Heritability: one word, three concepts

The term 'heritability', which evokes the image of transmission from parents to children, is used in biology to characterize the resemblance of related individuals in terms of a given characteristic, and to analyse the genetic and environmental causes of this resemblance. In fact, there are three definitions of heritability and it is important to distinguish among these carefully in order to avoid misinterpretations. Various techniques for measuring associated parameters are linked to these definitions. A rigorous analysis of the assumptions which permit the interpretation of parameter estimates is necessary to avoid false conclusions.     

Plant development: three steps for stomata

Three basic helix-loop-helix proteins regulate sequential steps in the formation of stomata: SPEECHLESS initiates entry into the stomatal lineage; MUTE controls asymmetric divisions of stomatal precursor cells; and FAMA promotes guard cell differentiation.     

Membrane trafficking: three steps to fusion

Membrane fusion involves the action of members of the SNARE protein family as well as Sec1/Munc18 (SM) proteins, which have been found to interact with SNAREs in three distinct ways. Recent work has established that Munc18-1 directly stimulates fusion and possibly uses all three modes of SNARE interaction.     

BRCT domains: Easy as one,two, three

BRCA1 C-terminal (BRCT) domains are integral signaling modules in the DNA damage response (DDR). Aside from their established roles as phospho-peptide binding modules, BRCT domains have been implicated in phosphorylation-independent protein interactions, DNA binding and poly(ADP-ribose) (PAR) binding. These numerous functions can be attributed to the diversity in BRCT domain structure and architecture, where domains can exist as isolated single domains or assemble into higher order homo- or hetero-domain complexes. In this review, we incorporate recent structural and biochemical studies to demonstrate how structural features allow single and tandem BRCT domains to attain a high degree of functional diversity.Key words: BRCT domain, DNA repair, phosphorylation, phospho-peptide interaction, protein interaction, DNA binding, DNA damage response     

Amazonian paleoecological histories: one hill, three watersheds

Data from the Hill of Six Lakes, in the northwestern Brazilian Amazon region, provide three records of paleoclimatic and vegetation change in lowland Amazonia that span the last 170,000 years. Three lakes, Verde, Pata and Dragão, which occupy separate watersheds on the hill, provide the most detailed image yet obtained of ice-age conditions in lowland Amazonia. Well-dated sedimentary records for fossil palynological, charcoal, cation, and pigment, data are presented.The data indicate the continuous presence of mesic forest throughout the last ice age. Oscillations of lake level are recorded and the lowstands are attributed to reduced precipitation inputs to systems delicately balanced between water loss (leakage through the floor of the basin) and gain (precipitation). Gross stratigraphy, algal remains, and paleochemistry suggest that the stands of high and low lake level were cyclic, apparently correlating precessional orbital variation. Times of lake lowstand coincide with wet season (December-January-February, DJF) insolation minima. The strongest of eight lowstand cycles occurred ca. 35,000 to 27,000 cal BP.Even during lowstand episodes, pollen is well preserved and provides a clear signal of uninterrupted forest cover. The principal lowland elements are continuously present in the record, suggesting the long-term (Quaternary) availability of the lowland forest biome in this region. However, during the late Pleistocene the forest changed in composition with the expansion or invasion of montane floral elements creating communities of the mesic forest biome without modern analogs. While precipitation cycles were causing lake levels to rise and fall, the principal influence on vegetation appears to have been cooling. In the late Pleistocene, the population expansion of montane elements at lower elevations is consistent with a cooling of 4-5 °C.     

Guidance for product category rule development: process,outcome, and next steps

Purpose

The development of product category rules (PCRs) is inconsistent among the program operators using ISO 14025 as the basis. Furthermore, the existence of several other product claim standards and specifications that require analogous rules for making product claims has the potential to reduce any consistency in PCRs present in the ISO 14025 domain and result in unnecessary duplication of PCRs. These inconsistencies and duplications can be attributed to (a) insufficient specificity in related standards, (b) the presence of several standards and specifications, (c) lack of/limited coordination among program operators, and (d) lack of a single global database for PCRs. As a result, current PCR development threatens the legitimacy of life cycle assessment-based product claims.

Process

Through discussions over the past few years, in multistakeholder organizations, it has become clear that more guidance on the development of PCRs is necessary. In response to this need, the Product Category Rule Guidance Development Initiative (www.pcrguidance.org) was launched as an independent multistakeholder effort in early 2012. The premise for the Initiative was that the Guidance would be created by a voluntary group of international stakeholders that would share ownership of the outputs.

Outcome

The Guidance is now published, along with supplementary materials, on the Initiative website. The guidance document specifies requirements, recommendations, and options on (1) steps to be taken before PCR creation; (2) elements of a PCR; (3) review, publication, and use of PCRs; and (4) best practices for PCR development and management. Supplementary materials include a PCR template, a conformity assessment form, and a list of program operators from around the world.

Conclusions

The Guidance will help reduce cost and time to develop a PCR by supporting the adaptation of an existing PCR or by building on elements from existing PCRs. It will help reduce confusion and frustration when creating PCRs that are based on one or more standards and programs. Overall, the Guidance is a robust handbook for consistency and clarity in the development of PCRs.     

Two steps forward, one step back: the pleiotropic effects of favoured alleles

Pleiotropy is one of the most commonly observed attributes of genes. Yet the extent and influence of pleiotropy have been underexplored in population genetics models. In this paper, I quantify the extent to which pleiotropy inhibits the spread of alleles in response to directional selection on a focal trait. Under the assumption that pleiotropic effects are extensive and deleterious, the fraction of alleles that are beneficial overall is severely limited by pleiotropy and rises nearly linearly with the strength of directional selection on the focal trait. Over a broad class of distribution of pleiotropic effects, the mean selective effect of those alleles that are beneficial overall is halved, on average, by pleiotropy. The fraction of new mutant alleles that are beneficial overall and that succeed in fixing within a population is even more severely limited when directional selection is weak, but it rises quadratically with the strength of directional selection. Finally, the mean selective effect of mutant alleles that are beneficial and succeed in fixing is reduced by one-third, on average, by pleiotropy. These results help to shape our understanding of the evolutionary inertia caused by pleiotropy.     

Raf phosphorylation: one step forward and two steps back

We understand Raf-1 activation relatively well but know less about how it is inactivated. An exciting study in this issue of Molecular Cell now describes the molecular basis underlying the transient nature of Raf-1 signaling.     

Plasma fibronectin: three steps to purification and stability.

Large amounts of soluble fibronectin were easily purified from cryoprecipitated or fresh citrated human blood plasma by a three-step combination of gelatin and heparin-cellufine affinity chromatography. The elution conditions were optimized to obtain a homogeneous fraction on SDS-PAGE and Western blot under reducing condition. No proteolytic activities were detected by zymography at acidic or neutral pH. Furthermore, the fibronectin preparation was stable over time up to 456 h at 37 degrees C in the presence of calcium, zinc, or mercury. This preparation of very stable fibronectin, called highly purified fibronectin (hpFN), gave a yield of 7.00 +/- 0.77 mg of fibronectin per gram of cryoprecipitated plasma and 0.16 mg of fibronectin per milliliter of fresh citrated, giving a yield of 32 to 53% (from presumed fibronectin concentration). This preparation may be useful for cellular tests and interaction analysis.     

Three,two, one yeast fatty acid desaturases: regulation and function

Fatty acid composition of biological membranes functionally adapts to environmental conditions by changing its composition through the activity of lipid biosynthetic enzymes, including the fatty acid desaturases. Three major desaturases are present in yeasts, responsible for the generation of double bonds in position C9–C10, C12–C13 and C15–C16 of the carbon backbone. In this review, we will report data addressed to define the functional role of basidiomycete and ascomycete yeast desaturase enzymes in response to various external signals and the regulation of the expression of their corresponding genes. Many yeast species have the complete set of three desaturases; however, only the Δ9 desaturase seems to be necessary and sufficient to ensure yeast viability. The evolutionary issue of this observation will be discussed.     

Reform of mental health care in Serbia: ten steps plus one

Disastrous events in the country and the region caused a 13.5% increasein the prevalence of mental and behavioral disorders in Serbia in the lastfew years, thus making them the second largest public health problem. Dueto prolonged adversities, the health system has deteriorated and is facingspecific challenges. However, the reform of mental health care has been initiated,with a lot of positive movements such as the preparation of a national policyfor mental health care and a law for protection of mentally ill individuals.The transformation of mental health services has started, with an accent oncommunity care, antistigma campaigns and continuing education. Based on anassessment carried out by the National Committee on Mental Health, serviceprovision, number of professionals working in services, funding arrangements,pathways into care, user/carer involvement and other specific issues are reported.     

Cracking the histone code: one,two, three methyls,you're out!

In this issue of Molecular Cell, Zhang et al. report the structure of a ternary complex between the SET domain histone methyltransferase DIM-5, its cofactor, and a histone H3 peptide. The insight gained from analysis of a key amino acid provides an exciting opportunity to dissect the possible functional meaning of mono-, di-, and trimethylation of histone lysine residues in vivo that will complement existing approaches in the quest to crack the histone methylation code.     

The three steps to cancer: A new concept of cancerigenesis

A new theory of carcinogenesis is presented. It is based on the premise that the initial step in the development of cancer is injury by a carcinogen of the coding units in the specialized cells which direct or control the elaboration of a specific “product” or “function”. Carcinogens are varied and number in the thousands, yet the end result, following exposure to them by target stem cells, is always the same, i.e. unbridled cell multiplication with invasion and metastasis. There must be one common denominator which, as stated, is the injury of the coding units of the specialist cells. This is the first step toward cancer; the carcinogen need no longer be present. The second is the uninhibited activity by a pertinent stimulator on functionally deficient cells which remain refractory to the demands for the differentiated “product” or “function”. However, the cells do remain responsive to the second aspect of the dual-roled stimulator, namely, the stimulus to divide. This results in hyperplasia and neoplasia. The events characterizing the third step are coincidental or accidental. There is cellular overcrowding, but the neovasculature is often initially or eventually inadequate. As a result, foci deficient in nutrients form, some cells die, and others become detached and thrive in the culture medium provided by the host through the rupture of capillaries, venules and/or arterioles, forming an area of hemorrhage and necrosis. Surviving cells become autonomous, anaplastic, cataplastic, cannibalistic, invasive and metastatic, i.e. cancer (Fig. 4). Since cancer is only possible in multicellular organisms, the author traces evolution of multicells from unicells. The latter are autonomous and cancer among them is a nonentity. The multicellular organism, on the other hand, is composed of inter-dependent organs, whose component cells are specialists by virtue of contained specific coding apparatuses. Concomitant with this development, an exquisitely sensitive “checks and balances” system of Inductors, Differentiators, Stimulators and Inhibitors, involving Neuroendocrine, Immune and other humeral factors evolved whereby harmonious orchestration of functions was attained and chaos avoided. The article includes clinical and experimental evidence in support of the thesis that the defective stem cell represents the initial step in the development of cancer. A discussion of the characteristics of the cancer cell follows, and an evaluation of the present modalities of treatment. Some of the shortcomings and failures are reviewed and suggestions for a completely different approach to therapy is presented. The essence of new therapy is the realization that cancer is not an infection, is not caused by foreign predators, but is the manifestation of the response of the body to its own, i.e. idiosomatic, predators. The cancer cell mass is not a cause but an effect, and its total eradication or destruction following spread is not feasible. The future may lie in measures which “reform”, rehabilitate and differentiate the anaplastic cell.     

Tyrosine aminotransferase from rat liver, a purification in three steps.

Tyrosine aminotransferase from rat liver was isolated by a three step purification method involving affinity chromatography, CM-50 chromatography and G-200 gel filtration. In order to synthesize the affinity gel, the coenzyme pyridoxamine-5′-phosphate was coupled via a spacer group to a sepharose matrix. The enzyme preparation showed a single band in SDS-acrylamide gel electrophoresis and contains three multiple enzyme forms. A molecular weight of 50,000 of the tyrosine aminotransferase subunit was estimated.