Mixed metal dielectric gratings for pulse compression.
We report on manufacturing and testing results of high efficiency mixed metal dielectric gratings (MMLD) for high power pulse compression applications. The gratings with 1780 l/mm are etched in the top low index layer of a Au-(SiO2/HfO2)4-SiO2 mirror stack. Various grating profiles manufactured in order to modify the near electric field distribution are damage tested on a facility operating at 1.053 µm, 500 fs pulse duration. We evidence that damage threshold is governed by the value of the maximum electric field intensity inside the grating pillar. Moreover thresholds close to 3 J/cm2 beam normal are obtained with this new MMLD grating being thus an interesting alternative to gold and pure dielectric gratings for pulse compression applications.


A three-dimensional analysis of the morphological evolution and locomotor behaviour of the carnivoran hind limb.
The shape of the appendicular bones in mammals usually reflects adaptations towards different locomotor abilities. However, other aspects such as body size and phylogeny also play an important role in shaping bone design.We used 3D landmark-based geometric morphometrics to analyse the shape of the hind limb bones (i.e., femur, tibia, and pelvic girdle bones) of living and extinct terrestrial carnivorans (Mammalia, Carnivora) to quantitatively investigate the influence of body size, phylogeny, and locomotor behaviour in shaping the morphology of these bones. We also investigated the main patterns of morphological variation within a phylogenetic context. Size and phylogeny strongly influence the shape of the hind limb bones. In contrast, adaptations towards different modes of locomotion seem to have little influence. Principal Components Analysis and the study of phylomorphospaces suggest that the main source of variation in bone shape is a gradient of slenderness-robustness. The shape of the hind limb bones is strongly influenced by body size and phylogeny, but not to a similar degree by locomotor behaviour. The slender-robust "morphological bipolarity" found in bone shape variability is probably related to a trade-off between maintaining energetic efficiency and withstanding resistance to stresses. The balance involved in this trade-off impedes the evolution of high phenotypic variability. In fact, both morphological extremes (slender/robust) are adaptive in different selective contexts and lead to a convergence in shape among taxa with extremely different ecologies but with similar biomechanical demands. Strikingly, this "one-to-many mapping" pattern of evolution between morphology and ecology in hind limb bones is in complete contrast to the "many-to-one mapping" pattern found in the evolution of carnivoran skull shape. The results suggest that there are more constraints in the evolution of the shape of the appendicular skeleton than in that of skull shape because of the strong biomechanical constraints imposed by terrestrial locomotion.


Enhanced drug loading in polymerized micellar cargo.
A new drug carrier system based on self-assembly and polymerization of polydiacetylenic amphiphiles is described. Although classical amphiphiles can help in solubilizing hydrophobic molecules upon self-arrangement into a variety of nanometric structures, a greater effect on drug loading was observed for our polymerized micelles as compared to the non-polymerized analogues. This permitted higher aqueous solubilization of lipophilic drugs with low micelle concentration. (14)C labeling of a model drug on one side and of the amphiphile on the other side permitted assessment, after intravenous injection, of biodistribution and excretion profiles of the drug cargo.


[The nature of a microcirculatory change in hypertensive patients during increased blood pressure].
To evaluate changes in the microcirculation (MC) of hypertensive patients during increased blood pressure (BP). The investigation enrolled 66 patients with grades 2-3 hypertension and 57 apparently healthy individuals. After 2-day discontinuation of antihypertensive drugs, the patients were divided into 2 groups: (1) BP < or = 140/90 mm Hg; (2) BP > or = 160/100 mm Hg. MC was examined by laser Doppler flowmetry. In the hypertensive patients, the episodes of higher BP are accompanied by the constriction of meta-arterioles and precapillaries, resulting in diminished capillary blood flow. A compensatory increase in pulse blood filling is attended by accelerated blood flow with decreased vessel diameters and increased shear stress. This creates conditions for the endothelial release of vasodilator mediators. However, the limited reserves of an endothelial relaxing effect are not enough to normalize BP. This resultant increase in tissue hemoperfusion is nonproductive since it is due to intensified shunt blood flow and venous plethora. Severe MC disorders in hypertensive patients with increased BP are characterized by incompetent compensatory mechanisms, reduced endothelial relaxing potential, and depressed capillary tissue diffusion. It may be believed that these disorders appreciably determine target organ involvements in hypertension.


Evaluation of the 7th American Joint Committee on cancer TNM staging system for prostate cancer in point of classification of bladder neck invasion.
To assess the validity of the 7th edition of the American Joint Committee on Cancer TNM staging system for prostate cancer, paying special attention to bladder neck invasion, in an Asian population. Clinicopathologic data of 368 men who underwent radical prostatectomy between 2003 and 2011 at our institution were reviewed. The main interest of this study was to confirm that both isolated positive bladder neck margin and positive bladder neck margin associated with other surgical margin have more favorable biochemical outcomes than seminal vesicle invasion (pT3b). The 3-year biochemical recurrence-free survival for men with organ confined disease, extraprostatic extension, isolated positive bladder neck margin, positive bladder neck margin with other surgical margin and seminal vesicle invasion was 88.9, 74.8, 51.2, 19.4 and 18.8%, respectively. On multivariate analysis, the increased risk of progression associated with an isolated positive bladder neck margin (hazard ratio 4.34, 95% confidence interval 1.40-13.46, P = 0.011) was less than that of seminal vesicle invasion (hazard ratio 9.67, 95% confidence interval 3.70-25.25, P < 0.001). As for the positive bladder neck margin with other surgical margin, the increased risk of progression (hazard ratio 9.32, 95% confidence interval 3.50-24.82, P < 0.001) was similar to that of men with seminal vesicle invasion. In our study, men with isolated positive bladder neck margin and positive bladder neck margin plus other surgical margin had no worse biochemical outcomes than those with seminal vesicle invasion (pT3b). It is reasonable to classify prostate cancer with bladder neck invasion (the 6th American Joint Committee on Cancer edition pT4 category) into the 7th edition pT3 category.


Association of Epileptic and Nonepileptic Seizures and Changes in Circulating Plasma Proteins Linked to Neuroinflammation.
To develop a diagnostic test that stratifies epileptic seizures (ES) from psychogenic nonepileptic seizures (PNES) by developing a multimodal algorithm that integrates plasma concentrations of selected immune response-associated proteins and patient clinical risk factors for seizure. Daily blood samples were collected from patients evaluated in the epilepsy monitoring unit within 24 hours after EEG confirmed ES or PNES and plasma was isolated. Levels of 51 candidate plasma proteins were quantified using an automated, multiplexed, sandwich ELISA and then integrated and analyzed using our diagnostic algorithm. A 51-protein multiplexed ELISA panel was used to determine the plasma concentrations of patients with ES, patients with PNES, and healthy controls. A combination of protein concentrations, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), intercellular adhesion molecule 1 (ICAM-1), monocyte chemoattractant protein-2 (MCP-2), and tumor necrosis factor-receptor 1 (TNF-R1) indicated a probability that a patient recently experienced a seizure, with TRAIL and ICAM-1 levels higher in PNES than ES and MCP-2 and TNF-R1 levels higher in ES than PNES. The diagnostic algorithm yielded an area under the receiver operating characteristic curve (AUC) of 0.94 ± 0.07, sensitivity of 82.6% (95% confidence interval [CI] 62.9-93.0), and specificity of 91.6% (95% CI 74.2-97.7). Expanding the diagnostic algorithm to include previously identified PNES risk factors enhanced diagnostic performance, with AUC of 0.97 ± 0.05, sensitivity of 91.3% (95% CI 73.2-97.6), and specificity of 95.8% (95% CI 79.8-99.3). These 4 plasma proteins could provide a rapid, cost-effective, and accurate blood-based diagnostic test to confirm recent ES or PNES. This study provides Class III evidence that variable levels of 4 plasma proteins, when analyzed by a diagnostic algorithm, can distinguish PNES from ES with sensitivity of 82.6% and specificity of 91.6%.


Reversible Encephalopathy due to Valproic Acid Induced Hyperammonemia in a Patient with Bipolar I Disorder: A Cautionary Report.
Valproic acid (VPA) is an FDA-approved medication widely prescribed for seizures, migraines, and mixed or manic episodes in bipolar disorder. Hyperammonemia is a rare complication of VPA use, which can result in high morbidity and occasionally fatal encephalopathy. The scant literature on Valproate Induced Hyperammonemic Encephalopathy (VIHE) is characterized by acute onset of decreasing level of consciousness, drowsiness, lethargy which in rare instances can lead to seizures, stupor, coma, and persistent morbidity and cortical damage. Below we describe a case report of a patient with Bipolar I Disorder with no primary evidence of hepatic dysfunction that was initiated on VPA and olanzapine to address manic and psychotic symptoms. This patient subsequently developed elevated ammonia (NH4) levels that led to a reversible encephalopathy. This cautionary case report highlights the potential for a rare but serious complication from VPA, a medication increasingly used in both neurologic and neuropsychiatric settings. It is imperative that clinicians perform a thorough physical, neurological and diagnostic evaluation, routinely check NH4 and VPA levels when prescribing these agents and exercise caution when VPA is concomitantly prescribed with antipsychotics and cytochrome P450 inducing antiepileptic medications.


Stimulant and depressant effects of cigarette smoking on brain activity in man.
Cigarette smoking was found to alter the E.E.G. negativity associated with attention: the 'contingent negative variation' was increased in some smokers and decreased in others. This finding is consistent with the known dual action of nicotine to stimulate or depress neural activity and suggests a means of investigating the effects of other centrally-acting drugs on the human brain.


Exploring innovative designs and heterojunctions in photocatalytic micromotors.
Photocatalytic micromotors that convert light energy into mechanical energy have garnered increased interest due to their fast photoactivation, and potential for precise control and manipulation. This feature article provides key insights into the design of photocatalytic micromotors by using single semiconductors, and heterostructures. It also highlights the different strategies to develop efficient light-driven micromotors by minimizing electron-hole pair recombination and improving charge transfer among components. The remaining challenges and possible solutions are also discussed.


Case study: breakthrough mpox infection in Aotearoa New Zealand and Australia after completed two-dose course of subcutaneous modified vaccinia Ankara (MVA-BN) vaccines.
In August 2022, in response to a global mpox outbreak, the World Health Organization recommended the Vaccinia vaccination for at-risk people. Case study. We describe a case of a HIV-negative bisexual man who developed a symptomatic mpox infection 13weeks after completing a two-dose course of subcutaneous third-generation modified vaccinia Ankara vaccines. The case likely acquired his mpox infection in the USA; was diagnosed in Aotearoa, New Zealand; and was followed-up in Australia, as he was actively travelling during his infection. This case highlights the importance of maintaining clinical suspicion for mpox in people who present with consistent symptoms, even if they are fully vaccinated. Also, as he travelled around Aotearoa, New Zealand, and Australia during his infection, this case highlights how public health authorities and clinicians can cooperate across jurisdictional boundaries to support cases and minimise the risk of onward transmission.


Halogen-Dependent Surface Confinement Governs Selective Alkane Functionalization to Olefins.
The product distribution in direct alkane functionalization by oxyhalogenation strongly depends on the halogen of choice. We demonstrate that the superior selectivity to olefins over an iron phosphate catalyst in oxychlorination is the consequence of a surface-confined reaction. By contrast, in oxybromination alkane activation follows a gas-phase radical-chain mechanism and yields a mixture of alkyl bromide, cracking, and combustion products. Surface-coverage analysis of the catalyst and identification of gas-phase radicals in operando mode are correlated to the catalytic performance by a multi-technique approach, which combines kinetic studies with advanced characterization techniques such as prompt-gamma activation analysis and photoelectron photoion coincidence spectroscopy. Rationalization of gas-phase and surface contributions by density functional theory reveals that the molecular level effects of chlorine are pivotal in determining the stark selectivity differences. These results provide strategies for unraveling detailed mechanisms within complex reaction networks.


Aggression and violence against health care workers in Germany--a cross sectional retrospective survey.
Although international scientific research on health issues has been dealing with the problem of aggression and violence towards those employed in health care, research activities in Germany are still at an early stage. In view of this, the aim of this study was to examine the frequency and consequences of aggressive behaviour towards nurses and health care workers in different health sectors in Germany and to assess the need for preventive measures. We conducted a cross-sectional retrospective survey. Nurses and health care workers from two nursing homes, a psychiatric clinic and a workshop for people with disabilities were interviewed using a standardised questionnaire. The sample covered 123 individuals (response rate 38.8%). The survey assessed the frequency, the type and the consequences of aggressive behaviour, and social support in connection with coping with aggression in the workplace. Odds ratios (OR) and 95% confidence intervals (CI) for putative risk factors which may influence the stress induced by aggression at the workplace were calculated using conditional logistic regression. During the previous twelve months 70.7% of the respondents experienced physical and 89.4% verbal aggression. Physical aggression more frequently occurred in nursing homes (83.9% of the employees) and verbal aggression was more common in the psychiatric clinic (96.7% of the employees). The proportion of the individuals affected in the workshop for people with disabilities was lower (41.9% and 77.4% respectively). The incidents impaired the physical (55%) and emotional well-being (77.2%) of the employees. The frequency of incidents (weekly: OR 2.7; 95% CI 1.1-6.4) combined with the lack of social support (OR 2.8; 95% CI 1.2-6.6) increased the probability of higher stress due to aggression. This study corroborates previous reports of frequent physical and verbal aggression towards care workers in the various areas of health care. The present study highlights differences between various areas of health care in Germany and the aggravating effect of prevention neglect such as missing social support at the workplace. Therefore our data suggest the need for improved target group specific prevention of aggressive incidents towards care workers and the need for effective aftercare in Germany.


The Nrf2-Keap1-ARE signaling pathway: The regulation and dual function of Nrf2 in cancer.
The NF-E2-related factor-2 (Nrf2) is a transcription factor that is ubiquitously expressed at low levels in all human organs. As Nrf2 regulates a major cellular defense mechanism, tight regulation is crucial to maintain cellular homeostasis. Activation of this pathway is important in preventing human diseases, such as cancer, neurodegenerative disease, cardiovascular diseases, ischemia, diabetes, pulmonary fibrosis, and inflammatory diseases. Conversely, high constitutive levels of Nrf2 occur in many tumors or cancer cell lines. Moreover, overexpression of Nrf2 in cancer cells protects them from the cytotoxic effects of anticancer therapies, resulting in chemo- and/or radioresistance. Therefore, understanding Nrf2 regulation and identifying Nrf2 activators or inhibitors for disease prevention or as sensitizing agents during cancer therapy, respectively, will have a significant impact on human health. The growing interest in Nrf2 is reflected by an exponentially increasing number of annual publications on this topic. The present forum provides a comprehensive review on research conducted since the initial discovery of the Nrf2-Keap1 pathway in 1999, provides readers with insight into contemporary research in this field, and assesses current known biological functions of this pathway. Additionally, the forum will serve as an important resource for both graduate students and active researchers who are interested in the Nrf2 field.


Effect of K, MG aspartate on some biological parameters of aging rats.
The effect of K and Mg salts of aspartic acid (Cardilan) on the serum concentration of selected proteins and phagocytic activity in aging male Wistar rats was investigated. Cardilan was administered in tap water for 7 days a month for 3 months before the last observed interval (12, 18 and 24 month). In a part of animals, the aging process was accelerated by sublethally gamma-irradiation. The administration of Cardilan slowed down the changes in the concentration of prealbumin, albumin, haptoglobin, haemopexin, C3 complement in non-irradiated rats (DC). This effect was extended to the changes in transferrin level in irradiated rats (IDC). The phagocytic activity in both DC, IDC rats was lower compared with controls drinking water (DW, IDW), but not significantly. The effect of Cardilan administration appears to be the greatest in 24-month-old rats, when the treated animals survived better by 25% in IDC group and by 26% better in DC rats, compared with those of the same age controls. Potassium and magnesium salts of aspartates are suitable compounds for life prolongation in the experimental conditions.


Personal and treatment factors associated with foot self-care among veterans with diabetes.
We developed and validated a survey of foot self-care education and behaviors in 772 diabetic patients with high-risk feet at eight Department of Veterans Affairs medical centers. Principal components analysis identified six subscales with satisfactory internal consistency: basic foot-care education, extended foot-care education, basic professional foot care, extended professional foot care, basic foot self-care, and extended foot self-care (alpha = 0.77-0.91). Despite high illness burden, adherence to foot self-care recommendations was less than optimal; only 32.2% of participants reported looking at the bottom of their feet daily. Independent predictors of greater adherence to basic foot self-care practices included African-American or Hispanic background, perceived neuropathy, foot ulcers in the last year, prior amputation (beta = 0.08- 0.12, p < 0.04-0.001), and provision of greater basic and extended education (beta = 0.16, p < 0.004, and beta = 0.15, p < 0.007). The survey subscales can now be used for evaluating foot care and education needs for persons with high-risk feet.


A co-opted steroid synthesis gene, maintained in sorghum but not maize, is associated with a divergence in leaf wax chemistry.
Virtually all land plants are coated in a cuticle, a waxy polyester that prevents nonstomatal water loss and is important for heat and drought tolerance. Here, we describe a likely genetic basis for a divergence in cuticular wax chemistry between Sorghum bicolor, a drought tolerant crop widely cultivated in hot climates, and its close relative Zea mays (maize). Combining chemical analyses, heterologous expression, and comparative genomics, we reveal that: 1) sorghum and maize leaf waxes are similar at the juvenile stage but, after the juvenile-to-adult transition, sorghum leaf waxes are rich in triterpenoids that are absent from maize; 2) biosynthesis of the majority of sorghum leaf triterpenoids is mediated by a gene that maize and sorghum both inherited from a common ancestor but that is only functionally maintained in sorghum; and 3) sorghum leaf triterpenoids accumulate in a spatial pattern that was previously shown to strengthen the cuticle and decrease water loss at high temperatures. These findings uncover the possibility for resurrection of a cuticular triterpenoid-synthesizing gene in maize that could create a more heat-tolerant water barrier on the plant's leaf surfaces. They also provide a fundamental understanding of sorghum leaf waxes that will inform efforts to divert surface carbon to intracellular storage for bioenergy and bioproduct innovations.


The role of noninvasive cellular imaging in developing cell-based therapies for neurodegenerative disorders.
Stem and progenitor cells from various sources are currently recognized as entities with potential for the treatment of numerous neurodegenerative diseases. It has been observed in many animal models that transplantation of stem cells induces functional improvement. As a result of these findings, the first clinical cell transplantation trials were initiated, including those for Parkinson's disease and cerebral ischemia patients. However, in many patients, although modest improvements have been observed, these improvements were not sufficient to warrant invasive and possibly risky cell therapy. Thus, it is apparent that therapeutic success requires a better understanding of the mechanisms of action and the ability to control these mechanisms that underlie functional improvements, permitting amplification of the therapeutic effect. Considering the complexity of the nervous system, the task of repairing damaged or dysfunctional brain tissue with naïve cellular elements that require spatially and temporally accurate governance may seem daunting. However, the hope for faster and more inclusive progress in this field arises from recent developments in medical biotechnology that offers scientists increasingly sophisticated tools to study and control biological processes. One such technology with great potential for neurotransplantation is noninvasive cellular imaging. This tool allows real-time 'supervision' of grafted cells, as well as monitoring biodistribution and development. In this review, we highlight the current challenges in the field of cell-based therapy for neurodegenerative disorders and outline the role and capabilities of different cellular imaging techniques in addressing those issues.


Cross-regulation between Aurora B and Citron kinase controls midbody architecture in cytokinesis.
Cytokinesis culminates in the final separation, or abscission, of the two daughter cells at the end of cell division. Abscission relies on an organelle, the midbody, which forms at the intercellular bridge and is composed of various proteins arranged in a precise stereotypic pattern. The molecular mechanisms controlling midbody organization and function, however, are obscure. Here we show that proper midbody architecture requires cross-regulation between two cell division kinases, Citron kinase (CIT-K) and Aurora B, the kinase component of the chromosomal passenger complex (CPC). CIT-K interacts directly with three CPC components and is required for proper midbody architecture and the orderly arrangement of midbody proteins, including the CPC. In addition, we show that CIT-K promotes Aurora B activity through phosphorylation of the INCENP CPC subunit at the TSS motif. In turn, Aurora B controls CIT-K localization and association with its central spindle partners through phosphorylation of CIT-K's coiled coil domain. Our results identify, for the first time, a cross-regulatory mechanism between two kinases during cytokinesis, which is crucial for establishing the stereotyped organization of midbody proteins.


Rate of complications among the recipients of intrathecal baclofen pump in Japan: a multicenter study.
To evaluate the incidence of complications of intrathecal baclofen (ITB) therapy for spasticity in Japan, where a unique training course and nationwide registration are required. An analysis of complications was performed in all patients who underwent ITB in Japan from 2005 to 2011. Prior to surgery, all the doctors involved took a one-day training course, which included hands-on training. Surgical techniques that avoided complications were emphasized. A total of 406 pumps were implanted in 400 patients (277 men, 123 women) having severe spasticity. Because this study is currently in progress, among the 400 patients, 78.3% (313/400) had finished a one-year observation follow-up. There were 369 adult and 31 juvenile (under 17 years old) patients, including 12 patients under nine years old. All-cause adverse events were seen in 148 patients (37%), and 93 (23.3%) of these were regarded as severe. Catheter problems were observed in 34 (8.5%) patients: catheter migration in 25 (6.3%), breakage in 6 (1.5%), obstruction in 2 (0.5%), kinking in 1 (0.3%), and dislodgement in 1 (0.3%). Pump trouble was observed in seven (1.8%) patients: alarm abnormality in one (0.3%), memory error in one (0.3%), delayed recovery in one (0.3%), rotation in one (0.3%), malfunction in one (0.3%), and abnormal infusion rate in two (0.6%). Device-related and surgical wound infection occurred in 12 patients (3%), and nine were regarded as severe. Leakage or subcutaneous accumulation of the cerebrospinal fluid was seen in 13 patients (3.3%). The requirement of taking of a training course before starting ITB seemed to reduce complications. Although there were surgery-related complications, the rate of complications in Japan appeared to be lower than those reported in larger series of ITB. However, whether the reported rates can be primarily ascribed to a mandatory training course requires further investigations.


GABAA receptor currents in the dorsal motor nucleus of the vagus in females: influence of ovarian cycle and 5α-reductase inhibition.
The dorsal motor nucleus of the vagus (DMV) contains the preganglionic motor neurons important in the regulation of glucose homeostasis and gastrointestinal function. Despite the role of sex in the regulation of these processes, few studies examine the role of sex and/or ovarian cycle in the regulation of synaptic neurotransmission to the DMV. Since GABAergic neurotransmission is critical to normal DMV function, the present study used in vitro whole cell patch-clamping to investigate whether sex differences exist in GABAergic neurotransmission to DMV neurons. It additionally investigated whether the ovarian cycle plays a role in those sex differences. The frequency of phasic GABAA receptor-mediated inhibitory postsynaptic currents in DMV neurons from females was lower compared with males, and this effect was TTX sensitive and abolished by ovariectomy (OVX). Amplitudes of GABAergic currents (both phasic and tonic) were not different. However, females demonstrated significantly more variability in the amplitude of both phasic and tonic GABAA receptor currents. This difference was eliminated by OVX in females, suggesting that these differences were related to reproductive hormone levels. This was confirmed for GABAergic tonic currents by comparing females in two ovarian stages, estrus versus diestrus. Female mice in diestrus had larger tonic current amplitudes compared with those in estrus, and this increase was abolished after administration of a 5α-reductase inhibitor but not modulation of estrogen. Taken together, these findings demonstrate that DMV neurons undergo GABAA receptor activity plasticity as a function of sex and/or sex steroids.NEW & NOTEWORTHY Results show that GABAergic signaling in dorsal vagal motor neurons (DMV) demonstrates sex differences and fluctuates across the ovarian cycle in females. These findings are the first to demonstrate that female GABAA receptor activity in this brain region is modulated by 5α-reductase-dependent hormones. Since DMV activity is critical to both glucose and gastrointestinal homeostasis, these results suggest that sex hormones, including those synthesized by 5α-reductase, contribute to visceral, autonomic function related to these physiological processes.


The effect of ethnicity and age on palatal size and shape: a study in a northern Chilean healthy population.
Race and ethnicity influence the form of the human craniofacial complex in varying ways. The aim of the present investigation was to quantify the effects of ethnicity (mestizos, Aymara, non-Aymara), age (adolescents and adults), and sex on the form (size and shape) of the hard palate in normal Native American individuals. From the dental casts of 51 individuals with a complete permanent dentition, the x, y, and z coordinates of several standardized palatal landmarks were obtained with a computerized 3-dimensional digitizer. Palatal landmarks were used to derive a mathematical equation for palatal shape in the frontal and sagittal planes. Palatal width and length, frontal and sagittal heights, sagittal slope, and deviation of the raphe from the midline were also calculated. In the Aymara subjects, there was no effect of sex on palatal size, but there was an effect on palatal shape independent of size, especially with respect to male growth. Indeed, female palates apparently did not change their shape between adolescence and adulthood, while male palates increased their posterior "height." Overall, the 3 ethnic groups appeared to possess similar palatal size, with small significant differences. In the adult individuals, ethnicity did not seem to influence palatal shape. In contrast, adolescent males showed differences: non-Aymara subjects had the "highest" palatal shape, Aymara the "lowest," and mestizos an intermediate position. In conclusion, ethnicity does not seem to be a factor of major variability of human hard palate morphology, at least in the present 3 northern Chilean groups, as already found for dental arch shape. Age probably has a larger effect, particularly in the posterior part of the palate, where the eruption of the second and third molars between adolescence and young adulthood may play a role. A further development of the present investigation may involve larger samples of individuals from different ethnic groups.


Evidence of natural reproduction of Atlantic sturgeon in the Connecticut River from unlikely sources.
Atlantic Sturgeon is listed under the U.S. Endangered Species Act as five Distinct Population Segments (DPS). The "endangered" New York Bight (NYB) DPS is thought to only harbor two populations; one in the Hudson River and a second smaller one in the Delaware River. Historically, the Connecticut River probably supported a spawning population of Atlantic Sturgeon that was believed extirpated many decades ago. In 2014, we successfully collected pre-migratory juvenile specimens from the lower Connecticut River which were subjected to mitochondrial DNA (mtDNA) control region sequence and microsatellite analyses to determine their genetic relatedness to other populations coastwide. Haplotype and allelic frequencies differed significantly between the Connecticut River collection and all other populations coastwide. Sibship analyses of the microsatellite data indicated that the Connecticut River collection was comprised of a small number of families that were likely the offspring of a limited number of breeders. This was supported by analysis of effective population size (Ne) and number of breeders (Nb). STRUCTURE analysis suggested that there were 11 genetic clusters among the coastwide collections and that from the Connecticut River was distinct from those in all other rivers. This was supported by UPGMA analyses of the microsatellite data. In AMOVA analyses, among region variation was maximized, and among population within regions variation minimized when the Connecticut River collection was separate from the other two populations in the NYB DPS indicating the dissimilarity between the Connecticut River collection and the other two populations in the NYB DPS. Use of mixed stock analysis indicated that the Connecticut River juvenile collection was comprised of specimens primarily of South Atlantic and Chesapeake Bay DPS origins. The most parsimonious explanation for these results is that the Connecticut River hosted successful natural reproduction in 2013 and that its offspring were descendants of a small number of colonizers from populations south of the NYB DPS, most notably the South Atlantic DPS. Our results run contrary to the belief that re-colonizers of extirpated populations primarily originate in proximal populations.


SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling.
The highly conserved NOTCH (neurogenic locus notch homolog protein) signaling pathway functions as a key cell-cell interaction mechanism controlling cell fate and tissue patterning, whereas its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls its signal transduction. Our previous study indicated the potential role of post-translational SUMO (small ubiquitin-like modifier) modification (SUMOylation) in vascular disorders. The aim of this study was to investigate the role of SUMOylation in endothelial NOTCH signaling and angiogenesis. Endothelial SENP1 (sentrin-specific protease 1) deletion, in newly generated endothelial SENP1 (the major protease of the SUMO system)-deficient mice, significantly delayed retinal vascularization by maintaining prolonged NOTCH1 signaling, as confirmed in cultured endothelial cells. An in vitro SUMOylation assay and immunoprecipitation revealed that when SENP1 associated with N1ICD (NOTCH1 intracellular domain), it functions as a deSUMOylase of N1ICD SUMOylation on conserved lysines. Immunoblot and immunoprecipitation analyses and dual-luciferase assays of natural and SUMO-conjugated/nonconjugated NOTCH1 forms demonstrated that SUMO conjugation facilitated NOTCH1 cleavage. This released N1ICD from the membrane and stabilized it for translocation to the nucleus where it functions as a cotranscriptional factor. Functionally, SENP1-mediated NOTCH1 deSUMOylation was required for NOTCH signal activation in response to DLL4 (Delta-like 4) stimulation. This in turn suppressed VEGF (vascular endothelial growth factor) receptor signaling and angiogenesis, as evidenced by immunoblotted signaling molecules and in vitro angiogenesis assays. These results establish reversible NOTCH1 SUMOylation as a regulatory mechanism in coordinating endothelial angiogenic signaling; SENP1 acts as a critical intrinsic mediator of this process. These findings may apply to NOTCH-regulated biological events in nonvascular tissues and provide a novel therapeutic strategy for vascular diseases and tumors.


Nurses' perception of the use of computerised information systems in practice: questionnaire development.
To develop and validate a questionnaire to explore the perceptions of nurses about the implementation of a computerised information system in clinical practice. A growing interest in understanding nurses' experience of developing and implementing clinically relevant Information Technology systems and the lack of measurement tools in this area, justifies further research into the development of instruments to provide an insight into nurses' experience. Survey and questionnaire development. An initial draft of the questionnaire was developed based on the literature and expert opinion. The questionnaire was piloted by ten nurses to check face validity, reliability and test-retest reliability. A revised version of the questionnaire was distributed to nurses working in the in-patient area of a university hospital in Spain (n = 227). Principal components analysis with oblique rotation was carried out to test theoretically developed underlying dimensions and to test construct validity. Cronbach's alpha coefficient was used to determine internal consistency. Cronbach's alpha for all the items included in the different scales was 0.88 in the pilot questionnaire and test-retest reliability was adequate. Principal components analysis of items related to mechanisms produced a three-component structure ('IT support', 'usability' and 'information characteristics'). The three factors explained 48.6% of the total variance and Cronbach's alpha ranged from 0.66-0.79. Principal components analysis of items related to outcomes produced a three factor solution ('impact on patient care', 'impact on communication' and 'image profile'). The factors explained 65.9% of the total variance and Cronbach's alpha ranged from 0.64-0.85. The study provides a detailed description and justification of an instrument development process. The instrument is valid and reliable for the setting where it has been used. The instrument could provide insight into nurses' experience of IT implementation that will guide further development of systems to enhance clinical practice.


MHC-based mate choice combines good genes and maintenance of MHC polymorphism.
Polymorphic genes of the major histocompatibility complex (MHC) are regarded as essential genes for individual fitness under conditions of natural and sexual selection. To test this hypothesis, we investigated the ultimate individual fitness trait--that of reproductive success. We used three-spined sticklebacks (Gasterosteus aculeatus) in seminatural enclosures, located in natural breeding areas where the experimental fish had been caught. During their reproductive period, fish were exposed continuously to their natural sympatric parasites. By genotyping almost 4000 eggs with nine microsatellites, we determined parenthood and inferred female mating decision. We found that with reference to their own MHC profile, female sticklebacks preferred to mate with males sharing an intermediate MHC diversity. In addition, males with a specific MHC haplotype were bigger and better at fighting a common parasite (Gyrodactylus sp.). This translated directly into Darwinian fitness since fish harbouring this specific MHC haplotype were more likely to be chosen and had a higher reproductive output. We conclude that females also based their mating decision on a specific MHC haplotype conferring resistance against a common parasite. This identifies and supports 'good genes'. We argue that such an interaction between host and parasite driving assortative mating is not only a prerequisite for negative frequency-dependent selection--a potential mechanism to explain the maintenance of MHC polymorphism, but also potentially speciation.


Robust and Reproducible Generation of Induced Neural Stem Cells from Human Somatic Cells by Defined Factors.
Recent studies have described direct reprogramming of mouse and human somatic cells into induced neural stem cells (iNSCs) using various combinations of transcription factors. Although iNSC technology holds a great potential for clinical applications, the low conversion efficiency and limited reproducibility of iNSC generation hinder its further translation into the clinic, strongly suggesting the necessity of highly reproducible method for human iNSCs (hiNSCs). Thus, in orderto develop a highly efficient and reproducible protocol for hiNSC generation, we revisited the reprogramming potentials of previously reported hiNSC reprogramming cocktails by comparing the reprogramming efficiency of distinct factor combinations including ours. We introduced distinct factor combinations, OSKM (OCT4+SOX2+KLF4+C-MYC), OCT4 alone, SOX2 alone, SOX2+HMGA2, BRN4+SKM+SV40LT (BSKMLT), SKLT, SMLT, and SKMLT and performed comparative analysis of reprogramming potentials of distinct factor combinations in hiNSC generation. Here we show that ectopic expression of five reprogramming factors, BSKMLT leads the robust hiNSC generation (>80 folds enhanced efficiency) from human somatic cells compared with previously described factor combinations. With our combination, we were able to observe hiNSC conversion within 7 days of transduction. Throughout further optimization steps, we found that both BRN4 and KLF4 are not essential for hiNSC conversion. Our factor combination could robustly and reproducibly generate hiNSCs from human somatic cells with distinct origins. Therefore, our novel reprogramming strategy might serve as a useful tool for hiNSC-based clinical application.


[Objective determination of the shape of the anterior chest wall using moiré topography. Method and development of dimension-free indices for the evaluation of funnel chest].
Stereophotogrammetric measurement of body surface results in data, which are dependent on shape, posture and positioning of the patient. In order to establish a valid description and characterization of funnel chest measured by stereophotogrammetric methods, index numbers must be defined, which are independent of posture und positioning of the patient. This procedure is exemplified in the analysis of moiré topograms from 29 patients with funnel chest and 21 normal persons. The sagittal cross section is characterized by the index TI I, which in essential is the sum of absolute values of angles in a polygon along the section (cf. fig. 7). The funnel in the coronal cross section is characterized by the index TI II, which gives the quotient (in %) of the mean funnel width and funnel depth (cf. fig. 8). Application of the index numbers shows a good differentiation of TI I, independent of sex, whereas TI II might be most useful in follow up measurements.


[Semont maneuver vs. particle repositioning maneuver: comparative study].
In the present study 80 consecutive cases of PPV of the posterior semicircular canal are presented, with the purpose to evaluate the effectiveness of the treatment and to analyze the secondary Ny and re-test as indicators of the effectiveness of the therapeutic maneuver. The patients were treated in 40 cases with Particle Repositioning Maneuver (PRM) and in the other 40 with the Semont Maneuver, in an attempt to determine the secondary Nystagmus induced during treatment and any residual Paroxysmal Positional Nystagmus (PPNy) upon repetition of the Hallpike positioning after 15 minutes (re-test). Recovery was achieved in 80% of cases after the first session and in 95% of cases with the third session. PRM seemed to be slightly more effective. Secondary liberating Ny was frequently evoked (80%) and was reliable (75%) with the Semont Maneuver, while PRM yielded the liberating Ny in only 25% of cases, with lower reliability (70%). Reliability of the re-test with the Hallpike maneuver was high (80%) and the difference between the two techniques was negligible (78% in PRM and 85% in Semont). In conclusion, in terms of indicators of effectiveness, the Semont liberating Maneuver appears better in that it combines high therapeutic effectiveness (75% recovery in a single session) with a like percentage of liberating Ny (80%): this makes it possible to reserve the re-test and repetition of the therapeutic maneuver, performed during the same session, only in those cases that do not present liberating Ny (20% of cases). On the other hand, when the PRM is used, it appears better to rely on the high likelihood of effectiveness (85% in a single session) and then review the case directly at the next check-up rather than perform the Hallpike re-test in all cases that did not present the liberating secondary Ny (75%). In this way it is possible to select a small number of patients (22%) that still show PPNy (positive re-test) and for whom the therapeutic maneuver must be repeated.


[Developmental venous anomaly presenting as a brain parenchymal abnormality mimicking a brain tumor:a report of 3 cases and review of literature].
Cases of brain parenchymal abnormality caused by a developmental venous anomaly (DVA) are rare. The purpose of this paper is to report 3 cases where DVA presented as abnormal lesions on magnetic resonance imaging (MRI) scans, mimicking brain tumors such as gliomas. CASE 1: the patient was a 60-year-old woman who underwent MRI for mild memory disturbance. MRI revealed an abnormal lesion in the left temporal lobe, and a diagnosis of glioma was considered. She was transferred to our hospital for surgery 6 days later when the lesion had spontaneously decreased in size. Gadolinium-enhanced MRI (Gd-MRI) and conventional angiography revealed dilated medullary veins in the lesion. The patient was followed-up conservatively; the lesion further decreased in size during the follow-up period, and only slight atrophy remained. CASE 2: the patient was a 17-year-old girl with left hemiparesis and facial palsy. She was transferred to our hospital for surgery of an abnormal lesion in the right frontal lobe. The lesion showed high intensity on T(2)weighted MRI and enlarged 2 weeks later, mimicking a glioma. Over the next 2 weeks, the size of the lesion spontaneously decreased, and the patient's symptoms improved. Gd-MRI and conventional angiography revealed the presence of typical caput medusae. The patient has been followed-up conservatively, and no further changes have been observed. CASE 3: the patient was a 61-year-old man whose T(2) weighted MRI scan incidentally revealed an abnormal high intensity lesion in the right frontal lobe. Gd-MRI was helped to detect the radially dilated medullary veins. the incidence of brain parenchymal abnormalities caused by DVAs may be higher than that reported previously. DVA should be included in the differential diagnosis of high intensity lesions on T(2) weighted MRI.


[Program and results of 10 weeks' physical training of myocardial infarct patients and patients with exertion stenocardia].
This is a report on the results of physical training in 52 patients who had myocardial infarction and in 8 patients with angina pectoris of effort who had not suffered infarction. The training lasted 10 weeks, 3 times a week using a bicycle ergometer. 75% of the patients have accomplished the entire program of training. Patients who had myocardial infarction showed threshold capacity increased by 22%, which is considerably higher than in the group with no training. The work equivalent to the exercise was performed after training with lower pulse rate and systolic arterial pressure. In the majority of patients the volume of the heart decreased, as determined by X-ray and the amplitude coefficient of apex cardiogram diminished which justifies the assumption of improvement in the state of the myocardium in these patients. In patients with angina pectoris of effort there was an increase of threshold capacity which is explained by decreased pulse rate and systolic arterial pressure after physical loading.


Transient pearling and vesiculation of membrane tubes under osmotic gradients.
We report the experimental observation of osmotically induced transient pearling instabilities in vesicular membranes. Giant phospholipid vesicles subjected to negative osmotic gradient, which drives the influx of water in to the vesicular interior, produces transient cylindrical protrusions. These protrusions exhibit a remarkable pearling intermediate, which facilitates their subsequent retraction. The pearling front propagates from the distal free end of the protrusion toward the vesicular source and accompanies gradual shortening of the protrusion via pearl-pearl coalescence. Real-time introduction of a positive osmotic gradient, on the other hand, drives vigorous shape fluctuations, which in turn produce cylindrical, prolate- and pear-shaped intermediates presumably due to an increased vesicular area relative to the encapsulated volume. These intermediates transiently produce a pearled state prior to their fission. In both cases, the transient pearling state gives rise to an array of stable spherical daughter vesicles, which may be connected to one another by fine tethers not resolved in our experiments. These results may have implications for self-reproduction in primitive, protein-free, cells.


[Humalog® 200 U/ml KwikPen™].
Insulin lispro (Humalog®) was the first short-acting insulin analogue to be indicated for the treatment of diabetes mellitus requiring insulin therapy. After subcutaneous injection, insulin lispro has a more favourable pharmacokinetics/pharmacodynamics profile than human insulin, characterized by a faster resorption and a more rapid and less prolonged glucose-lowering activity. These properties allow a better control of postprandial hyperglycaemia and a reduction of the risk of delayed hypoglycaemia, especially at night. The patient's quality of life is also improved because insulin lispro can be injected within the 15 minutes before meal and even possibly after meal when the amount of food intake is unpredictable. Already commercialized as Humalog® 100 U/ml, insulin lispro is now also available as Humalog® 200 U/ml. A pharmacokinetics/pharmacodynamics study confirmed the bioequivalence of the two formulations, based upon the analysis of both plasma free insulin concentrations and glucose infusion rates to maintain normoglycaemia. Humalog® 200 U/ml is available in a novel disposable 3 ml pen (KwikPen™), with lower glide force and injection volume; thus this new pen is more convenient for the patient compared with the current pen used to inject Humalog® 100 U/ml. The new formulation Humalog® 200 U/ml is indicated in Europe for adult patients with type 1 or type 2 diabetes who require more than 20 units of prandial insulin per day to cover their meals.


Health and the human spirit for occupation.
The relationship between engagement in occupation and healthfulness is explored. Health is viewed not as the absence of organ pathology, but as possession of a repertoire of skills that enables people to achieve their vital goals in their own environments. This sort of health, reflecting adaptability and a good quality of life, is possible for all people, including those with chronic impairments. Theoretical and research literature from an array of disciplines explores the influences of occupation on various aspects of health. These include interests, satisfaction in everyday doing, balance, the latent consequences of work, and transcendence. Support is provided for a relationship between activity level and survival. To improve the life opportunities of those they serve, occupational therapists need to become ardent students of life's daily activities, grappling with the ambiguity and complexity of occupation, the occupational human, and the contexts in which occupation takes place.


Conversion of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 to manifest ataxia (RISCA): a longitudinal cohort study.
Spinocerebellar ataxias (SCAs) are autosomal dominant neurodegenerative diseases. Our aim was to study the conversion to manifest ataxia among apparently healthy carriers of mutations associated with the most common SCAs (SCA1, SCA2, SCA3, and SCA6), and the sensitivity of clinical and functional measures to detect change in these individuals. In this prospective, longitudinal, observational cohort study, based at 14 referral centres in seven European countries, we enrolled children or siblings of patients with SCA1, SCA2, SCA3, or SCA6. Eligible individuals were those without ataxia, defined by a score on the Scale for the Assessment and Rating of Ataxia (SARA) of less than 3; participants had to be aged 18-50 years for children or siblings of patients with SCA1, SCA2, or SCA3, and 35-70 years for children or siblings of patients with SCA6. Study visits took place at recruitment and after 2, 4, and 6 years (plus or minus 3 months). We did genetic testing to identify mutation carriers, with results concealed to the participant and clinical investigator. We assessed patients with clinical scales, questionnaires of patient-reported outcome measures, a rating of the examiner's confidence of presence of ataxia, and performance-based coordination tests. Conversion to ataxia was defined by an SARA score of 3 or higher. We analysed the association of factors at baseline with conversion to ataxia and the evolution of outcome parameters on temporal scales (time from inclusion and time to predicted age at ataxia onset) in the context of mutation status and conversion status. This study is registered with ClinicalTrials.gov, NCT01037777. Between Sept 13, 2008, and Oct 28, 2015, 302 participants were enrolled. We analysed data for 252 participants with at least one follow-up visit. 83 (33%) participants were from families affected by SCA1, 99 (39%) by SCA2, 46 (18%) by SCA3, and 24 (10%) by SCA6. In participants who carried SCA mutations, 26 (52%) of 50 SCA1 carriers, 22 (59%) of 37 SCA2 carriers, 11 (42%) of 26 SCA3 carriers, and two (13%) of 15 SCA6 carriers converted to ataxia. One (3%) of 33 SCA1 non-carriers and one (2%) of 62 SCA2 non-carriers converted to ataxia. Owing to the small number of people who met our criteria for ataxia, subsequent analyses could not be done in carriers of the SCA6 mutation. Baseline factors associated with conversion were age (hazard ratio 1·13 [95% CI 1·03-1·24]; p=0·011), CAG repeat length (1·25 [1·11-1·41]; p=0·0002), and ataxia confidence rating (1·72 [1·23-2·41]; p=0·0015) for SCA1; age (1·08 [1·02-1·14]; p=0·0077) and CAG repeat length (1·65 [1·27-2·13]; p=0·0001) for SCA2; and age (1·27 [1·09-1·50]; p=0·0031), confidence rating (2·60 [1·23-5·47]; p=0·012), and double vision (14·83 [2·15-102·44]; p=0·0063) for SCA3. From the time of inclusion, the SARA scores of SCA1, SCA2, and SCA3 mutation carriers increased, whereas they remained stable in non-carriers. On a timescale defined by the predicted time of ataxia onset, SARA progression in SCA1, SCA2, and SCA3 mutation carriers was non-linear, with marginal progression before ataxia and increasing progression after ataxia onset. Our study provides quantitative data on the conversion of non-ataxic SCA1, SCA2, and SCA3 mutation carriers to manifest ataxia. Our data could prove useful for the design of preventive trials aimed at delaying the onset of ataxia by aiding sample size calculations and stratification of study participants. European Research Area Network for Research Programmes on Rare Diseases, Polish Ministry of Science and Higher Education, Italian Ministry of Health, European Community's Seventh Framework Programme.


Up-regulation of c-Jun inhibits proliferation and induces apoptosis via caspase-triggered c-Abl cleavage in human multiple myeloma.
Here we show the antimyeloma cytotoxicity of adaphostin and carried out expression profiling of adaphostin-treated multiple myeloma (MM) cells to identify its molecular targets. Surprisingly, c-Jun was the most up-regulated gene even at the earliest point of analysis (2 h). We also observed adaphostin-induced c-Abl cleavage in immunoblot analysis. Proteasome inhibitor bortezomib, but not melphalan or dexamethasone, induced similar effects, indicating unique agent-dependent mechanisms. Using caspase inhibitors, as well as caspase-resistant mutants of c-Abl (TM-c-Abl and D565A-Abl), we then showed that c-Abl cleavage in MM cells requires caspase activity. Importantly, both overexpression of the c-Abl fragment or c-Jun and knockdown of c-Abl and c-Jun expression by small interfering RNA confirmed that adaphostin-induced c-Jun up-regulation triggers downstream caspase-mediated c-Abl cleavage, inhibition of MM cell growth, and induction of apoptosis. Finally, our data suggest that this mechanism may not only be restricted to MM but may also be important in a broad range of malignancies including erythroleukemia and solid tumors.


[Reflections on Research and Development Institutions Becoming Medical Device Registrants].
As the special subject of the applicant for registration of medical device, the research and development institutions have insufficient conditions and abilities to become medical device registrants, and there are certain difficulties in the actual registration application process, such as not clearing the certification path for the research and development institutions to hold the certificate. In view of the existing problems, by comparing the path of medicine research and development institutions to become medical device registrants and combining with the actual medical device industry to give relevant suggestions, including improving quality management over the whole life cycle of medical devices, quality and safety responsibility ability of research and development institutions, establishing the registration and certification path of research and development institutions, supporting laws and regulations, etc., so as to ensure that the research and development institutions become medical device registrants successfully.


Treatment of Pulmonary Vasculitis.
Pulmonary vasculitis can be heterogeneous and have some pathophysiological, clinical, and biological specificities that might influence treatment choices. Main vasculitides associated with pulmonary vasculitis include antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex small vessel vasculitis, and antiglomerular basement membrane disease. Patient characteristics and association of lung involvement with other manifestations affecting disease severity may also influence treatment strategy. Alveolar hemorrhage frequently requires urgent treatment to control the underlying disease and provide supportive care such as mechanical ventilation. The level of evidence of each treatment strategy varies according to the underlying disease, but treatment is usually based on a combination of glucocorticoids and immunosuppressive agents, especially cyclophosphamide and rituximab. The role of plasma exchanges, widely used in patients with severe vasculitis, is controversial, based on results from recent prospective randomized controlled trials.


Racial differences in the association between heart rate variability and left ventricular mass.
What is the central question of this study? Decreased heart rate variability (HRV) is associated with increased cardiovascular disease (CVD) risk, including greater left ventricular mass (LVM). Despite their enhanced CVD risk profile, African Americans have been shown to exhibit higher HRV, relative to Whites; however, it is unclear whether this pattern extends to the association between HRV and LVM. What is the main finding and its importance? Using ECG and echocardiographic data, HRV was positively associated with LVM in a non-clinical sample of African Americans. These findings suggest that current assumptions regarding the meaning of higher HRV might not be universal, which might have implications for HRV as a risk marker among African Americans. Increased left ventricular mass (LVM) is an early precursor of target organ damage attributable to hypertension. Diminished parasympathetic cardiac control has been linked to both hypertension onset and left ventricular impairment; however, emerging evidence suggests that this pattern might be different in African Americans. The present study sought to determine whether race impacts the relationship between parasympathetic cardiac control and LVM. The LVM was assessed via echocardiography in a sample (n = 148) of African American and White adults (mean age 33.20 ± 5.71 years) with normal or mildly elevated blood pressure. Parasympathetic cardiac control was assessed by a measure of high-frequency heart rate variability (HF-HRV) determined from ECG recordings during 5 min of rest. In regression analysis, greater HF-HRV was associated with greater LVM among African Americans (P = 0.002) but was not related to LVM in Whites (P = 0.919). These are the first data to demonstrate that race moderates the relationship between HRV and LVM and further suggest that race might be an important factor in the association between parasympathetic cardiac control and other cardiovascular disease risk factors.


FHL3 is an actin-binding protein that regulates alpha-actinin-mediated actin bundling: FHL3 localizes to actin stress fibers and enhances cell spreading and stress fiber disassembly.
Four and a half LIM domain (FHL) proteins are members of the LIM protein superfamily. Several FHL proteins function as co-activators of CREM/CREB transcription factors and the androgen receptor. FHL3 is highly expressed in skeletal muscle, but its function is unknown. FHL3 localized to the nucleus in C2C12 myoblasts and, following integrin engagement, exited the nucleus and localized to actin stress fibers and focal adhesions. In mature skeletal muscle FHL3 was found at the Z-line. Actin was identified as a potential FHL3 binding partner in yeast two-hybrid screening of a skeletal muscle library. FHL3 complexed with actin both in vitro and in vivo as shown by glutathione S-transferase pull-down assays and co-immunoprecipitation of recombinant and endogenous proteins. FHL3 promoted cell spreading and when overexpressed in spread C2C12 cells disrupted actin stress fibers. Increased FHL3 expression was detected in highly motile cells migrating into an artificial wound, compared with non-motile cells. The molecular mechanism by which FHL3 induced actin stress fiber disassembly was demonstrated by low speed actin co-sedimentation assays and electron microscopy. FHL3 inhibited alpha-actinin-mediated actin bundling. These studies reveal FHL3 as a significant regulator of actin cytoskeletal dynamics in skeletal myoblasts.


Women who maintain optimal cognitive function into old age.
To determine whether older women who maintain optimal cognitive function into old age differ from those who experience minor cognitive decline typically associated with normal aging. Prospective cohort study. The Study of Osteoporotic Fractures. Nine thousand seven hundred four older women. A modified Mini-Mental State Examination (mMMSE) was performed at baseline and Years 6, 8, 10, and 15. Random-effects regression was used to classify subjects as cognitive maintainers (slope>/=0), minor decliners (slope < 0 but > lowest tertile), or major decliners (slope <or= lowest tertile). Stepwise logistic regression was used to identify factors most predictive of being a cognitive maintainer versus a minor decliner (excluding major decliners). Women had a mean age of 72 at baseline and 85 at follow-up. Nine percent maintained optimal cognitive function, 58% experienced minor decline, and 33% experienced major decline. Most factors differed progressively over the three cognitive groups. After adjustment for key confounders, odds ratios for factors most predictive of being a cognitive maintainer as opposed to minor decliner were 1.9 (95% confidence interval (CI)=1.2-2.9) for lack of diabetes mellitus, 1.2 (95% CI=1.0-1.4) for lack of hypertension, 1.7 (95% CI=1.3-2.3) for lack of smoking, 1.2 (95% CI=1.1-1.5) for moderate alcohol consumption, 1.4 (95% CI=1.1-1.7) for lack of difficulty with instrumental activities of daily living, and 1.2 (95% CI=1.0-1.4) for lack of low social network. Almost 10% of older women maintained optimal cognitive function into old age. Cognitive maintainers were less likely to have comorbid medical conditions, less likely to have difficulty with daily activities or poor social networks, and more likely to engage in healthy behaviors than minor cognitive decliners.


Human resource factors associated with workplace safety and health education of small manufacturing businesses in Korea.
Human resources (HR) are essential indicators of safety and health (SH) status, and HR can be key sources of workplace safety management such as safety and health education at work (SHEW). This study analyzed significant HR factors associated with SHEW of small manufacturing businesses in Korea. The secondary data of the 2012 Korea Occupational Safety and Health Trend Survey were used to achieve this research purpose. A total of 2,089 supervisors or managers employed in the small manufacturing businesses completed the interview survey. Survey businesses were selected by multiple stratified sampling method based on industry code, business size, and region in Korea. The survey included workplace characteristics of HR and SHEW. SHEW was significantly related to business size, occupational injury incidence in the previous year, foreign and elderly worker employment, presence of site supervisors, and presence of SH committees (p <.05). SHEW for office workers, non-office workers, and newcomers was associated with business size, presence of site supervisors, and presence of SH committees in logistic regression analysis (p <.001). Businesses with 30-49 workers conducted SHEW 3.64 times more than did businesses with 5 to fewer than 10 workers. The companies that had occupational injuries in the previous year conducted SHEW 1.68 times more than the others. The businesses that had site supervisors and committees conducted SHEW 2.30 and 2.18 times more, respectively, than others. Site supervisors and SH committees were significant HR factors that improved SHEW in small manufacturing businesses.


It's all about the six-pack: Boys' bodies in contemporary Western culture.
This is an article about boys and their construction of masculinities. It draws on 5 years of qualitative research data from the same group of boys from early childhood through to 10 years of age in an attempt to articulate the way in which boys come to view their bodies, and other male bodies, in contemporary Western culture. The research is based on focus groups and is a part of a longitudinal study with the same cohort of boys, at a school in Adelaide, Australia. The data were analysed using inductive thematic analysis to identify key emergent themes. The results indicate that there is an emerging trend among boys from early childhood through to middle primary school surrounding the acknowledgement of male body aesthetics as a signifier of being male. The use of terminology such as 'six-pack' is now commonplace among all of the groups. The consistency around muscularity as a signifier of being a man was very high among the boys of all ages. It is clear that greater emphasis needs to be placed on younger males' and boys' awareness of the meaning of the male body in contemporary Western society.


A modified peripheral neuropathy scale: the Overall Neuropathy Limitations Scale.
A new peripheral neuropathy activities measure, the Overall Neuropathy Limitations Scale (ONLS), was derived by modifying the Overall Disability Sum Score (ODSS) slightly. Its inter-rater reliability was found to be high and its correlation with the ODSS (r = 0.97), 36-item Short Form Questionnaire Physical Component Summary Score, and participation and impairment measures was significant. Acceptable responsiveness (standardised response mean 0.76) was shown by the ONLS. The results obtained from the questionnaire agreed closely with those obtained from observation of the tasks on the ONLS, but were not equivalent. The simplicity of the ODSS is shared by the ONLS, but the ONLS has better content validity and less ceiling effect, which may make it more useful for clinical practice and research.


Changes in tendon stiffness and running economy in highly trained distance runners.
The purpose of this study was to determine if changes in triceps-surae tendon stiffness (TST K) could affect running economy (RE) in highly trained distance runners. The intent was to induce increased TST K in a subgroup of runners by an added isometric training program. If TST K is a primary determinant of RE, then the energy cost of running (EC) should decrease in the trained subjects. EC was measured via open-circuit spirometry in 12 highly trained male distance runners, and TST K was measured using ultrasonography and dynamometry. Runners were randomly assigned to either a training or control group. The training group performed 4 × 20 s isometric contractions at 80% of maximum voluntary plantarflexion moment three times per week for 8 weeks. All subjects (V(O)₂(max)) = 67.4 ± 4.6 ml kg(-1) min(-1)) continued their usual training for running. TST K was measured every 2 weeks. EC was measured in both training and control groups before and after the 8 weeks at three submaximal velocities, corresponding to 75, 85 and 95% of the speed at lactate threshold (sLT). Isometric training did neither result in a mean increase in TST K (0.9 ± 25.8%) nor a mean improvement in RE (0.1 ± 3.6%); however, there was a significant relationship (r(2) = 0.43, p = 0.02) between the change in TST K and change in EC, regardless of the assigned group. It was concluded that TST K and EC are somewhat labile and change together.


Direct measurement of TRPV4 and PIEZO1 activity reveals multiple mechanotransduction pathways in chondrocytes.
The joints of mammals are lined with cartilage, comprised of individual chondrocytes embedded in a specialized extracellular matrix. Chondrocytes experience a complex mechanical environment and respond to changing mechanical loads in order to maintain cartilage homeostasis. It has been proposed that mechanically gated ion channels are of functional importance in chondrocyte mechanotransduction; however, direct evidence of mechanical current activation in these cells has been lacking. We have used high-speed pressure clamp and elastomeric pillar arrays to apply distinct mechanical stimuli to primary murine chondrocytes, stretch of the membrane and deflection of cell-substrate contacts points, respectively. Both TRPV4 and PIEZO1 channels contribute to currents activated by stimuli applied at cell-substrate contacts but only PIEZO1 mediates stretch-activated currents. These data demonstrate that there are separate, but overlapping, mechanoelectrical transduction pathways in chondrocytes.


Modeling the evolution of COVID-19 via compartmental and particle-based approaches: Application to the Cyprus case.
We present two different approaches for modeling the spread of the COVID-19 pandemic. Both approaches are based on the population classes susceptible, exposed, infectious, quarantined, and recovered and allow for an arbitrary number of subgroups with different infection rates and different levels of testing. The first model is derived from a set of ordinary differential equations that incorporates the rates at which population transitions take place among classes. The other is a particle model, which is a specific case of crowd simulation model, in which the disease is transmitted through particle collisions and infection rates are varied by adjusting the particle velocities. The parameters of these two models are tuned using information on COVID-19 from the literature and country-specific data, including the effect of restrictions as they were imposed and lifted. We demonstrate the applicability of both models using data from Cyprus, for which we find that both models yield very similar results, giving confidence in the predictions.


Stabilities and interrelations of multiple species of human adenovirus type 5 early region 1 proteins in infected and transformed cells.
Early region 1A (E1A) of human adenovirus type 5 (Ad5) produces two mRNAs coding for phosphoproteins of 289 and 243 residues (289R and 243R). Each of these products has been shown to migrate on sodium dodecyl sulfate gels as two major and two minor species. In the present study, the stabilities of E1A polypeptides, as well as those of some other early Ad5 proteins, were studied in infected KB cells that were pulse-labeled with [35S]methionine and then chased in the presence or absence of cycloheximide. The E1B 58,000- and 19,000-molecular-weight proteins (58K and 19K proteins; 496R and 176R) as well as the E2A 72K DNA-binding protein were relatively stable over the 4-h chase period; turnover was less than 30%. The E1A species were considerably more unstable, with an overall half-life of about 60 min. Interestingly, it was found that when cycloheximide was present during the chase, E1A proteins were much more stable, and the half-life increased to about 240 min. Analysis of the stabilities of individual E1A species indicated that the products of the 1.1-kilobase mRNA (289R) had half lives (about 55 min) somewhat shorter than those (about 90 min) of the 0.9-kilobase mRNA products (243R). In addition, the faster-migrating species produced from each mRNA (molecular weights, 48,500 and 45,000) had significantly shorter half-lives than did the slower-migrating species (52,000 and 50,000). In the presence of cycloheximide, the faster-migrating species were still quite short-lived, but the half-lives of the 52K and 50K species were considerably increased. An examination of the kinetics of turnover of the various E1A species suggested that the faster-migrating forms may be precursors to the slower-migrating ones. Somewhat similar stabilities were also found for the various E1A species in Ad5-transformed 293 cells.


Clinical Outcomes of Concomitant Use of Warfarin and Selective Serotonin Reuptake Inhibitors: A Multidatabase Observational Cohort Study.
Patients treated with warfarin are often coprescribed selective serotonin reuptake inhibitors (SSRIs) for coexisting depression. Some SSRIs are potent CYP2C9 inhibitors that may increase warfarin plasma concentrations and the risk of bleeding. We aimed to examine the effect of the putative CYP2C9-mediated warfarin-SSRI interaction on clinical outcomes. We conducted an observational cohort study among warfarin initiators who had a subsequent SSRI prescription in 5 US claims databases. Patients were followed for up to 180 days as long as they were exposed to both warfarin and their index SSRI groups. Cox regression models were used to estimate hazard ratios and 95% confidence intervals for bleeding events, ischemic or thromboembolic events, and mortality comparing patients treated with SSRIs that are potent CYP2C9 inhibitors (fluoxetine, fluvoxamine) with those treated with other SSRIs after propensity score matching. The eligible cohort comprised 52,129 patients. Hazard ratios were 1.14 (95% confidence interval [CI], 0.94-1.38) for bleeding events, 1.03 (95% CI, 0.87-1.21) for ischemic or thromboembolic events, and 0.90 (95% CI, 0.72-1.14) for mortality. Results were consistent across individual component outcomes, different warfarin stabilization periods, and subgroup analyses. Patients concomitantly treated with warfarin and SSRIs that are potent CYP2C9 inhibitors had comparable rates of bleeding events, ischemic or thromboembolic events, and mortality as did patients cotreated with warfarin and other SSRIs, although small but potentially meaningful effects on bleeding cannot be completely excluded. SSRI inhibition of CYP2C9 does not appear to affect major safety or effectiveness outcomes of warfarin treatment in clinical practice, where patients may be closely monitored.


Effect of adenine nucleotides on myo-inositol-1,4,5-trisphosphate-induced calcium release.
The effects of a whole series of adenine nucleotides on Ins(1,4,5)P3-induced Ca2+ release were characterized in permeabilized A7r5 smooth-muscle cells. Several adenine nucleotides activated the Ins(1, 4,5)P3 receptor. It was observed that 3'-phosphoadenosine 5'-phosphoulphate, CoA, di(adenosine-5')tetraphosphate (Ap4A) and di(adenosine-5')pentaphosphate (Ap5A) were more effective than ATP. Ap4A and Ap5A also interacted with a lower EC50 than ATP. In order to find out how these adenine nucleotides affected Ins(1,4, 5)P3-induced Ca2+ release, we have measured their effect on the response of permeabilized A7r5 cells to a progressively increasing Ins(1,4,5)P3 concentration. Stimulatory ATP and Ap5A concentrations had no effect on the threshold Ins(1,4,5)P3 concentration for initiating Ca2+ release, but they stimulated Ca2+ release in the presence of supra-threshold Ins(1,4,5)P3 concentrations by increasing the co-operativity of the release process. Inhibition of the Ins(1,4,5)P3-induced Ca2+ release at higher ATP concentrations was associated with a further increase in co-operativity and also with a shift in threshold towards higher Ins(1,4,5)P3 concentrations. ATP had no effect on the non-specific Ca2+ leak in the absence of Ins(1,4,5)P3. We conclude that the adenine-nucleotide-binding site can be activated by many different adenine nucleotides. Binding of these compounds to the transducing domain of the Ins(1,4,5)P3 receptor increases the efficiency of transmitting Ins(1,4,5)P3 binding to channel opening. The inhibition by high ATP concentrations is exerted at a different site, related to Ins(1,4,5)P3 binding.


A general approach for nanoparticle composite transport materials toward efficient perovskite solar cells.
The design of electron transport layers (ETLs) is crucial to the performance of optoelectronic devices. A composite ETL was constructed to overcome the poor carrier extraction issue in perovskite solar cells, resulting in a maximum PCE of 19.14% with reduced hysteresis. A similar enhancement phenomenon was observed in both devices based on TiO2 and SnO2 ETLs.


Validation of elevated levels of interleukin-8 in the cerebrospinal fluid, and discovery of new biomarkers in patients with GBS and CIDP using a proximity extension assay.
Biomarkers for diagnosis of inflammatory neuropathies, assessment of prognosis, and treatment response are lacking. CSF and EDTA plasma from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), healthy controls (HC) and disease controls were analyzed with Olink multiplex proximity extension assay (PEA) from two independent cohorts. Levels of interleukin-8 (IL8) were further analyzed with ELISA in patients with GBS, CIDP, paraproteinemia-related demyelinating polyneuropathy (PDN), multifocal motor neuropathy (MMN), HC and disease controls. ROC analysis was performed. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) score. In CSF, multiplex PEA analysis revealed up-regulation of IL8 in GBS compared to CIDP and HC respectively, and CIDP compared to HC. In addition, levels of IL2RA were upregulated in GBS compared to both HC and CIDP, SELE in GBS compared to HC, and ITGAM, IL6, and NRP1 in GBS compared to CIDP. In plasma, levels of MMP3, THBD and ITGAM were upregulated in CIDP compared to HC. Validation of multiplex IL8 results using ELISA, revealed increased levels of IL8 in CSF in patients with GBS and CIDP versus HC and non-inflammatory polyneuropathies (NIP) respectively, as well as in PDN versus NIP and HC. Levels of IL8 in CSF correlated with impairment in the acute phase of GBS as well as outcome at 6-months follow up. IL8 in CSF is validated as a diagnostic biomarker in GBS and CIDP, and a prognostic biomarker in GBS. Multiplex PEA hereby identifies several potential biomarkers in GBS and CIDP.


Facial fractures in road cyclists.
Despite the safety devices worn by bicycle riders and the road safety measures designed to protect them, road cycling is still associated with frequent traumas, notably to the extremities. Maxillofacial injuries are common, especially when road traffic accidents occur. There is a paucity of literature on the epidemiology of bicycle-related facial fractures in New Zealand. A retrospective database of patients presenting to the Oral and Maxillofacial Surgery Unit at Christchurch Hospital during an 11-year period was reviewed. Variables examined included demographics, types of fracture, mode of injury, and treatment delivered. Sixty-three patients were identified as having road bicycle-related facial fractures, with no increase in prevalence over the study period. Male to female ratio was 3:1, with 76 per cent involving patients aged between their first and third decade. Fall was the most common mechanism of injury, followed by collision. Fifty-two per cent of patients were hospitalized and 40 per cent required surgical intervention. The highest incidence of injury was during January. Road bicycle-related fractures accounted for a small proportion of the workload at our unit. They predominantly affected young male adults. More than half of the patients were hospitalized and a major proportion of these required surgery.


Changes of the gut microbiota composition and short chain fatty acid in patients with atrial fibrillation.
With the establishment of the cardiac-gut axis concept, increasing evidence has suggested the involvement and important regulatory role of the gut microbiota (GM) and short chain fatty acid (SCFA) in cardiovascular diseases. However, the relationship between GM and atrial fibrillation (AF) is still poorly understood. The aim of this study was to investigate whether there were differences in GM and SCFA between AF patients and healthy controls. In this study, we enrolled 30 hospitalized patients with AF and 30 matched patients with sinus rhythm (SR). GM species in fecal samples were evaluated through amplicon sequencing targeting the 16Sribosomal RNA gene. The feces SCFAs were describe step by step the quantitative analysis using gas chromatography-mass spectrometry (GC-MS). GM species richness, diversity, differential abundance of individual taxa between AF and SR were analyzed. AF patients showed decreased species richness and α-diversity compared to SR patients, but there was no statistical difference. The phylogenetic diversity was significant decreased in AF group. The β-diversity indexes revealed significant differences in GM community structure between the AF group and the SR group. After investigated the individual taxa, AF group showed altered relative abundance in several taxa compared to the SR group. linear discriminant analysis (LDA) effect size (LEfSe) analysis revealed, a significant decrease in Bifidobacterium and a greater abundance of Lactobacillus, Fusobacterium, Haemophilus in AF group compared with the SR group. The abundance of haemophilus was negative correlated with isovaleric acid and isobutyric acid. In AF patients, the GM phylogenetic diversity and β-diversity decreased, the relative abundance altered in several taxa and the bacterial community structure changed as well as the SCFA level. GM and SCFA dysbiosis might play a crucial part in the occurrence and development of AF.


Macronutrient content of pasteurised donor human milk: Variability between batches from single-donor pools at an Australian milk bank.
This study aimed to characterise the between-batch variability of pasteurised donor human milk (PDHM) produced from single-donor pools at Australian Red Cross Lifeblood's milk bank and identify key donor characteristics that predict macronutrient content. Macronutrient content from 200 batches of PDHM was measured using a mid-infrared human milk analyser (Miris, Uppsala, Sweden). Linear mixed models were used to study the impact of stage of lactation and gestational age on macronutrient content. Coefficients of determination (R2 ) were calculated to estimate the impact of the individual donor on overall variability. Macronutrient content of PDHM varied considerably, with between-batch variations of 2.8 and 6.4-fold for protein and fat content, respectively. Mean crude protein content was 1.16 g/100 mL, ranging from 0.7 to 1.96 g/100 mL. Mean fat content was 3.85 g/100 mL, ranging from 1.46 to 9.39 g/100 mL. Stage of lactation was identified as a predictor for protein content and gestational age at birth for fat content. Individual donor effect explained 55 and 35% of the variance for fat and protein content, respectively. This study highlights the variation in macronutrient content in PDHM at an Australian milk bank. Variability could be reduced through the implementation of targeted multiple-donor pooling using the key donor characteristics identified in this study along with the measurement of macronutrient content of individual donors at the time of first donation. However, the clinical benefit of a reduction in between-batch variation, achieved through multiple-donor pooling, would need to be assessed to justify additional efforts associated with PDHM processing changes.


What can we learn from the age- and race/ethnicity- specific rates of inflammatory breast carcinoma?
Inflammatory Breast Carcinoma (IBC), the most aggressive type of breast tumor with unique clinicopathological presentation, is hypothesized to have distinct etiology with a socioeconomic status (SES) component. Using the Surveillance, Epidemiology and End Results (SEER) Program data for 2004-2007, we compare incidence rates of IBC to non-inflammatory locally advanced breast cancer (LABC) among racial/ethnic groups with different SES. The analysis includes women 20-84 years of age. To examine evidence for the distinct etiology of IBC, we analyzed age-distribution patterns of IBC and non-inflammatory LABC, using a mathematical carcinogenesis model. Based on the Collaborative Staging Extension codes, 2,942 incident IBC cases (codes 71 and 73) and 5,721 non-inflammatory LABC cases (codes 40-62) were identified during the four-year study period. Age-adjusted rates of IBC among non-Hispanic White and Hispanic women were similar (2.5/100,000 in both groups). Similar rates were also found in non-inflammatory LABC in these two groups (4.8/100,000 and 4.2/100,000, respectively). In African-American women, the IBC (3.91/100,000) and non-inflammatory LABC (8.47/100,000) rates were greater compared with other ethnic/racial sub-groups. However, the ratio of rates of IBC/non-inflammatory LABC was similar among all the racial/ethnic groups, suggesting that African-American women are susceptible to aggressive breast tumors in general but not specifically to IBC. The mathematical model successfully predicted the observed age-specific rates of both examined breast tumors and revealed distinct patterns. IBC rates increased until age 65 and then slightly decreased, whereas non-inflammatory LABC rates steadily increased throughout the entire age interval. The number of critical transition carcinogenesis stages (m-stages) predicted by the model were 6.3 and 8.5 for IBC and non-inflammatory LABC, respectively, supporting different etiologies of these breast tumors.


Cellular Contraction Can Drive Rapid Epithelial Flows.
Single, isolated epithelial cells move randomly; however, during wound healing, organism development, cancer metastasis, and many other multicellular phenomena, motile cells group into a collective and migrate persistently in a directed manner. Recent work has examined the physics and biochemistry that coordinates the motions of these groups of cells. Of late, two mechanisms have been touted as being crucial to the physics of these systems: leader cells and jamming. However, the actual importance of these to collective migration remains circumstantial. Fundamentally, collective behavior must arise from the actions of individual cells. Here, we show how biophysical activity of an isolated cell impacts collective dynamics in epithelial layers. Although many reports suggest that wound closure rates depend on isolated cell speed and/or leader cells, we find that these correlations are not universally true, nor do collective dynamics follow the trends suggested by models for jamming. Instead, our experimental data, when coupled with a mathematical model for collective migration, shows that intracellular contractile stress, isolated cell speed, and adhesion all play a substantial role in influencing epithelial dynamics, and that alterations in contraction and/or substrate adhesion can cause confluent epithelial monolayers to exhibit an increase in motility, a feature reminiscent of cancer metastasis. These results directly question the validity of wound-healing assays as a general means for measuring cell migration, and provide further insight into the salient physics of collective migration.


Global ecological pattern of ammonia-oxidizing archaea.
The global distribution of ammonia-oxidizing archaea (AOA), which play a pivotal role in the nitrification process, has been confirmed through numerous ecological studies. Though newly available amoA (ammonia monooxygenase subunit A) gene sequences from new environments are accumulating rapidly in public repositories, a lack of information on the ecological and evolutionary factors shaping community assembly of AOA on the global scale is apparent. We conducted a meta-analysis on uncultured AOA using over ca. 6,200 archaeal amoA gene sequences, so as to reveal their community distribution patterns along a wide spectrum of physicochemical conditions and habitat types. The sequences were dereplicated at 95% identity level resulting in a dataset containing 1,476 archaeal amoA gene sequences from eight habitat types: namely soil, freshwater, freshwater sediment, estuarine sediment, marine water, marine sediment, geothermal system, and symbiosis. The updated comprehensive amoA phylogeny was composed of three major monophyletic clusters (i.e. Nitrosopumilus, Nitrosotalea, Nitrosocaldus) and a non-monophyletic cluster constituted mostly by soil and sediment sequences that we named Nitrososphaera. Diversity measurements indicated that marine and estuarine sediments as well as symbionts might be the largest reservoirs of AOA diversity. Phylogenetic analyses were further carried out using macroevolutionary analyses to explore the diversification pattern and rates of nitrifying archaea. In contrast to other habitats that displayed constant diversification rates, marine planktonic AOA interestingly exhibit a very recent and accelerating diversification rate congruent with the lowest phylogenetic diversity observed in their habitats. This result suggested the existence of AOA communities with different evolutionary history in the different habitats. Based on an up-to-date amoA phylogeny, this analysis provided insights into the possible evolutionary mechanisms and environmental parameters that shape AOA community assembly at global scale.


Darwin and Spencer on the origin of music: is music the food of love?
Finding an evolutionary explanation for the origins of music serves as a rich test of broader ideas on the emergence of mind and the evolution of mental processes. Charles Darwin and Herbert Spencer both offered evolutionary explanations for the origins of music, indicating the importance of the question for these two leading nineteenth-century students of "descent with modification." Their discussion unfolded between the publication of Spencer's "The origin and function of music" in 1857 and Darwin's commentaries on music in The Descent of Man in 1871 with an addendum Spencer offered to his original article in light of Darwin's views. They had conflicting views on the lines of causation, asked differing questions, and had fundamentally different approaches. Their exchange laid the foundation for the discussion among contemporary adaptationists and nonadaptationists and contributed to the thinking of those who argue for Mixed Origins of Music or that it is a Transformative Technology of Mind.


Fertility sparing treatment in borderline ovarian tumours.
Borderline ovarian tumours are low malignant potential tumours. They represent 10-15% of all epithelial ovarian malignancies. Patients with this type of tumour are younger at the time of diagnosis than patients with invasive ovarian cancer. Most of them are diagnosed in the early stages and have an excellent prognosis. It has been quite clearly established that the majority of borderline ovarian tumours should be managed with surgery alone. Because a high proportion of women with this malignancy are young and the prognosis is excellent, the preservation of fertility is an important issue in the management of these tumours. In this systemic review of the literature, we have evaluated in-depth oncological safety and reproductive outcomes in women with borderline ovarian tumours treated with fertility-sparing surgery, reviewing the indications, benefits, and disadvantages of each type of conservative surgery, as well as new alternative options to surgery to preserve fertility.


Inhibition of AFB1-induced liver cancer and induction of increased microsomal enzyme activity by dietary constituents.
A long-term study, using male Wistar rats, was initiated to determine whether the effects of dietary constituents on AFB1-induced liver cancer could be associated with altered microsomal enzyme activity. They were maintained on mice pellets mixed with specific dietary constituents for 7 days and then given a single carcinogenic dose of AFB1 (500 micrograms/rat). After three months, the dietary constituents were discontinued and the animals were left on mice pellets and drinking water only for a period of about 20 months. At the end of the trial period, it was observed that dietary mixtures containing small quantities of either beta-carotene, ascorbic acid, GSH, vitamin E, selenium salt, or uric acid, effectively inhibited the development of AFB1-induced liver cancer and induced increased microsomal enzyme activity. Whereas beta-carotene and uric acid were the most effective inhibitors, vitamin E was the least, yet a significant inhibitor of liver cancer. Hepatic levels of cytochrome P-450, aniline hydroxylase and chlorpromazine demethylase were significantly induced in rats fed fortified food followed by AFB1 treatment than in control animals. The inhibition of liver cancer by dietary factors was probably due to their ability to induce the activity of hepatic microsomal enzymes. Increased enzyme activity could lead to rapid activation of AFB1 metabolism, resulting in loss of activated AFB1 metabolites that attack cell components. Inhibition of liver cancer is therefore associated with induction of increased microsomal enzyme activity.


Effects of glyphosate residues and different concentrate feed proportions on performance, energy metabolism and health characteristics in lactating dairy cows.
The aim of this study was to examine the influence of glyphosate (GL) residues in feedstuffs on performance, energy balance and health-related characteristics of lactating dairy cows fed diets with different concentrate feed proportions. After an adaption period, 64 German Holstein cows (207 ± 49 d in milk; mean ± SD) were assigned to either groups receiving a GL contaminated total mixed ration (TMR) (GL groups) or an uncontaminated TMR (CON groups) during a 16 weeks trial. Contaminated feedstuffs used were legally GL-treated peas and wheat (straw and grain). GL and CON groups were subdivided into a "low concentrate" group (LC) fed on dry matter (DM) basis of 21% maize silage, 42% grass silage, 7% straw and 30% concentrate and a "high concentrate" group (HC) composed of 11% maize silage, 22% grass silage, 7% straw and 60% concentrate for ad libitum consumption. Body condition score, body weight, DM intake and milk performance parameters were recorded. In blood serum, β-hydroxybutyrate (BHB), non-esterified fatty acids (NEFA) and glucose were measured and energy balance was calculated. Milk was analysed for GL residues. At week 0, 7 and 15, general health status was evaluated by a modified clinical score. The average individual GL intake amounted for Groups CONLC, CONHC, GLLC and GLHC to 0.8, 0.8, 73.8 and 84.5 mg/d, respectively. No GL residues were detected in milk. GL contamination did not affect body condition score, body weight, DM intake, nutrient digestibility, net energy intake, net energy balance or BHB, glucose, NEFA and milk performance parameters; whereas concentrate feed proportion and time did affect most parameters. The clinical examination showed no adverse effect of GL-contaminated feedstuffs on cows' health condition. In the present study, GL-contaminated feedstuffs showed no influence on performance and energy balance of lactating dairy cows, irrespective of feed concentrate proportion.


Evidence of chondrocyte turnover in lung cartilage, with the probable participation of nestin-positive cells.
Healthy adult cartilage is thought to have little or no capacity to renewal, and cell turnover has not been reported in lung cartilage. We report that chondrocyte turnover occurs in lung cartilage, found in an unrelated study. Lung specimens from CD1 mice of 2, 6, 12, 18 or 24 months were fixed in 10% neutral-buffered formalin and paraffin-embedded. Apoptosis was analysed by in situ end-labelling of fragmented DNA. Proliferating cell nuclear antigen (PCNA) and nestin were examined by immunohistochemistry. Apoptosis and PCNA were detected in lung chondrocytes. Serial section analysis showed that cells in apoptosis were different from PCNA-positive cells, indicating that turnover was occurring. Chondrocytes were negative for nestin. Nestin-positive cells were present in connective tissue associated with cartilage, in some specimens in close proximity of it and in perivascular cells. Thus cell turnover in lung cartilage is possible, which may be mediated by nestin-positive cells.