Search

Vocal production learning (vocal learning) is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.

Gamete fusion is a critical event of mammalian fertilization. A random one-bead one-compound combinatorial peptide library represented synthetic human egg mimics and identified a previously unidentified ligand as Fc receptor-like 3, named MAIA after the mythological goddess intertwined with JUNO. This immunoglobulin super family receptor was expressed on human oolemma and played a major role during sperm-egg adhesion and fusion. MAIA forms a highly stable interaction with the known IZUMO1/JUNO sperm-egg complex, permitting specific gamete fusion. The complexity of the MAIA isotype may offer a cryptic sexual selection mechanism to avoid genetic incompatibility and achieve favorable fitness outcomes.

Mutations in glycosylation pathways, such as N-linked glycosylation, O-linked glycosylation, and GPI anchor synthesis, lead to Congenital Disorders of Glycosylation (CDG). CDG typically present with seizures, hypotonia, and developmental delay but display large clinical variability with symptoms affecting every system in the body. This variability suggests modifier genes might influence the phenotypes. Because of the similar physiology and clinical symptoms, there are likely common genetic modifiers between CDG. Here, we use evolution as a tool to identify common modifiers between CDG and glycosylation genes. Protein glycosylation is evolutionarily conserved from yeast to mammals. Evolutionary rate covariation (ERC) identifies proteins with similar evolutionary rates that indicate shared biological functions and pathways. Using ERC, we identified strong evolutionary rate signatures between proteins in the same and different glycosylation pathways. Genome-wide analysis of proteins showing significant ERC with GPI anchor synthesis proteins revealed strong signatures with ncRNA modification proteins and DNA repair proteins. We also identified strong patterns of ERC based on cellular sub-localization of the GPI anchor synthesis enzymes. Functional testing of the highest scoring candidates validated genetic interactions and identified novel genetic modifiers of CDG genes. ERC analysis of disease genes and biological pathways allows for rapid prioritization of potential genetic modifiers, which can provide a better understanding of disease pathophysiology and novel therapeutic targets. Author summary: Congenital Disorders of Glycosylation (CDG) are a group of rare disorders resulting from impaired protein glycosylation. Glycosylation is the addition of sugar chains onto proteins and is required for proper protein function. CDG patients typically present with seizures and hypotonia. However, they can have a large amount of clinical variability, which is likely influenced by modifier genes. Modifier genes are genes that affect a phenotype without causing the disease. Using an evolutionary method that examines proteins that evolve at similar rates, we identified proteins within glycosylation pathways and among other unexpected pathways, such as ncRNA modification and DNA repair, that could be potential genetic modifiers of CDG genes. We also tested top protein pairs using the Drosophila eye as a model and identified novel genetic modifiers of CDG genes. Broadening our understanding of CDG modifiers can help us to better understand why loss of glycosylation results in specific patient symptoms and could provide new treatment targets. [ABSTRACT FROM AUTHOR]

The article discusses the role of the U.S. Copyright Office's Copyright Claims Board (CCB) in resolving copyright disputes faster and less expensive than bringing a case in a federal court. Topics include the reason for the need for a copyright small claims forum, the number of copyright claims filed on an annual basis in Missouri from 1996-2018, the key features of CCB and an overview of its establishment by the Congress in 2020 under the Copyright Alternative in Small-Claims Enforcement Act.

Background: Off-label dosing of direct oral anticoagulants (DOACs) is both common and associated with adverse patient outcomes. Evidence describing best practices to support optimal direct oral anticoagulant (DOAC) dosing is limited. Objective: To describe the impact of clinical pharmacist intervention on DOAC prescribing. Methods: This retrospective study was a descriptive analysis conducted within an integrated healthcare system with a centralized, pharmacist-led Anticoagulation Management Service (AMS). Patients prescribed a DOAC between January 1, 2020 and December 31, 2020 were included. Pharmacy dispensing reports were generated for pharmacist review and anticoagulant drug therapy changes were recommended to physicians where appropriate. The primary objective was to describe the number and type of recommendations made. Secondary objectives were to determine the provider acceptance rate based on the intervention type and on clinical vs formulary recommendations. Results: Clinical pharmacists made 147 recommendations for 2331 unique patients included in the analysis. Twenty-three recommendations (16%) were to decrease the dose, 46 (31%) were to increase the dose, 14 (10%) were to change the medication due to clinical scenario, 62 (42%) were to change the medication due to cost, and 2 (1%) were another issue. One hundred twenty-three (84%) recommendations were accepted. The provider acceptance rate was similar for clinical and formulary recommendations (85% and 82% respectively). Conclusion: Implementation of report-driven clinical pharmacist intervention led to an improvement in appropriate DOAC medication selection and dosing. [ABSTRACT FROM AUTHOR]

PURPOSE: Systemic chemotherapy, depending on the regimen, can be administered through peripheral intravenous (pIV) access or through central venous access devices (CVADs). There is no current best practice regarding optimal access for chemotherapy for patients with testicular cancer (TC). We retrospectively evaluated patients undergoing systemic chemotherapy for TC and compared baseline characteristics and complications of patients using pIV versus CVADs. METHODS: We included patients with TC who underwent first-line systemic chemotherapy at the University of Colorado Hospitals from 2005 to 2020. Data were collected on demographics, cancer characteristics, type, duration of chemotherapy, pIV or CVAD use, and associated complication rates. We then performed univariate and multivariate regression analyses to compare complication rates and risk factors for each group. RESULTS: One hundred fifty-four patients met inclusion criteria. Ninety-two (60%) patients used CVADs, and 62 patients (40%) used pIV for their initial treatment. Only six (9.7%) of 62 patients transitioned from pIV to CVADs during therapy. Similarly, 10 of 92 (10.9%) patients with initial CVAD needed to transition to a different type of CVAD or to pIV (P =.81). There were a greater number of venous access–related complications (48 of 92 patients, 52.2%) and overall thrombotic events (33 of 92 patients, 35.9%) for the CVAD group (P >.001) when compared with the pIV group. We observed an association between the following factors and venous access–related complications during chemotherapy: higher stage TC, increased total chemotherapy cycles, and delayed therapy. CONCLUSION: Peripheral IV use for first-line nonvesicant chemotherapy in patients with TC appears to be well tolerated with high rates of therapy completion and lower rates of complications when compared with CVADs. These data support our preferred treatment approach and provide evidence that pIV access is a safe and effective way to deliver chemotherapy for patients with TC. With this article, we hope clinicians will consider pIV versus CVADs if able for patients with testicular cancer receiving chemotherapy. [ABSTRACT FROM AUTHOR]