bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurological malignancies in neurofibromatosis type 1
Authors: Eoli Marica , Saletti Veronica , Finocchiaro Gaetano
Published: August 2019

Purpose of review

The current review summarizes recent advances on three important issues in neurofibromatosis type 1 (NF1) management: the identification of specific NF1 gene mutations predicting the risk for developing neurological malignancies; the molecular features of NF1-associated tumors and their differences from sporadic neoplasms; genetic, epigenetic, or microenviromental factors leading benign tumors to a malignant transformation in NF1.

Recent findings

The association between the risk of developing optic pathway glioma and specific germiline NF1 mutations is still debated and further studies are needed with large, new cohorts of patients. The available evidences suggest that gliomas and malignant peripheral nerve sheath tumors (MPNSTs) in NF1 have a distinct genetic signatures, different from those observed in sporadic neoplasms. Some neoplasms, very rare in general population, such as subependymal giant cell astrocytoma, can be observed in NF1. A subgroup of low-grade NF1-gliomas, some MPNSTs and plexiform neurofibromas contain abundant T lymphocyte infiltrates suggesting that immunotherapy could be a potential therapeutic approach.

These data support the notion that next-generation sequencing efforts are helpful in the genetic characterization of NF1-associated malignancies A better knowledge of those tumors at the genomic level, is essential for addressing new treatments and may contribute to a deeper comprehension of NF1/RAS signaling also in sporadic cancers.
Extraskeletal Myxoid Chondrosarcomas
Authors: Bishop Andrew J. , Bird Justin E. , Conley Anthony P. , Roland Christina L. , Moon Bryan S. , Satcher Robert L. , Livingston John A. , Patel Shreyaskumar , Wang Wei-Lien , Lazar Alexander J. , Lewis Valerae O. , Lin Patrick P. , Guadagnolo B. Ashleigh
Published: August 2019

Objective:

We evaluated our experience treating patients with localized extraskeletal myxoid chondrosarcomas (EMCs) to evaluate outcomes and relapse rates in order to better inform treatment decisions for these rare soft tissue sarcomas.

Materials and Methods:

We reviewed the records of 41 consecutive patients with localized EMC treated at our institution from 1990 to 2016. Most patients (n=33, 80%) received combined modality therapy with surgery and radiation therapy, whereas only 8 (20%) underwent surgery alone. The Kaplan-Meier method was used to estimate rates of overall survival, disease-specific survival, local control (LC), and distant metastatic-free survival (DMFS).

Results:

Median follow-up time was 94 months (range, 8 to 316). The 10-year LC, DMFS, disease-specific survival, and overall survival rates were 90%, 69%, 85%, and 66%, respectively. There were 5 patients (12%) with local relapse at a median time of 75 months (range, 13 to 176). On univariate analysis, the only significant factor associated with poorer LC was the use of surgery alone (10 y LC, 63% vs. 100% for combined modality therapy, P=0.004), which remained the only factor also significant on the multivariable analysis (P=0.02; hazard ratio [HR], 12.7; 95% confidence interval [CI], 1.4-115.3). In total, 13 patients (32%) developed distant metastatic at a median time of 28 months (range, 3 to 154). Interestingly, local recurrence was the only factor associated with poorer DMFS on multivariate analysis (P=0.04; HR, 3.9; 95% CI, 1.1-14.7).

Conclusions:

For patients with EMC, surgery alone was associated with a higher risk of local recurrence. Therefore, we recommend optimal local therapeutic strategies upfront with both surgery and radiation therapy to reduce the risk of local and ultimately distant recurrence.
Vascular cognitive impairment associated with NOTCH3 Exon 33 mutation
Authors: Sun Yong , Wei Yan-Jun , Xing Ying
Published: August 2019

Rationale:

Vascular cognitive impairment (VCI) is a common cause of dementia. Research suggests that hereditary factors (gene mutations) play an important role in the pathogenesis of VCI, and a mutation of the NOTCH3 locus is frequently identified in affected patients. Herein, we report the case of a patient with confirmed VCI associated with a NOTCH3 exon 33 gene mutation and review the relevant VCI literature.

Patient concerns:

A 48-year-old man presented to our neurology clinic with gradually progressive cognitive impairment.

Diagnoses:

Brain magnetic resonance imaging revealed multiple punctate hyperintensities in the patient's periventricular white matter. Genetic analysis showed a c.6744C > T, p. Ala2223Val substitution in exon 33 of the NOTCH3 gene. We diagnosed thepatient with VCI secondary to a NOTCH3 gene mutation.

Interventions:

Donepezil (5 mg) and memantine (5 mg) daily.

Outcomes:

The patient showed symptom improvement at his 3-month and 6-month follow-up appointments.

Lessons:

This patient may have a new type of mutation that is different from the one seen in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, although it involves a NOTCH3 defect. We propose that the entire NOTCH3 gene should be sequenced in patients with suspected hereditary VCI. This practice could facilitate the discovery of newpathogenic mutations and diseases.
A Prospective Study on Child Morbidity and Gut Microbiota in Rural Malawi
Authors: Kortekangas Emma , Young Rebecca , Cheung Yin B. , Fan Yue‐Mei , Jorgensen Josh M. , Kamng’ona Arox W. , Chaima David , Ashorn Ulla , Dewey Kathryn G. , Maleta Kenneth , Ashorn Per
Published: August 2019

Objectives:

The determinants of gut microbiota composition and its effects on common childhood illnesses are only partly understood, especially in low‐income settings. The aim of the present study was to investigate whether morbidity predicts gut microbiota composition in Malawian children and whether microbiota predicts subsequent morbidity. We tested the hypothesis that common infectious disease symptoms would be predictive of lower microbiota maturity and diversity.

Methods:

We used data from 631 participants in a randomized‐controlled nutrition intervention trial, in which a small‐quantity lipid‐based nutrient supplement was provided to pregnant and lactating mothers and their children at 6 to 18 months of age. Fecal samples were collected from the children at 6, 12, 18, and 30 months of age and analyzed using 16S rRNA sequencing. Microbiota variables consisted of measures of microbiota diversity (Shannon Index), microbiota maturity (microbiota‐for‐age z score), and the relative abundances of taxa. Morbidity variables included gastrointestinal and respiratory symptoms and fever.

Results:

Diarrhea and respiratory symptoms from 11 to 12 months were predictive of lower microbiota‐for‐age z score and higher Shannon Index, respectively (P = 0.035 and P = 0.023). Morbidity preceding sample collection was predictive of the relative abundances of several bacterial taxa at all time points. Higher microbiota maturity and diversity at 6 months were predictive of a lower incidence rate of fever in the subsequent 6 months (P = 0.007 and P = 0.031).

Conclusions:

Our findings generally do not support the hypothesis that morbidity prevalence predicts a subsequent decrease in gut microbiota maturity or diversity in rural Malawian children. Certain morbidity symptoms may be predictive of microbiota maturity and diversity and relative abundances of several bacterial taxa. Furthermore, microbiota diversity and maturity may be associated with the subsequent incidence of fever.
Phenotypes of Chronic Hepatitis B in Children From a Large North American Cohort
Authors: Schwarz Kathleen B. , Lombardero Manuel , Di Bisceglie Adrian M. , Murray Karen F. , Rosenthal Philip , Ling Simon C. , Cloonan Yona Keich , Rodriguez‐Baez Norberto , Schwarzenberg Sarah Jane , Hoofnagle Jay H. , Teckman Jeffrey ,   Hepatitis B Research Network (HBRN)
Published: August 2019

Objective:

The aim of the study was to define chronic HBV phenotypes in a large, cohort of United States and Canadian children utilizing recently published population‐based upper limit of normal alanine aminotransferase levels (ULN ALT), compared with local laboratory ULN; identify relationships with host and viral factors.

Background:

Chronic hepatitis B virus (HBV) infection has been characterized by phases or phenotypes, possibly associated with prognosis and indications for therapy.

Methods:

Baseline enrollment data of children in the Hepatitis B Research Network were examined. Phenotype definitions were inactive carrier: HBeAg‐negative with low HBV DNA and normal ALT levels; immune‐tolerant: HBeAg‐positive with high HBV DNA but normal ALT levels; or chronic hepatitis B: HBeAg‐positive or ‐negative with high HBV DNA and abnormal ALT levels.

Results:

Three hundred seventy‐one participants were analyzed of whom 274 were HBeAg‐positive (74%). Younger participants were more likely be HBeAg‐positive with higher HBV DNA levels. If local laboratory ULN ALT levels were used, 35% were assigned the immune tolerant phenotype, but if updated ULN were applied, only 12% could be so defined, and the remaining 82% would be considered to have chronic hepatitis B. Among HBeAg‐negative participants, only 21 (22%) were defined as inactive carriers and 14 (14%) as HBeAg‐negative chronic hepatitis B; the majority (61%) had abnormal ALT and low levels of HBV DNA, thus having an indeterminant phenotype. Increasing age was associated with smaller proportions of HBeAg‐positive infection.

Conclusions:

Among children with chronic HBV infection living in North America, the immune tolerant phenotype is uncommon and HBeAg positivity decreases with age.
Photo-Integrated Conversation Moderated by Robots for Cognitive Health in Older Adults: A Randomized Controlled Trial
Authors: Otake-Matsuura Mihoko , Tokunaga Seiki , Watanabe Kumi , Abe Masato S. , Sekiguchi Takuya , Sugimoto Hikaru , Kishimoto Taishiro , Kudo Takashi
Published: August 2019

Background and Objectives

Social interaction might prevent or delay dementia, but little is known about the specific effects of various social activity interventions on cognition. This study conducted a single-site randomized controlled trial (RCT) of Photo-Integrated Conversation moderated by a Robot (PICMOR), a group conversation intervention program for resilience against cognitive decline and dementia.

Research Design and Methods

In the RCT, PICMOR was compared to an unstructured group conversation condition. Sixty-five community-living older adults participated in this study. The intervention was provided once a week for 12 weeks. Primary outcome measures were the cognitive functions; process outcome measures included the linguistic characteristics of speech to estimate interaction quality. Baseline and post-intervention data were collected. PICMOR contains two key features: (i) photos taken by the participants are displayed and discussed sequentially; and (ii) a robotic moderator manages turn-taking to make sure that participants are allocated the same amount of time.

Results

Among the primary outcome measures (i.e., cognitive functions), verbal fluency significantly improved in the intervention group. Among the process outcome measures (i.e., linguistic characteristics of speech), the amount of speech and richness of words were larger for the intervention group.

Discussion and Implications

This study demonstrated for the first time the positive effects of a robotic social activity intervention on cognitive function in healthy older adults via RCT. The group conversation generated by PICMOR may improve participants’ cognitive function controlling the amount of speech produced to make it equal. PICMOR is available and accessible to community-living older adults.
Social Media Surveillance for Perceived Therapeutic Effects of Cannabidiol (CBD) Products
Authors: Tran Tung , Kavuluru Ramakanth
Published: August 2019

Background

CBD products have risen in popularity given CBD’s therapeutic potential and lack of legal oversight, despite lacking conclusive scientific evidence for widespread over-the-counter usage for many of its perceived benefits. While medical evidence is being generated, social media surveillance offers a fast and inexpensive alternative to traditional surveys in ascertaining perceived therapeutic purposes and modes of consumption for CBD products.

Methods

We collected all comments from the CBD subreddit posted between January 1 and April 30, 2019 as well as comments submitted to the FDA regarding regulation of cannabis-derived products and analyzed them using a rule-based language processing method. A relative ranking of popular therapeutic uses and product groups for CBD is obtained based on frequency of pattern matches including precise queries that entail identifying mentions of the condition, a CBD product, and some “trigger” phrase indicating therapeutic use. We validated the social media-based findings using a similar analysis on comments to the U.S. Food and Drug Administration’s (FDA) 2019 request-for-comments on cannabis-derived products.

Results

CBD is mostly discussed as a remedy for anxiety disorders and pain and this is consistent across both comment sources. Of comments posted to the CBD subreddit during the monitored time span, 6.19% mentioned anxiety at least once with at least 6.02% of these comments specifically mentioning CBD as a treatment for anxiety (i.e., 0.37% of total comments). The most popular CBD product group is oil and tinctures.

Conclusion

Social media surveillance of CBD usage has the potential to surface new therapeutic use-cases as they are posted. Contemporary social media data indicate, for example, that stress and nausea are frequently mentioned as therapeutic use cases for CBD without corresponding evidence, that affirms or denies, in the research literature. However, the abundance of anecdotal claims warrants serious scientific exploration moving forward. Meanwhile, as FDA ponders regulation, our effort demonstrates that social data offers a convenient affordance to surveil for CBD usage patterns in a way that is fast and inexpensive and can inform conventional electronic surveys.
Deformable mirror-based two-photon microscopy for axial mammalian brain imaging
Authors: Peinado Alba , Bendek Eduardo , Yokoyama Sae , Poskanzer Kira E.
Published: August 2019

This work presents the design and implementation of an enhanced version of a traditional two-photon (2P) microscope with the addition of high-speed axial scanning for live mammalian brain imaging. Our implementation utilizes a deformable mirror (DM) that can rapidly apply different defocus shapes to manipulate the laser beam divergence and consequently control the axial position of the beam focus in the sample. We provide a mathematical model describing the DM curvature, then experimentally characterize the radius of curvature as well as the Zernike terms of the DM surface for a given set of defocuses. A description of the optical setup of the 2P microscope is detailed. We conduct a thorough calibration of the system, determining the point spread function, the total scanning range, the axial step size, and the intensity curvature as a function of depth. Finally, the instrument is used for imaging different neurobiological samples, including fixed brain slices and in vivo mouse cerebral cortex.
Enhancing sensitivity and controlling false discovery rate in somatic indel discovery
Authors: Köster Johannes , Dijkstra Louis J. , Marschall Tobias , Schönhuth Alexander
Published: August 2019

As witnessed by various population-scale cancer genome sequencing projects, accurate discovery of somatic variants has become of central importance in modern cancer research. However, count statistics on somatic insertions and deletions (indels) discovered so far point out that large amounts of discoveries must have been missed. The reason is that the combination of uncertainties relating to, for example, gap and alignment ambiguities, twilight zone indels, cancer heterogeneity, sample purity, sampling and strand bias are hard to accurately quantify. Here, a unifying statistical model is provided whose dependency structures enable to accurately quantify all inherent uncertainties in short time. As major consequence, false discovery rate (FDR) in somatic indel discovery can now be controlled at utmost accuracy. As demonstrated on simulated and real data, this enables to dramatically increase the amount of true discoveries while safely suppressing the FDR. Specifically supported by workflow design, our approach can be integrated as a post-processing step in large-scale projects.

The software is publicly available at https://varlociraptor.github.io and can be easily installed via Bioconda1 [Grüning et al., 2018].
BMP-signalling inhibition inDrosophilasecondary cells remodels the seminal proteome, and self and rival ejaculate functions
Authors: Hopkins Ben R. , Sepil Irem , Bonham Sarah , Miller Thomas , Charles Philip D. , Fischer Roman , Kessler Benedikt M. , Wilson Clive , Wigby Stuart
Published: August 2019

Seminal fluid proteins (SFPs) exert potent effects on male and female fitness. Rapidly evolving and molecularly diverse, they derive from multiple male secretory cells and tissues. InDrosophila melanogaster, most SFPs are produced in the accessory glands, which are composed of ∼1000 fertility-enhancing ‘main cells’ and ∼40, more functionally cryptic, ‘secondary cells’. Inhibition of BMP-signalling in secondary cells suppresses secretion, leading to a unique uncoupling of normal female post-mating responses to the ejaculate: refractoriness stimulation is impaired, but offspring production is not. Secondary cell secretions might therefore make a highly specific contribution to the seminal proteome and ejaculate function; alternatively, they might regulate more global – but hitherto-undiscovered – SFP functions and proteome composition. Here, we present data that supports the latter model. We show that in addition to previously reported phenotypes, secondary cell-specific BMP-signalling inhibition compromises sperm storage and increases female sperm use efficiency. It also impacts second male sperm, tending to slow entry into storage and delay ejection. First male paternity is enhanced, which suggests a novel constraint on ejaculate evolution whereby high female refractoriness and sperm competitiveness are mutually exclusive. Using quantitative proteomics, we reveal a mix of specific and widespread changes to the seminal proteome that surprisingly encompass alterations to main cell-derived proteins, indicating important cross-talk between classes of SFP-secreting cells. Our results demonstrate that ejaculate composition and function emerge from the integrated action of multiple secretory cell-types suggesting that modification to the cellular make-up of seminal fluid-producing tissues is an important factor in ejaculate evolution.
Metabolic cofactors act as initiating substrates for primase and affect replication primer processing
Authors: Julius Christina , Yuzenkova Yulia
Published: August 2019

Recently a new, non-canonical type of 5’-RNA capping with cellular metabolic cofactors was discovered in bacteria and eukaryotes. This type of capping is performed by RNA polymerases, the main enzymes of transcription, which initiate RNA synthesis with cofactors. Here we show that primase, the enzyme of replication which primes synthesis of DNA by making short RNA primers, initiates synthesis of replication primers using the number of metabolic cofactors. Primase DnaG ofE. colistarts synthesis of RNA with cofactors NAD+/NADH, FAD and DP-CoAin vitro. This activity does not affect primase specificity of initiation. ppGpp, the global starvation response regulator, strongly inhibits the non-canonical initiation by DnaG. Amino acid residues of a “basic ridge” define the binding determinant of cofactors to DnaG. Likewise, the human primase catalytic subunit P49 can use modified substrate m7GTP for synthesis initiation.

For correct genome duplication, the RNA primer needs to be removed and Okazaki fragments ligated. We show that the efficiency of primer processing by DNA polymerase I is strongly affected by cofactors on the 5’-end of RNA. Overall our results suggest that cofactors at the 5’ position of the primer influence regulation of initiation and Okazaki fragments processing.

Visual abstract

A. Non-canonical capping of RNA by RNA polymerase.RNA polymerase uses cellular cofactor as initiating substrate for RNA synthesis, instead of NTP. Then RNA chain grows, while cofactor remains attached and serves as cap.B. Proposed mechanism of non-canonical initiation of RNA primer synthesis by DnaG primase during replication.DnaG primase initiates synthesis of the primer for DNA replication using cellular cofactor. Primer stays annealed with the DNA template. DNApolI encounters cofactor, which affects the removal of primer.
Human cerebral organoids capture the spatiotemporal complexity and disease dynamics of UBE3A
Authors: Sen Dilara , Voulgaropoulos Alexis , Drobna Zuzana , Keung Albert J.
Published: August 2019

Human neurodevelopment and its associated diseases are complex and challenging to study. This has driven recent excitement for human cerebral organoids (hCOs) as research and screening tools. These models are steadily proving their utility; however, it remains unclear what limits they will face in recapitulating the complexities of neurodevelopment and disease. Here we show that their utility extends to key (epi)genetic and disease processes that are complex in space and time. Specifically, hCOs capture UBE3A’s dynamically imprinted expression and subcellular localization patterns. Furthermore, given UBE3A’s direct links to Angelman Syndrome and Autism Spectrum Disorder, we show that hCOs respond to candidate small molecule therapeutics. This work demonstrates that hCOs can provide important insights to focus the scope of mechanistic and therapeutic strategies including revealing difficult to access prenatal developmental time windows and cell types key to disease etiology.
Aquila_stLFR: diploid genome assembly based structural variant calling package for stLFR linked-read
Authors: Liu Yichen Henry , Grubbs Griffin L. , Zhang Lu , Fang Xiaodong , Dill David L. , Sidow Arend , Zhou Xin
Published: August 2019

Motivation

Identifying structural variants (SVs) is of critical importance in health and disease, however, detecting them remains a scientific and computing challenge. Several linked-read sequencing technologies, including 10X linked-read, TELL-Seq, and single tube long fragment read (stLFR), have been recently developed as cost-effective approaches to reconstruct multi-megabase haplotypes (phase blocks) from sequence data of a single sample. These technologies provide an optimal sequencing platform to characterize SVs, though few computational algorithms can utilize them. Thus, we developed Aquila_stLFR, an approach that resolves SVs through haplotype-based assembly of stLFR linked-reads.

Results

Aquila_stLFR first partitions LFRs into two haplotype-specific blocks, by taking advantage of the potential phasing ability of the linked-read itself. Each haplotype is then assembled independently, to achieve a complete diploid assembly to finally reconstruct the genome-wide SVs. We benchmarked Aquila_stLFR on a well-studied sample, NA24385, and showed Aquila_stLFR can detect medium to large size (50bp – 10kb) deletions with a high sensitivity and insertions with a high specificity.

Availability

Source code and documentation are available onhttps://github.com/maiziex/Aquila_stLFR.

Contact

maizie.zhou@vanderbilt.edu

Supplementary information

Supplementary data are available atBioinformaticsonline.
The Clinical Significance and Biological Function ofDPEP1in B-cell Acute Lymphoblastic Leukemia
Authors: Zhang Jia-Min , Xu Yan , Gale Robert Peter , Wu Li-Xin , Zhang Jing , Feng Yong-Huai , Qin Ya-Zhen , Jiang Hao , Jiang Qian , Jiang Bin , Liu Yan-Rong , Chen Yu-Hong , Wang Yu , Zhang Xiao-Hui , Xu Lan-Ping , Huang Xiao-Jun , Liu Kai-Yan , Ruan Guo-Rui
Published: August 2019

Dehydropeptidase-1 (DPEP1) is a zinc-dependent metalloproteinase abnormally expressed in many cancers. However, its potential role in adults with B-cell acute lymphoblastic leukaemia (ALL) is unknown.

We found that in adults with common-B-cell ALL highDPEP1transcript levels at diagnosis was independently-associated with an increased CIR and worse RFS compared with subjects with low transcript levels. We show an increased proliferation and pro-survival role ofDPEP1in B-cell ALL cellsviaregulation of phosphCREB and p53 which may be the biological basis of the clinical correlation we report. Our data implicateDPEP1expression in the biology of common B-cell ALL in adults. We report clinical correlates and provide a potential biological basis for these correlations. If confirmed, analyzingDPEP1transcript levels at diagnosis could help predict therapy-outcomes. Moreover, regulation ofDPEP1expression could be a therapy target in B-cell ALL.
Self-reported health behaviors and longitudinal cognitive performance: Results from the Wisconsin Registry for Alzheimer’s Prevention
Authors: Mueller Kimberly D. , Koscik Rebecca L. , Norton Derek , Morris Martha C. , Jonaitis Erin M. , Clark Lindsay R. , Fields Taylor , Allison Samantha , Berman Sara , Kraning Sarah , Zuelsdorff Megan , Okonkwo Ozioma , Chin Nathaniel , Carlsson Cynthia , Bendlin Barbara B. , Hermann Bruce , Johnson Sterling C.
Published: August 2019

Background

Studies have suggested associations between self-reported engagement in health behaviors and reduced risk of cognitive decline. Most studies explore these relationships using one health behavior, often cross-sectionally or with dementia as the outcome. In this study, we explored whether several individual self-reported health behaviors were associated with cognitive decline when considered simultaneously, using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), an Alzheimer’s disease risk-enriched cohort who were non-demented and in late midlife at baseline.

Method

We analyzed longitudinal cognitive data from 828 participants in WRAP, with a mean age at baseline cognitive assessment of 57 (range = 36-78, sd = 6.8) and an average of 6.3 years (standard deviation = 1.9, range = 2-10) of follow-up. The primary outcome was a multi-domain cognitive composite, and secondary outcomes were immediate/delayed memory and executive function composites. Predictors of interest were self-reported measures of physical activity, cognitive activity, adherence to a Mediterranean-style diet (MIND), and interactions with each other and age. We conducted linear mixed effects analyses within an Information-theoretic (IT) model averaging (MA) approach on a set of models including covariates and combinations of these 2- and 3-way interactions. The IT approach was selected due to the large number of interactions of interest and to avoid pitfalls of traditional model selection approaches.

Results

Model-averaged results identified no significant modifiable behavior*age interactions in relationship to the primary composite outcome. In secondary outcomes, higher MIND diet scores associated with slower decline in executive function. Men showed faster decline than women on delayed memory, independent of health behaviors. There were no other significant interactions among any other health behaviors and cognitive trajectories.

Conclusions

When multiple covariates and health behaviors were considered simultaneously, there were limited weak associations with cognitive decline in this age range. These results may be explained alone or in combination by three alternative explanations: 1) the range of cognitive decline is in middle age is too small to observe relationships with health behaviors, 2) the putative associations of these health behaviors on cognition may not be robust in this age range, or 3) the self-reported measures of the health behaviors may not be optimal for predicting cognitive decline. More study may be needed that incorporates sensitive measures of health behaviors, AD biomarker profiles, and/or other disease comorbidities.
Sirt3 mediated by lentiviral vector in the periaqueductal gray suppresses morphine withdrawal in rats: A preliminary study
Authors: Liu Shue , Yi Hyun , Gu Jun , Ikegami Daigo , Hayashi Kentaro , Hao Shuanglin
Published: August 2019

Opioid use disorder (OUD) is a significant clinical and social problem, inducing dependence/addiction and over-dose death. Opioid dependence/withdrawal contributes to the addiction vulnerability. Limited understanding of the exact mechanisms of morphine withdrawal leads to failure to adequately manage opioid withdrawal symptoms. Determining new molecular mechanisms of morphine withdrawal (MW) may allow development of novel therapeutic strategies for treating this disorder. Chronic morphine with naloxone precipitation induces MW behavioral response. Sirt3 (one member of sirtuins family) as a mitochondrial fidelity, plays an important role in mitochondrial homeostasis through the direct regulation of mitochondrial energy metabolism, ATP synthesis, detoxification of mitochondrial ROS, etc. In the pilot study, we found that (1) cultured neurons infected with lentiviral vector expressing Sirt3 induced over-expression of Sirt3, (2) microinjection of LV-Sirt3 into the vlPAG increased Sirt3 protein expression in rats, (3) MW lowered the expression of Sirt3 in the vlPAG, and (4) microinjection of LV-Sirt3 into the vlPAG decreased the MW behavioral response. Current preliminary study demonstrates that complement of Sirt3 in the PAG suppressed MW, providing a novel therapeutic approach to morphine physical withdrawal symptoms. The exact up-and/or down-stream factors of Sirt3 in the model are under the investigation.
Protein folding modulates the adhesion strategy of Gram positive pathogens
Authors: Alonso-Caballero Alvaro , Echelman Daniel J. , Tapia-Rojo Rafael , Haldar Shubhasis , Eckels Edward C. , Fernandez Julio M.
Published: August 2019

Gram positive bacteria colonize mucosal tissues against large mechanical perturbations, such as coughing, which generate large shear forces that exceed the ability of non-covalent bonds to remain attached. To overcome these challenges, the pathogen Streptococcus pyogenes utilizes the protein Cpa, a pilus tip-end adhesin equipped with a Cys-Gln thioester bond. The reactivity of this bond towards host surface ligands enables covalent anchoring of the bacterium, allowing it to resist large mechanical shocks; however, colonization also requires cell migration and spreading over surfaces. The molecular mechanisms underlying these seemingly incompatible requirements remain unknown. Here, we demonstrate a magnetic tweezers force spectroscopy assay that resolves the dynamics of Cpa thioester bond under force. While folded at forces < 6 pN, Cpa thioester bond reacts reversibly with amine ligands, of common occurrence in inflammation sites; however, mechanical unfolding and exposure to forces higher than 35 pN blocks thioester reactivity entirely. We propose that this folding-coupled thioester reactivity switch allows the adhesin to hop and sample host surface ligands at low force (nomadic mobility phase), and yet gets covalently anchored in place while under mechanical stress (locked phase). We dub such bonds “smart covalent bonds”, adding a novel class to the known repertoire of non-covalent adhesion strategies that include slip bonds, and catch bonds.
Distinct neuronal subtypes of the lateral habenula differentially target ventral tegmental area dopamine neurons
Authors: Wallace Michael L. , Huang Kee Wui , Hochbaum Daniel , Hyun Minsuk , Radeljic Gianna , Sabatini Bernardo L.
Published: August 2019

The lateral habenula (LHb) is an epithalamic brain structure critical for processing and adapting to negative action outcomes. However, despite the importance of LHb to behavior and the clear anatomical and molecular diversity of LHb neurons, the neuron types of the habenula remain unknown. Here we use high-throughput single-cell transcriptional profiling, monosynaptic retrograde tracing, and multiplexed FISH to characterize the cells of the mouse habenula. We find 5 subtypes of neurons in the medial habenula (MHb) that are organized into anatomical subregions. In the LHb we describe 4 neuronal subtypes and show that they differentially target dopaminergic and GABAergic cells in the ventral tegmental area (VTA). These data provide a valuable resource for future study of habenular function and dysfunction and demonstrate neuronal subtype specificity in the LHb-VTA circuit.
G-Protein-Coupled Receptor-Membrane Interactions Depend on the Receptor Activation state
Authors: Bhattarai Apurba , Wang Jinan , Miao Yinglong
Published: August 2019

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as primary targets of ∼1/3 of currently marketed drugs. In particular, adenosine A1 receptor (A1AR) is an important therapeutic target for treating cardiac ischemia-reperfusion injuries, neuropathic pain and renal diseases. As a prototypical GPCR, the A1AR is located within a phospholipid membrane bilayer and transmits cellular signals by changing between different conformational states. It is important to elucidate the lipid-protein interactions in order to understand the functional mechanism of GPCRs. Here, all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method were performed on both the inactive (antagonist bound) and active (agonist and G protein bound) A1AR, which was embedded in a 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) lipid bilayer. In the GaMD simulations, the membrane lipids played a key role in stabilizing different conformational states of the A1AR. Our simulations further identified important regions of the receptor that interacted distinctly with the lipids in highly correlated manner. Activation of the A1AR led to differential dynamics in the upper and lower leaflets of the lipid bilayer. In summary, GaMD enhanced simulations have revealed strongly coupled dynamics of the GPCR and lipids that depend on the receptor activation state.
Conserved abilities of individual recognition and genetically modulated social responses in young chicks (Gallus gallus)
Authors: Versace Elisabetta , Ragusa Morgana , Pallante Virginia
Published: August 2019

The ability to recognise familiar individuals and the motivation to stay in contact with conspecifics are important to establish social relationships from the beginning of life. To understand the genetic basis of early social behaviour, we studied the different responses to familiar/unfamiliar individuals and social reinstatement in 4-day-old domestic chicks (Gallus gallus) in three genetically isolated breeds: Padovana, Polverara and Robusta. All breeds showed a similar ability to discriminate between familiar and unfamiliar individuals, staying closer to familiar individuals. Social reinstatement motivation measured as the average distance between subjects, latency to the first step and exploration of the arena (a proxy for the lack of fear), differed between breeds. More socially motivated chicks that stayed in closer proximity, were also less fearful and explored the environment more extensively. These results suggest that modulation of social behaviour shows larger genetic variability than the ability to recognise social partners, which appears to be an adaptive ability widespread at the species level even for very young animals.
Structural characterization of a hybrid terpyridine–pyrazine ligand and its one-dimensional ZnII coordination polymer: a computational approach to conventional and nonconventional intermolecular interactions
Authors: Granifo Juan , Gaviño Rubén , Suárez Sebastián , Baggio Ricardo
Published: August 2019

The structures of a new hybrid terpyridine–pyrazine ligand, namely 4′-[4-(pyrazin-2-yl)phenyl]-4,2′:6′,4′′-terpyridine (L2), C25H17N5, and its one-dimensional coordination polymer catena-poly[[bis(acetylacetonato-κ2
O,O′)zinc]-μ-4′-[4-(pyrazin-2-yl-κN
4)phenyl]-4,2′:6′,4′′-terpyridine-κN
1], [Zn(C5H7O2)2(C25H17N5)]
n
or [Zn(acac)2(L2)]
n
(Hacac is acetylacetone), are reported. Packing interactions in both crystal structures are analyzed using Hirshfeld surface and enrichment ratio techniques. For the simpler structure of the monomeric ligand, further studies on the interaction hierarchy using the energy framework approach were made. The result was a complete picture of the intermolecular interaction landscape, which revealed some subtle details, for example, that some weak (at first sight negligible) C—H...N interactions in the structure of free L2 play a relevant role in the crystal stabilization.
The many flavours of halogen bonds – message from experimental electron density and Raman spectroscopy
Authors: Wang Ruimin , George Janine , Potts Shannon Kimberly , Kremer Marius , Dronskowski Richard , Englert Ulli
Published: August 2019

Experimental electron-density studies based on high-resolution diffraction experiments allow halogen bonds between heavy halogens to be classified. The topological properties of the electron density in Cl...Cl contacts vary smoothly as a function of the interaction distance. The situation is less straightforward for halogen bonds between iodine and small electronegative nucleophiles, such as nitrogen or oxygen, where the electron density in the bond critical point does not simply increase for shorter distances. The number of successful charge–density studies involving iodine is small, but at least individual examples for three cases have been observed. (a) Very short halogen bonds between electron-rich nucleophiles and heavy halogen atoms resemble three-centre–four-electron bonds, with a rather symmetric heavy halogen and without an appreciable σ hole. (b) For a narrow intermediate range of halogen bonds, the asymmetric electronic situation for the heavy halogen with a pronounced σ hole leads to rather low electron density in the (3,−1) critical point of the halogen bond; the properties of this bond critical point cannot fully describe the nature of the associated interaction. (c) For longer and presumably weaker contacts, the electron density in the halogen bond critical point is only to a minor extent reduced by the presence of the σ hole and hence may be higher than in the aforementioned case. In addition to the electron density and its derived properties, the halogen–carbon bond distance opposite to the σ hole and the Raman frequency for the associated vibration emerge as alternative criteria to gauge the halogen-bond strength. We find exceptionally long C—I distances for tetrafluorodiiodobenzene molecules in cocrystals with short halogen bonds and a significant red shift for their Raman vibrations.
Syntheses and crystal structures of 2-methyl-1,1,2,3,3-pentaphenyl-2-silapropane and 2-methyl-1,1,3,3-tetraphenyl-2-silapropan-2-ol
Authors: Williams Alexandra , Brown Michelle , Staples Richard J. , Biros Shannon M. , Winchester William R.
Published: August 2019

The sterically hindered silicon compound 2-methyl-1,1,2,3,3-pentaphenyl-2-silapropane, C33H30Si (I), was prepared via the reaction of two equivalents of diphenylmethyllithium (benzhydryllithium) and dichloromethylphenylsilane. This bisbenzhydryl-substituted silicon compound was then reacted with trifluoromethanesulfonic acid, followed by hydrolysis with water to give the silanol 2-methyl-1,1,3,3-tetraphenyl-2-silapropan-2-ol, C27H26OSi (II). Key geometric features for I are the Si—C bond lengths that range from 1.867 (2) to 1.914 (2) Å and a τ4 descriptor for fourfold coordination around the Si atom of 0.97 (indicating a nearly perfect tetrahedron). Key geometric features for compound II include Si—C bond lengths that range from 1.835 (4) to 1.905 (3) Å, a Si—O bond length of 1.665 (3) Å, and a τ4 descriptor for fourfold coordination around the Si atom of 0.96. In compound II, there is an intramolecular C—H...O hydrogen bond present. In the crystal of I, molecules are linked by two pairs of C—H...π interactions, forming dimers that are linked into ribbons propagating along the b-axis direction. In the crystal of II, molecules are linked by C—H...π and O—H...π interactions that result in the formation of ribbons that run along the a-axis direction.
Crystal structure of tetramethylammonium 1,1,7,7-tetracyanohepta-2,4,6-trienide
Authors: Bogdanov Georgii , Tillotson John P , Bustos Jenna , Fonari Marina , Timofeeva Tatiana V.
Published: August 2019

The title compound, C4H12N+·C11H5N4
−, contains one tetramethylammonium cation and one 1,1,7,7-tetracyanohepta-2,4,6-trienide anion in the asymmetric unit. The anion is in an all-trans conjugated C=C bonds conformation. Two terminal C(CN)2 dinitrile moieties are slightly twisted from the polymethine main chain to which they are attached [C(CN)2/C5 dihedral angles = 6.1 (2) and 7.1 (1)°]. The C—C bond distances along the heptadienyl chain vary in the narrow range 1.382 (2)–1.394 (2) Å, thus indicating the significant degree of conjugation. In the crystal, the anions are linked into zigzag chains along the [10\overline{1}] direction by C—H...N(nitrile) short contacts. The antiparallel chains stack along the [110] direction with alternating separations between the neighboring anions in stacks of 3.291 and 3.504 Å. The C—H...N short contacts and stacking interactions combine to link the anions into layers parallel to the (\overline{1}01) plane and separated by columns of tetramethylammonium cations.
Synthesis, characterization, crystal structure and supramolecularity of ethyl (E)-2-cyano-3-(3-methylthiophen-2-yl)acrylate and a new polymorph of ethyl (E)-2-cyano-3-(thiophen-2-yl)acrylate
Authors: Al-Refai Mahmoud , Ali Basem F. , Said Ala'a B. , Geyer Armin , Marsch Michael , Harms Klaus
Published: August 2019

The synthesis, crystal structure and structural motif of two thiophene-based cyanoacrylate derivatives, namely, ethyl (E)-2-cyano-3-(3-methylthiophen-2-yl)acrylate (1), C11H11NO2S, and ethyl (E)-2-cyano-3-(thiophen-2-yl)acrylate (2), C10H9NO2S, are reported. Derivative 1 crystallized with two independent molecules in the asymmetric unit, and derivative 2 represents a new monoclinic (C2/m) polymorph. The molecular conformations of 1 and the two polymorphs of 2 are very similar, as all non-H atoms are planar except for the methyl of the ethyl groups. The intermolecular interactions and crystal packing of 1 and 2 are described and compared with that of the reported monoclinic (C2/m) polymorph of derivative 2 [Castro Agudelo et al. (2017). Acta Cryst. E73, 1287–1289].
Crystal structure, Hirshfeld surface analysis and computational studies of 5-[(prop-2-en-1-yl)sulfanyl]-1-[2-(trifluoromethyl)phenyl]-1H-tetrazole
Authors: Slyvka Yurii , Goreshnik Evgeny , Pokhodylo Nazariy , Mys`kiv Marian
Published: August 2019

The title compound, C11H9F3N4S, was synthesized from 2-(trifluoromethyl)aniline by a multi-step reaction. It crystallizes in the non-centrosymmetric space groupPna21, with one molecule in the asymmetric unit, and is constructed from a pair of aromatic rings [2-(trifluoromethyl)phenyl and tetrazole], which are twisted by 76.8 (1)° relative to each other because of significant steric hindrance of the trifluoromethyl group at theorthoposition of the benzene ring. In the crystal, very weak C—H...N and C—H...F hydrogen bonds and aromatic π–π stacking interactions link the molecules into a three-dimensional network. To further analyse the intermolecular interactions, a Hirshfeld surface analysis, as well as interaction energy calculations, were performed.
Relationship between the induced-fit loop and the activity of Klebsiella pneumoniae pullulanase
Authors: Saka Naoki , Malle Dominggus , Iwamoto Hiroyuki , Takahashi Nobuyuki , Mizutani Kimihiko , Mikami Bunzo
Published: August 2019

Klebsiella pneumoniae pullulanase (KPP) belongs to glycoside hydrolase family 13 subfamily 13 (GH13_13) and is the only enzyme that is reported to perform an induced-fit motion of the active-site loop (residues 706–710). Comparison of pullulanase structures indicated that only KPP has Leu680 present behind the loop, in contrast to the glycine found in other GH13_13 members. Analysis of the structure and activity of recombinant pullulanase from K. pneumoniae ATCC 9621 (rKPP) and its mutant (rKPP-G680L) indicated that the side chain of residue 680 is important for the induced-fit motion of the loop 706–710 and alters the binding affinity of the substrate.
The subatomic resolution study of laccase inhibition by chloride and fluoride anions using single-crystal serial crystallography: insights into the enzymatic reaction mechanism
Authors: Polyakov Konstantin M. , Gavryushov Sergei , Fedorova Tatiana V. , Glazunova Olga A. , Popov Alexander N.
Published: August 2019

Laccases are enzymes that catalyze the oxidation of a wide range of organic and inorganic substrates accompanied by the reduction of molecular oxygen to water. Here, a subatomic resolution X-ray crystallographic study of the mechanism of inhibition of the laccase from the basidiomycete fungusSteccherinum murashkinskyiby chloride and fluoride ions is presented. Three series of X-ray diffraction data sets were collected with increasing doses of absorbed X-ray radiation from a nativeS. murashkinskyilaccase crystal and from crystals of complexes of the laccase with chloride and fluoride ions. The data for the native laccase crystal confirmed the previously deduced enzymatic mechanism of molecular oxygen reduction. The structures of the complexes allowed the localization of chloride and fluoride ions in the channel near the T2 copper ion. These ions replace the oxygen ligand of the T2 copper ion in this channel and can play the role of this ligand in the enzymatic reaction. As follows from analysis of the structures from the increasing dose series, the inhibition of laccases by chloride and fluoride anions can be explained by the fact that the binding of these negatively charged ions at the position of the oxygen ligand of the T2 copper ion impedes the reduction of the T2 copper ion.
1-(Cycloheptylidene)thiosemicarbazide
Authors: Singh Mulveer , Anthal Sumati , Sankpal Sandeep S. , Deshmukh Madhukar B. , Kant Rajni
Published: August 2019

The asymmetric unit of the title compound, C8H15N3S, contains two independent molecules. In both molecules, the seven-membered cycloheptane ring adopts a chair conformation. An intramolecular N—H...N hydrogen bond is observed in both molecules, forming S(5) graph-set motifs. In the crystal, the two independent molecules are connected through N—H...S hydrogen bonds, forming dimers which are in turn further connected by N—H...S hydrogen bonds into chains along [010].
Early career values and individual factors of objective career success
Authors: Giraud Laurent , Bernard Alain , Trinchera Laura
Published: August 2019

Purpose

The purpose of this paper is to investigate the early career values and individual factors of objective career success among graduates from a top-tier French business school.

Design/methodology/approach

The authors conducted a quantitative analysis of 629 graduates classified in three job markets according to income: the traditional business market, the alternative market and the high-potential business market. The graduation dates span a period of 12 years before the 2008 Recession.

Findings

The findings suggest that membership of each job market is associated with distinct early career values (when choosing/leaving the first job). Moreover, the authors confirm that the presence of a mentor, international experience, job-hopping and gender, all affect objective career success.

Practical implications

The paper discusses implications for business career development and higher business education.

Originality/value

The originality of this study lies in the identification of the individual factors of objective career success among French business graduates and the links between objective career success and early career values.