Construction of Comprehensive Dosage-Matching Core Histone Mutant Libraries for Saccharomyces cerevisiae.
Saccharomyces cerevisiae contains two genes for each core histone, which are presented as pairs under the control of a divergent promoter, i.e., HHT1-HHF1, HHT2-HHF2, HTA1-HTB1 and HTA2-HTB2HHT1-HHF1, and HHT2-HHF2 encode histone H3 and H4 with identical amino acid sequences but under the control of differently regulated promoters. Previous mutagenesis studies were carried out by deleting one pair and mutating the other one. Here, we present the design and construction of three additional libraries covering HTA1-HTB1, HTA2-HTB2, and HHT1-HHF1 respectively. Together with the previously described library of HHT2-HHF2 mutants, a systematic and complete collection of mutants for each of the eight core S. cerevisiae histone genes becomes available. Each designed mutant was incorporated into the genome, generating three more corresponding libraries of yeast strains. We demonstrated that, although, under normal growth conditions, strains with single-copy integrated histone genes lacked phenotypes, in some growth conditions, growth deficiencies were observed. Specifically, we showed that addition of a second copy of the mutant histone gene could rescue the lethality in some previously known mutants that cannot survive with a single copy. This resource enables systematic studies of function of each nucleosome residue in plasmid, single-copy, and double-copy integrated formats.


The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier.
Three-tiered kinase modules, such as the Raf-MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase)-ERK (extracellular signal-regulated kinase) mitogen-activated protein kinase pathway, are widespread in biology, suggesting that this structure conveys evolutionarily advantageous properties. We show that the three-tiered kinase amplifier module combined with negative feedback recapitulates the design principles of a negative feedback amplifier (NFA), which is used in electronic circuits to confer robustness, output stabilization, and linearization of nonlinear signal amplification. We used mathematical modeling and experimental validation to demonstrate that the ERK pathway has properties of an NFA that (i) converts intrinsic switch-like activation kinetics into graded linear responses, (ii) conveys robustness to changes in rates of reactions within the NFA module, and (iii) stabilizes outputs in response to drug-induced perturbations of the amplifier. These properties determine biological behavior, including activation kinetics and the response to drugs.


High enthusiasm about long lasting mentoring relationships and older mentors.
Mentoring plays a pivotal role in workplace-based learning, especially in the medical realm. Organising a formal mentoring programme can be labor and time intensive and generally impractical in resource constrained medical schools with limited numbers of mentors. Hence, informal mentoring offers a valuable alternative, but will be more likely to be effective when mentors and protégés share similar views. It is therefore important to gain more insight into factors influencing perceptions of informal mentoring. This study aims to explore mentors and protégés' perceptions of informal mentoring and how these vary (or not) with gender, age and the duration of the relationship. We administered an Informal Mentor Role Instrument (IMRI) to medical practitioners and academics from Egypt, Pakistan and Saudi Arabia. The questionnaire was developed for the study from other validated instruments. It contained 39 items grouped into 7 domains: acceptance, counselling, friendship, parenting, psychological support, role modelling and sociability. A total of 103 mentors and 91 protégés completed the IMRI. Mentors had a better appreciation for the interpersonal aspects of informal mentoring than protégés, especially regarding acceptance, counselling and friendship. Moreover, being older and engaged in a longer mentoring relationship contributed to more positive perceptions of interpersonal aspects of mentoring, regardless of one's role (mentor or protégé). It can be concluded that the expectations of mentors and protégés differed regarding the content and aim of the interpersonal characteristics of their mentoring relationship. We recommend mentors and protégés to more explicitly exchange their expectations of the informal mentoring relationship, as typically practiced in formal mentoring. Additionally, in our study, seniority and lasting relationships seem crucial for good informal mentoring. It appears beneficial to foster lasting informal mentoring relationships and to give more guidance to younger mentors.


Short-term outcomes after anatomic total shoulder arthroplasty in patients with osteoarthritis versus osteonecrosis.
The outcomes of anatomic total shoulder arthroplasty (TSA) for glenohumeral osteoarthritis (OA) have been extensively reported in the literature. However, there is a paucity of short-term outcomes data on perioperative and post-operative outcomes in patients receiving TSA for either glenoid or humeral head osteonecrosis (ON). We compared the short-term outcomes of TSA performed on patients who had glenohumeral OA and those who had ON. Specifically, we compared: (I) demographics; (II) length-of-stay (LOS); and (III) 30-day postoperative complication rates. Data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) was used to select 7,066 patients with a diagnosis of glenohumeral OA or ON who underwent TSA between January 1st, 2008 and December 31st, 2015. Propensity score matching was performed based on age, sex, race, and body mass index (BMI) with a 3:1 ratio of OA to ON patients. As a result, 387 patients who had a primary diagnosis of OA were compared with 129 patients who had ON. Analyses addressed perioperative complications and hospital disposition factors-including LOS and 30-day post-operative complications-using bivariate and logistic regression models. Overall complication rates were low in both groups, at 6.1% and 5.4% for the ON and OA cohorts respectively. The ON cohort had more comorbidities, including higher Charlson/Devo and American Society of Anesthesiologists (ASA) scores (P<0.05). Hospital disposition factors were not statistically different between the 2 groups. While not statistically significant, the ON cohort had a longer average (21.1% longer, P>0.05), an increased risk for developing any complication [odds ratio (OR) =2.07; 95% confidence interval (CI), 0.94 to 4.57; P=0.07], and a 134% higher risk for developing a minor complication compared to the OA (OR =2.34; 95% CI, 1.01 to 5.42; P=0.047). Although the patient populations who develop ON or shoulder OA have differences, there are not statistically or clinically meaningful differences in the short-term outcomes after anatomic TSA. Future studies are required to examine if differences exist in the long-term follow-up between the two groups.


A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound.
Bisphenol A (BPA) is a widely studied typical endocrine-disrupting chemical, and one of the major new issues is the safe replacement of this commonly used compound. Bisphenol S (BPS) and bisphenol F (BPF) are already or are planned to be used as BPA alternatives. With the use of a culture system that we developed (fetal testis assay [FeTA]), we previously showed that 10 nmol/L BPA reduces basal testosterone secretion of human fetal testis explants and that the susceptibility to BPA is at least 100-fold lower in rat and mouse fetal testes. Here, we show that addition of LH in the FeTA system considerably enhances BPA minimum effective concentration in mouse and human but not in rat fetal testes. Then, using the FeTA system without LH (the experimental conditions in which mouse and human fetal testes are most sensitive to BPA), we found that, as for BPA, 10 nmol/L BPS or BPF is sufficient to decrease basal testosterone secretion by human fetal testes with often nonmonotonic dose-response curves. In fetal mouse testes, the dose-response curves were mostly monotonic and the minimum effective concentrations were 1,000 nmol/L for BPA and BPF and 100 nmol/L for BPS. Finally, 10,000 nmol/L BPA, BPS, or BPF reduced Insl3 expression in cultured mouse fetal testes. This is the first report describing BPS and BPF adverse effects on a physiologic function in humans and rodents.


Evolution of influenza A virus PB2 genes: implications for evolution of the ribonucleoprotein complex and origin of human influenza A virus.
Phylogenetic analysis of 20 influenza A virus PB2 genes showed that PB2 genes have evolved into the following four major lineages: (i) equine/Prague/56 (EQPR56); (ii and iii) two distinct avian PB2 lineages, one containing FPV/34 and H13 gull virus strains and the other containing North American avian and recent equine strains; and (iv) human virus strains joined with classic swine virus strains (i.e., H1N1 swine virus strains related to swine/Iowa/15/30). The human virus lineage showed the greatest divergence from its root relative to other lineages. The estimated nucleotide evolutionary rate for the human PB2 lineage was 1.82 x 10(-3) changes per nucleotide per year, which is within the range of published estimates for NP and NS genes of human influenza A viruses. At the amino acid level, PB2s of human viruses have accumulated 34 amino acid changes over the past 55 years. In contrast, the avian PB2 lineages showed much less evolution, e.g., recent avian PB2s showed as few as three amino acid changes relative to the avian root. The completion of evolutionary analyses of the PB1, PB2, PA and NP genes of the ribonucleoprotein (RNP) complex permits comparison of evolutionary pathways. Different patterns of evolution among the RNP genes indicate that the genes of the complex are not coevolving as a unit. Evolution of the PB1 and PB2 genes is less correlated with host-specific factors, and their proteins appear to be evolving more slowly than NP and PA. This suggests that protein functional constraints are limiting the evolutionary divergence of PB1 and PB2 genes. The parallel host-specific evolutionary pathways of the NP and PA genes suggest that these proteins are coevolving in response to host-specific factors. PB2s of human influenza A viruses share a common ancestor with classic swine virus PB2s, and the pattern of evolution suggests that the ancestor was an avian virus PB2. This same pattern of evolution appears in the other genes of the RNP complex. Antigenic studies of HA and NA proteins and sequence comparisons of NS and M genes also suggest a close ancestry for these genes in human and classic swine viruses. From our review of the evolutionary patterns of influenza A virus genes, we propose the following hypothesis: the common ancestor to current strains of human and classic swine influenza viruses predated the 1918 human pandemic virus and was recently derived from the avian host reservoir.


Increased static dielectric constant in ZnMnO and ZnCoO thin films with bound magnetic polarons.
A novel small signal equivalent circuit model is proposed in the inversion regime of metal/(ZnO, ZnMnO, and ZnCoO) semiconductor/Si3N4 insulator/p-Si semiconductor (MSIS) structures to describe the distinctive nonlinear frequency dependent capacitance (C-F) and conductance (G-F) behaviour in the frequency range from 50 Hz to 1 MHz. We modelled the fully depleted ZnO thin films to extract the static dielectric constant (εr) of ZnO, ZnMnO, and ZnCoO. The extracted enhancement of static dielectric constant in magnetic n-type conducting ZnCoO (εr ≥ 13.0) and ZnMnO (εr ≥ 25.8) in comparison to unmagnetic ZnO (εr = 8.3-9.3) is related to the electrical polarizability of donor-type bound magnetic polarons (BMP) in the several hundred GHz range (120 GHz for CdMnTe). The formation of donor-BMP is enabled in n-type conducting, magnetic ZnO by the s-d exchange interaction between the electron spin of positively charged oxygen vacancies [Formula: see text] in the BMP center and the electron spins of substitutional Mn2+ and Co2+ ions in ZnMnO and ZnCoO, respectively. The BMP radius scales with the Bohr radius which is proportional to the static dielectric constant. Here we show how BMP overlap can be realized in magnetic n-ZnO by increasing its static dielectric constant and guide researchers in the field of transparent spintronics towards ferromagnetism in magnetic, n-ZnO.


Honey in dermatology and skin care: a review.
Honey is a bee-derived, supersaturated solution composed mainly of fructose and glucose, and containing proteins and amino acids, vitamins, enzymes, minerals, and other minor components. Historical records of honey skin uses date back to the earliest civilizations, showing that honey has been frequently used as a binder or vehicle, but also for its therapeutic virtues. Antimicrobial properties are pivotal in dermatological applications, owing to enzymatic H2 O2 release or the presence of active components, like methylglyoxal in manuka, while medical-grade honey is also available. Honey is particularly suitable as a dressing for wounds and burns and has also been included in treatments against pityriasis, tinea, seborrhea, dandruff, diaper dermatitis, psoriasis, hemorrhoids, and anal fissure. In cosmetic formulations, it exerts emollient, humectant, soothing, and hair conditioning effects, keeps the skin juvenile and retards wrinkle formation, regulates pH and prevents pathogen infections. Honey-based cosmetic products include lip ointments, cleansing milks, hydrating creams, after sun, tonic lotions, shampoos, and conditioners. The used amounts range between 1 and 10%, but concentrations up to 70% can be reached by mixing with oils, gel, and emulsifiers, or polymer entrapment. Intermediate-moisture, dried, and chemically modified honeys are also used. Mechanisms of action on skin cells are deeply conditioned by the botanical sources and include antioxidant activity, the induction of cytokines and matrix metalloproteinase expression, as well as epithelial-mesenchymal transition in wounded epidermis. Future achievements, throwing light on honey chemistry and pharmacological traits, will open the way to new therapeutic approaches and add considerable market value to the product.


A multimodal cortical network for the detection of changes in the sensory environment.
Sensory stimuli undergoing sudden changes draw attention and preferentially enter our awareness. We used event-related functional magnetic-resonance imaging (fMRI) to identify brain regions responsive to changes in visual, auditory and tactile stimuli. Unimodally responsive areas included visual, auditory and somatosensory association cortex. Multimodally responsive areas comprised a right-lateralized network including the temporoparietal junction, inferior frontal gyrus, insula and left cingulate and supplementary motor areas. These results reveal a distributed, multimodal network for involuntary attention to events in the sensory environment. This network contains areas thought to underlie the P300 event-related potential and closely corresponds to the set of cortical regions damaged in patients with hemineglect syndromes.


Annealed importance sampling of peptides.
Annealed importance sampling assigns equilibrium weights to a nonequilibrium sample that was generated by a simulated annealing protocol [R. M. Neal, Stat. Comput. 11, 125 (2001)]. The weights may then be used to calculate equilibrium averages, and also serve as an "adiabatic signature" of the chosen cooling schedule. In this paper we demonstrate the method on the 50-atom dileucine peptide and an alanine 5-mer, showing that equilibrium distributions are attained for manageable cooling schedules. For dileucine, as naively implemented here, the method is modestly more efficient than constant temperature simulation. The alanine application demonstrates the success of the method when there is little overlap between the high (unfolded) and low (folded) temperature distributions. The method is worth considering whenever any simulated heating or cooling is performed (as is often done at the beginning of a simulation project or during a NMR structure calculation), as it is simple to implement and requires minimal additional computational expense. Furthermore, the naive implementation presented here can be improved.


In vivo behavior of the human soleus muscle with increasing walking and running speeds.
The interaction between the muscle fascicle and tendon components of the human soleus (SO) muscle influences the capacity of the muscle to generate force and mechanical work during walking and running. In the present study, ultrasound-based measurements of in vivo SO muscle fascicle behavior were combined with an inverse dynamics analysis to investigate the interaction between the muscle fascicle and tendon components over a broad range of steady-state walking and running speeds: slow-paced walking (0.7 m/s) through to moderate-paced running (5.0 m/s). Irrespective of a change in locomotion mode (i.e., walking vs. running) or an increase in steady-state speed, SO muscle fascicles were found to exhibit minimal shortening compared with the muscle-tendon unit (MTU) throughout stance. During walking and running, the muscle fascicles contributed only 35 and 20% of the overall MTU length change and shortening velocity, respectively. Greater levels of muscle activity resulted in increasingly shorter SO muscle fascicles as locomotion speed increased, both of which facilitated greater tendon stretch and recoil. Thus the elastic tendon contributed the majority of the MTU length change during walking and running. When transitioning from walking to running near the preferred transition speed (2.0 m/s), greater, more economical ankle torque development is likely explained by the SO muscle fascicles shortening more slowly and operating on a more favorable portion (i.e., closer to the plateau) of the force-length curve.


[Toxic shock syndrome].
Toxic shock syndrome (TSS) is a rare, life-threatening, acute multisystem illness usually characterized by sudden onset of high fever, diffuse sunburn-like erythroderma and a variety of other signs and symptoms. It may progress rapidly to hypotension and shock with multiple organ failure. Its exact cause is unknown, but in almost all cases there has been an infection with exotoxin-producing strains of phage group I Staphylococcus aureus. Although initially described in association with the use of superabsorbent tampons in menstruation, TSS has complicated a variety of surgical procedures. Recently in head and neck surgery attention has focused on absorbent packing materials, such as those used in postoperative nasal care. TSS developed in a 12-year-old 28 hours after tonsillectomy, nasal septoplasty and inferior turbinectomy in which absorbent packing material was used. It is important to maintain a high index of suspicion for TSS in all postoperative patients with fever, hypotension and erythroderma.


Discretized diffusion processes
We study the properties of the "rigid Laplacian" operator; that is we consider solutions of the Laplacian equation in the presence of fixed truncation errors. The dynamics of convergence to the correct analytical solution displays the presence of a metastable set of numerical solutions, whose presence can be related to granularity. We provide some scaling analysis in order to determine the value of the exponents characterizing the process. We believe that this prototype model is also suitable to provide an explanation of the widespread presence of power law in a social and economic system where information and decision diffuse, with errors and delay from agent to agent.


Women's preferences for masculinity in male faces are highest during reproductive age range and lower around puberty and post-menopause.
Masculinity in male faces is thought to be a sign of mate quality and is associated with measures of long-term health. Previous studies have demonstrated that women's masculinity preferences change across the menstrual cycle with women preferring more masculine men during phases of the menstrual cycle where fertility is highest (i.e. the late follicular phase). Given the hormonal correlates of such preferences and that these hormones change across the life span, we tested for differences in female masculinity preferences at different ages. We compared the masculinity preferences of peri-pubescent girls and young adult women (Study 1), circum-menopausal women reporting to either be pre- or post-menopause (Study 2), and a large sample of women across a wide range of ages (Study 3). In all three studies, preferences for masculinity in male faces were highest in women who were at a reproductively active age. Preferences for masculinity were lower when females were peri-pubescent, post-menopausal, or at ages corresponding to these groups. These data support the notion that masculinity in male faces is an important trait for reproductively relevant mate choice decisions. These data also highlight a shift in female visual preferences for men that is associated with important stages of the lifespan. Visual preferences appear to track important hormonal changes associated with age; as women pass puberty their preferences shift towards facial traits associated with mate quality and as women undergo menopause their preferences for such facial traits decrease. Overall, these results demonstrate the important role of reproductive status and support the notion that preferences for male faces are tied to reproductively relevant hormones.


Ingestion of swimming pool water by recreational swimmers.
The volume of water ingested by swimmers while swimming is of great interest to individuals who develop risk assessments using quantitative microbial risk assessment or epidemiological approaches. We have used chloroisocyanurate disinfected swimming pool waters to determine the amount of water swallowed by swimmers during swimming activity. The chloroisocyanurate, which is in equilibrium with chlorine and cyanuric acid in the pool water, provides a biomarker, cyanuric acid, that once swallowed passes through the body into the urine unchanged. The concentration of cyanuric acid in a 24 hour urine specimen and the concentration in pool water can be used to calculate the amount of water swallowed. Our study population of 549 participants, which was about evenly divided by gender, and young and adult swimmers, indicated that swimmers ingest about 32 mL per hour (arithmetic mean) and that children swallowed about four times as much water as adults during swimming activities. It was also observed that males had a tendency to swallow more water than females during swimming activity and that children spent about twice as much time in the water than adults.


The transport of liquids in softwood: timber as a model porous medium.
Timber is the only widely used construction material we can grow. The wood from which it comes has evolved to provide structural support for the tree and to act as a conduit for fluid flow. These flow paths are crucial for engineers to exploit the full potential of timber, by allowing impregnation with liquids that modify the properties or resilience of this natural material. Accurately predicting the transport of these liquids enables more efficient industrial timber treatment processes to be developed, thereby extending the scope to use this sustainable construction material; moreover, it is of fundamental scientific value - as a fluid flow within a natural porous medium. Both structural and transport properties of wood depend on its micro-structure but, while a substantial body of research relates the structural performance of wood to its detailed architecture, no such knowledge exists for the transport properties. We present a model, based on increasingly refined geometric parameters, that accurately predicts the time-dependent ingress of liquids within softwood timber, thereby addressing this long-standing scientific challenge. Moreover, we show that for the minimalistic parameterisation the model predicts ingress with a square-root-of-time behaviour. However, experimental data show a potentially significant departure from this [Formula: see text] behaviour - a departure which is successfully predicted by our more advanced parametrisation. Our parameterisation of the timber microstructure was informed by computed tomographic measurements; model predictions were validated by comparison with experimental data. We show that accurate predictions require statistical representation of the variability in the timber pore space. The collapse of our dimensionless experimental data demonstrates clear potential for our results to be up-scaled to industrial treatment processes.


Development of the thalamus: From early patterning to regulation of cortical functions.
The thalamus is a brain structure of the vertebrate diencephalon that plays a central role in regulating diverse functions of the cerebral cortex. In traditional view of vertebrate neuroanatomy, the thalamus includes three regions, dorsal thalamus, ventral thalamus, and epithalamus. Recent molecular embryological studies have redefined the thalamus and the associated axial nomenclature of the diencephalon in the context of forebrain patterning. This new view has provided a useful conceptual framework for studies on molecular mechanisms of patterning, neurogenesis and fate specification in the thalamus as well as the guidance mechanisms for thalamocortical axons. Additionally, the availability of genetic tools in mice has led to important findings on how thalamic development is linked to the development of other brain regions, particularly the cerebral cortex. This article will give an overview of the organization of the embryonic thalamus and how progenitor cells in the thalamus generate neurons that are organized into discrete nuclei. I will then discuss how thalamic development is orchestrated with the development of the cerebral cortex and other brain regions. This article is categorized under: Nervous System Development > Vertebrates: Regional Development Nervous System Development > Vertebrates: General Principles.


The impact of physician supply on avoidable cancer deaths in Germany. A spatial analysis.
Measures of avoidable deaths incorporate the notion that deaths from certain causes should not occur within specified age groups given effective prevention or timely and appropriate access to health care. The present study investigated the impact on specific types of avoidable cancer deaths (ACD) of regional variations in the supply of health services over five years using German districts (Kreise und kreisfreie Städte) as units of analysis. Age-standardized, average ACD rates were calculated for 2000-2004 for each of the 439 districts in Germany using unit-record mortality data. The distribution of ACD was subsequently analyzed using country maps and negative binomial regression with random intercepts. Potential endogeneity of physician supply to ACD was controlled for using an instrumental variable approach. The panel data for the years 2000-2004 were merged from a range of official statistics including mortality and hospital records (DESTATIS) and statistics provided by the Federal Office for Building and Regional Planning (INKAR). In women, 27.81 per 100,000 died from preventable or treatable cancer types in an average year between 2000 and 2004. The rates for men were generally higher, with 40.07 standardized ACD per 100,000. The regression results showed that an increase in physician supply per 100,000 was significantly associated with lower ACD rates in cancer of the female breast, and cancer of the colon, rectosigmoid junction, rectum and anus in both sexes. The contribution ranged from a decrease by a factor of 0.9994 (female breast cancer) to a factor of 0.9986 (cancer of the colon, rectosigmoid junction, rectum and anus in men) in ACD rate as the physician-population ratio increased by one unit. An increase in physician density tended to be associated with a small reduction in some ACD rates. We suggest that better accessibility or quality of care might have linked increased physician density with improved health outcomes.


Setting-up a cross-border action-research project to control malaria in remote areas of the Amazon: describing the birth and milestones of a complex international project (Malakit).
In French Guiana, gold miners working illegally represents a major reservoir of malaria. This mobile population, mainly of Brazilian descent, enters the French Guianese forest from neighbouring countries, Suriname and Brazil. A complex and innovative intervention was piloted as a cooperation with the three involved countries involved to control malaria in this specific population. The principle was that health workers called "facilitators" provide the participants with a self-diagnosis and self-treatment kit along with adequate training and material to rapidly manage an episode of malaria symptoms on their own, when they find themselves isolated from health care services. This paper describes the design, development, content of the intervention and players' organization of this multi-country project, the opportunities and constraints encountered, and the lessons learnt at this stage. The choice not to implement the usual "Test and Treat" approach within the community is mainly driven by regulatory reasons. The content of medical messages tends to balance the tension between thoroughness, accuracy and efficacy. The wide range of tools developed through a participatory approach was intended to cope with the challenges of the literacy level of the target population. Despite the difficulties encountered due to language, regulation differences and distance between partners, cooperation was fruitful, due to the complementary of stakeholders, their involvement at all important stages and regular face-to-face meetings. This experience shows the feasibility of an ambitious project of action-research in a border malaria context, involving several countries and with a mobile and undocumented population. It reveals some factors of success which may be transferable in analogous settings.


Physical function in older men with hyperkyphosis.
Age-related hyperkyphosis has been associated with poor physical function and is a well-established predictor of adverse health outcomes in older women, but its impact on health in older men is less well understood. We conducted a cross-sectional study to evaluate the association of hyperkyphosis and physical function in 2,363 men, aged 71-98 (M = 79) from the Osteoporotic Fractures in Men Study. Kyphosis was measured using the Rancho Bernardo Study block method. Measurements of grip strength and lower extremity function, including gait speed over 6 m, narrow walk (measure of dynamic balance), repeated chair stands ability and time, and lower extremity power (Nottingham Power Rig) were included separately as primary outcomes. We investigated associations of kyphosis and each outcome in age-adjusted and multivariable linear or logistic regression models, controlling for age, clinic, education, race, bone mineral density, height, weight, diabetes, and physical activity. In multivariate linear regression, we observed a dose-related response of worse scores on each lower extremity physical function test as number of blocks increased, p for trend ≤.001. Using a cutoff of ≥4 blocks, 20% (N = 469) of men were characterized with hyperkyphosis. In multivariate logistic regression, men with hyperkyphosis had increased odds (range 1.5-1.8) of being in the worst quartile of performing lower extremity physical function tasks (p < .001 for each outcome). Kyphosis was not associated with grip strength in any multivariate analysis. Hyperkyphosis is associated with impaired lower extremity physical function in older men. Further studies are needed to determine the direction of causality.


The geographical distribution of leadership in globalized clinical trials.
Pharmaceutical trials are mainly initiated by sponsors and investigators in the United States, Western Europe and Japan. However, more and more patients are enrolled in Central and Eastern Europe, Latin America and Asia. The involvement of patients in new geographical settings raises questions about scientific and ethical integrity, especially when experience with those settings is lacking at the level of trial management. We therefore studied to what extent the geographical shift in patient enrolment is anticipated in the composition of trial management teams using the author nationalities on the primary outcome publication as an indicator of leadership. We conducted a cohort-study among 1,445 registered trials in www.clinicaltrials.gov that could be matched with a primary outcome publication using clinical trial registry numbers listed in publications. The name of the sponsor and the enrolment countries were extracted from all registrations. The author-addresses of all authors were extracted from the publications. We searched the author-address of all publications to determine whether enrolment countries and sponsors listed on registrations also appeared on a matched publication. Of all sponsors, 80.1% were listed with an author-address on the publication. Of all enrolment countries, 50.3% appeared with an author-address on the publication. The listing of enrolment countries was especially low for industry-funded trials (39.9%) as compared to government (90.4%) and not-for-profit funding (93.7%). We found that listing of enrolment countries in industry-funded trials was higher for traditional research locations such as the United States (98.2%) and Japan (72.0%) as compared to nontraditional research locations such as Poland (27.3%) and Mexico (14.1%). Despite patient enrolment efforts, the involvement of researchers from nontraditional locations in trial management as measured by their contribution to manuscript writing is modest. This division of labor has significant implications for the scientific and ethical integrity of global clinical research.


Population dynamics of Salmincola salmoneus on Atlantic salmon in a northern Norwegian river.
Atlantic salmon Salmo salar are often heavily infected by the gill maggot Salmincola salmoneus, but little information exists on the population dynamics of this parasite. Through a combination of in vivo field examination and laboratory analysis of gills from the Alta River S. salar population in northern Norway, we describe the population dynamics of the parasite and suggest a model for the host-parasite interactions. S. salar did not become infected with S. salmoneus until they returned to the river as first-time spawners. The infection increased rapidly until autumn, and just after spawning 96% of the spent fish (kelts) were infected with a mean intensity of 53 parasites per fish. In May, the prevalence of S. salmoneus on the descending kelts had increased to 100%, but the intensity exhibited little change. A small proportion of the adult S. salar population returned as immature to the river during autumn and had lower parasite intensities than the kelts the following spring. When the fish that had spawned previously (repeat spawners) returned from their second (or more) sea migration, they had an average infection rate of 36 S. salmoneus individuals per fish. The kelts seemed to be the main habitat for the parasite during winter and spring, and they stay long enough in the river to pass the infection to maiden S. salar that enter the river early in summer. These fish then became a source of infection for the maiden fish entering the river later. However, in years that have a possible mismatch between the opposite migration of kelts and maiden S. salar, the immature fall-running and returning repeat spawners will be crucial for maintaining the parasite population. We hypothesize that heavily infected S. salar may suffer reduced growth and survival at sea, potentially reducing the abundance of repeat spawners.


Tissue-specific transcript profiling for ABC transporters in the sequestering larvae of the phytophagous leaf beetle Chrysomela populi.
Insects evolved ingenious adaptations to use extraordinary food sources. Particularly, the diet of herbivores enriched with noxious plant secondary metabolites requires detoxification mechanisms. Sequestration, which involves the uptake, transfer, and concentration of occasionally modified phytochemicals into specialized tissues or hemolymph, is one of the most successful detoxification strategies found in most insect orders. Due to the ability of ATP-binding cassette (ABC) carriers to transport a wide range of molecules including phytochemicals and xenobiotics, it is highly likely that they play a role in this sequestration process. To shed light on the role of ABC proteins in sequestration, we describe an inventory of putative ABC transporters in various tissues in the sequestering juvenile poplar leaf beetle, Chrysomela populi. In the transcriptome of C. populi, we predicted 65 ABC transporters. To link the proteins with a possible function, we performed comparative phylogenetic analyses with ABC transporters of other insects and of humans. While tissue-specific profiling of each ABC transporter subfamily suggests that ABCB, C and G influence the plant metabolite absorption in the gut, ABCC with 14 members is the preferred subfamily responsible for the excretion of these metabolites via Malpighian tubules. Moreover, salicin, which is sequestered from poplar plants, is translocated into the defensive glands for further deterrent production. In these glands and among all identified ABC transporters, an exceptionally high transcript level was observed only for Cpabc35 (Cpmrp). RNAi revealed the deficiency of other ABC pumps to compensate the function of CpABC35, demonstrating its key role during sequestration. We provide the first comprehensive phylogenetic study of the ABC family in a phytophagous beetle species. RNA-seq data from different larval tissues propose the importance of ABC pumps to achieve a homeostasis of plant-derived compounds and offer a basis for future analyses of their physiological function in sequestration processes.


Sphingosine-1-phosphate and its mimetic FTY720 do not protect against radiation-induced ovarian fibrosis in the nonhuman primate†.
Oocytes are highly radiosensitive, so agents that prevent radiation-induced ovarian follicle destruction are important fertility preservation strategies. A previous study in rhesus macaques demonstrated that ovarian treatment with antiapoptotic agents, sphingosine-1-phosphate (S1P) and FTY720, its long-acting mimetic, preserved follicles following a single dose of 15 Gy X-ray radiation, and live offspring were obtained from FTY720-treated animals. However, it is unknown whether these antiapoptotic agents also protected the ovarian stroma from late effects of radiation, including vascular damage and fibrosis. Using ovarian histological sections from this study, we evaluated the vasculature and extracellular matrix in the following cohorts: vehicle + sham irradiation, vehicle + irradiation (OXI), S1P + irradiation (S1P), and FTY720 + irradiation (FTY720). One ovary from each animal was harvested prior to radiation whereas the contralateral ovary was harvested 10 months post-treatment. We assessed vasculature by immunohistochemistry with a PECAM1 antibody, hyaluronan by a hyaluronan binding protein assay, and collagen by picrosirius red and Masson's trichrome staining. Disorganized vessels were observed in the medulla in the OXI and S1P cohorts relative to the sham, but the vasculature in the FTY720 cohort appeared intact, which may partially explain fertoprotection. There were no differences in the hyaluronan matrix among the cohorts, but there was thickening of the tunica albuginea and fibrosis in the OXI cohort relative to the sham, which was not mitigated by either S1P or FTY720 treatment. Thus, the fertoprotective properties of S1P and FTY720 may be limited given their inability to protect the ovarian stroma against the late effects of radiation-induced fibrosis.


A social marketing perspective of young adults' concepts of eating for health: is it a question of morality?
Poor dietary choices are a risk factor for non-communicable diseases. Young adults have low levels of engagement towards their health and may not see the importance in the adoption of healthy eating behaviours at this stage in their lives. Here we utilise social marketing principles, digital ethnography and online conversations to gain insights into young adults' attitudes and sentiments towards healthy eating. Young Australian adults who use social media at least twice a day were recruited by a commercial field house. Using a mixture of methods, combining online polls, forums and conversations, participants (n = 195, 18-24 years old) engaged in facilitated discussions over an extended 4 week period about health and eating-related topics. Data were analysed using thematic analysis constant comparison approach. A post-hoc conceptual framework related to religion was theorised and used as a metaphor to describe the results. Findings demonstrate that different segments of young adults with varying attitudes and interest towards healthy eating exist. We developed a conceptual framework based on consumer segmentation which adopted religious metaphors as a typology of 'consumers'. Some young adults practice and believe in the message of healthy eating (saints), whilst some oppose these messages and are not motivated to make any change (sinners), another segment are both aware of and interested in the issues but do not put healthy eating behaviours as a current priority (person in the pew). Consumer segmentation and social marketing techniques assist health professionals to understand their target audience and tailor specific messages to different segments. Segmentation provides insights on which groups may be most easily influenced to adopt the desired behaviours. The typology presented may be a useful tool for health professionals and social marketers to design strategies to engage young adults in healthy eating, particularly those in the pew who are contemplating a change but lacking the motivation. The utilisation of marketing segmentation in health promotion has the potential to enhance health messaging by tailoring messages to specific segments based on their needs, beliefs and intentions and therefore drive the efficient use of resources towards those most likely to change.


Novel heterostructured Bi2S3/BiOI photocatalyst: facile preparation, characterization and visible light photocatalytic performance.
Novel Bi(2)S(3)/BiOI heterostructures were successfully synthesized through a facile and economical ion exchange method between BiOI and thioacetamide (CH(3)CSNH(2)), and characterized by multiform techniques, such as XRD, Raman, FT-IR, XPS, SEM, TEM, HRTEM, SAED, BET and DRS. The obtained Bi(2)S(3)/BiOI photocatalysts showed excellent photocatalytic performance for decomposing organic dye methyl orange (MO) compared with pure BiOI under visible light irradiation (λ > 420 nm). Among the Bi(2)S(3)/BiOI photocatalysts with different molar percentage of Bi(2)S(3) to initial BiOI (from 2 to 8%), 4% Bi(2)S(3)/BiOI exhibited the highest photocatalytic activity with apparent k(app) of 0.2968 h(-1). Differently, Bi(2)S(3)/BiOI displayed low photocatalytic activity for many colorless organic substrates, such as phenol, 2-chlorophenol, dimethyl phthalate and 5-sulfosalicylic acid. Moreover, the study on the mechanism suggested that the enhanced photocatalytic activity mainly resulted from the role of Bi(2)S(3)-BiOI heterojunctions formed in the Bi(2)S(3)/BiOI, which could lead to efficient separation of photoinduced carriers.


Computed radiographic measurement of limb-length discrepancy. Full-length standing anteroposterior radiograph compared with scanogram.
Although a scanogram is commonly used to measure limb-length discrepancy, there are several potential pitfalls associated with this imaging technique. The purpose of the present study was to evaluate the results obtained with use of a full-length standing anteroposterior radiograph of the lower extremities and to compare them with those obtained with use of a scanogram. Both imaging studies were performed using computed radiography. One hundred and eleven patients with limb-length discrepancy had a full-length standing anteroposterior radiograph and a scanogram made on the same day. The patients included seventy-nine children and thirty-two adults in whom the discrepancy was secondary to trauma (55%), congenital shortening (18%), Blount disease (14%), or another cause (13%). Limb length and limb-length discrepancy were measured utilizing both imaging studies. The agreement between the standing anteroposterior radiograph and the scanogram was assessed with use of the correlation coefficient r, and the limits of agreement between the two imaging studies were assessed. An average magnification of 4.6% (3.3 cm) was observed in association with the measurement of lower extremity length with use of the full-length standing anteroposterior radiograph. The mean difference in limb-length-discrepancy measurements between the two techniques was 0.5 cm, and the limits of agreement (that is, the mean plus or minus two standard deviations) were 0.5 to 1.5 cm. When the limb-length discrepancy on the standing anteroposterior radiograph was compared with that on the scanogram, the correlation coefficient r was 0.96. A difference of >0.5 cm between the limb-length discrepancy measured on the standing radiograph and that measured on the scanogram was associated with a mechanical axis deviation of >2 cm. Remaining variables, including age, gender, etiology, and scanogram ruler inclination, did not correlate with a difference in the measurement of limb-length discrepancy with use of these two imaging studies. The measurement of limb-length discrepancy on a standing anteroposterior radiograph was very similar to that on a scanogram, especially in the absence of substantial mechanical axis deviation. These findings support the use of a standing anteroposterior radiograph of the lower extremities as the initial imaging study for patients presenting with unequal limb lengths. This approach allows for a more comprehensive radiographic evaluation of the lower extremity, including deformity analysis, while reducing the expense and radiation exposure as compared with the use of additional imaging studies for the assessment of limb-length discrepancy.


Regulation of the fibrosis and angiogenesis promoter SPARC/osteonectin in human adipose tissue by weight change, leptin, insulin, and glucose.
Matricellular Secreted Protein, Acidic and Rich in Cysteine (SPARC), originally discovered in bone as osteonectin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines. Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 +/- 3.7 kg). Another six lean subjects underwent fast-food-based hyperalimentation for 4 weeks (weight gain: 7.2 +/- 1.6 kg). Finally, visceral adipose tissue explants were cultured with recombinant leptin, insulin, and glucose, and SPARC mRNA and protein expression determined by Western blot analyses. SPARC expression in human adipose tissue correlated with fat mass and was higher in SCAT. Weight loss induced by very-low-calorie diet lowered SPARC expression by 33% and increased by 30% in adipose tissue of subjects gaining weight after a fast-food diet. SPARC expression was correlated with leptin independent of fat mass and correlated with homeostasis model assessment-insulin resistance. In vitro experiments showed that leptin and insulin potently increased SPARC production dose dependently in visceral adipose tissue explants, while glucose decreased SPARC protein. Our data suggest that SPARC expression is predominant in subcutaneous fat and its expression and secretion in adipose tissue are influenced by fat mass, leptin, insulin, and glucose. The profibrotic effects of SPARC may contribute to metabolic dysregulation in obesity.


Effect of curcumin in the amelioration of pancreatic islets in streptozotocin-induced diabetic mice.
To evaluate the antidiabetic effect of curcumin and its potential in amelioration of pancreatic islets against damage under diabetic condition. Diabetic mice were induced by injection of STZ (60 mg/kg body weight). Male mice were divided into 3 groups: group I was normal mice, group II was diabetic mice and group III diabetic mice were treated with curcumin (200 mg/kg body weight). The blood glucose levels and body weights were recorded every two weeks. After 4 weeks, 8 weeks and 12 weeks, the animals in each group were sacrificed. Histopathology of pancreatic tissues, pancreatic islets areas and numbers were observed under light microscope. The weight loss and the elevation of blood glucose levels were observed in diabetic mice and diabetic mice treated with curcumin at 4 weeks, 8 weeks and 12 weeks. The reduction of pancreatic islets areas and numbers were presented in diabetic mice and diabetic mice fed with curcumin at 4 weeks. At 8 weeks of diabetic mice, the numbers of pancreatic islets were decreased however the pancreatic islets hyperplasia was prominently investigated, whereas the noticeable increase in numbers of small pancreatic islets were observed in diabetic mice fed with curcumin. Histopathological observation at 12 weeks revealed the accumulation of lymphocytes in the shrunken pancreatic islets of diabetic mice, while an absent lymphocytes infiltration in the pancreatic islets and the increase in numbers of small islets of Langerhans appeared nearly the ducts in the pancreas of diabetic mice treated with curcumin at 12 weeks. Curcumin treatment at 12 week can exert beneficial effect in diabetes mellitus, regarding the improvement of pancreatic islets. The islets of Langerhans neogenesis is characterize by the presentation of small islets increase in numbers nearly the ducts and no insulitis.


Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease.
Fibroblast growth factor 23 (FGF-23) is a phosphorus-regulating hormone. In chronic kidney disease (CKD), circulating FGF-23 levels are markedly elevated and independently associated with mortality. Left ventricular hypertrophy and coronary artery calcification are potent risk factors for mortality in CKD, and FGFs have been implicated in the pathogenesis of both myocardial hypertrophy and atherosclerosis. We conducted a cross-sectional study to test the hypothesis that elevated FGF-23 concentrations are associated with left ventricular hypertrophy and coronary artery calcification in patients with CKD. In this study, 162 subjects with CKD underwent echocardiograms and computed tomography scans to assess left ventricular mass index and coronary artery calcification; echocardiograms also were obtained in 58 subjects without CKD. In multivariable-adjusted regression analyses in the overall sample, increased log FGF-23 concentrations were independently associated with increased left ventricular mass index (5% increase per 1-SD increase in log FGF-23; P=0.01) and risk of left ventricular hypertrophy (odds ratio per 1-SD increase in log FGF-23, 2.1; 95% confidence interval, 1.03 to 4.2). These associations strengthened in analyses restricted to the CKD subjects (11% increase in left ventricular mass index per 1-SD increase in log FGF-23; P=0.01; odds ratio of left ventricular hypertrophy per 1-SD increase in log FGF-23, 2.3; 95% confidence interval, 1.2 to 4.2). Although the highest tertile of FGF-23 was associated with a 2.4-fold increased risk of coronary artery calcification > or =100 versus <100 U compared with the lowest tertile (95% confidence interval, 1.1 to 5.5), the association was no longer significant after multivariable adjustment. FGF-23 is independently associated with left ventricular mass index and left ventricular hypertrophy in patients with CKD. Whether increased FGF-23 is a marker or a potential mechanism of myocardial hypertrophy in CKD requires further study.


Quantitative structure-permeability relationships at various pH values for acidic and basic drugs and drug-like compounds.
Absorption in gastrointestinal tract compartments varies and is largely influenced by pH. Therefore, considering pH in studies and analyses of membrane permeability provides an opportunity to gain a better understanding of the behaviour of compounds and to obtain good permeability estimates for prediction purposes. This study concentrates on relationships between the chemical structure and membrane permeability of acidic and basic drugs and drug-like compounds. The membrane permeability of 36 acidic and 61 basic compounds was measured using the parallel artificial membrane permeability assay (PAMPA) at pH 3, 5, 7.4 and 9. Descriptive and/or predictive single-parameter quantitative structure-permeability relationships were derived for all pH values. For acidic compounds, membrane permeability is mainly influenced by hydrogen bond donor properties, as revealed by models with r(2) > 0.8 for pH 3 and pH 5. For basic compounds, the best (r(2) > 0.7) structure-permeability relationships are obtained with the octanol-water distribution coefficient for pH 7.4 and pH 9, indicating the importance of partition properties. In addition to the validation set, the prediction quality of the developed models was tested with folic acid and astemizole, showing good matches between experimental and calculated membrane permeabilities at key pHs. Selected QSAR models are available at the QsarDB repository ( http://dx.doi.org/10.15152/QDB.166 ).


Endogenous interleukin-18 improves the early antimicrobial host response in severe melioidosis.
Melioidosis is caused by the soil saprophyte Burkholderia pseudomallei and is endemic in Southeast Asia. The pathogenesis of melioidosis is still largely unknown, although gamma interferon (IFN-gamma) seems to play an obligatory role in host defense. Previously, we have shown that IFN-gamma production in melioidosis is controlled in part by interleukin-18 (IL-18). The aim of the present study was to determine the role of IL-18 in the immune response to B. pseudomallei. For this the following investigations were performed. (i) Plasma IL-18 and blood monocyte IL-18 mRNA levels were elevated in 34 patients with culture-proven melioidosis compared to the levels in 32 local healthy controls; in addition, IL-18 binding protein levels were markedly elevated in patients, strongly correlating with mortality. (ii) IL-18 gene-deficient (IL-18 knockout [KO]) mice showed accelerated mortality after intranasal infection with a lethal dose of B. pseudomallei, which was accompanied by enhanced bacterial growth in their lungs, livers, spleens, kidneys, and blood at 24 and 48 h postinfection, compared to wild-type mice. In addition, IL-18 KO mice displayed evidence of enhanced hepatocellular injury and renal insufficiency. Together, these data indicate that the enhanced production of IL-18 in melioidosis is an essential part of a protective immune response to this severe infection.


Origin of the human malaria parasite Plasmodium falciparum in gorillas.
Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here we develop a single-genome amplification strategy to identify and characterize Plasmodium spp. DNA sequences in faecal samples from wild-living apes. Among nearly 3,000 specimens collected from field sites throughout central Africa, we found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed and almost always made up of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from western gorillas comprised parasites that were nearly identical to P. falciparum. In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla origin and not of chimpanzee, bonobo or ancient human origin.


[Clinical relevance of bacterial resistance: a historical approach (1982-2007)].
Bacterial resistance is currently one of the most important problems of infectious pathology. The relation between in vitro and in vivo bacterial resistance is not always well defined because therapeutic failure is also related to other factors (pharmacokinetics and pharmacodynamics). In addition, there are disagreements between the in vitro and in vivo activity of several antimicrobials (especially ciprofloxacin) due to their low bactericidal activity. In infections due to ciprofloxacin susceptible S. pyogenes, S. aureus, S. epidermidis, E. faecalis, E. coli producing extended spectrum beta-lactamase (ESBL), K. pneumoniae and E. cloacae their clinical use is not associated to cure because of the development of resistances that are induced during the antibiotic treatment. Ceftazidime in infections due to susceptible strains of K. pneumoniae and E. cloacae and ceftriaxone in infections due to methicillin susceptible S. aureus also do not have a good correlation between in vitro and in vivo results due to their low bactericidal activity and to the development of resistances during treatment. The main clinical impact of resistant bacteria is related to the failure of empirical treatments, which is associated to a higher mortality, especially in severe infections with methicillin-resistant S. aureus, Enterobacteriae ESBL and multiresistant P. aeruginosa and A. baumannii. One of the main risk factors for the development of bacterial resistances is the increase of the consumption of several antibiotics. The development of protocols agreed upon by consensus may decrease the impact of bacterial resistances. The knowledge of the previous use of antibiotics is an especially relevant issue to suspect that an infection might be due to resistant bacteria. Resistant pathogens are a severe problem in the clinical setting and the question is of such a complexity that it requires a multidisciplinary effort that involves the different professionals of the Internal Medicine-Infectious Diseases, Microbiology, Pharmacology, Pharmacy and Preventive Medicine Departments and hospital directors and that results in unified and protocolized actions regarding the clinical and therapeutical approach for the management of severely infected patients.


Pneumonia in the immunocompetent patient.
Pneumonia is an acute inflammation of the lower respiratory tract. Lower respiratory tract infection is a major cause of mortality worldwide. Pneumonia is most common at the extremes of life. Predisposing factors in children include an under-developed immune system together with other factors, such as malnutrition and over-crowding. In adults, tobacco smoking is the single most important preventable risk factor. The commonest infecting organisms in children are respiratory viruses and Streptoccocus pneumoniae. In adults, pneumonia can be broadly classified, on the basis of chest radiographic appearance, into lobar pneumonia, bronchopneumonia and pneumonia producing an interstitial pattern. Lobar pneumonia is most commonly associated with community acquired pneumonia, bronchopneumonia with hospital acquired infection and an interstitial pattern with the so called atypical pneumonias, which can be caused by viruses or organisms such as Mycoplasma pneumoniae. Most cases of pneumonia can be managed with chest radiographs as the only form of imaging, but CT can detect pneumonia not visible on the chest radiograph and may be of value, particularly in the hospital setting. Complications of pneumonia include pleural effusion, empyema and lung abscess. The chest radiograph may initially indicate an effusion but ultrasound is more sensitive, allows characterisation in some cases and can guide catheter placement for drainage. CT can also be used to characterise and estimate the extent of pleural disease. Most lung abscesses respond to medical therapy, with surgery and image guided catheter drainage serving as options for those cases who do not respond.


Artificial Intelligence in Diabetic Eye Disease Screening.
Systematic or national screening programs for diabetic retinopathy (DR) and diabetic macular edema (DME), using digital fundus photography and optical coherence tomography (OCT), are currently implemented at primary care level, aiming to provide timely referral for vision-threatening DR and DME to ophthalmologists for timely treatment and vision loss prevention. However, interpretation of retinal images requires specialized knowledge and expertise in diabetic eye disease. Furthermore, current DR screening programs are capital- and labor-intensive, which makes it difficult to rapidly scale up and expand diabetic eye screening to meet the needs of this growing global epidemic. Deep learning (DL), a new branch of machine learning technology under the broad term of artificial intelligence (AI), has made remarkable breakthrough in medical imaging in particular for pattern recognition and image classification. In ophthalmology, AI and DL technology has been developed from big image datasets in assessment of retinal photographs for detection and screening of DR as well as the segmentation and assessment of OCT images for diagnosis and screening of DME. This review aimed to summarize the current progress and the development of using AI and DL technology for diabetic eye disease screening as well as current challenges in the actual implementation of DL in screening programs, and translating DL research into direct clinical applications of screening in a community setting.


Supramolecular photochemistry of encapsulated caged ortho-nitrobenzyl triggers.
ortho-Nitrobenzyl (oNB) triggers have been extensively used to release various molecules of interest. However, the toxicity and reactivity of the spent chromophore, o-nitrosobenzaldehyde, remains an unaddressed difficulty. In this study we have applied the well-established supramolecular photochemical concepts to retain the spent trigger o-nitrosobenzaldehyde within the organic capsule after release of water-soluble acids and alcohols. The sequestering power of organic capsules for spent chromophores during photorelease from ortho-nitrobenzyl esters, ethers and alcohols is demonstrated with several examples.


The association between changes in pressure pain sensitivity and changes in cardiovascular physiological factors associated with persistent stress.
To evaluate the possible association between pressure pain sensitivity of the chest bone (PPS) and cardiovascular physiological factors related to persistent stress in connection with a three-month PPS-guided stress-reducing experimental intervention programme. Forty-two office workers with an elevated PPS (≥ 60 arbitrary units) as a sign of increased level of persistent stress, completed a single-blinded cluster randomized controlled trial. The active treatment was a PPS (self-measurement)-guided stress management programme. Primary endpoints: Blood pressure (BP), heart rate (HR) and work of the heart measured as Pressure-Rate-Product (PRP); Secondary endpoints: Other features of the metabolic syndrome. PPS decreased and changes in PPS after the intervention period were significantly associated with HR, PRP, body mass index (BMI) and visceral fat index (all correlation coefficients > 0.2, p < 0.05). Compared to the control cluster group, the active cluster group obtained a significant reduction in PPS, Low-density lipoprotein (LDL) cholesterol and total number of elevated risk factors (p < 0.05). On an individual level, significant and clinically relevant between-group reductions were observed in respect to BP, HR, PRP, total and LDL cholesterol, and total number of elevated risk factors (p < 0.05). The stress intervention method applied in this study induced a decrease in PPS which was associated with a clinically relevant decrease in resting blood pressure, heart rate, work of the heart and serum cholesterols.


A Mechanical Analysis of Chemically Stimulated Linear Shape Memory Polymer Actuation.
In the present work, we study the role of programming strain (50% and 100%), end loads (0, 0.5, 1.0, and 1.5 MPa), and chemical environments (acetone, ethanol, and water) on the exploitable stroke of linear shape memory polymer (SMP) actuators made from ESTANE ETE 75DT3 (SMP‑E). Dynamic mechanical thermal analysis (DMTA) shows how the uptake of solvents results in a decrease in the glass temperature of the molecular switch component of SMP-E. A novel in situ technique allows chemically studying triggered shape recovery as a function of time. It is found that the velocity of actuation decreases in the order acetone > ethanol > water, while the exploitable strokes shows the inverse tendency and increases in the order water > ethanol > acetone. The results are interpreted on the basis of the underlying chemical (how solvents affect thermophysical properties) and micromechanical processes (the phenomenological spring dashpot model of Lethersich type rationalizes the behavior). The study provides initial data which can be used for micromechanical modeling of chemically triggered actuation of SMPs. The results are discussed in the light of underlying chemical and mechanical elementary processes, and areas in need of further work are highlighted.


Molecular insights into substrate recognition and catalytic mechanism of the chaperone and FKBP peptidyl-prolyl isomerase SlyD.
Peptidyl-prolyl isomerases (PPIases) catalyze cis/trans isomerization of peptidyl-prolyl bonds, which is often rate-limiting for protein folding. SlyD is a two-domain enzyme containing both a PPIase FK506-binding protein (FKBP) domain and an insert-in-flap (IF) chaperone domain. To date, the interactions of these domains with unfolded proteins have remained rather obscure, with structural information on binding to the FKBP domain being limited to complexes involving various inhibitor compounds or a chemically modified tetrapeptide. We have characterized the binding of 15-residue-long unmodified peptides to SlyD from Thermus thermophilus (TtSlyD) in terms of binding thermodynamics and enzyme kinetics through the use of isothermal titration calorimetry, nuclear magnetic resonance spectroscopy, and site-directed mutagenesis. We show that the affinities and enzymatic activity of TtSlyD towards these peptides are much higher than for the chemically modified tetrapeptides that are typically used for activity measurements on FKBPs. In addition, we present a series of crystal structures of TtSlyD with the inhibitor FK506 bound to the FKBP domain, and with 15-residue-long peptides bound to either one or both domains, which reveals that substrates bind in a highly adaptable fashion to the IF domain through β-strand augmentation, and can bind to the FKBP domain as both types VIa1 and VIb-like cis-proline β-turns. Our results furthermore provide important clues to the catalytic mechanism and support the notion of inter-domain cross talk. We found that 15-residue-long unmodified peptides can serve as better substrate mimics for the IF and FKBP domains than chemically modified tetrapeptides. We furthermore show how such peptides are recognized by each of these domains in TtSlyD, and propose a novel general model for the catalytic mechanism of FKBPs that involves C-terminal rotation around the peptidyl-prolyl bond mediated by stabilization of the twisted transition state in the hydrophobic binding site.


Helicobacter infection in patients with HCV-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma.
Chronic hepatitis may progress to cirrhosis and hepatocellular carcinoma (HCC). HCC represents one of the most common human cancers. Incidence rates for this tumor vary widely on a worldwide, suggesting that environmental factors such as infectious microorganisms, carcinogens, or nutrition play a role in its pathogenesis. Several Helicobacter spp. colonize the liver of animals and induce hepatitis. The aim of this study was to determine whether Helicobacter infection was associated with HCV-related liver diseases in humans. Liver tissue samples, including biopsy and surgically excised tissues, were collected from patients positive for hepatitis C viruses (HCV) RNA in the serum. Genomic DNA was extracted from sections of formalin-fixed paraffin-embedded tissues by using the QIAamp Tissue Kit and subjected to polymerase chain reaction (PCR) analysis using two sets of Helicobacter-specific 16S ribosomal RNA primers. To identify positive samples for H. pylori, a set of primers specific for a conserved region in the H. pylori vacA gene were also used. The patients' H. pylori status was determined by ELISA. Forty-one patients (mean age 54.9, range 19-78 years; 24 men) were studied. Thirty patients had chronic viral hepatitis (CH) without (N = 18) or with (N = 12) cirrhosis (CIR), and 11 patients had HCC. Anti-H. pylori IgG was detected in 54%. The expected 422- and 210-bp fragments of Helicobacter 16S rRNA were amplified from 27% of liver samples, including 17% of CH-CIR and 55% of HCC (P = 0.004). The vacA sequence was amplified in 10 of 41(24%) samples (27% of those with HCC). These data confirm the presence of H. pylori DNA sequences in human liver and suggest an association of Helicobacter spp. with HCV-related chronic liver diseases. Further studies are needed to ascertain whether Helicobacter spp. infection plays a role in the development of HCC.


Tolerance to the anxiolytic effects of the triazolobenzodiazepines triazolam and alprazolam, as measured by the ingestion of a hypertonic sodium chloride solution in rats.
Rats were adapted to a water-deprivation regimen that allowed daily 1-hr drinking sessions of a single fluid, either 1.5% NaCl solution or water. Oral, presession, acute doses of triazolam (0.05-1.6 mg/kg) or alprazolam (0.4-6.4 mg/kg) produced dose-related increases in session NaCl solution ingestion. The relative potencies found for these two drugs approximated their relative Ki values reported in the literature. The increased ingestion produced in this and other experiments by anxiolytic agents is presented as an alternative way of evaluating punishment attenuation, and hence anxiolytic activity. Chronic oral dosing (every 2nd day) with triazolam (0.2 mg/kg) or alprazolam (1.2 mg/kg) led, after several weeks, to partial, but surmountable, tolerance to the increased NaCl solution ingestion produced by these drugs, which was confirmed by a rightward shift in the dose-effect relations. During chronic dosing, no corresponding declines in the independently evaluated increases in water intake produced by these drugs occurred. Abrupt drug discontinuation produced a precipitous decrease in NaCl solution intake, with subsequent recovery. For triazolam, the initial discontinuation decrease in intake to below the original base line suggested the possible accrual of a mild physiological dependence under this moderate chronic dose regimen.


A developmental shift from positive to negative connectivity in human amygdala-prefrontal circuitry.
Recent human imaging and animal studies highlight the importance of frontoamygdala circuitry in the regulation of emotional behavior and its disruption in anxiety-related disorders. Although tracing studies have suggested changes in amygdala-cortical connectivity through the adolescent period in rodents, less is known about the reciprocal connections within this circuitry across human development, when these circuits are being fine-tuned and substantial changes in emotional control are observed. The present study examined developmental changes in amygdala-prefrontal circuitry across the ages of 4-22 years using task-based functional magnetic resonance imaging. Results suggest positive amygdala-prefrontal connectivity in early childhood that switches to negative functional connectivity during the transition to adolescence. Amygdala-medial prefrontal cortex functional connectivity was significantly positive (greater than zero) among participants younger than 10 years, whereas functional connectivity was significantly negative (less than zero) among participants 10 years and older, over and above the effect of amygdala reactivity. The developmental switch in functional connectivity was paralleled by a steady decline in amygdala reactivity. Moreover, the valence switch might explain age-related improvement in task performance and a developmentally normative decline in anxiety. Initial positive connectivity followed by a valence shift to negative connectivity provides a neurobiological basis for regulatory development and may present novel insight into a more general process of developing regulatory connections.


MK-801 has neuroprotective and antiproliferative effects in retinal laser injury.
Treatment of the retina by laser photocoagulation often is complicated by an immediate side effect of visual impairment, caused by unavoidable, laser-induced destruction of healthy tissue adjacent to the lesion. A neuroprotective therapy that salvages this healthy tissue might enhance the benefit obtained from the treatment. This study was proposed to determine whether glutamate-receptor blockers can provide adjuvant neuroprotection during laser photocoagulation. The effect of MK-801, an NMDA-receptor antagonist, on laser-induced retinal injury was examined, in a rat model. Argon laser lesions were created in the retinas of 36 DA rats, and were followed immediately by intraperitoneal injections of MK-801 (2 mg/kg) or saline. The animals were killed after 3, 20, or 60 days and the retinal lesions were evaluated histologically and morphometrically. Photoreceptor-cell loss was significantly less in MK-801-treated rats than in control animals. The proliferative membrane composed of retinal pigment epithelial cells and neovascular blood vessels, which was seen at the base of the lesion in control group retinas, was smaller in the MK-801-treated retinas. In rats treated with a higher dose of MK-801, the lesions showed almost no proliferative reaction. A potent noncompetitive NMDA-receptor blocker, MK-801 exhibits neuroprotective and antiproliferative properties in the retina. Glutamate-receptor blockers should be investigated further as potential adjuvant therapy in retinal photocoagulation treatments.


Causes and consequences of marine mammal population declines in southwest Alaska: a food-web perspective.
Populations of sea otters, seals and sea lions have collapsed across much of southwest Alaska over the past several decades. The sea otter decline set off a trophic cascade in which the coastal marine ecosystem underwent a phase shift from kelp forests to deforested sea urchin barrens. This interaction in turn affected the distribution, abundance and productivity of numerous other species. Ecological consequences of the pinniped declines are largely unknown. Increased predation by transient (marine mammal-eating) killer whales probably caused the sea otter declines and may have caused the pinniped declines as well. Springer et al. proposed that killer whales, which purportedly fed extensively on great whales, expanded their diets to include a higher percentage of sea otters and pinnipeds following a sharp reduction in great whale numbers from post World War II industrial whaling. Critics of this hypothesis claim that great whales are not now and probably never were an important nutritional resource for killer whales. We used demographic/energetic analyses to evaluate whether or not a predator-prey system involving killer whales and the smaller marine mammals would be sustainable without some nutritional contribution from the great whales. Our results indicate that while such a system is possible, it could only exist under a narrow range of extreme conditions and is therefore highly unlikely.


Time-Dependent Flow seen through Approximate Observer Killing Fields.
Flow fields are usually visualized relative to a global observer, i.e., a single frame of reference. However, often no global frame can depict all flow features equally well. Likewise, objective criteria for detecting features such as vortices often use either a global reference frame, or compute a separate frame for each point in space and time. We propose the first general framework that enables choosing a smooth trade-off between these two extremes. Using global optimization to minimize specific differential geometric properties, we compute a time-dependent observer velocity field that describes the motion of a continuous field of observers adapted to the input flow. This requires developing the novel notion of an observed time derivative. While individual observers are restricted to rigid motions, overall we compute an approximate Killing field, corresponding to almost-rigid motion. This enables continuous transitions between different observers. Instead of focusing only on flow features, we furthermore develop a novel general notion of visualizing how all observers jointly perceive the input field. This in fact requires introducing the concept of an observation time, with respect to which a visualization is computed. We develop the corresponding notions of observed stream, path, streak, and time lines. For efficiency, these characteristic curves can be computed using standard approaches, by first transforming the input field accordingly. Finally, we prove that the input flow perceived by the observer field is objective. This makes derived flow features, such as vortices, objective as well.


Comparison of two methods for measuring the pubococcygeal line from sagittal-plane magnetic resonance imaging.
The pubococcygeal line (PCL) is an important reference line for determining measures of pelvic organ support on sagittal-plane magnetic resonance imaging (MRI); however, there is no consensus on where to place the posterior point of the PCL. As coccyx movement produced during pelvic floor muscle (PFM) contractions may affect other measures, optimal placement of the posterior point is important. This study compared two methods for measuring the PCL, with different posterior points, on T2-weighted sagittal MRI to determine the effect of coccygeal movement on measures of pelvic organ support in older women. MRI of the pelvis was performed in the midsagittal plane, at rest and during PFM contractions, on 47 community-dwelling women 60 and over. The first PCL was measured to the tip of the coccyx (PCLtip) and the second to the sacrococcygeal joint (PCLjnt). Four measures of pelvic organ support were made using each PCL as the reference line: urethrovesical junction height, uterovaginal junction height, M-line and levator plate angle. During the PFM contraction the PCLtip shortened and lifted (P < 0.001); the PCLjnt did not change (P > 0.05). The changes in the four measures of pelvic organ support were smaller when measured relative to the PCLtip as compared to those to the PCLjnt (P < 0.001). Coccyx movement affected the length and position of the PCLtip, which resulted in underestimates of the pelvic-organ lift produced by the PFM contraction. Therefore, we recommend that the PCL be measured to the sacrococcygeal joint and not to the tip of the coccyx.


Surface effects on ferromagnetic resonance in magnetic nanocubes.
We study the effect of surface anisotropy on the spectrum of spin-wave excitations in a magnetic nanocluster and compute the corresponding absorbed power. For this, we develop a general numerical method based on the (undamped) Landau-Lifshitz equation, either linearized around the equilibrium state leading to an eigenvalue problem or solved using a symplectic technique. For box-shaped clusters, the numerical results are favorably compared to those of the finite-size linear spin-wave theory. Our numerical method allows us to disentangle the contributions of the core and surface spins to the spectral weight and absorbed power. In regard to the recent developments in synthesis and characterization of assemblies of well defined nano-elements, we study the effects of free boundaries and surface anisotropy on the spin-wave spectrum in iron nanocubes and give orders of magnitude of the expected spin-wave resonances. For an [Formula: see text] iron nanocube, we show that the absorbed power spectrum should exhibit a low-energy peak around 10 GHz, typical of the uniform mode, followed by other low-energy features that couple to the uniform mode but with a stronger contribution from the surface. There are also high-frequency exchange-mode peaks around 60 GHz.


Retinal and brain damage during multiple sclerosis course: inflammatory activity is a key factor in the first 5 years.
Understanding of the role of focal inflammation, a treatable feature, on neuro-axonal injury, is paramount to optimize neuroprotective strategy in MS. To quantify the impact of focal inflammatory activity on the rate of neuro-axonal injury over the MS course. We quantified the annualized rates of change in peripapillary retinal nerve fiber layer, ganglion cell plus inner plexiform layer (GCIPL), whole-brain, gray matter and thalamic volumes in patients with and without focal inflammatory activity in 161 patients followed over 5 years. We used mixed models including focal inflammatory activity (the presence of at least one relapse or a new/enlarging T2-FLAIR or gadolinium- enhancing lesion), and its interaction with time adjusted by age, sex, use of disease-modifying therapies and steroids, and prior optic neuritis. The increased rate of neuro-axonal injury during the first five years after onset was more prominent among active patients, as reflected by the changes in GCIPL thickness (p = 0.02), whole brain (p = 0.002) and thalamic volumes (p < 0.001). Thereafter, rates of retinal and brain changes stabilized and were similar in active and stable patients. Focal inflammatory activity is associated with neurodegeneration early in MS which reinforces the use of an early intensive anti-inflammatory therapy to prevent neurodegeneration in MS.


What will long-term care be like in 2040?
Many innovative long-term care models can now be found in nursing homes, assisted living, and community home care settings. Key forces that will shape the future include the aging of the baby-boomer generation, personal choice, concerns about quality, new technologies, dementia research, payment issues, financial pressures, and workforce needs.


[Assessment of fungal aerosol exposure at selected workplaces contaminated with organic dust of different origin].
In recent years, the number of people suffering from diseases caused by fungi has been increasing. However, knowledge of the biodiversity of fungal pathogens in the work environment is still insufficient. The aim of this work was to evaluate the exposure to fungi being disseminated in the air of workplaces contaminated with organic dust of plant and animal origin. Bioaerosol samples were collected at 3 occupational settings (poultry farm, biomass burning power plant and wastewater treatment plant) using button samplers. Quantitative and qualitative analysis of fungal aerosol was conducted by employing macro- and microscopic methods. Selected strains were then studied by polymerase chain reaction (PCR) using środointernal transcribed spacers (ITS): ITS1-ITS2, ITS3-ITS4 and ITS1-ITS4 primer pairs. Average concentrations of fungal aerosol at workplaces ranged 1.2×102-2.1×106 cfu/m3. The highest fungal concentrations were recorded in the poultry farm, while the lowest were noted at the wastewater treatment plant. Aspergillus fumigatus was a predominant component of the mycobiota in the power plant and wastewater treatment plant. Almost 100% identification agreement of this pathogen between the traditional and molecular method was noted. The fungal concentrations in poultry farms exceeded the Polish proposal for the threshold limit value (5×104 cfu/m3). The results of the study demonstrate a high compatibility of A. fumigatus' identification using the traditional and molecular methods. Taking into account the fact, that a long term exposure to A. fumigatus conidia at workplaces may result in numerous health complaints, the use of proper protective equipment by workers must be a standard procedure. Med Pr 2018;69(3):269-280.


Prospective estimation of mean axon diameter and extra-axonal space of the posterior limb of the internal capsule in patients with idiopathic normal pressure hydrocephalus before and after a lumboperitoneal shunt by using q-space diffusion MRI.
To prospectively estimate the mean axon diameter (MAD) and extracellular space of the posterior limb of the internal capsule (PLIC) in patients with idiopathic normal pressure hydrocephalus (iNPH) before and after a lumboperitoneal (LP) shunting operation using q-space diffusion MRI analysis. We studied 12 consecutive patients with iNPH and 12 controls at our institution. After conventional magnetic resonance imaging (MRI), q-space image (QSI) data were acquired with a 3-T MRI scanner. The MAD and extra-axonal space of the PLIC before and after LP shunting were calculated using two-component q-space imaging analyses; the before and after values were compared. After LP shunt surgery, the extracellular space of the PLIC was significantly higher than that of the same patients before the operation (one-way analysis of variance (ANOVA) with Scheffé's post-hoc test, P = 0.024). No significant differences were observed in the PLIC axon diameters among normal controls or in patients before and after surgery. Increases in the root mean square displacement in the extra-axonal space of the PLIC in patients with iNPH after an LP shunt procedure are associated with the microstructural changes of white matter and subsequent abatement of patient symptoms. • Q-space diffusion MRI provides information on microstructural changes in the corticospinal tract • Lumboperitoneal (LP) shunting operation is useful for idiopathic normal pressure hydrocephalus • Q-space measurement may be a biomarker for the effect of the LP shunt procedure.


Evolution of cortical neurogenesis.
The neurons of the mammalian neocortex are organised into six layers. By contrast, the reptilian and avian dorsal cortices only have three layers which are thought to be equivalent to layers I, V and VI of mammals. Increased repertoire of mammalian higher cognitive functions is likely a result of an expanded cortical surface area. The majority of cortical cell proliferation in mammals occurs in the ventricular zone (VZ) and subventricular zone (SVZ), with a small number of scattered divisions outside the germinal zone. Comparative developmental studies suggest that the appearance of SVZ coincides with the laminar expansion of the cortex to six layers, as well as the tangential expansion of the cortical sheet seen within mammals. In spite of great variation and further compartmentalisation in the mitotic compartments, the number of neurons in an arbitrary cortical column appears to be remarkably constant within mammals. The current challenge is to understand how the emergence and elaboration of the SVZ has contributed to increased cortical cell diversity, tangential expansion and gyrus formation of the mammalian neocortex. This review discusses neurogenic processes that are believed to underlie these major changes in cortical dimensions in vertebrates.


Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2.
Matrix metalloproteinases (MMPs) are a family of multidomain enzymes involved in the physiological degradation of connective tissue, as well as in pathological states such as tumor invasion and arthritis. Apart from transcriptional regulation, MMPs are controlled by proenzyme activation and a class of specific tissue inhibitors of metalloproteinases (TIMPs) that bind to the catalytic site. TIMP-2 is a potent inhibitor of MMPs, but it has also been implicated in a unique cell surface activation mechanism of latent MMP-2/gelatinase A/type IV collagenase (proMMP-2), through its binding to the hemopexin domain of proMMP-2 on the one hand and to a membrane-type MMP activator on the other. The present crystal structure of the human proMMP-2/TIMP-2 complex reveals an interaction between the hemopexin domain of proMMP-2 and the C-terminal domain of TIMP-2, leaving the catalytic site of MMP-2 and the inhibitory site of TIMP-2 distant and spatially isolated. The interfacial contact of these two proteins is characterized by two distinct binding regions composed of alternating hydrophobic and hydrophilic interactions. This unique structure provides information for how specificity for noninhibitory MMP/TIMP complex formation is achieved.


Influence of food on the pharmacokinetics of ketoconazole.
Eight healthy adults were given single oral doses of ketoconazole (200, 400, 600, and 800 mg) in the fasting state and with a standard breakfast at weekly intervals according to a balanced block design. Concentrations in serum were measured up to 32 h after the dose. Food did not reduce ketoconazole absorption or significantly alter peak ketoconazole concentrations in serum, though there was a food-related delay in achieving peak concentrations. At the 400- and 600-mg doses, food appeared to enhance absorption, but this effect was not seen at the 800-mg dose. With an increase in dose, the half-life and area under the serum concentration-time curve increased disproportionately, suggesting that the pharmacokinetics of ketoconazole may be dose dependent. Up to the 800-mg dose, the elimination of ketoconazole did not appear to be saturable. Administration of the drug with food is unlikely to be a cause of therapeutic failure.


Evidence for survival of Pleistocene climatic changes in Northern refugia by the land snail Trochoidea geyeri (Soós 1926) (Helicellinae, Stylommatophora).
The study of organisms with restricted dispersal abilities and presence in the fossil record is particularly adequate to understand the impact of climate changes on the distribution and genetic structure of species. Trochoidea geyeri (Soós 1926) is a land snail restricted to a patchy, insular distribution in Germany and France. Fossil evidence suggests that current populations of T. geyeri are relicts of a much more widespread distribution during more favourable climatic periods in the Pleistocene. Phylogeographic analysis of the mitochondrial 16S rDNA and nuclear ITS-1 sequence variation was used to infer the history of the remnant populations of T. geyeri. Nested clade analysis for both loci suggested that the origin of the species is in the Provence from where it expanded its range first to Southwest France and subsequently from there to Germany. Estimated divergence times predating the last glacial maximum between 25-17 ka implied that the colonization of the northern part of the current species range occurred during the Pleistocene. We conclude that T. geyeri could quite successfully persist in cryptic refugia during major climatic changes in the past, despite of a restricted capacity of individuals to actively avoid unfavourable conditions.


Update on therapy for narcolepsy.
Narcolepsy is a severe, incurable, neurological disorder that is treated by pharmacological management of its symptoms. The main symptoms are excessive daytime sleepiness (EDS) and cataplexy, although addition symptoms that may require treatment include sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. Sodium oxybate and modafinil/armodafinil are the first-line treatments for EDS, and sodium oxybate for cataplexy. Sodium oxybate treats all the symptoms of narcolepsy, whereas modafinil is effective for EDS only. Alternative medications for EDS include methylphenidate or amphetamines such as dextroamphetamine, lisdexamfetamine, methamphetamine, or combination amphetamine salts. Non-FDA approved medications for cataplexy include norepinephrine reuptake inhibitors such as venlafaxine or atomoxetine. Combination therapy can be more effective for sleepiness such as sodium oxybate and modafinil/armodafinil. Medication for narcolepsy is generally well tolerated and usually required life-long although does not eliminate all symptoms of narcolepsy.


QuickFF: A program for a quick and easy derivation of force fields for metal-organic frameworks from ab initio input.
QuickFF is a software package to derive accurate force fields for isolated and complex molecular systems in a quick and easy manner. Apart from its general applicability, the program has been designed to generate force fields for metal-organic frameworks in an automated fashion. The force field parameters for the covalent interaction are derived from ab initio data. The mathematical expression of the covalent energy is kept simple to ensure robustness and to avoid fitting deficiencies as much as possible. The user needs to produce an equilibrium structure and a Hessian matrix for one or more building units. Afterward, a force field is generated for the system using a three-step method implemented in QuickFF. The first two steps of the methodology are designed to minimize correlations among the force field parameters. In the last step, the parameters are refined by imposing the force field parameters to reproduce the ab initio Hessian matrix in Cartesian coordinate space as accurate as possible. The method is applied on a set of 1000 organic molecules to show the easiness of the software protocol. To illustrate its application to metal-organic frameworks (MOFs), QuickFF is used to determine force fields for MIL-53(Al) and MOF-5. For both materials, accurate force fields were already generated in literature but they requested a lot of manual interventions. QuickFF is a tool that can easily be used by anyone with a basic knowledge of performing ab initio calculations. As a result, accurate force fields are generated with minimal effort. © 2015 Wiley Periodicals, Inc.


Inhibition of Mitochondrial Bioenergetics by Esterase-Triggered COS/H2S Donors.
Hydrogen sulfide (H2S) is an important biological mediator, and synthetic H2S donating molecules provide an important class of investigative tools for H2S research. Here, we report esterase-activated H2S donors that function by first releasing carbonyl sulfide (COS), which is rapidly converted to H2S by the ubiquitous enzyme carbonic anhydrase (CA). We report the synthesis, self-immolative decomposition, and H2S release profiles of the developed scaffolds. In addition, the developed esterase-triggered COS/H2S donors exhibit higher levels of cytotoxicity than equivalent levels of Na2S or the common H2S donors GYY4137 and AP39. Using cellular bioenergetics measurements, we establish that the developed donors reduce cellular respiration and ATP synthesis in BEAS 2B human lung epithelial cells, which is consistent with COS/H2S inhibition of cytochrome c oxidase in the mitochondrial respiratory chain although not observed with common H2S donors at the same concentrations. Taken together, these results may suggest that COS functions differently than H2S in certain biological contexts or that the developed donors are more efficient at delivering H2S than other common H2S-releasing motifs.


Disrupting the memory of places induced by drugs of abuse weakens motivational withdrawal in a context-dependent manner.
Addicts repeatedly relapse to drug seeking even after years of abstinence, and this behavior is frequently induced by the recall of memories of the rewarding effects of the drug. Established memories, including those induced by drugs of abuse, can become transiently fragile if reactivated, and during this labile phase, known as reconsolidation, can be persistently disrupted. Here we show that, in rats, a morphine-induced place preference (mCPP) memory is linked to context-dependent withdrawal as disrupting the reconsolidation of the memory leads to a significant reduction of withdrawal evoked in the same context. Moreover, the hippocampus plays a critical role in linking the place preference memory with the context-conditioned withdrawal, as disrupting hippocampal protein synthesis and cAMP-dependent-protein kinase A after the reactivation of mCPP significantly weakens the withdrawal. Hence, targeting memories induced by drugs may represent an important strategy for attenuating context-conditioned withdrawal and therefore subsequent relapse in opiate addicts.