Vanishing nematic order beyond the pseudogap phase in overdoped cuprate superconductors.

During the last decade, translational and rotational symmetry-breaking phases-density wave order and electronic nematicity-have been established as generic and distinct features of many correlated electron systems, including pnictide and cuprate superconductors. However, in cuprates, the relationship between these electronic symmetry-breaking phases and the enigmatic pseudogap phase remains unclear. Here, we employ resonant X-ray scattering in a cuprate high-temperature superconductor [Formula: see text] (Nd-LSCO) to navigate the cuprate phase diagram, probing the relationship between electronic nematicity of the Cu 3d orbitals, charge order, and the pseudogap phase as a function of doping. We find evidence for a considerable decrease in electronic nematicity beyond the pseudogap phase, either by raising the temperature through the pseudogap onset temperature T* or increasing doping through the pseudogap critical point, p*. These results establish a clear link between electronic nematicity, the pseudogap, and its associated quantum criticality in overdoped cuprates. Our findings anticipate that electronic nematicity may play a larger role in understanding the cuprate phase diagram than previously recognized, possibly having a crucial role in the phenomenology of the pseudogap phase.

Administration of cyclic glycine-proline during infancy improves adult spatial memory, astrocyte plasticity, vascularization and GluR-1 expression in rats.

Cyclic glycine-proline (cGP) is a natural nutrient of breast milk and plays a role in regulating the function of insulin-like growth factor-1 (IGF-1). IGF-1 function is essential for post-natal brain development and adult cognitive function. We evaluated the effects of cGP on spatial memory and histological changes in the hippocampus of the adult rats following infancy administration. Infant rats were treated with either cGP or saline between post-natal days 8 and 22 via oral administration to lactating dams. The spatial memory was evaluated between post-natal days 70 and 75 using Morris water maze tests. The changes of capillaries, astrocytes, synaptophysin and glutamate receptor-1 were examined in the CA1 stratum radiatum of the hippocampus. Compared to saline-treated group, cGP-treated group showed higher path efficiency of entry and lower average heading errors to the platform zone. cGP-treated group also showed longer, larger and more astrocytic processes, more capillaries and higher glutamate receptor-1 expression. The rats made less average heading error to the platform zone have more capillaries, larger and longer astrocytic branches. Thus cGP treatment/supplementation during infancy moderately improved adulthood spatial memory. This long-lasting effect of cGP on memory could be mediated via promoting astrocytic plasticity, vascularization and glutamate trafficking. Therefore, cGP may have a role in regulating IGF-1 function during brain development.

Objective and Subjective Measures of Premature Ejaculation: How Closely Do They Correspond and How Well Are the Subjective Measures Recalled?

BACKGROUND: Clinical trials evaluating new treatments for premature ejaculation (PE) should ideally include both objective end points and patient reported outcomes (PROs), but there is no consensus currently over the optimal measures or combination of outcomes. In addition, many PROs use a 1-month recall period, despite concerns about potential recall bias. AIMS: Data from a clinical trial of men with lifelong PE were used to examine the consistency of 2 core items of the Premature Ejaculation Profile (PEP), a widely used PRO for assessing subjective aspects of PE. The specific aim was to assess the level of agreement between the original 1-month recall version compared with a new event-based version of the scale in men meeting current definitions of lifelong PE. A further aim was to investigate the convergent validity between an objective end point of intravaginal ejaculatory latency time (IELT), subjective PEP responses, and a patient's Clinical Global Impression of Change (CGIC) measure. METHODS: For assessment of consistency of PEP responses (short-term [ie, sexual event driven] vs 1-month recall), descriptive statistics, correlation coefficients (Pearson and Spearman), and Bland-Altman plots are presented for each time interval. For assessment of convergent validity, descriptive statistics and correlation coefficients (Pearson and Spearman) are presented for each assessment with geometric mean IELT values. Results are also depicted graphically. Geometric mean IELT over the last 4 weeks of treatment and change from baseline (absolute and fold change) were estimated via a general linear model for each category of change in PEP and CGIC, adjusting for baseline IELT. OUTCOMES: PEP items administered via 1-month recall and short-term event-driven responses gave virtually identical results. There was a strong correlation (very good convergent validity) between IELT and responses to PEP and the CGIC. CLINICAL TRANSLATION: Men with lifelong PE can accurately recall their level of sexual functioning over the previous month. The PEP and CGIC are appropriate instruments to measure the subjective response of men with PE to new treatments. STRENGTHS AND LIMITATIONS: Our analyses address gaps in previously published research on PE assessment methodology. Men with acquired PE, men without partners, and men in homosexual relationships were not studied. CONCLUSIONS: In a clinical trial setting, PEP and CGIC are appropriate end points and are likely the optimal combination of PROs for use with IELT to enable a global assessment of patient response to new PE treatments. Althof S, Rosen R, Harty B, et al. Objective and Subjective Measures of Premature Ejaculation: How Closely Do They Correspond and How Well Are the Subjective Measures Recalled? J Sex Med 2020;17:634-644.

The Oxytocin Antagonist Cligosiban Prolongs Intravaginal Ejaculatory Latency and Improves Patient-Reported Outcomes in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Proof-of-Concept Trial (PEPIX).

INTRODUCTION: Cligosiban is an orally administered oxytocin receptor antagonist being developed to treat premature ejaculation (PE). AIM: To determine the safety and efficacy of cligosiban capsules (dose range 400-800 mg) to improve intravaginal ejaculation latency time (IELT) and patient-reported outcomes in men with severe lifelong PE. METHODS: Patients recorded details of at least 4 sexual intercourse events during a 4-week run-in period, after which they underwent baseline assessments. Patients were eligible for the study if they rated their control of ejaculation as poor/very poor and their stopwatch-assessed IELT was ≤1 minute in ≥75% of intercourse attempts. Eligible patients were randomized to an 8-week treatment period with double-blind cligosiban or placebo (to be taken 1 to 6 hours prior to sexual activity). The starting dose was 400 mg (not more than 1 dose per day) which could be increased to 800 mg after 2 and/or 4 weeks of treatment. Assessments were conducted at 2, 4, and 8 weeks. MAIN OUTCOME MEASURE: Efficacy measures were comprised of IELT, self-rating of ejaculation control and ejaculation-related distress (recorded in an electronic diary after each intercourse attempt), premature ejaculation profile, and the Clinical Global Impression of Change. RESULTS: The mean ratio of fold change from baseline in IELT to the last 4 weeks of treatment (cligosiban/placebo) was 1.9 compared to a baseline of 1.0 (P = .0079). The mean increase in IELT from baseline to the last 4 weeks of treatment was 61.0 seconds for cligosiban, which was significantly different from (and 3.6-fold greater than) the mean increase of 16.4 seconds for placebo (P = .0086). Statistically significant improvements in ejaculation control and ejaculation-related personal distress scores were also observed for cligosiban compared to little or no change with placebo. Cligosiban was generally well tolerated, with no serious or severe adverse events or other safety parameters. CLINICAL IMPLICATIONS: This proof-of-concept study demonstrated the potential for cligosiban, an oxytocin antagonist, to successfully treat symptoms of severe lifelong PE. STRENGTHS AND LIMITATIONS: This was a Phase II, randomized, double-blind, placebo-controlled study that was adequately powered to detect a clinically meaningful difference in change in IELT between cligosiban and placebo. Larger studies will be needed to confirm these findings, determine the optimal dose of cligosiban and assess efficacy in men with acquired PE. CONCLUSIONS: Cligosiban was well tolerated, and resulted in significant benefits in both objective and subjective measures of ejaculatory control in men with lifelong PE and therefore offers significant potential as an on-demand, orally administered agent for the treatment of PE. McMahon C, Althof S, Rosen R, et al. The Oxytocin Antagonist Cligosiban Prolongs Intravaginal Ejaculatory Latency and Improves Patient-Reported Outcomes in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Proof-of-Concept Trial (PEPIX). J Sex Med 2019; 16:1178-1187.

Current diagnosis and management of erectile dysfunction.

Erectile dysfunction (ED) is a common male sexual dysfunction associated with a reduced quality of life for patients and their partners. ED is associated with increasing age, depression, obesity, lack of exercise, diabetes mellitus, hypertension, dyslipidaemia, cardiovascular disease and lower urinary tract symptoms related to benign prostatic hyperplasia. The evaluation of men with ED requires a full medical and personally and culturally sensitive sexual history, a focused clinical examination, fasting glucose levels, a fasting lipid profile and, in select cases, a total testosterone level and a prostate-specific antigen test. Treatment of ED requires lifestyle modification, reduction of comorbid vascular risk factors, and treatment of organic or psychosexual dysfunction with either pharmacotherapy alone or in combination with psychosexual therapy. Between 60% and 65% of men with ED, including those with hypertension, diabetes mellitus, spinal cord injury and other comorbid medical conditions, can successfully complete intercourse in response to the phosphodiesterase type 5 inhibitors (PDE5i) sildenafil, tadalafil, vardenafil and avanafil. Patient-administered intracorporal injection therapy using vasodilator drugs such as alprostadil is an effective treatment and is useful in men who fail to respond to oral pharmacological agents. Surgical treatment of ED with multicomponent inflatable penile implants is associated with high satisfaction rates. Penile arterial revascularisation and venous ligation surgery are associated with relatively poor outcome results in men with penile atherosclerotic disease or corporal veno-occlusive dysfunction.

Cyclic-glycine-proline accelerates mammary involution by promoting apoptosis and inhibiting IGF-1 function.

In rodents, post-lactational involution of mammary glands is characterized by the loss of mammary epithelial cells via apoptosis, which is associated with a decline in the expression of insulin-like growth factor-1 (IGF-1). Overexpression of IGF-1 delays involution by inhibiting apoptosis of epithelial cells and preserving the remaining secretory alveoli. Cyclic-glycine-proline (cGP), a metabolite of IGF-1, normalizes IGF-1 function under pathological conditions by regulating the bioavailability of IGF-1. The present study investigated the effect of cGP on the physiological decline in IGF-1 function during post-lactational mammary involution. Rat dams were gavaged with either cGP (3 mg/kg) or saline once per day from post-natal d8-22. Before collecting tissue on post-natal d23, a pair of mammary glands were sealed on d20 (72 hr-engorgement, thus representative of late-involution) and d22 (24 hr-engorgement, thus representative of mid-involution), while the remaining glands were allowed to involute naturally (early-involution). During early-involution, cGP accelerated the loss of mammary cells through apoptosis, resulting in an earlier clearance of intact secretory alveoli compared with the control group. This coincided with an earlier up-regulation of the cell survival factors, Bcl-xl and IGF-1R, in the early-involution cGP glands compared with the control glands. During late-involution, cGP reduced the bioactivity of IGF-1, which was evident through decreased phosphorylation of IGF-1R in the regressed alveoli. Maternal administration of cGP did not alter milk production and composition during early-, peak-, or late-stage of lactation. These data show that cGP accelerates post-lactational involution by promoting apoptosis and the physiological decline in IGF-1 function.

Tight Junction Protein Abundance and Apoptosis During Involution of Rat Mammary Glands.

To examine tight junction protein abundance and apoptosis of epithelial cells at the onset of involution in rodent mammary glands, milk accumulation and mammary engorgement were induced by teat-sealing with an adhesive for 0, 6, 12, 18, 24, and 36 h (n = 6 per group) at peak lactation. In non-sealed control glands, histological analysis confirmed a lactating phenotype, indicating suckling by pups throughout the experiment. In contrast, alveoli of teat-sealed glands were distended within 6 h, with maximal luminal size observed by 12 h of non-suckling. By 18 h following teat-sealing, an involuting phenotype was observed, indicated by alveolar lumina engorged with milk vesicles and increased leukocytes. Relative to non-sealed glands, mammary apoptosis was increased in engorged glands 18 h following teat-sealing. The abundance of ZO-1 and occludin proteins was decreased in engorged glands by 12 and 18 h, respectively, following teat-sealing. In contrast, the claudin-1 22 kDa band was increased by 6 h and peaked at 12-18 h, whereas the 28 kDa band declined by 36 h, relative to controls. There were no temporal changes in ZO-1, occludin, and claudin-1 22 kDa proteins within control glands, although there were minor differences in claudin-1 28 kDa. These data indicate that intramammary milk accumulation due to cessation of milk removal is associated with mammary apoptosis. The apoptotic event is preceded by a rapid loss of abundance of ZO-1, occludin and an initial increase in claudin-1. The loss of cell-cell communication may initiate involution and apoptosis of mammary epithelial cells and is a localized intramammary event, occurring only in non-suckled glands. J. Cell. Physiol. 232: 2075-2082, 2017. © 2016 Wiley Periodicals, Inc.

Orbital symmetry of charge-density-wave order in La1.875Ba0.125CuO4 and YBa2Cu3O6.67.

Recent theories of charge-density-wave (CDW) order in high-temperature superconductors have predicted a primarily d CDW orbital symmetry. Here, we report on the orbital symmetry of CDW order in the canonical cuprate superconductors La1.875Ba0.125CuO4 (LBCO) and YBa2Cu3O6.67 (YBCO), using resonant soft X-ray scattering and a model mapped to the CDW orbital symmetry. From measurements sensitive to the O sublattice, we conclude that LBCO has predominantly s' CDW orbital symmetry, in contrast to the d orbital symmetry recently reported in other cuprates. Furthermore, we show for YBCO that the CDW orbital symmetry differs along the a and b crystal axes and that these both differ from LBCO. This work highlights CDW orbital symmetry as an additional key property that distinguishes the different cuprate families. We discuss how the CDW symmetry may be related to the '1/8-anomaly' and to static spin ordering.

Integrated semiconductor laser with optical feedback: transition from short to long cavity regime.

A 4-section semiconductor laser with integrated optical feedback has been shown experimentally to be capable of operating in either the short- or long-cavity regime, by controlling the device relaxation oscillation frequency relative to the external cavity frequency. Systematic increase of the laser injection current, and the resulting increase in relaxation oscillation frequency, allowed the transition between the two regimes of operation to be observed. The system displayed a gradual transition from a dynamic dominated by regular pulse packages in the short-cavity regime to one dominated by broadband chaotic output when operating in the long-cavity regime. This suggests that the "short cavity" regular pulse packages continue to co-exist with the "long cavity" broadband chaotic dynamic in the system studied. It is the relative power associated with each of these dynamics that changes. This may occur more generally in similar systems.

Impact of quenched oxygen disorder on charge density wave order in YBa2Cu3O6+x.

The competition between superconductivity and charge density wave (CDW) order in underdoped cuprates has now been widely reported, but the role of disorder in this competition has yet to be fully resolved. A central question is whether disorder sets the length scale of the CDW order, for instance by pinning charge density fluctuations or disrupting an otherwise long-range order. Using resonant soft x-ray scattering, we investigate the sensitivity of CDW order in YBa2Cu3O6+x (YBCO) to varying levels of oxygen disorder. We find that quench cooling YBCO6.67 (YBCO6.75) crystals to destroy their o-V and o-VIII (o-III) chains decreases the intensity of the CDW superlattice peak by a factor of 1.9 (1.3), but has little effect on the CDW correlation length, incommensurability, and temperature dependence. This reveals that while quenched oxygen disorder influences the CDW order parameter, the spatial extent of the CDW order is insensitive to the level of quenched oxygen disorder and may instead be a consequence of competition with superconductivity.

Identification and expression of a novel transcript of the growth and differentiation factor-11 gene.

The growth and differentiation factor-11 (GDF-11) gene is thought to code for a single protein that plays a crucial role in regulating the development of multiple tissues. In this study, we aimed to investigate if the GDF-11 gene has another transcript and, if so, to characterise this transcript and determine its tissue-specific and developmental expression. We have identified a novel transcript of GDF-11 in mouse muscle, which contains the 3' region of intron 1, exon 2, exon 3 and 3'UTR, and has two transcription initiation sites and a single termination site. We named the novel transcript GDF-11ΔEx1 because it does not contain exon 1 of canonical GDF-11. The GDF-11ΔEx1 transcript was expressed in the skeletal muscles, heart, brain and kidney, but was undetectable in the liver and gut. The concentration of the GDF-11ΔEx1 transcript was increased in gastrocnemius muscles from three to 6 weeks of age, a period of accelerated muscle growth, steadily declined thereafter and was higher in male than female mice (P < 0.001 for age and sex). GDF-11ΔEx1 cDNA was predicted to code for a putative N-terminal-truncated propeptide and the canonical ligand for GDF-11. However, propeptide-specific antibodies could not identify proteins of the expected size in skeletal muscle. Interestingly, in silico analysis of the GDF-11ΔEx1 RNA predicted a secondary structure with the potential to coordinate multiple protein interactions as a molecular scaffold. Therefore, we postulate that GDF-11ΔEx1 may act as a long non-coding RNA to regulate the transcription of canonical GDF-11 and/or other genes in skeletal muscle and other tissues.

Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson's disease.

In pursuit of treating Parkinson's disease with cell replacement therapy, differentiated induced pluripotent stem cells (iPSC) are an ideal source of midbrain dopaminergic (mDA) cells. We previously established a protocol for differentiating iPSC-derived post-mitotic mDA neurons capable of reversing 6-hydroxydopamine-induced hemiparkinsonism in rats. In the present study, we transitioned the iPSC starting material and defined an adapted differentiation protocol for further translation into a clinical cell transplantation therapy. We examined the effects of cellular maturity on survival and efficacy of the transplants by engrafting mDA progenitors (cryopreserved at 17 days of differentiation, D17), immature neurons (D24), and post-mitotic neurons (D37) into immunocompromised hemiparkinsonian rats. We found that D17 progenitors were markedly superior to immature D24 or mature D37 neurons in terms of survival, fiber outgrowth and effects on motor deficits. Intranigral engraftment to the ventral midbrain demonstrated that D17 cells had a greater capacity than D24 cells to innervate over long distance to forebrain structures, including the striatum. When D17 cells were assessed across a wide dose range (7,500-450,000 injected cells per striatum), there was a clear dose response with regards to numbers of surviving neurons, innervation, and functional recovery. Importantly, although these grafts were derived from iPSCs, we did not observe teratoma formation or significant outgrowth of other cells in any animal. These data support the concept that human iPSC-derived D17 mDA progenitors are suitable for clinical development with the aim of transplantation trials in patients with Parkinson's disease.

A dataset of simulated patient-physician medical interviews with a focus on respiratory cases.

Artificial Intelligence (AI) is playing a major role in medical education, diagnosis, and outbreak detection through Natural Language Processing (NLP), machine learning models and deep learning tools. However, in order to train AI to facilitate these medical fields, well-documented and accurate medical conversations are needed. The dataset presented covers a series of medical conversations in the format of Objective Structured Clinical Examinations (OSCE), with a focus on respiratory cases in audio format and corresponding text documents. These cases were simulated, recorded, transcribed, and manually corrected with the underlying aim of providing a comprehensive set of medical conversation data to the academic and industry community. Potential applications include speech recognition detection for speech-to-text errors, training NLP models to extract symptoms, detecting diseases, or for educational purposes, including training an avatar to converse with healthcare professional students as a standardized patient during clinical examinations. The application opportunities for the presented dataset are vast, given that this calibre of data is difficult to access and costly to develop.

Effects of feeding high volumes of milk replacer on reproductive performance and on concentrations of metabolites and hormones in blood of Japanese black heifer calves.

We evaluated the effects of feeding high volumes of milk replacer on growth and reproductive performances in Japanese black heifers. Fifty-one heifers were fed milk replacer at 9 L/day for 60 days (9 L × 60 days; n = 18) or 41 days (9 L × 41 days; n = 15), or at 7 L/day for 40 days (7 L × 40 days; n = 18). Artificial insemination (AI) was performed on heifers with ≥270 kg body weight and ≥116 cm body height at 300 days of age. The age at the first AI was 0.35 month later for 7 L × 40 days than the other groups (p < .01). However, age at calving did not differ among treatments (22.1 months). The interval from the first AI to pregnancy tended to be ~2 months longer for the 9 L × 60 days than the other groups (p = .07). Our results showed that feeding high volumes of milk replacer may reduce the age at calving via an improved rate of growth. In addition, we propose that feeding a maximum of 7 L milk replacer for 40 days may be the most appropriate rearing regime because the success of pregnancy per AI may be reduced in calves fed a maximum of 9 L for 41 and 60 days.

Mitomycin-C treatment during differentiation of induced pluripotent stem cell-derived dopamine neurons reduces proliferation without compromising survival or function in vivo.

Nongenetic methodologies to reduce undesirable proliferation would be valuable when generating dopamine neurons from stem cells for transplantation in Parkinson's disease (PD). To this end, we modified an established method for controlled differentiation of human induced pluripotent stem cells (iPSCs) into midbrain dopamine neurons using two distinct methods: omission of FGF8 or the in-process use of the DNA cross-linker mitomycin-C (MMC). We transplanted the cells to athymic rats with unilateral 6-hydroxydopamine lesions and monitored long-term survival and function of the grafts. Transplants of cells manufactured using MMC had low proliferation while still permitting robust survival and function comparable to that seen with transplanted dopamine neurons derived using genetic drug selection. Conversely, cells manufactured without FGF8 survived transplantation but exhibited poor in vivo function. Our results suggest that MMC can be used to reduce the number of proliferative cells in stem cell-derived postmitotic neuron preparations for use in PD cell therapy.

IGF1 does not overcome sexual dimorphism of body and muscle size in Mstn-/- mice.

Insulin-like growth factor-1 (IGF1) is crucial for regulating post-natal growth and, along with myostatin (MSTN), regulates muscle size. Here, we sought to clarify the roles of these two genes in regulating sexually dimorphic growth of body and muscle mass. In the first study, we established that Igf1 mRNA was increased to a greater extent and Igf1 receptor mRNA increased earlier in male, than in female, gastrocnemius muscles during the rapid phase of growth (from 2 to 6 weeks) were unchanged, thereafter, to 32 weeks of age in WT mice (P < 0.001). In the second study, we sought to determine if supplemental IGF1 could overcome the sexual dimorphism of muscle and body mass, when myostatin is absent. We crossed myostatin null (Mstn-/-) mice with mice over-expressing Igf1 in skeletal muscle (Igf1+) to generate six genotypes; control (Mstn+/+), Mstn+/-, Mstn-/-, Mstn+/+:Igf1+, Mstn+/-:Igf1+ and Mstn-/-:Igf1+ (n = 8 per genotype and sex). In both sexes, body mass at 12 weeks was increased by at least 1.6-fold and muscle mass by at least 3-fold in Mstn-/-:Igf1+ compared with Mstn+/+ mice (P < 0.001). The abundance of AKT was increased in muscles of mice transgenic for Mstn, while phosphorylation of AKTS473 was increased in both male and female mice transgenic for Igf1+. The ratio of phosphorylated to total AKT was 1.9-fold greater in male mice (P < 0.001). Thus, despite increased growth of skeletal muscle and body size when myostatin was absent and IGF1 was in excess, sexual dimorphism persisted, an effect consistent with greater IGF1-induced activation of AKT in skeletal muscles of males.

Orbital symmetries of charge density wave order in YBa2Cu3O6+x.

Charge density wave (CDW) order has been shown to compete and coexist with superconductivity in underdoped cuprates. Theoretical proposals for the CDW order include an unconventional d-symmetry form factor CDW, evidence for which has emerged from measurements, including resonant soft x-ray scattering (RSXS) in YBa2Cu3O6+x (YBCO). Here, we revisit RSXS measurements of the CDW symmetry in YBCO, using a variation in the measurement geometry to provide enhanced sensitivity to orbital symmetry. We show that the (0 0.31 L) CDW peak measured at the Cu L edge is dominated by an s form factor rather than a d form factor as was reported previously. In addition, by measuring both (0.31 0 L) and (0 0.31 L) peaks, we identify a pronounced difference in the orbital symmetry of the CDW order along the a and b axes, with the CDW along the a axis exhibiting orbital order in addition to charge order.

The decrease in mature myostatin protein in male skeletal muscle is developmentally regulated by growth hormone.

Myostatin inhibits myogenesis and there is reduced abundance of the mature protein in skeletal muscles of adult male compared with female mice. This reduction probably occurs after translation, which suggests that it is a regulated mechanism to reduce the availability of myostatin in males. Reduced myostatin may, thereby, contribute to the development of sexually dimorphic growth of skeletal muscle. Our first objective was to determine if the decrease in mature myostatin protein occurs before the linear growth phase to aid growth, or afterwards to maintain the mass of adult muscle. Mice were killed from 2 to 32 weeks and the gastrocnemius muscle was excised. Myostatin mRNA increased from 2 to 32 weeks and was higher in males than females (P < 0.001). In contrast, mature protein decreased in males after 6 weeks (P < 0.001). Our second objective was to determine if growth hormone (GH) induces the decrease in mature myostatin protein. GH increased myostatin mRNA and decreased the abundance of mature protein in hypophysectomised mice (P < 0.05). Our final objective was to determine if the decrease in mature protein occurs in skeletal muscles of male Stat5b(-/-) mice (Stat5b mediates the actions of GH). As expected, mature myostatin protein was not reduced in Stat5b(-/-) males compared with females. However, myostatin mRNA remained higher in males than females irrespective of genotype. These data suggest that: (1) the decrease in mature myostatin protein is developmentally regulated, (2) GH acting via Stat5b regulates the abundance of mature myostatin and (3) GH acts via a non-Stat5b pathway to regulate myostatin mRNA.

Mechano-growth factor reduces loss of cardiac function in acute myocardial infarction.

BACKGROUND: Mechano-growth factor (MGF) is a splice-variant of IGF-I sharing an identical mature region, but with a different E domain. Our objective was to determine if MGF would reduce the area of 'at-risk' myocardium and improve cardiac function in the post-infarct heart. METHODS: Infarcts were induced by injection of microspheres. In experiment 1, sheep were treated with vehicle, 200 nM each of mature IGF-I, MGF E domain, or full-length MGF. In experiment 2, sheep were treated with vehicle or 200 nM of MGF E domain alone. Cardiac function was assessed using echocardiography and sheep were killed eight days post-MI. Evans Blue dye was injected before death to stain the compromised myocardium. Immunohistochemistry was used to assess the abundance of pAkt(T308) and cleaved caspase 3. RESULTS: In experiment 1, cardiac function improved in sheep treated with the MGF E domain, while in experiment 2, MGF E domain preserved cardiac function and there was 35% less compromised cardiac muscle than controls. Furthermore, immunostaining of cleaved caspase 3 was absent in MGF E domain-treated hearts, suggesting that MGF E domain reduced infarct expansion. CONCLUSIONS: We conclude that the E domain of MGF protects the myocardium against ischaemia, thus improving cardiac function post-MI.

Insights on correlation dimension from dynamics mapping of three experimental nonlinear laser systems.

BACKGROUND: We have analysed large data sets consisting of tens of thousands of time series from three Type B laser systems: a semiconductor laser in a photonic integrated chip, a semiconductor laser subject to optical feedback from a long free-space-external-cavity, and a solid-state laser subject to optical injection from a master laser. The lasers can deliver either constant, periodic, pulsed, or chaotic outputs when parameters such as the injection current and the level of external perturbation are varied. The systems represent examples of experimental nonlinear systems more generally and cover a broad range of complexity including systematically varying complexity in some regions. METHODS: In this work we have introduced a new procedure for semi-automatically interrogating experimental laser system output power time series to calculate the correlation dimension (CD) using the commonly adopted Grassberger-Proccacia algorithm. The new CD procedure is called the 'minimum gradient detection algorithm'. A value of minimum gradient is returned for all time series in a data set. In some cases this can be identified as a CD, with uncertainty. FINDINGS: Applying the new 'minimum gradient detection algorithm' CD procedure, we obtained robust measurements of the correlation dimension for many of the time series measured from each laser system. By mapping the results across an extended parameter space for operation of each laser system, we were able to confidently identify regions of low CD (CD < 3) and assign these robust values for the correlation dimension. However, in all three laser systems, we were not able to measure the correlation dimension at all parts of the parameter space. Nevertheless, by mapping the staged progress of the algorithm, we were able to broadly classify the dynamical output of the lasers at all parts of their respective parameter spaces. For two of the laser systems this included displaying regions of high-complexity chaos and dynamic noise. These high-complexity regions are differentiated from regions where the time series are dominated by technical noise. This is the first time such differentiation has been achieved using a CD analysis approach. CONCLUSIONS: More can be known of the CD for a system when it is interrogated in a mapping context, than from calculations using isolated time series. This has been shown for three laser systems and the approach is expected to be useful in other areas of nonlinear science where large data sets are available and need to be semi-automatically analysed to provide real dimensional information about the complex dynamics. The CD/minimum gradient algorithm measure provides additional information that complements other measures of complexity and relative complexity, such as the permutation entropy; and conventional physical measurements.