Insights on molecular modeling and supramolecular arrangement of bilastine polymorphs.

CONTEXT: The advancement in the development of second-generation drugs in the field of antihistamines represents a significant milestone in the management of allergic diseases, targeting the effects of histamine. The efficacy of bilastine in treating allergic disorders has sparked interest in investigating its polymorphism, a crucial property that impacts quality, safety, and effectiveness as per regulatory guidelines. This study examines the polymorphism of bilastine, focusing on two crystalline forms labeled as Form I and Form II. Utilizing advanced analytical techniques, the research explores the structural characteristics and molecular interactions within these forms. Geometric parameters, such as bond lengths, bond angles, and torsion angles, are examined to comprehend molecular conformations and crystal packing arrangements. Hydrogen bonding, covalent bonds, and van der Waals forces contribute to the unique supramolecular arrangements in these forms. This study provides a significant contribution to understanding bilastine's polymorphism, offering critical insights to researchers and regulatory bodies to ensure the quality, efficacy, and safety of antihistamine products. METHODS: The molecular conformation of two bilastine forms was obtained through DFT with the exchange-correlation functional M06-2X and the 6-311 + + G(d,p) basis set, and the results were compared with the experimental X-ray. The atomic coordinates were obtained directly from the crystalline structures, and charge transfer was also investigated using frontier molecular orbitals (HOMO and LUMO), and MEP map in order to evaluate the energies associated with charge transfers and regions of high electron affinity. The geometric and topological parameters and intermolecular interactions in the crystals were analyzed using Hirshfeld Surface.

Tibial Spine Fractures in the Child and Adolescent Athlete: A Systematic Review and Meta-analysis.

BACKGROUND: Tibial spine fractures (TSFs) are uncommon injuries that may result in substantial morbidity in children. A variety of open and arthroscopic techniques are used to treat these fractures, but no single standardized operative method has been identified. PURPOSE: To systematically review the literature on pediatric TSFs to determine the current treatment approaches, outcomes, and complications. STUDY DESIGN: Meta-analysis; Level of evidence, 4. METHODS: A systematic review of the literature was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines using PubMed, Embase, and Cochrane databases. Studies evaluating treatment and outcomes of patients <18 years old were included. Patient demographic characteristics, fracture characteristics, treatments, and outcomes were abstracted. Descriptive statistics were used to summarize categorical and quantitative variables, and a meta-analytic technique was used to compare observational studies with sufficient data. RESULTS: A total of 47 studies were included, totaling 1922 TSFs in patients (66.4% male) with a mean age of 12 years (range, 3-18 years). The operative approach was open reduction and internal fixation in 291 cases and arthroscopic reduction and internal fixation in 1236 cases; screw fixation was used in 411 cases and suture fixation, in 586 cases. A total of 13 nonunions were reported, occurring most frequently in Meyers and McKeever type III fractures (n = 6) and in fractures that were treated nonoperatively (n = 10). Arthrofibrosis rates were reported in 33 studies (n = 1700), and arthrofibrosis was present in 190 patients (11.2%). Range of motion loss occurred significantly more frequently in patients with type III and IV fractures (P < .001), and secondary anterior cruciate ligament (ACL) injury occurred most frequently in patients with type I and II fractures (P = .008). No statistically significant differences were found with regard to rates of nonunion, arthrofibrosis, range of motion loss, laxity, or secondary ACL injury between fixation methods (screw vs suture). CONCLUSION: Despite variation in TSF treatment, good overall outcomes have been reported with low complication rates in both open and arthroscopic treatment and with both screw and suture fixation. Arthrofibrosis remains a concern after surgical treatment for TSF, but no significant difference in incidence was found between the analysis groups. Larger studies are necessary to compare outcomes and form a consensus on how to treat and manage patients with TSFs.

Description, life cycle, and phylogenetics of Proterometra wigglewomble n. sp. (Digenea: Azygiidae) from the Cahaba River, Alabama, U.S.A.

We herein describe Proterometra wigglewomble n. sp. (Digenea: Azygiidae: Azygiinae) from the Cahaba River, Alabama, USA, which asexually reproduces in the compact elimia, Elimia showalteri (Lea, 1860) (Cerithioidea: Pleuroceridae) and matures in the oesophagus of the blackbanded darter, Percina nigrofasciata (Agassiz, 1854) (Perciformes: Percidae). Adults of the new species differ from congeners by having a small body and eggs having a wholly fimbriated surface that appears as a cilia-like brush border. Live naturally-shed cercariae of the new species differ from those of its congeners by having a strongly claviform tail stem bearing aspinose mammillae, a single furca, excretory pores that open on the posterior margin of the single furca, and few eggs in the cercarial distome. The behaviour of the cercaria further differentiates the new species. Naturally-shed cercariae of P. wigglewomble secrete a jelly-like adhesive that coats the surface of the furca and evidently facilitates attachment to the surface of glass, plastic, and snail shell. Attached cercariae vigorously wiggle and thrash about once attached, as if mimicking the larva of a stream insect so as to lure the blackbanded darter to eat it. Phylogenetic analyses recovered monophyletic Azygiidae, comprising monophyletic Leuceruthrinae Goldberger, 1911 and polyphyletic Azygiinae Lühe, 1909. The present study is the largest taxon sampling for Azygiidae and the first to include 28S sequences of Leuceruthrus. Compact elimia and blackbanded darter are new host records for Proterometra. The new species is the 3rd congener reported from the Cahaba River, a region renowned for its fish and snail endemic biodiversity.

Preventing Production Escape Using an Engineered Glucose-Inducible Genetic Circuit.

A proper balance of metabolic pathways is crucial for engineering microbial strains that can efficiently produce biochemicals on an industrial scale while maintaining cell fitness. High production loads can negatively impact cell fitness and hinder industrial-scale production. To address this, fine-tuning gene expression using engineered promoters and genetic circuits can promote control over multiple targets in pathways and reduce the burden. We took advantage of the robust carbon catabolite repression system of Bacillus subtilis to engineer a glucose-inducible genetic circuit that supports growth and production. The circuit is resilient, enabling a quick switch in the production status when exposed to the correct carbon source. By performing serial cultivations for 61 generations under repressive conditions, we preserved the production capacity of the cells, which could be fully accessed by switching to glucose in the next cultivation step. Switching to glucose after 61 generations resulted in 34-fold activation and generated 70% higher production in comparison to standard cultivation in glucose. Conversely, serial cultivation under permanent induction resulted in 62% production loss after 67 generations alongside an increase in the culture growth rate. As a pathway-independent circuit activated by the preferred carbon source, our engineered glucose-inducible genetic circuit is broadly useful and imposes no additional cost to traditional production processes.

Single-cell lipidomics enabled by dual-polarity ionization and ion mobility-mass spectrometry imaging.

Single-cell (SC) analysis provides unique insight into individual cell dynamics and cell-to-cell heterogeneity. Here, we utilize trapped ion mobility separation coupled with dual-polarity ionization mass spectrometry imaging (MSI) to enable high-throughput in situ profiling of the SC lipidome. Multimodal SC imaging, in which dual-polarity-mode MSI is used to perform serial data acquisition runs on individual cells, significantly enhanced SC lipidome coverage. High-spatial resolution SC-MSI identifies both inter- and intracellular lipid heterogeneity; this heterogeneity is further explicated by Uniform Manifold Approximation and Projection and machine learning-driven classifications. We characterize SC lipidome alteration in response to stearoyl-CoA desaturase 1 inhibition and, additionally, identify cell-layer specific lipid distribution patterns in mouse cerebellar cortex. This integrated multimodal SC-MSI technology enables high-resolution spatial mapping of intercellular and cell-to-cell lipidome heterogeneity, SC lipidome remodeling induced by pharmacological intervention, and region-specific lipid diversity within tissue.

Using genomics, morphometrics, and environmental niche modeling to test the validity of a narrow-range endemic snail, Pateranantahala (Gastropoda, Polygyridae).

Terrestrial gastropods are among the most imperiled groups of organisms on Earth. Many species have a complex taxonomic history, often including poorly defined subspecies, most of which have not been the focus of modern systematics research. Genomic tools, geometric morphometrics, and environmental niche modeling were used to assess the taxonomic status of Pateraclarkiinantahala (Clench & Banks, 1932), a subspecies of high conservation concern with a restricted range of approximately 3.3 km2 in North Carolina, USA. A genome-scale dataset was generated that included individuals with morphologies matching P.c.nantahala, P.c.clarkii, and one individual with an intermediate form between P.c.nantahala and P.c.clarkii that was initially hypothesized as a potential hybrid. Mitochondrial phylogenetics, nuclear species tree inference, and phylogenetic networks were used to assess relationships and gene flow. Differences in shell shape via geometric morphometrics and whether the environmental niches of the two subspecies were significantly different were also examined. Molecular analyses indicated an absence of gene flow among lineages of P.clarkii sensu lato. Analyses rejected our hypothesis that the intermediate shelled form represented a hybrid, but instead indicated that it was a distinct lineage. Environmental niche models indicated significant differences in environmental niche between P.c.clarkii and P.c.nantahala, and geometric morphometrics indicated that P.c.nantahala had a significantly different shell shape. Given multiple lines of evidence, species-level recognition of P.nantahala is warranted.

A novel assembly pipeline and functional annotations for targeted sequencing: A case study on the globally threatened Margaritiferidae (Bivalvia: Unionida).

The proliferation of genomic sequencing approaches has significantly impacted the field of phylogenetics. Target capture approaches provide a cost-effective, fast and easily applied strategy for phylogenetic inference of non-model organisms. However, several existing target capture processing pipelines are incapable of incorporating whole genome sequencing (WGS). Here, we develop a new pipeline for capture and de novo assembly of the targeted regions using whole genome re-sequencing reads. This new pipeline captured targeted loci accurately, and given its unbiased nature, can be used with any target capture probe set. Moreover, due to its low computational demand, this new pipeline may be ideal for users with limited resources and when high-coverage sequencing outputs are required. We demonstrate the utility of our approach by incorporating WGS data into the first comprehensive phylogenomic reconstruction of the freshwater mussel family Margaritiferidae. We also provide a catalogue of well-curated functional annotations of these previously uncharacterized freshwater mussel-specific target regions, representing a complementary tool for scrutinizing phylogenetic inferences while expanding future applications of the probe set.

Development of a More Environmentally Friendly Silk Fibroin Scaffold for Soft Tissue Applications.

A push for environmentally friendly approaches to biomaterials fabrication has emerged from growing conservational concerns in recent years. Different stages in silk fibroin scaffold production, including sodium carbonate (Na2CO3)-based degumming and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)-based fabrication, have drawn attention for their associated environmental concerns. Environmentally friendly alternatives have been proposed for each processing stage; however, an integrated green fibroin scaffold approach has not been characterized or used for soft tissue applications. Here, we show that the combination of sodium hydroxide (NaOH) as a substitute degumming agent with the popular "aqueous-based" alternative silk fibroin gelation method yields fibroin scaffolds with comparable properties to traditional Na2CO3-degummed aqueous-based scaffolds. The more environmentally friendly scaffolds were found to have comparable protein structure, morphology, compressive modulus, and degradation kinetics, with increased porosity and cell seeding density relative to traditional scaffolds. Human adipose-derived stem cells showed high viability after three days of culture while seeded in each scaffold type, with uniform cell attachment to pore walls. Adipocytes from human whole adipose tissue seeded into scaffolds were found to have similar levels of lipolytic and metabolic function between conditions, in addition to a healthy unilocular morphology. Results indicate that our more environmentally friendly methodology for silk scaffold production is a viable alternative and well suited to soft tissue applications.

Pharmacy Resident Perspectives on the Layered Learning Practice Model.

Objective: To describe pharmacy resident perspectives on the layered learning practice model (LLPM) at large academic medical centers in the United States and identify the types of training residents receive to prepare for the LLPM. Methods: This was a cross-sectional, mixed methods study that surveyed pharmacy residents completing training at large, academic medical centers on their perspectives of the LLPM. Residents with at least 4 weeks of precepting experience were eligible to complete an online survey. Descriptive statistics were generated for demographic and Likert data while themes were identified from narrative free responses. Results: Twenty-seven resident responses from 10 institutions were included. Likert data showed generally positive perspectives toward overall experience with the LLPM and perceived LLPM impact on clinical knowledge and professional practice, with 100.0% of respondents agreeing they enjoyed precepting under the LLPM. However, 44.4% also agreed that precepting was stressful. LLPM impact on resident behavior received positive to neutral responses; 63.0% neither agreed nor disagreed that the LLPM changed their approach to patient care. Written comments revealed themes such as sources of stress within the LLPM, increased depth of learning, improved comprehensive patient care, and improved professional growth. The most common forms of LLPM training occurred through preceptor and student evaluations (73.1% and 61.5%, respectively) and orientation (50.0%). Conclusion: These findings identified a variety of resident perspectives on the LLPM ranging from positive to negative and revealed possible areas of improvement related to LLPM implementation. Residency programs may consider exploring stressors on the resident role in the LLPM to better structure resident precepting training and maximize their clinical learning experience.

Associations between stuttering avoidance and perceived patient-centeredness of health care interactions.

PURPOSE: To determine the relationships between (1) stuttering severity and (2) avoidance of speaking on patient centeredness of healthcare system interactions in a sample of persons who stutter. METHODS: This quantitative study utilized cross-sectional electronic surveys to assess the experiences of one-hundred-twenty-two adults who stutter in the United States with primary care physicians. The surveys evaluated: (1) self-reported stuttering severity and avoidance of speaking; and (2) self-reported patient-centeredness of healthcare interactions. We used multivariate linear regression to model relationships between independent and dependent variables, controlling for age, gender, patient-provider relationship duration, race/ethnicity, the presence of comorbid conditions, and household income. RESULTS: Patient self-reported avoidance of speaking was significantly negatively associated with self-reported patient-centeredness of healthcare interactions. Patient self-reported stuttering severity was not significantly associated with patient-centeredness. CONCLUSION: Our findings present evidence that internal non-observable behaviors among persons who stutter, such as avoiding speaking, are associated with negative impact on healthcare interactions. Speech-language pathologists may want to discuss healthcare challenges with their clients and elicit communication barriers to inspire positive interactions within the healthcare system.

Trends in Pediatric Anterior Cruciate Ligament Reconstruction: The Effect of COVID-19.

CONTEXT: The number of pediatric anterior cruciate ligament reconstructions (ACLRs) occurring yearly increased almost 6-fold from 2004-2014. We find it interesting that limited recent data exist on rates of ACL injury and reconstruction in children and adolescents, especially in the context of COVID-19. OBJECTIVE: Given the effect of the COVID-19 pandemic on youth sports seasons and the postponement of many elective surgeries, we sought to examine the changes in rates of ACLR during this period. DESIGN: Retrospective cohort study. SETTING: This study used the Pediatric Health Information System (PHIS) database to identify eligible patients at PHIS-participating hospitals nationwide from January 2016-June 2021, with March 1, 2020, considered the start of the COVID-19 pandemic. PATIENTS OR OTHER PARTICIPANTS: Using Current Procedural Terminology codes, patients 18 years old and younger who underwent ACLR surgery were identified. MAIN OUTCOME MEASURE(S): Patient demographics and overall rates of surgery prepandemic and intrapandemic were compared. Data were analyzed using bivariate, mixed-model, and time series analyses. RESULTS: A total of 24 843 ACLRs were identified during this time period. In total, 1853 fewer surgeries than expected were performed after March 2020 given prepandemic trends. Intrapandemic demographics revealed an increase in the proportion of patients who identified as White and with private insurance and a decrease in the proportion who identified as Black and with public insurance. Also, the proportion of ACLRs by region shifted, with more surgeries performed in the Midwest and fewer in the Northeast. In the model adjusted for hospital-level variability, only race and insurance status remained significant. CONCLUSIONS: Based on prepandemic trends, fewer patients than projected underwent ACLR once the pandemic began, likely due to a combination of decreased rates of injury and delayed surgery.

On-tissue amidation of sialic acid with aniline for sensitive imaging of sialylated N-glycans from FFPE tissue sections via MALDI mass spectrometry.

Spatial visualization of glycans within clinical tissue samples is critical for discovery of disease-relevant glycan dysregulations. Herein, we develop an on-tissue derivatization strategy for sensitive spatial visualization of N-glycans from formalin-fixed paraffin-embedded (FFPE) tissue sections, based on amidation of sialic acid residues with aniline. The sialylated N-glycans were stabilized and given enhanced signal intensity owing to selective capping of a phenyl group to the sialic acid residue after aniline labeling. Proof-of-concept experiments, including determinations of sialylglycopeptide and N-glycans enzymatically released from glycoproteins, were performed. Further, mass spectrometry (MS) imaging of N-glycans on human laryngeal cancer FFPE tissue sections was conducted via matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), based on our strategy for on-tissue amidation of sialylated N-glycans. We obtained higher sialylated N-glycan coverages for both the glycoproteins and cancer tissue samples, demonstrating that the detection sensitivity for sialylated N-glycans is notably improved by amidation derivatization. We also characterized N-glycan heterogeneity across the human laryngeal cancer tissue section, showing N-glycan dysregulation in the tumor region.

Subterranean freshwater gastropod biodiversity and conservation in the United States and Mexico.

Many taxonomic groups successfully exploit groundwater environments and have adapted to a subterranean (stygobiotic) existence. Among these groups are freshwater gastropods (stygosnails), which represent a widespread and taxonomically diverse component of groundwater ecosystems in North America. However, owing to sampling difficulty and lack of targeted study, stygosnails remain among the most understudied of all subterranean groups. We conducted a literature review to assess the biodiversity and geographic associations of stygosnails, along with the threats, management activities, and policy considerations related to the groundwater systems they inhabit. We identified 39 stygosnail species known to occur in a range of groundwater habitats from karst regions in the United States and Mexico. Most stygosnails exhibit extreme narrow-range endemism, resulting in a high risk of extinction from a single catastrophic event. We found that anthropogenically driven changes to surface environments have led to changes in local hydrology and degradation of groundwater systems inhabited by stygosnails such as increased sedimentation, introduction of invasive species, groundwater extraction, or physical collapse of water-bearing passages. Consequently, 32 of the 39 described stygosnail species in the United States and Mexico have been assessed as imperiled under NatureServe criteria, and 10 species have been assessed as threatened under International Union for Conservation of Nature criteria. Compared with surface species of freshwater snails, stygosnail conservation is uniquely hindered by difficulties associated with accessing subterranean habitats for monitoring and management. Furthermore, only three species were found to have federal protection in either the United States or Mexico, and current laws regulating wildlife and water pollution at the state and federal level may be inadequate for protecting stygosnail habitats. As groundwater systems continue to be manipulated and relied on by humans, groundwater-restricted fauna such as stygosnails should be studied so unique biodiversity can be protected.

Diversidad y Conservación de Gasterópodos Subterráneos de Agua Dulce en los Estados Unidos y en México Resumen Muchos grupos taxonómicos aprovechan exitosamente los ambientes de aguas subterráneas y se han adaptado eficazmente a una existencia subterránea (estigobiótica). Entre estos grupos están los gasterópodos (estigocaracoles), los cuales representan un componente taxonómicamente diverso y de amplia distribución en los ecosistemas de aguas subterráneas en América del Norte. Sin embargo, debido a la dificultad del muestreo y a la falta de estudios enfocados, los estigocaracoles todavía son de los grupos menos estudiados de los taxones subterráneos. Realizamos una revisión de la literatura para evaluar las asociaciones geográficas y la biodiversidad de los estigocaracoles, junto con las amenazas, actividades de manejo y consideraciones políticas relacionadas con los sistemas de aguas subterráneas que habitan. Identificamos a 39 especies de estigocaracoles que se sabe se encuentran en una gama de hábitats de aguas subterráneas de las regiones kársticas en los Estados Unidos y en México. La mayoría de los estigocaracoles exhiben un endemismo extremo de extensión limitada, lo que resulta en un riesgo elevado de extinción a partir de un evento catastrófico único. Descubrimos que los cambios causados por el hombre en los ambientes superficiales han resultado en cambios en la hidrología local y en la degradación de los sistemas de aguas subterráneas habitadas por los estigocaracoles. Dichos cambios incluyen incremento de la sedimentación, la introducción de especies invasoras, la extracción de aguas subterráneas y el colapso físico de los pasos de agua. Como consecuencia, 32 de las 39 especies descritas de estigocaracoles en los Estados Unidos y en México han sido valoradas como en peligro bajo los criterios de NatureServe, y diez especies han sido valoradas como amenazadas bajo los criterios de la Unión Internacional para la Conservación de la Naturaleza. Comparada con las especies superficiales de caracoles de agua dulce, la conservación de los estigocaracoles está singularmente obstaculizada por las dificultades asociadas con el acceso a los hábitats subterráneos para su monitoreo y manejo. Además, se encontró que sólo tres especies cuentan con protección federal ya sea en Estados Unidos o en México, y puede que las leyes actuales que regulan la vida silvestre y la contaminación del agua a nivel estatal y federal sean inadecuadas para la protección de los hábitats de los estigocaracoles. Mientras los sistemas de aguas subterráneas sigan siendo manipulados y los humanos sigan dependiendo de ellos, la fauna restringida a las aguas subterráneas, como los estigocaracoles, debería ser estudiada para proteger a la biodiversidad tan única.

Intersectionality Within Critical Autism Studies: A Narrative Review.

The aim of this narrative review was to examine intersectionality within critical autism studies. A growing body of evidence has demonstrated the importance of intersectional frameworks in highlighting the diverse experiences of marginalized communities. Many disability studies researchers investigated intersectionality to elucidate the impact of race, gender, sexuality, class, and other constructs on disability identification. Within critical autism studies, a field that emerged to challenge the deficit-laden, pathologizing autism discourses favored by the medical community, intersectionality has started to become an integral component of the literature. This review highlights intersectional frameworks utilized to explore autism in both academic and nonacademic contexts, to provide a foundation for future study. Upon analysis, we found overarching themes regarding the explicit, implicit, and descriptive approaches to intersectionality, racial and gender biases within critical autism studies, and the multidisciplinary nature of intersectionality and critical autism studies. We finish the review with recommendations for how to more fully address the experiences of all autistic people-particularly of racial, gender, and sexual minority individuals-in future study. Our recommendations include utilizing intersectionality as an analytical lens for describing previously overlooked phenomena and questioning central tenets of methodology and processes, including developing research questions, analyzing data, and writing results.

Why is this topic important?: Intersectionality means that many different social influences make up a person's experiences. Examples of these social influences are gender and sexism, ethnicity and racism, and disability and ableism. This topic is important because different autistic people may have different experiences depending on these other social factors. Studying intersectionality helps us to understand these differences and better serve those autistic communities that may be ignored. What is the purpose of this article?: We looked at how authors of published studies and community projects have thought about intersectionality in autistic communities. What personal or professional perspectives do the researchers bring to this topic?: Both authors have invisible disabilities. We have both done research on disability and social influences, and we have worked with people in disability communities, including autistic communities. We have also noticed how our gender, race, and sexual orientation have affected how we experience our disabilities. What results did the researchers find?: We found three main ways that authors talked about intersectionality. (1) Sometimes authors directly talk about intersectionality. This means that some authors use the idea of intersectionality to help them think of a research question or to help them understand their data. In these cases, authors use the word "intersectionality" in their articles. (2) Sometimes authors talk about intersectionality, but not directly. This means that some authors do not use the word "intersectionality" to talk about their research, but they still use similar ideas. For example, sometimes authors looked at what it is like to be an autistic woman. This topic is intersectional because it talks about two different social influences (autism and gender). However, the authors did not directly write that it was intersectional. (3) Finally, sometimes authors do not talk about intersectionality, but their study can be used as a starting point for talking about intersectionality later. For example, sometimes authors look at differences in whether people are diagnosed with autism, based on their race. Research such as this can be helpful because other researchers can use it to make studies to learn about why differences between autistic groups happen. What do the researchers recommend?: We recommend that researchers in many fields and people working with autistic communities think about how intersectionality and social influences affect autistic people. They can do this when thinking of research questions, understanding their data, and writing about their results. We also recommend that researchers think more about racial, gender, and sexual minority group experiences within the autistic community. This is important because sometimes researchers or stakeholders have forgotten about certain groups of autistic people. How will these recommendations help autistic adults now or in the future?: Thinking about intersectionality can help people understand autistic people's different experiences, especially in terms of how these experiences are affected by social influences. We hope that our article leads to research that makes life better for all autistic people and fits better for autistic people who have been ignored or forgotten about in some research or advocacy projects.

A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich's ataxia.

Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. A source of damage to Fe-S clusters is cuprous (Cu1+) ions. Since histone H3 enzymatically produces Cu1+ for copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3­mediated Cu1+ toxicity is a major determinant of cellular functional pool of Fe-S clusters. Inadequate Fe-S cluster supply, due to diminished assembly as occurs in Friedreich's ataxia or defective distribution, causes severe metabolic and growth defects in Saccharomyces cerevisiae. Decreasing Cu1+ abundance, through attenuation of histone cupric reductase activity or depletion of total cellular copper, restored Fe-S cluster­dependent metabolism and growth. Our findings reveal an interplay between chromatin and mitochondria in Fe-S cluster homeostasis and a potential pathogenic role for histone enzyme activity and Cu1+ in diseases with Fe-S cluster dysfunction.

An atlas of protein turnover rates in mouse tissues.

Protein turnover is critical to cellular physiology as well as to the growth and maintenance of tissues. The unique synthesis and degradation rates of each protein help to define tissue phenotype, and knowledge of tissue- and protein-specific half-lives is directly relevant to protein-related drug development as well as the administration of medical therapies. Using stable isotope labeling and mass spectrometry, we determine the in vivo turnover rates of thousands of proteins-including those of the extracellular matrix-in a set of biologically important mouse tissues. We additionally develop a data visualization platform, named ApplE Turnover, that enables facile searching for any protein of interest in a tissue of interest and then displays its half-life, confidence interval, and supporting measurements. This extensive dataset and the corresponding visualization software provide a reference to guide future studies of mammalian protein turnover in response to physiologic perturbation, disease, or therapeutic intervention.

Assessing Genomic Diversity, Connectivity, and Riverscape Genetics Hypotheses in the Endangered Rough Hornsnail, Pleurocera Foremani, Following Habitat Disruption.

The southeastern United States is home to some of the richest biodiversity in the world. Over the last 200 years, however, rapid industrialization and urbanization have threatened many natural areas, including freshwater habitats. River impoundments have also rapidly altered freshwater habitats, often resulting in species extirpation or extinction. The Coosa River in Alabama experienced one of the largest faunal declines in modern history after impoundment, making it an ideal system for studying how invertebrate species are affected by reservoir creation. One such species, the Rough Hornsnail, Pleurocera foremani, is an endangered freshwater snail in the family Pleuroceridae. We sampled all known localities of P. foremani and used 2bRAD-seq to measure genetic diversity. We assessed riverscape genomic patterns across the current range of P. foremani and measured gene flow within and between impoundments. We also investigated the degree to which P. foremani displays an isolation by distance pattern and conforms to broad hypotheses that have been put forth for population genetics of riverine species like the Mighty Headwater Hypothesis that predicts greater genetic diversity in headwater reaches compared with mainstem populations. Like most other freshwater species, a pattern of isolation by distance was observed in P. foremani. We also found that Coosa River dams are a barrier to gene flow, and genetic fragmentation of P. foremani is likely to increase. However, gene flow appeared common within reservoirs and tributaries. Additionally, we found that spatial genetic structure of P. foremani deviates from what is expected under the Mighty Headwaters Hypothesis, adding to a growing body of research suggesting that the majority of genetic diversity in low-dispersing gastropods is found in mainstem populations.

Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.

PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.