bluuebunny/crossref_metadata_2025_split huggingface dataset:
X‐ray Diffraction at Synchrotron Light Sources
Authors: Helliwell John R 
Published: October 2010

Abstract

The elucidation of biological structure and function for macromolecules and their complexes is undertaken extensively using X‐ray diffraction. Synchrotron X‐radiation is widely used, due to its exceptional X‐ray brightness and tunability properties, in protein crystallography, fibre diffraction and solution scattering. The synchrotron is also now increasingly used in chemical crystallography of smaller molecules which obviously are very important with respect to all the various ligands that bind to biomolecules; a special feature is the use of the X‐ray intensity to overcome small crystal volume, in ways entirely analogous to biomolecular microcrystals. Techniques that are complementary to crystallography are electron microscopy (EM) and NMR spectroscopy for structure determination and the study of dynamics. Spectral monitoring of samples is undertaken in time‐resolved crystallography to identify structural intermediates and to monitor for radiation damage of biomolecules including metal atom oxidation state changes.

Key Concepts:

Structure and function relationships are key to understanding of biomolecules and their roles in life processes, the details of which are revealed at the atomic level by X‐ray diffraction.

Conformational changes and information on the dynamics of biomolecules can be determined from several structures in comparison or directly via freeze trapped or time‐resolved structures that have been determined by diffraction studies.

Multi‐macromolecular complexes being large and often flexible are especially challenging for crystallisation of sufficiently ordered crystals.

Synchrotron radiation sources provide intense and tunable X‐rays that are widely used properties but also the properties of the polarisation and the pulsed nature of these sources can be harnessed in special experiments.

Free Electron Lasers (FELs) and X‐ray FELs considerably extend the peak brightnesses available by upto 10 orders of magnitude and shorten the pulse lengths to a few tens of femtoseconds (from sub‐nanoseconds in synchrotrons).

Solving a crystal structure has presented special obstacles since the discovery of X‐ray diffraction but synchrotron radiation has opened up new possibilities based on anomalous X‐ray scattering.

Pharmaceutical design is possible based on a knowledge of the three‐dimensional structure of a protein receptor site for a ligand, an approach known as structure‐based drug discovery and optimisation.

Proteins and their ligands are studied extensively by crystallography either together or separately with the techniques of macromolecular and chemical crystallography, respectively.
Development and Evolution of the Vertebrate Ear's Neurosensory System
Authors: Fritzsch Bernd , Crapon de Caprona Marie‐Dominique 
Published: October 2010

AbstractEar development transforms an area of head ectoderm into a complex three‐dimensional structure carrying three types of sensory systems for gravistatic and angular acceleration sensation as well as hearing. Transformation of the otic ectoderm starts with the specification of neurosensory cells that differentiate into the essential components for the sensory processes, the hair cells, supporting cells and neurons. The role of proneural bHLH genes in this process is presented and put into the context of ear evolution to appreciate how cellular diversity is embedded into the diversification of the ear as whole as well as the evolution of novel sensory capacities in the ear. Ear neurosensory development is characterised by extensive cross‐regulation of multiple factors for cell type specification and fate fixation. Data suggesting that sensory epithelia may directly regulate the formation of their associated structures to guide specific stimuli to the sensory epithelia are presented.Key Concepts:Numerous coexpressed factors regulate transformation of general epidermis to prosensory otic ectoderm.Proneural basic‐Helix–Loop–Helix proteins define cell fate through cross‐regulative interaction.Sensory epithelia regulate formation of accessory structures including aspects of ear morphogenesis.Ear development can best be understood in the context of ear evolution.
Micro
RNAs
and Human Disease
Authors: Marin‐Muller Christian , Yao Qizhi , Chen Changyi 
Published: October 2010

Abstract

Micro
ribonucleic acids
(miRNAs) are a group of small, noncoding RNA molecules 20–22 nucleotides (nt) in length that are predicted to control the activity of approximately 30% of all protein‐coding genes in mammals. Their importance in fine‐tuning the regulation of gene expression is evident in the fact that miRNA dysregulation plays important roles in many diseases, including cancer, cardiovascular disease, diabetes, mental disorders and viral infection. As our understanding of the biogenesis and mechanisms of action of miRNAs has grown over the past decade, so has the promise that miRNAs can serve as valuable therapeutic targets for a large number of diseases. Thus, using miRNAs as therapeutics is the next frontier for the study of these molecules in human disease.

Key Concepts:

The first miRNA (
lin‐4
) was identified in nematodes in 1993.

miRNAs are now predicted to control the activity of approximately 30% of all protein‐coding genes in mammals.

miRNAs regulate gene expression at the posttranscriptional level.

miRNAs function by targeting a specific region of a target mRNA typically located in the 3′ untranslated region (UTR).

miRNAs can function indirectly as either tumour suppressors or oncogenes.

miR‐1 was observed to play a key role in cardiomyocyte differentiation.

miR‐375 regulates insulin secretion by targeting myotrophin.

Expression of miR‐107 decreases early in Alzheimer disease.

miR‐122 is essential for hepatitis C virus (HCV) replication in the liver.
Gap Junctions and Connexins: The Molecular Genetics of Deafness
Authors: Nickel Regina , Forge Andrew 
Published: October 2010

Abstract

Mutations in the gene

GJB2

encoding the gap‐junction protein
connexin 26
(
Cx26
), in particular, and in

GJB6

coding for
connexin 30
(
Cx30
) are the most common cause of autosomal recessive sensorineural hearing loss in many world populations. Variants of

GJB2

are also associated with dominant forms of both nonsyndromic and syndromic deafness. A complex picture of the roles of gap junctions in cochlear physiology has emerged. Rather than being mere conduits for the circulation of potassium ions in the inner ear, gap junctions have been implicated in the maintenance of metabolic homeostasis and in intercellular signalling among nonsensory cells. Studies of mutant channels and mouse models for
connexin
‐related deafness have provided valuable insights into the heterogeneous mechanisms by which
connexin
mutations may cause cochlear dysfunction. Despite recent advances it is still not fully understood what roles gap junctions play in the inner ear and how
connexin
mutations cause deafness.

Key Concepts:

GJB2
and
GJB6
have been mapped to the DFNB1 locus, which accounts for up to 50% of all cases of autosomal recessive nonsyndromic hearing loss.

Molecular genetic tests for DFNB1 should include DNA sequencing of the
GJB2
exons and mutation analysis for
GJB6
deletions.

The identification of factors underlying the phenotypic variability of connexin‐related hearing loss may improve clinical diagnosis and genetic counselling.

A better understanding of the role of gap‐junctional communication in the inner ear and the structure–function relationships of connexin proteins is required for the development of mechanism‐based treatments of connexin‐associated hearing loss.
Membrane Transport in Guard Cells
Authors: Chen Zhong‐Hua , Blatt Michael R 
Published: October 2010

Abstract

One of the most fascinating processes in land plants is the ability to regulate gas exchange and transpiration by the opening and closing of the stomatal pore. The guard cells of stomata serve dual, sometimes conflicting functions in regulating photosynthetic carbon dioxide uptake while minimising water loss by transpiration. Guard cells incorporate complex, flexible and robust membrane transport and control mechanisms. The dominant pathways for potassium, anion, calcium and proton transport have been characterised, both at the plasma membrane and tonoplast, much of this work drawing on electrophysiological techniques such as voltage and patch clamping. Recent genetic and genomic advances have led to the identification of the corresponding genes for several of these transporters. This article summarises the recent progress in guard cell membrane transport and outlooks for a systems biological approach using quantitative kinetic and homeostatic modelling to guide future research work.

Key Concepts:

Guard cells depend on concurrent regulation of parallel and antiparallel transport pathways.

Plasma membrane and tonoplast transport must be coordinated for stomatal function.

Quantitative approaches to kinetic and homeostatic modelling in guard cells will greatly benefit stomatal biology.
Autism: Animal Models
Authors: Bauman Melissa D , Crawley Jacqueline N , Berman Robert F 
Published: October 2010

Abstract

Autism is a life‐long pervasive neurodevelopmental disorder characterised by deficits in social interaction, language development and communication, abnormal repetitive behaviours and severely restricted interests. Autism has proven difficult to study because of the complexity of its behavioural symptoms, complicated genetics and lack of reliable biomarkers. Progress has been made, however, in the development of animal models that allow investigators to model some of the core symptoms of autism, including deficits in social interactions, aspects of social communication and stereotyped, repetitive behaviours. Specific hypotheses can now be formulated and tested using these animal models. This article describes some of the major behavioural approaches and animal models developed to study neurodevelopmental disorders, with a focus on autism spectrum disorders.

Key Concepts:

Autism is a complex disorder whose underlying biology is being studied using rodent and nonhuman primate animal models.

Rodents and nonhuman primates are social animals with rich and complex behavioural repertories that make them useful for modelling neurodevelopmental disorders.

Many of the behaviours that reflect core deficits in autism, including social communication, social interaction and stereotypies, can be modelled in rodents and nonhuman primates.

Inbred strains of mice can be used to discover genes important for the expression of complex behaviours and can provide insight into the neurobiology of social interactions and social communication.

Genetic manipulations possible in mice provide a powerful strategy for investigating the genetic substrates of the disorder, including deletions or overexpression of genes thought to be involved in the aetiology of autism.

Animal models of neurodevelopmental disorders, while important and useful, typically only model specific aspects of a disorder rather that recapitulating its full symptomatology.
Non‐BDNAStructure and Mutations Causing Human Genetic Disease
Authors: Bacolla Albino , Cooper David N , Vasquez Karen M 
Published: October 2010

AbstractIn addition to the canonical right‐handed double helix, several noncanonicaldeoxyribonucleic acid(DNA) secondary structures have been characterised, including quadruplexes, triplexes, slipped/hairpins, Z‐DNA and cruciforms. The formation of these structures is mediated by repetitive sequence motifs, such as G‐rich sequences, purine/pyrimidine tracts, direct (tandem) repeats, alternating purine–pyrimidines and inverted repeats, respectively. Such repeats are abundant in the human genome and are found in association with specific classes of genes, supporting a role for them in gene regulation or protein function. Repetitive sequence motifs are also commonly found at sites of chromosomal alteration, including gross rearrangements and copy number variations (CNVs) associated with both disease and phenotypic variation. Finally, variable number tandem repeats (VNTRs) or microsatellites are present in many gene regulatory regions. Characterised by an inherent capacity to expand spontaneously, such sequences are not only known to cause >30 neurological diseases but may also contribute to human disease susceptibility. The formation of alternative non‐B DNA structures is believed to promote genomic alterations by impeding efficient DNA replication and repair.Key Concepts:The structure of DNA is polymorphic as well as its sequence; in addition to the canonical right‐handed double helix (B‐DNA), repetitive sequences can also adopt alternative (non‐B DNA) conformations such as quadruplexes, triplexes, slipped/hairpins, Z‐DNA and cruciforms.Repetitive DNA sequences are found at locations within many human genes that suggest they can either affect transcription or alternatively encode homopolymeric amino acid runs that could be important for either protein–protein or protein–DNA/RNA interactions.The integrity of the Y‐chromosome depends on large inverted repeats, which have the capacity to form cruciform structures that may potentiate intrachromosomal recombination.Copy number variation (CNV) is a form of genetic alteration that, by involving thousands of loci in the genome, contributes to human individuality.Repetitive sequences capable of forming non‐B DNA are found at sites of chromosomal breaks, CNVs and other rearrangements such as translocations and gene conversion events, which can contribute to human genetic disease.The recurrent translocation t(22;11) events associated with Emanuel syndrome are mediated by cruciform structures that occur at inverted repeats.Tandem repeats (microsatellites) may expand within gene sequences, contributing to more than 30 neurological diseases. Present in variable number in genes in the population, they may contribute to human disease susceptibility.Experiments in model systems and bioinformatic analyses support the conclusion that repetitive sequences trigger genomic instability by adopting non‐B DNA conformations.Non‐B DNA structures stimulate mutations via mechanisms that alter DNA synthesis and repair.
Reproductive Strategies of the Malaria Parasite
Authors: Merino Santiago , Martínez‐de la Puente Josué 
Published: October 2010

AbstractIn spite of its tiny size and its apparent simply life cycle, several recent studies have shown that malaria parasites and their close relatives are able to modify in a relatively complex way their reproductive strategies. Malaria parasites are able to change population sex ratios to optimise reproductive success according to postulates of ‘local mate competition’ theory but also to assure fertilisation following predictions of ‘fertility insurance’ hypothesis. In addition, other potential reproductive strategies of these parasites, as multiple erythrocytic infections, are more probably a defensive mechanism of hosts than a parasitic adaptation. Malaria parasites adapt to environmental circumstances including hosts defences and number of competing parasite lineages present in the host to maximise reproductive and transmission success. The knowledge of these adaptive mechanisms will allow advances in the fight against malaria parasites.Key Concepts:Malaria parasites adapt to hosts responses and parasite competition by changing sex ratios in a way that maximise reproductive and transmission success.Multiple erythrocytic invasions are not a parasite reproductive strategy but could be a defensive mechanism of hosts.
Rates of change and sensitivity to change in cartilage morphology in healthy knees and in knees with mild, moderate, and end‐stage radiographic osteoarthritis: Results from 831 participants from the osteoarthritis initiative
Authors: Eckstein Felix , Nevitt Michael , Gimona Alberto , Picha Kristen , Lee Jennifer H. , Davies Richard Y. , Dreher Donatus , Benichou Olivier , Le Graverand Marie‐Pierre Hellio , Hudelmaier Martin , Maschek Susanne , Wirth Wolfgang ,   Osteoarthritis Initiative Investigators Group
Published: October 2010

AbstractObjectiveTo study the longitudinal rate of (and sensitivity to) change of knee cartilage thickness across defined stages of radiographic osteoarthritis (OA), specifically healthy knees and knees with end‐stage radiographic OA.MethodsOne knee of 831 Osteoarthritis Initiative participants was examined: 112 healthy knees, without radiographic OA or risk factors for knee OA, and 719 radiographic OA knees (310 calculated Kellgren/Lawrence [K/L] grade 2, 300 calculated K/L grade 3, and 109 calculated K/L grade 4). Subregional change in thickness was assessed after segmentation of weight‐bearing femorotibial cartilage at baseline and 1 year from coronal magnetic resonance imaging (MRI). Regional and ordered values (OVs) of change were compared by baseline radiographic OA status.ResultsHealthy knees displayed small changes in plates and subregions (±0.7%; standardized response mean [SRM] ±0.15), with OVs being symmetrically distributed close to zero. In calculated K/L grade 2 knees, changes in cartilage thickness were small (<1%; minimal SRM −0.22) and not significantly different from healthy knees. Knees with calculated K/L grade 3 showed substantial loss of cartilage thickness (up to −2.5%; minimal SRM −0.35), with OV1 changes being significantly (P < 0.05) greater than those in healthy knees. Calculated K/L grade 4 knees displayed the largest rate of loss across radiographic OA grades (up to −3.9%; minimal SRM −0.51), with OV1 changes also significantly (P < 0.05) greater than in healthy knees.ConclusionMRI‐based cartilage thickness showed high rates of loss in knees with moderate and end‐stage radiographic OA, and small rates (indistinguishable from healthy knees) in mild radiographic OA. From the perspective of sensitivity to change, end‐stage radiographic OA knees need not be excluded from longitudinal studies using MRI cartilage morphology as an end point.
Systematic review and meta‐analysis: Anti–tumor necrosis factor α therapy and cardiovascular events in rheumatoid arthritis
Authors: Barnabe Cheryl , Martin Billie‐Jean , Ghali William A. 
Published: October 2010

AbstractObjectiveControl of rheumatoid arthritis (RA) may reduce the risk of cardiovascular events. We sought to systematically assess the association between anti–tumor necrosis factor α (anti‐TNFα) therapy in RA and cardiovascular event rates.MethodsObservational cohorts and randomized controlled trials (RCTs) reporting on cardiovascular events (all events, myocardial infarction [MI], congestive heart failure, and cerebrovascular accident [CVA]) in RA patients treated with anti‐TNFα therapy compared to traditional disease‐modifying antirheumatic drugs were identified from a search of PubMed (1950 to November 2009), EMBase (1980 to November 2009), and conference abstracts. Relative risks (RRs) or hazard ratios and 95% confidence intervals (95% CIs) were extracted. If the incidence was reported, additional data were extracted to calculate an incidence density ratio and its variance.ResultsThe systematic review and meta‐analysis include 16 and 11 publications, respectively. In cohort studies, anti‐TNFα therapy was associated with a reduced risk for all cardiovascular events (pooled adjusted RR 0.46; 95% CI 0.28, 0.77), MI (pooled adjusted RR 0.81; 95% CI 0.68, 0.96), and CVA (pooled adjusted RR 0.69; 95% CI 0.53, 0.89). Meta‐analysis of RCTs also produced a point estimate indicating lower risk of cardiovascular events, but this was not statistically significant (pooled RR 0.85; 95% CI 0.28, 2.59).ConclusionAnti‐TNFα therapy is associated with a reduced risk of all cardiovascular events, MI, and CVA in observational cohorts. There was heterogeneity among cohort studies and possible publication bias. The point estimate of the effect from RCTs is underpowered with wide 95% CIs, and cardiovascular events were secondary outcomes, but RCTs also demonstrated a trend toward decreased risk.
Pain sensitivity and pain reactivity in osteoarthritis
Authors: Lee Yvonne C. , Lu Bing , Bathon Joan M. , Haythornthwaite Jennifer A. , Smith Michael T. , Page Gayle G. , Edwards Robert R. 
Published: October 2010

AbstractObjectiveTo assess experimental pain sensitivity and compare the inflammatory response to pain in 26 osteoarthritis (OA) patients and 33 age‐ and sex‐matched controls from the general population in order to examine the nature of the association between pain and inflammation in OA.MethodsThe participants underwent psychophysical pain testing to assess pain sensitivity in response to heat, cold, and mechanical stimuli. Blood samples were taken at baseline and at 4 time points after testing to determine the effect of acute pain on C‐reactive protein (CRP), interleukin‐6 (IL‐6), IL‐1β, and tumor necrosis factor α levels.ResultsOA patients had lower pressure pain thresholds (P ≤ 0.003) and higher heat pain ratings (P ≤ 0.04) than controls across multiple body sites. OA patients had higher CRP levels than controls (P = 0.007). CRP levels did not change in response to pain testing. Although not statistically significant, OA patients tended to have higher IL‐6 levels than controls (P = 0.12). IL‐6 levels increased after pain testing in OA patients and controls (P < 0.0001), but the amount of increase was not different between the 2 groups. Among OA patients, heightened pain sensitivity was associated with elevated CRP and IL‐6 levels (P ≤ 0.05).ConclusionCompared with controls, OA patients are more sensitive to experimental pain at multiple body sites. IL‐6 levels in OA patients and controls exhibited reactivity to acute painful stimuli, increasing at similar rates after psychophysical pain testing.
The impact of a genome‐wide supported psychosis variant in the ZNF804A gene on memory function in schizophrenia
Authors: Hashimoto Ryota , Ohi Kazutaka , Yasuda Yuka , Fukumoto Motoyuki , Iwase Masao , Iike Naomi , Azechi Michiyo , Ikezawa Koji , Takaya Masahiko , Takahashi Hidetoshi , Yamamori Hidenaga , Okochi Tomo , Tanimukai Hitoshi , Tagami Shinji , Morihara Takashi , Okochi Masayasu , Tanaka Toshihisa , Kudo Takashi , Kazui Hiroaki , Iwata Nakao , Takeda Masatoshi 
Published: October 2010

AbstractA recent genome‐wide association study showed that a variant (rs1344706) in the ZNF804A gene was associated with schizophrenia and bipolar disorder. Replication studies supported the evidence for association between this variant in the ZNF804A gene and schizophrenia and that this variant is the most likely susceptibility variant. Subsequent functional magnetic resonance imaging studies in healthy subjects demonstrated the association of the high‐risk ZNF804A variant with neural activation during a memory task and a theory of mind task. As these cognitive performances are disturbed in patients with schizophrenia, this gene may play a role in cognitive dysfunction in schizophrenia. The aim of the current study was to investigate the potential relationship between this ZNF804A polymorphism and memory function. The effects of the high‐risk ZNF804A genotype, diagnosis, and genotype–diagnosis interaction on verbal memory, visual memory (VisM), attention/concentration, and delayed recall (measured by the Wechsler Memory Scale‐Revised) were analyzed by two‐way analysis of covariance in 113 patients with schizophrenia and 184 healthy subjects. Consistent with previous studies, patients with schizophrenia exhibited poorer performance on all indices as compared to healthy control subjects (P < 0.001). A significant ZNF804A genotype–diagnosis interaction was found for VisM performance (P = 0.0012). Patients with the high‐risk T/T genotype scored significantly lower on VisM than G carriers did (P = 0.018). In contrast, there was no genotype effect for any index in the healthy control subjects (P > 0.05). Our data suggest that rs1344706 may be related to memory dysfunction in schizophrenia. © 2010 Wiley‐Liss, Inc.