A Phase I Trial of Allogeneic γδ T Lymphocytes From Haploidentical Donors in Patients With Refractory or Relapsed Acute Myeloid Leukemia.

Introduction We report the results of a phase I clinical trial NCT03790072 of an adoptive transfer of γδ T lymphocytes from haploidentical donors in patients with refractory/relapsed acute myeloid leukemia after lymphodepletion regimen. Patients and methods Healthy donor mononuclear cells collected by leukapheresis were consistently expanded to generate products of 10 to 10 γδ T cells. Seven patients received donor-derived T cell product at doses of 10/kg (n = 3), 10/kg (n = 3), and 10/kg (n = 1).

First Detection of the Invasive Asian Longhorned Tick (Acari: Ixodidae) on Migratory Passerines in the Americas.

The Asian longhorned tick (Haemaphysalis longicornis Neumann), native to East Asia, was first reported in the United States in 2017 and is now established in at least 17 states. Haemaphysalis longicornis feeds on birds in its range outside of the United States, and migratory birds disperse this tick and tick-borne pathogens. However, early studies in the United States did not find H.

Microplastic transfer from the American horseshoe crab to shorebirds through consumption of horseshoe crab eggs in Jamaica Bay, NY.

Microplastic transfer between horseshoe crabs (Limulus polyphemus) and migratory shorebirds through consumption of crab eggs was examined in Jamaica Bay, New York. Fertilized and unfertilized crab eggs, shorebird fecal pellets, beach sand, and bay water were processed with a hydrogen peroxide solution to remove organic material, then stained with a Nile Red to identify microplastics using fluorescence microscopy. Microplastics were present in all samples and ranged from approximately26-1300 μm.

Urban green roofs provide habitat for migrating and breeding birds and their arthropod prey.

The world is rapidly urbanizing, and many previously biodiverse areas are now mostly composed of impervious surface. This loss of natural habitat causes local bird communities to become dominated by urban dweller and urban utilizer species and reduces the amount of habitat available for migrating and breeding birds. Green roofs can increase green space in urban landscapes, potentially providing new habitat for wildlife.

Patient-directed self-management of pain (PaDSMaP) compared to treatment as usual following total knee replacement; a randomised controlled trial.

Background: Self-administration of medicines by patients whilst in hospital is being increasingly promoted despite little evidence to show the risks and benefits. Pain control after total knee replacement (TKR) is known to be poor. The aim of the study was to determine if patients operated on with a TKR who self-medicate their oral analgesics in the immediate post-operative period have better pain control than those who receive their pain control by nurse-led drug rounds (Treatment as Usual (TAU)).

Age- and sex-based recovery curves to track functional outcomes in older adults with total knee arthroplasty.

Background: older adults with total knee arthroplasty (TKA) frequently undergo rehabilitation to address limited knee flexion range-of-motion, quadriceps weakness and gait speed limitations. This study aimed to develop age- and sex-specific recovery curves of knee flexion range-of-motion, quadriceps strength and fast gait speed post-TKA.

Methods: a population-based sample of 2,987 patients undergoing primary TKA participated, of whom 2015 (68%) were 65 years of age or older.

Quality-of-life outcomes after sinus surgery in allergic fungal rhinosinusitis versus nonfungal chronic rhinosinusitis.

Background: Given the differences in pathophysiology between allergic fungal rhinosinusitis (AFRS) and other chronic rhinosinusitis (CRS) subgroups, it remains unclear about whether these patients respond differently to a combination of surgical and medical treatments.

Objective: To evaluate differences in quality-of-life (QoL) outcomes for a cohort of patients who underwent endoscopic sinus surgery (ESS) for CRS.

Methods: This retrospective review included patients with CRS who underwent ESS between 2010 and 2013.

Stimulation of Chromosomal Rearrangements by Ribonucleotides.

We show by whole genome sequence analysis that loss of RNase H2 activity increases loss of heterozygosity (LOH) in Saccharomyces cerevisiae diploid strains harboring the pol2-M644G allele encoding a mutant version of DNA polymerase ε that increases ribonucleotide incorporation. This led us to analyze the effects of loss of RNase H2 on LOH and on nonallelic homologous recombination (NAHR) in mutant diploid strains with deletions of genes encoding RNase H2 subunits (rnh201Δ, rnh202Δ, and rnh203Δ), topoisomerase 1 (TOP1Δ), and/or carrying mutant alleles of DNA polymerases ε, α, and δ. We observed an ∼7-fold elevation of the LOH rate in RNase H2 mutants encoding wild-type DNA polymerases.

Discovery of a novel Kv7 channel opener as a treatment for epilepsy.

Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.

Differences in genome-wide repeat sequence instability conferred by proofreading and mismatch repair defects.

Mutation rates are used to calibrate molecular clocks and to link genetic variants with human disease. However, mutation rates are not uniform across each eukaryotic genome. Rates for insertion/deletion (indel) mutations have been found to vary widely when examined in vitro and at specific loci in vivo.

Evidence that processing of ribonucleotides in DNA by topoisomerase 1 is leading-strand specific.

Ribonucleotides incorporated during DNA replication are removed by RNase H2-dependent ribonucleotide excision repair (RER). In RER-defective yeast, topoisomerase 1 (Top1) incises DNA at unrepaired ribonucleotides, initiating their removal, but this is accompanied by RNA-DNA-damage phenotypes. Here we show that these phenotypes are incurred by a high level of ribonucleotides incorporated by a leading strand-replicase variant, DNA polymerase (Pol) ɛ, but not by orthologous variants of the lagging-strand replicases, Pols α or δ.

Time dependent analysis of assay comparability: a novel approach to understand intra- and inter-site variability over time.

We demonstrate here a novel use of statistical tools to study intra- and inter-site assay variability of five early drug metabolism and pharmacokinetics in vitro assays over time. Firstly, a tool for process control is presented. It shows the overall assay variability but allows also the following of changes due to assay adjustments and can additionally highlight other, potentially unexpected variations.

A qualitative examination of the GST proteome of the blow fly, Lucilia cuprina: use of cross-database matching of MALDI data.

This study was aimed at determining whether, in the absence of a full genetic database for the Sheep Blowfly (Lucilia cuprina) glutathione transferases from this insect could be characterized by cross-database matching of MALDI TOF data with the database for other metazoan organisms. Glutathione transferases of L. cuprina were partially purified by the sequential use of affinity chromatography media; first on glutathione immobilized on epichlorohydrin-activated Sepharose 6B and subsequently on dinitrophenyl-glutathione immobilized on the same matrix.

Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition.

Mutational heterogeneity must be taken into account when reconstructing evolutionary histories, calibrating molecular clocks, and predicting links between genes and disease. Selective pressures and various DNA transactions have been invoked to explain the heterogeneous distribution of genetic variation between species, within populations, and in tissue-specific tumors. To examine relationships between such heterogeneity and variations in leading- and lagging-strand replication fidelity and mismatch repair, we accumulated 40,000 spontaneous mutations in eight diploid yeast strains in the absence of selective pressure.

Mitochondrial DNA sequence variation and phylogeography of Neotropic pumas (Puma concolor).

Pumas occupy the largest latitudinal range of any New World terrestrial mammal. Human population growth and associated habitat reduction has reduced their North American range by nearly two-thirds, but the impact of human expansion in Central and South America on puma populations is not clear. We examined mitochondrial DNA diversity of pumas across the majority of their range, with a focus on Central and South America.

Mammalian Exo1 encodes both structural and catalytic functions that play distinct roles in essential biological processes.

Mammalian Exonuclease 1 (EXO1) is an evolutionarily conserved, multifunctional exonuclease involved in DNA damage repair, replication, immunoglobulin diversity, meiosis, and telomere maintenance. It has been assumed that EXO1 participates in these processes primarily through its exonuclease activity, but recent studies also suggest that EXO1 has a structural function in the assembly of higher-order protein complexes. To dissect the enzymatic and nonenzymatic roles of EXO1 in the different biological processes in vivo, we generated an EXO1-E109K knockin (Exo1(EK)) mouse expressing a stable exonuclease-deficient protein and, for comparison, a fully EXO1-deficient (Exo1(null)) mouse.

Ribonucleotides are signals for mismatch repair of leading-strand replication errors.

To maintain genome stability, mismatch repair of nuclear DNA replication errors must be directed to the nascent strand, likely by DNA ends and PCNA. Here we show that the efficiency of mismatch repair in Saccharomyces cerevisiae is reduced by inactivating RNase H2, which nicks DNA containing ribonucleotides incorporated during replication. In strains encoding mutator polymerases, this reduction is preferential for repair of mismatches made by leading-strand DNA polymerase ε as compared to lagging-strand DNA polymerase δ.

Mismatch repair balances leading and lagging strand DNA replication fidelity.

The two DNA strands of the nuclear genome are replicated asymmetrically using three DNA polymerases, α, δ, and ε. Current evidence suggests that DNA polymerase ε (Pol ε) is the primary leading strand replicase, whereas Pols α and δ primarily perform lagging strand replication. The fact that these polymerases differ in fidelity and error specificity is interesting in light of the fact that the stability of the nuclear genome depends in part on the ability of mismatch repair (MMR) to correct different mismatches generated in different contexts during replication.

MHC diversity and mate choice in the magellanic penguin, Spheniscus magellanicus.

We estimated levels of diversity at the major histocompatibility complex (MHC) class II DRß1 gene in 50 breeding pairs of the Magellanic penguin and compared those to estimates from Humboldt and Galapagos penguins. We tested for positive selection and 2 conditions required for the evolution of MHC-based disassortative mating: 1) greater MHC diversity between breeding pairs compared to random mating, and 2) associations between MHC genotype and fitness. Cloning and sequencing of the DRß1 gene showed that Magellanic penguins had higher levels of genetic variation than Galapagos and Humboldt penguins.

Avian pox in Magellanic Penguins (Spheniscus magellanicus).

Avian pox is an enveloped double-stranded DNA virus that is mechanically transmitted via arthropod vectors or mucosal membrane contact with infectious particles or birds. Magellanic Penguins (Spheniscus magellanicus) from two colonies (Punta Tombo and Cabo Dos Bahías) in Argentina showed sporadic, nonepidemic signs of avian pox during five and two of 29 breeding seasons (1982-2010), respectively. In Magellanic Penguins, avian pox expresses externally as wart-like lesions around the beak, flippers, cloaca, feet, and eyes.

Deuterium isotope effects on drug pharmacokinetics. I. System-dependent effects of specific deuteration with aldehyde oxidase cleared drugs.

The pharmacokinetic properties of drugs may be altered by kinetic deuterium isotope effects. With specifically deuterated model substrates and drugs metabolized by aldehyde oxidase, we demonstrate how knowledge of the enzyme's reaction mechanism, species differences in the role played by other enzymes in a drug's metabolic clearance, and differences in systemic clearance mechanisms are critically important for the pharmacokinetic application of deuterium isotope effects. Ex vivo methods to project the in vivo outcome using deuterated carbazeran and zoniporide with hepatic systems demonstrate the importance of establishing the extent to which other metabolic enzymes contribute to the metabolic clearance mechanism.

Developmental studies on the Sigma and Delta-1 glutathione transferases of Lucilia cuprina.

The glutathione transferases (GSTs) are a large group of enzymes having both detoxication roles and specialist metabolic functions. The present work represents an initial approach to identifying some of these roles by examining the variation of specific members of the family under differing conditions. The GSTs from Lucilia cuprina have been partially purified, members of two families being isolated, by the use of glutathione immobilised on epichlorhydrin-activated Sepharose 6B.

Increasing breeding behaviors in a captive colony of Northern Bald Ibis through conspecific acoustic enrichment.

The goal of this study was to increase reproductive behaviors in a captive colony of Northern Bald Ibis (Geronticus eremita) at the Bronx Zoo. The Northern Bald Ibis is classified as critically endangered by the IUCN, with only about 100 known breeding pairs in the wild. Our analysis of zoo breeding and colony size data confirmed earlier observations that small captive colonies of this species do not breed as well as larger colonies, possibly because of insufficient social cues.

Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I.

The ribonuclease (RNase) H class of enzymes degrades the RNA component of RNA:DNA hybrids and is important in nucleic acid metabolism. RNase H2 is specialized to remove single ribonucleotides [ribonucleoside monophosphates (rNMPs)] from duplex DNA, and its absence in budding yeast has been associated with the accumulation of deletions within short tandem repeats. Here, we demonstrate that rNMP-associated deletion formation requires the activity of Top1, a topoisomerase that relaxes supercoils by reversibly nicking duplex DNA.