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In response to predation by bacteriophages and invasion by other mobile genetic elements such as plasmids, bacteria have evolved specialized defense systems that are often clustered together on genomic islands. The O1 El Tor strains of Vibrio cholerae responsible for the ongoing seventh cholera pandemic (7PET) contain a characteristic set of genomic islands involved in host colonization and disease, many of which contain defense systems. Notably, Vibrio pathogenicity island 2 contains several characterized defense systems as well as a putative type I restriction-modification (T1RM) system, which, interestingly, is interrupted by two genes of unknown function. Here, we demonstrate that the T1RM system is active, methylates the host genomes of a representative set of 7PET strains, and identify a specific recognition sequence that targets non-methylated plasmids for restriction. We go on to show that the two genes embedded within the T1RM system encode a novel two-protein modification-dependent restriction system related to the GmrSD family of type IV restriction enzymes. Indeed, we show that this system has potent anti-phage activity against diverse members of the Tevenvirinae , a subfamily of bacteriophages with hypermodified genomes. Taken together, these results expand our understanding of how this highly conserved genomic island contributes to the defense of pandemic V. cholerae against foreign DNA., Importance: Defense systems are immunity systems that allow bacteria to counter the threat posed by bacteriophages and other mobile genetic elements. Although these systems are numerous and highly diverse, the most common types are restriction enzymes that can specifically recognize and degrade non-self DNA. Here, we show that the Vibrio pathogenicity island 2, present in the pathogen Vibrio cholerae , encodes two types of restriction systems that use distinct mechanisms to sense non-self DNA. The first system is a classical Type I restriction-modification system, and the second is a novel modification-dependent type IV restriction system that recognizes hypermodified cytosines. Interestingly, these systems are embedded within each other, suggesting that they are complementary to each other by targeting both modified and non-modified phages., Competing Interests: The authors declare no conflict of interest.

Seventh-pandemic Vibrio cholerae strains contain two pathogenicity islands that encode the DNA defense modules DdmABC and DdmDE. In this study, we used cryogenic electron microscopy to determine the mechanistic basis for plasmid defense by DdmDE. The helicase-nuclease DdmD adopts an autoinhibited dimeric architecture. The prokaryotic Argonaute protein DdmE uses a DNA guide to target plasmid DNA. The structure of the DdmDE complex, validated by in vivo mutational studies, shows that DNA binding by DdmE triggers disassembly of the DdmD dimer and loading of monomeric DdmD onto the nontarget DNA strand. In vitro studies indicate that DdmD translocates in the 5'-to-3' direction, while partially degrading the plasmid DNA. These findings provide critical insights into the mechanism of DdmDE systems in plasmid elimination.

Views on the clinical presentation and symptomatology of celiac disease have evolved alongside advances in disease detection and understanding of disease pathogenesis. Although historically regarded as a pediatric illness characterized by malabsorption, it is now better viewed as an immune illness of gluten-specific T cells with systemic manifestations affecting all ages. Its broad presentation, including frequent extraintestinal manifestations and asymptomatic disease, contributes to suboptimal disease detection. Adverse symptoms greatly impact patient quality of life and can result from chronic gluten exposure in untreated disease or those poorly responsive to the gluten-free diet. They can also present as acute symptoms after episodic gluten exposure. Functional gastrointestinal disease is a common comorbidity. Biomarkers like interleukin-2 that are highly sensitive and specific for celiac disease highlight a role for gluten-specific T cells in acute gluten symptomatology. A mechanistic understanding of symptoms will inform approaches to better measure and treat them effectively., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

SRSF1 is the founding member of the SR protein family. It is required-interchangeably with other SR proteins-for pre-mRNA splicing in vitro, and it regulates various alternative splicing events. Dysregulation of SRSF1 expression contributes to cancer and other pathologies. Here, we characterized SRSF1's interactome using proximity labeling and mass spectrometry. This approach yielded 190 proteins enriched in the SRSF1 samples, independently of the N- or C-terminal location of the biotin-labeling domain. The detected proteins reflect established functions of SRSF1 in pre-mRNA splicing and reveal additional connections to spliceosome proteins, in addition to other recently identified functions. We validated a robust interaction with the spliceosomal RNA helicase DDX23/PRP28 using bimolecular fluorescence complementation and in vitro binding assays. The interaction is mediated by the N-terminal RS-like domain of DDX23 and both RRM1 and the RS domain of SRSF1. During pre-mRNA splicing, DDX23's ATPase activity is essential for the pre-B to B spliceosome complex transition and for release of U1 snRNP from the 5' splice site. We show that the RS-like region of DDX23's N-terminal domain is important for spliceosome incorporation, while larger deletions in this domain alter subnuclear localization. We discuss how the identified interaction of DDX23 with SRSF1 and other SR proteins may be involved in the regulation of these processes., Competing Interests: Competing interests statement:A.R.K. is a co-founder, Director, and shareholder of Stoke Therapeutics, a member of the SABs of Skyhawk Therapeutics, Envisagenics, and Autoimmunity BioSolutions, and a consultant for Biogen. These relationships are unrelated to the present work.

Development relies on the exquisite control of both the timing and the levels of gene expression to achieve robust developmental transitions. How cis- and trans-acting factors control both aspects simultaneously is unclear. We show that transcriptional pulses of the temporal patterning microRNA (miRNA) lin-4 are generated by two nuclear hormone receptors (NHRs) in C. elegans, NHR-85 and NHR-23, whose mammalian orthologs, Rev-Erb and ROR, function in the circadian clock. Although Rev-Erb and ROR antagonize each other to control once-daily transcription in mammals, NHR-85/NHR-23 heterodimers bind cooperatively to lin-4 regulatory elements to induce a single pulse of expression during each larval stage. Each pulse's timing, amplitude, and duration are dictated by the phased expression of these NHRs and the C. elegans Period ortholog, LIN-42, that binds to and represses NHR-85. Therefore, during nematode temporal patterning, an evolutionary rewiring of circadian clock components couples the timing of gene expression to the control of transcriptional dosage., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Nucleosomes block access to DNA methyltransferase, unless they are remodeled by DECREASE in DNA METHYLATION 1 (DDM1 LSH / HELLS ), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 promotes replacement of histone variant H3.3 by H3.1. In ddm1 mutants, DNA methylation is partly restored by loss of the H3.3 chaperone HIRA, while the H3.1 chaperone CAF-1 becomes essential. The single-particle cryo-EM structure at 3.2 Å of DDM1 with a variant nucleosome reveals engagement with histone H3.3 near residues required for assembly and with the unmodified H4 tail. An N-terminal autoinhibitory domain inhibits activity, while a disulfide bond in the helicase domain supports activity. DDM1 co-localizes with H3.1 and H3.3 during the cell cycle, and with the DNA methyltransferase MET1 Dnmt1 , but is blocked by H4K16 acetylation. The male germline H3.3 variant MGH3/HTR10 is resistant to remodeling by DDM1 and acts as a placeholder nucleosome in sperm cells for epigenetic inheritance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Historical horticultural plant sales influence native and nonnative species assemblages in contemporary ecosystems. Over half of nonnative, invasive plants naturalized in the United States were introduced as ornamentals, and the spatial and temporal patterns of early introduction undoubtedly influence current invasion ecology. While thousands of digitized nursery catalogs documenting these introductions are publicly available, they have not been standardized in a single database. To fill this gap, we obtained the names of all plant taxa (species, subspecies, and varieties) present in the Biodiversity Heritage Library's (BHL) Seed and Nursery Catalog Collection. We then searched the BHL database for these names and downloaded all available records. We combined BHL records with data from an encyclopedia of heirloom ornamental plants to create a single database of historical nursery sales in the US. Each record represents an individual taxon offered for sale at an individual time in a specific nursery's catalog. We standardized records to the current World Flora Online (http://worldfloraonline.org) accepted taxonomy and appended accepted USDA code, growth habit, and introduction status. We also appended whether taxa were reported as invasive in the Global Plant Invaders (GPI) data set or the Global Invasive Species Database (GISD) or regulated in the conterminous US. Lastly, we geocoded all reported publication locations. The data set contains 2,445,875 records from nurseries in at least 2795 unique locations, with the majority of catalogs published between 1890 and 1950. Nurseries were located in all conterminous states but were concentrated in the eastern US and California. We identified 19,140 unique horticultural taxa, of which 8642 matched taxa in the USDA Plants database. The USDA Plants database is limited to native and naturalized taxa in the US. Native or introduced status was listed in USDA Plants for 7018 of included taxa, while 1642 had an unknown status. The remaining 10,498 taxa are not naturalized according to USDA Plants or are of varieties of native and introduced taxa that did not match USDA Plants taxonomy. The majority of taxa in the Historical Plant Sales (HPS) database with an identified status are native (65.5%; 4596 of 7018 taxa), of which 393 taxa are reported as invasive outside of the US. Of the 2381 introduced taxa, 1103 (46.3%) are reported as invasive somewhere globally. Despite a richer pool of native taxa, most cataloged plant records with an identified status were of introduced taxa (54.1%; 1,045,684 of 1,933,925 records). Plants reported as invasive somewhere globally comprised a large portion of records with an identified status (38.7%; 747,953 of 1,933,925 records) underscoring the large role of ornamental introductions in facilitating plant invasions. The HPS database provides a consolidated and standardized perspective on the history of native, introduced, and invasive plant sales in the US. We release these data into the public domain under a Creative Commons Zero license waiver (https://creativecommons.org/share-your-work/publicdomain/cc0/). Individuals who use these data for publication may cite the associated data paper., (© 2023 The Ecological Society of America.)

Horizontal gene transfer can trigger rapid shifts in bacterial evolution. Driven by a variety of mobile genetic elements-in particular bacteriophages and plasmids-the ability to share genes within and across species underpins the exceptional adaptability of bacteria. Nevertheless, invasive mobile genetic elements can also present grave risks to the host; bacteria have therefore evolved a vast array of defences against these elements 1 . Here we identify two plasmid defence systems conserved in the Vibrio cholerae El Tor strains responsible for the ongoing seventh cholera pandemic 2-4 . These systems, termed DdmABC and DdmDE, are encoded on two major pathogenicity islands that are a hallmark of current pandemic strains. We show that the modules cooperate to rapidly eliminate small multicopy plasmids by degradation. Moreover, the DdmABC system is widespread and can defend against bacteriophage infection by triggering cell suicide (abortive infection, or Abi). Notably, we go on to show that, through an Abi-like mechanism, DdmABC increases the burden of large low-copy-number conjugative plasmids, including a broad-host IncC multidrug resistance plasmid, which creates a fitness disadvantage that counterselects against plasmid-carrying cells. Our results answer the long-standing question of why plasmids, although abundant in environmental strains, are rare in pandemic strains; have implications for understanding the dissemination of antibiotic resistance plasmids; and provide insights into how the interplay between two defence systems has shaped the evolution of the most successful lineage of pandemic V. cholerae., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Aims: The objective of this study was to identify the prevalence of avoidant/restrictive food intake disorder (ARFID) in patients with celiac disease (CD) and assess metabolic complications, disease control, diet adherence, and correlation with symptom and quality-of-life metrics., Methods: This was a retrospective study of 137 adult patients with CD who completed an ARFID survey in the CD clinic between 2018 and 2020. Demographics, clinical results, standardized diet assessment, and results of Celiac Disease Symptom Diary and Impact of a Gluten-free Diet Questionnaire were reviewed. The primary outcome measured was the rate of suspected ARFID based on patient-reported survey responses., Results: Seventy-eight patients (57%) met suspected ARFID criteria. There were no differences in age, gender, body mass index, micronutrient deficiencies, or bone disease in those with or without ARFID. Patients with ARFID did not have a difference in biopsy activity or better adherence to a gluten-free diet compared with non-ARFID patients. Food and social burden on Impact of a Gluten-free Diet Questionnaire was most predictive of ARFID., Conclusion: ARFID is common and has a high impact in patients with CD. Although some eating behavior is certainly due to their CD, there was no distinct difference in disease control between those with or without suspected ARFID, suggesting these maladaptive behaviors are not necessary for disease control. We did not find increased metabolic complications, but this was a 2-year snapshot. We need to further understand the social and food impacts on patients who score high on this survey to prevent further deficiencies and impaired, long-term detrimental eating behaviors., (© 2022 The Authors.)

Comprehensive cancer data sets recently generated by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) offer great potential for advancing our understanding of how to combat cancer. These data sets include DNA, RNA, protein, and clinical characterization for tumor and normal samples from large cohorts of many different cancer types. The raw data are publicly available at various Cancer Research Data Commons. However, widespread reuse of these data sets is also facilitated by easy access to the processed quantitative data tables. We have created a data application programming interface (API) to distribute these processed tables, implemented as a Python package called cptac. We implement it such that users who prefer to work in R can easily use our package for data access and then transfer the data into R for analysis. Our package distributes the finalized processed CPTAC data sets in a consistent, up-to-date format. This consistency makes it easy to integrate the data with common graphing, statistical, and machine-learning packages for advanced analysis. Additionally, consistent formatting across all cancer types promotes the investigation of pan-cancer trends. The data API structure of directly streaming data within a programming environment enhances the reproducibility. Finally, with the accompanying tutorials, this package provides a novel resource for cancer research education. View the software documentation at https://paynelab.github.io/cptac/. View the GitHub repository at https://github.com/PayneLab/cptac.

Altered barrier function is a part of celiac disease (CeD) pathophysiology that we currently cannot reliably measure. Catheter-based mucosal integrity (MI) is an endoscopic technology that has identified altered esophageal barrier function in esophageal disease. 1 The aim of this study was to evaluate feasibility, safety, and clinical utility of measuring duodenal integrity with an MI catheter in patients with and without CeD., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Smoking is a strong risk factor for disease severity in Crohn's disease (CD) and cessation improves outcomes. The nicotine metabolite ratio (NMR) predicts cessation success with pharmacotherapy: varenicline doubles cessation over nicotine replacement therapy (NRT) for "normal", but not "slow" metabolizers. Varenicline side effects are heightened in slow metabolizers. Methods using NMR to optimize cessation pharmacotherapy have not been evaluated in CD., Aims: We aim to determine the prevalence of smoking in a CD population and then assess these smokers' attitudes toward a personalized metabolism-informed care (MIC) approach to cessation., Methods: In this observational study, we surveyed 1098 patients visiting an inflammatory bowel disease center about their smoking history. We then evaluated a subgroup of individuals with CD (n = 32) who participated in a randomized controlled trial of smoking cessation using MIC versus usual care. For MIC, medication selection was informed by the NMR (normal ≥0.31 vs. slow <0.31). The primary outcomes were intervention satisfaction and match rates between NMR and medication choice., Results: The baseline prevalence of smoking in our CD population was 13%. Intervention participants reported high rates of satisfaction (85%) and chose a medication that matched their NMR result more often in the MIC group (100% vs. 64%, p = 0.01). Six of 16 (37.5%) patients prescribed varenicline discontinued due to side effects., Conclusion: MIC produced high rates of satisfaction and matching between NMR and medication in CD patients, supporting patient acceptance and feasibility of precision smoking cessation in this population. To reduce smoking in CD, therapies such as MIC are needed to maximize efficacy and minimize side effects., Competing Interests: David A. Schwartz has consultancy agreements with Abbvie, UCB, Janssen, Takeda, and Tigenix. Dawn B. Beaulieu has consultancy agreements with Abbvie, Janssen, and Takeda. Sara N. Horst has consultancy agreements with UCB, Janssen, and Salix. However, these agreements and grants had no relationship to the current research study. The remaining authors declare no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets., Competing Interests: Declaration Of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Type IV pili are dynamic cell surface appendages found throughout the bacteria. The ability of these structures to undergo repetitive cycles of extension and retraction underpins their crucial roles in adhesion, motility and natural competence for transformation. In the best-studied systems a dedicated retraction ATPase PilT powers pilus retraction. Curiously, a second presumed retraction ATPase PilU is often encoded immediately downstream of pilT. However, despite the presence of two potential retraction ATPases, pilT deletions lead to a total loss of pilus function, raising the question of why PilU fails to take over. Here, using the DNA-uptake pilus and mannose-sensitive haemagglutinin (MSHA) pilus of Vibrio cholerae as model systems, we show that inactivated PilT variants, defective for either ATP-binding or hydrolysis, have unexpected intermediate phenotypes that are PilU-dependent. In addition to demonstrating that PilU can function as a bona fide retraction ATPase, we go on to make the surprising discovery that PilU functions exclusively in a PilT-dependent manner and identify a naturally occurring pandemic V. cholerae PilT variant that renders PilU essential for pilus function. Finally, we show that Pseudomonas aeruginosa PilU also functions as a PilT-dependent retraction ATPase, providing evidence that the functional coupling between PilT and PilU could be a widespread mechanism for optimal pilus retraction., Competing Interests: The authors have declared that no competing interests exist.

How bacteria colonize surfaces and how they distinguish the individuals around them are fundamental biological questions. Type IV pili are a widespread and multipurpose class of cell surface polymers. Here we directly visualize the DNA-uptake pilus of Vibrio cholerae, which is produced specifically during growth on its natural habitat-chitinous surfaces. As predicted, these pili are highly dynamic and retract before DNA uptake during competence for natural transformation. Interestingly, DNA-uptake pili can also self-interact to mediate auto-aggregation. This capability is conserved in disease-causing pandemic strains, which typically encode the same major pilin subunit, PilA. Unexpectedly, however, we discovered that extensive strain-to-strain variability in PilA (present in environmental isolates) creates a set of highly specific interactions, enabling cells producing pili composed of different PilA subunits to distinguish between one another. We go on to show that DNA-uptake pili bind to chitinous surfaces and are required for chitin colonization under flow, and that pili capable of self-interaction connect cells on chitin within dense pili networks. Our results suggest a model whereby DNA-uptake pili function to promote inter-bacterial interactions during surface colonization. Moreover, they provide evidence that type IV pili could offer a simple and potentially widespread mechanism for bacterial kin recognition.

Crohn's disease (CD) has been associated with an increased consumption of n-6 polyunsaturated fatty acid (PUFA), while greater intake of n-3 PUFA has been associated with a reduced risk. We sought to investigate serum fatty acid composition in CD, and associations of fatty acids with disease activity, cytokines, and adipokines. Serum was prospectively collected from 116 CD subjects and 27 non-IBD controls. Clinical disease activity was assessed by the Harvey Bradshaw Index (HBI). Serum fatty acids were measured by gas chromatography. Serum cytokines and adipokines were measured by Luminex assay. Dietary histories were obtained from a subset of patients. Nine serum cytokines and adipokines were increased in CD versus controls. CD subjects had increased percentage serum monounsaturated fatty acids (MUFA), dihomo-gamma linolenic acid (DGLA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and oleic acid, but decreased arachidonic acid (AA) versus controls. The % total n-3 fatty acids and % EPA directly correlated with pro-inflammatory cytokine levels and HBI, whereas the % total n-6 fatty acids were inversely correlated with pro-inflammatory cytokine levels and HBI. CD subjects had increased caloric intake versus controls, but no alterations in total fat or PUFA intake. We found differences in serum fatty acids, most notably PUFA, in CD that correlated both with clinical disease activity and inflammatory cytokines. Our findings indicate that altered fatty acid metabolism or utilization is present in CD and is related to disease activity.

Celiac disease is an autoimmune disorder due to the inflammatory response to gluten in genetically predisposed individuals. It causes an enteropathy associated with several nutritional complications. Strict compliance to a gluten-free diet (GFD) is the current primary therapy. Nonceliac gluten sensitivity (NCGS) is a condition in which gluten ingestion leads to systemic symptoms but is not associated with small bowel atrophy or abnormal celiac serologies. A GFD heals celiac disease enteropathy and improves symptoms in NCGS. However, a long-term GFD can be associated with nutritional deficiencies and requires monitoring and guidance., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Parenteral nutrition (PN) is a life-sustaining therapy in patients with intestinal failure who are unable to tolerate enteral feedings. Patient selection should be based on a thorough assessment to identify those at high nutrition risk based on both disease severity and nutritional status. This article reviews both the acute and chronic indications for PN as well as special formulation consideration in specific disease states, vascular access, and complications of both short-term and long-term PN., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Biomarkers are needed in inflammatory bowel disease (IBD) to help define disease activity and identify underlying pathogenic mechanisms. We hypothesized that serum metabolomics, which produces unique metabolite profiles, can aid in this search., Objectives: The aim of this study was to characterize serum metabolomic profiles in patients with IBD, and to assess for differences between patients with ulcerative colitis (UC), Crohn's disease (CD), and non- IBD subjects., Methods: Serum samples from 20 UC, 20 CD, and 20 non-IBD control subjects were obtained along with patient characteristics, including medication use and clinical disease activity. Non-targeted metabolomic profiling was performed using ultra-high performance liquid chromatography/mass spectrometry (UPLC-MS/MS) optimized for basic or acidic species and hydrophilic interaction liquid chromatography (HILIC/UPLC-MS/MS)., Results: In total, 671 metabolites were identified. Comparing IBD and control subjects revealed 173 significantly altered metabolites (27 increased and 146 decreased). The majority of the alterations occurred in lipid-, amino acid-, and energy-related metabolites. Comparing only CD and control subjects revealed 286 significantly altered metabolites (54 increased and 232 decreased), whereas comparing UC and control subjects revealed only 5 significantly altered metabolites (all decreased). Hierarchal clustering using significant metabolites separated CD from UC and control subjects., Conclusions: We demonstrate that a number of lipid-, amino acid-, and tricarboxylic acid (TCA) cycle- related metabolites were significantly altered in IBD patients, more specifically in CD. Therefore, alterations in lipid and amino acid metabolism and energy homeostasis may play a key role in the pathogenesis of CD., Competing Interests: Conflicts of Interest: David A. Schwartz has consultancy agreements with Abbvie, UCB, Janssen, Takeda, and Tigenix. Dawn B. Beaulieu has a consultancy agreement with Abbvie. Sara N. Horst has consultancy agreements with UCB and Salix. However, these agreements and grants had no relationship to the current research study. Keith T. Wilson has had a consulting agreement with Immune Pharmaceuticals. However, this agreement had no relationship to the current research study and is no longer active. The remainder of the authors declare that they have no conflict of interest.

Background: Inflammatory bowel disease (IBD) is associated with altered body composition, such as low muscle mass, which affects clinical outcomes. Body composition changes in overweight patients with IBD are less understood. The study aim was to determine the prevalence of sarcopenic overweight and obese patients in a cohort of patients with IBD starting new anti-tumor necrosis factor-α therapy and examine differences in response., Methods: This is a retrospective review of patients with IBD starting a new anti-tumor necrosis factor-α medication that had computed tomography within 3 months of initiation. L3 vertebral slice was used for segmentation of body composition and identification of sarcopenia. CRP, ESR, Harvey Bradshaw Index, albumin, 25-OH vitamin D, and body mass index at anti-tumor necrosis factor-α initiation and at 6 months were collected. Outcomes included hospitalization, need for surgery, or new biological medication., Results: Ninety patients were studied. Forty-one of ninety (45%) were sarcopenic; of these, 17 (41.5%) had a normal body mass index and 8 (19.5%) were overweight/obese. More men were sarcopenic (68% versus 32%, P < 0.001). CRP was higher and albumin lower in sarcopenic subjects. Sarcopenia did not predict outcomes in the cohort but was the only significant predictor of need for surgery in overweight and obese subjects (P = 0.002)., Conclusions: Almost half of our cohort was sarcopenic. Most of these patients are normal or overweight and would not be identified as malnourished by traditional measures. Sarcopenia was a predictor of surgery in patients with a body mass index ≥ 25. Identification of sarcopenia has implications for medical nutrition therapy as typically efforts are focused on underweight patients.

In almost all bacteria, cell division is co-ordinated by the essential tubulin homologue FtsZ and represents an attractive but as yet unexploited target for new antibiotics. The benzamides, e.g. PC190723, are potent FtsZ inhibitors that have the potential to yield an important new class of antibiotic. However, the evolution of resistance poses a challenge to their development. Here we show that a collection of PC190723-resistant and -dependent strains of Staphylococcus aureus exhibit severe growth and morphological defects, questioning whether these ftsZ mutations would be clinically relevant. Importantly, we show that the most commonly isolated substitution remains sensitive to the simplest benzamide 3-MBA and likely works by occluding compound binding. Extending this analysis to Bacillus subtilis, we isolated a novel benzamide-dependent strain that divides using unusual helical division events. The ftsZ mutation responsible encodes the substitution of a highly conserved residue, which lies outside the benzamide-binding site and forms part of an interface between the N- and C-terminal domains that we show is necessary for normal FtsZ function. Together with an intragenic suppressor mutation that mimics benzamide binding, the results provide genetic evidence that benzamides restrict conformational changes in FtsZ and also highlights their utility as tools to probe bacterial division., (© 2015 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

To proliferate efficiently, cells must co-ordinate division with chromosome segregation. In Bacillus subtilis, the nucleoid occlusion protein Noc binds to specific DNA sequences (NBSs) scattered around the chromosome and helps to protect genomic integrity by coupling the initiation of division to the progression of chromosome replication and segregation. However, how it inhibits division has remained unclear. Here, we demonstrate that Noc associates with the cell membrane via an N-terminal amphipathic helix, which is necessary for function. Importantly, the membrane-binding affinity of this helix is weak and requires the assembly of nucleoprotein complexes, thus establishing a mechanism for DNA-dependent activation of Noc. Furthermore, division inhibition by Noc requires recruitment of NBS DNA to the cell membrane and is dependent on its ability to bind DNA and membrane simultaneously. Indeed, Noc production in a heterologous system is sufficient for recruitment of chromosomal DNA to the membrane. Our results suggest a simple model in which the formation of large membrane-associated nucleoprotein complexes physically occludes assembly of the division machinery., (© 2015 The Authors. Published under the terms of the CC BY 4.0 license.)

Division site selection presents a fundamental challenge to all organisms. Bacterial cells are small and the chromosome (nucleoid) often fills most of the cell volume. Thus, in order to maximise fitness and avoid damaging the genetic material, cell division must be tightly co-ordinated with chromosome replication and segregation. To achieve this, bacteria employ a number of different mechanisms to regulate division site selection. One such mechanism, termed nucleoid occlusion, allows the nucleoid to protect itself by acting as a template for nucleoid occlusion factors, which prevent Z-ring assembly over the DNA. These factors are sequence-specific DNA-binding proteins that exploit the precise organisation of the nucleoid, allowing them to act as both spatial and temporal regulators of bacterial cell division. The identification of proteins responsible for this process has provided a molecular understanding of nucleoid occlusion but it has also prompted the realisation that substantial levels of redundancy exist between the diverse systems that bacteria employ to ensure that division occurs in the right place, at the right time.

Background: Shoe contact dermatitis is common in both the pediatric and the adult populations. Severity of the reaction can vary greatly by patient., Objectives: Health Care Professionals of all types should be familiar with shoe related dermatitis and aware of potential antigens that can precipitate a shoe contact dermatitis., Methods: This article reviews one of the most common patch test, the T.R.U.E., Thin-layer Rapid Use of Epicutaneous test, for determination of the causative agent in a case of shoe contact dermatitis., Results: This article outlines a severe reaction to dichromate in a shoe and the clinical treatment required for a severe, limb threatening, reaction which included in-patient and out-patient management of the condition., Conclusion: The clinician will become familiar with several common antigens responsible for contact dermatitis, including rubber, dichromate, thimerosal and other medications and other non-shoe products that can contain these agents., (Copyright © 2012. Published by Elsevier Ltd.)

Cell division in almost all bacteria is orchestrated by the essential tubulin homologue FtsZ, which assembles into a ring-like structure and acts as a scaffold for the division machinery. Division was recently validated as an important target for antibiotics by the demonstration that low-molecular-weight inhibitors of FtsZ, called benzamides, can cure mice infected with Staphylococcus aureus. In treated cells of Bacillus subtilis we show that FtsZ assembles into foci throughout the cell, including abnormal locations at the cell poles and over the nucleoid. These foci are not inactive aggregates because they remain dynamic, turning over almost as rapidly as untreated polymers. Remarkably, although division is completely blocked, the foci efficiently recruit division proteins that normally co-assemble with FtsZ. However, they show no affinity for components of the Min or Nucleoid occlusion systems. In vitro, the benzamides strongly promote the polymerization of FtsZ, into hyperstable polymers, which are highly curved. Importantly, even at low concentrations, benzamides transform the structure of the Z ring, resulting in abnormal helical cell division events. We propose that benzamides act principally by promoting an FtsZ protomer conformation that is incompatible with a higher-order level of assembly needed to make a division ring., (© 2011 Blackwell Publishing Ltd.)

Bacterial cell division is orchestrated by a tubulin homologue, FtsZ, which polymerizes to form a ring-like structure that is both a scaffold for the assembly of the bacterial cytokinetic machinery and, at least in part, a source of the energy for constriction. FtsZ assembly is tightly regulated, and a diverse repertoire of accessory proteins contributes to the formation of a functional division machine that is responsive to cell cycle status and environmental stress. In this Review, we describe the interaction of these proteins with FtsZ and discuss recent advances in our understanding of Z ring assembly.

Although foot and ankle specialists are well versed in treating insect bites and foreign bodies, many physicians in the United States are unfamiliar with parasitic organisms that are common in other parts of the world. This article presents a case of a patient inoculated in the posterior heel with the larva of a Dermatobia hominis, or human bot fly. Excision of the larva provided a complete resolution of the patient's symptoms. Although the initial clinical presentation suggested a simple foreign body, the patient's recent travel history to Brazil shows that a thorough history is essential to establishing a complete list of differential diagnoses.

The accuracy rates of board-registered pharmacy technicians and pharmacists in checking unit dose medication cassettes in the inpatient setting at two separate institutions were examined. Cedars-Sinai Medical Center and Long Beach Memorial Medical Center, both in Los Angeles county, petitioned the California State Board of Pharmacy to approve a waiver of the California Code of Regulations to conduct an experimental program to compare the accuracy of unit dose medication cassettes checked by pharmacists with that of cassettes checked by trained, certified pharmacy technicians. The study consisted of three parts: assessing pharmacist baseline checking accuracy (Phase I), developing a technician-training program and certifying technicians who completed the didactic and practical training (Phase II), and evaluating the accuracy of certified technicians checking unit dose medication cassettes as a daily function (Phase III). Twenty-nine pharmacists and 41 technicians (3 of whom were pharmacy interns) participated in the study. Of the technicians, all 41 successfully completed the didactic and practical training, 39 successfully completed the audits and became certified checkers, and 2 (including 1 of the interns) did not complete the certification audits because they were reassigned to another work area or had resigned. In Phase II, the observed accuracy rate and its lower confidence limit exceeded the predetermined minimum requirement of 99.8% for a certified checker. The mean accuracy rates for technicians were identical at the two institutions (p = 1.0). The difference in mean accuracy rates between pharmacists (99.52%; 95% confidence interval [CI] 99.44-99.58%) and technicians, (99.89%; 95% CI 99.87-99.90%) was significant (p < 0.0001). Inpatient technicians who had been trained and certified in a closely supervised program that incorporated quality assurance mechanisms could safely and accurately check unit dose medication cassettes filled by other technicians.

Objective: To determine whether market changes have resulted in a decrease in the number or geographic distribution of pharmacies available to ambulatory patients in Virginia., Design: Retrospective review of Virginia Board of Pharmacy records of pharmacy registrations in 1994 and 1999., Setting: The Commonwealth of Virginia., Participants: All pharmacies classified as outpatient pharmacies (including community and other types of ambulatory pharmacies) and operating in Virginia in 1994 and 1999., Interventions: Not applicable., Main Outcome Measures: Changes in the total number, geographic distribution, and metropolitan/nonmetropolitan distribution of outpatient pharmacies between 1994 and 1999., Results: The total number of outpatient pharmacies increased from 1,290 to 1,337 between 1994 and 1999. Chain pharmacies, mass merchandiser, and grocery pharmacies increased in number while independent pharmacies declined. There was little change in the geographic or metropolitan/nonmetropolitan distribution of pharmacies., Conclusion: Changes in the number and distribution of community and other ambulatory pharmacies in Virginia have not diminished their availability to consumers.

Purpose: To investigate the refractive and biometric changes associated with adult-onset and adult-progression of myopia in an occupational group., Methods: The sample population consisted of 251 clinical microscopists aged 21 to 63 years. Subjects had their refraction and ocular dimensions measured on four occasions during a 2-year period, and a total of 166 subjects (332 eyes) completed the longitudinal aspect of the study. Refraction was measured objectively with a Canon R-1 autorefractor and subjectively by an optometrist using standard procedures. Corneal curvature and axial ocular dimensions were measured with a keratometer and A-scan ultrasonography, respectively., Results: Of eyes emmetropic at the start of the study, a total of 39% underwent a myopic change in refraction greater than 0.37 diopter (D), with a mean change of -0.58 +/- 0.04 D (mean +/- standard error of the mean; n = 37). This was associated with an elongation of the vitreous chamber of 0.26 +/- 0.05 mm (P < 0.01). Eyes emmetropic at the start of the study that did not undergo a refractive change > 0.37 D (n = 58) during the 2-year study period had a mean change in refraction of 0.02 +/- 0.03 D (P = 0.69) associated with a change in vitreous chamber depth of 0.05 +/- 0.02 mm. Changes in corneal curvature, anterior chamber depth, or lens thickness between the initially emmetropic groups were not significant. The median age of onset of myopia in initially emmetropic eyes was 26.3 years. Of eyes that were myopic at the start of the study, 48% progressed further into myopia by 0.37 D or more during the 2-year period. The mean increase in myopia for the "myopia progressor" group was 0.77 +/- 0.03 D (n = 108 eyes) compared to -0.01 +/- 0.02 D (n = 115 eyes; P = 0.49) for myopes who did not undergo a refractive change > 0.37 D during the study period. The only significant difference in ocular component dimension changes during the study period for these two initially myopic groups was elongation of the vitreous chamber depth (0.24 +/- 0.04 mm versus 0.03 +/- 0.03 mm, P < 0.01). The average age of the myopes who progressed further into myopia during the study was 29.3 years. Axial length-corneal radius ratio at the start of the study was not significantly different between initially emmetropic eyes in which adult onset myopia developed or emmetropic eyes that remained refractively stable. The incidence of adult myopia development during a 2-year period in this occupational group was 45%., Conclusions: The structural cause of adult-onset and adult-progression of myopia is vitreous chamber elongation.

The frequency of refractive errors in a population of clinical microscopists is presented. The prevalence of myopia in this population (N = 251) was found to be 71%, with 49% of the population reporting onset or progression of myopia after entry into clinical microscopy (after 21 years of age). Of subjects undergoing renewed progression of an existing myopia since starting clinical microscopy, 56% reported no refractive change for the 5 years before entering their profession. Accuracy of reporting refractive changes was found to be high. No differences were found in task-related functions between those subjects reporting myopic change in adulthood from those who did not report myopic change.

This article describes a study on the impact of utilizing technicians in the dispensing of prescriptions for ambulatory patients. The two hypotheses were 1) there is no difference in error rate for prescriptions dispensed by pharmacists versus technicians, and 2) there is no change in the amount of time pharmacists spend counseling patients after technicians begin dispensing prescriptions. Power analysis indicated that a sample size of 900 prescriptions would need to be randomized into each group to adequately compare error rates. Results showed that there was no significant difference in error rate between pharmacists (5.17 per cent) versus technicians (4.17 per cent), supporting the first null hypothesis. Pharmacists did spend significantly more time counseling patients (p less than 0.001), leading to a rejection of the second null hypothesis. Since the number of staff did not change during the study, it is calculated that, based on annual salary plus fringe benefits, +20,080 in additional pharmacists' time was freed up for patient counseling when technicians were dispensing the prescriptions.

The implementation of pharmacy services in an ambulatory pediatric clinic has met with initial success in acceptance by the medical and nursing staffs, the administrator, and the patient population. Errors in medication dispensing and prescription labeling have decreased, and patient understanding of prescribed therapy has improved. The number of ER visits by clinic patients has been reduced since the implementation of our service. The importance of patients' understanding directions for use and of dispensing medications in childproof containers for the pediatric population cannot be overstressed. A future goal of our service is to expand the pharmacist's clinical role to allow further participation in pharmacokinetics, specialty clinics, teaching, and patient education. Further documentation of the value of such services is essential to the expansion of the pharmacist's role in patient care.

Three undergraduate social-work students were placed in the University Department of Family Medicine for their field practice. This was the first time an element of social work had been introduced in this particular setting. A before and after analysis of opinions from all three parties revealed that the experience was a worthwhile one for all concerned. The services provided by the social workers were wide ranging and perceived to be important by residents and staff.