Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular <i>Leishmania donovani</i> Amastigotes, with a Focus on Human-Derived Host Cells

This study characterised in vitro potencies of anti-leishmanial agents against intracellular Leishmania donovani amastigotes in primary human macrophages, obtained with or without CD14-positive monocyte enrichment, phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 cells and mouse peritoneal exudate macrophages (PEMs). Host cell dependent potency was confirmed for pentavalent and trivalent antimony. Fexinidazole was inactive against intracellular amastigotes across the host cell panel. Fexinidazole sulfone, (R)-PA-824, (S)-PA-824 and VL-2098 displayed similar potency in all host cells tested

Maine Won\u27t Wait One-Year Progress Report, 2021

This document, an “Maine Climate Science Update 2021”, is an interim communication to the Maine Climate Council and the public about the ongoing work of the scientific community and recent events associated with climate change. It is divided into three sections: (1) current events that reflect the acceleration of extreme weather events in Maine and elsewhere with possible connections to climate change; (2) noteworthy scientific reports with national and international scope released in 2021; and (3) examples of recent peer-reviewed publications from the ongoing work of the scientific community to understand climate change in Maine

Scientific Assessment of Climate Change and Its Effects in Maine

Climate change has already made its presence known in Maine, from shorter winters and warmer summers with ocean heat waves, to stronger storms, new species showing up in our backyards and the Gulf of Maine, aquatic algal blooms, acidic ocean waters that affect shellfish, and new pests and diseases that harm our iconic forests and fisheries. The health of Maine people is also being affected by climate change, from high heat index days driving increased emergency room visits to the ravages of Lyme and other vector-borne diseases. And our economy is feeling the effects, too — with farmers trying to adapt to longer growing seasons but dealing with severe storms and late frosts, aquaculturists already adapting to a more acidic ocean, and winter sports like skiing and snowmobiling being impacted by our shrinking winter season. This is the first report from the Maine Climate Council’s Scientific and Technical Subcommittee, produced by more than 50 scientists from around the State representing Scientific and Technical Subcommittee members, other co-authors, and contributors. This report is part of the 2020 Maine Climate Action Plan. The report summarizes how climate change has already impacted Maine and how it might continue affecting our State in the future

Outer Membrane Protein A of Bovine and Ovine Isolates of Mannheimia haemolytica Is Surface Exposed and Contains Host Species-Specific Epitopes ▿

Mannheimia haemolytica is the etiological agent of pneumonic pasteurellosis of cattle and sheep; two different OmpA subclasses, OmpA1 and OmpA2, are associated with bovine and ovine isolates, respectively. These proteins differ at the distal ends of four external loops, are involved in adherence, and are likely to play important roles in host adaptation. M. haemolytica is surrounded by a polysaccharide capsule, and the degree of OmpA surface exposure is unknown. To investigate surface exposure and immune specificity of OmpA among bovine and ovine M. haemolytica isolates, recombinant proteins representing the transmembrane domain of OmpA from a bovine serotype A1 isolate (rOmpA1) and an ovine serotype A2 isolate (rOmpA2) were overexpressed, purified, and used to generate anti-rOmpA1 and anti-rOmpA2 antibodies, respectively. Immunogold electron microscopy and immunofluorescence techniques demonstrated that OmpA1 and OmpA2 are surface exposed, and are not masked by the polysaccharide capsule, in a selection of M. haemolytica isolates of various serotypes and grown under different growth conditions. To explore epitope specificity, anti-rOmpA1 and anti-rOmpA2 antibodies were cross-absorbed with the heterologous isolate to remove cross-reacting antibodies. These cross-absorbed antibodies were highly specific and recognized only the OmpA protein of the homologous isolate in Western blot assays. A wider examination of the binding specificities of these antibodies for M. haemolytica isolates representing different OmpA subclasses revealed that cross-absorbed anti-rOmpA1 antibodies recognized OmpA1-type proteins but not OmpA2-type proteins; conversely, cross-absorbed anti-rOmpA2 antibodies recognized OmpA2-type proteins but not OmpA1-type proteins. Our results demonstrate that OmpA1 and OmpA2 are surface exposed and could potentially bind to different receptors in cattle and sheep

A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease

OBJECTIVE: To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) and a serotonin and norepinephrine reuptake inhibitor (SNRI) in the treatment of depression in Parkinson disease (PD). METHODS: A total of 115 subjects with PD were enrolled at 20 sites. Subjects were randomized to receive an SSRI (paroxetine; n = 42), an SNRI (venlafaxine extended release [XR]; n = 34), or placebo (n = 39). Subjects met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression, and scored >12 on the first 17 items of the Hamilton Rating Scale for Depression (HAM-D). Subjects were followed for 12 weeks (6-week dosage adjustment, 6-week maintenance). Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR. The primary outcome measure was change in the HAM-D score from baseline to week 12. RESULTS: Treatment effects (relative to placebo), expressed as mean 12-week reductions in HAM-D score, were 6.2 points (97.5% confidence interval [CI] 2.2 to 10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5% CI 0.1 to 8.4, p = 0.02) in the venlafaxine XR group. No treatment effects were seen on motor function. CONCLUSIONS: Both paroxetine and venlafaxine XR significantly improved depression in subjects with PD. Both medications were generally safe and well tolerated and did not worsen motor function. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD