Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach.

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.

Biochemical signatures of disease severity in multiple sulfatase deficiency.

Sulfatases catalyze essential cellular reactions, including degradation of glycosaminoglycans (GAGs). All sulfatases are post-translationally activated by the formylglycine generating enzyme (FGE) which is deficient in multiple sulfatase deficiency (MSD), a neurodegenerative lysosomal storage disease. Historically, patients were presumed to be deficient of all sulfatase activities; however, a more nuanced relationship is emerging. Each sulfatase may differ in their degree of post-translational modification by FGE, which may influence the phenotypic spectrum of MSD. Here, we evaluate if residual sulfatase activity and accumulating GAG patterns distinguish cases from controls and stratify clinical severity groups in MSD. We quantify sulfatase activities and GAG accumulation using three complementary methods in MSD participants. Sulfatases differed greatly in their tolerance of reduction in FGE-mediated activation. Enzymes that degrade heparan sulfate (HS) demonstrated lower residual activities than those that act on other GAGs. Similarly, HS-derived urinary GAG subspecies preferentially accumulated, distinguished cases from controls, and correlated with disease severity. Accumulation patterns of specific sulfatase substrates in MSD provide fundamental insights into sulfatase regulation and will serve as much-needed biomakers for upcoming clinical trials. This work highlights that biomarker investigation of an ultra-rare disease can simultaneously inform our understanding of fundamental biology and advance clinical trial readiness efforts.

Loss of dlx5a/dlx6a Locus Alters Non-Canonical Wnt Signaling and Meckel's Cartilage Morphology.

The dlx genes encode transcription factors that establish a proximal-distal polarity within neural crest cells to bestow a regional identity during craniofacial development. The expression regions of dlx paralogs are overlapping yet distinct within the zebrafish pharyngeal arches and may also be involved in progressive morphologic changes and organization of chondrocytes of the face. However, how each dlx paralog of dlx1a, dlx2a, dlx5a and dlx6a affects craniofacial development is still largely unknown. We report here that the average lengths of the Meckel's, palatoquadrate and ceratohyal cartilages in different dlx mutants were altered. Mutants for dlx5a-/- and dlx5i6-/-, where the entire dlx5a/dlx6a locus was deleted, have the shortest lengths for all three structures at 5 days post fertilization (dpf). This phenotype was also observed in 14 dpf larvae. Loss of dlx5i6 also resulted in increased proliferation of neural crest cells and expression of chondrogenic markers. Additionally, altered expression and function of non-canonical Wnt signaling were observed in these mutants suggesting a novel interaction between dlx5i6 locus and non-canonical Wnt pathway regulating ventral cartilage morphogenesis.

Effect of Extremely Preterm Birth on Adolescent Brain Network Organization.

Introduction: Extremely preterm (EPT) birth, defined as birth at a gestational age (GA) <28 weeks, can have a lasting impact on cognition throughout the life span. Previous investigations reveal differences in brain structure and connectivity between infants born preterm and full-term (FT), but how does preterm birth impact the adolescent connectome? Methods: In this study, we investigate how EPT birth can alter broadscale network organization later in life by comparing resting-state functional magnetic resonance imaging connectome-based parcellations of the entire cortex in adolescents born EPT (N = 22) to age-matched adolescents born FT (GA ≥37 weeks, N = 28). We compare these parcellations to adult parcellations from previous studies and explore the relationship between an individual's network organization and behavior. Results: Primary (occipital and sensorimotor) and frontoparietal networks were observed in both groups. However, there existed notable differences in the limbic and insular networks. Surprisingly, the connectivity profile of the limbic network of EPT adolescents was more adultlike than the same network in FT adolescents. Finally, we found a relationship between adolescents' overall cognition score and their limbic network maturity. Discussion: Overall, preterm birth may contribute to the atypical development of broadscale network organization in adolescence and may partially explain the observed cognitive deficits.

Striatal µ-opioid receptor activation triggers direct-pathway GABAergic plasticity and induces negative affect.

Withdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which may drive relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain µ-opioid receptors (MORs). It remains unclear how chronic opioid exposure and withdrawal impact these MOR-expressing dMSNs and their outputs. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, withdrawal from repeated morphine or fentanyl administration potentiated this GABAergic transmission. Furthermore, intravenous fentanyl self-administration enhanced GABAergic striatonigral transmission and reduced midbrain dopaminergic activity. Fentanyl-activated striatal neurons mediated contextual memory retrieval required for conditioned place preference tests. Importantly, chemogenetic inhibition of striatal MOR+ neurons rescued fentanyl withdrawal-induced physical symptoms and anxiety-like behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, which may promote negative emotions and relapse.

Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications.

The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function.

Self-Assembly of Ir-Based Nanosheets with Ordered Interlayer Space for Enhanced Electrocatalytic Water Oxidation.

Iridium (Ir)-based electrocatalysts are widely explored as benchmarks for acidic oxygen evolution reactions (OERs). However, further enhancing their catalytic activity remains challenging due to the difficulty in identifying active species and unfavorable architectures. In this work, we synthesized ultrathin Ir-IrOx/C nanosheets with ordered interlayer space for enhanced OER by a nanoconfined self-assembly strategy, employing block copolymer formed stable end-merged lamellar micelles. The interlayer distance of the prepared Ir-IrOx/C nanosheets was well controlled at ∼20 nm and Ir-IrOx nanoparticles (∼2 nm) were uniformly distributed within the nanosheets. Importantly, the fabricated Ir-IrOx/C electrocatalysts display one of the lowest overpotential (η) of 198 mV at 10 mA cm-2geo during OER in an acid medium, benefiting from their features of mixed-valence states, rich electrophilic oxygen species (O(II-δ)-), and favorable mesostructured architectures. Both experimental and computational results reveal that the mixed valence and O(II-δ)- moieties of the 2D mesoporous Ir-IrOx/C catalysts with a shortened Ir-O(II-δ)- bond (1.91 Å) is the key active species for the enhancement of OER by balancing the adsorption free energy of oxygen-containing intermediates. This strategy thus opens an avenue for designing high performance 2D ordered mesoporous electrocatalysts through a nanoconfined self-assembly strategy for water oxidation and beyond.

Novel cross-regulation interactions between dlx genes in larval zebrafish.

The homeodomain-containing transcription factors dlx1a, dlx2a, dlx5a and dlx6a are expressed in the zebrafish brain in overlapping patterns and are important in vertebrate development. Previous work in mice have suggested the overlapping expression pattern is in part due to cross-regulatory interactions among the aforementioned dlx genes. However, the extent of these interactions and whether they are conserved among vertebrates remains to be determined. Through whole-mount in situ hybridization in zebrafish dlx mutants produced by CRISPR-Cas9 mutagenesis, cross-regulatory interactions between dlx1a, dlx2a, dlx5a and dlx6a were examined from 24 to 72 h post fertilization (hpf). Notably, and different from previous work done in mouse, zebrafish dlx2a-/- mutants continue to express dlx5a until 72hpf, whereas deletion of both enhancers within the dlx5a/dlx6a locus resulted in delayed dlx5a/dlx6a expression and relative increased dlx2a expression. These results suggest alternative regulatory elements and pathways exist to mediate dlx expression in zebrafish and may highlight evolutionary differences in gene interactions between vertebrates.

Tailoring Surface Self-Organization for Nanoscale Polygonal Morphology on Germanium.

The evolution of polygonal-shaped nanoholes on the (100) surface of germanium, aided by focused ion beam induced self-organization, is presented. The energetic beam of ions creates a viscous phase which, at a thermodynamical minimum, leads to surface self-organization. A directed viscous-flow along the predefined nanoholes provides well-ordered polygonal nanostructures, ranging from triangles to hexagons and octagons, as desired. The amorphization exhibiting a confined viscous-flow at the walls of nanoholes is attributed to the localized melting zones induced by site-specific thermal spikes during ion irradiation, as revealed by microscopy and molecular dynamics studies. This leads to a local self-organization in the vicinity of each circular nanohole via a viscous-fingering process at the nanoscale. Such controlled self-organization, with the help of a predefined scanning grid, transforms the circular holes into the desired polygonal shape. The present morphology manipulation promises to surmount the barriers concerning the size reduction efforts in the field of nanofabrication.

Occupational Exposure in Health Care Personnel to Antineoplastic Drugs and Initiation of Safe Handling in Hong Kong: A Literature Review.

Despite the benefits for patients as cancer treatment, antineoplastic drugs may cause adverse effects not only in patients but also in health care personnel. Apart from minor symptoms, antineoplastic agents can cause serious health problems. However, protection from occupational exposures to antineoplastic drugs varies between pharmacy staff and nurses. While protection used for pharmacy staff are more advanced, personal protective equipment seems to be the only protection for most nurses around the world. Exposure can never be totally prevented, but it should be minimized at all costs. Guidelines and recommendations have been published; however, these guidelines do not have legal enforcement power. This article aims to provide a literature review on the occupational exposure of health care personnel to antineoplastic drugs and to reflect the current status in Hong Kong.

Characterization of the Competitive Pneumocin Peptides of Streptococcus pneumoniae.

In the polymicrobial environment of the human nasopharynx, Streptococcus pneumoniae (pneumococcus) competes with other members of the microbial community for limited nutrients in part by secreting small peptide bacteriocins called pneumocins. Pneumocin production is controlled by a quorum sensing system encoded by the blp locus. Although the locus is found in all pneumococci, there is significant variability in the repertoire of pneumocins and associated immunity proteins encoded in the Bacteriocin Immunity Region (BIR) and in the presence or absence of a functional Blp transporter. Strains without an active Blp transporter are inactive in plate overlay assays and rely on a homologous transporter that is only produced during brief periods of competence to stimulate the blp locus and secrete pneumocins. The variability of the locus suggests that selective pressure is influencing the content to promote the optimal competitive environment. Much of the variability in the blp locus has been described at the genome level; the phenotypic activity attributable to the various BIR genes has not been fully described. To examine the role of the predicted pneumocin peptides in competition, 454 isolates were screened for competence independent blp pheromone secretion using plate assays. Active strains were characterized for inhibition, BIR content, BlpC pherotype and serotype. Deletion analysis on inhibitory strains demonstrated that BlpI and BlpJ peptides function as a two-peptide bacteriocin and that BlpIJ immunity is encoded by the co-transcribed blpU4/5 genes. BlpIJ secretion promotes inhibitory activity against the majority of pneumococcal isolates when expressed in a Blp transporter intact background. Intermediate levels of competition in biofilms were noted when BlpIJ containing strains carried the non-functional Blp transporter. Based on genome data, the combination of BlpIJ in a Blp transporter intact strain is surprisingly rare, despite clear advantages during colonization and biofilm growth. In contrast, we show that the blpK/pncF operon encoding the single-peptide pneumocin BlpK and its immunity protein is found in the majority of isolates. Unlike, BlpIJ and BlpK were shown to promote a limited spectrum of inhibition due in part to immunity that is independent of activation of the blp locus.

Otologic Disease Following Palatoplasty In International Cleft Palate Cohort.

OBJECTIVE: Study the prevalence of otologic disease in a pediatric post-palatoplasty population with no prior ear tube placement in resource-deprived countries and assess patient characteristics associated with these abnormal results. DESIGN: Retrospective data review. PARTICIPANTS: Ecuadorian and Chinese children identified during humanitarian cleft lip and palate repair trips with cleft palates undergoing palatoplasty from 2007 to 2010. INTERVENTIONS: Tympanometry and otoacoustic emission (OAE) testing performed following palatoplasty. Patients' parents administered surveys regarding perceived hearing deficits. MAIN OUTCOME MEASURES: Age, gender, Veau classification, follow-up time, laterality, and country of origin were evaluated for possible association with type B tympanogram, "Refer" Otoacoustic results, and presence of hearing difficulty as identified by a parent. Significant predictors were further evaluated with multivariate analysis. RESULTS: The cohorts included 237 patients (129 Ecuadorian, 108 Chinese); mean age: 3.9 years; mean follow-up: 4.2 years. Thirty-nine percent scored type B, 38% failed OAE testing, and 8% of parents noted hearing deficits. The country of origin and a younger age were identified as predictive variables regarding type B tympanogram. Follow-up time, country of origin, and bilateral OAE "Refer" results all significantly predicted parental questionnaire results. Subsequent multivariable analysis further demonstrated effect modification between the 2 variables of age at palatoplasty and country of origin when predicting type B vs type A tympanometry. CONCLUSION: Without otologic intervention, cleft palate children in resource-deprived settings suffer type B tympanometry and failed OAE results with similar to increased incidences to other studied cleft palate populations with otologic interventions available.

Palatal Fistula Risk after Primary Palatoplasty: A Retrospective Comparison of a Humanitarian Organization and Tertiary Hospitals.

BACKGROUND: Humanitarian surgical organizations provide palatoplasties for patients without access to surgical care. Few organizations have evaluated the outcomes of these trips. This study evaluates the palatal fistula rate in patients from two cohorts in rural China and one in the United States. METHODS: This study compared the odds of fistula formation among three cohorts whose palates were repaired between 2005 and 2009. One cohort included 97 Chinese patients operated on by teams from the United States and Canada under the auspices of Resurge International. They were compared to cohorts at Huaxi Stomatology Hospital and the University of California San Francisco (UCSF). Age, fistula presence, and Veau class were compared among cohorts using Chi-square tests. Logistic regression was used to analyze predictors of fistula formation. RESULTS: The fistula risk was 35.4% in patients treated by humanitarian teams, 12.8% at Huaxi University Hospital and 2.5% at UCSF ( P < 0.001). Age and Veau class were associated with fistula formation (Age P = 0.0015; Veau P < 0.001). ReSurge and Huaxi patients had 20.2 and 5.6 times the odds of developing a fistula, respectively, compared to UCSF patients ( P < 0.01, both). A multivariable model controlling for surgical group, age, and gender showed an association between Veau class and the odds of fistula formation. CONCLUSIONS: Chinese children undergoing palatoplasty by international teams had higher odds of palatal fistula than children treated by Chinese surgeons in established institutions and children treated in the United States. More research is required to identify factors affecting complication rates in low-resource environments.

Manipulating the structure and mechanical properties of thermoplastic polyurethane/polycaprolactone hybrid small diameter vascular scaffolds fabricated via electrospinning using an assembled rotating collector.

The success of blood vessel transplants with vascular scaffolds (VSs) highly depends on their structure and mechanical properties. The fabrication of small diameter vascular scaffolds (SDVSs) mimicking the properties of native blood vessels has been a challenge. Herein, we propose a facile method to fabricate thermoplastic polyurethane (TPU)/polycaprolactone (PCL) hybrid SDVSs via electrospinning using a modified rotating collector. By varying the ratio between the TPU and the PCL, and changing the electrospinning volume, SDVSs with a wavy configuration and different properties could be obtained. Detailed investigation revealed that certain TPU/PCL hybrid SDVSs closely resembled the mechanical behaviors of blood vessels due to the presence of a wavy region and the combination of flexible TPU and rigid PCL, which mimicked the properties of elastin and collagen in blood vessels. The fabricated TPU/PCL SDVSs achieved lumen diameters of 1-3mm, wall thicknesses of 100-570µm, circumferential moduli of 1-6MPa, ultimate strengths of 2-8MPa, over 250% elongation-at-break values, toe regions of 5.3-9.4%, high recoverability, and compliances close to those of human veins. Moreover, these TPU/PCL SDVSs possessed sufficient suture retention strength and burst pressure to fulfill transplantation requirements and maintain normal blood flow. Human endothelial cell culture revealed good biocompatibility of the scaffolds, and cells were able to grow on the inner surface of the tubular scaffolds, indicating promising prospects for use as tissue-engineered vascular grafts.

Development of biomimetic thermoplastic polyurethane/fibroin small-diameter vascular grafts via a novel electrospinning approach.

A new electrospinning approach for fabricating vascular grafts with a layered, circumferentially aligned, and micro-wavy fibrous structure similar to natural elastic tissues has been developed. The customized electrospinning collector was able to generate wavy fibers using the dynamic "jump rope" collecting process, which also solved the sample removal problem for mandrel-type collectors. In this study, natural silk fibroin and synthetic thermoplastic polyurethane (TPU) were combined at different weight ratios to produce hybrid small-diameter vascular grafts. The purpose of combining these two materials was to leverage the bioactivity and tunable mechanical properties of these natural and synthetic materials. Results showed that the electrospun fiber morphology was highly influenced by the material compositions and solvents employed. All of the TPU/fibroin hybrid grafts had mechanical properties comparable to natural blood vessels. The circumferentially aligned and wavy biomimetic configuration provided the grafts with a sufficient toe region and the capacity for long-term usage under repeated dilatation and contraction. Cell culture tests with human endothelial cells (EC) also revealed high cell viability and good biocompatibility for these grafts. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 985-996, 2018.

Elucidating transmission dynamics and host-parasite-vector relationships for rodent-borne Bartonella spp. in Madagascar.

Bartonella spp. are erythrocytic bacteria transmitted via arthropod vectors, which infect a broad range of vertebrate hosts, including humans. We investigated transmission dynamics and host-parasite-vector relationships for potentially zoonotic Bartonella spp. in invasive Rattus rattus hosts and associated arthropod ectoparasites in Madagascar. We identified five distinct species of Bartonella (B. elizabethae 1, B. elizabethae 2, B. phoceensis 1, B. rattimassiliensis 1, and B. tribocorum 1) infecting R. rattus rodents and their ectoparasites. We fit standard epidemiological models to species-specific age-prevalence data for the four Bartonella spp. with sufficient data, thus quantifying age-structured force of infection. Known zoonotic agents, B. elizabethae 1 and 2, were best described by models exhibiting high forces of infection in early age class individuals and allowing for recovery from infection, while B. phoceensis 1 and B. rattimassiliensis 1 were best fit by models of lifelong infection without recovery and substantially lower forces of infection. Nested sequences of B. elizabethae 1 and 2 were recovered from rodent hosts and their Synopsyllus fonquerniei and Xenopsylla cheopsis fleas, with a particularly high prevalence in the outdoor-dwelling, highland-endemic S. fonquerniei. These findings expand on force of infection analyses to elucidate the ecological niche of the zoonotic Bartonella elizabethae complex in Madagascar, hinting at a potential vector role for S. fonquerniei. Our analyses underscore the uniqueness of such ecologies for Bartonella species, which pose a variable range of potential zoonotic threats.

Informal processing of electronic waste at Agbogbloshie, Ghana: workers' knowledge about associated health hazards and alternative livelihoods.

AIMS: This study was conducted to investigate the electronic waste workers' knowledge about the potential health hazards associated with their work as well as the livelihood alternatives that they would prefer if they were given the opportunity. METHODS: A qualitative cross-sectional study was conducted to gather empirical information on e-waste workers' knowledge about the potential hazards associated with their work and the livelihood alternatives to e-waste recycling with a sample consisting of twenty all-male electronic waste workers at the Agbogbloshie scrap metal yard in Accra, Ghana. RESULTS: Electronic waste workers at Agbogbloshie were found to be exposed to a variety of injuries and illnesses. The workers' knowledge of the association between their health status and their work was generally poor. Apart from the physical injuries, they did not believe their work played any negative role in their health conditions. They preferred occupations such as farming or professional driving located in the northern region of Ghana to be closer to their families. CONCLUSIONS: The study concludes that the low knowledge level of the workers on the hazards that are associated with their work has implications for them accepting technologies to protect them and the natural environment from contamination. It is therefore imperative for any intervention to consider the current low level of knowledge and actively educate the workers to raise their awareness level, taking into account the provision of opportunities for workers to acquire applicable skills for future employment in other fields.

Characterization of a Multipeptide Lantibiotic Locus in Streptococcus pneumoniae.

UNLABELLED: Bacterial communities are established through a combination of cooperative and antagonistic interactions between the inhabitants. Competitive interactions often involve the production of antimicrobial substances, including bacteriocins, which are small antimicrobial peptides that target other community members. Despite the nearly ubiquitous presence of bacteriocin-encoding loci, inhibitory activity has been attributed to only a small fraction of gene clusters. In this study, we characterized a novel locus (the pld locus) in the pathogen Streptococcus pneumoniae that drives the production of a bacteriocin called pneumolancidin, which has broad antimicrobial activity. The locus encodes an unusual tandem array of four inhibitory peptides, three of which are absolutely required for antibacterial activity. The three peptide sequences are similar but appear to play distinct roles in regulation and inhibition. A modification enzyme typically found in loci encoding a class of highly modified bacteriocins called lantibiotics was required for inhibitory activity. The production of pneumolancidin is controlled by a two-component regulatory system that is activated by the accumulation of modified peptides. The locus is located on a mobile element that has been found in many pneumococcal lineages, although not all elements carry the pld genes. Intriguingly, a minimal region containing only the genes required for pneumolancidin immunity was found in several Streptococcus mitis strains. The pneumolancidin-producing strain can inhibit nearly all pneumococci tested to date and provided a competitive advantage in vivo. These peptides not only represent a unique strategy for bacterial competition but also are an important resource to guide the development of new antimicrobials. IMPORTANCE: Successful colonization of a polymicrobial host surface is a prerequisite for the subsequent development of disease for many bacterial pathogens. Bacterial factors that directly inhibit the growth of neighbors may provide an advantage during colonization if the inhibition of competitors outweighs the energy for production. In this work, we found that production of a potent antimicrobial called pneumolancidin conferred a competitive advantage to the pathogen Streptococcus pneumoniae. S. pneumoniae secreting pneumolancidin inhibits a wide array of Gram-positive organisms, including all but one tested pneumococcal strain. The pneumolancidin genetic locus is of particular interest because it encodes three similar modified peptides (lantibiotics), each of which has a distinct role in the function of the locus. Lantibiotics represent a relatively untapped resource for the development of clinically useful antibiotics which are desperately needed. The broad inhibitory activity of pneumolancidin makes it an ideal candidate for further characterization and development.