Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity.

Methionine aminopeptidase type 2 (METAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. METAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of METAP2-specific substrates whose biological activity may be altered following METAP2 inhibition, and additionally, that METAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of METAP2 using fumagillin analogues has established the anti-angiogenic and anti-tumor characteristics of these derivatives; however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting central nervous system (CNS) toxicity.

Soft Tick Relapsing Fever - United States, 2012-2021.

Soft tick relapsing fever (STRF) (also known as tickborne relapsing fever) is a rare infection caused by certain Borrelia spirochetes and transmitted to humans by soft-bodied Ornithodoros ticks. In the United States, acquisition of STRF is commonly associated with exposure to rustic cabins, camping, and caves. Antibiotic treatment is highly effective for STRF, but without timely treatment, STRF can result in severe complications, including death.

The effects of stocking density on behavior and biological functioning of penned sheep under continuous heat load conditions.

Stocking density may impact sheep welfare during live export voyages that occur under hot and humid conditions. The aim of this study was to assess the welfare implications for sheep housed at three allometric stocking densities (k = 0.030, 0.

Measurement of the ν_{e}-Nucleus Charged-Current Double-Differential Cross Section at ⟨E_{ν}⟩=2.4 GeV Using NOvA.

The inclusive electron neutrino charged-current cross section is measured in the NOvA near detector using 8.02×10^{20} protons-on-target in the NuMI beam. The sample of GeV electron neutrino interactions is the largest analyzed to date and is limited by ≃17% systematic rather than the ≃7.

Corrigendum: Stocking density, restricted trough space, and implications for sheep behaviour and biological functioning.

[This corrects the article DOI: 10.3389/fvets.2022.

Stocking density, restricted trough space, and implications for sheep behaviour and biological functioning.

Stocking density and trough space allowance can potentially impact sheep welfare during live export voyages. The aim of this study was to assess the welfare implications for sheep housed at five allometric stocking densities, with either unrestricted or restricted trough space allowance. Merino wethers ( = 720) were housed in 40 pens of 18 heads for 18 days.

Search for Active-Sterile Antineutrino Mixing Using Neutral-Current Interactions with the NOvA Experiment.

This Letter reports results from the first long-baseline search for sterile antineutrinos mixing in an accelerator-based antineutrino-dominated beam. The rate of neutral-current interactions in the two NOvA detectors, at distances of 1 and 810 km from the beam source, is analyzed using an exposure of 12.51×10^{20} protons-on-target from the NuMI beam at Fermilab running in antineutrino mode.

The epidemiology of human ehrlichiosis in Texas, 2008-2017.

Tick-borne diseases in the United States, including ehrlichiosis, represent a growing public health problem. The purpose of this study was to examine the contemporary epidemiology of human ehrlichiosis in Texas by analyzing cases reported to the Texas Department of State Health Services. In Texas, 101 cases of ehrlichiosis were reported during 2008-2017.

As we age: listening to the voice of LGBTQ older adults.

The LGBT+ community is gaining long-overdue public health attention within the rapidly expanding demographic of older adults. As a group, LGBT+ older adults represent a range of diverse biopsychosocial needs and life experiences that may differ markedly from the general population. This has translated into health disparities experienced by this group and the emergence of policies calling for improved services for this community.

The Influence of Predictability and Controllability on Stress Responses to the Aversive Component of a Virtual Fence.

To ensure animal welfare is not compromised, virtual fencing must be predictable and controllable, and this is achieved through associative learning. To assess the influence of predictability and controllability on physiological and behavioral responses to the aversive component of a virtual fence, two methods of training animals were compared. In the first method, positive punishment training involved sheep learning that after an audio stimulus, an electrical stimulus would follow only when they did not respond by stopping or turning at the virtual fence (predictable controllability).

Acute and Delayed Deaths after West Nile Virus Infection, Texas, USA, 2002-2012.

Infection with West Nile virus (WNV) has a well-characterized acute disease process. However, long-term consequences are less understood. We searched death records for 4,142 residents of Texas, USA, infected with WNV during 2002-2012 and identified 557 (13%) deaths.

Chagas Disease Surveillance Activities - Seven States, 2017.

Chagas disease, a potentially life-threatening disease caused by the protozoan parasite Trypanosoma cruzi, has become a concern in the United States as a result of human emigration from Latin America where Chagas disease is endemic (1). It is estimated that as many as 8 million people living in Mexico, and Central and South America have Chagas disease.* Most cases of Chagas disease in the United States are chronic infections; however, rare cases of acute congenital infections and autochthonous vectorborne transmission have been reported (2).

Outcomes of Community-Based Prenatal Education Programs for Pregnant Women in Rural Texas.

A prenatal, evidenced-based education program was implemented in 7 rural counties and provided by trained staff at the Texas Department of State Health Services. This was implemented to address health disparities, in regard to birth outcomes, in rural minorities of Southeast Texas. The participants were given a preassessment (N = 382) and a postassessment (N = 326) of relevant health knowledge and a follow-up assessment (N = 149) to document the outcomes of their birth as well as health practices they were employing as new parents.

PREVALENCE AND INTENSITY OF THE SINUS ROUNDWORM ( SKRJABINGYLUS CHITWOODORUM) IN RABIES-NEGATIVE SKUNKS OF TEXAS, USA.

:  Estimates of the distribution and prevalence of the sinus roundworm ( Skrjabingylus chitwoodorum) have been based largely on the inspection of skunk (Mephitidae) skulls showing damage from infections. We examined 595 striped skunks ( Mephitis mephitis) and nine hog-nosed skunks ( Conepatus leuconotus) that had tested negative for rabies by the Texas Department of State Health Services (US) between November 2010 and April 2015 to determine species of Skrjabingylus, prevalence and intensity of infection, and distribution of infection in Texas by county. We expected ecoregions with more precipitation to have higher rates of infection than more-arid ecoregions.

Fatal Flea-Borne Typhus in Texas: A Retrospective Case Series, 1985-2015.

AbstractFlea-borne (murine) typhus is a global rickettsiosis caused by . Although flea-borne typhus is no longer nationally notifiable, cases are reported for surveillance purposes in a few U.S.

Typhus Group Rickettsiosis, Texas, USA, 2003-2013.

We characterized the epidemiology of typhus group rickettsiosis in Texas, USA. During 2003-2013, a total of 1,762 cases were reported to the state health department. The number of diagnosed cases and geographic expansion increased over time.

Trypanosome species, including Trypanosoma cruzi, in sylvatic and peridomestic bats of Texas, USA.

In contrast to other mammalian reservoirs, many bat species migrate long-distances and have the potential to introduce exotic pathogens to new areas. Bats have long been associated with blood-borne protozoal trypanosomes of the Schizotrypanum subgenus, which includes the zoonotic parasite Trypanosoma cruzi, agent of Chagas disease. Another member of the subgenus, Trypanosoma dionisii, infects bats of Europe and South America, and genetic similarities between strains from the two continents suggest transcontinental movement of this parasite via bats.

The First-Time Seizure Emergency Department Electroencephalogram Study.

Study Objective: Seizures account for 1.2% of all emergency department (ED) visits, with 24% of those representing first-time seizures. Our primary goal is to determine whether obtaining an electroencephalogram (EEG) in the ED after a first-time seizure can identify individuals appropriate for initiation of anticonvulsant therapy on ED discharge.

Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor.

Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant.

Pharmacokinetics of IDX184, a liver-targeted oral prodrug of 2'-methylguanosine-5'-monophosphate, in the monkey and formulation optimization for human exposure.

IDX184 is a phosphoramidate prodrug of 2'-methylguanosine-5'-monophosphate, developed to treat patients infected with hepatitis C virus. A mass balance study of radiolabeled IDX184 and pharmacokinetic studies of IDX184 in portal vein-cannulated monkeys revealed relatively low IDX184 absorption but higher exposure of IDX184 in the portal vein than in the systemic circulation, indicating >90 % of the absorbed dose was subject to hepatic extraction. Systemic exposures to the main metabolite, 2'-methylguanosine (2'-MeG), were used as a surrogate for liver levels of the pharmacologically active entity 2'-MeG triphosphate, and accordingly, systemic levels of 2'-MeG in the monkey were used to optimize formulations for further clinical development of IDX184.

Synthesis of 2,3-dideoxy-2-fluoro-2,3-endo-methylene- and 2,3-Dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses and their use in the preparation of conformationally locked bicyclic nucleosides.

Construction of protected 2,3-dideoxy-2-fluoro-2,3-endo-methylene-pentofuranoses from d-glyceraldehyde and 2,3-dideoxy-2-fluoro-3-C-hydroxymethyl-2,3-endo-methylene-pentofuranoses from d-isoascorbic acid, via Simmons-Smith-type stereoselective cyclopropanations on the respective fluoroallyl alcohols, is described. Synthesis of the corresponding conformationally locked sugar modified uridine and guanosine nucleosides was achieved via Vorbrüggen or Mitsunobu methodologies. Stereochemical confirmation of the novel nucleosides was performed on the basis of 2D NOESY NMR experiments.

Stereoselective cyclopropanation in the synthesis of 3'-deoxy-3'-C-hydroxymethyl-2',3'-methylene-uridine.

The synthesis of the novel 2',3'-cyclopropane nucleoside 3'-deoxy-3'-C-hydroxymethyl-2',3'-methylene-uridine is described. Stereoselective construction of the cyclopropane ring was achieved via Simmons-Smith cyclopropanation of a benzyl protected silyl enol ether, which was itself derived from 1,2-O-isopropylidene-α-D-xylofuranose.

Synthesis of 2'-O,4'-C-alkylene-bridged ribonucleosides and their evaluation as inhibitors of HCV NS5B polymerase.

The synthesis of 2'-O,4'-C-methylene-bridged bicyclic guanine ribonucleosides bearing 2'-C-methyl or 5'-C-methyl modifications is described. Key to the successful installation of the methyl functionality in both cases was the use of a one-pot oxidation-Grignard procedure to avoid formation of the respective unreactive hydrates prior to alkylation. The 2'-C-methyl- and 5'-C-methyl-modified bicyclic guanosines were evaluated, along with the known uracil-, cytosine-, adenine-, guanine-LNA and guanine-ENA nucleosides, as potential antiviral agents and found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay.

The phylogeography and spatiotemporal spread of south-central skunk rabies virus.

The south-central skunk rabies virus (SCSK) is the most broadly distributed terrestrial viral lineage in North America. Skunk rabies has not been efficiently targeted by oral vaccination campaigns and represents a natural system of pathogen invasion, yielding insights to rabies emergence. In the present study we reconstructed spatiotemporal spread of SCSK in the whole territory of its circulation using a combination of Bayesian methods.