Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates.

Tambjamines as Fast-Acting Multistage Antimalarials.

Well-tolerated and novel antimalarials that can combat multiple stages of the parasite life cycle are desirable but challenging to discover and develop. Herein, we report results for natural product-inspired novel tambjamine antimalarials. We show that they are potent against liver, asexual erythrocytic, and sexual erythrocytic parasite life cycle stages.

Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5)-(8)-(14)-Mycothiazole Analogue.

Scale-up isolation of (+)-(5)-(8)-(14)-mycothiazole () from Vanuatu specimens of to semisynthesize (+)-(5)-(8)-8--acetyl-(14)-mycothiazole () revealed a new diastereomer, (-)-(5)-(8)-(14)-mycothiazole (). The structure of was determined using HRMS, NMR, and comparing optical rotation to (-)-(5)-(8)-(14)-mycothiazole () and . The maximum tolerated dose of in mice was 0.

Compassionate Principlism: Towards a Novel Alternative to Standard Principlism in Bioethics.

Principlism appears to be the prevailing applied ethical framework in bioethics. Despite the view's various strengths, critics point out that since the principles are ad hoc, conflicts indubitably emerge leading to inconsistency. There is debate around whether principlism can provide definitive action-guiding moral prescriptions or only help structure intelligent analyses and justifications of moral choices.

Planetary health learning objectives: foundational knowledge for global health education in an era of climate change.

Planetary health is an emerging field that emphasises that humans depend on a healthy Earth for survival and, conversely, that the sustainability of Earth systems is dependent on human behaviours. In response to member demands for resources to support teaching and learning related to planetary health, the Consortium of Universities for Global Health (CUGH) convened a working group to develop a set of planetary health learning objectives (PHLOs) that would complement the existing ten CUGH global health learning objectives. The eight PHLOs feature Earth system changes, planetary boundaries, and climate change science; ecological systems and One Health; human health outcomes; risk assessment, vulnerability, and resilience; policy, governance, and laws (including the UN Framework Convention on Climate Change and the Paris Agreement); roles and responsibilities of governments, businesses, civil society organisations, other institutions, communities, and individuals for mitigation, adaptation, conservation, restoration, and sustainability; environmental ethics, human rights, and climate justice; and environmental literacy and communication.

susceptibilities to ganaplacide and diversity in potential resistance mediators in Ugandan isolates.

Novel antimalarials are urgently needed to combat rising resistance to available drugs. The imidazolopiperazine ganaplacide is a promising drug candidate, but decreased susceptibility of laboratory strains has been linked to polymorphisms in the cyclic amine resistance locus (PfCARL), acetyl-CoA transporter (PfACT), and UDP-galactose transporter (PfUGT). To characterize parasites causing disease in Africa, we assessed drug susceptibilities to ganaplacide in 750 .

Aperiodic and periodic components of oscillatory brain activity in relation to cognition and symptoms in pediatric ADHD.

Children with attention-deficit/hyperactivity disorder show deficits in processing speed, as well as aberrant neural oscillations, including both periodic (oscillatory) and aperiodic (1/f-like) activity, reflecting the pattern of power across frequencies. Both components were suggested as underlying neural mechanisms of cognitive dysfunctions in attention-deficit/hyperactivity disorder. Here, we examined differences in processing speed and resting-state-Electroencephalogram neural oscillations and their associations between 6- and 12-year-old children with (n = 33) and without (n = 33) attention-deficit/hyperactivity disorder.

Genetic bias in repeated evolution of pigment loss in cave populations of the Asellus aquaticus species complex.

Similar phenotypes can evolve repeatedly under the same evolutionary pressures. A compelling example is the evolution of pigment loss and eye loss in cave-dwelling animals. While specific genomic regions or genes associated with these phenotypes have been identified in model species, it remains uncertain whether a bias towards particular genetic mechanisms exists.

Racial and gender differences in relapse potential and treatment acceptance among rural residents in a substance use disorder treatment program.

Purpose: To examine racial and gender differences in treatment acceptance and relapse potential among rural residents admitted to a substance use disorder (SUD) treatment program.

Methods: A cross-sectional study using data collected from a sample of 1850 rural residents admitted to a South Carolina state-run SUD treatment center between the years of 2018 and 2020. Chi-square and t-tests were used to compare treatment acceptance and relapse potential by race and gender.

Investigating impacts of the mycothiazole chemotype as a chemical probe for the study of mitochondrial function and aging.

Small molecule inhibitors of the mitochondrial electron transport chain (ETC) hold significant promise to provide valuable insights to the field of mitochondrial research and aging biology. In this study, we investigated two molecules: mycothiazole (MTZ) - from the marine sponge C. mycofijiensis and its more stable semisynthetic analog 8-O-acetylmycothiazole (8-OAc) as potent and selective chemical probes based on their high efficiency to inhibit ETC complex I function.

New Features of Laboratory-Generated EPFRs from 1,2-Dichlorobenzene (DCB) and 2-Monochlorophenol (MCP).

The present research is primarily focused on investigating the characteristics of environmentally persistent free radicals (EPFRs) generated from commonly recognized aromatic precursors, namely, 1,2-dichlorobenzene (DCB) and 2-monochlorophenol (MCP), within controlled laboratory conditions at a temperature of 230 °C, termed as DCB230 and MCP230 EPFRs, respectively. An intriguing observation has emerged during the creation of EPFRs from MCP and DCB utilizing a catalyst 5% CuO/SiO, which was prepared through various methods. A previously proposed mechanism, advanced by Dellinger and colleagues (a conventional model), postulated a positive correlation between the degree of hydroxylation on the catalyst's surface (higher hydroxylated, HH and less hydroxylated, LH) and the anticipated EPFR yields.

drug susceptibility and resistance mediating genetic polymorphisms of in Bobo-Dioulasso, Burkina Faso.

Malaria remains a leading cause of morbidity and mortality in Burkina Faso, which utilizes artemether-lumefantrine as the principal therapy to treat uncomplicated malaria and seasonal malaria chemoprevention with monthly sulfadoxine-pyrimethamine plus amodiaquine in children during the transmission season. Monitoring the activities of available antimalarial drugs is a high priority. We assessed the susceptibility of to 11 drugs in isolates from patients presenting with uncomplicated malaria in Bobo-Dioulasso in 2021 and 2022.

Assessment of salivary cadmium levels and breast density in the Marin Women's Study.

Background: We aimed to determine if salivary cadmium (Cd) levels had any association with breast density, hoping to establish a less invasive cost-effective method of stratifying Cd burden as an environmental breast cancer risk factor.

Methods: Salivary Cd levels were quantified from the Marin Women's Study, a Marin County, California population composite. Volumetric compositional breast density (BD ) data were measured by single x-ray absorptiometry techniques.

Building blocks for a happy life: Longitudinal associations between early life income, mentorship and later well-being.

Longitudinal data from the Panel Study of Income Dynamics (PSID; N = 2996) were used to test hypotheses about the link between well-being and financial and social developmental resources. Results suggest that higher average family income from birth to age 18, and personal and professional mentoring received between 17 and 30, were positively associated with indicators of positive well-being and negatively related to negative indicators of well-being. Interactions between early life family income and mentoring during emerging adulthood were not significant predictors of any of the well-being outcomes.

Discovery of Potent Antimalarial Type II Kinase Inhibitors with Selectivity over Human Kinases.

While progress has been made in the effort to eradicate malaria, the disease remains a significant threat to global health. Acquired resistance to frontline treatments is emerging in Africa, urging a need for the development of novel antimalarial agents. Repurposing human kinase inhibitors provides a potential expedited route given the availability of a diverse array of kinase-targeting drugs that are approved or in clinical trials.

Long-term trends and spatial patterns of West Nile Virus emergence in California, 2004-2021.

Aims: West Nile Virus (WNV) has remained a persistent source of vector-borne disease risk in California since first being identified in the state in 2003. The geographic distribution of WNV activity is relatively widespread, but varies considerably across different regions within the state. Spatial variation in human WNV infection depends upon social-ecological factors that influence mosquito populations and virus transmission dynamics.

Bacterial communities of the threatened Western Pond Turtle may be impacted by land use.

As semi-aquatic species that use both terrestrial and aquatic habitats, freshwater turtles and their microbial communities are especially sensitive to the impacts of habitat disturbance. In this study, we use 16S rRNA amplicon sequencing to characterize the shell and cloacal bacterial communities of turtles in the San Francisco Bay Area. We captured western pond turtles (Actinemys/Emys marmorata) across eight sites located in urban and rural environments, along with invasive red-eared sliders (Trachemys scripta elegans).

Exploring Experiences of Pain Management Among Family Caregivers of Community-Dwelling Older Adults With Dementia.

Background: Pain is often underreported and under-treated in older adults with dementia. The role of family caregivers (FCGs) in managing pain for their loved ones with dementia living in community has been significantly burdensome. Surprisingly, research has not delved into the experiences of FCGs' concerning pain management in this context.

CD38 regulates ovarian function and fecundity via NAD metabolism.

Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD+ levels. However, the mechanisms underlying this loss of ovarian NAD+ are unclear. Here, we show that CD38, an NAD+ consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age.

First report of Phytophthora ramorum on Cotoneaster sp. in the USA.

Cotoneaster (Rosaceae) is a genus of woody plants native to the Palearctic region which includes popular ornamental plants; some are invasive in parts of the USA. In May 2022 symptomatic leaves were detected on Cotoneaster pannosus (Silverleaf Cotoneaster) in Marin County, California (37.89165, -122.

Reliable change in developmental outcomes of Brain Balance participants stratified by baseline severity.

The effects of comprehensive multimodal programs on developmental outcomes have not been well-studied. Emerging evidence suggests a possible role for the Brain Balance (BB) program, a multimodal training program, in serving as a nonpharmacologic approach to addressing cognitive, attentional, and emotional issues in youth. In this analysis, we examined the effects of 3 months of participation in the BB program on the outcomes of children and adolescents with developmental difficulties ( = 4,041; aged 4-18 years; 69.