bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomedical Strategies for Axonal Regeneration
Authors: Saxena Tarun , Gilbert Ryan J , Pai Balakrishna S , Bellamkonda Ravi V 
Published: April 2013

Abstract

Deficits of the nervous system can be classified into two categories: ‘biochemical’, where replacement of a neurotransmitter like dopamine to a large measure corrects most Parkinsonian motor symptoms, and ‘networking’ deficits, where the connections between two sets of neurons or neurons and muscles are interrupted due to trauma or tumour resection. The underlying theme of all nervous system deficits is the loss of neuronal function. Consequently, the response of the body to an injury or lesion can be classified as being either pro‐regenerative or antiregenerative. Therefore, the goal of all therapies to treat nervous system disorders, ranging from Alzheimer disease to traumatic brain injury, is to foster pro‐regenerative repair mechanisms in nervous tissue. In an attempt to repair such deficits, various biomedical strategies that seek to promote axonal regeneration and plasticity, are being investigated.

Key Concepts:

A key difference between the CNS and the PNS is their differential abilities to repair traumatic damage. The PNS has an inherent capability to repair small injuries; the CNS has little or no ability to repair itself.

Schwann cells provide an organised matrix facilitating functional regeneration and repair in the PNS.

The gold standard in PNS repair using artificial nerve guidance channels is to match or exceed the performance of an autograft.

The glial scar in the CNS presents a highly inhibitory and disorganised terrain to regenerating neurites.

CNS and PNS repair strategies in the future must include multiple therapies acting synergistically.
SRY, Sex Determination and Gonadal Differentiation
Authors: Koopman Peter , Wilhelm Dagmar 
Published: April 2013

AbstractThe commitment to develop into a male or female embryo is dependent on whether testes or ovaries develop from the primordial gonads. This decision is in turn controlled by the function of a gene,SRY, found on the Y chromosome in mammals. The proper expression and function ofSRYin supporting cell precursors induces a cascade of gene expression that causes these cells to differentiate into Sertoli cells. Subsequently, Sertoli cells orchestrate the development of all other cell types resulting in the formation of testes, which produce hormones required for other aspects of male development. In the absence ofSRY, or ifSRYfunction is impaired, the supporting cells differentiate into granulosa cells, ovaries form and the embryo develops as a female.Key Concepts:Sex determination in mammals depends on the presence or absence of the Y‐chromosome geneSRY.SRYinduces a program of gene expression in the sexually ambiguous primordial gonads of the embryo to induce differentiation of Sertoli cells.Once Sertoli cells form, they influence other bipotential cell lineages to differentiate into cell types appropriate for a testis.WhenSRYis absent or dysfunctional, a default genetic program instead causes granulosa cell differentiation and ovary development.Mutations in genes involved in the testis and ovarian differentiation programs can cause human disorders of sex development.
Drosophila
Eye Development and Photoreceptor Specification
Authors: Şahin H Bahar , Çelik Arzu 
Published: April 2013

Abstract

The compound eye of the fruitfly

Drosophila melanogaster

is composed of 800 unit eyes called ommatidia, which are composed of eight neural photoreceptor cells and 12 supporting cells. All these cells are generated from an epithelial sheet called the eye imaginal disc through sequential specification and differentiation achieved by the spatially and temporally restricted expression of transcription factors and signalling pathways. Many of these factors and signals and their mode of action have been identified in recent years. Here, the authors give a brief overview of the molecular pathways that play major roles in photoreceptor specification and their terminal differentiation. Thus, the fly eye has provided important data to current understanding of developmental signalling processes and the specification of neural cell types, their patterning and structure and thus represents one of the most powerful genetic model systems for studying nervous system development.

Key Concepts:

The
Drosophila
eye is a highly preferred model system to dissect molecular interactions and developmental mechanisms of the nervous system.

It consists of ∼800 units called ommatidia; each has eight neural (photoreceptors) and 12 non‐neural (cone, pigment and bristle) cells.

The
Drosophila
eye emerges during late larval and pupal stage, from a monolayer epithelium called the eye‐antenna imaginal disc.

The morphogenetic furrow is a wave of differentiation sweeping across the eye imaginal disc from posterior to anterior initiating sequential differentiation at each line of cells it passes.

The morphogenetic furrow is initiated and pushed by a Hedgehog signal; this short‐range signal induces a long‐range Dpp signal to induce neurogenesis via Atonal, while the Dpp signal is suppressed by a Wingless signal secreted from the anterior margin of the eye imaginal disc.

Once the Morphogenetic Furrow passes a point in the eye imaginal disc, it creates a cluster of proneural cells resembling rosettes; a single cell out of this cluster is selected to become the the founder cell, R8. The rest of the photoreceptor cells are specified with the help of R8, using a network of molecular interactions.

During the development of the retina, the cellular cytoskeleton and cell–cell junctions are actively reorganised.

Although the outer photoreceptors (R1–R6) express dim light‐sensitive rhodopsin Rh1, the inner photoreceptors 7 express either UV‐sensitive rhodopsin Rh3 or rhodopsin Rh4, where the blue‐sensitive rhodopsin Rh5 is always accompanied with Rh6 in photoreceptor 8.

Sequential activation of different transcription factors leads to regional or stochastic determination of photoreceptor subtypes.
Lymphocytes: Recirculation
Authors: Jalkanen Sirpa , Salmi Marko 
Published: April 2013

Abstract

Successful immunosurveillance requires endless patrolling of lymphoid tissues by lymphocytes in search of foreign antigens. Lymphocytes enter the lymphoid tissues either through the blood vessel walls or via the afferent lymphatic vessels. To leave the circulation, bloodborne lymphocytes first tether to the endothelial lining of the vessels and start to roll. After an activation step they firmly adhere and transmigrate through the vessel wall. They then navigate through the tissue stroma following chemotactic and other guidance molecules, possibly encounter their cognate antigens and eventually return via the lymphatic vessels back into the blood to be dispersed to the other tissues of the body. In this tightly controlled process called lymphocyte recirculation, different adhesion molecules and activation signals on the two opposing cell types play a critical role. Dysregulated lymphocyte recirculation is involved in the pathogenesis of many inflammatory diseases and immunodeficiencies, and nowadays several drugs target this process.

Key Concepts:

Lymphocytes continuously recirculate between blood and lymphoid organs.

Majority of the lymphocytes enter the lymph nodes via specialised vessels called high endothelial venules (HEV).

The remaining lymphocytes (15–20%), together with dendritic cells and antigens, enter the lymph nodes via afferent lymphatics.

Lymphocytes leave the lymph nodes via efferent lymphatics.

Lymphocyte recirculation allows the lymphocytes to meet their cognate antigens and other leucocyte subsets to evoke an efficient immune response.

Lymphocytes interact with the vessel wall in a multistep fashion, using several leucocyte surface molecules, which recognise their counter receptors on endothelial cells.

The rolling and tethering of lymphocytes on the vessel wall is mediated by selectins.

Chemokines and their receptors are needed to activate leucocyte integrins.

Activated integrins mediate firm adhesion between lymphocytes and endothelium.

The transmigration of leucocytes into the tissues requires adhesion molecules, proteinases and repair mechanisms.
T Lymphocytes: Cytotoxic
Authors: Gotch Frances M 
Published: April 2013

AbstractCytotoxic T lymphocytes (CTLs) are T cells that have the ability to recognise and destroy other nucleated target cells that express ‘nonself’ or ‘foreign’ peptide (e.g. derived from viral proteins) in the context of major histocompatibility complex (MHC) class I or class II molecules on their surface. Most CTLs are MHC class I restricted CD8 T cells, but some CD4 T cells (besides their well‐known helper and regulatory functions) also have the capacity to recognise and kill infected cells. Cytotoxic T cells are of great importance in host defence against cytosolic pathogens in general.Key Concepts:Cytotoxic T‐cells (cytotoxic T lymphocytes, CTLs) are a subset of lymphocytes that participate in cellular immunity.They originate from haematopoietic stem cells in the bone marrow but develop in the thymus.Their main role is to combat intracellular infection.They possess antigen‐specific receptors (T‐cell receptor, TCR) on their cell surface.Most CTL are CD8+and recognise antigen‐derived peptides presented by MHC class I molecules on the surface of the infected cell.A minority of CTL are CD4+and recognise peptides presented by MHC class II molecules.In addition to destroying infected cells, CTL also play a role in antitumour and autoimmune responses.They destroy infected cells by induction of apoptotic cell death in the target cell.Apoptosis can be induced in the target cell using the granzyme/perforin, Fas/Fas ligand or tumour necrosis factor (TNF)/TNF receptor pathways.
Animal Models of Human Primary Immunodeficiency Diseases
Authors: Blundell Michael P , Kinnon Christine 
Published: April 2013

Abstract

Animals with immunodeficiencies provide useful model systems for the study of corresponding immunological disorders in man. There has been substantial progress made in the availability and numbers of animal models since the 1970s when naturally occurring models were the only source. Improved molecular biology techniques, embryonic stem (ES) cell technologies and the sequencing of whole animal genomes has not only increased the number of models but also has led to improved models, particularly in mice. The increased understanding of the immune system, immune disorders and the generation of novel therapies owes much to animal models of disease. Further work is now in generating larger animal models which in addition to expressing the immunological disorders have a more directly comparable physiology.

Key Concepts:

Animal models of human immunodeficiency have been useful in studying the immune system.

The phenotypes resulting from genetic defects in animals do not always mirror those seen in humans.

Technologies exist to knock‐out, knock‐in and knock‐down relevant genes as well as replace them with human loci in animal models to improve the comparability of the phenotype.

Murine models are the most commonly described and used animal models but technologies are being developed for larger animal models.

Animal models have been crucial in the development of novel therapies for immunodeficiencies.
Immunosuppressive Drugs
Authors: Braun Felix , Becker Thomas , Renders Lutz , Ringe Burckhardt 
Published: April 2013

AbstractImmunosuppressive drugs are used for the prevention or treatment of rejection after transplantation of solid organs, tissues and cells, as well as therapy of autoimmune and a variety of other diseases. Primary goals of immunosuppression are: (1) to effectively control immune responses against foreign antigens and (2) to minimise any undesired drug side effects and toxicities. The development of numerous substances, together with the understanding of their molecular action has paved the way to meet these goals, and to individualise immunosuppression. The objective of this inventory is to give a systematic overview on immunosuppressive agents currently in use or under evaluation for transplantation, as a guide for scientific research and clinical practice.Key Concepts:Immunosuppressive drugs are required for prophylaxis and therapy of rejection in solid organ transplantation.A broad spectrum of immunosuppressive drugs is available and new drugs are in the pipeline or under development.Some immunosuppressive drugs are critical dose drugs with a narrow therapeutic index and require therapeutic drug monitoring.Calcineurin inhibitors are commonly used as the basic immunosuppressives despite their nephrotoxic potential.Immunosuppressive drug combinations with different mode of actions are helpful to lower single drug dosages and avoid drug‐related adverse effects as well as to use synergistic or additive immunosuppressive effects.Many factors (e.g. age, gender, liver or renal dysfunction, genetic polymorphism, drug–drug interactions, etc.) can alter the pharmacokinetics of immunosuppressive drugs.Withdrawal of immunosuppressive medication in solid organ transplantation can cause graft failure.
Xenotransplantation
Authors: Cooper David KC , Ekser Burcin , Ezzelarab Mohamed , Hara Hidetaka 
Published: April 2013

AbstractThe transplantation of organs and tissues across species is called xenotransplantation. The most likely source of animal organs and cells for transplantation into humans is the pig. Pigs, therefore, have been genetically engineered to provide their tissues with some protection against the human immune response. The classical ‘rejection’ of pig organs has largely been overcome, but thromboses (clots) occur in the small blood vessels of the graft. Pigs with human ‘antithrombotic’ genes are now becoming available and it is hoped will prevent this complication. Hearts from genetically engineered pigs have functioned in nonhuman primates for up to 8 months, and pig pancreatic islets (that produce insulin) have controlled diabetes in monkeys for longer than 1 year. The safety of xenotransplantation remains of some concern. Is there a risk of the transfer of a pig infectious microorganism into the community? Present evidence is that this potential risk is low. This potential, however, has legal and regulatory implications.Key Concepts:There is a critical shortage of organs from deceased humans for transplantation into patients with vital organ failure.There are an estimated one and a half million people in the USA alone with Type 1 (juvenile) diabetes who might benefit by the transplantation of pancreatic islets (which secrete insulin).Because of its anatomical and physiological similarities to humans, the pig is in many ways a suitable source of organs and cells for transplantation into patients.Protection from the primate immune response can be achieved in pigs by genetic engineering, which largely consists of introducing into the pig one or more human ‘protective’ genes.The major remaining problem appears to be a tendency for thromboses (clots) to form in the blood vessels of the pig organ graft, but it is hoped this will be resolved by the introduction of human ‘antithrombotic’ genes into the pig.There is some concern that a pig infectious microorganism could be transferred to the human recipient of a pig organ and that this microorganism could be passed on to the recipient's contacts, but this risk is now considered to be low.Clinical trials of pig organ and cell transplantation will need to be regulated by national regulatory agencies such as the FDA in the USA.
Muscle Contraction
Authors: Squire John M 
Published: April 2013

Abstract

Muscular contraction is one of the few biological processes that can be appreciated directly in our everyday lives. In the past few decades a detailed understanding of the underlying molecular processes that produce force and movement has been obtained. Striated muscles contain well organised repeating units called sarcomeres which each include overlapping arrays of filaments of the proteins myosin and actin. Myosin filaments have projections on their surfaces known as crossbridges. These are the myosin head parts of the myosin molecules which form the myosin filament. It is the myosin heads, which are enzymes (ATPases) which interact with actin filaments to produce force and movement. Actin filaments contain additional proteins troponin and tropomyosin which are involved in switching muscle activity on and off (muscle regulation).

Key Concepts:

Vertebrates have two types of striated muscle namely cardiac muscle, which drives our heart and skeletal muscles which move our skeleton.

Vertebrate skeletal muscles contain long thin fibres (multinucleate cells) about 20–100 μm in diameter and very long (mms to cms).

Muscle fibres are parallel arrays of long, thin myofibrils about 2–5 μm in diameter and sometimes as long as the fibres.

Cardiac muscle cells (myocytes) are much shorter than skeletal muscle fibres and link end‐to‐end to provide long lengths of muscle. They also contain myofibrils.

The basic repeating unit in all striated muscles is the sarcomere. In vertebrates this is about 2–2.5 μm long. A myofibril is a long string of sarcomeres.

The sarcomere comprises overlapping arrays of myosin and actin filaments.

Myosin filaments are made of myosin molecules which consist of a rod‐shaped region with two heads on.

The myosin heads projecting from the myosin filament surface can hydrolyse ATP (adenosine triphosphate; they are ATPase enzymes), a process which is accelerated when heads interact with actin to produce force and movement.

In striated muscles the interaction of myosin heads with actin is controlled by the proteins troponin and tropomyosin on the actin filaments.

It is calcium ions released by the sarcoplasmic reticulum around myofibrils in response to nervous stimulus that interact with troponin, move tropomyosin and allow the actin–myosin interaction to proceed.
Calcium Signalling and Regulation of Cell Function
Authors: Bootman Martin D , Rietdorf Katja , Hardy Holly , Dautova Yana , Corps Elaine , Pierro Cristina , Stapleton Eloise , Kang Esther , Proudfoot Diane 
Published: April 2013

Abstract

The calcium ion (Ca
2+
) is a versatile intracellular messenger. It provides dynamic regulation of vast array of cellular processes such as gene transcription, differentiation and contraction. Ca
2+
signals range from microsecond, nanoscopic events to intercellular waves lasting for many seconds. This diversity of Ca
2+
signals arises from the wide assortment of Ca
2+
transport and Ca
2+
buffering processes employed by cells. Additional diversity in Ca
2+
signalling stems from the ability of cells to utilise different sources of Ca
2+
. The cytosol is the principal Ca
2+
signalling compartment. When Ca
2+
ions enter the cytosol they interact with numerous Ca
2+
‐binding proteins, thereby leading to activation, or inhibition, of cellular processes. Specificity is achieved by regulating the spatial and kinetic properties of Ca
2+
signal. In this way, many concurrent Ca
2+
‐sensitive cellular processes can be discretely regulated. A number of pathologies have been related to the breakdown of cellular Ca
2+
homoeostasis or to aberrant Ca
2+
signalling.

Key Concepts:

Calcium is a critical intracellular signal that controls key cell fate decisions.

Calcium signals derive from multiple sources that are accessed by a diverse range of transport mechanisms.

The kinetics and spatial properties of calcium signals determine their impact on cellular activity.

Ca
2+
signals are tissue‐specific and are appropriate to regulate the physiological functions of individual cell types.
Antibody Engineering
Authors: Paul Sudhir , Planque Stephanie 
Published: April 2013

AbstractThe antigen‐binding site of antibodies is composed of the heavy and light chain variable domains (V domains). Therapeutic human antibodies specific for individual antigen can be obtained by inducing adaptive B cell development in transgenic animal or by test‐tube affinity maturation of cloned antibody V domain repertoires. The V domains are recloned as full‐length antibodies to improve their pharmacokinetic behaviour and incorporate effector functions residing in the constant domains. Assembly of the V domains into multivalent constructs improves the binding avidity. Linkage to enzymes, toxins or delivery proteins imparts novel functions to the constructs. Emerging engineering strategies include the development of antibodies with catalytic activity and antibodies that can target intracellular antigens.Key Concepts:Antibodies are highly adaptive structures. They are encoded by germline genes that have diversified over evolutionary time and then undergo further antigen‐driven adaptive development over the life time of an individual organism.The antigen combining site is composed of the antibody light and heavy chain subunit variable domains. The constant domain contributes effector functions such complement activation and Fc receptor binding.Monoclonal antibodies have emerged as a major class of biological drugs for various diseases. The efficacy and safety of monoclonal antibody drugs depend on their antigen recognition affinity, specificity andin vivopharmacokinetics.Understanding the natural process underlying adaptive sequence diversification has permitted isolation of monoclonal antibodies meeting the criteria for therapeutic applications. Antibody display and cloning methods have enabled identification of individual antibodies with defined antigenic specificities from vast repertoires.Improvement of antibody functions can be attained in the test tube by rational or random mutagenesis coupled with directed selection of the mutants.Catalytic antibodies combining the specificity of the antigen‐binding site with the turnover capability of enzymatic sites have emerged as a viable second generation technology for novel antibody applications.
Autoimmune Disease: Diagnosis
Authors: Dey Ida Dzifa , Isenberg David A 
Published: April 2013

Abstract

The diagnosis of autoimmune diseases invariably requires the detection of autoantibodies, in association with suggestive clinical symptoms, which develop in relation to the involvement of specific or nonspecific organ systems. Many autoantibodies have well‐defined target antigens and can be detected with high analytical sensitivity. Autoantibodies act as biomarkers helping to diagnose disease subsets and monitor autoimmune diseases. The indirect immunoflorescence technique remains the hallmark of diagnosis, but is increasingly being replaced by enzyme immunoassays or multiplexed assays. Comprehensive methods of analysing multiple antibodies simultaneously using multiplex assays are being developed for routine use in the diagnosis, study of the specificity and pathophysiology of autoimmune diseases and the development of antigen specific therapies. Clinical proteomics offers the opportunity to identify new disease biomarkers to help in diagnosing and managing autoimmune diseases.

Key Concepts:

The diagnosis of autoimmune diseases depends on clinical suspicion and supportive immunological tests.

Test for autoantibodies only when there is a clinical suspicion of autoimmune disease as weakly positive ANAs may be present in the normal healthy population.

Autoantibodies can be used in diagnosis, monitoring of disease flares and remission, sub‐setting disease, evaluating severity and prognosis.

The indirect immunoflorescence technique remains the hallmark of diagnosis, but is increasingly being replaced by enzyme immunoassays or multiplexed assays.

Multiplexed immunoassays support the identification of multiple autoantibodies from a single determination simultaneously without having to do follow up testing.

Multiplex assays are advantageous as a single test may be used for both screening and determining antibodies of clinical significance.

Clinical proteomics offers the opportunity to identify new disease biomarkers in body fluids, cells and tissues to help diagnose diseases.