In utero delivery of targeted ionizable lipid nanoparticles facilitates in vivo gene editing of hematopoietic stem cells.

Monogenic blood diseases are among the most common genetic disorders worldwide. These diseases result in significant pediatric and adult morbidity, and some can result in death prior to birth. Novel ex vivo hematopoietic stem cell (HSC) gene editing therapies hold tremendous promise to alter the therapeutic landscape but are not without potential limitations.

An Interpretable Machine Learning Framework for Rare Disease: A Case Study to Stratify Infection Risk in Pediatric Leukemia.

: Datasets on rare diseases, like pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), have small sample sizes that hinder machine learning (ML). The objective was to develop an interpretable ML framework to elucidate actionable insights from small tabular rare disease datasets. : The comprehensive framework employed optimized data imputation and sampling, supervised and unsupervised learning, and literature-based discovery (LBD).

Catalytic Light-Driven Strategy for Transforming Oximes to Carbonyls.

Oxime and carbonyl functional groups serve as powerful chemical hubs for constructing complex synthetic targets and valuable molecular scaffolds. In furthering this value, we report a photopromoted catalytic deoximation protocol for converting oximes and their derivatives to carbonyl functional groups. This strategic approach benefits from the use of renewable light energy input and ambient air conditions, in addition to demonstrating good substrate scope, functional group tolerance, and product yields.

A Boron Scan of Ethyl Acetoacetate Leads to Versatile Building Blocks.

Discovered in the 19th century, ethyl acetoacetate has been central to the development of organic chemistry, including its pedagogy and applications. In this study, we present borylated derivatives of this venerable molecule. A boron handle has been installed at either - or -position of acetoacetate by homologation of acyl-MIDA (N-methyliminodiacetic acid) boronates with diazoacetates.

Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease.

Delivery of mRNA-based therapeutics to the perinatal brain holds great potential in treating congenital brain diseases. However, nonviral delivery platforms that facilitate nucleic acid delivery in this environment have yet to be rigorously studied. Here, we screen a diverse library of ionizable lipid nanoparticles (LNPs) via intracerebroventricular (ICV) injection in both fetal and neonatal mice and identify an LNP formulation with greater functional mRNA delivery in the perinatal brain than an FDA-approved industry standard LNP.

Fetal allotransplant recipients are resistant to graft-versus-host disease.

In utero hematopoietic cell transplantation (IUHCT) is an experimental treatment for congenital hemoglobinopathies, including Sickle cell disease and thalassemias. One of the principal advantages of IUHCT is the predisposition of the developing fetus toward immunologic tolerance. This allows for engraftment across immune barriers without immunosuppression and, potentially, decreased susceptibility to graft-versus-host disease (GVHD).

Enteral nutrition support for infants with pulmonary hypoplasia: A qualitative evaluation of caregiver and provider perspectives.

Background: Enteral nutrition is a critical intervention that supports the growth of children with pulmonary hypoplasia (PH). We explored the experiences of caregivers and providers caring for children with PH to better understand gaps in knowledge transfer and identify barriers and facilitators to caregiving to inform interventions that may improve support.

Methods: This qualitative study included 10 interviews with caregivers and 10 clinical team members at a single integrated care program for children with PH.

Generation and reactivity of an elusive base-stabilised phosphinidene.

Reduction of phosphorus dichloride 6, supported by the diaryloxyphenyl group (OCO) featuring two bulky phenoxy wingtips, by PMe, generates a reactive intermediate that behaves as a base-stabilized phosphinidene (OCO)P (5). Warming up a solution of this species in toluene to room temperature results in trimerization to give the isolable cyclic triphosphine [(OCO)P], whereas trapping with 2,3-dimethylbutadiene-1,3 afforded a 3,4-dimethylphospholene-3. Investigation of the reduction of 6 by the phosphine PMe by NMR led to the observation of a persistent species between -10 °C and 10 °C.

Amniotic fluid stabilized lipid nanoparticles for in utero intra-amniotic mRNA delivery.

Congenital disorders resulting in pathological protein deficiencies are most often treated postnatally with protein or enzyme replacement therapies. However, treatment of these disorders in utero before irreversible disease onset could significantly minimize disease burden, morbidity, and mortality. One possible strategy for the prenatal treatment of congenital disorders is in utero delivery of messenger RNA (mRNA).

In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease.

In utero base editing has the potential to correct disease-causing mutations before the onset of pathology. Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a lysosomal storage disease (LSD) affecting multiple organs, often leading to early postnatal cardiopulmonary demise. We assessed in utero adeno-associated virus serotype 9 (AAV9) delivery of an adenine base editor (ABE) targeting the Idua G→A (W392X) mutation in the MPS-IH mouse, corresponding to the common IDUA G→A (W402X) mutation in MPS-IH patients.

Mandible Biomechanics and Continuously Erupting Teeth: A New Defect Model for Studying Load-Bearing Biomaterials.

Animals with elodont dentition and unfused mandible symphyses are hypothesized to have symmetric incisor morphology. Since these animals maintain their teeth by gnawing, they may provide physiologic feedback on mechanical function when unilateral mandible defects are created that manifest as ipsilateral changes in tooth structure. This defect model would potentially generate important information on the functional/mechanical properties of implants.

Biomedical Text Link Prediction for Drug Discovery: A Case Study with COVID-19.

Link prediction in artificial intelligence is used to identify missing links or derive future relationships that can occur in complex networks. A link prediction model was developed using the complex heterogeneous biomedical knowledge graph, SemNet, to predict missing links in biomedical literature for drug discovery. A web application visualized knowledge graph embeddings and link prediction results using TransE, CompleX, and RotatE based methods.

Effects of a Bioprocessed Soybean Meal Ingredient on the Intestinal Microbiota of Hybrid Striped Bass, .

The hybrid striped bass () is a carnivorous species and a major product of US aquaculture. To reduce costs and improve resource sustainability, traditional ingredients used in fish diets are becoming more broadly replaced by plant-based products; however, plant meals can be problematic for carnivorous fish. Bioprocessing has improved nutritional quality and allowed higher inclusions in fish diets, but these could potentially affect other systems such as the gut microbiome.

Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.

Tyrosine kinase inhibitors (TKIs) are the frontline therapy for BCR-ABL (Ph+) chronic myeloid leukemia (CML). A systematic meta-analysis of 43 peer-reviewed studies with 10,769 CML patients compared the incidence of gastrointestinal adverse events (GI AEs) in a large heterogeneous CML population as a function of TKI type. Incidence and severity of nausea, vomiting, and diarrhea were assessed for imatinib, dasatinib, bosutinib, and nilotinib.

Ionizable lipid nanoparticles for in utero mRNA delivery.

Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)-mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent.

Molecular Differentiation of Four Species of Oropsylla (Siphonaptera: Ceratophyllidae) Using PCR-Based Single Strand Conformation Polymorphism Analyses and DNA Sequencing.

It is often difficult to distinguish morphologically between closely related species of fleas (Siphonaptera). Morphological identification of fleas often requires microscopic examination of internal structures in specimens cleared using caustic solutions. This process degrades DNA and/or inhibits DNA extraction from specimens, which limits molecular-based studies on individual fleas and their microbiomes.

Publisher Correction: Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection.

Deregulation of transcription factors (TFs) is an important driver of tumorigenesis, but non-invasive assays for assessing transcription factor activity are lacking. Here we develop and validate a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyze whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a bioinformatics pipeline developed by us that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns.

Machine learning enables detection of early-stage colorectal cancer by whole-genome sequencing of plasma cell-free DNA.

Background: Blood-based methods using cell-free DNA (cfDNA) are under development as an alternative to existing screening tests. However, early-stage detection of cancer using tumor-derived cfDNA has proven challenging because of the small proportion of cfDNA derived from tumor tissue in early-stage disease. A machine learning approach to discover signatures in cfDNA, potentially reflective of both tumor and non-tumor contributions, may represent a promising direction for the early detection of cancer.

Reliability of the supraorbital ethmoid cell vs Keros classification in predicting the course of the anterior ethmoid artery.

Background: We previously showed that the supraorbital ethmoid cell (SOEC) is a reliable landmark for identifying the anterior ethmoid artery (AEA). Recent data have suggested that Keros classification is also a dependable predictor. We aim to characterize the location of the AEA and its relation to the skull base in patients with and without SOEC using the Keros classification.

Notch transactivates Rheb to maintain the multipotency of TSC-null cells.

Differentiation abnormalities are a hallmark of tuberous sclerosis complex (TSC) manifestations; however, the genesis of these abnormalities remains unclear. Here we report on mechanisms controlling the multi-lineage, early neuronal progenitor and neural stem-like cell characteristics of lymphangioleiomyomatosis (LAM) and angiomyolipoma cells. These mechanisms include the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event.

Signal distortion in atomic force microscopy photodetector.

The frequency-dependent complex impedance of an atomic force microscope photodetector is measured. The inverse problem is solved obtaining the voltage that would have been collected with a hypothetical, perfectly flat-frequency-response photodetector from the experimentally available voltage. This information is used to study the distortion that the true input signal undergoes as it passes through the photodetector on the way to becoming the experimentally measured output signal.

Effect of Silicate Slag Application on Wheat Grown Under Two Nitrogen Rates.

Field studies were established on the alluvial floodplain soils in Louisiana, from 2013 to 2015, to evaluate the effect of silicate slag applications on productivity of wheat (), under sufficient and high nitrogen (N) application rates. Treatments were arranged in a randomized complete block design, with four replications consisting of twelve treatments: a factorial combination of two N (101 and 145 kg N ha) and five silicate slag rates (0, 1, 2, 4.5, and 9 Mg ha), and two control plots (with and without lime).

Opossum peptide that can neutralize rattlesnake venom is expressed in Escherichia coli.

An eleven amino acid ribosomal peptide was shown to completely neutralize Western Diamondback Rattlesnake (Crotalus atrox) venom in mice when a lethal dose of the venom was pre-incubated with the peptide prior to intravenous injection. We have expressed the peptide as a concatenated chain of peptides and cleaved them apart from an immobilized metal affinity column using a protease. After ultrafiltration steps, the mixture was shown to partially neutralize rattlesnake venom in mice.