Plasmodium falciparum parasites in the merozoite stage invade human erythrocytes and cause malaria. Invasion requires multiple interactions between merozoite ligands and erythrocyte receptors. ...P. falciparum reticulocyte binding homolog 5 (PfRh5) forms a complex with the PfRh5-interacting protein (PfRipr) and Cysteine-rich protective antigen (CyRPA) and binds erythrocytes via the host receptor basigin. However, the specific role that PfRipr and CyRPA play during invasion is unclear. Using P. falciparum lines conditionally expressing PfRipr and CyRPA, we show that loss of PfRipr or CyRPA function blocks growth due to the inability of merozoites to invade erythrocytes. Super-resolution microscopy revealed that PfRipr, CyRPA, and PfRh5 colocalize at the junction between merozoites and erythrocytes during invasion. PfRipr, CyRPA, and PfRipr/CyRPA/PfRh5-basigin complex is required for triggering the Ca2+ release and establishing the tight junction. Together, these results establish that the PfRh5/PfRipr/CyRPA complex is essential in the sequential molecular events leading to parasite invasion of human erythrocytes.
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•P. falciparum PfRh5-binding partners PfRipr and CyRPA are essential for merozoite invasion•PfRipr and CyRPA are linked to release of calcium into the erythrocyte•PfRh5/PfRipr/CyRPA complex binding to host receptor basigin is required for Ca2+ release•PfRh5/PfRipr/CyRPA complex forms at the interface between the merozoite and erythrocyte
Plasmodium falciparum PfRipr and CyRPA form a complex with PfRh5, which mediates erythrocyte invasion. The specific role of PfRipr and CyRPA is unclear. Volz et al. (2016) show that PfRipr and CyRPA are essential for invasion and required for Ca2+ release during the sequential molecular events for invasion of erythrocytes.
Visceral adipose tissue (VAT) is associated with adverse health effects including cardiovascular disease and type 2 diabetes. We developed a dual‐energy X‐ray absorptiometry (DXA) measurement of ...visceral adipose tissue (DXA‐VAT) as a low cost and low radiation alternative to computed tomography (CT). DXA‐VAT was compared to VAT assessed using CT by an expert reader (E‐VAT). In addition, the same CT slice was also read by a clinical radiographer (C‐VAT) and a best‐fit anthropomorphic and demographic VAT model (A‐VAT) was developed. Whole body DXA, CT at L4–L5, and anthropometry were measured on 272 black and white South African women (age 29 ± 8 years, BMI 28 ± 7 kg/m2, waist circumference (WC) 89 ± 16 cm). Approximately one‐half of the dataset (n = 141) was randomly selected and used as a training set for the development of DXA‐VAT and A‐VAT, which were then used to estimate VAT on the remaining 131 women in a blinded fashion. DXA‐VAT (r = 0.93, standard error of the estimate (SEE) = 16 cm2) and C‐VAT (r = 0.93, SEE = 16 cm2) were strongly correlated to E‐VAT. These correlations with E‐VAT were significantly stronger (P < 0.001) than the correlations of individual anthropometry measurements and the A‐VAT model (WC + age, r = 0.79, SEE = 27 cm2). The inclusion of anthropometric and demographic measurements did not substantially improve the correlation between DXA‐VAT and E‐VAT. DXA‐VAT performed as well as a clinical read of VAT from a CT scan and better than anthropomorphic and demographic models.
Tuning metal oxidation states in metal–organic framework (MOF) nodes by switching between two discrete linker photoisomers via an external stimulus was probed for the first time. On the examples of ...three novel photochromic copper-based frameworks, we demonstrated the capability of switching between +2 and +1 oxidation states, on demand. In addition to crystallographic methods used for material characterization, the role of the photochromic moieties for tuning the oxidation state was probed via conductivity measurements, cyclic voltammetry, and electron paramagnetic resonance, X-ray photoelectron, and diffuse reflectance spectroscopies. We confirmed the reversible photoswitching activity including photoisomerization rate determination of spiropyran- and diarylethene-containing linkers in extended frameworks, resulting in changes in metal oxidation states as a function of alternating excitation wavelengths. To elucidate the switching process between two states, the photoisomerization quantum yield of photochromic MOFs was determined for the first time. Overall, the introduced noninvasive concept of metal oxidation state modulation on the examples of stimuli-responsive MOFs foreshadows a new pathway for alternation of material properties toward targeted applications.
Erythrocyte invasion by the merozoite is an obligatory stage in Plasmodium parasite infection and essential to malaria disease progression. Attempts to study this process have been hindered by the ...poor invasion synchrony of merozoites from the only in vitro culture-adapted human malaria parasite, Plasmodium falciparum. Using fluorescence, three-dimensional structured illumination, and immunoelectron microscopy of filtered merozoites, we analyze cellular and molecular events underlying each discrete step of invasion. Monitoring the dynamics of these events revealed that commitment to the process is mediated through merozoite attachment to the erythrocyte, triggering all subsequent invasion events, which then proceed without obvious checkpoints. Instead, coordination of the invasion process involves formation of the merozoite-erythrocyte tight junction, which acts as a nexus for rhoptry secretion, surface-protein shedding, and actomyosin motor activation. The ability to break down each molecular step allows us to propose a comprehensive model for the molecular basis of parasite invasion.
•Lack of comparable private/public tapwater (TW) data undermines decision-making.•TW (10 private, 10 public), with same groundwater source, compared at Cape Cod, MA.•487 organics/38 inorganics/8 ...microbial indicators/3 bioactivities assessed.•Comparable private/public TW health concerns found in shared source-water setting.
Humans are primary drivers of environmental contamination worldwide, including in drinking-water resources. In the United States (US), federal and state agencies regulate and monitor public-supply drinking water while private-supply monitoring is rare; the current lack of directly comparable information on contaminant-mixture exposures and risks between private- and public-supplies undermines tapwater (TW) consumer decision-making.
We compared private- and public-supply residential point-of-use TW at Cape Cod, Massachusetts, where both supplies share the same groundwater source. TW from 10 private- and 10 public-supply homes was analyzed for 487 organic, 38 inorganic, 8 microbial indicators, and 3 in vitro bioactivities. Concentrations were compared to existing protective health-based benchmarks, and aggregated Hazard Indices (HI) of regulated and unregulated TW contaminants were calculated along with ratios of in vitro exposure-activity cutoffs.
Seventy organic and 28 inorganic constituents were detected in TW. Median detections were comparable, but median cumulative concentrations were substantially higher in public supply due to 6 chlorine–disinfected samples characterized by disinfection byproducts and corresponding lower heterotrophic plate counts. Public-supply applicable maximum contaminant (nitrate) and treatment action (lead and copper) levels were exceeded in private-supply TW samples only. Exceedances of health-based HI screening levels of concern were common to both TW supplies.
These Cape Cod results indicate comparable cumulative human-health concerns from contaminant exposures in private- and public-supply TW in a shared source-water setting. Importantly, although this study’s analytical coverage exceeds that currently feasible for water purveyors or homeowners, it nevertheless is a substantial underestimation of the full breadth of contaminant mixtures documented in the environment and potentially present in drinking water.
Regardless of the supply, increased public engagement in source-water protection and drinking-water treatment, including consumer point-of-use treatment, is warranted to reduce risks associated with long-term TW contaminant exposures, especially in vulnerable populations.
With emerging resistance to frontline treatments, it is vital that new antimalarial drugs are identified to target Plasmodium falciparum. We have recently described a compound, MMV020291, as a ...specific inhibitor of red blood cell (RBC) invasion, and have generated analogues with improved potency. Here, we generated resistance to MMV020291 and performed whole genome sequencing of 3 MMV020291-resistant populations. This revealed 3 nonsynonymous single nucleotide polymorphisms in 2 genes; 2 in profilin (N154Y, K124N) and a third one in actin-1 (M356L). Using CRISPR-Cas9, we engineered these mutations into wild-type parasites, which rendered them resistant to MMV020291. We demonstrate that MMV020291 reduces actin polymerisation that is required by the merozoite stage parasites to invade RBCs. Additionally, the series inhibits the actin-1-dependent process of apicoplast segregation, leading to a delayed death phenotype. In vitro cosedimentation experiments using recombinant P. falciparum proteins indicate that potent MMV020291 analogues disrupt the formation of filamentous actin in the presence of profilin. Altogether, this study identifies the first compound series interfering with the actin-1/profilin interaction in P. falciparum and paves the way for future antimalarial development against the highly dynamic process of actin polymerisation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
More than 70% of new HIV infections in Asia occurred in eight countries in 2020: Cambodia, China, India, Indonesia, Myanmar, Nepal, Thailand, and Vietnam-with a rising incidence among men who have ...sex with men (MSM). The World Health Organization (WHO) recommends pre-exposure prophylaxis (PrEP) for those at risk of acquiring HIV, yet wide-scale implementation of PrEP, on a daily or event-driven basis, has been limited in Asia.
The Optima HIV model was applied to examine the impact of scaling-up PrEP over five-years to cover an additional 15% of MSM compared with baseline coverage, a target deemed feasible by regional experts. Based on behavioral survey data, we assume that covering 15% of higher-risk MSM will cover 30% of all sexual acts in this group. Scenarios to compare the impact of generic-brand daily dosing of PrEP with generic event-driven dosing (15 days a month) were modelled from the start of 2022 to the end of 2026. Cost-effectiveness of generic versus branded PrEP was also assessed for China, the only country with an active patent for branded, higher cost PrEP. The impact on new HIV infections among the entire population and cost per HIV-related disability-adjusted life year (DALY) averted were estimated from the beginning of 2022 to the end of 2031 and from 2022 to 2051.
If PrEP were scaled-up to cover an additional 15% of MSM engaging in higher-risk behavior from the beginning of 2022 to the end of 2026 in the eight Asian countries considered, an additional 100,000 (66,000-130,000) HIV infections (17%) and 300,000 (198,000-390,000) HIV-related DALYs (3%) could be averted over the 2022 to 2031 period. The estimated cost per HIV-related DALY averted from 2022 to 2031 ranged from US$600 for event-driven generic PrEP in Indonesia to US$34,400 for daily branded PrEP in Thailand. Over a longer timeframe from 2022 to 2051, the cost per HIV-related DALY averted could be reduced to US$100-US$12,700.
PrEP is a critical tool to further reduce HIV incidence in highly concentrated epidemics. Implementing PrEP in Asia may be cost-effective in settings with increasing HIV prevalence among MSM and if PrEP drug costs can be reduced, PrEP could be more cost-effective over longer timeframes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction Eswatini achieved a 44% decrease in new HIV infections from 2014 to 2019 through substantial scale-up of testing and treatment. However, it still has one of the highest rates of HIV ...incidence in the world, with 14 infections per 1,000 adults 15–49 years estimated for 2017. The Government of Eswatini has called for an 85% reduction in new infections by 2023 over 2017 levels. To make further progress towards this target and to achieve maximum health gains, this study aims to model optimized investments of available HIV resources. Methods The Optima HIV model was applied to estimate the impact of efficiency strategies to accelerate prevention of HIV infections and HIV-related deaths. We estimated the number of infections and deaths that could be prevented by optimizing HIV investments. We optimize across HIV programs, then across service delivery modalities for voluntary medical male circumcision (VMMC), HIV testing, and antiretroviral refill, as well as switching to a lower cost antiretroviral regimen. Findings Under an optimized budget, prioritising HIV testing for the general population followed by key preventative interventions may result in approximately 1,000 more new infections (2% more) being averted by 2023. More infections could be averted with further optimization between service delivery modalities across the HIV cascade. Scaling-up index and self-testing could lead to 100,000 more people getting tested for HIV (25% more tests) with the same budget. By prioritizing Fast-Track, community-based, and facility-based antiretroviral refill options, an estimated 30,000 more people could receive treatment, 17% more than baseline or US$5.5 million could be saved, 4% of the total budget. Finally, switching non-pregnant HIV-positive adults to a Dolutegravir-based antiretroviral therapy regimen and concentrating delivery of VMMC to existing fixed facilities over mobile clinics, US$4.5 million (7% of total budget) and US$6.6 million (10% of total budget) could be saved, respectively. Significance With a relatively short five-year timeframe, even under a substantially increased and optimized budget, Eswatini is unlikely to reach their ambitious national prevention target by 2023. However, by optimizing investment of the same budget towards highly cost-effective VMMC, testing, and treatment modalities, further reductions in HIV incidence and cost savings could be realized.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cooperative behavior and orthogonal responses of two classes of coordinatively integrated photochromic molecules towards distinct external stimuli were demonstrated on the first example of a ...photo‐thermo‐responsive hierarchical platform. Synergetic and orthogonal responses to temperature and excitation wavelength are achieved by confining the stimuli‐responsive moieties within a metal–organic framework (MOF), leading to the preparation of a novel photo‐thermo‐responsive spiropyran‐diarylethene based material. Synergistic behavior of two photoswitches enables the study of stimuli‐responsive resonance energy transfer as well as control of the photoinduced charge transfer processes, milestones required to advance optoelectronics development. Spectroscopic studies in combination with theoretical modeling revealed a nonlinear effect on the material electronic structure arising from the coordinative integration of photoresponsive molecules with distinct photoisomerization mechanisms. Thus, the reported work covers multivariable facets of not only fundamental aspects of photoswitch cooperativity, but also provides a pathway to modulate photophysics and electronics of multidimensional functional materials exhibiting thermo‐photochromism.
Like two color‐changing chameleons coming face to face, integration of two distinct stimuli‐responsive moieties within the same platform results in their synergistic behavior. Perturbation of the chameleons’ environment upon a different external stimulus breaks the synergy, promoting their orthogonal behavior, a concept highlighted for a novel hierarchical photo‐thermo‐responsive metal–organic framework.
Hispanics experience a higher prevalence of sexually transmitted infections (STIs) than non-Hispanics. Specifically, Hispanic teenagers are more at risk for HIV, have close to four times the rate of ...primary and secondary syphilis, and close to two times the rate of chlamydia and gonorrhea compared with non-Hispanic white teenagers. Hispanic youth engage in sexual activity at a younger age than non-Hispanic white youth and are less likely to use condoms in these encounters, thereby contributing to increased rates of teenage pregnancy and STIs. Prevention of STIs is needed for unmarried Hispanic teenage mothers. The purpose of this study was to examine whether Project Mothers and Schools (Project MAS), a support program for parenting teenagers, changed condom use to prevent STIs among Hispanic participants.
A longitudinal study was conducted among 84 Hispanic teenage mothers. Generalized estimating equations were used to identify factors associated with participants' reported condom use to prevent STIs.
Overall, participants were 3.21 times more likely to report condom use to prevent STIs from baseline to 12-month follow-up (
= 0.030). Those using condoms to prevent pregnancy at 12-month follow-up were significantly more likely to report using a condom to prevent STIs (OR = 3.23,
= 0.017).
Participation in Program MAS improved condom use patterns for STI prevention. These services and supports have potential to change unmarried Hispanic teenage mothers' condom use behaviors and decrease STI infection disparities among the teenage Hispanic population.
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