biodistribution imaging before and after irradiation demonstrated a preferential uptake and release of the liposomes and their cargo at the site of local tumor irradiation. Finally, a potent metabolite of the commonly used chemotherapy irinotecan, SN-38, was loaded into RTL along with near infrared (NIR) fluorescent dyes for imaging studies and measuring tumor cell cytotoxicity alone or combined with radiation exposure, in vitro and in vivo. Fully loaded RTLs were found to increase tumor cell killing with radiation in vitro and enhance tumor growth delay in vivo after three IV injections combined with three, 5 Gy local tumor radiation exposures compared to either treatment modality alone.

The Misperception of Orientation in Depth When Processing Multiple Pictures With Linear Perspective Cues.

The leaning tower illusion suggests that combining perspective cues across multiple images can affect the perceived orientation of objects in space. We measured the accuracy of orientation perception when viewing multiple pictures. Across several experiments, 11-16 participants viewed two pictures: a sidewalk and either another sidewalk, a nature scene, or no picture. Participants adjusted an on-screen line to match the remembered orientation of one of the sidewalks. Participants also made a judgment about the parallelism of the sidewalks. Sidewalks perceived as parallel were perceived to have orientations more similar to each other than when they were paired with a nature scene or no picture. The degree of misperception can be approximately twice as large as in the leaning tower illusion, and this effect survived inversion and partially survived alternating presentation of the images. The misperception was eliminated when the participants were cued on which sidewalk they would be judging; however, when forced to process both sidewalks, the misperception reappeared. We conclude that the orientation of objects with perspective cues is misperceived when viewing multiple pictures with perspective cues and this misperception appears to be related at least in part to how parallel those objects are perceived to be.

Accelerated Protein Folding Using Greedy-Proximal A.

The protein folding problem has been studied in the field of molecular biophysics and biochemistry for many years. Even small changes in folding patterns may lead to serious diseases such as Alzheimer's or Parkinson's where proteins are folded either too quickly or too slowly. Molecular dynamics (MD) is one of the tools used to understand how proteins fold into native conformations. While it captures sequences of conformations that lead over time to the folded state, limitations in simulation timescales remain problematic. Although many approaches have been suggested to speed up the simulation process using rapid changes in temperature or pressure, we propose a rational approach, Greedy-proximal A* (GPA*), derived from path finding algorithms to explore the supposed shortest path folding pathway from the unfolded to a given folded conformation. We introduce several new protein structure comparison metrics based on the contact map distance to help mitigate the challenges faced by "standard" metrics. We test our approach on proteins which represent the two main types of secondary structure: (a) the Trp-cage miniprotein construct TC5b (1L2Y) which is a short, fast-folding protein that represents an α-helical secondary structure formed because of a locked tryptophan in the middle, (b) the immunoglobulin binding domain of the streptococcal protein G (1GB1), containing an α-helix and several ß-sheets, and (c) the chicken villin subdomain HP-35, N68H protein (1YRF)-one of the fastest folding proteins which forms three α-helices. We compare our algorithm to replica-exchange MD and steered MD methods which represent the main algorithms used for accelerating folding proteins with MD. We find that GPA* not only reduces the computational time needed to obtain the folded conformation without adding artificial energy bias but also makes it possible to generate trajectories which contain minimal motions needed for the folding transition.

A data-driven approach to modeling the tripartite structure of multidrug resistance efflux pumps.

Many bacterial pathogens are becoming increasingly resistant to antibiotic treatments, and a detailed understanding of the molecular basis of antibiotic resistance is critical for the development of next-generation approaches for combating bacterial infections. Studies focusing on pathogens have revealed the profile of resistance in these organisms to be due primarily to the presence of multidrug resistance efflux pumps: tripartite protein complexes which span the periplasm bridging the inner and outer membranes of Gram-negative bacteria. An atomic-level resolution tripartite structure remains imperative to advancing our understanding of the molecular mechanisms of pump function using both theoretical and experimental approaches. We develop a fast and consistent method for constructing tripartite structures which leverages existing data-driven models and provide molecular modeling approaches for constructing tripartite structures of multidrug resistance efflux pumps. Our modeling studies reveal that conformational changes in the inner membrane component responsible for drug translocation have limited impact on the conformations of the other pump components, and that two distinct models derived from conflicting experimental data are both consistent with all currently available measurements. Additionally, we investigate putative drug translocation pathways via geometric simulations based on the available crystal structures of the inner membrane pump component, AcrB, bound to two drugs which occupy distinct binding sites: doxorubicin and linezolid. These simulations suggest that smaller drugs may enter the pump through a channel from the cytoplasmic leaflet of the inner membrane, while both smaller and larger drug molecules may enter through a vestibule accessible from the periplasm.

Effect of Ankle Joint Contact Angle and Ground Contact Time on Depth Jump Performance.

Athletes often need to both jump high and get off the ground quickly, but getting off the ground quickly can decrease the vertical ground reaction force (VGRF) impulse, impeding jump height. Energy stored in the muscle-tendon complex during the stretch-shortening cycle (SSC) may mitigate the effects of short ground contact times (GCTs). To take advantage of the SSC, several coaches recommend "attacking" the ground with the foot in a dorsiflexed (DF) position at contact. However, the efficacy of this technique has not been tested. This investigation tested the hypotheses that shorter GCTs would lead to smaller vertical depth jump heights (VDJH), and that this difference could be mitigated by instructing the athletes to land in a DF as opposed to a plantar flexed (PF) foot position. Eighteen healthy junior college athletes performed depth jumps from a 45-cm box onto force platforms under instruction to achieve one of the 2 objectives (maximum jump height [hmax] or minimal GCT [tmin]), with one of the 2 foot conditions (DF or PF). These variations created 4 distinct jump conditions: DF-hmax, DF-tmin, PF-hmax, and PF-tmin. For all variables examined, there were no significant interactions. For all 4 conditions, the ankle was PF during landing, but the DF condition was 28.87% less PF than the PF condition. The tmin conditions had a 23.48% shorter GCT than hmax. There were no significant main effects for jump height. The peak impact force for tmin was 22.14% greater than hmax and 19.11% greater for DF compared with PF conditions. A shorter GCT did not necessitate a smaller jump height, and a less PF foot did not lead to improvements in jump height or contact time during a depth jump from a 45-cm box. The same jump height was attained in less PF and shorter GCT conditions by larger impact forces. To decrease contact time while maintaining jump height, athletes should be instructed to "get off the ground as fast as possible." This cue seems to be more important than foot position. However, it should be acknowledged that this technique leads to larger impact forces, which should be considered when prescribing the number of foot contacts in a plyometrics program. The ability of athletes to truly land in a DF position during depth jumps is questioned and needs further investigation.

A Case of Spontaneous Splenic Rupture After a Hemicolectomy on Anticoagulation.

Spontaneous or atraumatic splenic rupture (ASR) is a rare but life-threatening condition that requires swift recognition and intervention. We report the case of a 66-year-old female with a history of hypothyroidism, appendiceal goblet cell adenocarcinoma, and new-onset atrial fibrillation (Afib) requiring anticoagulation. She initially presented with right upper quadrant abdominal pain. She had previously undergone an appendectomy followed by a right hemicolectomy to achieve clear surgical margins after the appendiceal carcinoma diagnosis. In the post-anesthesia care unit, she developed Afib and was started on therapeutic anticoagulation. Cardiac catheterization later revealed three-vessel coronary artery disease, prompting a transition from heparin to apixaban. Three days later, the patient suddenly experienced left shoulder pain and was found to be diaphoretic and hypotensive. Three days post-catheterization, the patient developed sudden left shoulder pain, along with diaphoresis and hypotension. An initial concern for post-catheterization myocardial infarction was ruled out. A subsequent CT of the abdomen and pelvis revealed a large splenic hematoma with rupture and hemoperitoneum, necessitating emergent open splenectomy. Post-operatively, the patient required intensive care monitoring and transfusion support before being discharged to a long-term acute care facility. ASR is typically associated with identifiable pathological conditions; however, this case highlights the complexity of multifactorial etiologies. It emphasizes the need to consider ASR in patients presenting with sudden left shoulder pain and hemodynamic instability, particularly when anticoagulation therapy or recent abdominal surgery are factors. This case underscores the importance of a high index of suspicion and timely intervention to prevent fatal outcomes. Further research is warranted to explore the relationship between anticoagulation therapy and ASR.

Dynamic electrophoretic fingerprinting of the HIV-1 envelope glycoprotein.

BACKGROUND: Interactions between the HIV-1 envelope glycoprotein (Env) and its primary receptor CD4 are influenced by the physiological setting in which these events take place. In this study, we explored the surface chemistry of HIV-1 Env constructs at a range of pH and salinities relevant to mucosal and systemic compartments through electrophoretic mobility (EM) measurements. Sexual transmission events provide a more acidic environment for HIV-1 compared to dissemination and spread of infection occurring in blood or lymph node. We hypothesize functional, trimeric Env behaves differently than monomeric forms. RESULTS: The dynamic electrophoretic fingerprint of trimeric gp140 revealed a change in EM from strongly negative to strongly positive as pH increased from that of the lower female genital tract (pHx) to that of the blood (pHy). Similar findings were observed using a trimeric influenza Haemagglutinin (HA) glycoprotein, indicating that this may be a general attribute of trimeric viral envelope glycoproteins. These findings were supported by computationally modeling the surface charge of various gp120 and HA crystal structures. To identify the behavior of the infectious agent and its target cells, EM measurements were made on purified whole HIV-1 virions and primary T-lymphocytes. Viral particles had a largely negative surface charge, and lacked the regions of positivity near neutral pH that were observed with trimeric Env. T cells changed their surface chemistry as a function of activation state, becoming more negative over a wider range of pH after activation. Soluble recombinant CD4 (sCD4) was found to be positively charged under a wide range of conditions. Binding studies between sCD4 and gp140 show that the affinity of CD4-gp140 interactions depends on pH. CONCLUSIONS: Taken together, these findings allow a more complete model of the electrochemical forces involved in HIV-1 Env functionality. These results indicate that the influence of the localized environment on the interactions of HIV with target cells are more pronounced than previously appreciated. There is differential chemistry of trimeric, but not monomeric, Env under conditions which mimic the mucosa compared to those found systemically. This should be taken into consideration during design of immunogens which targets virus at mucosal portals of entry.

Rosai-Dorfman Disease of the Rectum: Newly Identified Genetic Point Mutations and Robotic Resection.

Rosai-Dorfman disease (RDD) is a rare disease characterized by histiocytic proliferation which typically presents as massive, painless, cervical lymphadenopathy in children or young adults. GI involvement is exceedingly rare with only 20 documented cases to date. Of those 20 cases, only 3 cases have involved the rectum. Here, we present 2 cases of rectal RDD with attention paid to the diagnostic and technical challenges presented by this disease. When presenting as a perirectal mass, RDD can be mistaken for other lesions to include malignancy, leading to surgical removal. We present a video of a robotic low-anterior resection with intracorporeal anastomosis in order to remove a pelvic mass involving the rectum, initially considered to be a stromal tumor. In addition, we describe a copy number variation in AKT and 3 point mutations detected by next generation sequencing, which had not been previously reported in association with this disease.

Serum insulin-like growth factors and mortality in localised and advanced clinically detected prostate cancer.

CONTEXT: Many studies have reported associations of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with prostate cancer development, but none have investigated their association with fatal progression of prostate cancer. OBJECTIVE: We investigated associations of circulating IGF-I, IGF-II, IGFBP-2 and IGFBP-3 with all-cause and prostate cancer mortality in men with clinically identified prostate cancer, stratified by whether localised (stage T1 or T2) or advanced (T3, T4, N1 or M1) at diagnosis. DESIGN, SETTING AND PARTICIPANTS: UK hospital-based cohort study of 396 men with prostate cancer, diagnosed between 1990 and 2008, with mean follow-up of 3.7 years. MAIN OUTCOME MEASURES: All-cause and prostate cancer-specific mortality. RESULTS: In men with advanced cancer, there was some evidence that IGF-I was positively associated (HR 1.20; 95% CI: 0.96, 1.49; p = 0.11) and IGFBP-3 was inversely associated (HR 0.84; 95% CI: 0.70, 1.01; p = 0.07) with all-cause mortality after controlling for age, treatment status, smoking, prostate-specific antigen and Gleason grade at diagnosis. There was some evidence that IGF-I was positively associated with prostate cancer mortality in advanced cases (HR 1.23; 95% CI: 0.94, 1.62; p = 0.13). In advanced cancers, associations of IGF-I with all-cause (HR 1.68; 95% CI: 1.28, 2.23; p < 0.001) and prostate cancer-specific (HR 1.59; 95% CI: 1.11, 2.28; p = 0.01) mortality strengthened (and were conventionally statistically significant) after further controlling for IGFBP-3. CONCLUSIONS: Measures of IGF-I and IGFBP-3 may have potential as prognostic markers in predicting risk of death in men with advanced prostate cancer. Large, prospective studies with repeat IGFs and IGFBPs are now required.

A bimodal distribution of two distinct categories of intrinsically disordered structures with separate functions in FG nucleoporins.

Nuclear pore complexes (NPCs) gate the only conduits for nucleocytoplasmic transport in eukaryotes. Their gate is formed by nucleoporins containing large intrinsically disordered domains with multiple phenylalanine-glycine repeats (FG domains). In combination, these are hypothesized to form a structurally and chemically homogeneous network of random coils at the NPC center, which sorts macromolecules by size and hydrophobicity. Instead, we found that FG domains are structurally and chemically heterogeneous. They adopt distinct categories of intrinsically disordered structures in non-random distributions. Some adopt globular, collapsed coil configurations and are characterized by a low charge content. Others are highly charged and adopt more dynamic, extended coil conformations. Interestingly, several FG nucleoporins feature both types of structures in a bimodal distribution along their polypeptide chain. This distribution functionally correlates with the attractive or repulsive character of their interactions with collapsed coil FG domains displaying cohesion toward one another and extended coil FG domains displaying repulsion. Topologically, these bipartite FG domains may resemble sticky molten globules connected to the tip of relaxed or extended coils. Within the NPC, the crowding of FG nucleoporins and the segregation of their disordered structures based on their topology, dimensions, and cohesive character could force the FG domains to form a tubular gate structure or transporter at the NPC center featuring two separate zones of traffic with distinct physicochemical properties.

Acute Large Bowel Obstruction Caused by Endometriosis Requiring Sigmoidectomy.

Large bowel obstruction (LBO) accounts for nearly 25% of all bowel occlusions. LBO is managed as a surgical emergency due to its increased risk of bowel perforation. Nearly, 2% to 4% of all surgical admissions are a result of LBO. The most common pathological development of LBO remains colonic malignancy, representing approximately 60% of cases. Other etiology includes abdominal adhesions, diverticulosis, hernia, inflammatory bowel disease (IBD), and in rare cases endometriosis. In this report, the patient is a 36-year-old female with an LBO, originally thought to be a complication of diverticulitis. However, it was confirmed that the obstruction was a result of endometriosis tissue adherence to the colonic wall narrowing the intestinal lumen. The patient presented to the emergency department (ED) with nausea, vomiting, and abdominal pain that started six weeks prior. In this case report, we will discuss the rare complication of endometriosis causing LBO, clinical presentation, diagnosis, and management.

Validating clustering of molecular dynamics simulations using polymer models.

BACKGROUND: Molecular dynamics (MD) simulation is a powerful technique for sampling the meta-stable and transitional conformations of proteins and other biomolecules. Computational data clustering has emerged as a useful, automated technique for extracting conformational states from MD simulation data. Despite extensive application, relatively little work has been done to determine if the clustering algorithms are actually extracting useful information. A primary goal of this paper therefore is to provide such an understanding through a detailed analysis of data clustering applied to a series of increasingly complex biopolymer models. RESULTS: We develop a novel series of models using basic polymer theory that have intuitive, clearly-defined dynamics and exhibit the essential properties that we are seeking to identify in MD simulations of real biomolecules. We then apply spectral clustering, an algorithm particularly well-suited for clustering polymer structures, to our models and MD simulations of several intrinsically disordered proteins. Clustering results for the polymer models provide clear evidence that the meta-stable and transitional conformations are detected by the algorithm. The results for the polymer models also help guide the analysis of the disordered protein simulations by comparing and contrasting the statistical properties of the extracted clusters. CONCLUSIONS: We have developed a framework for validating the performance and utility of clustering algorithms for studying molecular biopolymer simulations that utilizes several analytic and dynamic polymer models which exhibit well-behaved dynamics including: meta-stable states, transition states, helical structures, and stochastic dynamics. We show that spectral clustering is robust to anomalies introduced by structural alignment and that different structural classes of intrinsically disordered proteins can be reliably discriminated from the clustering results. To our knowledge, our framework is the first to utilize model polymers to rigorously test the utility of clustering algorithms for studying biopolymers.

Systemic reactions to subcutaneous allergen immunotherapy and the response to epinephrine.

The use of epinephrine for anaphylaxis to subcutaneous allergen immunotherapy (SCIT) is the standard of care, but its use for mild systemic reactions (SRs) is somewhat controversial. The objective of this study is to determine the rate of SR to SCIT, the symptoms reported, and the response to intramuscular (i.m.) epinephrine over a 1 year period. This retrospective study was designed to evaluate SRs to SCIT to any combination of approximately 20 allergens (pollens, animal emanations, molds, and Hymenoptera) in 773 subjects representing 14,707 visits, receiving approximately 28,000 injections over 1 year. Nurses were instructed to administer epinephrine (1:1000 v/v) 0.2 mL i.m. for signs or symptoms of a SR. SRs were graded using the universal grading system proposed by the World Allergy Organization (WAO) Joint Task Force for Grading SR to Immunotherapy. Thirty-one patients (4%) had 32 SRs, 22 (71%) female, average age 40 yr. Nineteen (61%) had a history of asthma; 7 (22.6%) had a history of a previous SR. SRs were reported on average 24 minutes after injection. Symptoms included: generalized pruritus, 34.4%; upper airway pruritus, 28.1%; cough, 25.0%; shortness of breath, 21.9%. Fourteen SRs were classified as Grade 1, thirteen Grade 2, two Grade 3, and three Grade 4. No Grade 5 or late phase reactions were reported. 29 (90.6%) reactions were treated with epinephrine, 27 (84.4%) glucocorticosteroid, and 30 (93.8%) H1 antihistamine. SRs occurred in 4% of patients receiving SCIT and all who received early intervention with epinephrine responded successfully. The WAO Grading system was useful.

Outcomes of Sleeve Gastrectomy at a Veterans Affairs Medical Center.

Introduction: Bariatric surgery is the most effective treatment for obesity while improving comorbid conditions and decreasing mortality rates. The purpose of this analysis was to identify the predictive factors associated with the short-term outcomes of laparoscopic sleeve gastrectomy (LSG) at a single Veterans Affairs Medical Center (VAMC). Methods: This is a retrospective analysis of LSG performed at a VAMC from 2013 to 2019. Veterans were followed for 12 months postoperatively. The primary outcomes of interest were excess weight loss (EWL) and total weight loss (TWL) at 3, 6, 9, and 12 months along with resolution of comorbidities. Independent predictors included: demographics, pre- and postoperative findings, geographic distance from VAMC, and per-capita salary of the veteran's residence. Results: A total of 128 patients, including 50 males, completed 12 months' follow-up after LSG. There were no mortalities, transfusions, or conversions to open surgery. The mean length of stay was 2.3 days. At 3, 6, 9, and 12 months, EWL was 27.2%, 33.7%, 35.9%, and 36.6%, respectively; TWL was 12.3%, 15.3%, 16.3%, and 16.7%, respectively. Postoperative hemoglobin A1c and oral hyperglycemic medication usage significantly decreased. High-density lipoprotein levels significantly increased. At 6 months' follow-up, preoperative body mass index (BMI; odds ratio [OR] = 0.7 [95% confidence interval, CI 0.6-0.9]) and age (OR = 0.9 [95% CI 0.8-1.0]) were significant predictors of 50% EWL and EWL broadly (P = .002). Conclusion: Similar to the private sector, LSG is a safe and effective tool for morbid obesity with clinical and serological improvements. For Veterans, increasing BMI and age may portend less weight loss but does not affect resolution of some comorbidities.

Natural product derivatives with bactericidal activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis.

We have shown that the intentional engineering of a natural product biosynthesis pathway is a useful way to generate stereochemically complex scaffolds for use in the generation of combinatorial libraries that capture the structural features of both natural products and synthetic compounds. Analysis of a prototype library based upon nonactic acid lead to the discovery of triazole-containing nonactic acid analogs, a new structural class of antibiotic that exhibits bactericidal activity against drug resistant, Gram-positive pathogens including Staphylococcus aureus and Enterococcus faecalis.

Important Florida botanical aeroallergens.

Florida is home to approximately 4 million allergy sufferers and almost 15,000 individual species of plants. Only a few of these plants produce pollen with documented allergenicity via in vivo/in vitro testing and provocation challenges. Many plant species with proven allergenicity are present only to a limited degree. Furthermore, allergenic plants in Florida do not follow the same pollinating patterns as the rest of the country, i.e., trees in the spring, grasses in the summer, and weeds in the fall. Media outlets that report pollen counts to the general public may mislead patients without appropriate interpretation. This review highlights clinical studies that document the allergenicity of some pollens and summarizes expert opinion regarding other prevalent and allergenic pollens throughout the state.

Semantic web data warehousing for caGrid.

The National Cancer Institute (NCI) is developing caGrid as a means for sharing cancer-related data and services. As more data sets become available on caGrid, we need effective ways of accessing and integrating this information. Although the data models exposed on caGrid are semantically well annotated, it is currently up to the caGrid client to infer relationships between the different models and their classes. In this paper, we present a Semantic Web-based data warehouse (Corvus) for creating relationships among caGrid models. This is accomplished through the transformation of semantically-annotated caBIG Unified Modeling Language (UML) information models into Web Ontology Language (OWL) ontologies that preserve those semantics. We demonstrate the validity of the approach by Semantic Extraction, Transformation and Loading (SETL) of data from two caGrid data sources, caTissue and caArray, as well as alignment and query of those sources in Corvus. We argue that semantic integration is necessary for integration of data from distributed web services and that Corvus is a useful way of accomplishing this. Our approach is generalizable and of broad utility to researchers facing similar integration challenges.

Nonactin biosynthesis: setting limits on what can be achieved with precursor-directed biosynthesis.

Nonactin, produced by Streptomyces griseus ETH A7796, is a macrotetrolide assembled from nonactic acid. It is an effective inhibitor of drug efflux in multidrug resistant erythroleukemia K562 cells at sub-toxic concentrations and has been shown to possess both antibacterial and antitumor activity. As total synthesis is impractical for the generation of nonactin analogs we have studied precursor-directed biosynthesis as an alternative as it is known that nonactic acid can serve as a nonactin precursor in vivo. To determine the scope of the approach we prepared and evaluated a furan-based nonactic acid derivative, 11. Although no new nonactin analogs were detected when 11 was administered to S. griseus fermentative cultures, a significant inhibition of nonactin biosynthesis was noted (IC(50) approximately 100 microM). Cell mass, nonactic acid production and the generation of other secondary metabolites in the culture were unaffected by 11 demonstrating that 11 selectively inhibited the assembly of nonactin from nonactic acid. While we were unable to generate new nonactin analogs we have discovered, however, a useful inhibitor that we can use to probe the mechanism of nonactin assembly with the ultimate goal of developing more successful precursor-directed biosynthesis transformations.