Theory of cooperative transitions in protein molecules. I. Why denaturation of globular protein is a first-order phase transition

A theory of equilibrium denaturation of proteins is suggested. According to this theory, a cornerstone of protein denaturation is disruption of tight packing of side chains in protein core. Investigation of this disruption is the object of this paper. It is shown that this disruption is an "all-or-none" transition (independent of how compact is the denatured state of a protein and independent of the protein-solvent interactions) because expansion of a globule must exceed some threshold to release rotational isomerization of side chains. Smaller expansion cannot produce entropy compensation of nonbonded energy loss; this is the origin of a free-energy barrier (transition state) between the native and denatured states. The density of the transition state is so high that the solvent cannot penetrate into protein in this state. The results obtained in this paper make it possible to present in the following paper a general phase diagram of protein molecule in solution.     

1-Methyladenine in urine of an adenosine deaminase-deficient adult without immunodeficiency

Procedures are described for the isolation and identification of 1-methyladenine from the urine of an adult female with adenosine deaminase deficiency but no immunodeficiency. Evidence is provided indicating that much of the usual urinary excretion product, 1-methyladenosine, is converted to 1-methyladenine in this subject prior to excretion. Since the nucleoside phosphorylases present in normal individuals do not act on 1-methyladenosine, this suggests that a phosphorylase with unusual properties is present in this adenosine deaminase-deficient subject. A possible role for this phosphorylase in removal of deoxyadenosine in this subject is discussed.     

Components and mechanisms of thermal hyperpnea.

The pattern of breathing during a hyperthermia-induced hyperventilation varies across different species. Thermal tachypnea is a first phase panting response adopted during hyperthermia when tidal volume is minimized and the frequency of breathing is maximized. Blood-gas tensions and pH are maintained during this hyperventilation, and the associated heat loss helps the animal regulate its body temperature. A second pattern of breathing adopted in hyperthermia is thermal hyperpnea; this response is the focus of this review. This form of hyperventilation is evident after an increase in core temperature and it is apparent in humans. Increases of tidal volume as well as frequency of breathing are evident during this response that results in a respiratory alkalosis. The cause of thermal hyperpnea is not resolved; evidence of the potential mechanisms underlying this response support that modulators of the response act in either a multiplicative or additive manner with body temperatures. The details of the designs and methodologies of the studies supporting or refuting these two views are discussed. A physiological rationale for thermal hyperpnea is presented in which it is suggested this response serves a heat-loss role and contributes to selective brain cooling in hyperthermic humans. Ongoing research in this area is focused on resolving the mechanisms underlying thermal hyperpnea and its contribution to cranial thermoregulation. The direct application of this research is for the care of febrile and hyperthermic patients.     

The relationship between the stiffness and the mineral content of bone

The modulus of elasticity (E) of bone increases very rapidly with increase in mineral content, and in this is atypical of most composite materials. It is proposed that this apparent anomaly is caused by the end-to-end fusion of apatite crystals as the matrix becomes saturated with mineral. There is electron microscopic evidence that this occurs. Calculations using a fairly simple model show that this mechanism could be effective in life.     

Establishment of the primary imprint of the HYMAI/PLAGL1 imprint control region during oogenesis

Imprinting within domains occurs through epigenetic alterations to imprinting centers (ICs) that result in the establishment of parental-specific differences in gene expression. One candidate IC lies within the imprinted domain on human chromosome region 6q24. This domain contains two paternally expressed genes, the zinc finger protein gene PLAGL1 (ZAC/LOT1) and an untranslated mRNAcalled HYMAI. The putative IC overlaps exon 1 of HYMAI and is differentially methylated in somatic tissues. In humans, loss of methylation within this region is seen in some patients with transient neonatal diabetes mellitus, and hypermethylation of this region is found in ovarian cancer and is associated with changes in expression of PLAGL1, suggesting that it plays a key role in regulating gene expression. Differential methylation within this region is conserved in the homologous region on mouse chromosome 10A and is present on the maternal allele. In this paper, we report that DNA methylation is established during the growth phase of oogenesis and that this coincides with the establishment of monoallelic expression from this region lending further support to the hypothesis that this region functions as an IC.     

Phenotypic variation of lionfish supraocular tentacles

A previous observation suggested that a novel phenotype of lionfish supraocular tentacle is evolving rapidly in the Red Sea and Indian Ocean. We confirm the existence of this phenotype in high prevalence in invasive populations of lionfish in the Western North Atlantic. Observations of individual lionfish from the Atlantic populations indicate that supraocular tentacles are more prevalent on juvenile and young adult lionfish suggesting this characteristic is size specific and is not associated with a genetic lineage. The high prevalence of this novel phenotype in the Atlantic may be a founder effect rather than continued selection. Genetic analysis further supports this conclusion as this phenotype is present in two Pterois species found in the Atlantic.     

Splicing and transport of eukaryotic mRNAs: a theoretical model

Several years have already elapsed since the first discovery of splicing in eukaryotic mRNAs. In this process sections of the precursor mRNAs are spliced out (these are named introns) and the two remaining excised sites, 5′ and 3′ are ligated to form the mature mRNA chains.Very little is known about the splicing and ligation mechanism or about its location inside the cell. It is known to take place in the nucleus, but it is unknown whether it occurs inside the nuclear matter or on the surface of its membrane. Since nearly all eukaryotic messengers undergo splicing, this is a central question.From the theoretical point of view this is an intriguing problem. A lot of data have recently accumulated which have a bearing on this question. Based on current knowledge, this paper proposes a model in which splicing is carried out on the surface of the nuclear membrane and in concert with transport across it. It is suggested that the enzymes that take part in this process are loosely associated with the membrane pore complex. Evidence and results which are relevant to this question are given and discussed.     

On the 'rate of aging' in heterogeneous populations

It is well known that the rate of aging is constant for populations described by the Gompertz law of mortality. However, this is true only when a population is homogeneous. In this note, we consider the multiplicative frailty model with the baseline distribution that follows the Gompertz law and study the impact of heterogeneity on the rate of aging in this population. We show that the rate of aging in this case is a function of age and that it increases in (calendar) time when the baseline mortality rate decreases.     

Even if the fetus is not a person,abortion is immoral: The impairment argument

Much of the debate about the ethics of abortion has centered on whether the fetus is a person. In an attempt to sidestep this complex issue, I argue that, even if the fetus is not a person, abortion is immoral. To arrive at this conclusion, I argue that giving a fetus fetal alcohol syndrome is immoral, and that if this is so, then killing the fetus is immoral. Roughly, this is because killing the fetus impairs it more than giving it fetal alcohol syndrome. Since abortion (in most cases) amounts to killing the fetus, this means that abortion (in most cases) is immoral. I defend the premises of this argument against a plethora of objections, concluding that they either do not work, or commit their proponent to a controversial position.     

The control of sexual identity in the Drosophila germline

Whether to be male or female is a critical decision in development. Nowhere is this more important than in the germ cells, which must produce either the sperm or eggs necessary for the perpetuation of the species. How does a germ cell make this decision and how is it executed? One thing that is clear is that this process is very different in germ cells compared with other cells of the embryo. Here, we explore how sexual identity is established in the Drosophila germline, how this affects other aspects of germ cell development and what studies in Drosophila can teach us about mammalian germ cells.     

INTRACELLULAR DISTRIBUTION OF ALKALINE PHOSPHATASE IN RAT LIVER CELLS

1. Cytochemical studies of the intracellular distribution of alkaline phosphatase in rat liver have been made, using a fractionation procedure recently developed in this laboratory (8) and a similar but modified method not described previously. Aqueous media were used in both cases. 2. The alkaline phosphatase was found to consist of two forms, one of which is strongly activated by magnesium and one of which is not sensitive to this metal. 3. The form of the enzyme that is not activated by magnesium occurs mainly in the nuclear fraction, where it seems to be rather firmly bound. Some of this form of the enzyme is also found in the microsomes, but very little if any occurs in the soluble supernatant fraction. 4. The form of alkaline phosphatase which is activated by magnesium occurs mainly in the soluble supernatant fraction, but what is believed are significant amounts also occur in nuclei. A significant portion of this form of the enzyme can be extracted from the isolated nuclei with cold, isotonic saline solution. Some activity of this form of the enzyme is also found in the microsomal fraction. 5. Mitochondria appear to contain relatively little alkaline phosphatase of either kind. 6. The concept of a porous nuclear membrane has been invoked to explain some of the results obtained in this work. It is postulated that part at least of the form of the enzyme that is activated by magnesium is free to diffuse back and forth through pores in the nuclear membrane, whereas this is considered not to be possible for the form of the enzyme that is insensitive to magnesium as a result of the firm binding of the latter to nuclear substance.     

Does "ichthyosis uteri" have malignant potential? : A case report of squamous cell carcinoma of endometrium associated with extensive ichthyosis uteri

This short report discusses a case of solitary colonic polypoid ganglioneuroma associated with melanosis coli in a woman with no systemic manifestations. To our knowledge this is the first ganglioneuroma reported in the literature in association with melanosis coli. The nature and significance of this event remains unclear, although this may be coincidental due to the laxative intake. Further investigation is necessary to clarify this point. The interest of this case lies moreover in the rarity of this entity and its endoscopic and histologic resemblance to sessile polyps frequent in the clinical practice.     

The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein

Copper toxicosis in Bedlington terriers is an autosomal recessive disorder characterized by excessive hepatic copper accumulation in association with a marked decrease in biliary copper excretion. Recent genetic data have revealed that MURR1, a single copy gene on dog chromosome 10q26, is mutated in this disorder. This gene encodes a 190-amino acid open reading frame of unknown function that is highly conserved in vertebrate species. The Wilson disease protein is a copper transporting ATPase shown to play a critical role in biliary copper excretion. Here we demonstrate that the Wilson disease protein directly interacts with the human homologue of Murr1 in vitro and in vivo and that this interaction is mediated via the copper binding, amino terminus of this ATPase. Importantly, this interaction is specific for this copper transporter, a finding consistent with the observation that impaired copper homeostasis in affected terriers is confined to the liver. Our findings reveal involvement of Murr1 in the defined pathway of hepatic biliary copper excretion, suggest a potential mechanism for Murr1 function in this process, and provide biochemical evidence in support of the proposed role of the MURR1 gene in hepatic copper toxicosis.     

A human placental hormone (UTPH) with uterine growth and DNA promoting effects.

A human placental protein previously described is studied in order to expand its biological characterization. Dose-response-curve of its action on uterine growth of prepuberal mice showed to be a significant logarithmic function and this effect is neutralized by its specific antiserum. It is also demonstrated that the uterine growth-promoting effect is not due either to estrogen, protein-bound estrogen, progesterone or chorionic gonadotrophin. Experimental evidence is given to demonstrate that the mechanism of action of this placental protein is to stimulate the synthesis and to increase the concentration of DNA in uterine tissue, differing then in this respect from the effect of estrogen. Previous work has shown that this placental protein is present in full-term placentas within similar ranges as HCG and HPL. It is also detected in blood during pregnancy and acts biologically in at least two target organs: uterus and mammary gland. Therefore the name of uterotrophic placental protein (UTPH) has been suggested for this substance.     

Price of disorder in the lac repressor hinge helix

The Lac system of genes has been pivotal in understanding gene regulation. When the lac repressor protein binds to the correct DNA sequence, the hinge region of the protein goes through a disorder to order transition. The structure of this region of the protein is well understood when it is in this bound conformation, but less so when it is not. Structural studies show that this region is flexible. Our simulations show this region is extremely flexible in solution; however, a high concentration of salt can help kinetically trap the hinge helix. Thermodynamically, disorder is more favorable without the DNA present.     

Experience of an interactive program in undergraduate investigative practicals

A microcomputer program is described which has been used by first-year undergraduates throughout an investigation in microbiology, totalling five hours of practical work. The computer is used by students to check their suggestions of possible lines of investigation, the results of practical procedures, and the decisions made on the basis of this experimental evidence. The program offers advice when entries which are inadvisable or incorrect are entered thus providing guidance without usurping student control of the investigation. Evidence for the effectiveness of this program is presented and the potential for this type of consultative program in other areas is indicated. Based on this experience, advice is offered on the general design of this type of program.     

作物生长温度效应的非线性模型及其比较研究

通过严密的数学证明,发现了前人关于作物生长温度效应非线性模型之间的内在联系,修正了有关学者对模型参数定义的局限性,提出了一个通用的作物生长温度效应非线性模型,本研究还将该模型与笔者最近提出的基于高斯方程的非线性模型进行了比较研究,介绍了应用SAS软件求取两个模型相关参数的方法,并以马铃薯生育期模拟为例进行了实证研究,表明这两个模型均有良好的适用性。     

Stages of life: A new metaphysics of conceptionism

When a human being comes into existence is crucial in bioethics. Conceptionism is the view that a human being comes into existence at conception. The twinning argument is an influential objection to this view. All versions of the twinning argument rely on a metaphysics of material objects, namely, endurantism. Given this, a strategy for defending conceptionism against the twinning argument is to deny endurantism and adopt an alternative metaphysics of material objects. A version of this strategy which has been debated in this journal is to adopt perdurantism, or the ‘multiple occupancy view’, on which monozygotic twins share the zygote region as a temporal part. We present a novel version of this strategy: conceptionists can evade the twinning argument by adopting an exdurantist metaphysics of material objects. We suggest reasons for thinking that this is a plausible and, indeed, preferable way for conceptionists to avoid the twinning argument.     

Drug-induced phospholipidosis: are there functional consequences?

Phospholipidosis induced by drugs with a cationic amphiphilic structure is a generalized condition in humans and animals that is characterized by an intracellular accumulation of phospholipids and the concurrent development of concentric lamellar bodies. The primary mechanism responsible for the development of phospholipidosis is an inhibition of lysosomal phospholipase activity by the drugs. While the biochemical and ultrastructural features of the condition have been well characterized, much less effort has been directed toward understanding whether the condition has adverse effects on the organism. While there are a few cationic amphiphilic drugs that have been reported to cause phospholipidosis in humans, the principal concern with this condition is in the pharmaceutical industry during preclinical testing. While this class of drugs should technically be referred to as cationic lipophilic, the term cationic amphiphilic is widely used and recognized in this field, and for this reason, the terminology cationic amphiphilic drugs (CADs) will be employed in this Minireview. The aim of this Minireview is to provide an evaluation of the state of knowledge on the functional consequences of CAD-induced phospholipidosis.