Miracle-dz/UniFAR-FTUs huggingface dataset:
Synergistic Lethality of a Binary Inhibitor of Mycobacterium tuberculosis KasA

Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars. ABSTRACT We report GSK3011724A (DG167) as a binary inhibitor of β-ketoacyl-ACP synthase (KasA) in Mycobacterium tuberculosis. Genetic and biochemical studies established KasA as the primary target. The X-ray crystal structure of the KasA-DG167 complex refined to 2.0-Å resolution revealed two interacting DG167 molecules occupying nonidentical sites in the substrate-binding channel of KasA. The binding affinities of KasA to DG167 and its analog, 5g, which binds only once in the substrate-binding channel, were determined, along with the KasA-5g X-ray crystal structure. DG167 strongly augmented the in vitro activity of isoniazid (INH), leading to synergistic lethality, and also synergized in an acute mouse model of M. tuberculosis infection. Synergistic lethality correlated with a unique transcriptional signature, including upregulation of oxidoreductases and downregulation of molecular chaperones. The lead structure-activity relationships (SAR), pharmacokinetic profile, and detailed interactions with the KasA protein that we describe may be applied to evolve a next-generation therapeutic strategy for tuberculosis (TB). IMPORTANCE Cell wall biosynthesis inhibitors have proven highly effective for treating tuberculosis (TB). We discovered and validated members of the indazole sulfonamide class of small molecules as inhibitors of Mycobacterium tuberculosis KasA—a key component for biosynthesis of the mycolic acid layer of the bacterium’s cell wall and the same pathway as that inhibited by the first-line antitubercular drug isoniazid (INH). One lead compound, DG167, demonstrated synergistic lethality in combination with INH and a transcriptional pattern consistent with bactericidality and loss of persisters. Our results also detail a novel dual-binding mechanism for this compound as well as substantial structure-activity relationships (SAR) that may help in lead optimization activities. Together, these results suggest that KasA inhibition, specifically, that shown by the DG167 series, may be developed into a potent therapy that can synergize with existing antituberculars.
An effective dendritic cell‐based vaccine containing glioma stem‐like cell lysate and CpG adjuvant for an orthotopic mouse model of glioma

Owing to the limited therapeutic efficacy of glioma vaccines, new strategies are required to improve cancer vaccines. Our study aimed to assess the therapeutic efficacy of a glioma vaccine called STDENVANT. This vaccine, comprising glioma stem‐like cell (GSC) lysate, dendritic cells (DCs), and Toll‐like receptor (TLR) 9 agonist CpG motif‐containing oligodeoxynucleotides (CpG ODNs), was assessed using a GL261‐C57BL/6 orthotopic mouse model of glioma. STDENVANT markedly improved survival and tumor regression by enhancing anti‐tumor immune function. Moreover, STDENVANT upregulated programmed death 1 (PD‐1) and its ligand PD‐L1 on effector T cells, DCs, and glioma tissues, resulting in the accumulation of regulatory T (Treg) cells in the brain and lymph nodes. Combinatorial administration of anti‐PD‐L1 antibody and STDENVANT conferred a greater survival advantage and decreased the Treg cell population in the brain. The present results indicate that PD‐L1 blockade can promote tumor regression via STDENVANT in a mouse model of glioma, and combinatorial administration of anti‐PD‐L1 antibody and STDENVANT increases the therapeutic anti‐tumor efficacy of treatment.
Can we use human odors to diagnose malaria?

After declining steadily during the early part of the twenty-first century, the worldwide incidence of malaria has recently reached a plateau [1]. Further progress toward the eradication of this devastating disease will likely require overcoming a number of serious challenges, including a need for improved methods of detecting asymptomatic infections, which currently often go undetected and untreated. Infected individuals who do not present symptoms remain capable of transmitting malaria parasites and in fact may account for 20–50% of onward transmission [1,2]. Identifying and treating these asymptomatic individuals is therefore a key goal for eradication efforts, but currently available methods for diagnostic screening of human populations, including microscopy and antibody-based rapid diagnostic tests (RDTs), have significant limitations. A significant proportion of asymptomatic malaria cases are caused by incipient or otherwise low-level infections that are not readily detectable via microscopy [3]. RDTs may produce high rates of false negatives for these submicroscopic infections [4] and can also be unreliable for the detection of parasite species other than Plasmodium falciparum [5]. Furthermore, widely used RDTs based on the detection of PfHRP-2 are exhibiting increasing rates of false negatives for P. falciparum in some regions of Africa, India and Peru due to parasite gene deletions [5,6], raising concerns about the evolution of diagnostic resistance. A further drawback of both RDTs and microscopy-based detection methods is the need to collect blood droplets for testing, which can pose health risks in areas where blood-borne infections, such as HIV, are widespread [5]. These and other limitations of existing diagnostic methods have led to calls for the development of new detection methods that are reliable and noninvasive, and which can be easily and affordably deployed for screening of human populations [5]. Volatile compounds are an under-explored class of potential diagnostic biomarkers that could conceivably be employed for population screening to detect malarial infection. It is possible, for example, to envision the development of an easy-to-use portable device for detecting malaria-specific biomarkers that could be readily deployed in areas with limited medical infrastructure. Recently, several studies have explored the ability to detect human malaria infections via volatiles from the skin and breath, and their results suggest that volatile biomarkers may hold significant potential for the reliable detection of infected people, including those with asymptomatic infections. These promising results make a volatile diagnostic for malaria a realistic option, particularly with regard to population-wide diagnostic screening and monitoring aimed at malaria eradication.
Derivation and validation of a clinical prediction rule for sleep apnoea syndrome for use in primary care

Background Several clinical prediction rules (CPRs) are available for sleep apnoea-hypopnoea syndrome (OSAH), but they are difficult to apply in primary care (PC). Aim Derivation and validation of a CPR using simple measurements available in PC. Design & setting A prospective study conducted in health centres from the area of influence of three Spanish hospitals. Method Patients (aged 18–70 years) who attended for any reason; who presented with at least one of the three key symptoms for OSAH (snoring, breathing pauses while sleeping, and daytime sleepiness); and who were not undergoing non-invasive ventilation or prior treatment with continuous positive airway pressure (CPAP) were included. Anthropometric data, smoking habit, comorbidities, and Epworth test were collected. Patients were subsequently referred to the sleep unit (SU), where the decision was taken whether or not to instigate treatment. A multivariate logistic model was constructed using a sub-sample and scores assigned based on the regression coefficients; the CPR was validated with the remaining sample. Both receiver operating characteristic (ROC) curves were plotted and the sensitivity, specificity, and predictive values calculated. Results The derivation sample comprised 352 patients, with 260 in the validation sample. The final factors (arterial hypertension [AHT], age, body mass index [BMI], and sex) were used to develop a rule with scores ranging from 0.00–5.50. The cut-off point that optimises the area under the curve (AUC) is ≥2.50 points (AUC = 0.78; sensitivity = 86%; specificity = 54%; positive predictive value [PPV] = 45%; negative predictive value [NPV] = 90%; likelihood ratio [LR] = 0.26). The properties for the validation sample with this cut-off point are as follows: AUC = 0.68; sensitivity = 81%; specificity = 43%; PPV = 61%; NPV = 68%; LR = 0.44. Conclusion As in similar cases, the specificity is low, meaning that healthy people are referred to a specialist. A negative result rules out the disease in most cases.
Papillary renal cell carcinoma in contrast-enhanced ultrasound (CEUS) - A diagnostic performance study.

BACKGROUND Renal cell carcinomas (RCC) represent a heterogeneous group of hypo- and hypervascularized malignancies. Using contrast-enhanced ultrasound (CEUS) specific imaging features of clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC) subtypes have been demonstrated. However, some RCCs show atypical imaging features making it difficult to distinguish between the subtypes. OBJECTIVE This study was performed to evaluate the observed enhancement features of pRCC in CEUS and to assess the sensitivity in the diagnosis of suspected renal malignancies in a 10 year retrospective analysis at our institution. METHODS The study population consisted of 60 patients with histologically confirmed pRCC. All patients underwent CEUS imaging between 2005 and 2015 as part of their diagnostic workup. RESULTS In 45 out of 60 (75%) cases the examined pRCC showed typical hypoenhancement and wash-out. 15 out of 60 (25%) pRCC showed atypical enhancement features; in 14 cases the contrast enhancement indicated a ccRCC. 1 complex cyst was falsely reported as IIF lesion. 59 out of 60 malignancies were reported as malignant using CEUS resulting in a sensitivity of 98.4%. CONCLUSIONS CEUS is an eligible imaging technique to visualize the contrast enhancement features of pRCC. However, up to 25% of pRCCs show an atypical enhancement pattern making it difficult to distinguish it from other renal lesions.
Performance of Single-Nucleotide Polymorphisms in Breast Cancer Risk Prediction Models: A Systematic Review and Meta-analysis

Background: SNP risk information can potentially improve the accuracy of breast cancer risk prediction. We aim to review and assess the performance of SNP-enhanced risk prediction models. Methods: Studies that reported area under the ROC curve (AUC) and/or net reclassification improvement (NRI) for both traditional and SNP-enhanced risk models were identified. Meta-analyses were conducted to compare across all models and within similar baseline risk models. Results: Twenty-six of 406 studies were included. Pooled estimate of AUC improvement is 0.044 [95% confidence interval (CI), 0.038–0.049] for all 38 models, while estimates by baseline models ranged from 0.033 (95% CI, 0.025–0.041) for BCRAT to 0.053 (95% CI, 0.018–0.087) for partial BCRAT. There was no observable trend between AUC improvement and number of SNPs. One study found that the NRI was significantly larger when only intermediate-risk women were included. Two other studies showed that majority of the risk reclassification occurred in intermediate-risk women. Conclusions: Addition of SNP risk information may be more beneficial for women with intermediate risk. Impact: Screening could be a two-step process where a questionnaire is first used to identify intermediate-risk individuals, followed by SNP testing for these women only.
Factors influencing recruitment and appearance of bull kelp, Nereocystis luetkeana (phylum Ochrophyta)

The dynamics of annual species are strongly tied to their capacity for recruitment each year. We examined how competition and propagule availability influence recruitment and appearance and tracked survivorship of an annual species of marine macroalgae, the bull kelp (Nereocystis luetkeana), which serves as major biogenic habitat in the Salish Sea of Washington State. We hypothesized that (i) juvenile N. luetkeana would exhibit a seasonal appearance as a cohort in the spring and (ii) competition for space would be more limiting than propagules (spores) to recruitment at sites adjacent to established N. luetkeana beds. We tagged N. luetkeana recruits in the field to track appearance and survivorship across seasons (spring, summer, fall, and winter), using a two‐factor crossed design to assess effects of competition and propagule availability on appearance of new N. luetkeana sporophytes. Survivorship of N. luetkeana recruits was low and, whereas most new individuals arose in the spring, some appeared in every season. New N. luetkeana recruits also appeared the earliest (median 8 weeks vs. >20 weeks) after experimental “seeding” in the spring as compared to other seasons. Eliminating macroalgal competitors (“clearing”) influenced the appearance of recruits more than enhancement of propagules in the spring. An improved understanding of factors regulating the seasonal appearance of new N. luetkeana sporophytes furthers our understanding of this crucial foundation species' appearance and persistence across seasons, which is increasingly important as global ocean conditions change, and highlights the importance of studying organisms with complex life histories across multiple stages and geographical regions.
Phylogenetic Comparative Methods can Provide Important Insights into the Evolution of Toxic Weaponry

The literature on chemical weaponry of organisms is vast and provides a rich understanding of the composition and mechanisms of the toxins and other components involved. However, an ecological or evolutionary perspective has often been lacking and is largely limited to (1) molecular evolutionary studies of particular toxins (lacking an ecological view); (2) comparisons across different species that ignore phylogenetic relatedness (lacking an evolutionary view); or (3) descriptive studies of venom composition and toxicology that contain post hoc and untested ecological or evolutionary interpretations (a common event but essentially uninformative speculation). Conveniently, comparative biologists have prolifically been developing and using a wide range of phylogenetic comparative methods that allow us to explicitly address many ecological and evolutionary questions relating to venoms and poisons. Nevertheless, these analytical tools and approaches are rarely used and poorly known by biological toxinologists and toxicologists. In this review I aim to (1) introduce phylogenetic comparative methods to the latter audience; (2) highlight the range of questions that can be addressed using them; and (3) encourage biological toxinologists and toxicologists to either seek out adequate training in comparative biology or seek collaboration with comparative biologists to reap the fruits of a powerful interdisciplinary approach to the field.
Comorbidity of Symptoms of Alcohol and Cannabis Use Disorders among a Population-Based Sample of Simultaneous Users. Insight from a Network Perspective

Research into comorbidity of alcohol and cannabis use disorders has resulted in inconsistent findings, especially among simultaneous users, who used alcohol and cannabis together on a single occasion. This study investigated the association of alcohol and cannabis use disorders among simultaneous users using a network perspective, which considers direct relationships between symptoms. We used a subset of simultaneous alcohol and cannabis users driven from the representative population-based sample of young Swiss men cohort study on substance use risk factors (C-SURF) (n = 1559 at baseline and n = 991 at follow-up). Self-reported symptoms of alcohol and cannabis use disorders were collected. Network analyses included network estimation, visualization, and community detection tests. Alcohol and cannabis use symptoms were separated in two distinct clusters, with few paths between them (eleven positive edges at baseline, three at follow-up). Withdrawal symptoms were likely to connect the two disorders at baseline, but not at follow-up. Alcohol and cannabis use disorders appeared as separate disorders among simultaneous users. Our findings mitigated previous findings on the detrimental association between alcohol and cannabis use. Future studies should incorporate network analyses as a means to study comorbidity in other community and clinical samples to confirm our preliminary findings.
An Environmentally-Adaptive Positioning Method Based on Integration of GPS/DTMB/FM

The Global Positioning System (GPS) yields good precision and availability in open outdoor environment. However, the errors of GPS may suffer degradation in some complex environments, such as forests and urban canyons. To solve this problem, a new positioning method is designed integrating GPS, Digital Terrestrial Multimedia Broadcast (DTMB) and frequency-modulated (FM) radio signal. In this method, the DTMB transmitter acts as a pseudo-satellite to assist GPS positioning. Furthermore, the FM fingerprint positioning is used to correct the positioning bias. An adaptive selection scheme is proposed to provide an optimal integration mode of the sensors. Field experiments in complex environment were carried out for evaluation. Comparing to the GPS-only and GPS + DTMB approach, positioning accuracy was improved by at least 68.21% and 21.27% with the proposed method, respectively.
A Novel Connectivity-Based LEACH-MEEC Routing Protocol for Mobile Wireless Sensor Network

In mobile wireless sensor network (MWSN), the lifetime of the network largely depends on energy efficient routing protocol. In the literature, cluster leader (CL) is selected based on remaining energy of mobile sensor nodes to enhance sensor network lifetime. In this study, a novel connectivity-based Low-Energy Adaptive Clustering Hierarchy-Mobile Energy Efficient and Connected (LEACH-MEEC) routing protocol was proposed, where CL is selected based on connectivity among neighboring nodes and the remaining energy of mobile sensor nodes. Consequently, it improves data delivery, network lifetime and balances the energy consumption. We studied various performance metrics including the number of alive nodes (NAN), remaining energy (RE) and packet delivery ratio (PDR). Our proposed LEACH-MEEC outperforms all other algorithms due to the connectivity metric. Moreover, the performance of mobility models was investigated through graphical and statistically tabulated results. The results show that Reference Point Group Mobility model (RPGM) is better than other mobility models.
Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis

Rationale: The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. Objectives: To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. Methods: We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using in situ RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. Measurements and Main Results: We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. Conclusions: We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.
Noncontrast MR angiography: An update

Both computed tomography (CT) angiography (CTA) and contrast‐enhanced MR angiography (CEMRA) have proven to be useful and accurate cross‐sectional imaging modalities over a wide range of vascular territories and vascular disorders. A key advantage of MRA is that, unlike CTA, it can be performed without the administration of a contrast agent. In this review article we consider the motivations for using noncontrast MRA, potential contrast mechanisms, imaging techniques, advantages, and drawbacks with respect to CTA and CEMRA, and the level of evidence for using the various MRA techniques. In addition, we explore new developments that promise to expand the reliability and range of clinical applications for noncontrast MRA, along with functional MRA capabilities not available with CTA or CEMRA.
Arylsulfonamide 64B Inhibits Hypoxia/HIF-Induced Expression of c-Met and CXCR4 and Reduces Primary Tumor Growth and Metastasis of Uveal Melanoma

Purpose: Uveal melanoma (UM) is the most prevalent and lethal intraocular malignancy in adults. Here, we examined the importance of hypoxia in UM growth and tested the antitumor effects of arylsulfonamide 64B, an inhibitor of the hypoxia-induced factor (HIF) pathway in animal models of UM and investigated the related mechanisms. Experimental Design: UM cells were implanted in the uvea of mice eyes and mice systemically treated with 64B. Drug effect on primary eye tumor growth, circulating tumor cells, metastasis formation in liver, and survival were examined. 64B effects on UM cell growth, invasion and hypoxia-induced expression of C-X-C chemokine receptor type 4 (CXCR4) and mesenchymal–epithelial transition factor (c-Met) were measured. Luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and cellular thermal shift assays were used to determine how 64B interferes with the HIF transcriptional complex. Results: Systemic administration of 64B had potent antitumor effects against UM in several orthotopic mouse models, suppressing UM growth in the eye (∼70% reduction) and spontaneous liver metastasis (∼50% reduction), and extending mice survival (P < 0.001) while being well tolerated. 64B inhibited hypoxia-induced expression of CXCR4 and c-Met, 2 key drivers of tumor invasion and metastasis. 64B disrupted the HIF-1 complex by interfering with HIF-1α binding to p300/CBP co-factors, thus reducing p300 recruitment to the MET and CXCR4 gene promoters. 64B could thermostabilize p300, supporting direct 64B binding to p300. Conclusions: Our preclinical efficacy studies support the further optimization of the 64B chemical scaffold toward a clinical candidate for the treatment of UM.