bluuebunny/crossref_metadata_2025_split huggingface dataset:
History of Drug Discovery
Authors: Patrick Graham L 
Published: June 2013

AbstractUntil the nineteenth century, natural extracts from the natural world were the only source of medicines. In the nineteenth century, experimental procedures were developed that were used to purify active principles from these extracts. The first of the semisynthetic analogues were also prepared during the nineteenth century. Towards the end of the century, purely synthetic agents were being prepared and organic synthesis became increasingly important throughout the twentieth century in preparing novel agents. The discovery of penicillin from a fungus sparked a postwar search for other antibiotics, and for lead compounds that were useful in other areas of medicine. In more recent years, advances in genomics and proteomics identified numerous potential drug targets, which initiated the development of automated synthetic methods in order to meet the demand for novel lead compounds. The principles of drug design have evolved over the last century, aided significantly by the development of X‐ray crystallography and computer‐based molecular modelling.Key Concepts:Up until the nineteenth century, the only medicinal therapies available were minerals or crude extracts obtained from natural sources such as plants, herbs and animals.From the nineteenth century, purification methods have been used to isolate the active principles of natural extracts, resulting in the use of many of these agents in medicine.Synthetic methods have been developed since the mid‐nineteenth century permitting the synthesis of clinically useful semisynthetic analogues of pharmacologically active natural products.Synthetic methods have resulted in the generation of purely synthetic structures that are not found in the natural world and have been investigated as potential therapeutic agents.The development of automated parallel and combinatorial syntheses has vastly increased the number of compounds that can be synthesised in any given period of time.Drug design strategies have been developed since the mid‐twentieth century allowing a more focussed approach to the discovery of novel agents.In the last couple of decades, genomics and proteomics have identified huge numbers of novel targets for future drug research.Structure‐based drug design involving X‐ray crystallography and molecular modelling has been developed over the last 30 years allowing researchers to investigate how active compounds interact with their targets at the molecular level, and allowing the rational design of new and improved analogues.De‐novodrug design has been developed over a similar period allowing scientists to study a binding site, then design novel structuresin silicoas potential lead compounds.In the past 20 years, fragment‐based drug design has been used to discover novel ligands for protein targets.
Fitness: Philosophical Problems
Authors: Ramsey Grant , Pence Charles H 
Published: June 2013

AbstractFitness plays many roles throughout evolutionary theory, from a measure of populations in the wild to a central element in abstract theoretical presentations of natural selection. It has thus been the subject of an extensive philosophical literature, which has primarily centred on the way to understand the relationship between fitness values and reproductive outcomes. If fitness is a probabilistic or statistical quantity, how is it to be defined in general theoretical contexts? How can it be measured? Can a single conceptual model for fitness be offered that applies to all biological cases, or must fitness measures be case‐specific? Philosophers have explored these questions over the last several decades, largely in the context of an influential definition of fitness proposed in the late 1970s: the propensity interpretation. This interpretation as first described undeniably suffers from significant difficulties, and debate regarding the tenability of amendments and alternatives to it remains unsettled.Key Concepts:Actual offspring production is an unsuitable definition of fitness.The propensity interpretation of fitness was proposed as a way to base fitness on expected, rather than actual, offspring production.The propensity interpretation is problematic, as it makes fitness difficult to measure, relies centrally on the arithmetic mean and fails to take into account local environmental factors.Some philosophers have rejected the propensity interpretation in favour of an ecological fitness concept or a purely statistical fitness concept.Others have attempted to modify the propensity interpretation in order to resolve its problems.The debate over which of these concepts of fitness best solves the philosophical problems at hand remains unsettled.
Fixation Probabilities and Times
Authors: Otto Sarah P , Whitlock Michael C 
Published: June 2013

Abstract

The fixation probability of an allele is the probability that it will eventually be the ancestor of all the alleles within a population at that locus. Population genetics theory has demonstrated that the probability of fixation is approximately proportional to the selection coefficient of a weak beneficial mutation, because such mutations are susceptible to stochastic loss while being rare despite their advantage. The time to fixation is the number of generations that it takes for an allele to progress from its initial frequency to fixation. This time is inversely proportional to the selection coefficient of a beneficial allele. Interestingly, though deleterious alleles are much less likely to fix, the time that they take to do so is, on average, the same as for a beneficial allele with the same magnitude of selective effect.

Key Concepts:

The fixation probability of an allele is the probability that it will eventually be the ancestor of all the alleles within a population at that locus.

Even beneficial mutations may not fix within a population.

The fixation probability of a beneficial allele is approximately proportional to its selection coefficient.

Deleterious mutations are unlikely to fix, but they can fix if their selective disadvantage is sufficiently weak and the population size sufficiently small.

The time for a new allele to fix within a population is inversely proportional to the magnitude of selection for both beneficial and deleterious alleles.
Ethylene
Authors: Chang Caren , Schaller G Eric , Resnick Josephine S 
Published: June 2013

Abstract

Ethylene, a simple hydrocarbon gas, is a plant growth regulator that profoundly affects growth and development. Ethylene plays an important role in a wide range of processes, including fruit ripening, abscission, senescence and responses to biotic and abiotic stresses. Plants synthesise ethylene in response to diverse developmental factors and environmental stimuli. Responses to ethylene occur through a conserved ethylene signalling pathway that was first elucidated by molecular genetic dissection in the plant

Arabidopsis thaliana

. The ethylene‐signalling pathway comprises a unique combination of signalling components, beginning with ethylene receptors localised primarily at the endoplasmic reticulum membrane. Ethylene signalling leads to changes in gene expression in the nucleus. Ethylene also exhibits complex interactions with the signalling pathways of a number of other plant signals. An understanding of the regulatory mechanisms involved in ethylene biosynthesis and ethylene signalling has important agricultural and economic implications.

Key Concepts:

Ethylene gas (C
2
H
4
) is a plant growth regulator that has profound effects on growth and development.

Plants synthesise ethylene from the amino acid
l
‐methionine via a simple biosynthetic pathway consisting of three enzymatic steps.

Gene family members encoding the ethylene biosynthesis enzymes are differentially expressed in response to diverse developmental and environmental factors; additionally, ACC synthase isozymes, which catalyse the penultimate step in the pathway, are regulated by protein turnover.

The ethylene signalling pathway, which was genetically dissected in the reference plant
Arabidopsis
, is conserved in plants and involves a unique combination of signalling components.

The ethylene signal is perceived by protein complexes residing at the ER membrane and transduction of the signal activates a transcriptional cascade resulting in rapid changes in gene expression.

Protein turnover plays a critical role in both ethylene biosynthesis and ethylene signalling.

Ethylene displays complex interactions with a variety of other signals to control a wide array of processes.

The ability to control ethylene biology has far‐reaching consequences in agriculture and horticulture.
Molecular Genetics of Achondroplasia
Authors: Narayana Jyoti , Horton William A 
Published: June 2013

Abstract

Affecting approximately 250 000 individuals worldwide, achondroplasia (Ach) represents a family of skeletal dysplasias. Although inherited as an autosomal dominant trait, it results most often from a new mutation to unaffected parents. Virtually all patients have the same mutation in the gene that codes for the receptor tyrosine kinase, FGFR3. The mutation exaggerates the receptor's inhibitory functions on bone growth resulting in characteristic clinical features. Similar mutations of
FGFR3
cause other members of this disease family. Our understanding of how mutant FGFR3 antagonises bone growth remains incomplete, and delineating the relevant molecular details has proved challenging. Nevertheless, new insights into the FGFR3 biology, that is, downstream FGFR3 signals are modulated by the paracrine hormone CNP, FGFR3 is processed to a fragment with potential nuclear function and FGFR3 signal output is influenced by the molecular chaperone Hsp90, have advanced the field and provided a glimpse into future growth stimulating treatments for Ach.

Key Concepts:

Achondroplasia is the prototype of a ‘family’ of human skeletal dysplasias characterised by dwarfism and characteristic craniofacial manifestations.

Achondroplasia results from gain of function mutations of the tyrosine kinase‐mediated receptor, FGFR3, which is an important negative regulator of linear bone growth.

Although achondroplasia can be inherited as an autosomal dominant trait, it most often results from
de‐novo
mutations to nonachondroplastic parents. The new mutations display a paternal age effect. Virtually all patients with achondroplasia have the same
FGFR3
mutation.

Other mutations of
FGFR3
that enhance its function cause similar but more or less severe dwarfing conditions, such as thanatophoric dysplasia and hypochondroplasia.

FGFR3 acts through ‘signals’ it transmits to the cellular machinery that regulates the proliferation and other behaviours of cells responsible for bone growth – chondrocytes that occupy the growth plates of growing bones. The predominant signalling output involves tyrosine kinase cascades collectively referred to as the MAPK signalling pathway. FGFR3 receptors bearing the achondroplasia mutation exhibit exaggerated MAPK signalling when investigated in both cell culture and mouse models of achondroplasia.

The major goal in developing treatments for achondroplasia has been to safely reduce the output of FGFR3 signals to or towards normal. Strategies have ranged from blocking receptor activation to inhibiting FGFR3 tyrosine kinase activity to shortening the survival of actively signalling receptor to antagonising signals downstream of the receptor. These strategies are based on understanding the relevant molecular events. The most promising strategy at present involves administration of the peptide, CNP, which antagonises MAPK signals initiated by FGFR3.
Genetics of Lipodystrophies
Authors: Vigouroux Corinne , Bidault Guillaume , Capeau Jacqueline 
Published: June 2013

Abstract

Human genetic lipodystrophic syndromes are rare conditions with total or partial body fat loss, severe lipid and glucose alterations and insulin resistance, leading to early diabetes, cardiovascular and hepatic complications. Most generalised forms, recessively inherited, result from mutations in four proteins, mainly 1‐acylglycerol‐3‐phosphate‐O‐acyltransferase‐2 (AGPAT2) involved in triglyceride synthesis, or seipin involved in the adipocyte lipid droplet formation/maintenance but also in caveolin‐1 and cavin‐1/polymerase I and transcript release factor, expressed in caveolae and at the lipid droplet surface. Partial lipodystrophic syndromes, generally dominantly inherited, mainly involve A‐type lamins (
LMNA)
, forming the nuclear lamina, or the adipogenic transcription factor peroxisome proliferator‐activated‐receptor‐gamma. Less frequently Akt2, in the insulin signalling pathway, perilipin and cell‐death‐inducing‐DFF45‐like‐effector‐C, controlling adipocyte triglyceride storage, are affected. Insulin resistance and lipodystrophy can also be present in genetic syndromes of premature ageing as the Hutchinson–Gilford progeria or mandibuloacral dysplasia (
LMNA
or
ZMPSTE24
) and the Werner syndrome (affecting the helicase WRN). Patients’ management is difficult and recombinant human leptin treatment could be helpful.

Key Concepts:

Adipose tissue releases a number of factors and hormones and plays an important physiological role, only recently considered.

Genetic lipodystrophic syndromes are a heterogeneous group of diseases with lipoatrophy either generalised or partial.

The very limited fat expansion seen in lipodystrophies results in severe metabolic alterations and early complications as a result of fat overwhelming by nutriments.

Partial lipodystrophies due to a single gene mutation associate both fat hypertrophy and fat atrophy, stressing for the differential physiology of differently located fat depots.

A number of genetic lipodystrophies affect proteins involved in lipid droplet function, which stresses the underrecognised role of lipid droplet in adipocyte physiology.

The transcription factor PPARγ plays important roles in adipogenesis but also at the level of the vascular wall.

Mutations in the gene encoding lamin A/C result in a wide range of diseases collectively called laminopathies.

Human recombinant leptin can improve the metabolic alterations present in lipodystrophic patients with a low leptin level.
PEGylated Micelle Nanoparticles Encapsulating a Non‐Fluorescent Near‐Infrared Organic Dye as a Safe and Highly‐Effective Photothermal Agent for In Vivo Cancer Therapy
Authors: Cheng Liang , He Weiwei , Gong Hua , Wang Chao , Chen Qian , Cheng Zhengping , Liu Zhuang 
Published: June 2013

AbstractPhotothermal therapy (PTT), as a minimally invasive and highly effective cancer treatment approach, has received widespread attention in recent years. Tremendous effort has been devoted to explore various types of photothermal agents with high near‐infrared (NIR) absorbance for PTT cancer treatment. Despite many exciting progresses in the area, effective yet safe photothermal agents with good biocompatibility and biodegradability are still highly desired. In this work, a new organic PTT agent based on polyethylene glycol (PEG) coated micelle nanoparticles encapsulating a heptamethine indocyanine dye IR825 is developed, showing a strong NIR absorption band and a rather low quantum yield, for in vivo photothermal treatment of cancer. It is found that the IR825–PEG nanoparticles show ultra‐high in vivo tumor uptake after intravenous injection, and appear to be an excellent PTT agent for tumor ablation under a low‐power laser irradiation, without rendering any appreciable toxicity to the treated animals. Compared with inorganic nanomaterials and conjugated polymers being explored in PTT, the NIR‐absorbing micelle nanoparticles presented here may have the least safety concern while showing excellent treatment efficacy, and thus may be a new photothermal agent potentially useful in clinical applications.
Toward Strong and Tough Glass and Ceramic Scaffolds for Bone Repair
Authors: Fu Qiang , Saiz Eduardo , Rahaman Mohamed N. , Tomsia Antoni P. 
Published: June 2013

AbstractThe need for implants to repair large bone defects is driving the development of porous synthetic scaffolds with the requisite mechanical strength and toughness in vivo. Recent developments in the use of design principles and novel fabrication technologies are paving the way to create synthetic scaffolds with promising potential for reconstituting bone in load‐bearing sites. Here, the state of the art in the design and fabrication of bioactive glass and ceramic scaffolds that have improved mechanical properties for structural bone repair is reviewed. Scaffolds with anisotropic and periodic structures can be prepared with compressive strengths comparable to human cortical bone (100−150 MPa), while scaffolds with an isotropic structure typically have strengths in the range of trabecular bone (2−12 MPa). However, the mechanical response of bioactive glass and ceramic scaffolds in multiple loading modes such as flexure and torsion—as well as their mechanical reliability, fracture toughness, and fatigue resistance—has received little attention. Inspired by the designs of natural materials such as cortical bone and nacre, glass‐ceramic and inorganic/polymer composite scaffolds created with extrinsic toughening mechanisms are showing potential for both high strength and mechanical reliability. Future research should include improved designs that provide strong scaffolds with microstructures conducive to bone ingrowth, and evaluation of these scaffolds in large animal models for eventual translation into clinical applications.
Understanding the Role of Nanostructures for Efficient Hydrogen Generation on Immobilized Photocatalysts
Authors: Jiang Zhelong , Tang Yuxin , Tay Qiuling , Zhang Yanyan , Malyi Oleksandr I. , Wang Danping , Deng Jiyang , Lai Yuekun , Zhou Huanfu , Chen Xiaodong , Dong Zhili , Chen Zhong 
Published: June 2013

AbstractFor the purpose of efficiently utilizing the renewable solar energy, it is of vital importance to understand the key factors that contribute to the performance merits for photocatalysis applications. In this work, we find that anatase titania nanostructures with high efficiency in photoelectrochemical cell (PEC) do not necessarily retain the same good performance when used in direct heterogeneous reaction (DHR). Investigation is carried out to elucidate how the electronic properties of the different nanostructures are correlated with the PEC and DHR efficiencies. Good PEC cell performance is identified to be related to topotactically formed samples with intimately connected particles that facilitate easy charge transfer. Additional benefit for PEC cell is found to be achieved from the vectorial conduction pathway in the pseudo one dimensional structure. On the other hand, high activity of DHR photocatalysis is attributed mainly to the exposed high reactivity crystal facets. The presence of anatase TiO2 {010} facets is identified to enhance electron‐hole separation and create specific surface states that facilitate interactions across the semiconductor/electrolyte interfaces.
Asymmetric binuclear metallocene complexes and their application for olefin polymerization
Authors: Xu Sheng , Huang Jiling 
Published: June 2013

ABSTRACTAsymmetric double silylene‐bridged binuclear complexes [(η5‐RC5H4)MCl2]2[μ, μ‐(SiMe2)2(η5‐t‐BuC5H2)(η5‐C5H3)][R = H, M = Ti (1); R = Me, M = Ti (2); R = allyl, M = Ti(3); R = H, M = Zr (4); R = allyl, M= Zr (6)]; and [(η5‐C5H5)TiCl2]2[μ, μ‐(SiMe2)2(η5‐Me3SiC5H2)(η5‐C5H3)] (5) were synthesized by the reaction of (η5‐RC5H4) TiCl3 or (η5‐RC5H4)ZrCl3·DME (R = H, allyl) with [μ, μ‐ (SiMe2)2(η5‐t‐BuC5H2)(η5‐C5H3)] Li2 or [μ, μ‐(SiMe2)2(η5‐Me3Si C5H2)(η5‐C5H3)]Li2 in THF, and they were all well characterized by 1H NMR, MS, IR, and EA. When activated with methylaluminoxane (MAO), they are efficient catalysts for the polymerization of ethylene (Complex 4, 5.99 × 105 g‐PE/mol·Zr·h) and the polymer with multipeak broaden molecular weight distribution (PD = Mw/Mn) was obtained (polymer sample gained by complex 3, PD = 25.03). The copolymerization results indicate that 1‐hexene could incorporate into the growing PE chain with these complexes in the presence of MAO (Complex 4, 1.07 × 106 g‐PE/mol·Zr·h; 1‐hexene content, 1.57% mol). © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 2891–2900, 2013
Hydrophobically associating acrylamide‐based copolymer for chemically enhanced oil recovery
Authors: Ye Zhongbin , Feng Mingming , Gou Shaohua , Liu Man , Huang Ziyan , Liu Tongyi 
Published: June 2013

ABSTRACTA hydrophobically associating copolymer was prepared by free‐radical polymerization with acrylamide (AM), acrylic acid (AA), and N‐allyloctadec‐9‐enamide (NAE) as monomers. The structure was characterized by Fourier transform infrared spectroscopy, 1H‐NMR, 13C‐NMR, and scanning electron microscopy. The rheological experiments indicated that the copolymer possessed superior properties compared with partially hydrolyzed polyacryamide. It was found that an AM/AA/NAE/Tween‐80 system could effectively decrease the interfacial tension and reduce the surfactant loss caused by stratum adsorption in polymer–surfactant flooding. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 2901–2911, 2013
Shear effect in beta‐phase induction of polypropylene in a single screw extruder
Authors: Navarro‐Pardo Fabiola , Laria Julio , Lozano Tomas , Morales‐Cepeda Ana B. , Lafleur Pierre G. , Sánchez‐Valdés Saul , Rodríguez‐González Francisco 
Published: June 2013

ABSTRACTIn this work, we investigated the effect of four different configurations at the exit of a single‐screw extruder on the induction of beta phase in PP for four different rotational speeds. The configuration of a breaker plate with 120 orifices of 1‐mm diameter and 7‐mm length each, give the highest content of beta‐phase (56.92%), for a screw rotational speed of 20 rpm. It was due to the shear caused separation of the melt when it passes through the orifices of the breaker plate. The breaker plate of configuration 4 (breaker plate with the greatest number of orifices) provided the largest number of contacts between the melt and the orifice walls resulting in chain alignment. The results show that the beta‐phase can be induced in the polymer without any further additives, especially without any nucleating agents, but rather by using a special breaker plate configuration at the exit of the single‐screw extruder. The skin‐core structure of the polymer was only developed with one type of extruder configuration. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 2932–2937, 2013
Facile surface modification of PVDF microfiltration membrane by strong physical adsorption of amphiphilic copolymers
Authors: Peng Bo , Li Yuyan , Zhao Zhiguo , Chen Yongming , Han Charles C. 
Published: June 2013

ABSTRACTTo endow the surface of poly(vinylidene fluoride) (PVDF) microfiltration (MF) membranes with hydrophilicity and antifouling property, physical adsorption of amphiphilic random copolymers of poly(ethylene glycol) methacrylate (PEGMA) and poly(methyl methacrylate) (PMMA) (P(PEGMA‐r‐MMA)) onto the PVDF membrane was performed. Scanning electron microscopy (SEM) images showed that the adsorption process had no influence on the membrane structure. Operation parameters including adsorption time, polymer concentration, and composition were explored in detail through X‐ray photoelectron spectroscopy (XPS), static water contact angle (CA), and water flux measurements. The results demonstrated that P(PEGMA‐r‐MMA) copolymers adsorbed successfully onto the membrane surface, and hydrophilicity of the PVDF MF membrane was greatly enhanced. The antifouling performance and adsorption stability were also characterized, respectively. It was notable that PVDF MF membranes modified by facile physical adsorption of P(PEGMA58‐r‐MMA33) even showed higher water flux and better antifouling property than the commercial hydrophilic PVDF MF membranes. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 130: 3112–3121, 2013