bluuebunny/crossref_metadata_2025 huggingface dataset:
Atherosclerosis: Pathogenesis, Genetics and Experimental Models
Authors: Mota Roberto , Homeister Jonathon W , Willis Monte S , Bahnson Edward M
Published: October 2017

Atherosclerosis is a progressive disease of the arteries that results in the development of heart disease and stroke – the most common causes of death in developed countries and a growing socioeconomic burden in developing countries. Atherosclerosis results from an initial injury to the artery endothelium caused by mechanical and environmental factors, resulting in an inflammatory response in the vessel wall. The location and morphology of the atherosclerotic lesions predict the nature of the resulting vascular disease. Many risk factors for the disease are well known, and current therapies are largely directed at modifying them; however, the large array of poorly understood polygenetic factors affects the development of atherosclerosis. Recent developments in genetic studies have been applied to atherosclerosis and are beginning to rapidly reveal the genetic factors that modulate the pathogenesis of this disease.

Key Concepts

Atherosclerosis is a common, costly and deadly vascular disease that affects peoples of developed countries and increasingly burdens developing countries.

Atherosclerosis is an inflammatory disease of the arterial vascular wall.

The pathogenesis of atherosclerosis is complex but is generally explained by the ‘response to injury’ hypothesis for which recent studies in the field extend such hypothesis towards the degree of the inflammatory response to such injury.

Atherosclerotic lesions in humans have distinctive morphological characteristics and complications that differ in current animal models, the clinical manifestations correlate mostly with lesion type and location.

Both environmental and heritable risk factors modulate atherosclerosis development.

Candidate gene and linkage analysis studies have failed to identify previously unknown pathways in the pathogenesis of atherosclerosis.

Recent genome‐wide association studies have reproducibly identified several loci involved in the pathogenesis of atherosclerosis, and most of the identified genes are newly implicated in the disease process.

Rodent models such as APOE‐ and LDLR‐deficient mice are widely used to study the pathogenesis of atherosclerosis because of its reproducibility and genetic manipulation; however, recent studies with novel and bigger animal models more accurately resemble human disease.
Pathological Mutations in 5′ Untranslated Regions of Human Genes
Authors: Chatterjee Sangeeta , Rao Shilpa J , Pal Jayanta K
Published: October 2017

The 5′ untranslated region (5′‐UTR) of a messenger ribonucleic acid (mRNA) plays a critical role in translational regulation by influencing mRNA stability and translation efficiency. Functional elements in the 5′‐UTR such as internal ribosome entry site (IRES), upstream open‐reading frames (uORFs) and iron‐responsive element (IRE) serve to fine tune protein expression in response to cellular requirement. Genetic variations such as mutations and single nucleotide polymorphisms (SNPs) in the 5′‐UTR are associated with a number of human diseases and increased susceptibility to diseases. Such pathological variations disrupt the motifs at the 5′‐UTR and cause diseases such as X‐linked Charcot‐Marie‐Tooth (CMTX) disease, multiple myeloma, hereditary hyperferritinaemia/cataract syndrome (HHCS), familial predisposition to melanoma, Marie Unna hereditary hypotrichosis (MUHH), oesophageal cancer and many others. Genetic and molecular profiling of many diseases has shown that a holistic approach including the UTRs in regular diagnostic deoxyribonucleic acid (DNA) screening would aid in better disease profiling and disease management.

Key Concepts

5′ Untranslated regions (UTRs) are noncoding regions of messenger ribonucleic acids (mRNAs).

The 5′‐UTR is delimited by transcriptional initiation site at 5′ end and the physiological start codon (AUG) at the 3′ end.

Motifs such as internal ribosome entry site (IRES), upstream open‐reading frames (uORFs), iron‐responsive element (IRE) and others are involved in mRNA stability and translational control.

mRNAs encoding regulatory proteins need to be strongly and precisely regulated. These mRNAs are often endowed with longer than average 5′‐UTR, uORFs and stable secondary structures that regulate their translation efficiency.

Mutations are changes in the DNA/genes of an organism, which are heritable.

Mutations that disrupt the functional elements of the 5′‐UTR are often associated with diseases.

Single nucleotide polymorphisms (SNPs) in the 5′‐UTR are associated with drug response and disease risk in an individual.
Neurogenomics of Behavioural Plasticity in Socioecological Contexts
Authors: Baker Matthew R , Hofmann Hans A , Wong Ryan Y
Published: October 2017

Social and ecological challenges often elicit behavioural and physiological responses that are adaptive and subject to selection. The varying behavioural states and traits of animals are a direct output of the nervous system and underlying molecular substrates. Changes in gene expression in response to a variety of contexts such as mate choice, aggression and developmental experience can alter a number of cellular and neural pathways that lead to changes in behaviour. A common framework has emerged to understand the role of the transcriptome in animal behaviour. Behavioural plasticity describes both an individual's ability to modify behavioural states and correlated suites of behaviour in populations, which may constrain variance across contexts. By integrating the study of behavioural plasticity with genome scale, bioinformatics and candidate gene analyses, we are rapidly expanding our understanding of this kind of organismal flexibility, its relationship with the genome and its evolutionary implications.

Key Concepts

To understand animal behaviour fully, both the proximate (causation and ontogeny) and the ultimate (function and evolution) mechanisms of behaviour must be considered and integrated.

Utilising both forward and reverse genetics, candidate genes underlying a behaviour can be better identified and characterised.

The genome is plastic and flexible in response to social or environmental cues, which can lead to changes in behaviour.

Comparative transcriptomics across species can help identify and characterise conserved mechanisms of animal behaviour.

The relationship between behavioural evolution and the processes that generate structural variation in the genome is not well understood and needs to be considered.

The proposed framework will streamline future studies to uncover not only the genetic and neural mechanisms of complex animal behaviours but also its adaptive function and evolution.
Protein–Protein Interactions and Genetic Disease
Authors: Brender Jeffrey R , Zhang Yang
Published: October 2017

The advent of high‐throughput experiments to measure protein–protein interactions has created a flood of proteomic information parallel to the influx of data caused by the advent of next‐generation sequencing technologies. The creation of whole organism protein interaction maps has opened new avenues of predicting genetic disease. Advances in network science now allow the association of genes with disease directly from the characteristics of the protein map without reference to the characteristics of the gene itself. However, none of these techniques has reached the ‘black box’ level and require careful consideration of the systematic errors in both the underlying experimental data and the computational methods to give reliable results. Here, we review the main methods to characterise protein interactions
in vitro
and
in vivo
, the methods by which protein networks are constructed and the characteristics of the major protein interaction databases, and the techniques used to predict the functional impact of mutations on protein interaction networks.

Key Concepts

Protein–protein interactions are the driving force for cellular responses and disruption of protein–protein interfaces.

The sequence conservation of functionally important residues across protein interfaces allows the prediction of disease‐associated mutations.

Disease‐associated mutations often affect protein–protein binding affinities that can be measured with high accuracy
in vitro
using purified proteins by a variety of biophysical techniques.

High‐throughput techniques to measure protein interactions
in vivo
are prone to both high false‐positive and high false‐negative rates.

Each method of identifying protein interactions has systematic errors associated with it that can be partly corrected by cross validating the results with two techniques.

Functional associations between genes can be inferred by bioinformatic approaches, but the results do not necessarily imply a physical interaction between proteins.

Protein–protein interaction databases may include both complexes between proteins and purely functional associations. This distinction must be kept in mind when analysing results from protein–protein interaction databases.

Disease‐associated genes tend to be clustered together in protein–protein interaction networks. It is possible to predict new genes for a disease by a random walk across the protein interaction network from genes already known to be associated with the disease.

Currently, protein–protein interaction surfaces are mostly considered undruggable by small molecules. This belief is changing with new concepts in drug design.
White Matter Tractography and Diffusion‐Weighted Imaging
Authors: Vettel Jean M , Cooper Nicole , Garcia Javier O , Yeh Fang‐Cheng , Verstynen Timothy D
Published: October 2017

Human cognition requires coordinated communication across macroscopic brain networks. This coordination is fundamentally constrained by how populations of neurons are connected together. Understanding how structural connectivity between brain regions constrains or predicts variability within and between individuals is a pervasive topic of cutting edge research in neuroscience and the focus of multimillion dollar investments in brain research (e.g. Human Connectome Project, the White House's B.R.A.I.N initiative). Currently, diffusion‐weighted imaging is the only noninvasive tool for studying the anatomical connectivity of macroscopic networks in the living human brain. Recent innovations in the acquisition and analysis of diffusion‐weighted imaging provide an unprecedented opportunity to examine how an individual's unique structural wiring constrains brain function and cognition and how this unique wiring is sculpted by both genetics and experience across the lifespan.

Key Concepts

The brain consists of 86 billion neurons that have macroscopic gray matter that represents and processes information (brain regions) and white matter that communicates information between disparate brain regions (axonal connections).

To study structural connectivity, diffusion‐weighted imaging (DWI) measures water diffusion using magnetic resonance imaging (MRI) technology, relying on the clever insight that the presence of an axon will restrict the movement of water molecules to align with the direction of the axon's trajectory.

The most popular DWI sampling schemes (DTI, HARDI, and DSI) differ in parameters that trade off between the total time of the scanning session and the resolution of water diffusion direction, which elucidates the direction and size of structural connections.

After diffusion images have been collected using a DWI sequence, reconstruction algorithms convert the raw MR diffusion signal to an estimate of the pattern of directional water movement in each voxel.

Once the fibre directions are reconstructed within a voxel, fibre tractography approaches can be applied to map the trajectories of axon bundles and delineate the path of major structural pathways between the brain regions.

Structural connectivity estimates from tractography have been productively employed to study macroscopic anatomical connections known as the structural human connectome.

To study brain networks, methods from network science represent neuroimaging data as graphs: gray matter brain regions serve as the nodes of the graph, and white matter tractography defines the edges that connect the nodes.

DWI provides an informative lens to investigate how genetics and learning interact and influence our unique structural wiring, including research that can identify an individual from their wiring alone at near perfect accuracy yet still capture plasticity at both short‐term (6 weeks) and long‐term (decades) timescales.
Shaken Baby Syndrome
Authors: Squier Waney
Published: October 2017

The shaken baby syndrome is highly contentious. The term is characteristically applied to infants showing a triad of subdural haemorrhage, retinal haemorrhage and encephalopathy. These three features form part of a cascade of events due to a variety of natural diseases and impact, whether inflicted or accidental. Subdural bleeding and retinal bleeding are very common after birth and reflect immaturity of the brain and its coverings. The demographics of babies with the triad overlap with SIDS (sudden infant death syndrome), suggesting that they may be a subgroup of SIDS.

Over 40 years after the shaking hypothesis was proposed, a systematic review has concluded that it is unjustifiable to infer that shaking has taken place on the basis of this triad. Unless doctors and the courts are aware of this and of the alternative causes of the triad, we risk wrongful convictions and wrongful removal of babies from innocent parents and carers.

Key Concepts

Shaken baby syndrome is a hypothesis and has not to date been supported by science.

There is insufficient evidence to infer that shaking has occurred on the basis of patterns of intracranial bleeding.

Bleeding into the dural membrane around the brain is common in infants and a function of immaturity.

Bleeding into the eyes (retinal haemorrhage) results from raised pressure within the head from any cause.

Retinal haemorrhage is commonly associated with subdural bleeding of any cause and may serve as a marker for it.

Encephalopathy is a nonspecific response of the brain.

An understanding of the specific pathophysiology of the infant brain is essential to determining causes of retinodural bleeding.

Until it is widely recognised that shaking cannot be diagnosed on the basis of patterns of intracranial bleeding, we risk miscarriage of justice and wrongful allegations of abuse.
Using Zebrafish to Study Human Genetic Disease
Authors: Kaslin Jan , Gibert Yann
Published: October 2017

Zebrafish is becoming a more and more popular model organism to study human genetic disease. Recent advances in genome editing, including but not limited to the CRISPR/cas technology, have made zebrafish model one of the fastest, cheapest and easiest model to generate mutations similar to the ones identified in human genetic disorders. Based on its size, zebrafish mutant embryos are also a perfect model to be used in chemical preclinical screens to identify novel molecules that are able to compensate for the partial or total inactivation of a gene. Progress in human genome sequencing has recently identified several novel alleles linked to genetic disorders that can now be tested for the identification of novel therapeutics in a zebrafish mutant modelled to phenocopy the human mutation.

Key Concepts

Zebrafish is a remarkable model to study human genetic diseases

The zebrafish genetic tool box has a novel reliable tool: the CRISPR/cas9 technology for reverse genetics

Zebrafish as a model for drug discovery

Development of zebrafish as a now tool for cure in personalised/precision medicine
Molecular Genetics of the Paroxysmal Dyskinesias
Authors: Kaiyrzhanov Rauan , Houlden Henry
Published: October 2017

Paroxysmal or episodic neurological disorders are frequent in the population and include many common conditions such as migraine, epilepsy and movement disorders. Paroxysmal movement disorders are particularly heterogeneous and difficult to accurately diagnose, but the identification of many new genes and the advent of genetic testing have improved accuracy significantly. Many disease genes in paroxysmal disorders are critical to synaptic function, particularly at the presynaptic terminal where defects in a number of genes that are channels, involved in vesicle release and neurotransmitter receptors have been identified.

Key Concepts

Paroxysmal dyskinesias are clinically complex and often difficult to define.

The genotype–phenotype correlations are not reliable.

Paroxysmal dyskinesias are different from channelopathies.

The major genes are PRRT2, SLC2A1 and MR1.

Multigene diagnostic panels should be used in genetic analysis.
In Cellular Senescence, the Third Circle of the Cell Life's Network,
p53
Acts Vital Role
Authors: Izmirli Muzeyyen
Published: October 2017

The cells rotationally live as Gap 1 (G1), DNA (deoxyribonucleic acid) synthesis (S), Gap 2(G2) and mitosis (M). In response to DNA damage, telomere‐shortening proliferating cells enter the quiescence phase (G0) in which DNA is repaired. If DNA is repaired, the cell can reenter the cell cycle. However, if DNA has double‐strand DNA damage, cellular senescence appears. Thus, cellular senescence is a cell cycle process in which abnormal, DNA‐damaged or ageing cells are gripped irreversibly and permanently during cell cycle as a common stress reaction. Cellular senescence is of five groups according to initiating factor of senescence: replicative senescence, metabolic stress‐induced senescence, DNA damage‐induced senescence, Fas ligand‐induced senescence and oncogene‐induced senescence. Moreover, there are some biomarkers such as p53, p21, mTOR (mechanistic target of rapamycin), ATM/ATR and pRB for senescence. However, the molecular mechanism underlying senescence has been revealed; however, answers have not arisen regarding the precise nature and physiological significance of the senescence for years. Thus, these processes are highlighted in which recent studies of cell cycle events might need to be reviewed with recent molecular studies of senescence by emphasising the key molecular players, p53 and p53‐dependent players.

Key Concepts

What is cell cycle and life?

Why do cells choose senescence or quiescence or apoptosis?

How do cells choose senescence?

When do cells choose senescence?

Which cells choose senescence?

Which important hallmarks do change during cellular apoptosis?

Which physiological things do occur during cellular apoptosis?

Does the alteration of senescence cause pathological situations?
Junk
DNA
and Genome Evolution
Authors: Diaz‐Castillo Carlos
Published: October 2017

Junk DNA (deoxyribonucleic acid) is a remarkably enduring concept considering the difficulty in describing it with a precise undisputed definition and the serious doubts for its usefulness posed by researchers in different biological fields. At the moment, the main value of the junk DNA concept might not depend on what it clearly defines but how it relates with our difficulties in providing satisfying models for the integration of genome organisation, expression and evolution. In a way, junk DNA is not a measure of our knowledge, as much as it reflects our uncertainties. While sanctioning such uncertainties with a specific term might be of very limiting use for areas of research that employ reductionist approaches to mine genomes or find solutions to biomedical and biotechnological problems, the junk DNA concept might still act as enticing fuel for areas that aim to offer an integrative view of biological systems, their diversity and evolutionary history.

Key Concepts

Some biological concepts are difficult to describe with simple definitions accepted by all scientific fields.

Junk DNA is controversial because it is usually defined in virtue of its uselessness for biological systems well being, and it is unclear which is the best demonstration for the lack of function or effect.

Junk DNA might directly descend from protogenomic entities in the RNA world.

Junk DNA might facilitate genome evolution by promoting evolutionary capacitance.

Junk DNA could be better described as vestiges and facilitators of genome evolution.
Role of Protein Phosphorylation among Oxidative Phosphorylation Components
Authors: Bou Marine , Guedouari Hala , Bujold Justin , Hebert‐Chatelain Etienne
Published: October 2017

Mitochondria are important organelles for cellular physiology considering their role in generation of ATP and reactive oxygen species, calcium homeostasis and programmed cell death. In particular, mitochondria produce ATP via oxidative phosphorylation. Mitochondrial activity must be tightly regulated as alteration to the organelle functions can lead to different pathologies including neurodegenerative and metabolic diseases. Phosphorylation of mitochondrial proteins, including the enzymes involved in oxidative phosphorylation, emerged as an important way to modulate mitochondrial metabolism according to physiological conditions. In recent years, several kinases and phosphatases were observed within mitochondria. Numerous phosphorylation sites among the components of the oxidative phosphorylation machinery were observed. These findings open a new field in mitochondrial physiology and cellular biology, showing that well‐known signalling pathways can reach proteins within mitochondria to adjust the organelle activity to extramitochondrial stimuli.

Key Concepts

Mitochondria provide the most part of ATP used by cells via oxidative phosphorylation.

Kinases and phosphatases are present within mitochondria.

Intramitochondrial kinases target several components of the oxidative phosphorylation machinery.

Phosphorylation of mitochondrial proteins represents an important mean to modulate oxidative phosphorylation and other mitochondrial functions.

Better knowledge about translocation of kinases and phosphatases inside mitochondria is needed.
Antigen Processing and Cross‐Presentation
Authors: Pawlak Joanna B , van Kasteren Sander I
Published: October 2017

The human immune system has evolved to defend us from infections by a diverse array of pathogens. To achieve such a feat – especially in the face of species capable of fare, more rapid evolution than ourselves – it has evolved a two‐tiered defence system consisting of an innate part, which has evolved to recognise and respond to evolutionary conserved molecular patterns for which evolution is very slow, and an adaptive part, which has the ability to respond to specific molecular patterns on specific pathogens and can tailor the response against the pathogen. These two branches of the immune system are in intimate interplay: A key information transfer event between the innate and the adaptive immune system is the process by which phagocytic immune cells capture, process and present antigens and peptides from the pathogenic proteome to the body's diverse population of T cells. Recognition of these peptides by specific T cells results in their activation and not in the activation of T cells that are not capable of recognising the pathogenic peptides. This activation leads to T cells activating and adopting its role as orchestrator/executioner in the antipathogen response and is thus a pivotal event in host defence.

Key Concepts

Antigen‐presenting cells take up antigen through endo‐, phago‐ and macropinocytosis.

This material is subjected to a host of degradative enzymes. The proteases found in the endolysosomal system hydrolyse the protein content of the material that was taken up.

Peptides resulting from this degradation can be loaded onto MHC‐II complexes (which are themselves converted to a peptide‐receptive state by lysosomal proteases), resulting in the activation of CD4
+
helper T cells.

Not all resulting peptides are loaded onto MHC‐II complexes. A certain proportion of peptides is also loaded on MHC‐I complexes for activating CD8
+
cytotoxic T cells, which is one of the key steps in the immune‐mediated clearance of tumours and virus‐infected cells.

These MHC‐I complexes normally reside in the endoplasmic reticulum. This presents a trafficking problem: how does endolysosomally located material encounters a peptide complex that is resident in ER?

A wide variety of routing options have been proposed by which this class of antigenic peptide can reach and be loaded onto MHC‐I, such as routes via the cytosol, via ER‐vesicle fusion and many others.
Organocatalytic Enantioselective Friedel–Crafts Alkylation/Lactonization Reaction of Hydroxyindoles with Methyleneoxindoles
Authors: Xiao Mengjie , Xu Dengfeng , Liang Weihong , Wu Wenyu , Chan Albert S. C. , Zhao Junling
Published: October 2017

Functionalization of the indole benzene ring was achieved by using an organocatalytic enantioselective Friedel–Crafts alkylation/lactonization reaction of hydroxyindoles with a variety of substituted methyleneoxindoles. This reaction was applicable to indoles substituted with the hydroxy group at different positions of the benzene ring, and the corresponding pyrrolodihydrocoumarins were obtained in moderate to high yields (37–99%) with high stereoselectivities (up to 99% ee and >20:1 dr) in most cases. A scale‐up reaction and derivatization of the representative products were also carried out to investigate the usefulness of this protocol.

magnified image
Through‐Bond Energy Transfer Cassette with Dual‐Stokes Shifts for “Double Checked” Cell Imaging
Authors: Xue Xiangdong , Jin Shubin , Li Zhipeng , Zhang Chunqiu , Guo Weisheng , Hu Liming , Wang Paul C. , Zhang Jinchao , Liang Xing‐Jie
Published: October 2017

Organic dyes generally suffer from small Stokes shift that usually leads to self‐quenching and ‐gaining errors during the fluorescent imaging process. Here, a through‐bond energy transfer (TBET) cassette is developed with large Stokes shift to pursue precise cell imaging. The TBET is constructed by covalently conjugated tetraphenylethene (acts as donor) and rhodamine (acceptor) through an acetylene bond. The constructed TBET cassette distinctly behaves as dual‐Stokes shifts, including a large pseudo‐Stokes shift caused by energy transfer, from donor's absorption to acceptor's emission (up to 260 nm) and a smaller Stokes shift of acceptor molecules itself. Due to the intrinsic dual‐Stokes shifts, TBET cassette exhibits specific “dual distinct absorbances, single shared emission” properties, which can be excitated under two different laser channels. By colocalization of the imaging readouts of these two channels, the precisely “double checked” fluorescent imaging is achieved in living cells.
Obesity as a surgical risk factor
Authors: Ri Motonari , Aikou Susumu , Seto Yasuyuki
Published: October 2017

In recent years, both the actual number of overweight/obese individuals and their proportion of the population have steadily been rising worldwide and obesity‐related diseases have become major health concerns. In addition, as obesity is associated with an increased incidence of gastroenterological cancer, the number of obese patients has also been increasing in the field of gastroenterological surgery. While the influence of obesity on gastroenterological surgery has been widely studied, very few reports have focused on individual organs or surgical procedures, using a cross‐sectional study design. In the present review, we aimed to summarize the impacts of obesity on surgeries for the esophagus, stomach, colorectum, liver and pancreas. In general, obesity prolongs operative time. As to short‐term postoperative outcomes, obesity might be a risk for certain complications, depending on the procedure carried out. In contrast, it is possible that obesity doesn't adversely impact long‐term surgical outcomes. The influences of obesity on surgery are made even more complex by various categories of operative outcomes, surgical procedures, and differences in obesity among races. Therefore, it is important to appropriately evaluate perioperative risk factors, including obesity.
MYD88 mutation status does not impact overall survival in Waldenström macroglobulinemia
Authors: Abeykoon Jithma P. , Paludo Jonas , King Rebecca L. , Ansell Stephen M. , Gertz Morie A. , LaPlant Betsy R. , Halvorson Alese E. , Gonsalves Wilson I. , Dingli David , Fang Hong , Rajkumar S. Vincent , Lacy Martha Q. , He Rong , Kourelis Taxiarchis , Reeder Craig B. , Novak Anne J. , McPhail Ellen D. , Viswanatha David S. , Witzig Thomas E. , Go Ronald S. , Habermann Thomas M. , Buadi Francis K. , Dispenzieri Angela , Leung Nelson , Lin Yi , Thompson Carrie A. , Hayman Suzanne R. , Kyle Robert A. , Kumar Shaji K. , Kapoor Prashant
Published: October 2017

Waldenström macroglobulinemia (WM) is an immunoglobulin M‐associated lymphoma, with majority of cases demonstrating MYD88 locus alteration, most commonly, MYD88L265P. Owing to low prevalence of the wild‐type (WT) MYD88 genotype in WM, clinically relevant data in this patient population are sparse, with one study showing nearly a 10‐fold increased risk of mortality in this subgroup compared to patients with MYD88L265P mutation. We studied a large cohort of patients with MYD88L265P and MYD88WT WM, evaluated at Mayo Clinic, Rochester, between 1995 and 2016, to specifically assess the impact of these genotypes on clinical course. Of 557 patients, MYD88L265P mutation status, as determined by allele‐specific polymerase chain reaction, was known in 219, and 174 (79%) of those exhibited MYD88L265P, 157 of 174 patients had active disease. Of 45 (21%) patients with MYD88WT genotype, 44 had active disease. The estimated median follow‐up was 7.0 years; median overall survival was 10.2 years (95% CI: 8.4‐16.5) for MYD88L265P versus 13.9 years (95% CI: 6.4‐29.3) for the MYD88WT (P = 0.86). The time‐to‐next therapy from frontline treatment and the presenting features were similar in the two patient populations. For patients with smoldering WM at diagnosis, the median time‐to‐progression to active disease was 2.8 years (95% CI: 2.2‐3.8) in the MYD88L265P cohort and 1.9 years (95% CI: 0.7‐3.1) in the MYD88WT cohort (P = 0.21). The frequency of transformation to high‐grade lymphoma, or the development of therapy‐elated myelodysplastic syndrome was higher in the MYD88WT cohort (16% versus 4% in the MYD88L265P, P = 0.009). In conclusion, MYD88L265P mutation does not appear to be a determinant of outcome, and its presence may not be a disease‐defining feature in WM. Our findings warrant external validation, preferably through prospective studies.
Aneurysmal bone cysts and pathologic fracture associated with supernumerary ring chromosome 6 in two unrelated patients
Authors: Hurd Lauren M. , Thacker Mihir M. , Okenfuss Ericka , Duker Angela L. , Lou Yang , Harty Mary P. , Conard Katrina , Lian Jane B. , Bober Michael B.
Published: October 2017

Small supernumerary ring chromosome 6 (sSRC[6]) is a rare chromosomal abnormality characterized by a broad clinical phenotype. The spectrum of this disorder can range from phenotypically normal to severe developmental delay and congenital anomalies. We describe two unrelated patients with small SRCs derived from chromosome 6 with a novel bone phenotype. Both patients presented with a complex bone disorder characterized by severe osteopenia, pathologic fractures, and cyst‐like lesions within the bone. Imaging revealed decreased bone mineral density, mutiple multiloculated cysts and cortical thinning. Lesion pathology in both patients demonstrated a bland cyst wall with woven dysplastic appearing bone entrapped within it. In patient 1, array comparative genomic hybridization (CGH) detected a tandem duplication of region 6p12.3 to 6q12 per marker chromosome. Cytogenetic analysis further revealed a complex patient of mosaicism with some cell lines displaying either one or two copies of the marker indicative of both tetrasomy and hexasomy of this region. Patient 2 was mosaic for a sSRC that encompassed a 26.8 Mb gain from 6p21.2 to 6q12. We performed an in‐depth clinical analysis of a phenotype not previously observed in sSRC(6) patients and discuss the potential influence of genes located within this region on the skeletal presentation observed.
OPTN p.Met468Arg and ATXN2 intermediate length polyQ extension in families with C9orf72 mediated amyotrophic lateral sclerosis and frontotemporal dementia
Authors: Farhan Sali M. K. , Gendron Tania F. , Petrucelli Leonard , Hegele Robert A. , Strong Michael J.
Published: October 2017

We have ascertained two families affected with familial amyotrophic lateral sclerosis (ALS) in which they both carry a hexanucleotide repeat expansion in the C9orf72 gene, specifically in individuals who also presented with frontotemporal dementia (FTD) or behavioral variant FTD (bvFTD). While some reports attribute this phenotypic heterogeneity to the C9orf72 expansion alone, we screened for additional genetic variation in known ALS‐FTD genes that may also contribute to or modify the phenotypes. We performed genetic testing consisting of C9orf72 hexanucleotide expansion, ATXN2 polyglutamine (polyQ) expansion, and targeted next generation sequencing using the ONDRISeq, a gene panel consisting of 80 genes known to be associated with neurodegenerative diseases such as ALS, FTD, Alzheimer's disease, Parkinson's disease, and vascular cognitive impairment. In addition to the C9orf72 expansion, we observed an ATXN2 polyQ intermediate length expansion, and OPTN p.Met468Arg in patients who exhibited ALS and FTD or bvFTD. We conclude that the C9orf72 expansion likely explains much of the ALS‐FTD phenotype; however, inheritance of these additional variants likely modifies the disease course and may provide further evidence for biologically relevant oligogenic inheritance in ALS.
Formation of Polymeric Nanocubes by Self‐Assembly and Crystallization of Dithiolane‐Containing Triblock Copolymers
Authors: Margulis Katherine , Zhang Xiangyi , Joubert Lydia‐Marie , Bruening Karsten , Tassone Christopher J. , Zare Richard N. , Waymouth Robert M.
Published: October 2017

Template‐free fabrication of non‐spherical polymeric nanoparticles is desirable for various applications, but has had limited success owing to thermodynamic favorability of sphere formation. Herein we present a simple way to prepare cubic nanoparticles of block copolymers by self‐assembly from aqueous solutions at room temperature. Nanocubes with edges of 40–200 nm are formed spontaneously on different surfaces upon water evaporation from micellar solutions of triblock copolymers containing a central poly(ethylene oxide) block and terminal trimethylene carbonate/dithiolane blocks. These polymers self‐assemble into 28±5 nm micelles in water. Upon drying, micelle aggregation and a kinetically controlled crystallization of central blocks evidently induce solid cubic particle formation. An approach for preserving the structures of these cubes in water by thiol‐ or photo‐induced crosslinking was developed. The ability to solubilize a model hydrophobic drug, curcumin, was also explored.
Gold‐Catalyzed Asymmetric Intramolecular Cyclization of N‐Allenamides for the Synthesis of Chiral Tetrahydrocarbolines
Authors: Wang Yidong , Zhang Peichao , Di Xiaoyu , Dai Qiang , Zhang Zhan‐Ming , Zhang Junliang
Published: October 2017

Highly enantioselective gold‐catalyzed intramolecular cyclization of N‐allenamides was implemented by utilizing a designed chiral sulfinamide phosphine ligand (PC‐Phos). This represents the first example of highly enantioselective intramolecular cyclization of N‐allenamides. The practicality of this reaction was validated in the total synthesis of (R)‐desbromoarborescidine A and formal synthesis of (R)‐desbromoarborescidine C and (R)‐deplancheine. Moreover, the catalyst system PC‐Phos/AuNTf2 proved to be specifically efficient to promote the desymmetrization of N‐allenamides in excellent yields with satisfactory ee values.
Genomes in Focus: Development and Applications of CRISPR‐Cas9 Imaging Technologies
Authors: Knight Spencer C. , Tjian Robert , Doudna Jennifer A.
Published: October 2017

The discovery of the CRISPR‐Cas9 endonuclease has enabled facile genome editing in living cells and organisms. Catalytically inactive Cas9 (dCas9) retains the ability to bind DNA in an RNA‐guided fashion, and has additionally been explored as a tool for transcriptional modulation, epigenetic editing, and genome imaging. This Review highlights recent progress and challenges in the development of dCas9 for imaging genomic loci. The emergence and maturation of this technology offers the potential to answer mechanistic questions about chromosome dynamics and three‐dimensional genome organization in vivo.
Auditory brainstem response in infants and children with autism spectrum disorder: A meta‐analysis of wave V
Authors: Miron Oren , Beam Andrew L. , Kohane Isaac S.
Published: October 2017

Infants with autism spectrum disorder (ASD) were recently found to have prolonged auditory brainstem response (ABR); however, at older ages, findings are contradictory. We compared ABR differences between participants with ASD and controls with respect to age using a meta‐analysis. Data sources included MEDLINE, EMBASE, Web of Science, Google Scholar, HOLLIS, and ScienceDirect from their inception to June 2016. The 25 studies that were included had a total of 1349 participants (727 participants with ASD and 622 controls) and an age range of 0–40 years. Prolongation of the absolute latency of wave V in ASD had a significant negative correlation with age (R2 = 0.23; P = 0.01). The 22 studies below age 18 years showed a significantly prolonged wave V in ASD (Standard Mean Difference = 0.6 [95% CI, 0.5–0.8]; P < 0.001). The 3 studies above 18 years of age showed a significantly shorter wave V in ASD (SMD = −0.6 [95% CI, −1.0 to −0.2]; P = 0.004). Prolonged ABR was consistent in infants and children with ASD, suggesting it can serve as an ASD biomarker at infancy. As the ABR is routinely used to screen infants for hearing impairment, the opportunity for replication studies is extensive. Autism Res 2018, 11: 355–363. © 2017 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc.

Lay Summary

Our analysis of previous studies showed that infants and children with autism spectrum disorder (ASD) have a slower brain response to sound, while adults have a faster brain response to sound. This suggests that slower brain response in infants may predict ASD risk. Brain response to sound is routinely tested on newborns to screen hearing impairment, which has created large data sets to afford replication of these results.
Pupillary Response and Phenotype in ASD: Latency to Constriction Discriminates ASD from Typically Developing Adolescents
Authors: Lynch Georgina T.F. , James Stephen M. , VanDam Mark
Published: October 2017

Brain imaging data describe differences in the ASD brain, including amygdala overgrowth, neural interconnectivity, and a three‐phase model of neuroanatomical changes from early post‐natal development through late adolescence. The pupil reflex test (PRT), a noninvasive measure of brain function, may help improve early diagnosis and elucidate underlying physiology in expression of ASD endophenotype. Commonly observed characteristics of ASD include normal visual acuity but difficulty with eye gaze and photosensitivity, suggesting deficient neuromodulation of cranial nerves. Aims of this study were to confirm sensitivity of the PRT for identifying adolescents with ASD, determine if a phenotype for a subtype of ASD marked by pupil response is present in adolescence, and determine whether differences could be observed on a neurologic exam testing cranial nerves II and III (CNII; CNIII). Using pupillometry, constriction latency was measured serving as a proxy for recording neuromodulation of cranial nerves underlying the pupillary reflex. The swinging flashlight method, used to perform the PRT for measuring constriction latency and return to baseline, discriminated ASD participants from typically developing adolescents on 72.2% of trials. Results further confirmed this measure's sensitivity within a subtype of ASD in later stages of development, serving as a correlate of neural activity within the locus–coeruleus norepinephrine (LC–NE) system. A brainstem model of atypical PRT in ASD is examined in relation to modulation of cranial nerves and atypical arousal levels subserving the atypical pupillary reflex. Autism Res 2018, 11: 364–375. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Lay Summary

Milder forms of autism spectrum disorder (ASD) can be difficult to diagnose based on behavioral testing alone. This study used eye‐tracking equipment and a hand‐held penlight to measure the pupil reflex in adolescents with “high functioning” ASD and in adolescents without ASD. The ASD group showed a delay in pupil response. This is the first eye‐tracking study to conduct this test as typically performed by a clinical provider, demonstrating differences in older individuals with a subtype of ASD.
Structure‐based analysis of Clot as a thioredoxin‐related protein of 14 kDa in Drosophila via experimental and computational approaches
Authors: Kim Kiyoung
Published: October 2017

The clot gene is required for the biosynthesis of drosopterins, the red components of Drosophila eye pigments. However, the enzymatic role of Clot in Drosophila eye pigment formation and the molecular mechanisms underlying Clot function are not fully elucidated. In this study, we cloned and characterized Clot derived from Drosophila cDNA, and results showed that Clot exhibited ∼30% sequence identity with mammalian TRP14. In addition, we reported the three‐dimensional structure of Drosophila Clot based on homology modeling. Furthermore, we identified NFκB as a novel Clot substrate using the I‐TASSER program. The NFκB fragment can bind near the active site of Clot. These findings predicted the novel regulatory mechanisms underlying Clot function in the pyrimidodiazepine synthesis pathway and increased the understanding of the molecular mechanisms and physiological function of Clot in Drosophila eye pigment formation.
Dynamic modeling of green algae cultivation in a photobioreactor for sustainable biodiesel production
Authors: del Rio‐Chanona Ehecatl A. , Liu Jiao , Wagner Jonathan L. , Zhang Dongda , Meng Yingying , Xue Song , Shah Nilay
Published: October 2017

Biodiesel produced from microalgae has been extensively studied due to its potentially outstanding advantages over traditional transportation fuels. In order to facilitate its industrialization and improve the process profitability, it is vital to construct highly accurate models capable of predicting the complex behavior of the investigated biosystem for process optimization and control, which forms the current research goal. Three original contributions are described in this paper. Firstly, a dynamic model is constructed to simulate the complicated effect of light intensity, nutrient supply and light attenuation on both biomass growth and biolipid production. Secondly, chlorophyll fluorescence, an instantly measurable variable and indicator of photosynthetic activity, is embedded into the model to monitor and update model accuracy especially for the purpose of future process optimal control, and its correlation between intracellular nitrogen content is quantified, which to the best of our knowledge has never been addressed so far. Thirdly, a thorough experimental verification is conducted under different scenarios including both continuous illumination and light/dark cycle conditions to testify the model predictive capability particularly for long‐term operation, and it is concluded that the current model is characterized by a high level of predictive capability. Based on the model, the optimal light intensity for algal biomass growth and lipid synthesis is estimated. This work, therefore, paves the way to forward future process design and real‐time optimization.
Metabolic phenotyping of CHO cells varying in cellular biomass accumulation and maintenance during fed‐batch culture
Authors: Fernandez‐Martell Alejandro , Johari Yusuf B. , James David C.
Published: October 2017

CHO cell lines capable of high‐level recombinant protein product biosynthesis during fed‐batch culture are still generally obtained by intensive empirical screening of transfected cells rather than knowledge‐guided cellular engineering. In this study, we investigate how CHO cell lines create and maintain cellular biosynthetic capacity during fed‐batch culture to achieve the optimal combination of rapid exponential proliferation and extended maintenance of high cell biomass concentration. We perform a comparative meta‐analysis of mitochondrial and glycolytic functions of 22 discrete parental CHO cell lineages varying in fed‐batch culture performance to test the hypotheses that (i) “biomass‐intensive” CHO cells exhibit conserved differences in metabolic programming and (ii) it is possible to isolate parental CHO cell lines with a biomass‐intensive phenotype to support fed‐batch bioproduction processes. We show that for most parental CHO cell lines, rapid proliferation and high late‐stage culture performance are mutually exclusive objectives. However, quantitative dissection of mitochondrial and glycolytic functions revealed that a small proportion of clones utilize a conserved metabolic program that significantly enhances cellular glycolytic and mitochondrial oxidative capacity at the onset of late‐stage culture. We reveal the central importance of dynamic metabolic re‐programming to activate oxidative mitochondrial function as a necessary mechanism to support CHO cell biosynthetic performance during culture.
MiR‐29b expression is associated with a dexmedetomidine‐mediated protective effect against oxygen‐glucose deprivation‐induced injury to SK‐N‐SH cells in vitro
Authors: Huang Zhi , Liu Guoli , Zeng Qingfan , Gao Rui , Zhang Shuai , Wang Lizhou , Liu Bingjie , Yu YanLong , Zhao Ansu , Li Rui , Zhou Shi , Yu Wenfeng
Published: October 2017

Ischemic cerebral stroke is a leading cause of death and long‐term disability world‐wide. Neuronal injury following cerebral ischemia initiates a complex series of signaling cascades that lead to neuronal cell death. MicroRNA 29b (miR‐29b) has reported involvement in the pathogenic process of ischemic brain injury. Dexmedetomidine (Dex) is a highly selective α2 adrenergic receptor stimulant that exerts a protective effect on brain tissue. To determine whether Dex might directly influence miR‐29b expression after an ischemic injury, human neuroblastoma SK‐N‐SH cells were subjected to oxygen‐glucose deprivation (OGD) for the purpose of creating a neuronal injury model that mimics the effects of brain ischemia in vitro. Next, the association of miR‐29b with the protective effect of Dex against ischemic brain injury was studied through the enhancement or inhibition of miR‐29b expression by transfection with an miR‐29b mimic or inhibitor. We demonstrated that Dex treatment could reduce miR‐29b expression, increase cell viability, and inhibit cell apoptosis in the OGD‐induced neuronal injury model in vitro. Furthermore, down‐regulation of miR‐29b expression produced effects on OGD‐induced neuronal injuries that were similar to those produced by Dex treatment. Moreover, up‐regulation of miR‐29b reversed the protective effect of Dex treatment against OGD‐induced neuronal injury. Therefore, down‐regulation of miR‐29b expression might play a role in anti‐apoptotic signaling similar to that played by Dex. Elucidation of the role played by miR‐29b in ischemia, and identification of a definite association between Dex and miR‐29b may lead to the development of new strategies for treating ischemic brain injuries.