bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteoporosis: Genetics
Authors: Li Wen‐Feng , Hou Shu‐Xun , Férec Claude , Chen Jian‐Min 
Published: April 2013

Abstract

Osteoporosis is characterised by comprised bone strength predisposing to an increased risk of fracture. It is a complex trait that is influenced by many genetic variants and their interactions with environmental factors. In the past four to five years, we have witnessed an accelerated pace in identifying and validating osteoporosis susceptibility loci, which was largely attributable to the use of genome‐wide association studies (GWAS). At least 15 genes (i.e.

VDR

,

ESR1

,

ESR2

,

LRP5

,

LRP4

,

SOST

,

GRP177

,

OPG

,

RANK

,

RANKL

,

COLIA1

,

SPP1

,

ITGA1

,

SP7

and

SOX6

) may be reasonably assigned as confirmed osteoporosis genes; and new osteoporosis‐associated genes are being increasingly reported. Notably, confirmed and promising osteoporosis genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/β‐catenin signalling pathway and the
RANKL
/
RANK
/
OPG
pathway. The ultimate promise of osteoporosis genetics is not only to better understand the disease process, but more importantly, to lead better therapeutic and preventive interventions.

Key Concepts:

Osteoporosis is characterised by low bone mineral density (BMD) and structural deterioration of bone tissue, leading to an increased risk of fractures that occur mostly at the hip, spine and wrist.

Osteoporosis is the most common metabolic bone disorder worldwide.

The burden of osteoporosis on the healthcare system is extremely large.

Osteoporosis is a complex trait that is influenced by many genetic variants and their interactions with environmental factors.

An accelerated pace in identifying and validating osteoporosis susceptibility loci has been observed in the past four to five years, which was largely attributable to the use of genome‐wide association studies (GWAS).

At least 15 genes (i.e.
VDR
,
ESR1
,
ESR2
,
LRP5
,
LRP4
,
SOST
,
GRP177
,
OPG
,
RANK
,
RANKL
,
COLIA1
,
SPP1
,
ITGA1
,
SP7
and
SOX6
) have recently been assigned as confirmed osteoporosis genes.

The currently reported osteoporosis‐associated genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/β‐catenin signalling pathway and the RANKL/RANK/OPG pathway.

Some newly found genes may be classified into the aforementioned three biological pathways once a clearer picture of their functional roles is developed. New biological pathways may also emerge once more if association and functional data are available.

Both common and rare genetic variants are likely to contribute to osteoporosis.

The advances in the genetics of osteoporosis hold promise for personalised medicine.
Protein Degradation in Cell Cycle
Authors: Shaik Shavali , Liu Pengda , Fukushima Hidefumi , Wang Zhiwei , Wei Wenyi 
Published: April 2013

Abstract

Cell cycle is a series of events that take place within a cell, leading to its division and duplication. Protein degradation through ubiquitin‐mediated proteolysis plays an important role in the cell‐cycle regulation. Most importantly, the Anaphase Promoting Complex/Cyclosome (APC/C) and the Skp1‐Cullin‐1‐F‐box complex (SCF) are the two major E3 ubiquitin ligase complexes that regulate proper cell cycle transitions by timely degrading the various key cell cycle regulators. The SCF complex controls the G1/S and the G2/M transitions by degrading Cyclin D, Cyclin E, p27, CDC6 and Wee1, whereas the APC complex facilitates the transition from metaphase to anaphase by degrading Cyclin A, Cyclin B, Securin and many other substrates. The APC complex also plays an integral role in the maintenance of chromatin metabolism, particularly in G1 and G0 via destruction of the aurora A kinase. These cell cycle transitions are tightly regulated, and defective regulation of cell cycle leads to genomic instability and ultimately cancer development.

Key Concepts:

Cell cycle is an essential physiological process, which generates additional number of cells when the body needs them.

Cell cycle checkpoints are the built‐in control mechanisms that ensure the accuracy of cell division in eukaryotic cells.

The timely destruction of various cell cycle regulators by the APC/C and the SCF complexes is necessary for proper cell cycle progression.

The protein degradation pathways involve the ubiquitin‐mediated modification of substrates, which are subsequently targeted for degradation by the 26S proteasome.

Misregulation of the cell cycle processes leads to abnormal cell division, chromosomal instability and subsequently cancer development.
Baculovirus Expression Strategies for Protein Complex Production
Authors: Sumitra Vijayachandran Lakshmi , Viola Cristina , Berger Imre 
Published: April 2013

Abstract

Protein complexes often contain multiple subunits, and it is these complexes that are at the core of biological function in the cell. Inherently low quantities of protein complexes in eukaryotes can prohibit the extraction of these essential cellular machines from native source material, posing a considerable challenge for functional analysis at the molecular level. The baculovirus expression vector system (BEVS) is particularly useful for recombinantly producing eukaryotic proteins in the quality and quantity required for deciphering their structure and function. Recent efforts have focused on improving reagents and streamlining protocols to routinely express protein complexes by recombinant baculoviruses. The challenge of integration of baculovirus expression in high‐throughput production pipelines for proteins and their complexes is being addressed.

Key Concepts:

Protein complexes are a cornerstone of biological function in the cell.

Recombinant production is essential to study many multiprotein complexes.

Ongoing development of expression systems for producing multiprotein complexes.

BEVS as a method of choice for large‐scale production of complexes requires integration of all genes in a single multigene baculovirus rather than coinfecting insect cell cultures with many baculoviruses.

Creation of new reagents and streamlined protocols to address the challenge of generating multigene baculoviruses for routine laboratory use.

Engineering baculoviruses and new host cell lines to further enhance protein production by BEVS.

Multigene vector generation incorporated into automation pipelines to increase the throughput of protein complex expression by BEVS.
Cyclooxygenase‐2: Biology of Prostanoid Biosynthesis and Metabolism
Authors: Patrignani Paola , Maenthaisong Ratree , Tacconelli Stefania 
Published: April 2013

Abstract

Cyclooxygenase (COX)
‐2 is a key enzyme in the conversion of
arachidonic acid (AA)
to
prostanoids
. Inhibition of COX‐2‐dependent
prostanoids
by nonsteroidal anti‐inflammatory drugs (NSAIDs) (both traditional(t) and selective for COX‐2, named coxibs) is involved in their efficacy in affecting pain and inflammation and in reducing the recurrence of colorectal polyps. However, the use of tNSAIDs and coxibs is associated with a small but consistent increase of cardiovascular (CV) risk which is believed to be due to the reduction of the biosynthesis of endothelial

COX‐2‐dependent prostacyclin (PGI
2
)

. Novel knowledge on the biology of COX‐2 show that endocannabinoids may be the substrate for the COX‐isozyme. Endocannabinoids and endocannabinoid‐derived products of COX‐2‐mediated oxidative metabolism serve a variety of regulatory functions. Interference with endocannabinoid metabolism by NSAIDs might contribute to their pharmacological effects.

Key Concepts:

COX‐2 is overexpressed in inflammation and cancer mainly through posttranscriptional mechanisms involving stabilisation of its mRNA.

Enhanced cytoplasmic levels of RNA stability factors, such as HuR, and reduced levels of microRNAs govern COX‐2 mRNA stability and translational efficiency.

The constitutive expression of COX‐2 in endothelial cells plays an important role in cardiovascular homoeostasis through the generation of prostacyclin.

COX‐2 is the target of NSAIDs, traditional and coxibs, thus leading to therapeutic effects and cardiovascular hazard, in some individuals.

The major mechanism of action of NSAIDs is through the inhibition of the conversion of AA to biologically active prostanoids.

Novel knowledge on the biology of COX‐2 shows that the activity of the COX‐isozyme may be involved in the generation of novel biologically active lipid mediators through the metabolism of endocannabionids.

COX‐2 might affect endocannabinoid tone by contributing to its reduction.

Endocannabinoids activate cannabinoid receptors to serve a variety of regulatory functions.

These novel actions of COX‐2 may suggest their contribution to the therapeutic effects of NSAIDs.

The (R) enantiomers of ibuprofen, naproxen and flurbiprofen, which are inactive to inhibit the metabolism of AA by COX‐2, are potent substrate‐selective inhibitors of endocannabinoid oxygenation.

The discovery of these novel effects of (R) enantiomers of NSAIDs opens the way to develop novel analgesic drugs based on this mechanism of action.
Intrinsically Disordered Proteins
Authors: Rezaei‐Ghaleh Nasrollah , Zweckstetter Markus 
Published: April 2013

Abstract

Intrinsically disordered proteins (IDPs) represent a growing category of proteins, especially in the eukaryotic proteomes. They are linked to a wide variety of biological functions, including those which are commonly impaired in cancer and neurodegenerative diseases. Since IDPs by definition do not adopt a well‐defined native structure in solution but exist as an ensemble of rapidly interconverting conformations, their structural characterisation is highly challenging. However, a large body of evidence accumulated mainly through nuclear magnetic resonance spectroscopy and small‐angle X‐ray scattering techniques indicates that IDPs are far from the statistical random coil polypeptide chains such as chemically denatured proteins, but exhibit a rich diversity of transient local and long‐range structural propensities. Such structural preferences are likely to be of functional importance and may be considered as potential drug targets.

Key Concepts:

A large proportion of proteins, especially in eukaryotic proteomes, do not adopt a well‐ordered structure in near‐physiologic conditions.

The classical tenet of biochemistry, the so‐called ‘structure–function paradigm’, that proteins need to have a well‐ordered structure to be functional, presents a restricted view. Instead, a wide variety of proteins from highly structured to almost completely unstructured ones play functional roles in biological systems.

Intrinsically disordered proteins play crucial roles in cellular processes as diverse as signalling, cell cycle control, molecular recognition, transcription, replication and chaperoning. Accordingly, they are closely linked to pathologic states such as cancer and neurodegenerative disorders.

Biophysical techniques, in particular NMR spectroscopy, SAXS and single‐molecule fluorescence measurements, provide detailed insight into the conformations populated by intrinsically disordered proteins.

The intrinsically disordered proteins are not like statistical coil‐like polypeptide chains, but show local and even long‐range structural preferences.

The ‘ensemble view’ of intrinsically disordered proteins resolves the ‘reconciliation problem’, the apparent inconsistence between their coil‐like hydrodynamic behaviour and presence of secondary and even tertiary contacts.

A more‐detailed structural knowledge of intrinsically disordered proteins might provide a basis for rational drug design against them.
Virocell Concept, The
Authors: Patrick Forterre 
Published: April 2013

AbstractViruses have been historically defined as viral particles (virions). The virocell concept has been proposed to put instead emphasis on the intracellular cycle of virus reproduction. In that view, viral infection transforms the infected cells (either a bacterium, an archaeon or a eukaryote) into a novel type of cellular organism, a virocell, whose aim is to produce virions. The virocell concept has several implications for the question of the origin and nature of viruses. It emphasises that viruses originated after ribosome‐encoding cells (ribocells) and can be considered asbona fide, cellular, living organisms. Notably, the virocell concept helps to realise that novel proteins could originate in two different cellular contexts (either ribocell or virocell) during genome replication/recombination. Considering the diversity, ubiquity and abundance of viruses, a huge proportion of proteins in the biosphere have therefore probably abona fideviral origin. Many of them were later on transferred to genomes of ribocells by viral/plasmid integrations. The concept of virocell thus helps to understand the fundamental role that viruses have played in biological evolution.Key Concepts:Virocells correspond to infected cells producing virons.Ribovirocell are Infected cells that produce virions but can still divide.The virus is a living entity during the intracellular phase of its life cycle.Different organisms (archaea, bacteria, eucaryote or virus) can share the same cell, each one being defined by its own evolutionary trajectory.The ancestors of modern viruses appeared after the invention of the ribosome and modern proteins but before the divergence of modern cells from their last common ancestor.Viruses are a huge source of new genes that originated during replication/recombination of viral genomes.
Protein Conservation in Virus Evolution
Authors: Krupovic Mart , Bamford Dennis H 
Published: April 2013

Abstract

Evolution of viruses is considerably more rapid than that of the cellular organisms that they infect. The reach of sequence‐based evolutionary studies on viruses is therefore rather limited. The tertiary protein structure is generally conserved over longer time periods than the primary one. Indeed, structural studies proved to be more informative for reconstructing deep evolutionary connections between distantly related viruses. It has become apparent that certain viruses infecting hosts from different domains of life are remarkably similar in their virion assembly and architecture, suggesting a common ancestry for these structurally related viruses. Furthermore, the presence of several distinct architectural principles employed by viruses suggested that the origin of the current virosphere has multiple evolutionary origins. Insights obtained from numerous structural studies may not only be successfully used to refine the existing virus classification scheme, but may also lead to a major shift in our understanding on the origin, evolution and organisation of the viral domain.

Key Concepts:

Tertiary protein structure is conserved over longer periods of time than the primary one and thus allows recognising deep evolutionary connections between viruses that have diverged in a distant past.

The ability to build virions (i.e., presence of capsid proteins) is a hallmark feature of viruses that distinguishes them from other mobile genetic elements, such as plasmids and transposons.

Structural studies suggest that certain viruses infecting bacteria, archaea and eukaryotes are evolutionarily related.

Viral lineage hypothesis predicts a common origin for structurally related viruses, infecting hosts from different domains of life.

There are several different viral lineages of structurally distinct viruses, suggesting that the contemporary virosphere has multiple evolutionary origins.

The molecular virion complexity shared by viruses in different domains of life suggests that at the time of the last universal cellular ancestor (LUCA) viruses were already very sophisticated.
Nucleo‐cytoplasmic Large
DNA
Viruses (
NCLDV
) of Eukaryotes
Authors: Koonin Eugene V , Yutin Natalya 
Published: April 2013

Abstract

A group of diverse viruses with large
deoxyribonucleic acid (DNA)
genomes that replicate in the cytoplasm and in some cases partly in the nucleus of eukaryotic cells share a set of conserved genes and probably have evolved from a common ancestral virus. Known as nucleo‐cytoplasmic large
DNA
viruses (NCLDV), this class of viruses encompasses seven families:
Poxviridae, Asfarviridae, Iridoviridae, Ascoviridae, Phycodnaviridae, Mimiviridae
, and a probable new family represented by Marseillevirus and Lausannevirus. The family
Mimiviridae
includes giant viruses that possess genomes of a million or more basepairs that are comparable in size and complexity with some bacterial genomes. Phylogenetic analysis of the conserved genes of the NCLDV and mapping of the resulting phylogeny of the NCLDV onto the phylogeny of their eukaryotic hosts suggest an early origin and primary radiation of the NCLDV, possibly concomitant with the primary radiation of eukaryotes.

Key Concepts:

Seven families of viruses with large double‐stranded DNA genomes together constitute a monophyletic class of viruses known as Nucleo‐Cytoplasmic Large DNA Viruses (NCLDV).

All NCLDV share several genes that encode essential proteins involved in viral genome replication and virion formation.

An evolutionary reconstruction using a maximum‐likelihood model assigns approximately 50 genes coding for most of the key virus functions to the common ancestor of all extant NCLDV.

Some of the NCLDV families infect many diverse eukaryotes whereas many groups of eukaryotes are infected by diverse NCLDV suggesting that the major radiation of the NCLDV occurred at an early stage of evolution, perhaps concomitantly with eukaryogenesis.

The NCLDV includes the largest known viruses: Mimiviruses which encode over 1000 genes and are comparable to bacteria in size and complexity.
MMR
Controversy
Authors: Fitzpatrick Michael 
Published: April 2013

Abstract

The measles, mumps and rubella (MMR) controversy erupted in 1998 when Andrew Wakefield, a medical researcher at a London teaching hospital, suggested that the MMR vaccine, given routinely in the second year of life, caused inflammatory bowel disease and autism. Though the MMR‐autism theory was scientifically discredited by studies in epidemiology and virology, the campaign against MMR was taken up by parents and lawyers, politicians and journalists. It resulted in a fall in the uptake of MMR and outbreaks of measles as well as imposing a new burden of guilt and blame on parents of children with autism. A decade later Wakefield was found guilty by the General Medical Council of serious professional misconduct in relation to the conduct and publication of his research and struck off the medical register. His work was subsequently shown to be fraudulent.

Key Concepts:

The Andrew Wakefield theory that the MMR vaccine caused inflammatory bowel disease and autism provoked a major controversy between 1998 and 2010.

Epidemiological studies in different populations, using different methods, failed to confirm a causal link between MMR and autism.

Virological studies failed to confirm persistent measles infection in children with autism.

The notion of a distinctive inflammatory bowel condition in children with autism – ‘autistic enterocolitis’ – has not been generally accepted by gastroenterologists.

Litigation based on claims of a link between MMR and autism collapsed in the UK in 2003, in the USA in 2009.

Influential journalists promoted Wakefield as a scientific maverick, as a champion of autistic children and as a victim of the medical establishment.

The exposure of ethical violations and other forms of malpractice in the Wakefield research by the journalist Brian Deer led to his disgrace.

In 2010 Wakefield was found guilty of serious professional misconduct and struck off the medical register.

In 2011 the
BMJ
concluded that the Wakefield campaign against MMR ‘was based not on bad science but on a deliberate fraud’.
CRISPR
/
Cas
System and Resistance to Bacteriophage Infection
Authors: Garneau Josiane E , Moineau Sylvain 
Published: April 2013

Abstract

Bacteria and phages co‐evolve in their environments through an arm‐race with bacteria developing strategies to combat infection by diverse phages, while phages finding ways to circumvent them. Clustered regularly interspaced short palindromic repeats (CRISPR) loci, along with several Cas (CRISPR‐associated) proteins, represents a form of immune system widespread in Bacteria and Archaea. The CRISPR loci evolve through the incorporation of short
deoxyribonucleic acid
(DNA) sequences (spacers), derived mostly from extrachromosomal DNA such as phage or plasmid sequences, between two partially palindromic repeats. A CRISPR transcript is produced and cleaved within the repeats by Cas protein(s) with or without other host proteins to produce smaller
ribonucleic acid
fragments (RNAs). These small mature RNAs and Cas proteins target and cleave through base complementarity the invading nucleic acids to ensure cell defence. Phages can also evade the CRISPR/Cas system through point mutations or deletions, forcing the host to adapt by either acquiring new spacers or relying on other defence systems. Hence, phage/host interactions can be appreciated at a microbial population‐wide level through the dynamism of CRISPR/Cas loci.

Key Concepts:

CRISPR/Cas loci are composed of multiple repeat‐spacer units associated with a group of specific genes (
cas
genes).

The spacers (short DNA sequences mainly from extrachromosomal elements including foreign DNA) are inserted into CRISPR loci and serve as a molecular directory and memory to prevent future invasion.

CRISPR/Cas system prevents bacteriophage infection and plasmid transfer.

Depending on the CRISPR/Cas system, the DNA (or RNA) target is cleaved within the proto‐spacer (homologous spacer sequence in the invading element).

The successful cleavage of the target relies on the identity between the bacterial spacer and the target (proto‐spacer).

CRISPR loci are highly variable and constantly respond to a phage/host or plasmid/host co‐evolution.

The CRISPR/Cas can inadvertently acquire self‐DNA and be responsible for some form of auto‐immunity, presumably leading to cell death. To survive this self‐attack, either the targeted genomic DNA is altered by mutation/deletion or the CRISPR/Cas locus is inactivated.

By preventing introduction of plasmid, the CRISPR/Cas system can be used to limit the spread of antibiotic resistance genes.

Natural
bacteriophage insensitive mutants
or
plasmid interfering mutants
can be generated to respectively increase the efficiency or the safety of industrial strains.