Malaria remains a global health threat and growing resistance to artemisinin-based therapies calls for therapeutic agents with novel mechanisms of action. The Plasmodium spp M1 and M17 ...metalloaminopeptidases have been identified as attractive new antimalarial drug targets as inhibition of these enzymes results in antiplasmodial activity. Previously identified novel hydroxamic acid 2 as a moderate inhibitor of PfA-M1 and PfA-M17 and a potent inhibitor of P. falciparum. This study has sought to improve the enzymatic inhibitory properties in addition to increasing the drug-likeness of this scaffold by introducing polar moieties into the S1’ region of the active site. Structural biology studies on the co-crystallised structures of potent dual-inhibitor 9aa bound to PfA-M1 and PfA-M17 have revealed that there are few direct interactions between the inhibitor and the S1’ domain of these enzymes. Structure-based compound design led to the identification of a variety of novel hydroxamic acids that show improved inhibitory activity against PfA-M1 and PfA-M17, in addition to displaying antiplasmodial activity. Notably, compounds with substitutions on the aniline ring resulted in a loss of potency (Ki > 500 nM) toward PfA-M1 and PfA-M17. ioisosteric replacement of the S1-region biaryl ring system with a bromophenyl moiety resulted in increased potency compared to parent 9aa. Elaboration of 9aa to bioisosterically replace the S1 moiety with an aryl bromide, combined with substituted anilines has resulted in potent selective PfA-M1 inhibitors which show strong activity against Pf-3D7, with meta- and para-fluoroaniline groups of 15ag and 15ah forming hydrogen-bonds with residues within the active site. These findings establish the importance of the previously under-utilised S1’ domain and will aid the design of future PfA-M1 and PfA-M17 inhibitors.
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•PfA-M1 and PfA-M17 are promising antimalarial targets.•Using X-ray crystallography, a series of novel inhibitors was designed and synthesised.•Compound 9aa proved to be a potent dual-inhibitor of PfA-M1 and PfA-M17.•Compound 15aj and related analogues proved to be potent selective inhibitors of PfA-M1.•Interactions between inhibitor and S1’ are important for M1 selectivity.
The proportional cover of rubble on reefs is predicted to increase as disturbances increase in intensity and frequency. Unstable rubble can kill coral recruits and impair binding processes that ...transform rubble into a stable substrate for coral recruitment. A clearer understanding of the mechanisms of inhibited coral recovery on rubble requires characterisation of the hydrodynamic conditions that trigger rubble mobilisation. Here, we investigated rubble mobilisation under regular wave conditions in a wave flume and irregular wave conditions in situ on a coral reef in the Maldives. We examined how changes in near-bed wave orbital velocity influenced the likelihood of rubble motion (e.g. rocking) and transport (by walking, sliding or flipping). Rubble mobilisation was considered as a function of rubble length, branchiness (branched vs. unbranched) and underlying substrate (rubble vs. sand). The effect of near-bed wave orbital velocity on rubble mobilisation was comparable between flume and reef observations. As near-bed wave orbital velocity increased, rubble was more likely to rock, be transported and travel greater distances. Averaged across length, branchiness and substrate, loose rubble had a 50 % chance of transport when near-bed wave orbital velocities reached 0.30 m s−1 in both the wave flume and on the reef. However, small and/or unbranched rubble pieces were generally mobilised more and at lower velocities than larger, branched rubble. Rubble also travelled further distances per day (∼2 cm) on substrates composed of sand than rubble. Importantly, if rubble was interlocked, it was very unlikely to move (< 7 % chance) even at the highest velocity tested (0.4 m s−1). Furthermore, the probability of rubble transport declined over 3 d deployments in the field, suggesting rubble had snagged or settled into more hydrodynamically stable positions within the first days of deployment. We expect that snagged or settled rubble is transported more commonly in locations with higher-energy events and more variable wave environments. At our field site in the Maldives, we expect recovery windows for binding (when rubble is stable) to predominantly occur during the calmer north-eastern monsoon when wave energy impacting the atoll is less and wave heights are smaller. Our results show that rubble beds comprised of small rubble pieces and/or pieces with fewer branches are more likely to have shorter windows of recovery (stability) between mobilisation events, and thus be good candidates for rubble stabilisation interventions to enhance coral recruitment and binding.
Under-skin browning (USB) is an unsightly physiological disorder that afflicts ‘Honey Gold’ mango fruit. Under-skin browning symptoms develop after harvest upon the interaction of physical abrasion ...and physiological chilling stresses. Less understood preharvest and/or harvest factors may also influence fruit susceptibility to USB. In this study, we examined the impact of harvest time during the diurnal cycle and fruit sap components on USB development. Fruits were harvested at 4- to 6-h intervals, lightly abraded with sandpaper to simulate vibration damage during refrigerated road transport, held at 12 ± 1°C for 6 days, transported to the research facilities and ripened before USB assessment. Spurt and ooze sap from the fruit were collected at each harvest time. The samples were separated and analysed by gas chromatography–mass spectrometry. Fruit harvested at 10:00, 14:00 and 18:00 h had 3- to 5-fold higher incidence of USB than did those picked at 22:00, 2:00 and 6:00 h. Sap concentrations of the key aroma volatile compounds 2-carene, 3-carene, α-terpinene,
p
-cymene, limonene and α-terpinolene were higher for fruit harvested at 14:00 h compared to those picked at other times. In the fruits harvested in the afternoon, abraded skin treated with spurt sap sampled at 14:00 h had 14.3- and 29.0-fold higher incidence and severity, respectively, of induced browning than did those treated with sap collected at 6:00 h. The results showed that fruit harvested in the afternoon were more susceptible to USB than those picked at night or in early morning. The diurnal variation in fruit sensitivity was evidently associated with specific compositional differences in sap phytotoxicity. Topical application to the fruit skin of pure terpinolene and limonene resulted in induced USB damage, whereas pure carene and distilled water did not. Microscopy examination showed that while skin damage caused by pure terpinolene and limonene was not identical to USB per se, similarities suggested that sap components cause USB under inductive commercial conditions. Considered collectively, these findings suggest that night and early morning harvesting will reduce USB and thus improve the postharvest quality of Honey Gold mango fruit.
Objective ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ...ATL1103 as a treatment for acromegaly. Design Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period. Methods The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events. Results and conclusions Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P = 0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P = 0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P = 0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P = 0.027) and 16.7% (P = 0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P = 0.027 and P = 0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.
Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, ...their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3
mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell-driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.
Michael C. Webb explores a central question about postwar economic history: how has the growth of international markets affected the coordination of economic policy among nations?.
Positron emission tomography (PET) is a highly sensitive and versatile molecular imaging modality that leverages radiolabeled molecules, known as radiotracers, to interrogate biochemical processes ...such as metabolism, enzymatic activity, and receptor expression. The ability to probe specific molecular and cellular events longitudinally in a noninvasive manner makes PET imaging a particularly powerful technique for studying the central nervous system (CNS) in both health and disease. Unfortunately, developing and translating a single CNS PET tracer for clinical use is typically an extremely resource-intensive endeavor, often requiring synthesis and evaluation of numerous candidate molecules. While existing in vitro methods are beginning to address the challenge of derisking molecules prior to costly in vivo PET studies, most require a significant investment of resources and possess substantial limitations. In the context of CNS drug development, significant time and resources have been invested into the development and optimization of computational methods, particularly involving machine learning, to streamline the design of better CNS therapeutics. However, analogous efforts developed and validated for CNS radiotracer design are conspicuously limited. In this Perspective, we overview the requirements and challenges of CNS PET tracer design, survey the most promising computational methods for in silico CNS drug design, and bridge these two areas by discussing the potential applications and impact of computational design tools in CNS radiotracer design.
Archean geological records are increasingly interpreted to indicate a ≤3.2 Ga initiation of plate tectonics on Earth. This hypothesis contrasts with dominant plate tectonic interpretations for the ...Eoarchean (ca. 4.0–3.6 Ga) Isua supracrustal belt (southwest Greenland). Alternatively, recent work shows the belt could have formed via heat‐pipe tectonics. Predicted strain distributions across the belt vary between models. Plate tectonic models predict a dominant unidirectional shear sense, corresponding to subduction vergence, and strain localization within ∼10‐m‐scale shear zones. In contrast, the proposed heat‐pipe model predicts two opposing shear senses, corresponding to opposite limbs of 0.1‐m to km‐scale a‐type folds (i.e., sheath and curtain folds), with relatively equal strain distributed across the belt. Here, we present the first microstructure study using thin‐section petrography and electron backscatter diffraction analysis on quartz of oriented samples from throughout the Isua supracrustal belt. Key findings are: (1) the Eoarchean Isua supracrustal belt was deformed at ∼500°C–650°C, with potential postdeformational recovery at similar or lower temperatures, (2) the spatial distribution of the two opposing shear senses which dominate the belt (top‐to‐southeast and top‐to‐northwest) appears to be random, and (3) the strain intensity across the belt appears to be quasiuniform as evidenced by the uniformly low (mostly <0.1) M‐indexes of quartz fabrics, such that no ≤ 100 ‐m‐scale shear zones can be detected. Our findings are only consistent with the predictions of the heat‐pipe model and do not require plate tectonics, so the geology of the belt is compatible with a ≤3.2 Ga initiation of plate tectonics.
Key Points
Microstructures of the Isua supracrustal belt show two dominant opposing shear senses and quasiuniform strain intensities
Deformation of the Isua supracrustal belt occurred under amphibolite facies conditions
The Isua supracrustal belt could have formed via heat‐pipe tectonics before ca. 3.7 Ga and deformed via a‐type folding within ca. 3.66–3.5 Ga
In a randomized double-blind, placebo-controlled trial, treatment with spironolactone in early-stage CKD reduced left ventricular mass and arterial stiffness compared with placebo. It is not known if ...these effects were due to BP reduction or specific vascular and myocardial effects of spironolactone.
A prospective, randomized, open-label, blinded end point study conducted in four UK centers (Birmingham, Cambridge, Edinburgh, and London) comparing spironolactone 25 mg to chlorthalidone 25 mg once daily for 40 weeks in 154 participants with nondiabetic stage 2 and 3 CKD (eGFR 30-89 ml/min per 1.73 m
). The primary end point was change in left ventricular mass on cardiac magnetic resonance imaging. Participants were on treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and had controlled BP (target ≤130/80 mm Hg).
There was no significant difference in left ventricular mass regression; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was -3.8 g (95% confidence interval, -8.1 to 0.5 g,
=0.08). Office and 24-hour ambulatory BPs fell in response to both drugs with no significant differences between treatment. Pulse wave velocity was not significantly different between groups; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was 0.04 m/s (-0.4 m/s, 0.5 m/s,
=0.90). Hyperkalemia (defined ≥5.4 mEq/L) occurred more frequently with spironolactone (12 versus two participants, adjusted relative risk was 5.5, 95% confidence interval, 1.4 to 22.1,
=0.02), but there were no patients with severe hyperkalemia (defined ≥6.5 mEq/L). A decline in eGFR >30% occurred in eight participants treated with chlorthalidone compared with two participants with spironolactone (adjusted relative risk was 0.2, 95% confidence interval, 0.05 to 1.1,
=0.07).
Spironolactone was not superior to chlorthalidone in reducing left ventricular mass, BP, or arterial stiffness in nondiabetic CKD.
Clinical trials have revealed that Ivacaftor significantly reduces sweat chloride in patients with cystic fibrosis who carry the G551D mutation. This finding has been incorporated into the ...commissioning guidelines in the UK with a sweat chloride reduction of 30% or below 60 mmol/L, specified as the main criteria for continued funding of Ivacaftor for individual patients. In a cohort of 24 adults who were prescribed Ivacaftor, there was no correlation between absolute or relative reductions in sweat chloride and improvements in lung function. This questions the validity of sweat chloride as a surrogate marker of clinical efficacy.
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