Chemical Synthesis and Antifibrotic Properties of (±)-Cochlearol T, (±)-Ganocochlearin A, and (±)-Cochlearol Y.

The cochlearols and ganocochlearins are natural products with unique antifibrotic and renoprotective activities in models of kidney disease. They represent compelling lead compounds for pharmacological intervention against kidney disease, often characterized by renal fibrosis. We report a four-step synthesis of (±)-cochlearol T () and the first reported syntheses of (±)-ganocochlearin A () and (±)-cochlearol Y () through a strategy that includes a Robinson annulation and unexpected oxidative aromatization.

The Structural Diversity of Encapsulin Protein Shells.

Subcellular compartmentalization is a universal feature of all cells. Spatially distinct compartments, be they lipid- or protein-based, enable cells to optimize local reaction environments, store nutrients, and sequester toxic processes. Prokaryotes generally lack intracellular membrane systems and usually rely on protein-based compartments and organelles to regulate and optimize their metabolism.

Structural Evolution of Photoexcited Methylcobalamin toward a CarH-like Metastable State: Evidence from Time-Resolved X-ray Absorption and X-ray Emission.

CarH is a protein photoreceptor that uses a form of B, adenosylcobalamin (AdoCbl), to sense light via formation of a metastable excited state. Aside from AdoCbl bound to CarH, methylcobalamin (MeCbl) is the only other example─to date─of photoexcited cobalamins forming metastable excited states with lifetimes of nanoseconds or longer. The UV-visible spectra of the excited states of MeCbl and AdoCbl bound to CarH are similar.

Long-term evolution of human seasonal influenza virus A(H3N2) is associated with an increase in polymerase complex activity.

Since the influenza pandemic in 1968, influenza A(H3N2) viruses have become endemic. In this state, H3N2 viruses continuously evolve to overcome immune pressure as a result of prior infection or vaccination, as is evident from the accumulation of mutations in the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). However, phylogenetic studies have also demonstrated ongoing evolution in the influenza A(H3N2) virus RNA polymerase complex genes.

Minimal Determinants for Lifelong Antiviral Antibody Responses in Mice from a Single Exposure to Virus-like Immunogens at Low Doses.

The durability of an antibody (Ab) response is highly important for antiviral vaccines. However, due to the complex compositions of natural virions, the molecular determinants of Ab durability from viral infection or inactivated viral vaccines have been incompletely understood. Here we used a reductionist system of liposome-based virus-like structures to examine the durability of Abs from primary immune responses in mice.

When simplicity triumphs: niche specialization of gut bacteria exists even for simple fiber structures.

Structurally complex corn bran arabinoxylan (CAX) was used as a model glycan to investigate gut bacteria growth and competition on different AX-based fine structures. Nine hydrolyzate segments of the CAX polymer varying in chemical structure (sugars and linkages), CAX, five less complex non-corn arabinoxylans, and xylose and glucose were ranked from structurally complex to simple. The substrate panel promoted different overall growth and rates of growth of eight xylan-degrading strains.

Gestational testosterone excess early to mid-pregnancy disrupts maternal lipid homeostasis and activates biosynthesis of phosphoinositides and phosphatidylethanolamines in sheep.

Gestational hyperandrogenism is a risk factor for adverse maternal and offspring outcomes with effects likely mediated in part via disruptions in maternal lipid homeostasis. Using a translationally relevant sheep model of gestational testosterone (T) excess that manifests maternal hyperinsulinemia, intrauterine growth restriction (IUGR), and adverse offspring cardiometabolic outcomes, we tested if gestational T excess disrupts maternal lipidome. Dimensionality reduction models following shotgun lipidomics of gestational day 127.

An optimized purification protocol for enzymatically synthesized S-adenosyl-L-methionine (SAM) for applications in solution state infrared spectroscopic studies.

S-adenosyl-L-methionine (SAM) is an abundant biomolecule used by methyltransferases to regulate a wide range of essential cellular processes such as gene expression, cell signaling, protein functions, and metabolism. Despite considerable effort, there remain many specificity challenges associated with designing small molecule inhibitors for methyltransferases, most of which exhibit off-target effects. Interestingly, NMR evidence suggests that SAM undergoes conformeric exchange between several states when free in solution.

Nephronophthisis: a pathological and genetic perspective.

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and is one of the most frequent genetic causes for kidney failure (KF) in children and adolescents. Over 20 genes cause NPHP and over 90 genes contribute to renal ciliopathies often involving multiple organs. About 15-20% of NPHP patients have additional extrarenal symptoms affecting other organs than the kidneys.

Placental assessment using spectral analysis of the envelope of umbilical venous waveforms in sheep.

Introduction: This study was designed to test the efficacy of an ultrasound flow measurement method to evaluate placental function in a hyperandrogenic sheep model that produces placental morphologic changes and an intrauterine growth restriction (IUGR) phenotype.

Materials And Methods: Pregnant ewes were assigned randomly between control (n = 12) and testosterone-treatment (T-treated, n = 22) groups. The T-treated group was injected twice weekly intramuscularly (IM) with 100 mg testosterone propionate.

Mutant HRas Signaling and Rationale for Use of Farnesyltransferase Inhibitors in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) are often associated with poor outcomes, due at least in part to the limited number of treatment options available for those patients who develop recurrent and/or metastatic disease (R/M HNSCC). Even with the recent validation and approval of immunotherapies in the first-line setting for these patients, the need for the development of new and alternative precision medicine strategies with survival benefit is clear. Oncogenic alterations in the HRAS (Harvey rat sarcoma virus) proto-oncogene are seen in approximately 4-8% of R/M HNSCC tumors.

Apolipoprotein-mimetic nanodiscs reduce lipid accumulation and improve liver function in acid sphingomyelinase deficiency.

Acid sphingomyelinase deficiency (ASMD) is a severe lipid storage disorder caused by the diminished activity of the acid sphingomyelinase enzyme. ASMD is characterized by the accumulation of sphingomyelin in late endosomes and lysosomes leading to progressive neurological dysfunction and hepatosplenomegaly. Our objective was to investigate the utility of synthetic apolipoprotein A-I (ApoA-I) mimetics designed to act as lipid scavengers for the treatment of ASMD.

Optogenetics reveals paradoxical network stabilizations in hippocampal CA1 and CA3.

Recurrent connectivity between excitatory neurons and the strength of feedback from inhibitory neurons are critical determinants of the dynamics and computational properties of neuronal circuits. Toward a better understanding of these circuit properties in regions CA1 and CA3 of the hippocampus, we performed optogenetic manipulations combined with large-scale unit recordings in rats under anesthesia and in quiet waking, using photoinhibition and photoexcitation with different light-sensitive opsins. In both regions, we saw striking paradoxical responses: subsets of cells increased firing during photoinhibition, while other cells decreased firing during photoexcitation.

Opposing effects of β-2 and β-1 adrenergic receptor signaling on neuroinflammation and dopaminergic neuron survival in α-synuclein-mediated neurotoxicity.

Background: Noradrenergic neurons in the locus coeruleus (LC) are the primary source of norepinephrine (NE) in the brain and degeneration of these neurons is reported in the early stages of Parkinson's disease (PD), even prior to dopaminergic neuron degeneration in the substantia nigra (SN), which is a hallmark of PD pathology. NE depletion is generally associated with increased PD pathology in neurotoxin-based PD models. The effect of NE depletion in other models of PD-like α-synuclein-based models is largely unexplored.

Epigenetics and stroke: role of DNA methylation and effect of aging on blood-brain barrier recovery.

Incomplete recovery of blood-brain barrier (BBB) function contributes to stroke outcomes. How the BBB recovers after stroke remains largely unknown. Emerging evidence suggests that epigenetic factors play a significant role in regulating post-stroke BBB recovery.

Sleep loss diminishes hippocampal reactivation and replay.

Memories benefit from sleep, and sleep loss immediately following learning has a negative impact on subsequent memory storage. Several prominent hypotheses ascribe a central role to hippocampal sharp-wave ripples (SWRs), and the concurrent reactivation and replay of neuronal patterns from waking experience, in the offline memory consolidation process that occurs during sleep. However, little is known about how SWRs, reactivation, and replay are affected when animals are subjected to sleep deprivation.

Creating opportunities to engage with prospective historically marginalized trainees with clinical simulation.

Background: Recruiting a diverse group of medical students, house officers, and faculty in medicine is challenging-particularly for predominantly white, midwest institutions that may not be racially or ethnically diverse.

Purpose: To evaluate a novel clinical simulation program, SiMfest, for recruiting house officers from historically marginalized populations to our institution to demonstrate our leadership's commitment to high-quality education and recruitment of these students to enhance diversity in academic medicine.

Methods: The Office for Health Equity and Inclusion, institutional leadership, and clinical department chairs developed a novel and engaging series of clinical simulations, SiMfest, to engage the pipeline of historically marginalized trainees and demonstrate our leadership's commitment to high-quality education.

Effect of pulmonary embolism response team on advanced therapies administered: The University of Michigan experience.

Background: Pulmonary Embolism Response Teams (PERT) were employed at multiple institutions to bridge the gap between varied treatment options for acute PE and unclear evidence for optimal management. There is limited data regarding the impact of PERT on the use of advanced therapies and clinical outcomes.

Methods: We performed a retrospective single-center cohort study comparing patients that presented to the ED with an acute PE before and after the creation of PERT in June 2017 at our institution.

Heme delivery to heme oxygenase-2 involves glyceraldehyde-3-phosphate dehydrogenase.

Heme regulatory motifs (HRMs) are found in a variety of proteins with diverse biological functions. In heme oxygenase-2 (HO2), heme binds to the HRMs and is readily transferred to the catalytic site in the core of the protein. To further define this heme transfer mechanism, we evaluated the ability of GAPDH, a known heme chaperone, to transfer heme to the HRMs and/or the catalytic core of HO2.