bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Development of Single-Isomer Molecules: Why and How
Authors: Hutt Andrew J. 
Published: August 2016

ABSTRACTUntil relatively recently the three-dimensional nature of drug molecules has been largely neglected, with approximately 25% of marketed drugs being mixtures of agents rather than single chemical entities. These mixtures are not combinations of drugs but mixtures of stereoisomers, generally racemates of synthetic chiral drugs. The individual enantiomers present in such mixtures frequently differ in both their pharmacodynamic and pharmacokinetic profiles as a result of stereochemical discrimination on interaction with chiral biological macromolecules (enzymes and receptors). The use of such mixtures may present problems if their adverse effects are associated with the less active stereoisomer or do not show stereoselectivity. In addition, interactions between enantiomers may occur such that the observed activity of the racemate is not simply the product of the effects of the individual enantiomers. Since the mid-1980s there has been an ongoing “racemate-versus-enantiomer” debate with the potential advantages of single-isomer products, including improved selectivity of action and potential increase in therapeutic index, being highlighted. As a result, regulatory authorities have issued guidelines for dealing with chiral molecules, and the number of single enantiomer agents presented for evaluation has increased. Racemic mixtures may still be developed but require justification such that the risk-benefit ratio may be assessed. In addition to new chemical entities, a number of “old” mixtures are being re-examined as potential single-isomer products, the chiral switches, with the potential for an improved therapeutic profile and possibly new indications. However, for the majority of agents currently marketed as mixtures, relatively little is known concerning the pharmacological or toxicological properties of the individual enantiomers.
Great Expectations in Stereochemistry: Focus on Antidepressants
Authors: DeVane C. Lindsay , Boulton David W. 
Published: August 2016

ABSTRACTChirality has become an increasingly important consideration in the development of psychoactive drugs because enantiomers often show major differences in their pharmacokinetic and pharmacologic properties. This review illustrates the implications of stereochemistry in clinical psychopharmacology using the antidepressant class of drugs as a focus. In many cases, a better understanding of stereochemistry can improve therapeutic outcomes. For example, with citalopram, the racemic formulation is effective for depression as well as panic and obsessive-compulsive disorders. However, the S-enantiomer, escitalopram, is at least twice as potent as racemic citalopram as an inhibitor of serotonin reuptake, implying that it can be used at lower doses, while offering an improved therapeutic index as well as an improved safety profile and reduced drug interaction liability. Clinical trial data support these advantages. Continuing research on the stereochemical properties of psychoactive drugs should simplify the characterization of dose-response relationships, and clarify the effects of disease states, genetic polymorphisms, pregnancy, age, and gender on stereoselective pharmacokinetics and pharmacodynamics. Better understanding of the fate of chiral psychotropic agents and the factors that influence their stereoselective disposition and actions will provide a rational basis for their expanded use in various patient populations.
Classified or Coverup? The Effect of Redactions on Conspiracy Theory Beliefs
Authors: Nyhan Brendan , Dickinson Franklin , Dudding Sasha , Dylgjeri Enxhi , Neiley Eric , Pullerits Christopher , Seog Minae , Simpson Andy , Szilagyi Heather , Walmsley Colin 
Published: August 2016

AbstractConspiracy theories are prevalent among the public. Governments frequently release official documents attempting to explain events that inspire these beliefs. However, these documents are often heavily redacted, a practice that lay epistemic theory suggests might be interpreted as evidence for a conspiracy. To investigate this possibility, we tested the effect of redactions on beliefs in a well-known conspiracy theory. Results from two preregistered experiments indicate that conspiracy beliefs were higher when people were exposed to seemingly redacted documents compared to when they were exposed to unredacted documents that were otherwise identical. In addition, unredacted documents consistently lowered conspiracy beliefs relative to controls while redacted documents had reduced or null effects, suggesting that lay epistemic interpretations of the redactions undermined the effect of information in the documents. Our findings, which do not vary by conspiracy predispositions, suggest policymakers should be more transparent when releasing documents to refute misinformation.
The Effects of Nicotine and Nicotine Abstinence on Stress-Induced	Cardiovascular Reactivity
Authors: VanderKaay Tomasulo Melissa M. , Scanlin Matthew C. , Patterson Stephen M. 
Published: August 2016

Abstract. The effects of 12 hr nicotine administration and abstinence on stress-induced cardiovascular reactivity were assessed within Light/Intermittent cigarette smokers and Habitual cigarette smokers. One hundred thirty-two male smokers (66 Habitual, 66 Light/Intermittent) were assigned to a Nicotine (21 mg) or Placebo patch condition. Cardiovascular reactivity was assessed during Baseline, a 6-min mental arithmetic task (Paced Auditory Serial Arithmetic Task) and a 5-min mirror-tracing task (Star Mirror Tracing Task). Within the Nicotine condition, Light/Intermittent smokers showed greater cardiac output (CO) increases, smaller stroke volume decreases, and smaller total peripheral resistance (TPR) increases than Light/Intermittent smokers in the Placebo condition. No condition differences in cardiovascular reactivity were demonstrated for Habitual smokers. Light/Intermittent smokers also showed greater CO increases than Habitual smokers during the mirror-tracing task but during the Nicotine condition only. During mental arithmetic, Light/Intermittent smokers had greater CO increases and smaller TPR increases than Habitual smokers across nicotine conditions. Habitual smokers responded to stress with increases in peripheral responses whereas Light/Intermittent smokers responded myocardially. Light/Intermittent smokers may have increased density of β-adrenergic receptors whereas Habitual smokers may have decreased density due to chronic smoking.
Transcriptional landscapes at the intersection of neuronal apoptosis and substance P-induced survival: exploring pathways and drug targets
Authors: Paparone S , Severini C , Ciotti M T , D’Agata V , Calissano P , Cavallaro S 
Published: August 2016

AbstractA change in the delicate equilibrium between apoptosis and survival regulates the neurons fate during the development of nervous system and its homeostasis in adulthood. Signaling pathways promoting or protecting from apoptosis are activated by multiple signals, including those elicited by neurotrophic factors, and depend upon specific transcriptional programs. To decipher the rescue program induced by substance P (SP) in cerebellar granule neurons, we analyzed their whole-genome expression profiles after induction of apoptosis and treatment with SP. Transcriptional pathways associated with the survival effect of SP included genes encoding for proteins that may act as pharmacological targets. Inhibition of one of these, theMycpro-oncogene by treatment with 10058-F4, reverted in a dose-dependent manner the rescue effect of SP. In addition to elucidate the transcriptional mechanisms at the intersection of neuronal apoptosis and survival, our systems biology-based perspective paves the way towards an innovative pharmacology based on targets downstream of neurotrophic factor receptors.
Ascarosides coordinate the dispersal of a plant-parasitic nematode with the metamorphosis of its vector beetle
Authors: Zhao Lilin , Zhang Xinxing , Wei Yanan , Zhou Jiao , Zhang Wei , Qin Peijun , Chinta Satya , Kong Xiangbo , Liu Yunpeng , Yu Haiying , Hu Songnian , Zou Zhen , Butcher Rebecca A. , Sun Jianghua 
Published: August 2016

AbstractInsect vectors are required for the transmission of many species of parasitic nematodes, but the mechanisms by which the vectors and nematodes coordinate their life cycles are poorly understood. Here, we report that ascarosides, an evolutionarily conserved family of nematode pheromones, are produced not only by a plant-parasitic nematode, but also by its vector beetle. The pinewood nematode and its vector beetle cause pine wilt disease, which threatens forest ecosystems world-wide. Ascarosides secreted by the dispersal third-stage nematode LIII larvae promote beetle pupation by inducing ecdysone production in the beetle and up-regulating ecdysone-dependent gene expression. Once the beetle develops into the adult stage, it secretes ascarosides that attract the dispersal fourth-stage nematode LIV larvae, potentially facilitating their movement into the beetle trachea for transport to the next pine tree. These results demonstrate that ascarosides play a key role in the survival and spread of pine wilt disease.
Type 2 diabetes, but not obesity, prevalence is positively associated with ambient temperature
Authors: Speakman John R. , Heidari-Bakavoli Sahar 
Published: August 2016

AbstractCold exposure stimulates energy expenditure and glucose disposal. If these factors play a significant role in whole body energy balance, and glucose homeostasis, it is predicted that both obesity and type 2 diabetes prevalence would be lower where it is colder. Previous studies have noted connections between ambient temperature and obesity, but the direction of the effect is confused. No previous studies have explored the link of type 2 diabetes to ambient temperature. We used county level data for obesity and diabetes prevalence across the mainland USA and matched this to county level ambient temperature data. Average ambient temperature explained 5.7% of the spatial variation in obesity and 29.6% of the spatial variation in type 2 diabetes prevalence. Correcting the type 2 diabetes data for the effect of obesity reduced the explained variation to 26.8%. Even when correcting for obesity, poverty and race, ambient temperature explained 12.4% of the variation in the prevalence of type 2 diabetes, and this significant effect remained when latitude was entered into the model as a predictor. When obesity prevalence was corrected for poverty and race the significant effect of temperature disappeared. Enhancing energy expenditure by cold exposure will likely not impact obesity significantly, but may be useful to combat type 2 diabetes.
Inactivation of hypoxia-induced YAP by statins overcomes hypoxic resistance tosorafenib in hepatocellular carcinoma cells
Authors: Zhou Tian-yi , Zhuang Lin-han , Hu Yan , Zhou Yu-lu , Lin Wen-kai , Wang Dan-dan , Wan Zi-qian , Chang Lin-lin , Chen Ying , Ying Mei-dan , Chen Zi-bo , Ye Song , Lou Jian-shu , He Qiao-jun , Zhu Hong , Yang Bo 
Published: August 2016

AbstractSorafenib is a multikinase inhibitor used as a first-line treatment for advanced hepatocellular carcinoma (HCC), but it has shown modest to low response rates. The characteristic tumour hypoxia of advanced HCC maybe a major factor underlying hypoxia-mediated treatment failure. Thus, it is urgent to elucidate the mechanisms of hypoxia-mediated sorafenib resistance in HCC. In this study, we found that hypoxia induced the nuclear translocation of Yes associate-Protein (YAP) and the subsequent transactivation of target genes that promote cell survival and escape apoptosis, thereby leading to sorafenib resistance. Statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could ameliorate hypoxia-induced nuclear translocation of YAP and suppress mRNA levels of YAP target genes both in vivo and in vitro. Combined treatment of statins with sorafenib greatly rescued the loss of anti-proliferative effects of sorafenib under hypoxia and improved the inhibitory effects on HepG2 xenograft tumour growth, accompanied by enhanced apoptosis as evidenced by the increased sub-G1 population and PARP cleavage. The expression levels of YAP and its target genes were highly correlated with poor prognosis and predicted a high risk of HCC patients. These findings collectively suggest that statins utilization maybe a promising new strategy to counteract hypoxia-mediated resistance to sorafenib in HCC patients.
IL-2 in the tumor microenvironment is necessary for Wiskott-Aldrich syndrome protein deficient NK cells to respond to tumors in vivo
Authors: Kritikou Joanna S. , Dahlberg Carin I. M. , Baptista Marisa A. P. , Wagner Arnika K. , Banerjee Pinaki P. , Gwalani Lavesh Amar , Poli Cecilia , Panda Sudeepta K. , Kärre Klas , Kaech Susan M. , Wermeling Fredrik , Andersson John , Orange Jordan S. , Brauner Hanna , Westerberg Lisa S. 
Published: August 2016

AbstractTo kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNγ upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts. Pre-treatment of WASp KO NK cells with IL-2 ex vivo restored degranulation, IFNγ production and killing of MHC class I negative hematopoietic grafts. Moreover, WASp KO mice controlled growth of A20 lymphoma cells that naturally produced IL-2. WASp KO NK cells showed increased expression of DNAM-1, LAG-3 and KLRG1, all receptors associated with cellular exhaustion and NK cell memory. NK cells isolated from WAS patient spleen cells showed increased expression of DNAM-1 and had low to negative expression of CD56, a phenotype associated with NK cells exhaustion. Finally, in a cohort of neuroblastoma patients we identified a strong correlation between WASp, IL-2 and patient survival.
A high-throughput in vitro ring assay for vasoactivity using magnetic 3D bioprinting
Authors: Tseng Hubert , Gage Jacob A. , Haisler William L. , Neeley Shane K. , Shen Tsaiwei , Hebel Chris , Barthlow Herbert G. , Wagoner Matthew , Souza Glauco R. 
Published: August 2016

AbstractVasoactive liabilities are typically assayed using wire myography, which is limited by its high cost and low throughput. To meet the demand for higher throughput in vitro alternatives, this study introduces a magnetic 3D bioprinting-based vasoactivity assay. The principle behind this assay is the magnetic printing of vascular smooth muscle cells into 3D rings that functionally represent blood vessel segments, whose contraction can be altered by vasodilators and vasoconstrictors. A cost-effective imaging modality employing a mobile device is used to capture contraction with high throughput. The goal of this study was to validate ring contraction as a measure of vasoactivity, using a small panel of known vasoactive drugs. In vitro responses of the rings matched outcomes predicted by in vivo pharmacology and were supported by immunohistochemistry. Altogether, this ring assay robustly models vasoactivity, which could meet the need for higher throughput in vitro alternatives.
The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific
Authors: Dafnis Ioannis , Argyri Letta , Sagnou Marina , Tzinia Athina , Tsilibary Effie C. , Stratikos Efstratios , Chroni Angeliki 
Published: August 2016

AbstractThe apolipoprotein (apo) E4 isoform is the strongest risk factor for late-onset Alzheimer’s disease (AD). ApoE4 is more susceptible to proteolysis than apoE2 and apoE3 isoforms and carboxyl-terminal truncated apoE4 forms have been found in AD patients’ brain. We have previously shown that a specific apoE4 fragment, apoE4-165, promotes amyloid-peptide beta 42 (Aβ42) accumulation in human neuroblastoma SK-N-SH cells and increased intracellular reactive oxygen species formation, two events considered to occur early in AD pathogenesis. Here, we show that these effects are allele-dependent and absolutely require the apoE4 background. Furthermore, the exact length of the fragment is critical since longer or shorter length carboxyl-terminal truncated apoE4 forms do not elicit the same effects. Structural and thermodynamic analyses showed that apoE4-165 has a compact structure, in contrast to other carboxyl-terminal truncated apoE4 forms that are instead destabilized. Compared however to other allelic backgrounds, apoE4-165 is structurally distinct and less thermodynamically stable suggesting that the combination of a well-folded structure with structural plasticity is a unique characteristic of this fragment. Overall, our findings suggest that the ability of apoE fragments to promote Aβ42 intraneuronal accumulation is specific for both the apoE4 isoform and the particular structural and thermodynamic properties of the fragment.
Acid-Sensing Ion Channel 2a (ASIC2a) Promotes Surface Trafficking of ASIC2b via Heteromeric Assembly
Authors: Kweon Hae-Jin , Kim Dong-Il , Bae Yeonju , Park Jae-Yong , Suh Byung-Chang 
Published: August 2016

AbstractAcid-sensing ion channels (ASICs) are proton-activated cation channels that play important roles as typical proton sensors during pathophysiological conditions and normal synaptic activities. Among the ASIC subunits, ASIC2a and ASIC2b are alternative splicing products from the same gene, ACCN1. It has been shown that ASIC2 isoforms have differential subcellular distribution: ASIC2a targets the cell surface by itself, while ASIC2b resides in the ER. However, the underlying mechanism for this differential subcellular localization remained to be further elucidated. By constructing ASIC2 chimeras, we found that the first transmembrane (TM1) domain and the proximal post-TM1 domain (17 amino acids) of ASIC2a are critical for membrane targeting of the proteins. We also observed that replacement of corresponding residues in ASIC2b by those of ASIC2a conferred proton-sensitivity as well as surface expression to ASIC2b. We finally confirmed that ASIC2b is delivered to the cell surface from the ER by forming heteromers with ASIC2a, and that the N-terminal region of ASIC2a is additionally required for the ASIC2a-dependent membrane targeting of ASIC2b. Together, our study supports an important role of ASIC2a in membrane targeting of ASIC2b.
Internal pH regulation facilitates in situ long-term acclimation of massive corals to end-of-century carbon dioxide conditions
Authors: Wall M. , Fietzke J. , Schmidt G. M. , Fink A , Hofmann L. C. , de Beer D. , Fabricius K. E. 
Published: August 2016

AbstractThe resilience of tropical corals to ocean acidification depends on their ability to regulate the pH within their calcifying fluid (pHcf). Recent work suggests pHcf homeostasis under short-term exposure to pCO2 conditions predicted for 2100, but it is still unclear if pHcf homeostasis can be maintained throughout a corals lifetime. At CO2 seeps in Papua New Guinea, massive Porites corals have grown along a natural seawater pH gradient for decades. This natural gradient, ranging from pH 8.1–7.4, provides an ideal platform to determine corals’ pHcf (using boron isotopes). Porites maintained a similar pHcf (~8.24) at both a control (pH 8.1) and seep-influenced site (pH 7.9). Internal pHcf was slightly reduced (8.12) at seawater pH 7.6 and decreased to 7.94 at a site with a seawater pH of 7.4. A growth response model based on pHcf mirrors the observed distribution patterns of this species in the field. We suggest Porites has the capacity to acclimate after long-time exposure to end-of-century reduced seawater pH conditions and that strong control over pHcf represents a key mechanism to persist in future oceans. Only beyond end-of-century pCO2 conditions do they face their current physiological limit of pH homeostasis and pHcf begins to decrease.
Human Prostate Cancer Hallmarks Map
Authors: Datta Dipamoy , Aftabuddin Md. , Gupta Dinesh Kumar , Raha Sanghamitra , Sen Prosenjit 
Published: August 2016

AbstractHuman prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process.
Three-dimensional Reconstruction of the Microstructure of Human Acellular Nerve Allograft
Authors: Zhu Shuang , Zhu Qingtang , Liu Xiaolin , Yang Weihong , Jian Yutao , Zhou Xiang , He Bo , Gu Liqiang , Yan Liwei , Lin Tao , Xiang Jianping , Qi Jian 
Published: August 2016

AbstractThe exact inner 3D microstructure of the human peripheral nerve has been a mystery for decades. Therefore, it has been difficult to solve several problems regarding peripheral nerve injury and repair. We used high-resolution X-ray computed microtomography (microCT) to scan a freeze-dried human acellular nerve allograft (hANA). The microCT images were then used to reconstruct a 3D digital model, which was used to print a 3D resin model of the nerve graft. The 3D digital model of the hANA allowed visualization of all planes. The magnified 3D resin model clearly showed the nerve bundles and basement membrane tubes of the hANA. Scanning electron microscopy (SEM) was used to analyse the microstructure of the hANA. Compared to the SEM images, the microCT image clearly demonstrated the microstructure of the hANA cross section at a resolution of up to 1.2 μm. The 3D digital model of the hANA facilitates a clear and easy understanding of peripheral nerve microstructure. Furthermore, the enlarged 3D resin model duplicates the unique inner structure of each individual hANA. This is a crucial step towards achieving 3D printing of a hANA or nerve that can be used as a nerve graft.