Goldilocks Principle Research Articles

Dose dependency with electro physical agents: both the Arndt Schulz law and the Goldilocks principle provide an explanatory model

Dose Responses with Electro Physical Agents: There is strong published evidence from all Electro Physical Agents (EPA’s) evaluated that demonstrates a DOSE DEPENDENCE in the lab & clinical environments. The critical parameters vary with the energy type being delivered (electrical, thermal, mechanical) and include: FREQUENCY; INTENSITY; POWER; POWER DENSITY; TOTAL ENERGY; ENERGY DENSITY combined with TREATMENT DURATION AND TREATMENT FREQUENCY. A substantial proportion of quality doseresponse studies with electro physical agents are derived from animal based research but have potential to transfer to human dosimetry research. A stronger understanding of dose responses with EPA’s could lead to focussed dosimetry research which will in turn, serve to underpin clinical practice. Conclusion: Both the Arndt Schulz Law and the Goldilocks Principle can be usefully employed to describe the response of a biological system to an externally applied energy. Both have the potential to provide a model which results in a more easily identified optimal delivery (or dose) when using electro physical agents in practice, education or research. Future research considering dose dependency is considered essential in order to refine the currently dosimetry models which are often generated retrospectively. Example 1 : Laser

The Children's Health Insurance Program and the Goldilocks Effect

The Children's Health Insurance Program and the Goldilocks Effect

Goldilocks on the couch: Moderate levels of psychodynamic and process-experiential technique predict outcome in psychodynamic therapy

Objectives: Greater symptom change is often assumed to follow greater technique use, a “more is better” approach. We tested whether psychodynamic techniques, as well as common factors and techniques from other orientations, had a curvilinear relation to outcome (i.e., whether moderate or “just right” intervention levels predict better outcome than lower or higher levels). Methods: For 33 patients receiving supportive-expressive psychodynamic psychotherapy for depression, interventions were assessed at Week 4 using the multitheoretical list of therapeutic interventions and symptoms were rated with the Hamilton Rating Scale for Depression. Results: Moderate psychodynamic and experiential techniques predicted greater symptom change compared to lower or higher levels. Conclusion: This “Goldilocks effect” suggests a more complex relation of intervention use to outcome might exist.

Mitigating the Goldilocks effect: the effects of different substrate models on track formation potential.

In ichnology, the Goldilocks effect describes a scenario in which a substrate must be ‘just right’ in order for tracks to form—too soft, the animal will be unable to traverse the area, and too firm, the substrate will not deform. Any given substrate can therefore only preserve a range of tracks from those animals which exert an underfoot pressure at approximately the yield strength of the sediment. However, rarely are substrates vertically homogeneous for any great depth, varying either due to heterogeneity across sediment layers, or from mechanical behaviour such as strain hardening. Here, we explore the specificity of the Goldilocks effect in a number of virtual substrates simulated using finite-element analysis. We find that the inclusion of strain hardening into the model increases the potential range of trackmaker sizes somewhat, compared with a simple elastic–perfectly plastic model. The simulation of a vertically heterogeneous, strain hardening substrate showed a much larger range of potential trackmakers than strain hardening alone. We therefore show that the Goldilocks effect is lessened to varying degrees by the inclusion of more realistic soil parameters, though there still remains an upper and lower limit to the size of trackmaker able to traverse the area while leaving footprints.

Freshwater Limestone In An Arid Rift Basin: A Goldilocks Effect

Abstract The Olduvai Basin (3° S), situated just west of the East African Rift System in northern Tanzania, contains a two-million-year record of paleoclimate and paleoenvironmental change, as well as a rich archive of vertebrate paleontology (including hominins). Milankovitch precession cycles (∼ 20 kyr) regulate the mean annual precipitation (250–700 mm/yr), and the ∼ 2500 mm/yr evapotranspiration results in a negative hydrologic balance. Despite persistent aridity, extensive deposits of freshwater limestone punctuate the stratigraphic record. Between 2 and 1 Ma, Lake Olduvai occupied the basin, and its sediments are a proxy for climate-driven cycles. Three limestones (1.84, 1.80, and 1.36 Ma in age), which formed within lake-margin floodplains adjacent to the lake, were studied to determine their depositional environment using field relations, sedimentary structures, fossils, petrography, and stable-isotope and major-element geochemistry. The three limestones are similar in that they contain peloidal micrite, siliciclastic detrital grains, and rhizoconcretions. Abundant faunal remains (gastropods, ostracods, Charaphytes, and fish) indicate that ponded water was relatively fresh and alkaline. Geochemical and stable-isotope data indicate two types of groundwater-sourced carbonate-producing waters: a deeper-sourced fluid that was enriched in iron and manganese due to extended water–rock interactions, and a shallower groundwater that traveled through alluvial-fan deposits. Regional faults tapped the deeper groundwater, producing carbonate at spring sites, while seeps associated with basinward changes in alluvial-fan slopes drew on shallower groundwater sources. Isotope compositions indicate that fault-related waters experienced some evaporation as water moved away from the spring sites while compositions of the seep-related carbonate remained relatively constant. Pedogenic alteration and meteoric calcite cementation affected the carbonate when the spring and seep sites dried out. Secondary strontium-rich dolomite precipitated within the limestones during burial under paleo–Lake Olduvai sediments and fluids during periods of lake expansion. Integrating these data within the geological context of regional paleoclimatic and local environmental change indicates that the freshwater carbonates formed periodically when the conditions were just right, i.e., a “Goldilocks Effect.” Carbonates near the basin center formed from groundwater flowing under a hydraulic head from faults or fractures during the falling limbs of Milankovitch cycles when the lake was in recession. Carbonates near the basin margin formed from an increased rate of groundwater seepage that occurred only on the rising limbs of cycles. In both contexts, the continuous flow of groundwater with surface evaporation and CO2 degassing optimizes the conditions for limestone formation in this arid environment. These results help explain the formation of freshwater limestones in the rift basin, link the carbonates to specific portions of Milankovitch cycles, and document that localized sources of potable water were present for use by hominins in Olduvai Gorge during an important period of human evolution.

Analogy and the Societal Implications of Astrobiology

The impact of finding life beyond Earth, whether microbial, complex, or intelligent, is an important and timely problem given recent discoveries in the field of astrobiology. Analogy is one of the tools that may be used cautiously to explore potential impacts of discovering extraterrestrial life under different scenarios. After a brief examination of the problems and promise of analogy, this article suggests four analogs useful for providing guidelines in the event of such a discovery: the microbe analogy, the culture contact analogy, the transmission/translation analogy, and the worldview analogy. We offer what we term the “Goldilocks Principle of Analogy”: analogy must not be so general as to be meaningless, nor so specific as to be misleading. As in other fields, the middle “Goldilocks” ground is where analogies may serve as useful guideposts for astrobiology and its impact. And although the discovery of life beyond Earth will be a unique event, these guidelines may be useful for policy decisions both before and after the discovery of life.

The science of style: in fashion, colors should match only moderately.

Fashion is an essential part of human experience and an industry worth over $1.7 trillion. Important choices such as hiring or dating someone are often based on the clothing people wear, and yet we understand almost nothing about the objective features that make an outfit fashionable. In this study, we provide an empirical approach to this key aesthetic domain, examining the link between color coordination and fashionableness. Studies reveal a robust quadratic effect, such that that maximum fashionableness is attained when outfits are neither too coordinated nor too different. In other words, fashionable outfits are those that are moderately matched, not those that are ultra-matched (“matchy-matchy”) or zero-matched (“clashing”). This balance of extremes supports a broader hypothesis regarding aesthetic preferences–the Goldilocks principle–that seeks to balance simplicity and complexity.

The Goldilocks effect in infant auditory attention.

Infants must learn about many cognitive domains (e.g., language, music) from auditory statistics, yet capacity limits on their cognitive resources restrict the quantity that they can encode. Previous research has established that infants can attend to only a subset of available acoustic input. Yet few previous studies have directly examined infant auditory attention, and none have directly tested theorized mechanisms of attentional selection based on stimulus complexity. This work utilizes model-based behavioral methods that were recently developed to examine visual attention in infants (e.g., Kidd, Piantadosi, & Aslin, 2012). The present results demonstrate that 7- to 8-month-old infants selectively attend to nonsocial auditory stimuli that are intermediately predictable/complex with respect to their current implicit beliefs and expectations. These findings provide evidence of a broad principle of infant attention across modalities and suggest that sound-to-sound transitional statistics heavily influence the allocation of auditory attention in human infants.

The Goldilocks Principle: Too Much and Too Little in the Resolution of Hong Kong's Financial Disputes

The Goldilocks Principle: Too Much and Too Little in the Resolution of Hong Kong's Financial Disputes

Genomics, evolution and development of amphioxus and tunicates: The Goldilocks principle

Morphological comparisons among extant animals have long been used to infer their long-extinct ancestors for which the fossil record is poor or non-existent. For evolution of the vertebrates, the comparison has typically involved amphioxus and vertebrates. Both groups are evolving relatively slowly, and their genomes share a high level of synteny. Both vertebrates and amphioxus have regulative development in which cell fates become fixed only gradually during embryogenesis. Thus, their development fits a modified hourglass model in which constraints are greatest at the phylotypic stage (i.e., the late neurula/early larva), but are somewhat greater on earlier development than on later development. In contrast, the third group of chordates, the tunicates, which are sister group to vertebrates, are evolving rapidly. Constraints on evolution of tunicate genomes are relaxed, and they have discarded key developmental genes and organized much of their coding sequences into operons, which are transcribed as a single mRNA that undergoes trans-splicing. This contrasts with vertebrates and amphioxus, whose genomes are not organized into operons. Concomitantly, tunicates have switched to determinant development with very early fixation of cell fates. Thus, tunicate development more closely fits a progressive divergence model (shaped more like a wine glass than an hourglass) in which the constraints on the zygote and very early development are greatest. This model can help explain why tunicate body plans are so very diverse. The relaxed constraints on development after early cleavage stages are correlated with relaxed constraints on genome evolution. The question remains: which came first?

HCMV Reprogramming of Infected Monocyte Survival and Differentiation: A Goldilocks Phenomenon

The wide range of disease pathologies seen in multiple organ sites associated with human cytomegalovirus (HCMV) infection results from the systemic hematogenous dissemination of the virus, which is mediated predominately by infected monocytes. In addition to their role in viral spread, infected monocytes are also known to play a key role in viral latency and life-long persistence. However, in order to utilize infected monocytes for viral spread and persistence, HCMV must overcome a number of monocyte biological hurdles, including their naturally short lifespan and their inability to support viral gene expression and replication. Our laboratory has shown that HCMV is able to manipulate the biology of infected monocytes in order to overcome these biological hurdles by inducing the survival and differentiation of infected monocytes into long-lived macrophages capable of supporting viral gene expression and replication. In this current review, we describe the unique aspects of how HCMV promotes monocyte survival and differentiation by inducing a “finely-tuned” macrophage cell type following infection. Specifically, we describe the induction of a uniquely polarized macrophage subset from infected monocytes, which we argue is the ideal cellular environment for the initiation of viral gene expression and replication and, ultimately, viral spread and persistence within the infected host.

Old Statutes, New Problems

Congress is more ideologically polarized than at any time in the modern regulatory era, which makes legislation ever harder to pass. As a result, Congress is increasingly absent from the policymaking process, and fails to regularly update statutes in the face of social, economic and technological change. This leaves agencies to adapt old statutes to new problems. The challenge of managing statutory obsolescence affects many agencies, and arises in areas as diverse as financial, telecommunications, and food and drug regulation. We examine this dynamic in two fast-moving policy domains, environmental and energy regulation, where Congress has been remarkably absent in recent decades. Contrary to what some might suspect, we find that agencies manage these statutory fit problems carefully, strategically and often with deliberate restraint. Rather than “going for broke,” they tend to choose policies that stop short of open conflict with Congress, yet reflect the agency’s mission, the president’s priorities, and the limits of their statutory authority. We show how, following the Goldilocks principle, agencies seek to get it “just right.” We then explore the implications of this dynamic — in which agencies are the primary statutory updaters — for the institutions in our Separation of Powers scheme: the president, Congress, the courts and the agencies. We argue that the absence of Congress from the policy process can inure to the president’s benefit in the contest to shape agency decisions, especially when the president’s priorities are consistent with the agency’s traditional mission, meaning that the White House and agency are aligned. Finally, we focus on what this new strategic environment of agency policymaking means for judicial review of agency efforts to update the regulatory regime. We argue that, for a variety of reasons, agencies are better suited than courts to do that updating work, and that the case for deferring to agencies in that task is stronger than ever with Congress absent from the updating process. Our account also challenges the view that courts should return important regulatory matters to Congress rather than allow agencies to adapt statutes, because to do so is “democracy forcing.” We argue that the normative commitment to democracy forcing is based on a flawed empirical assumption about the probability of congressional action. Indeed, because the agency is the legally designated custodian of the statute (so designated by the enacting Congress), the agency may have the superior claim to interpret the statute’s application to new problems during periods of congressional quiescence.

Nonlinear Shrinkage of the Covariance Matrix for Portfolio Selection: Markowitz Meets Goldilocks

Markowitz (1952) portfolio selection requires estimates of (i) the vector of expected returns and (ii) the covariance matrix of returns. Many successful proposals to address the first estimation problem exist by now. This paper addresses the second estimation problem. We promote a nonlinear shrinkage estimator of the covariance matrix that is more flexible than previous linear shrinkage estimators and has 'just the right number' of free parameters to estimate (that is, the Goldilocks principle). It turns out that this number is the same as the number of assets in the investment universe. Under certain high-level assumptions, we show that our nonlinear shrinkage estimator is asymptotically optimal for portfolio selection in the setting where the number of assets is of the same magnitude as the sample size. For example, this is the relevant setting for mutual fund managers who invest in a large universe of stocks. In addition to theoretical analysis, we study the real-life performance of our new estimator using backtest exercises on historical stock return data. We find that it performs better than previous proposals for portfolio selection from the literature and, in particular, that it dominates linear shrinkage.

Kid Algebra: Radiohead's Euclidean and Maximally Even Rhythms

KID ALGEBRA: RADIOHEAD’S EUCLIDEAN AND MAXIMALLY EVEN RHYTHMS BRAD OSBORN HE BRITISH ROCK GROUP Radiohead has carved out a unique place in the post-millennial rock milieu by tempering their highly experimental idiolect with structures more commonly heard in Top Forty rock styles.1 In what I describe as a Goldilocks principle, much of their music after OK Computer (1997) inhabits a space between banal convention and sheer experimentation—a dichotomy which I have elsewhere dubbed the ‘Spears–Stockhausen Continuum.’2 In the timbral domain, the band often introduces sounds rather foreign to rock music such as the ondes Martenot and highly processed lead vocals within textures otherwise dominated by guitar, bass, and drums (e.g., ‘The National Anthem,’ 2000), and song forms that begin with paradigmatic verse–chorus structures often end with new material instead of a recapitulated chorus (e.g., ‘All I Need,’ 2007). In this T 82 Perspectives of New Music article I will demonstrate a particular rhythmic manifestation of this Goldilocks principle known as Euclidean rhythms. Euclidean rhythms inhabit a space between two rhythmic extremes, namely binary metrical structures with regular beat divisions and irregular, unpredictable groupings at multiple levels of structure. After establishing a mathematical model for understanding these rhythms, I will identify and analyze several examples from Radiohead’s post-millennial catalog. Throughout the article, additional consideration will be devoted to further ramifications for the formalization of rhythm in this way, as well as how hearing rhythm in this way may be linked to interpreting the lyrical content of Radiohead’s music. After doing so, I will suggest a prescriptive model for hearing these rhythms, and will then conclude with some remarks on how Radiohead’s rhythmic practices may relate to larger concerns such as style and genre. EUCLIDEAN RHYTHMS: SOME MATHEMATICAL PRELIMINARIES A familiar example from Radiohead’s recent song ‘Codex’ (2011, see Example 1) will serve to illustrate the mathematics involved in the rest of this article. Stylistically competent rock listeners will entrain to a sixteen-semiquaver subdivision in each measure. That is to say, the lowest common denominator that encompasses all rhythmic onsets in the voice, piano, and quiet kick drum involves sixteen evenly spaced time points per notated measure.3 Observing the underlying piano rhythm in this section (notated in full in measures 1, 3, and 5–7 of example 1—the remaining measures are rhythmic subsets of this same riff), notice that there are five onsets per measure, meaning that there are five onsets played for every sixteen possible time points. But, these are not just any five onsets within that space of sixteen. In fact, the particular spacing of those five onsets represents a maximally even spacing of five onsets within a grid of sixteen evenly spaced time points. That is to say, although one cannot divide sixteen by five evenly, the rhythm we hear in the piano is the closest-to-even distribution possible of sixteen units into five sets (4+3+3+3+3). There exists only one such possible distribution given k onsets over n evenly spaced time points, and this is the rhythm that I will henceforth refer to as the Euclidean distribution.4 Here it will be useful to establish a notation system that will be used consistently throughout the rest of the article. For any abstract Euclidean distribution, the unordered set will be notated within curly Kid Algebra: Radiohead’s Euclidean and Maximally Even Rhythms 83 braces with the smallest inter-onset intervals packed to the left. Specific ordered presentations of that rhythm will be enclosed within angle brackets, placing the inter-onset intervals in order beginning on the perceptual downbeat. ‘Codex’ could then be related abstractly to other Euclidean distributions of five in sixteen by notating the unordered multi-set of inter-onset intervals {3,3,3,3,4} (notated in order from lowest to highest values), and, of the five possible rotations of that set, the specific ordering heard here is . At other times in this article, I will find it necessary to notate numbered onsets in a string of n evenly spaced time points (numbered 0 through n–1), so that the attack points heard in the ‘Codex...

Optimal rates for electron transfer in Marcus theory

We examine electron transfer between two quantum states in the presence of a dissipative environment represented as a set of independent harmonic oscillators. For this simple model, the Marcus transfer rates can be derived from the equations of motion for electronic operators and we show that these rates are associated to an explicit expression for the environment correlation time. We demonstrate that as a manifestation of the Goldilocks principle, the optimal transfer is governed by a single parameter which is equal to just the inverse square root of 2.

Telomeres Hold Considerable Sway Over Our Health

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessTelomeres Hold Considerable Sway Over Our HealthAaron LevinAaron LevinSearch for more papers by this authorPublished Online:25 Jun 2013https://doi.org/10.1176/appi.pn.2013.7a8AbstractFinding a way to halt the shortening of telomeres might reduce the severity or incidence of certain serious illnesses.Telomeres, the DNA that cap the ends of our chromosomes, play a central role in the longevity of our cells, and they may also affect and be affected by psychiatric disorders, said Elizabeth Blackburn, Ph.D., at APA’s annual meeting in San Francisco in May.Elizabeth Blackburn, Ph.D., notes that compromised telomere maintenance is exacerbated by chronic psychological stress and interferes with the replenishment and function of human cells.David HathcoxLeft to their own devices, telomeres shorten with each cell division. Compromising telomere maintenance eventually impairs the cell replenishment and function. When they get too short, the cell ceases to divide, senescence sets in, and the cell puts out pro-inflammatory and tumorigenic factors, said Blackburn, a professor of biochemistry and biophysics at the University of California, San Francisco.This wreaks havoc in the neighborhood, she said. “They’re like a rotten apple in a barrel, affecting the other cells around them.” But humans live for decades, so something must counteract those ever-shrinking telomeres. That something is the enzyme telomerase. Discovering how telomeres and telomerase protect chromosomes led to the Nobel Prize in Physiology or Medicine in 2009 for Blackburn, Carol Greider, Ph.D., and Jack Szostak, Ph.D.Telomerase acts to counter telomere shortening in cell division, said Blackburn. “Telomerase is trying to ‘rescue’ telomeres as they get too short.”Given its critical role in physiology, telomerase is under “exquisite and tight control at every level of control you can think of,” said Blackburn. These include transcription, RNA splicing, assembly of ribonuclear proteins, trafficking, signaling inputs, and post-transcriptional modification.Such control is important because telomerase abides by the Goldilocks principle. Too little allows telomeres to get shorter, but a combination of short telomeres and high telomerase levels is associated with worse health outcomes including risk of depression and cancer.Telomere maintenance integrates many inputs, both genetic and nongenetic.A broad range of environmental stressors can affect telomere length and the risk of mortality and morbidity: intrauterine stress, traumatic childhood events, lifetime duration of depression, and low educational attainment.Perturbation in telomere maintenance, whether by causation or association, is linked to many age-related disorders, she said.“Telomere length is both a cause or contributor to and a marker of disease,” said Blackburn. For instance, people with one rare, extreme mutation (dyskeratosis congenita) have higher rates of neuropsychiatric morbidity.However, more complex relationships exist, as well.Bladder cancer patients with both depression and short telomeres have an average survival of 31 months, compared with 60 months for those with depression alone and 200 months for those with neither condition.Another study found that mothers stressed by caring for chronically ill children had shorter immune-cell telomere lengths. And the Whitehall study in Britain reported that “cynical hostility” was related to telomere shortness, Blackburn said.A study of 100,000 Kaiser Permanente patients that included 20 years of clinical data, surveys, interviews, and environmental exposure data found higher risks of mortality in the lowest versus the highest quartile of telomere length.Observational research, she noted, has suggested that short telomeres are associated in the general population with a number of illnesses, including cancers, pulmonary fibrosis, cardiovascular diseases, vascular dementia, and diabetes. Stress reduction techniques like physical exercise, better sleep quality, or meditation may counteract telomere shortening, but these must be tested in controlled trials, said Blackburn. ■ ISSUES NewArchived

Prognostic effect of EIF4EBP1 on ovarian cancer: A single gene biomarker for overall survival and platinum response.

5565 Background: Using a novel computational approach, Gene Set Outcome Analysis (GSOA), we were able to identify an area of amplification on chromosome 8p12 that leads to worse prognosis in high grade/high stage ovarian cancer. Located within this amplicon is EIF4EBP1, an effector of DNA translation that is activated by mTOR. Methods: We utilized the MSKCC CBIO cancer genetics portal and the ovarian TCGA clinical dataset, to detect variation in mRNA expression (EXP), (z-scores thresholds ± 2) and copy number variation (CNV), determined using GISTIC 2.0, that are associated with significant differences in PFS and overall survival in grade 3 and stage III/IV ovarian cancer. Results: 6.7% of tumors exhibited upregulation of EIF4EBP1 (CNV amplified and mRNA z > 2) and poorer prognosis with OS of 30.2 vs. 43.8 months (p = 0.0007, n = 445) in tumors not upregulated. Patients with upregulated vs. normal expression showed inferior PFS with first line, platinum based therapy, 10.0 vs. 15.2 months (p = 0.0406, n = 400), respectively. An additional 4.9% of cases had downregulation of EIF4EBP1, with homozygous deletion or mRNA expression z-scores < -2. Downregulation vs. normal expression also showed worse OS of 27.0 vs. 42.1 months (p = 0.0178) and PFS of 11.0 vs. 15.0 months (p = 0.028), respectively. As these groups are mutually exclusive and show a similar trend towards poor prognosis, when combined to compare aberrant vs. normal mRNA expression and copy number, we found an OS of 28.2 vs. 44.6 months (p = <0.0001) and PFS for first line platinum therapy of 10.2 vs. 15.3 months (p = 0.0024), respectively. Conclusions: In this dataset of 445 high-risk ovarian cancer patients, 11.8% exhibited aberrant expression of EIF4EBP1. While amplification of this region showed highly significant changes in OS and PFS, inclusion of both increased and decreased EIF4EBP1 mRNA expression achieved high statistical significance, demonstrating a “Goldilocks effect”, wherein normal expression leads to better outcomes. The potential relationship of gene expression levels of EIF4EBP1 to responsiveness to mTOR inhibitors should be explored in ovarian carcinomas.

The Goldilocks Principle and Developmental Androgens in Males, What Is “Just Right”?

Goldilocks famously rejected items that did not fit her criteria of “just right.” In the endocrinology of reproductive development, appropriate feedback along the hypothalamo-pituitary-gonad axis, and indeed the other axes (thyroid, adrenal, etc), is essential in humans and other species in which the fetal hypothalamo-pituitarygonad axis is active during gestation (1). This complicates our understanding of appropriate levels of developmentally important hormones because feedback effects actively modulate the endocrine system, even in utero. Androgens, principally secreted from the developing fetal testes, are a classic example of critical endocrine signaling during development (2) and are the subject of an important new study in this volume by Connolly et al (25). It is well known that in mammals the establishment of the male phenotype and development of a functionally healthy male adult, is androgen dependent. This is clearly seen when there is disruption of androgen signaling (eg, reviewed in Ref. 3) leading to a gradient of impaired masculinization that, at the extreme of complete androgen insensitivity syndrome, leaves the individual with an apparent normal female phenotype, although infertile (4). Less extreme versions, partial and moderate androgen insensitivity syndrome, are characterized by greater degrees of masculinization of the individual and are associated with less severe androgen receptor mutations. Therefore, in general the availability of inadequate androgen or inadequate androgen signaling is associated with a clear spectrum of disorders of male reproductive development. From the other perspective, in the XX fetus developmental excess of androgen has serious consequences leading to masculinization of the external genitalia (virilization). In humans the most common problems arise from congenital adrenal hyperplasia (CAH), which leads to excess androgen production by the adrenal gland. In addition to virilization of the female fetus (although there is no evidence for retention of the Wolffian ducts, and the Mullerian ducts develop normally), individuals of both sexes with CAH are more likely to show increased blood pressure, obesity, and poor hormone control (5, 6). In addition, adult men with CAH have impaired fertility and lower testosterone to estradiol ratios (7), although it remains uncertain by exactly how much the total androgen tone was raised in these males in utero (Figure 1). Another example of abnormally raised gestational androgens is polycystic ovarian syndrome (PCOS). Maternal androgen levels are thought to be a prime driver of PCOS in female offpsring, but in a recent study (8) female neonates had very high levels of testosterone (similar to unaffected male neonate levels) if their mother had PCOS. In contrast, in male neonates from women with PCOS, testosterone was at levels similar to unaffected males. This is likely to be due to the fact that normal endogenous fetal androgen levels are high and, in the human, approach adult male levels (9). The developmental trajectory programmed by in utero androgen action is important for more than just male reproductive competence. In a number of studies, men with lower testosterone have health deficits such as metabolic syndrome, including increased incidence of obesity, diabetes, and cardiovascular disease (10–12). Therefore, from both a reproductive and a health and well-being point of view, it is very important that the developing male

The Goldilocks principle in action: synthesis and structural characterization of a novel {Cu4(μ3-OH)4} cubane stabilized by monodentate ligands

A {Cu4(μ3-OH)4} compound, where four copper(II) and four μ3-bridging oxygen atoms occupy alternate corners of a slightly distorted cube, has been prepared and structurally characterized. This species, formulated as [Cu4(μ3-OH)4(Htmpz)8](ClO4)4·1.5Et2O (Htmpz = 3,4,5-1H-trimethyl pyrazole), can be classified as belonging to type I Cu4O4 cubane complexes, and is better described as two Cu(II)-(μ-OH)2-Cu(II) units held together by four long Cu-O bonds. The central distorted cubane core is stabilized by neutral monodentate ligands (Htmpz) and perchlorate anions, as demonstrated by single-crystal X-ray structure analysis. The title compound was obtained by hydrolysis of a dinuclear methoxo-bridged species, [Cu(μ-OCH3)(Htmpz)2]2(ClO4)2, which was prepared by reaction of [Cu(Htmpz)4(ClO4)2] with methanol. All these reactions represent a nice example of the Goldilocks principle in action in coordination chemistry, since each single actor (solvent, counteranion, and ligand) has the "just right" electronic, steric or coordinative properties which determine the fate of the final products.

Alpha Particle Radiobiology for Radium-223 (“Alpharadin”): The Fortuitous “Goldilocks” Effect Observed for Hormone-resistant Metastatic Prostate Cancer

Purpose/Objectives: The ALSYMPCA Trial of 223 Ra (“Alpharadin”) for men with metastatic castrate-resistant prostate cancer was a Phase III randomized trial comparing 223 Ra plus SOC vs best SOC. This trial was stopped early after 921 patients enrolled at over 100 centers achieved highly significant improvements in primary (overall survival) and all secondary endpoints.These extremely positive results prompted us to review some of the unique aspects of alpha particle radiobiology and ultra-short range molecular targeting capabilities resulting from endosteal surface new bone localization. The anatomic relationships between endosteal surfaces where isotope localization occurs and the positions of metastatic target cells and nearby marrow reserves were especially considered. Materials and Methods: Literature analysis and review of published radium autoradiographs Results: Highly energetic alpha particles such as those released during decay of 223 Ra (T 1/2 = 11.4 days) display unique radiobiologic and dosimetric aspects which may make them ideal for treating bony metastatic disease. The nuclear dose required in vitro for approximately 90% target cell kill by alpha particles is estimated to be less than 1 Gy and electron micrographs of various cell types obtained shortly after exposure confirm bizarre blebbing and condensation of chromosomal material characteristic of apoptosis. These radiobiologic effects may depend heavily on cell culture condition with more nonuniform DNA strand break damage observed in isolated detached cells. The 20-100 micron alpha particle path length (2-10 cells) appears to allow specific target cell populations to be killed within bony stroma without excessive damage to nearby sensitive hematopoietic cells. There may also be advantageous secondary cytokine signals produced as bystander effects. Calculated dosimetry models suggest bone surface to nearby marrow dose ratios of >10:1. 223 Ra treatment in rodent models showed that this family of Ca ++ analogs delivers extremely high doses to stromal elements such as bone-resorbing osteoclasts and this selectivity may aid in decreasing SREs and in pain relief. Conclusions: We highlight the fact that some basic radiobiologic and cell compartment-specific stromal localization principles known to be important in alpha particle radiopharmaceutical therapy may contribute to the very positive clinical outcomes observed while allowing minimal damage accumulation to nontarget cell groups. The highly localized cytotoxicity and fortuitous endosteal uptake patterns oberved (close enough to target cells and destructive osteoclasts for treatment efficacy but far enough away from marrow reserves to limit hemotoxicity) may serve to produce a salubrious Goldilocks effect and thereby aid in the observed treatment success. #3304