bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strain Prioritization and Genome Mining for Enediyne Natural Products
Authors: Yan Xiaohui , Ge Huiming , Huang Tingting , Hindra  , Yang Dong , Teng Qihui , Crnovčić Ivana , Li Xiuling , Rudolf Jeffrey D. , Lohman Jeremy R. , Gansemans Yannick , Zhu Xiangcheng , Huang Yong , Zhao Li-Xing , Jiang Yi , Van Nieuwerburgh Filip , Rader Christoph , Duan Yanwen , Shen Ben 
Published: December 2016

ABSTRACT
The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection.

IMPORTANCE
Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family.
Epidemiology and Host Factors
Authors: Mehta Jay B. , Dutt Asim K. 
Published: December 2016

ABSTRACTIn 2014, WHO reported approximately 9.6 million new cases of tuberculosis (TB) in the world, more than half of which are contributed by developing countries in Asia and Africa. Lack of modern diagnostic tools, underreporting of the new cases and underutilization of directly observed therapy (DOT) remain a concern in developing countries. Transient resurgence of TB during the HIV epidemic has subsided and the annual decline has resumed in developed countries including the USA. In 2014 though, the rate of decline has slowed down resulting in leveling of TB incidence in the USA. In developed countries like the USA, the incidence of TB remains high in those with certain risk factors for TB. This group includes immunocompromised patients, particularly those with positive HIV infection. Others at high risk include those with diabetes, cancer, those taking immunosuppressive drugs, and those with other medical conditions that reduce host immunity. If we look at age and ethnicity, elderly patients are at higher risk of developing TB. African-American, foreign-born, and homeless populations are also at higher risk of developing tuberculosis. Virulence of the mycobacteria, and immunological and genetically mediated factors are also mentioned, but these topics are not the primary goal of this article. This review, thus discusses the epidemiology, host factors, and those at high risk for developing active TB. A brief review of the current trends in drug resistance of mycobacteria is also presented.
Diabetes and Tuberculosis
Authors: Restrepo Blanca I. 
Published: December 2016

ABSTRACTThe increase in type 2 diabetes mellitus (DM) patients in countries where tuberculosis (TB) is also endemic has led to the reemerging importance of DM as a risk factor for TB. DM causes a 3-fold increase in TB risk and a 2-fold increase in adverse TB treatment outcomes. Given the sheer numbers of DM patients worldwide, there are now more TB patients with TB-DM comorbidity than TB-HIV coinfection. There is an urgent need to implement strategies for TB prevention and control among the millions of DM patients exposed toMycobacterium tuberculosis. This chapter summarizes the current epidemiological, clinical, and immunological knowledge on TB and DM and their clinical and public health implications. These include the underlying mechanisms for TB risk in DM patients and their clinical and sociodemographic characteristics that distinguish them from TB patients without DM. TB-DM comorbidity is posing a new challenge for integrating the short-term care for TB with the long-term care for DM, particularly in low- and middle-income countries.
Biologic Agents and Tuberculosis
Authors: Dobler Claudia C. 
Published: December 2016

ABSTRACT
Treatment with biologic agents, in particular tumor necrosis factor alpha (TNF-α) inhibitors, is associated with an increased risk of tuberculosis (TB), and screening and treatment for latent TB infection (LTBI) in patients undergoing such treatment is therefore indicated. The risk of TB associated with different biologics varies significantly, with the highest relative risks, 29.3 and 18.6, associated with adalimumab and infliximab, respectively. The risk of TB with newer TNF-α inhibitors and other biologics appears to be lower. Performance of LTBI screening tests is affected by immune-mediated inflammatory diseases and immunosuppressive therapy in patients due to commence TNF-α inhibitor treatment. Interferon gamma release assays (IGRAs) have a higher specificity than the tuberculin skin test (TST) in patients with Bacillus Calmette–Guérin (BCG) vaccination and have probably a better sensitivity than TST in immunosuppressed patients. LTBI screening programs prior to commencement of anti-TNF-α treatment significantly reduce the incidence of TB, but the optimal screening algorithm, in particular the question of whether a combination of IGRA and TST or a single test only should be used, is a matter of ongoing debate. Use of TST in combination with IGRA is justified to increase sensitivity. Repeat testing for LTBI should be limited to patients at increased risk of TB. If TB develops during anti-TNF-α treatment, it is more likely to be disseminated and extrapulmonary than are other TB cases. Discontinuation of anti-TNF-α treatment in patients diagnosed with TB is associated with an increased risk of immune reconstitution inflammatory syndrome, which is probably best managed by reintroduction of anti-TNF-α treatment.
Electronic and magnetic properties of monolayer MnS2
Authors: Yue Yunliang 
Published: December 2016

First-principles calculations are performed to study the electronic and magnetic properties of monolayer MnS2. Based on the electronic structure, a half-metallic state is predicted for monolayer MnS2. The magnetic moment is 3.0 [Formula: see text] per formula unit, and the main contribution is localized at the transition metal site Mn with a local moment of 3.733 [Formula: see text]. The magnetic anisotropy energy (MAE) is 0.056 meV per formula unit with an easy axis perpendicular to the plane, and it indicates that monolayer MnS2 belongs to the category of Ising magnets. The positive MAE of nanosheets mainly stems from the area around [Formula: see text] in the reciprocal space. To find the microscopic origin, we take the method of the second-order spin orbit coupling. The occupied spin-up dz2 state and the unoccupied spin-down dyz states in the [Formula: see text] point through the [Formula: see text] operator make positive contributions to the MAE.
Water and the city of Milan at the end of the nineteenth century
Authors: Porro Alessandro , Franchini Antonia Francesca , Falconi Bruno , Galimberti Paolo Maria , Lorusso Lorenzo 
Published: December 2016

Abstract
Since the Middle Ages Milan obtained its water supply satisfactorily from shallow wells. Significant problems developed during the nineteenth century, however, prompting the Lombard Institute to announce the Cagnola Award for a three-year study project to analyse the water both chemically and physically and to remedy the problem of pollution. The award was made to Angelo Pavesi (1830–96), a chemist, and Ermenegildo Rotondi (1845–1915), a civil engineer. They concluded that cemetery wastewater should be prevented from entering the city and that the number of deep artesian wells should be increased. Some years later, another problem regarding hygiene and water supply arose and it seemed doubtful whether the principal hospital of the city could fulfil the new hygiene requirements. Pietro Canetta (1836–1903) studied the records of the main hospital's water supply and disposal from 1457, demonstrating that it could be regarded as a model for the supply of good-quality water and for wastewater disposal without polluting the city. Since 1906 all of Milan's drinking water has been derived from groundwater; untreated wastewater continued to be discharged into rivers until 2004 but since then all water has been treated.
The role of sympathetic and vagal cardiac control on complexity of heart rate dynamics
Authors: Silva Luiz Eduardo Virgilio , Silva Carlos Alberto Aguiar , Salgado Helio Cesar , Fazan Rubens 
Published: December 2016

Analysis of heart rate variability (HRV) by nonlinear approaches has been gaining interest due to their ability to extract additional information from heart rate (HR) dynamics that are not detectable by traditional approaches. Nevertheless, the physiological interpretation of nonlinear approaches remains unclear. Therefore, we propose long-term (60 min) protocols involving selective blockade of cardiac autonomic receptors to investigate the contribution of sympathetic and parasympathetic function upon nonlinear dynamics of HRV. Conscious male Wistar rats had their electrocardiogram (ECG) recorded under three distinct conditions: basal, selective (atenolol or atropine), or combined (atenolol plus atropine) pharmacological blockade of autonomic muscarinic or β1-adrenergic receptors. Time series of RR interval were assessed by multiscale entropy (MSE) and detrended fluctuation analysis (DFA). Entropy over short (1 to 5, MSE1–5) and long (6 to 30, MSE6–30) time scales was computed, as well as DFA scaling exponents at short (αshort, 5 ≤ n ≤ 15), mid (αmid, 30 ≤ n ≤ 200), and long (αlong, 200 ≤ n ≤ 1,700) window sizes. The results show that MSE1–5 is reduced under atropine blockade and MSE6–30 is reduced under atropine, atenolol, or combined blockade. In addition, while atropine expressed its maximal effect at scale six, the effect of atenolol on MSE increased with scale. For DFA, αshort decreased during atenolol blockade, while the αmid increased under atropine blockade. Double blockade decreased αshort and increased αlong. Results with surrogate data show that the dynamics during combined blockade is not random. In summary, sympathetic and vagal control differently affect entropy (MSE) and fractal properties (DFA) of HRV. These findings are important to guide future studies. NEW & NOTEWORTHY Although multiscale entropy (MSE) and detrended fluctuation analysis (DFA) are recognizably useful prognostic/diagnostic methods, their physiological interpretation remains unclear. The present study clarifies the effect of the cardiac autonomic control on MSE and DFA, assessed during long periods (1 h). These findings are important to help the interpretation of future studies.
Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure
Authors: Kaimoto Satoshi , Hoshino Atsushi , Ariyoshi Makoto , Okawa Yoshifumi , Tateishi Shuhei , Ono Kazunori , Uchihashi Motoki , Fukai Kuniyoshi , Iwai-Kanai Eri , Matoba Satoaki 
Published: December 2016

Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor α (PPAR-α) is a key regulator of this substrate shift. However, its role during heart failure is complex and remains unclear. Recent studies reported that heart failure develops in the heart of myosin heavy chain-PPAR-α transgenic mice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPAR-α knockout mice in response to chronic pressure overload. We created a pressure-overload heart failure model in mice through transverse aortic constriction (TAC) and activated PPAR-α during heart failure using an inducible transgenic model. After 8 wk of TAC, left ventricular (LV) function had decreased with the reduction of PPAR-α expression in wild-type mice. We examined the effect of PPAR-α induction during heart failure using the Tet-Off system. Eight weeks after the TAC operation, LV construction was preserved significantly by PPAR-α induction with an increase in PPAR-α-targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPAR-α induction. Metabolic rates measured by isolated heart perfusions showed a reduction in FAO and glucose oxidation in TAC hearts, but the rate of FAO preserved significantly owing to the induction of PPAR-α. Myocardial high-energy phosphates were significantly preserved by PPAR-α induction. These results suggest that PPAR-α activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus activating PPAR-α and modulation of FAO could be a promising therapeutic strategy for heart failure. NEW & NOTEWORTHY The present study demonstrates the role of PPAR-α activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-α preserved heart function, and myocardial energetics. Activating PPAR-α and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure.
Maternal-engineered nanomaterial exposure disrupts progeny cardiac function and bioenergetics
Authors: Hathaway Quincy A. , Nichols Cody E. , Shepherd Danielle L. , Stapleton Phoebe A. , McLaughlin Sarah L. , Stricker Janelle C. , Rellick Stephanie L. , Pinti Mark V. , Abukabda Alaeddin B. , McBride Carroll R. , Yi Jinghai , Stine Seth M. , Nurkiewicz Timothy R. , Hollander John M. 
Published: December 2016

Nanomaterial production is expanding as new industrial and consumer applications are introduced. Nevertheless, the impacts of exposure to these compounds are not fully realized. The present study was designed to determine whether gestational nano-sized titanium dioxide exposure impacts cardiac and metabolic function of developing progeny. Pregnant Sprague-Dawley rats were exposed to nano-aerosols (~10 mg/m3, 130- to 150-nm count median aerodynamic diameter) for 7–8 nonconsecutive days, beginning at gestational day 5–6. Physiological and bioenergetic effects on heart function and cardiomyocytes across three time points, fetal (gestational day 20), neonatal (4–10 days), and young adult (6–12 wk), were evaluated. Functional analysis utilizing echocardiography, speckle-tracking based strain, and cardiomyocyte contractility, coupled with mitochondrial energetics, revealed effects of nano-exposure. Maternal exposed progeny demonstrated a decrease in E- and A-wave velocities, with a 15% higher E-to-A ratio than controls. Myocytes isolated from exposed animals exhibited ~30% decrease in total contractility, departure velocity, and area of contraction. Bioenergetic analysis revealed a significant increase in proton leak across all ages, accompanied by decreases in metabolic function, including basal respiration, maximal respiration, and spare capacity. Finally, electron transport chain complex I and IV activities were negatively impacted in the exposed group, which may be linked to a metabolic shift. Molecular data suggest that an increase in fatty acid metabolism, uncoupling, and cellular stress proteins may be associated with functional deficits of the heart. In conclusion, gestational nano-exposure significantly impairs the functional capabilities of the heart through cardiomyocyte impairment, which is associated with mitochondrial dysfunction. NEW & NOTEWORTHY Cardiac function is evaluated, for the first time, in progeny following maternal nanomaterial inhalation. The findings indicate that exposure to nano-sized titanium dioxide (nano-TiO2) during gestation negatively impacts cardiac function and mitochondrial respiration and bioenergetics. We conclude that maternal nano-TiO2 inhalation contributes to adverse cardiovascular health effects, lasting into adulthood. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/gestational-nanomaterial-exposure-and-cardiac-dysfunction/ .
B-type natriuretic peptide increases cortisol and catecholamine concentrations in healthy subjects
Authors: Grimm Gabriele , Resl Michael , Heinisch Birgit B. , Hülsmann Martin , Luger Anton , Clodi Martin , Vila Greisa 
Published: December 2016

B-type natriuretic peptide (BNP) is a hormone released by the heart in response to volume load and exerts natriuretic properties. It is clinically used as a diagnostic and prognostic biomarker and investigated as a pharmacological agent in the therapy of heart failure. Here we investigate the changes in pituitary, adrenal, and thyroid hormones in response to BNP administration in a randomized single-blinded crossover study conducted in ten healthy men aged 21–29 yr. Participants received in two study sessions a continuous intravenous infusion during 4 h (once placebo and once 3 pmol·kg−1·min−1 BNP) and remained in supine position throughout the study. Circulating concentrations of pituitary, adrenal, and thyroid hormones, heart rate, and blood pressure were measured at baseline and hourly afterwards. BNP prevented the physiological decrease in cortisol during the late morning hours leading to elevated serum cortisol levels ( P = 0.022) and increased circulating epinephrine and norepinephrine concentrations ( P = 0.018 and P = 0.036, respectively). These hormone changes were accompanied by an increase in heart rate ( P = 0.019) but no differences in blood pressure. Taken together, the impact of BNP on the endocrine system extends beyond the well-known inhibition of the renin-angiotensin-aldosterone system and includes increased adrenergic activity and cortisol concentrations. This neuroendocrine activation might impact the outcome of therapeutical BNP administrations and should be further investigated in conditions associated with increased BNP secretion. NEW & NOTEWORTHY The heart hormone B-type natriuretic peptide (BNP) is increased in patients with heart failure, where it is thought to have beneficial effects by reducing the preload. Here we report that intravenous administration of BNP in men leads to increases in adrenal hormones cortisol, epinephrine, and norepinephrine. Cortisol and catecholamine levels are independent predictors of increased cardiovascular mortality risk; therefore, drugs targeting the BNP system should be evaluated regarding their effects on the neuroendocrine activation accompanying heart failure.
Velopharyngeal mucosal surface topography in healthy subjects and subjects with obstructive sleep apnea
Authors: Lambeth Christopher , Amatoury Jason , Wang Ziyu , Foster Sheryl , Amis Terence , Kairaitis Kristina 
Published: December 2016

Macroscopic pharyngeal anatomical abnormalities are thought to contribute to the pathogenesis of upper airway (UA) obstruction in obstructive sleep apnea (OSA). Microscopic changes in the UA mucosal lining of OSA subjects are reported; however, the impact of these changes on UA mucosal surface topography is unknown. This study aimed to 1) develop methodology to measure UA mucosal surface topography, and 2) compare findings from healthy and OSA subjects. Ten healthy and eleven OSA subjects were studied. Awake, gated (end expiration), head and neck position controlled magnetic resonance images (MRIs) of the velopharynx (VP) were obtained. VP mucosal surfaces were segmented from axial images, and three-dimensional VP mucosal surface models were constructed. Curvature analysis of the models was used to study the VP mucosal surface topography. Principal, mean, and Gaussian curvatures were used to define surface shape composition and surface roughness of the VP mucosal surface models. Significant differences were found in the surface shape composition, with more saddle/spherical and less flat/cylindrical shapes in OSA than healthy VP mucosal surface models ( P < 0.01). OSA VP mucosal surface models were also found to have more mucosal surface roughness ( P < 0.0001) than healthy VP mucosal surface models. Our novel methodology was utilized to model the VP mucosal surface of OSA and healthy subjects. OSA subjects were found to have different VP mucosal surface topography, composed of increased irregular shapes and increased roughness. We speculate increased irregularity in VP mucosal surface may increase pharyngeal collapsibility as a consequence of friction-related pressure loss.NEW & NOTEWORTHY A new methodology was used to model the upper airway mucosal surface topography from magnetic resonance images of patients with obstructive sleep apnea and healthy adults. Curvature analysis was used to analyze the topography of the models, and a new metric was derived to describe the mucosal surface roughness. Increased roughness was found in the obstructive sleep apnea vs. healthy group, but further research is required to determine the functional effects of the measured difference on upper airway airflow mechanics.
Melatonin protects against uric acid-induced mitochondrial dysfunction, oxidative stress, and triglyceride accumulation in C2C12myotubes
Authors: Maarman Gerald J. , Andrew Brittany M. , Blackhurst Dee M. , Ojuka Edward O. 
Published: December 2016

Excess uric acid has been shown to induce oxidative stress, triglyceride accumulation, and mitochondrial dysfunction in the liver and is an independent predictor of type-2 diabetes. Skeletal muscle plays a dominant role in type 2 diabetes and presents a large surface area to plasma uric acid. However, the effects of uric acid on skeletal muscle are underinvestigated. Our aim was therefore to characterize the effects of excessive uric acid on oxidative stress, triglyceride content, and mitochondrial function in skeletal muscle C2C12myotubes and assess how these are modulated by the antioxidant molecule melatonin. Differentiated C2C12myotubes were exposed to 750 µM uric acid or uric acid + 10 nM melatonin for 72 h. Compared with control, uric acid increased triglyceride content by ~237%, oxidative stress by 32%, and antioxidant capacity by 135%. Uric acid also reduced endogenous ROUTINE respiration, complex II-linked oxidative phosphorylation, and electron transfer system capacities. Melatonin counteracted the effects of uric acid without further altering antioxidant capacity. Our data demonstrate that excess uric acid has adverse effects on skeletal muscle similar to those previously reported in hepatocytes and suggest that melatonin at a low physiological concentration of 10 nM may be a possible therapy against some adverse effects of excess uric acid.NEW & NOTEWORTHY Few studies have investigated the effects of uric acid on skeletal muscle. This study shows that hyperuricemia induces mitochondrial dysfunction and triglyceride accumulation in skeletal muscle. The findings may explain why hyperuricemia is an independent predictor of diabetes.