A fused dihydropyrrolidino-pyrimidine hit with low lipophilicity and excellent ligand efficiency was identified in a biochemical screen of the Global Health Chemical Diversity Library (GHCDL) against Plasmodium lysyl-tRNA synthetase (KRS). Structure-guided lead optimization delivered analogues with potent parasite growth inhibition, excellent biochemical and cellular selectivity (>1000-fold), and oral efficacy in the malaria NOD-scid-IL2Rγnull (SCID) mouse model. Structural information and computational methods were deployed to identify a potent and selective basic KRS inhibitor (30) with an extended half-life to reduce the dose regimen to a single-dose cure. Compound 30 displayed a long half-life across preclinical species, favorable safety, and activity across Plasmodium species as well as against drug-resistant and sensitive P. falciparum strains and field isolates. Unfortunately, 30 lacked oral bioavailability, which could not be mitigated with a prodrug approach. Nevertheless, learnings from this series will assist future KRS programs in delivering a clinical candidate with this novel mode of action.

Background:With rising temperatures and an aging population, understanding how to prevent heat-related illness among older adults will be increasingly crucial. Despite biological plausibility, no study to date has investigated how exposure to fine particulate matter air pollution (PM2.5) may contribute to the risk of hospitalization with a diagnosis code indicating heat-related illness, referred to as heat-related hospitalization. This study aims to fill this gap by investigating the independent and combined effects of temperature and PM2.5 exposures on heat-related hospitalization risk. Methods:We identified Medicare fee-for-service beneficiaries in the contiguous United States who experienced a heat-related hospitalization between 2008 and 2016. Using a case-crossover design and fitting Bayesian conditional logistic regression models, we characterized the associations of temperature and PM2.5 exposures with heat-related hospitalization. We then estimated the relative excess risk due to interaction to quantify the additive-scale interaction of simultaneous exposure to heat and PM2.5. Results:We observed 112,969 heat-related hospitalizations among 29,345,820 Medicare beneficiaries in the study sample. Fixing PM2.5 at the case day median, the odds ratio for increasing temperature from its case day median to the 95th percentile was 1.05 (95% CI: 1.03, 1.06). Fixing temperature at the case day median, the odds ratio for increasing PM2.5 from its median to the 95th percentile was 1.01 (95% CI: 0.99, 1.04). The risk due to interaction for simultaneous median-to-95th percentile increases in temperature and PM2.5 was 0.03 (95% CI: 0.01, 0.06). Conclusions:Our study is the first to observe synergism between temperature and PM2.5 exposures associated with the risk of heat-related hospitalization. These findings highlight the importance of considering air pollution in effective public health and clinical interventions to prevent heat-related illness.

Background:Multiple studies from countries with relatively lower PM 2.5 level demonstrated that acute and chronic exposure even at lower than recommended level, e.g., 9 μg/m 3 in the US increased the risk of cardiovascular (CV) events. However, limited studies using individual level data exist from countries with a wider range of PM levels to illustrate shape of the exposure-response curve throughout the range including > 20 μg/m 3 PM 2·5 concentrations. Taiwan with its policies reduced PM 2.5 over time provide opportunities to illustrate the dose response curves and how reductions of PM 2.5 over time correlated with CV events incidence in a nationwide sample. Methods:Using data from the 2009-2019 Taiwan National Health Insurance Database linked to nationwide PM2.5 data. We examined the shape and magnitude of the exposure-response curve between seasonal average PM 2·5 level and CV events-related hospitalizations among older adults at high-risk for CV events. We used history-adjusted marginal structural models including potential confounding by individual demographic factors, baseline comorbidities, and health service measures. To quantify the risk below and above 20 μg/m 3 we conducted stratified Cox regression. We also plotted PM 2.5 and CV events from 2009-2019 as well as average temperature as a comparison. Findings:Using the PM 2.5 concentration <15 μg/m 3 (Taiwan regulatory standard) as a reference, the seasonal average PM 2.5 concentration (15-23.5μg/m 3 and > 23.5 μg/m 3 ) were associated with hazard ration of 1.13 (95%CI 1.09-1.18) and 1.19 (95%CI 1.14-1.24), 1.07 (95%CI 1.03-1.11) and 1.14 (95%CI 1.10-1.18), 1.22 (95%CI 1.08-1.38) and 1.31 (95%CI 1.16-1.48), 1.04 (95%CI 0.98-1.10) and 1.10 (95%CI 1.04-1.16) respectively for HF, IS/TIA,PE/DVT and MI/ACS. A nonlinear relationship between PM 2·5 and CV events outcomes was observed at PM 2·5 levels above 20 μg/m 3 . Interpretation:A nonlinear exposure-response relationship between PM2·5 concentration and the incidence of cardiovascular events exists when PM2.5 is higher than the levels recommended by WHO Air Quality Guidelines. Further lowering PM2·5 levels beyond current regulatory standards may effectively reduce the incidence of cardiovascular events, particularly HF and DVT, and can lead to tangible health benefits in high-risk elderly population.

Objective: To measure the association between ambient heat and hypoglycemia-related ED visit or hospitalization in insulin users. Research Design and Methods: We identified cases of serious hypoglycemia among adults using insulin aged ≥65 in the US (via Medicare Part A/B/D-eligible beneficiaries) and Taiwan (via National Health Insurance Database) from June to September, 2016-2019). We then estimated odds of hypoglycemia by heat index (HI) percentile categories using conditional logistic regression with a time-stratified case-crossover design. Results: Among ~2 million insulin users in the US (32,461 hypoglycemia cases), ORs for HI >99th, 95-98th, 85 94th, and 75-84th percentiles compared to the 25-74th percentile were 1.38 (95% CI, 1.28-1.48), 1.14 (1.08-1.20), 1.12 (1.08-1.17), and 1.09 (1.04-1.13) respectively. Overall patterns of associations were similar for insulin users in the Taiwan sample (~283,000 insulin users, 10,162 hypoglycemia cases). Conclusions: In two national samples of older insulin users, higher ambient temperature was associated with increased hypoglycemia risk.

Click to increase image sizeClick to decrease image size Additional informationNotes on contributorsDavid A. RobinsonDAVID A. ROBINSON is a Distinguished Professor of Geography at Rutgers University and is the New Jersey State Climatologist.Thanks to Mathieu Gerbush, Thomas Estilow, and Meghan Anderson at Rutgers University, and colleagues in State Climate, National Weather Service, and NOAA Regional Climate Center offices for assisting with information gathering. The tremendous efforts of the intrepid observers who daily head out into the elements to take snow measurements are also greatly appreciated.

Background: A trend of warmer nights and higher daily minimum temperatures (T min ) during summer is a leading indicator of climate change. The impact of increased T min on hospitalizations in low-income older adults with heart failure (HF) remains unknown. Hypothesis: Higher T min increases the risk of HF hospitalization among older adults and low-income patients will be more impacted. Methods: We conducted a time-stratified case-crossover study among older adults (age ≥ 66 years) hospitalized for HF during summer months (May-Sept) between 2008-2019 using 20% Medicare data. We employed bidirectional sampling to select controls. Data on daily T min from the Parameter-elevation Relationships on Independent Slopes Model were linked using patient zip code. The non-linear effect of T min was estimated using conditional logistic regression with a restricted cubic spline in all patients and by Medicaid eligibility. Results: Among 460,072 patients hospitalized for HF (mean age 78 years, 62% female, 86% white), the risk of HF hospitalization increased nearly linearly with higher T min (OR: 74 °F = 1.09 [1.09 - 1.10], 84 °F = 1.18 [1.16 - 1.20]) relative to the median summer T min (64 °F) (Figure 1). Patients with Medicaid dual eligibility experienced greater risk of HF hospitalization than their counterparts (Figure 2). Conclusions: Among older US adults, summer days with higher T min were associated with increased risk of HF hospitalization. Low-income patients were at greater risk, possibly secondary to behavioral differences. This effect may be mediated through physiological stress from warmer nights; increased ambient temperatures are associated with inflammation and myocyte damage.

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.

This study investigates variability in moisture transport patterns within the eastern USA and adjacent Atlantic Ocean during the twentieth and early twenty-first centuries and relates these patterns to heavy precipitation. Daily integrated water vapor transport (IVT) from the European Centre for Medium-Range Weather Forecasts ERA-20C reanalysis for the eastern USA (30°–50°N × 60°–90°W) from 1900 to 2010 is classified into previously defined moisture transport patterns. Over the 111-year study period, annual counts of the high-IVT patterns increase at the expense of low-IVT pattern counts, with the rates of these changes varying by pattern and by season. Additionally, the frequency of intense IVT patterns persisting for consecutive days increases and weak IVT patterns are interrupted more frequently. Moisture transport in each of the patterns increases over the study period, particularly in the highest percentiles of IVT, indicating an intensification of IVT in the eastern USA. This intensification is expressed in the moisture transport patterns with spatial and seasonal variability. When heavy precipitation days from 1900 to 2010 from eleven stations are related to the water vapor transport patterns, several patterns emerge as major contributors to the regional heavy precipitation regimes within the study area. Over the study period, the occurrence of heavy precipitation increases with meridional, high-IVT patterns and decreases with frequent, zonal patterns. This indicates an increasing influence of synoptic-scale meridional moisture transport on heavy precipitation across the eastern USA. This study demonstrates the utility of a moisture transport approach to contextualize regional precipitation shifts within the changing global hydroclimatic system.

Direct and indirect pathways mediating the vestibulo-ocular reflexes, considering contributions made by the vestibular commissure, cerebellum, and vestibular efferent neurons are reviewed. This background leads to a detailed treatment of three-dimensional aspects of the vestibulo-ocular reflex, comparing the planes of the labyrinthine semicircular canals with the pulling directions of the extraocular muscles. By applying matrix algebra and rotational vectors, Robinson provides insights into the comparative anatomy of the vestibular system in different species, how central circuits process raw vestibular signals in three dimensions, and how the directions of eye movement caused by brainstem and cerebellar lesions can be explained.

This chapter starts by comparing two different models to account for optokinetic-vestibular symbiosis. In the first, there are two separate velocity storage (integrator) elements for vestibular and optokinetic systems, and in the second model, velocity storage is shared between the two systems. Behavioral and electrophysiological evidence is presented to support the model with shared velocity storage and its ability to provide a linear addition of vestibular and optokinetic signals, account for different time constants of optokinetic and vestibular responses and separate adaptive properties of the two systems. This model is then extended to account for an unexplained clinical disorder-periodic alternating nystagmus-and provide insights into its pathogenesis and treatment.

This chapter provides a review of early studies into the neural substrate for optokinetic-vestibular responses. Properties and connections of retinal and brainstem neurons contributing to optokinetic responses in the afoveate rabbit are summarized. Electrophysiological and lesion studies provide support for confluence of optokinetic and vestibular signals in the vestibular nucleus to provide the brain's estimate of self-rotation. Evidence for optokinetic-vestibular symbiosis in humans comes from the observation that individuals who have lost vestibular function show no optokinetic after-nystagmus in darkness, following full-field stimulus motion. An anatomical scheme for brainstem elaboration of optokinetic responses is proposed and cerebellar contributions are reviewed.

Optokinetic responses in several species are compared, describing differences in afoveate and foveate animals, and the effects of visual testing conditions, including directions of stimulus motion. Smooth pursuit contributes to responses to full-field visual motion in foveate species; in the latter, measurement of optokinetic after-nystagmus in darkness allows investigation of the optokinetic system. The concept of optokinetic-vestibular symbiosis and velocity storage are discussed, pertinent electrophysiological studies (such as vestibular nucleus neurons that respond to both optokinetic and vestibular stimuli) are reviewed and a model is developed. The different purposes and properties of optokinetic responses (to maintain clear vision during self-rotation) and smooth pursuit (to visually track a moving target) are clarified.

The biophysical properties of the labyrinthine semicircular canals, and the electrophysiological properties of peripheral vestibular afferent neurons over a range of stimulus frequencies, are reviewed. Resting discharge activity and adaptive properties of vestibular neurons are discussed. Central processing of vestibular signals is then examined, including push-pull organization and the velocity storage mechanism. A detailed treatment of the final common neural integrator for oculomotor signals follows with consideration of its neural substrate and how distributed networks of neurons can overcome several problems posed by conventional control-systems models, such as why neural signals, but not background discharge, are integrated. Next, the behavior of the vestibulo-ocular reflex in darkness is compared with how it satisfies visual demands during natural activities. Finally, the reflex's performance at high frequencies of head rotation is discussed.

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.

This chapter deals with mathematical models for smooth-pursuit eye movements, starting with simple negative-feedback schemes. After pointing out their deficiencies, Robinson developed models that account for specific dynamic properties of pursuit behavior, such as the transient ocular oscillations that may occur at onset, and the adaptive properties of pursuit. The challenges posed by the inherent latency of visual responses to target motion-specifically the instability of a negative feedback model-are resolved by including an efference copy internal positive feedback loop, and distributing system delays throughout the model's pathways. A model for smooth combined eye-head tracking is presented in which the brain sends an efference copy of the planned head movement to null out the vestibular signal expected.

This chapter summarizes early electrophysiological and lesion studies to elucidate cortical, subcortical and cerebellar mechanisms for extracting visual target motion and programming a smooth-pursuit response. The importance of a descending pursuit pathway from the middle temporal (MT) cortical visual area, which extracts the speed and direction of a moving target, the projections to dorsolateral pontine nuclei, and onto the cerebellum are outlined. Contributions of the cerebellum to pursuit are discussed and models are presented to account for the ways in which floccular gaze Purkinje cells behave during smooth pursuit, combined eye-head tracking, and during head rotation while viewing a stationary target.

There is a pressing need for new medicines to prevent and treat malaria. Most antimalarial drug discovery is reliant upon phenotypic screening. However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Here, we describe the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase (PfKRS). The toolkit includes resistant mutants to probe resistance mechanisms and on-target engagement for specific chemotypes; a hybrid KRS protein capable of producing crystals suitable for ligand soaking, thus providing high-resolution structural information to guide compound optimization; chemical probes to facilitate pulldown studies aimed at revealing the full range of specifically interacting proteins and thermal proteome profiling (TPP); as well as streamlined isothermal TPP methods to provide unbiased confirmation of on-target engagement within a biologically relevant milieu. This combination of tools and methodologies acts as a template for the development of future target-enabling packages.