A Systematic Review of Extracellular Matrix-Related Alterations in Parkinson's Disease.

The role of the extracellular matrix (ECM) in Parkinson's disease (PD) is not well understood, even though it is critical for neuronal structure and signaling. This systematic review identified the top deregulated ECM-related pathways in studies that used gene set enrichment analyses (GSEA) to document transcriptomic, proteomic, or genomic alterations in PD. PubMed and Google scholar were searched for transcriptomics, proteomics, or genomics studies that employed GSEA on data from PD tissues or cells and reported ECM-related pathways among the top-10 most enriched versus controls. Twenty-seven studies were included, two of which used multiple omics analyses. Transcriptomics and proteomics studies were conducted on a variety of tissue and cell types. Of the 17 transcriptomics studies (16 data sets), 13 identified one or more adhesion pathways in the top-10 deregulated gene sets or pathways, primarily related to cell adhesion and focal adhesion. Among the 8 proteomics studies, 5 identified altered overarching ECM gene sets or pathways among the top 10. Among the 4 genomics studies, 3 identified focal adhesion pathways among the top 10. The findings summarized here suggest that ECM organization/structure and cell adhesion (particularly focal adhesion) are altered in PD and should be the focus of future studies.

Campylobacter devanensis sp. nov., Campylobacter porcelli sp. nov., and Campylobacter vicugnae sp. nov., three novel Campylobacter lanienae-like species recovered from swine, small ruminants, and camelids.

In a previous study characterizing Campylobacter strains deficient in selenium metabolism, 50 strains were found to be similar to, but distinct from, the selenonegative species Campylobacter lanienae. Initial characterization based on multilocus sequence typing and the phylogeny of a set of 20 core genes determined that these strains form three putative taxa within the selenonegative cluster. A polyphasic study was undertaken here to further clarify their taxonomic position within the genus. The 50 selenonegative strains underwent phylogenetic analyses based on the sequences of the 16S rRNA gene and an expanded set of 330 core genes. Standard phenotypic testing was also performed. All strains were microaerobic and anaerobic, Gram-negative, spiral or curved cells with some displaying coccoid morphologies. Strains were motile, oxidase, catalase, and alkaline phosphatase positive, urease negative, and reduced nitrate. Strains within each clade had unique phenotypic profiles that distinguished them from other members of the genus. Core genome phylogeny clearly placed the 50 strains into three clades. Pairwise average nucleotide identity and digital DNA-DNA hybridization values were all below the recommended cut-offs for species delineation with respect to C. lanienae and other related Campylobacter species. The data presented here clearly show that these strains represent three novel species within the genus, for which the names Campylobacter devanensis sp. nov. (type strain RM3662T=LMG 33097T=NCTC 15074T), Campylobacter porcelli sp. nov. (type strain RM6137T=LMG 33098T=CCUG 77054T=NCTC 15075T) and Campylobacter vicugnae sp. nov. (type strain RM12175T=LMG 33099T=CCUG 77055T=NCTC 15076T) are proposed.

Trace metal transfer to passerines inhabiting wastewater treatment wetlands.

Wastewater treatment wetlands are cost-effective strategies for remediating trace metals in industrial effluent. However, biogeochemical exchange between wastewater treatment wetlands and adjacent environments provides opportunities for trace metals to cycle in surrounding ecosystems. The transfer of trace metals to wildlife inhabiting treatment wetlands must be considered when evaluating wetland success. Using passerine birds as bioindicators, we conducted a multi-tissue analysis to investigate the mobilization of zinc, copper, and lead derived from wastewater to terrestrial wildlife in treatment wetlands and surrounding habitat. In addition, we evaluate the strength of relationships between metal concentrations in non-lethal (blood and feathers) and lethal (muscle and liver) sample types for estimation of toxicity risk. From July 2020 to August 2021, 177 passerines of seven species were captured at two wetlands constructed to treat industrial wastewater and two reference wetlands in the coastal plain of South Carolina. Feather, blood, liver, and muscle samples from each bird were analyzed for fourteen metals using inductively coupled plasma mass spectrometry and direct mercury analysis. Passerines inhabiting wastewater treatment wetlands accumulated higher concentrations of zinc in liver, copper in blood, and lead in feathers than passerines in reference wetlands, but neither blood nor feather concentrations were correlated with internal tissue concentrations. Of all the detected metals, only mercury in the blood showed a strong predictive relationship with mercury in internal tissues. This study indicates that trace metals derived from wastewater are bioavailable and exported to terrestrial wildlife and that passerine biomonitoring is a valuable tool for assessing metal transfer from treatment wetlands. Regular blood sampling can reveal proximate trace metal exposure but cannot predict internal body burdens for most metals.

Genomic Analysis Points to Multiple Genetic Mechanisms for Non-Transformable Campylobacter jejuni ST-50.

Campylobacter jejuni and Campylobacter coli are well known for their natural competence, i.e., their capacity for the uptake of naked DNA with subsequent transformation. This study identifies non-transformable C. jejuni and C. coli strains from domestic animals and employs genomic analysis to investigate the strain genotypes and their associated genetic mechanisms. The results reveal genetic associations leading to a non-transformable state, including functional DNase genes from bacteriophages and mutations within the cts-encoded DNA-uptake system, which impact the initial steps of the DNA uptake during natural transformation. Interestingly, all 38 tested C. jejuni ST-50 strains from the United States exhibit a high prevalence of non-transformability, and the strains harbor a variety of these genetic markers. This research emphasizes the role of these genetic markers in hindering the transfer of antimicrobial resistance (AMR) determinants, providing valuable insights into the genetic diversity of Campylobacter. As ST-50 is a major clone of C. jejuni globally, we additionally determined the prevalence of the genetic markers for non-transformability among C. jejuni ST-50 from different regions of the world, revealing distinct patterns of evolution and a strong selective pressure on the loss of competence in ST-50 strains, particularly in the agricultural environment in the United States. Our findings contribute to a comprehensive understanding of genetic exchange mechanisms within Campylobacter strains, and their implications for antimicrobial resistance dissemination and evolutionary pathways within specific lineages.

Emergency Department point-of-care antiviral host response testing is accurate during periods of multiple respiratory virus co-circulation.

OBJECTIVES: FebriDx is a CE-marked, FDA-approved point-of-care test that detects the antiviral host response protein Myxovirus Resistance Protein A (MxA), in addition to C-reactive protein, using finger-prick blood. FebriDx MxA detection had a high negative predictive value for COVID-19 in symptomatic adults presenting to hospital in the first waves of the pandemic and was used subsequently as a 'rule out' triage tool in Emergency departments. The diagnostic accuracy of FebriDx MxA in the current context of co-circulation of influenza, SARS-CoV-2, and Respiratory Syncytial Virus (RSV), and in the era of COVID-19 vaccination, is unknown. METHODS: We retrospectively evaluated the diagnostic performance of FebriDx MxA in adults with acute respiratory symptoms presenting to the Emergency Department (ED) of a large UK teaching hospital using Reverse Transcription Polymerase Chain Reaction (RT-PCR) as the reference standard (Cepheid Xpert Xpress SARS-CoV-2/Flu/RSV). RESULTS: Between March 9th 2022 and March 8th 2023, 5426 patients had both FebriDx and RT-PCR testing with valid results. 999 (18.4%) of patients had influenza detected, 520 (9.6%) SARS-CoV-2, and 190 (3.5%) RSV. Negative Predictive Value (NPV) of MxA detection by FebriDx was 97.5% (96.9-98.0) for influenza, 97.1% (96.4-97.7) for SARS-CoV-2, 98.1% (97.5-98.6) for RSV, and 92.8% (91.8-93.7) for all viruses combined. CONCLUSIONS: In symptomatic adults, FebriDx MxA had a high NPV for influenza and RSV, and retained a high NPV for SARS-CoV-2, in the context of virus co-circulation and widespread COVID-19 vaccination. FebriDx continues to be a useful 'rule out' triage tool in the ED and could potentially be scaled to provide a national triage solution for future viral pandemics.

Dental complications in homocystinurias.

Background: Cystathionine beta synthase deficiency (causing classical homocystinuria) has been associated with high-arched palates and crowded teeth, but little has been said about other oral health complications. Other homocystinurias (e.g., the remethylation defects) also have had little reported in terms of oral health. Individuals with the homocystinurias have been described as having bone density issues which can correlate with oral health. Moreover, elevations in homocysteine have a theoretical impact on tooth health and the paucity of clinical reports of oral health issues in homocystinuria may be the consequence of lack of attention by the medical community. Significance: Oral health is essential to overall health. If inadequate attention is paid to the oral health complications which can be seen in homocystinurias, then appropriate referrals and attention in therapeutic guidelines will not reflect the importance of oral health. Specific aims/research question: What oral health complications are reported by individuals with homocystinurias? Do these differ according to diagnosis? Methods: Data were collected from patients with homocystinurias by a series of questionnaires using the RARE-X platform. All subjects were consented prior to the collection of their data. All research was performed in accordance with the Declaration of Helsinki. Demographic data were collected as the initial questionnaire and other data were collected via the oral health questionnaire. Analysis: Questionnaires were opened to the community in mid-2022 and collection of data for this study ended with data submitted up to November 2022. Descriptive statistics were done. Due to the small size of the cohort, additional statistical analyses were not attempted. Results: Patients with homocystinuria, not related to cystathionine beta synthase deficiency, are reporting some tooth structure differences. The cohort taken as a whole does not have increased risk for gingivitis, but there appears to be a risk for long-term gum disease possibly due to the rate of osteoporosis/osteopenia in this population. A large number of individuals have malalignment and malocclusion of the teeth. These data highlight oral health as an important component of care in individuals with the homocystinurias as is true of the general population at large.

Complete Genome Sequence of the Arcobacter canalis Type Strain LMG 29148.

Arcobacter canalis was originally recovered from shellfish and from a sewage-contaminated canal. Arcobacter canalis is closely related to the marine bacterium Arcobacter marinus This study describes the complete whole-genome sequence of the A. canalis type strain LMG 29148 (=F138-33T; =CECT 8984T), which was recovered from oysters.

Draft Genome Sequences of Nine Campylobacter hyointestinalis subsp. lawsonii Strains.

With increasing reports of Campylobacter hyointestinalis species associated with human diseases, more genome sequences are required to understand the virulence mechanisms of this emerging pathogen. Here, we describe the genome sequences of nine C. hyointestinalis subsp. lawsonii strains.

A Case Study of Genomic Instability in an Industrial Strain of Saccharomyces cerevisiae.

The Saccharomyces cerevisiae strain JAY270/PE2 is a highly efficient biocatalyst used in the production of bioethanol from sugarcane feedstock. This strain is heterothallic and diploid, and its genome is characterized by abundant structural and nucleotide polymorphisms between homologous chromosomes. One of the reasons it is favored by many distilleries is that its cells do not normally aggregate, a trait that facilitates cell recycling during batch-fed fermentations. However, long-term propagation makes the yeast population vulnerable to the effects of genomic instability, which may trigger the appearance of undesirable phenotypes such as cellular aggregation. In pure cultures of JAY270, we identified the recurrent appearance of mutants displaying a mother-daughter cell separation defect resulting in rough colonies in agar media and fast sedimentation in liquid culture. We investigated the genetic basis of the colony morphology phenotype and found that JAY270 is heterozygous for a frameshift mutation in the ACE2 gene (ACE2/ace2-A7), which encodes a transcriptional regulator of mother-daughter cell separation. All spontaneous rough colony JAY270-derived isolates analyzed carried copy-neutral loss-of-heterozygosity (LOH) at the region of chromosome XII where ACE2 is located (ace2-A7/ace2-A7). We specifically measured LOH rates at the ACE2 locus, and at three additional chromosomal regions in JAY270 and in a conventional homozygous diploid laboratory strain. This direct comparison showed that LOH rates at all sites were quite similar between the two strain backgrounds. In this case study of genomic instability in an industrial strain, we showed that the JAY270 genome is dynamic and that structural changes to its chromosomes can lead to new phenotypes. However, our analysis also indicated that the inherent level of genomic instability in this industrial strain is normal relative to a laboratory strain. Our work provides an important frame of reference to contextualize the interpretation of instability processes observed in the complex genomes of industrial yeast strains.

Survival of foodborne pathogens on commercially packed table grapes under simulated refrigerated transit conditions.

We examined the survival of Listeria monocytogenes, Escherichia coli O157:H7, and Salmonella enterica Thompson inoculated on commercially packed table grapes under simulated refrigerated transit conditions (1.1 ± 0.5 °C; 90% RH). Grapes were placed in perforated polyethylene cluster bags, within a commercial expanded polystyrene box equipped with either a SO2-generating pad; a perforated polyethylene box liner; a SO2-generating pad and a box liner; or none of them. L. monocytogenes was most sensitive to SO2-generating pad. SO2-generating pad or SO2-generating pad with box liner inactivated this pathogen completely on day 12 following the inoculation. S. enterica Thompson displayed a similar cold sensitivity as L. monocytogenes, but was more resistant to SO2-generating pad than L. monocytogenes. While SO2-generating pad eliminated S. enterica Thompson on day 20, a combination of box liner with SO2-generating pad inactivated this pathogen completely on day 13. E. coli O157:H7 had the highest tolerance to transit temperature and to SO2-generating pad; SO2-generating pad inactivated this pathogen completely on Day 20. Our data suggest that use of SO2-generating pad combined with box liner is effective in reducing foodborne pathogens L. monocytogenes and S. enterica Thompson, while the use of SO2-generating pad alone was more effective on E. coli O157:H7.

The Role of Biosimilars in Patient Access to Therapeutic Antibodies for Immune Mediated Inflammatory Diseases.

BACKGROUND: Biosimilars have the potential to create competition, lower costs, and increase patient access to biological medications. However, biological medications are sensitive to their manufacturing processes and difficult to precisely characterize, leading to questions about substitution and interchangeability among products. METHODS: This article reviews the role of biosimilars in patient access to therapeutic antibodies. RESULTS: Although pathways for the approval of biosimilars have been developed, important issues remain unresolved. Interchangeability, or the designation of one medicine as clinically similar to and/or substitutable for another, is specified in some countries but restricted or awaiting policy resolution in others. Non-medical switching, or the switching among biological medications to select a less expensive product, for reasons unrelated to patient health and safety, is controversial because of the potential for complications related to repeated switching (e.g., immunogenicity and loss of therapeutic effect), and transfer of prescribing responsibility for patient medications from the physician to the insurance company. Although biosimilars have different names in different countries, the World Health Organization (WHO) calls for nomenclature that incorporates the international nonproprietary name of the original biological medication followed by a distinguishing suffix qualifier. Naming consistency across countries seems sensible, and adoption of the WHO recommended suffix would greatly simplify pharmacovigilance. CONCLUSIONS: Support for the WHO proposal is advised by numerous stakeholders, and resolution of the remaining outstanding issues is urged so that patients and physicians can safely access biosimilars.

Complete Genome Sequence of the Hippuricase-Positive Campylobacter avium Type Strain LMG 24591.

Campylobacter avium is a thermotolerant Campylobacter species that has been isolated from poultry. C. avium was also the second hippuricase-positive species to be identified within Campylobacter Here, we present the genome sequence of the C. avium type strain LMG 24591 (=CCUG 56292T), isolated in 2006 from a broiler chicken in Italy.

Comparative Genomic Analysis Identifies a Campylobacter Clade Deficient in Selenium Metabolism.

The nonthermotolerant Campylobacter species C. fetus, C. hyointestinalis, C. iguaniorum, and C. lanienae form a distinct phylogenetic cluster within the genus. These species are primarily isolated from foraging (swine) or grazing (e.g., cattle, sheep) animals and cause sporadic and infrequent human illness. Previous typing studies identified three putative novel C. lanienae-related taxa, based on either MLST or atpA sequence data. To further characterize these putative novel taxa and the C. fetus group as a whole, 76 genomes were sequenced, either to completion or to draft level. These genomes represent 26 C. lanienae strains and 50 strains of the three novel taxa. C. fetus, C. hyointestinalis and C. iguaniorum genomes were previously sequenced to completion; therefore, a comparative genomic analysis across the entire C. fetus group was conducted (including average nucleotide identity analysis) that supports the initial identification of these three novel Campylobacter species. Furthermore, C. lanienae and the three putative novel species form a discrete clade within the C. fetus group, which we have termed the C. lanienae clade. This clade is distinguished from other members of the C. fetus group by a reduced genome size and distinct CRISPR/Cas systems. Moreover, there are two signature characteristics of the C. lanienae clade. C. lanienae clade genomes carry four to ten unlinked and similar, but nonidentical, flagellin genes. Additionally, all 76 C. lanienae clade genomes sequenced demonstrate a complete absence of genes related to selenium metabolism, including genes encoding the selenocysteine insertion machinery, selenoproteins, and the selenocysteinyl tRNA.

Campylobacter pinnipediorum sp. nov., isolated from pinnipeds, comprising Campylobacter pinnipediorum subsp. pinnipediorum subsp. nov. and Campylobacter pinnipediorum subsp. caledonicus subsp. nov.

During independent diagnostic screenings of otariid seals in California (USA) and phocid seals in Scotland (UK), Campylobacter-like isolates, which differed from the established taxa of the genus Campylobacter, were cultured from abscesses and internal organs of different seal species. A polyphasic study was undertaken to determine the taxonomic position of these six isolates. The isolates were characterized by 16S rRNA gene and AtpA sequence analysis and by conventional phenotypic testing. The whole-genome sequences were determined for all isolates, and the average nucleotide identity (ANI) was determined. The isolates formed a separate phylogenetic clade, divergent from all other taxa of the genus Campylobacter and most closely related to Campylobactermucosalis. Although all isolates showed 100 % 16S rRNA gene sequence homology, AtpA and ANI analyses indicated divergence between the otariid isolates from California and the phocid isolates from Scotland, which warrants subspecies status for each clade. The two subspecies could also be distinguished phenotypically on the basis of catalase activity. This study shows clearly that the isolates obtained from pinnipeds represent a novel species within the genus Campylobacter, for which the name Campylobacter pinnipediorum sp. nov. is proposed. Within this novel species, the Californian isolates represent a separate subspecies, for which the name C. pinnipediorum subsp. pinnipediorum subsp. nov. is proposed. The type strain for both this novel species and subspecies is RM17260T (=LMG 29472T=CCUG 69570T). The Scottish isolates represent another subspecies, for which the name C. pinnipediorum subsp. caledonicus subsp. nov. is proposed. The type strain of this subspecies is M302/10/6T (=LMG 29473T=CCUG 68650T).

Comparative Genomics of All Three Campylobacter sputorum Biovars and a Novel Cattle-Associated C. sputorum Clade.

Campylobacter sputorum is a nonthermotolerant campylobacter that is primarily isolated from food animals such as cattle and sheep. C. sputorum is also infrequently associated with human illness. Based on catalase and urease activity, three biovars are currently recognized within C. sputorum: bv. sputorum (catalase negative, urease negative), bv. fecalis (catalase positive, urease negative), and bv. paraureolyticus (catalase negative, urease positive). A multi-locus sequence typing (MLST) method was recently constructed for C. sputorum. MLST typing of several cattle-associated C. sputorum isolates suggested that they are members of a divergent C. sputorum clade. Although catalase positive, and thus technically bv. fecalis, the taxonomic position of these strains could not be determined solely by MLST. To further characterize C. sputorum, the genomes of four strains, representing all three biovars and the divergent clade, were sequenced to completion. Here we present a comparative genomic analysis of the four C. sputorum genomes. This analysis indicates that the three biovars and the cattle-associated strains are highly related at the genome level with similarities in gene content. Furthermore, the four genomes are strongly syntenic with one or two minor inversions. However, substantial differences in gene content were observed among the three biovars. Finally, although the strain representing the cattle-associated isolates was shown to be C. sputorum, it is possible that this strain is a member of a novel C. sputorum subspecies; thus, these cattle-associated strains may form a second taxon within C. sputorum.

Complete Genome Sequences of Campylobacter hyointestinalis subsp. hyointestinalis Strain LMG 9260 and C. hyointestinalis subsp. lawsonii Strain LMG 15993.

Campylobacter hyointestinalis is isolated primarily from ruminants and swine, but is also occasionally isolated from humans. C. hyointestinalis is currently divided into two subspecies, C. hyointestinalis subsp. hyointestinalis and C. hyointestinalis subsp. lawsonii This study describes the first closed whole-genome sequences of C. hyointestinalis subsp. hyointestinalis isolate LMG 9260 and C. hyointestinalis subsp. lawsonii isolate LMG 15993.

Complete Genome Sequence of Campylobacter iguaniorum Strain RM11343, Isolated from an Alpaca.

Campylobacter iguaniorum is a member of the C. fetus group of campylobacters and is one of two Campylobacter taxa isolated from reptiles. This study describes the whole-genome sequence of the C. iguaniorum strain RM11343, which was isolated from a California alpaca fecal sample.

Regenerative Medicine: Charting a New Course in Wound Healing.

Significance: Chronic wounds are a prevalent and costly problem in the United States. Improved treatments are needed to heal these wounds and prevent serious complications such as infection and amputation. Recent Advances: In wound healing, as in other areas of medicine, technologies that have the potential to regenerate as opposed to repair tissue are gaining ground. These include customizable nanofiber matrices incorporating novel materials; a variety of autologous and allogeneic cell types at various stages of differentiation (e.g., pluripotent, terminally differentiated); peptides; proteins; small molecules; RNA inhibitors; and gene therapies. Critical Issues: Wound healing is a logical target for regenerative medicine due to the accessibility and structure of skin, the regenerative nature of healing, the lack of good limb salvage treatments, and the current use of cell therapies. However, more extensive knowledge of pathophysiologic targets is needed to inform regenerative strategies, and new technologies must demonstrate value in terms of outcomes and related health economic measures to achieve successful market access and penetration. Future Directions: Due to similarities in cell pathways and developmental mechanisms, regenerative technologies developed in one therapeutic area may be applicable to others. Approaches that proceed from human genomic or other big data sources to models are becoming increasingly common and will likely suggest novel therapeutic avenues. To fully capitalize on the advances in regenerative medicine, studies must demonstrate the value of new therapies in identified patient populations, and sponsors must work with regulatory agencies to develop appropriate dossiers supporting timely approval.

Memory load as a cognitive antidote to performance decrements in data entry.

In two experiments, subjects trained in data entry, typing one 4-digit number at a time. At training, subjects either typed the numbers immediately after they appeared (immediate) or typed the previous number from memory while viewing the next number (delayed). In Experiment 2 stimulus presentation time was limited and either nothing or a space (gap) was inserted between the second and third digits. In both experiments after training, all subjects completed a test with no gap and typed numbers immediately. Training with a memory load improved speed across training blocks (Experiment 1) and eliminated the decline in accuracy across training blocks (Experiment 2), thus serving as a cognitive antidote to performance decrements. An analysis of each keystroke revealed different underlying processes and strategies for the two training conditions, including when encoding took place. Chunking (in which the first and last two digits are treated separately) was more evident in the immediate than in the delayed condition and was exaggerated with a gap, even at test when there was no gap. These results suggest that such two-digit chunking is due to stimulus encoding and motor planning processes as well as memory, and those processes transferred from training to testing.

Stimulation of Chromosomal Rearrangements by Ribonucleotides.

We show by whole genome sequence analysis that loss of RNase H2 activity increases loss of heterozygosity (LOH) in Saccharomyces cerevisiae diploid strains harboring the pol2-M644G allele encoding a mutant version of DNA polymerase ε that increases ribonucleotide incorporation. This led us to analyze the effects of loss of RNase H2 on LOH and on nonallelic homologous recombination (NAHR) in mutant diploid strains with deletions of genes encoding RNase H2 subunits (rnh201Δ, rnh202Δ, and rnh203Δ), topoisomerase 1 (TOP1Δ), and/or carrying mutant alleles of DNA polymerases ε, α, and δ. We observed an ∼7-fold elevation of the LOH rate in RNase H2 mutants encoding wild-type DNA polymerases. Strains carrying the pol2-M644G allele displayed a 7-fold elevation in the LOH rate, and synergistic 23-fold elevation in combination with rnh201Δ. In comparison, strains carrying the pol2-M644L mutation that decreases ribonucleotide incorporation displayed lower LOH rates. The LOH rate was not elevated in strains carrying the pol1-L868M or pol3-L612M alleles that result in increased incorporation of ribonucleotides during DNA synthesis by polymerases α and δ, respectively. A similar trend was observed in an NAHR assay, albeit with smaller phenotypic differentials. The ribonucleotide-mediated increases in the LOH and NAHR rates were strongly dependent on TOP1. These data add to recent reports on the asymmetric mutagenicity of ribonucleotides caused by topoisomerase 1 processing of ribonucleotides incorporated during DNA replication.