Insecticide application prevents honey bees from realizing benefits of native forage in an agricultural landscape.

Health and population status of bees is negatively affected by anthropogenic stressors, many of which co-occur in agricultural settings. While pollinator habitat (often involving plantings of native forbs) holds promise to benefit both managed and wild bees, important issues remain unresolved. These include whether conventional, broad-spectrum insecticide use negates these benefits and how non-native, managed honey bees affect wild bees in these areas.

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies.

Correction: Synthetic ramoplanin analogues are accessible by effective incorporation of arylglycines in solid-phase peptide synthesis.

[This corrects the article DOI: 10.1039/D3SC01944F.].

Catalytic Cleavage of Disulfide Bonds in Small Molecules and Linkers of Antibody-Drug Conjugates.

In cells, catalytic disulfide cleavage is an essential mechanism in protein folding and synthesis. However, detailed enzymatic catalytic mechanism relating cleavage of disulfide bonds in xenobiotics is not well understood. This study reports an enzymatic mechanism of cleavage of disulfide bonds in xenobiotic small molecules and antibody conjugate (ADC) linkers.

Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2).

Tryptophan 2,3-dioxygenase 2 (TDO2) catalyzes the conversion of tryptophan to the immunosuppressive metabolite kynurenine. TDO2 overexpression has been observed in a number of cancers; therefore, TDO inhibition may be a useful therapeutic intervention for cancers. We identified an aminoisoxazole series as potent TDO2 inhibitors from a high-throughput screen (HTS).

Plazomicin is effective in a non-human primate pneumonic plague model.

The efficacy of plazomicin for pneumonic plague was evaluated in a non-human primate model. African Green monkeys challenged with a lethal aerosol of Yersinia pestis [median (range) of 98 (15-331) LD] received placebo (n=12) or 'humanized' dose regimens (6.25, 12.

Rate-Determining and Rate-Limiting Steps in the Clearance and Excretion of a Potent and Selective p21-Activated Kinase Inhibitor: A Case Study of Rapid Hepatic Uptake and Slow Elimination in Rat.

Background: Significant under-prediction of in vivo clearance in rat was observed for a potent p21-activated kinase (PAK1) inhibitor, GNE1.

Objective: Rate-determining (rapid uptake) and rate-limiting (slow excretion) steps in systemic clearance and elimination of GNE1, respectively, were evaluated to better understand the cause of the in vitro-in vivo (IVIV) disconnect.

Methods: A series of in vivo, ex vivo, and in vitro experiments were carried out: 1) the role of organic cation transporters (Oct or Slc22a) was investigated in transporter knock-out and wild-type animals with or without 1-aminobenzotriazole (ABT) pretreatment; 2) the concentration-dependent hepatic extraction ratio was determined in isolated perfused rat liver; and 3) excreta were collected from both bile duct cannulated and non-cannulated rats after intravenous injection.

Natural History of Francisella tularensis in Aerosol-Challenged BALB/c Mice.

The objective of this study was to evaluate the natural history and pathogenesis of Francisella tularensis in a murine model of inhalational tularemia with the SchuS4 strain. Before the efficacy of antimicrobials could be assessed in this model, further model development was required to determine the optimal time to start therapy. This study helped define the time course of infection after aerosol challenge by quantifying the presence of bacteria in lung, blood, and spleen at multiple harvest points.

Natural history of Yersinia pestis pneumonia in aerosol-challenged BALB/c mice.

After a relatively short untreated interval, pneumonic plague has a mortality approaching 100%. We employed a murine model of aerosol challenge with Yersinia pestis to investigate the early course of pneumonic plague in the lung, blood, and spleen. We fit a mathematical model to all data simultaneously.

Pharmacokinetics and safety of single and multiple doses of ACHN-490 injection administered intravenously in healthy subjects.

ACHN-490 is an aminoglycoside with activity against multidrug-resistant pathogens, including those resistant to currently used aminoglycosides. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD).

Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus.

The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms.

Increasing the efficiency of pharmacokinetic sample procurement, preparation and analysis by liquid chromatography/tandem mass spectrometry.

The movement towards a 96-well format has greatly increased productivity and throughput in bioanalytical laboratories. Improvements in automated sample preparation and analytical methods have further contributed to increased productivity. We have focused on sample collection and transfer to the bioanalyst and have found improvements to the current available methods.

Tuberculosis screening among foreign-born persons applying for permanent US residence.

Objectives: This study sought to determine adherence of physicians to tuberculosis (TB) screening guidelines among foreign-born persons living in the United States who were applying for permanent residency.

Methods: Medical forms of applicants from 5 geographic areas were reviewed, along with information from a national physician database on attending physicians. Applicant and corresponding physician characteristics were compared among those who were and were not correctly screened.

Rapid bioanalysis of vancomycin in serum and urine by high-performance liquid chromatography tandem mass spectrometry using on-line sample extraction and parallel analytical columns.

A novel high-performance liquid chromatography tandem mass spectrometry (LC/MS/MS) method is described for the determination of vancomycin in serum and urine. After the addition of internal standard (teicoplanin), serum and urine samples were directly injected onto an HPLC system consisting of an extraction column and dual analytical columns. The columns are plumbed through two switching valves.

Development of housing programs to aid in the treatment of tuberculosis in homeless individuals: a pilot study.

Study Objectives: To describe our experience with novel supervised housing programs developed to aid in the treatment of tuberculosis (TB) in homeless individuals, including a preliminary analysis of their effectiveness and estimate of potential cost savings.

Design: Retrospective chart review.

Setting: A county TB control program.

Spontaneous abdominal hematoma in dermatomyositis.

Dermatomyositis is associated with a number of systemic manifestations and diseases. We present 2 patients with dermatomyositis, aged 11 and 50 years, who developed acute abdominal pain, both a result of spontaneous hemorrhage. Hemorrhage was detectable by physical examination in one and on computed tomography scan of the abdomen in the other.

In crystals of complexes of streptavidin with peptide ligands containing the HPQ sequence the pKa of the peptide histidine is less than 3.0.

The pH dependences of the affinities for streptavidin of linear and cyclic peptide ligands containing the HPQ sequence discovered by phage display were determined by plasmon resonance measurements. At pH values ranging from 3.0 to 9.

Homodimerization of erythropoietin receptor by a bivalent monoclonal antibody triggers cell proliferation and differentiation of erythroid precursors.

Erythropoietin (EPO) stimulates proliferation and differentiation of erythroid progenitor cells. Several lines of evidence indicate that the most likely mechanism of EPO receptor (EPO-R) activation by EPO is homodimerization of the receptor on the surface of erythrocyte precursors. Therefore, we argued that it should be possible to raise EPO-R monoclonal antibodies (MoAbs) that would activate the receptor by dimerization and thus mimic EPO action.

A sequential dimerization mechanism for erythropoietin receptor activation.

We have probed the interaction of human erythropoietin (EPO) with its receptor (EPO-R) by analyzing a panel of 17 EPO mutants in a variety of in vitro assays. Mutant proteins were expressed in 293s cells and quantified by using an N-terminal epitope tag in conjunction with a surface plasmon resonance assay. Receptor binding was studied using both a soluble form of the EPO-R extracellular domain in an ELISA-format binding competition assay and full-length EPO-R in transfected BaF3 cells.

Metabolic risk factors for cardiovascular disease in a working population: a retrospective cohort study.

Risk factors for cardiovascular disease (CVD) appear to cluster in individuals, possibly because of a single, underlying metabolic disorder. We describe the prevalence of metabolic risk factors for CVD in a young working population and the tendency for individuals with some risk factors to acquire additional factors. This was a retrospective three-year follow-up study of baseline CVD risk factors assessing (1) incidence of risk factors and (2) fatal CVD.

Topochemical catalysis achieved by structure-based ligand design.

Recently, a cyclic peptide ligand, cyclo-Ac-[CHPQG-PPC]-NH2, that binds to streptavidin with high affinity was discovered by screening phage libraries. From the streptavidin-bound crystal structures of cyclo-Ac-[CHPQGPPC]-NH2 and of a related but more weakly binding linear ligand, FSHPQNT, we designed linear thiol-containing streptavidin binding ligands, FCH-PQNT-NH2 and Ac-CHPQNT-NH2, which are dimerized catalytically by the streptavidin crystal lattice of space group I222, as demonstrated by high performance liquid chromatography and mass spectrometry. The catalytic dimerization relies on presentation of the ligand thiols toward one another in the lattice.