Author Correction: Design of amidobenzimidazole STING receptor agonists with systemic activity.

Change history: In this Letter, author Ana Puhl was inadvertently omitted; this error has been corrected online.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Design of amidobenzimidazole STING receptor agonists with systemic activity.

Stimulator of interferon genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen-derived and self DNA1. The development of compounds that modulate STING has recently been the focus of intense research for the treatment of cancer and infectious diseases and as vaccine adjuvants2. To our knowledge, current efforts are focused on the development of modified cyclic dinucleotides that mimic the endogenous STING ligand cGAMP; these have progressed into clinical trials in patients with solid accessible tumours amenable to intratumoral delivery3. Here we report the discovery of a small molecule STING agonist that is not a cyclic dinucleotide and is systemically efficacious for treating tumours in mice. We developed a linking strategy to synergize the effect of two symmetry-related amidobenzimidazole (ABZI)-based compounds to create linked ABZIs (diABZIs) with enhanced binding to STING and cellular function. Intravenous administration of a diABZI STING agonist to immunocompetent mice with established syngeneic colon tumours elicited strong anti-tumour activity, with complete and lasting regression of tumours. Our findings represent a milestone in the rapidly growing field of immune-modifying cancer therapies.

Comparative Analysis of Major Machine-Learning-Based Path Loss Models for Enclosed Indoor Channels.

Unlimited access to information and data sharing wherever and at any time for anyone and anything is a fundamental component of fifth-generation (5G) wireless communication and beyond. Therefore, it has become inevitable to exploit the super-high frequency (SHF) and millimeter-wave (mmWave) frequency bands for future wireless networks due to their attractive ability to provide extremely high data rates because of the availability of vast amounts of bandwidth. However, due to the characteristics and sensitivity of wireless signals to the propagation effects in these frequency bands, more accurate path loss prediction models are vital for the planning, evaluating, and optimizing future wireless communication networks. This paper presents and evaluates the performance of several well-known machine learning methods, including multiple linear regression (MLR), polynomial regression (PR), support vector regression (SVR), as well as the methods using decision trees (DT), random forests (RF), K-nearest neighbors (KNN), artificial neural networks (ANN), and artificial recurrent neural networks (RNN). RNNs are mainly based on long short-term memory (LSTM). The models are compared based on measurement data to provide the best fitting machine-learning-based path loss prediction models. The main results obtained from this study show that the best root-mean-square error (RMSE) performance is given by the ANN and RNN-LSTM methods, while the worst is for the MLR method. All the RMSE values for the given learning techniques are in the range of 0.0216 to 2.9008 dB. Furthermore, this work shows that the models (except for the MLR model) perform excellently in fitting actual measurement data for wireless communications in enclosed indoor environments since they provide R-squared and correlation values higher than 0.91 and 0.96, respectively. The paper shows that these learning methods could be used as accurate and stable models for predicting path loss in the mmWave frequency regime.

Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia.

Decreased erythropoietin (EPO) production, shortened erythrocyte survival, and other factors reducing the response to EPO contribute to anemia in patients who have a variety of underlying pathologies such as chronic kidney disease. Treatment with recombinant human EPO (rHuEPO) at supraphysiologic concentrations has proven to be efficacious. However, it does not ameliorate the condition in all patients, and it presents its own risks, including cardiovascular complications. The transcription factors hypoxia-inducible factor (HIF) 1α and HIF2α control the physiologic response to hypoxia and invoke a program of increased erythropoiesis. Levels of HIFα are modulated by oxygen tension via the action of a family of HIF-prolyl hydroxylases (PHDs), which tag HIFα for proteasomal degradation. Inhibition of these PHDs simulates conditions of mild hypoxia, leading to a potentially more physiologic erythropoietic response and presenting a potential alternative to high doses of rHuEPO. Here we describe the discovery and characterization of GSK1278863 [2-(1,3-dicyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamido) acetic acid], a pyrimidinetrione-glycinamide low nanomolar inhibitor of PHDs 1-3 that stabilizes HIFα in cell lines, resulting in the production of increased levels of EPO. In normal mice, a single dose of GSK1278863 induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. GSK1278863 significantly increased reticulocytes and red cell mass parameters in preclinical species after once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile, supporting continued clinical development. GSK1278863 is currently in phase 3 clinical trials for treatment of anemia in patients with chronic kidney disease.

Effects of the Density of Invasive Lantana camara Plants on the Biodiversity of Large and Small Mammals in the Groenkloof Nature Reserve (GNR) in South Africa.

Multi-scale approaches have been used to determine scales at which mammal species are responding to habitat destruction due to invasion, but the impacts of weeds on mammals have not been extensively studied, especially in Africa. Inside the Groenkloof Nature Reserve (GNR), we assessed how mammals are affected by an invasive weed Lantana camara. A series of models were applied to determine the differences in species abundance as well as richness, separated for large and small mammals. When diversity indices were used, an Analysis of Variance (ANOVA) revealed no statistically significant difference between treatments (F5 = 0.233, p = 0.945) for large mammals. The results of a Generalised Linear Mixed Model (GLMM) showed that vegetation type (Wald χ22 = 120.156; p < 0.01) and foraging guilds (Wald χ23 = 76.771; p < 0.01) were significant predictors of large mammal species richness. However, for small mammals, the results of a GLMM showed that only treatment type (Wald χ25 = 10.62; p = 0.050) was a significant predictor of the number of small mammals trapped. In addition, the ANOVA revealed statistically significant differences in species diversity between treatments (F5 = 0.934; p < 0.001) and by season (F1 = 9.122 p = 0.003) for small mammals. The presence of L. camara coupled with other predictors was associated with differences in large mammal abundances and diversity, and differences in how these large mammals were distributed across the landscape. Furthermore, the highest species diversity was found in the spring for small mammals. Therefore, for all the mammals studied, the presence of L. camara negatively affected species abundance, richness, and diversity, as well as how these species were distributed across the invaded and cleared areas.

Path loss modeling based on neural networks and ensemble method for future wireless networks.

In light of the technological advancements that require faster data speeds, there has been an increasing demand for higher frequency bands. Consequently, numerous path loss prediction models have been developed for 5G and beyond communication networks, particularly in the millimeter-wave and subterahertz frequency ranges. Despite these efforts, there is a pressing need for more sophisticated models that offer greater flexibility and accuracy, particularly in challenging environments. These advanced models will help in deploying wireless networks with the guarantee of covering communication environments with optimum quality of service. This paper presents path loss prediction models based on machine learning algorithms, namely artificial neural network (ANN), artificial recurrent neural network (RNN) based on long short-term memory (LSTM), shortly known as RNN-LSTM, and convolutional neural network (CNN). Moreover, an ensemble-method-based neural network path loss model is proposed in this paper. Finally, an extensive performance analysis of the four models is provided regarding prediction accuracy, stability, the contribution of input features, and the time needed to run the model. The data used for training and testing in this study were obtained from measurement campaigns conducted in an indoor corridor setting, covering both line-of-sight and non-line-of-sight communication scenarios. The main result of this study demonstrates that the ensemble-method-based model outperforms the other models (ANN, RNN-LSTM, and CNN) in terms of efficiency and high prediction accuracy, and could be trusted as a promising model for path loss in complex environments at high-frequency bands.

Preischemic targeting of HIF prolyl hydroxylation inhibits fibrosis associated with acute kidney injury.

Acute kidney injury (AKI) due to ischemia is an important contributor to the progression of chronic kidney disease (CKD). Key mediators of cellular adaptation to hypoxia are oxygen-sensitive hypoxia-inducible factors (HIF), which are regulated by prolyl-4-hydroxylase domain (PHD)-containing dioxygenases. While activation of HIF protects from ischemic cell death, HIF has been shown to promote fibrosis in experimental models of CKD. The impact of HIF activation on AKI-induced fibrosis has not been defined. Here, we investigated the role of pharmacologic HIF activation in AKI-associated fibrosis and inflammation. We found that pharmacologic inhibition of HIF prolyl hydroxylation before AKI ameliorated fibrosis and prevented anemia, while inhibition of HIF prolyl hydroxylation in the early recovery phase of AKI did not affect short- or long-term clinical outcome. Therefore, preischemic targeting of the PHD/HIF pathway represents an effective therapeutic strategy for the prevention of CKD resulting from AKI, and it warrants further investigation in clinical trials.

Stable isotope series from elephant ivory reveal lifetime histories of a true dietary generalist.

Longitudinal studies have revealed how variation in resource use within consumer populations can impact their dynamics and functional significance in communities. Here, we investigate multi-decadal diet variations within individuals of a keystone megaherbivore species, the African elephant (Loxodonta africana), using serial stable isotope analysis of tusks from the Kruger National Park, South Africa. These records, representing the longest continuous diet histories documented for any extant species, reveal extensive seasonal and annual variations in isotopic--and hence dietary--niches of individuals, but little variation between them. Lack of niche distinction across individuals contrasts several recent studies, which found relatively high levels of individual niche specialization in various taxa. Our result is consistent with theory that individual mammal herbivores are nutritionally constrained to maintain broad diet niches. Individual diet specialization would also be a costly strategy for large-bodied taxa foraging over wide areas in spatio-temporally heterogeneous environments. High levels of within-individual diet variability occurred within and across seasons, and persisted despite an overall increase in inferred C(4) grass consumption through the twentieth century. We suggest that switching between C(3) browsing and C(4) grazing over extended time scales facilitates elephant survival through environmental change, and could even allow recovery of overused resources.

Landscape-scale feeding patterns of African elephant inferred from carbon isotope analysis of feces.

The African elephant (Loxodonta africana) is a large-bodied, generalist herbivore that eats both browse and grass. The proportions of browse and grass consumed are largely expected to reflect the relative availability of these resources. We investigated variations in browse (C(3) biomass) and grass (C(4)) intake of the African elephant across seasons and habitats by stable carbon isotope analysis of elephant feces collected from Kruger National Park, South Africa. The results reflect a shift in diet from higher C(4) grass intake during wet season months to more C(3) browse-dominated diets in the dry season. Seasonal trends were correlated with changes in rainfall and with nitrogen (%N) content of available grasses, supporting predictions that grass is favored when its availability and nutritional value increase. However, switches to dry season browsing were significantly smaller in woodland and grassland habitats where tree communities are dominated by mopane (Colophospermum mopane), suggesting that grasses were favored here even in the dry season. Regional differences in diet did not reflect differences in grass biomass, tree density, or canopy cover. There was a consistent relationship between %C(4) intake and tree species diversity, implying that extensive browsing is avoided in habitats characterized by low tree species diversity and strong dominance patterns, i.e., mopane-dominated habitats. Although mopane is known to be a preferred species, maintaining dietary diversity appears to be a constraint to elephants, which they can overcome by supplementing their diets with less abundant resources (dry season grass). Such variations in feeding behavior likely influence the degree of impact on plant communities and can therefore provide key information for managing elephants over large, spatially diverse, areas.

Determining the effects of wind-aided midge movement on the outbreak and coexistence of multiple bluetongue virus serotypes in patchy environments.

Bluetongue virus (BTV) has 27 serotypes with some of them coexisting in different environments which make its control difficult. Wind-aided midge movement is a known mechanism in the spread of BTV. However, its effects on the dynamics of multiple BTV serotypes are not clear. Ordinary differential equation (ODE) and continuous-time Markov chain (CTMC) models for two BTV serotypes in an environment divided into two patches depending on the risk of infection are formulated and analysed. By approximating the CTMC model with a multitype branching process, an estimate for the probability of a major outbreak of two BTV serotypes is obtained. It is shown that without movement a major outbreak occurs in the high-risk patch, but with cattle or midge movement it occurs in both patches. When a major outbreak occurs, numerical simulations of the ODE model illustrate possible coexistence in both patches if the patches are connected by midge or cattle movement. Sensitivity analysis, based on the Latin hypercube sampling method, identified midge mortality and biting rates as being the most important in determining the magnitude of the probability of a major outbreak. These results indicate the significance of wind-aided midge movement on the outbreak and coexistence of multiple BTV serotypes in patchy environments.

Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist.

Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34(+) bone marrow cells into CD41(+) megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production.

Chronic inhibition of hypoxia-inducible factor prolyl 4-hydroxylase improves ventricular performance, remodeling, and vascularity after myocardial infarction in the rat.

BACKGROUND: Hypoxia inducible factors (HIFs) are transcription factors that are regulated by HIF-prolyl 4-hydroxylases (PHDs) in response to changes in oxygen tension. Once activated, HIFs play an important role in angiogenesis, erythropoiesis, proliferation, cell survival, inflammation, and energy metabolism. We hypothesized that GSK360A, a novel orally active HIF-PHD inhibitor, could facilitate local and systemic HIF-1 alpha signaling and protect the failing heart after myocardial infarction (MI). METHODS AND RESULTS: GSK360A is a potent (nanomolar) inhibitor of HIF-PHDs (PHD1>PHD2 = PHD3) capable of activating the HIF-1 alpha pathway in a variety of cell types including neonatal rat ventricular myocytes and H9C2 cells. Male rats treated orally with GSK360A (30 mg x kg x d) had a sustained elevation in circulating levels of erythropoietin and hemoglobin and increased hemoxygenase-1 expression in the heart and skeletal muscle. In a rat model of established heart failure with systolic dysfunction induced by ligation of left anterior descending coronary artery, chronic treatment with GSK360A for 28 days prevented the progressive reduction in ejection fraction, ventricular dilation, and increased lung weight, which were observed in the vehicle-treated animals, for up to 3 months. In addition, the microvascular density in the periinfarct region was increased (>2-fold) in GSK360A-treated animals. Treatment was well tolerated (survival was 89% in the GSK360A group vs. 82% in the placebo group). CONCLUSIONS: Chronic post-myocardial infarction treatment with a selective HIF PHD inhibitor (GSK360A) exerts systemic and local effects by stabilizing HIF-1 alpha signaling and improves long-term ventricular function, remodeling, and vascularity in a model of established ventricular dysfunction. These results suggest that HIF-PHD inhibitors may be suitable for the treatment of post-MI remodeling and heart failure.

Estimating the impact of lock-down, quarantine and sensitization in a COVID-19 outbreak: lessons from the COVID-19 outbreak in China.

In recent history, COVID-19 is one of the worst infectious disease outbreaks currently affecting humanity globally. Using real data on the COVID-19 outbreak from 22 January 2020 to 30 March 2020, we developed a mathematical model to investigate the impact of control measures in reducing the spread of the disease. Analyses of the model were carried out to determine the dynamics. The results of the analyses reveal that, using the data from China, implementing all possible control measures best reduced the rate of secondary infections. However, quarantine (isolation) of infectious individuals is shown to have the most dominant effect. This possibility emphasizes the need for extensive testing due to the possible prevalence of asymptomatic COVID-19 cases.

Synthesis and biological activity of heteroaryl 3-(1,1-dioxo-2H-(1,2,4)-benzothiadizin-3-yl)-4-hydroxy-2(1H)-quinolinone derivatives as hepatitis C virus NS5B polymerase inhibitors.

Modification of the benzo rings of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones into heteroaromatic systems was investigated to enhance physicochemical properties and potency profile of this class of inhibitors. The synthesis and biological activity of the derived compounds is discussed.

Substituted benzothiadizine inhibitors of Hepatitis C virus polymerase.

The synthesis and optimisation of HCV NS5B polymerase inhibitors with improved potency versus the existing compound 1 is described. Substitution in the benzothiadiazine portion of the molecule, furnishing improvement in potency in the high protein Replicon assay, is highlighted, culminating in the discovery of 12h, a highly potent oxyacetamide derivative.

STING Activation and its Application in Immuno-Oncology.

Recent regulatory approval of several immune checkpoint inhibitors has ushered in a new era of cancer immunotherapies with the promise of achieving a durable response. This represents a paradigm shift in cancer treatment from directly targeting tumor cells to harnessing the power of a patient's own immune system to destroy them. The cGAS-STING pathway is the major cytosolic dsDNA sensing pathway that plays a pivotal role in the innate antitumor immune response. With a fundamentally different mode of action (MOA) than immune checkpoint modulators, STING activation can potentially enhance tumor immunogenicity and improve patient responses as a single agent or by synergizing with existing anti-cancer drugs. Therefore, there has been intense interest from the pharmaceutical industry and academic institutions in the search for potent STING agonists as immunotherapies in oncology. In this article, we review briefly the cGAS-STING pathway and STING agonists that are in the clinical and preclinical studies, summarize recently disclosed patent applications and published journal articles in the field and cover both cyclic dinucleotide (CDN) analogs and non-nucleic acid derived STING agonists.

Consumer-resource coexistence as a means of reducing infectious disease.

Maintaining sustainable ecosystems are important for all the inhabitants of earth. Also, an important component of sustainable ecosystems is the maintenance of healthy coexistence of consumers and their resources which can include diseases in the species involved. We formulate a model, where the resources are plants, to explore how consumer-resource coexistence could of itself limit the spread of infectious diseases. The important mathematical features of the model are discussed using the basic reproduction number and the consumption number. The results show an association between species coexistence and a decrease in ecosystem resource disease. The possible importance of these results are discussed.

Novel ATP-competitive kinesin spindle protein inhibitors.

Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during mitosis that is present only in proliferating cells, has become a novel and attractive anticancer target with potential for reduced side effects compared to currently available therapies. We report herein the discovery of the first known ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the known loop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this series led to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferative activity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D130V). In a murine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity following intraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSP inhibitor versus tumors that are resistant to the other known KSP inhibitors.

Global pattern of plant utilization across different organisms: Does plant apparency or plant phylogeny matter?

The present study is the first to consider human and nonhuman consumers together to reveal several general patterns of plant utilization. We provide evidence that at a global scale, plant apparency and phylogenetic isolation can be important predictors of plant utilization and consumer diversity. Using the number of species or genera or the distribution area of each plant family as the island "area" and the minimum phylogenetic distance to common plant families as the island "distance", we fitted presence-area relationships and presence-distance relationships with a binomial GLM (generalized linear model) with a logit link. The presence-absence of consumers among each plant family strongly depended on plant apparency (family size and distribution area); the diversity of consumers increased with plant apparency but decreased with phylogenetic isolation. When consumers extended their host breadth, unapparent plants became more likely to be used. Common uses occurred more often on common plants and their relatives, showing higher host phylogenetic clustering than uncommon uses. On the contrary, highly specialized uses might be related to the rarity of plant chemicals and were therefore very species-specific. In summary, our results provide a global illustration of plant-consumer combinations and reveal several general patterns of plant utilization across humans, insects and microbes. First, plant apparency and plant phylogenetic isolation generally govern plant utilization value, with uncommon and isolated plants suffering fewer parasites. Second, extension of the breadth of utilized hosts helps explain the presence of consumers on unapparent plants. Finally, the phylogenetic clustering structure of host plants is different between common uses and uncommon uses. The strength of such consistent plant utilization patterns across a diverse set of usage types suggests that the persistence and accumulation of consumer diversity and use value for plant species are determined by similar ecological and evolutionary processes.

Quantitative sensory testing measures individual pain responses in emergency department patients.

BACKGROUND: Refining and individualizing treatment of acute pain in the emergency department (ED) is a high priority, given that painful complaints are the most common reasons for ED visits. Few tools exist to objectively measure pain perception in the ED setting. We speculated that variation in perception of fixed painful stimuli would explain individual variation in reported pain and response to treatment among ED patients. MATERIALS AND METHODS: In three studies, we 1) describe performance characteristics of brief quantitative sensory testing (QST) in 50 healthy volunteers, 2) test effects of 10 mg oxycodone versus placebo on QST measures in 18 healthy volunteers, and 3) measure interindividual differences in nociception and treatment responses in 198 ED patients with a painful complaint during ED treatment. QST measures adapted for use in the ED included pressure sensation threshold, pressure pain threshold (PPT), pressure pain response (PPR), and cold pain tolerance (CPT) tests. RESULTS: First, all QST measures had high inter-rater reliability and test-retest reproducibility. Second, 10 mg oxycodone reduced PPR, increased PPT, and prolonged CPT. Third, baseline PPT and PPR revealed hyperalgesia in 31 (16%) ED subjects relative to healthy volunteers. In 173 (88%) ED subjects who completed repeat testing 30 minutes after pain treatment, PPT increased and PPR decreased (Cohen's dz 0.10-0.19). Verbal pain scores (0-10) for the ED complaint decreased by 2.2 (95% confidence intervals [CI]: 1.9, 2.6) (Cohen's dz 0.97) but did not covary with the changes in PPT and PPR (r=0.05-0.13). Treatment effects were greatest in ED subjects with a history of treatment for anxiety or depression (Cohen's dz 0.26-0.43) or with baseline hyperalgesia (Cohen's dz 0.40-0.88). CONCLUSION: QST reveals individual differences in perception of fixed painful stimuli in ED patients, including hyperalgesia. Subgroups of ED patients with hyperalgesia and psychiatric history report larger treatment effects on ED pain and QST measures.