bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein–Protein Interactions and Genetic Disease
Authors: Brender Jeffrey R , Zhang Yang 
Published: October 2017

Abstract

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

Abstract

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

AbstractThe 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 ConceptsShaken 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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

AbstractFunctionalization 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

AbstractOrganic 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

AbstractIn 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

AbstractWaldenström 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.