bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paradoxical Associations Between Familial Affective Responsiveness, Stress, and Amygdala Reactivity
Authors: Farber Madeline J. , Romer Adrienne L. , Justin Kim M. , Knodt Annchen R. , Elsayed Nourhan M. , Williamson Douglas E. , Hariri Ahmad R. 
Published: July 2017

AbstractStudies of early life extremes such as trauma, abuse, and neglect highlight the critical importance of quality caregiving in the development of brain circuits supporting emotional behavior and mental health. The impact of normative variability in caregiving on such biobehavioral processes, however, is poorly understood. Here, we provide initial evidence that even subtle variability in normative caregiving shapes threat-related brain function and, potentially, associated psychopathology in adolescence. Specifically, we report that greater familial affective responsiveness is associated with heightened amygdala reactivity to interpersonal threat, particularly in adolescents having experienced relatively low recent stress. These findings extend the literature on the effects of caregiving extremes on brain function to subtle, normative variability, but suggest that presumably protective factors may be associated with increased risk-related amygdala reactivity. We consider these paradoxical associations with regard to studies of basic associative threat learning and further consider their relevance for understanding potential effects of caregiving on psychological development.
Computational design of Small Transcription Activating RNAs (STARs) for versatile and dynamic gene regulation
Authors: Chappell James , Westbrook Alexandra , Verosloff Matthew , Lucks Julius B. 
Published: July 2017

AbstractA longstanding goal of synthetic biology has been the programmable control of cellular functions. Central to this goal is the creation of versatile regulatory toolsets that allow for programmable control of gene expression. Of the many regulatory molecules available, RNA regulators offer the intriguing possibility ofde novodesign – allowing for the bottom-up molecular-level design of genetic control systems. Here we present a computational design approach for the creation of a bacterial regulator called Small Transcription Activating RNAs (STARs) and create a library of high-performing and orthogonal STARs that achieve up to ∼9000-fold gene activation. We then demonstrate the versatility of RNA-based transcription control by showing the broad utility of STARs – from acting synergistically with existing constitutive and inducible regulators, to reprogramming cellular phenotypes and controlling multigene metabolic pathway expression. Finally, we combine these new STARs with themselves and CRISPRi transcriptional repressors to deliver new types of RNA-based genetic circuitry that allow for sophisticated and temporal control of gene expression.
Comprehensive Characterization of Toxicity of Fermentative Metabolites on Microbial Growth
Authors: Wilbanks Brandon , Trinh Cong T. 
Published: July 2017

ABSTRACTBackgroundVolatile carboxylic acids, alcohols, and esters are natural fermentative products, typically derived from anaerobic digestion. These metabolites have important functional roles to regulate cellular metabolisms and broad use as food supplements, flavors and fragrances, solvents, and fuels. Comprehensive characterization of toxic effects of these metabolites on microbial growth under similar conditions is very limited.ResultsWe characterized a comprehensive list of 32 short-chain carboxylic acids, alcohols, and esters on microbial growth ofEscherichia coliMG1655 under anaerobic conditions. We analyzed toxic effects of these metabolites onE. colihealth, quantified by growth rate and cell mass, as a function of metabolite types, concentrations, and physiochemical properties including carbon chain lengths and associated functional groups, chain branching features, hydrophobicity, and energy density. Strain characterization reveals these metabolites exerted distinct toxic effects onE. colihealth. We find that higher concentrations and/or longer carbon lengths of metabolites cause more severe growth inhibition. For the same carbon lengths and metabolite concentrations, alcohols are most toxic followed by acids then esters. We also discover that branched chain metabolites are less toxic than linear chain metabolites for the same carbon lengths and metabolite concentrations. Remarkably, shorter alkyl esters (e.g., ethyl butyrate) are found to be less toxic than longer alkyl esters (e.g., butyl acetate) for the same carbon lengths and metabolite concentrations. Regardless of metabolite types, longer chain metabolites are less soluble and have higher energy densities but are more toxic to microbial growth.ConclusionsMetabolite hydrophobicity, correlated with carbon chain length, associated functional group, chain branching feature, and energy density, is a good quantitative index to evaluate toxic effect of a metabolite on microbial health. The results provide better understanding of degrees of toxicity of fermentative metabolites on microbial growth and further help selection of desirable metabolites and hosts for industrial fermentation to overproduce them.
Evaluating the accuracy of the umbrella sampling plots with different dissociation paths, conformational changes, and structure preparation
Authors: You Wanli , Tang Zhiye , Chang Chia-en A. 
Published: July 2017

AbstractThe kinetics of ligand dissociation has been found to be crucial for a good drug candidate. Therefore, examining the underlying free energy profile of the dissociation that governs the kinetics becomes important. Umbrella sampling (US), a widely used free energy calculation method, has long been used to explore the dissociation process of ligand-receptor systems. The potential of mean force (PMF) computed from US seems to always produce binding affinity and energy barriers that more or less agree with experiments. However, such PMFs are influenced by many practical aspects, like the method used to generate the initial dissociation pathway, collective variables (CVs) that used to describe the reaction coordinate (RC), and how intensive the sampling is in the conformational space restrained by the CVs. These critical factors were rarely studied. Here we applied US to study the dissociation processes of β-cyclodextrin (β-CD) and p38α complex systems. For β-CD, we used three different β-CD conformations to generate the dissociation path manually. For p38α, we generated the dissociation pathway using accelerated molecular dynamics (AMD) followed by conformational relaxing with short conventional molecular dynamics (MD), steered molecular dynamics (SMD) and manual pulling. We found that even for small β-CD complexes, different β-CD conformations will alter the height of the PMF and different dissociation directions result in appearance/disappearance of local minima. SMD poorly samples the residue sidechain movement, leading to overestimated height of PMF. On the other hand, the AMD pathway relaxed by short conventional MD sampled more accurate structures, resulting in reasonable PMF.
Recasting the cancer stem cell hypothesis: unification using a continuum model of microenvironmental forces
Authors: Scott Jacob G. , Dhawan Andrew , Hjelmeland Anita , Lathia Justin , Chumakova Anastasia , Hitomi Masahiro , Fletcher Alexander G. , Maini Philip K. , Anderson Alexander R. A. 
Published: July 2017

ABSTRACTSince the first evidence for cancer stem cells in leukemia, experimentalists have sought to identify tumorigenic subpopulations in solid tumors. In parallel, scientists have argued over the implications of the existence of this subpopulation. On one side, the cancer stem cell hypothesis posits that a small subset of cells within a tumor are responsible for tumorigenesis and are capable of recapitulating the entire tumor on their own. Under this hypothesis, a tumor may be conceptualized as a series of coupled compartments, representing populations of progressively differentiated cell types, starting from stem cells. The allure of this model is that it elegantly explains our therapeutic failures: we have been targeting the wrong cells. Alternatively, the stochastic model states that all cells in a tumor can have stem-like properties, and have an equally small capability of forming a tumor. As tumors are, by nature, heterogeneous, there is ample evidence to support both hypotheses. We propose a mechanistic mathematical description that integrates these two theories, settling the dissonance between the schools of thought and providing a road map for integrating disparate experimental results into a single theoretical framework. We present experimental results from clonogenic assays that demonstrate the importance of defining this novel formulation, and the clarity that is provided when interpreting these results through the lens of this formulation.
Neuronal origin of the temporal dynamics of spontaneous BOLD activity correlation
Authors: Matsui Teppei , Murakami Tomonari , Ohki Kenichi 
Published: July 2017

AbstractResting-state functional connectivity (FC) has become a major fMRI method to study network organization of human brains. There has been recent interest in the temporal fluctuations of FC calculated using short time windows (“dynamic FC”) because this method could provide information inaccessible with conventional “static” FC, which is typically calculated using the entire scan lasting several tens of minutes. Although multiple studies have revealed considerable temporal fluctuations in FC, it is still unclear whether the fluctuations of FC measured in hemodynamics reflect the dynamics of underlying neural activity. We addressed this question using simultaneous imaging of neuronal calcium and hemodynamic signals in mice and found coordinated temporal dynamics of calcium FC and hemodynamic FC measured in the same short time windows. Moreover, we found that variation in transient neuronal coactivation patterns (CAPs) was significantly related to temporal fluctuations of sliding window FC in hemodynamics. Finally, we show that the observed dynamics of FC cannot be fully accounted for by simulated data assuming stationary FC. These results provide evidence for the neuronal origin of dynamic FC and further suggest that information relevant to FC is condensed in temporally sparse events that can be extracted using a small number of time points.
First Characterization of a Biphasic, Switch-like DNA Amplification
Authors: Özay Burcu , Robertus Cara M , Negri Jackson L , McCalla Stephanie E 
Published: July 2017

ABSTRACTWe report the first DNA amplification chemistry with switch-like characteristics: the chemistry is biphasic, with an expected initial phase followed by an unprecedented high gain burst of product oligonucleotide in a second phase. The first and second phases are separated by a temporary plateau, with the second phase producing 10 to 100 times more product than the first. The reaction is initiated when an oligonucleotide binds and opens a palindromic looped DNA template with two binding domains. Upon loop opening, the oligonucleotide trigger is rapidly amplified through cyclic extension and nicking of the bound trigger. Loop opening and DNA association drive the amplification reaction, such that reaction acceleration in the second phase is correlated with DNA association thermodynamics. Without a palindromic sequence, the chemistry resembles the exponential amplification reaction (EXPAR). EXPAR terminates at the initial plateau, revealing a previously unknown phenomenon that causes early reaction cessation in this popular oligonucleotide amplification reaction. Here we present two distinct types of this biphasic reaction chemistry and propose dominant reaction pathways for each type based on thermodynamic arguments. These reactions create an endogenous switch-like output that reacts to approximately 1pM oligonucleotide trigger. The chemistry is isothermal and can be adapted to respond to a broad range of input target molecules such as proteins, genomic bacterial DNA, viral DNA, and microRNA. This rapid DNA amplification reaction could potentially impact a variety of disciplines such as synthetic biology, biosensors, DNA computing, and clinical diagnostics.
Anticipating complexity in the deployment of gene drive insects in agriculture
Authors: Baltzegar Jennifer , Barnes Jessica Cavin , Elsensohn Johanna E. , Gutzmann Nicole , Jones Michael S. , King Sheron , Sudweeks Jayce 
Published: July 2017

AbstractInsects cause substantial losses to agricultural crops each year and require intensive management approaches. Genetic pest management (GPM) has emerged as a viable, non-chemical alternative for managing insect pests. The development of engineered gene drives for agricultural use is promising, though unproven, and has the potential to impact farmers as well as broader socio-ecological systems in several ways. Drawing on lessons from the deployment of other pest control technologies, this paper considers how gene drive insects could intersect with some of the complexities that characterize agricultural systems. The development of gene drives is emerging in a landscape of pest management shaped by past and current approaches, experiences, regulations, public opinion and pest invasions. Because gene drive insects may spread well beyond their release area, stakeholder groups at different spatial scales need to be engaged in decisions about their deployment. This new paradigm both complicates and offers great promise for future pest management efforts.
Tropomyosin and α-actinin cooperation inhibits fimbrin association with actin filament networks in fission yeast
Authors: Christensen Jenna R. , Homa Kaitlin E. , O’Connell Meghan E. , Kovar David R. 
Published: July 2017

ABSTRACTWe previously discovered that competition between fission yeast actin binding proteins (ABPs) for association with F-actin helps facilitate their sorting to different F-actin networks. Specifically, competition between actin patch ABPs fimbrin Fim1 and cofilin Adf1 enhances each other’s activities, and rapidly displaces tropomyosin Cdc8 from the F-actin network. However, these interactions don’t explain how Fim1, a robust competitor, is prevented from associating equally well with other F-actin networks. Here, with a combination of fission yeast genetics, live cell fluorescent imaging, and in vitro TIRF microscopy, we identified the contractile ring ABP α-actinin Ain1 as a key sorting factor. Fim1 competes with Ain1 for association with F-actin, which is dependent upon their residence time on F-actin. Remarkably, although Fim1 outcompetes both contractile ring ABPs Ain1 and Cdc8 individually, Cdc8 enhances the bundling activity of Ain1 10-fold, allowing the combination of Ain1 and Cdc8 to inhibit Fim1 association with contractile ring F-actin.
Estrogen repressesTgfbr1andBmpr1aexpression via estrogen receptor beta in MC3T3-E1 cells
Authors: He Hanliang , Wang Chunqing , Tang Qifeng , Yang Fan , Xu Youjia 
Published: July 2017

AbstractMC3T3-E1 is a clonal pre-osteoblastic cell line derived from newborn mouse calvaria, which is commonly used in osteoblast studies. To investigate the effects of estrogen on osteoblasts, we treated MC3T3-E1 cells with various concentrations of estrogen and assessed their proliferation. Next, we performed RNA deep sequencing to investigate the effects on estrogen target genes.Bmpr1aandTgfbr1, important participants in the TGF-beta signaling pathway, were down-regulated in our deep sequencing results. Bioinformatics analysis revealed that estrogen receptor response elements (EREs) were present in theBmpr1aandTgfbr1promoters. Culturing the cells with the estrogen receptor (ER) alpha or beta antagonists 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP) or 4-[2-phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-alpha]pyrimidin-3-yl] phenol (PTHPP), respectively, demonstrated that ER beta is involved in the estrogen-mediated repression ofTgfbr1andBmpr1a.The chromatin immunoprecipitation (ChIP) results were consistent with the conclusion that E2 increased the binding of ER beta at the EREs located in theTgfbr1andBmpr1apromoters. Our research provides new insight into the role of estrogen in bone metabolisms.
The Na+(K+)/H+ exchanger Nhx1 controls multivesicular body-vacuolar lysosome fusion
Authors: Karim Mahmoud Abdul , Brett Christopher Leonard 
Published: July 2017

ABSTRACTLoss-of-function mutations in human endosomal Na+(K+)/H+ Exchangers (NHEs) NHE6 and NHE9 are implicated in neurological disorders including Christianson Syndrome, autism and attention deficit and hyperactivity disorder (ADHD). These mutations disrupt retention of surface receptors within neurons and glial cells by affecting their delivery to lysosomes for degradation. However, the molecular basis of how these endosomal NHEs control endocytic trafficking is unclear. Using Saccharomyces cerevisiae as a model, we conducted cell-free organelle fusion assays to show that transport activity of the orthologous endosomal NHE Nhx1 is important for multivesicular body (MVB)-vacuolar lysosome fusion, the last step of endocytosis required for surface protein degradation. We find that deleting Nhx1 disrupts the fusogenicity of the MVB, not vacuole, by targeting pH-sensitive machinery downstream of the Rab-GTPase Ypt7 needed for SNARE-mediated lipid bilayer merger. All contributing mechanisms are evolutionarily conserved offering new insight into the etiology of human disorders linked to loss of endosomal NHE function.
Placental abruption in parents who were born small: registry‐based cohort study
Authors: Rasmussen S , Ebbing C , Linde LE , Baghestan E 
Published: July 2017

ObjectiveTo assess whether parents who were born small for gestational age (below the 10th birthweight centile, SGA) have increased risk of severe or mild placental abruption. To assess whether a history of SGA in other family members modifies this intergenerational effect.DesignProspective population‐based observational study.SettingThe Medical Birth Registry of Norway.PopulationFrom 1967 to 2013, 785 333 mother–offspring pairs, 643 066 father–offspring pairs, 272 941 maternal tetrads (i.e. her offspring, sibling, and niece/nephew), and 265 505 paternal tetrads were identified.MethodsCohort study based on linked data from the Medical Birth Registry of Norway.Main outcome measuresRelative risk (RR) of severe placental abruption (preterm birth, birthweight below the 10th centile, or perinatal death) and mild placental abruption (other cases) in families with SGA.ResultsMothers who were born SGA had increased risk of severe placental abruption (RR 1.5; 95% confidence interval, 95% CI 1.3–1.8), but not mild abruption. The paternal effects were weaker. The combined effect of SGA in the mother and her sibling on severe abruption was twofold (RR 2.4; 95% CI 1.7–3.3) compared with birthweight centiles ≥10 for both. Similarly, the effect of adding an SGA niece/nephew was twofold (RR 2.3; 95% CI 1.3–3.9), whereas the combined effect of SGA in the mother, her sibling and her niece/nephew was fourfold (RR 3.6; 95% CI 1.9–6.8).ConclusionsWomen who were born SGA have an increased risk of severe placental abruption. The corresponding paternal effect was modest. A history of SGA in other family members increases the generational effect.Tweetable abstractWomen born small for gestational age have excess risk of placental abruption.
High expression of long non‐coding HOX antisense transcript RNA and its clinical significance in cancer tissues: A meta‐analysis
Authors: Wang Lei , Zhao Yandong , Qin Yi , Xuan Yunpeng , Qiu Tong , Fu Bo , Ren Xiaoyang , Jiao Wenjie 
Published: July 2017

BackgroundHOX antisense transcript RNA (HOTAIR) is a 2148 nt long, intergenic, non‐coding RNA molecule, which is reported to be highly expressed in many types of cancers. This meta‐analysis summarizes its expression in cancer.MethodsWe searched all eligible papers on the prognostic impact of HOTAIR in cancer from inception to 30 September 2015 in PubMed, CBMdisc, and the CNKI database. Only full texts were included. Revman 5.3 was used for meta‐analysis.ResultsA total of 11 studies of 1010 cases were included in the meta‐analysis. HOTAIR expression was higher in: cancer tissues in than adjacent or normal tissues (odds ratio [OR] 37.52, 95% confidence interval [CI] 18.94–74.31;
P
< 0.00001); in cancer tissues with lymph node metastasis than in those without lymph node metastasis (OR 3.37, 95% CI 2.36–4.82;
P
< 0.00001); and in histological grades II–III than in histological gradeI(OR 0.47, 95% CI 0.29–0.75;
P
= 0.002).ConclusionThis study shows that HOTAIR may play an important role in cancer occurrence and development, but whether it is a marker of cancer diagnosis and reliable prognosis remains to be confirmed. More rigorous design and meticulous quality epidemiological studies are required.
Structure‐based discovery of new selective small‐molecule sirtuin 5 inhibitors
Authors: Liu Sha , Ji Sen , Yu Zhu‐Jun , Wang Hua‐Li , Cheng Xu , Li Wei‐Jian , Jing Li , Yu Yamei , Chen Qiang , Yang Ling‐Ling , Li Guo‐Bo , Wu Yong 
Published: July 2017

Human sirtuin 5 (SIRT5) is a protein deacylase regulating metabolic pathways and stress responses and is implicated in metabolism‐related diseases. Small‐molecule inhibitors for SIRT5 are sought as chemical tools and potential therapeutics. Herein, we proposed a customized virtual screening approach targeting catalytically important and unique residues Tyr102 and Arg105 of SIRT5. Of the 20 tested virtual screening hits, six compounds displayed marked inhibitory activities against SIRT5. For the hit compound 19, a series of newly synthesized (E)‐2‐cyano‐N‐phenyl‐3‐(5‐phenylfuran‐2‐yl)acrylamide derivatives/analogues were carried out structure–activity relationship analyses, resulting in new more potent inhibitors, among which 37 displayed the most potent inhibition to SIRT5 with an IC50 value of 5.59 ± 0.75 μM. The biochemical studies revealed that 37 likely acts via competitive inhibition with the succinyl‐lysine substrate, rather than the NAD+ cofactor, and it manifested substantial selectivity for SIRT5 over SIRT2 and SIRT6. This study will aid further efforts to develop new selective SIRT5 inhibitors as tools and therapeutics.