RAD51 paralogs synergize with RAD51 to protect reversed forks from cellular nucleases.
Fork reversal is a conserved mechanism to prevent stalled replication forks from collapsing. Formation and protection of reversed forks are two crucial steps in ensuring fork integrity and stability. Five RAD51 paralogs, namely, RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3, which share sequence and structural similarity to the recombinase RAD51, play poorly defined mechanistic roles in these processes. Here, using purified BCDX2 (RAD51BCD-XRCC2) and CX3 (RAD51C-XRCC3) complexes and in vitro reconstituted biochemical systems, we mechanistically dissect their functions in forming and protecting reversed forks. We show that both RAD51 paralog complexes lack fork reversal activities. Whereas CX3 exhibits modest fork protection activity, BCDX2 significantly synergizes with RAD51 to protect DNA against attack by the nucleases MRE11 and EXO1. DNA protection is contingent upon the ability of RAD51 to form a functional nucleoprotein filament on DNA. Collectively, our results provide evidence for a hitherto unknown function of RAD51 paralogs in synergizing with RAD51 nucleoprotein filament to prevent degradation of stressed replication forks.


Parents' decision-making for their foetus or neonate with a severe congenital heart defect.
Parents who receive a diagnosis of a severe, life-threatening CHD for their foetus or neonate face a complex and stressful decision between termination, palliative care, or surgery. Understanding how parents make this initial treatment decision is critical for developing interventions to improve counselling for these families. We conducted focus groups in four academic medical centres across the United States of America with a purposive sample of parents who chose termination, palliative care, or surgery for their foetus or neonate diagnosed with severe CHD. Ten focus groups were conducted with 56 parents (Mage = 34 years; 80% female; 89% White). Results were constructed around three domains: decision-making approaches; values and beliefs; and decision-making challenges. Parents discussed varying approaches to making the decision, ranging from relying on their "gut feeling" to desiring statistics and probabilities. Religious and spiritual beliefs often guided the decision to not terminate the pregnancy. Quality of life was an important consideration, including how each option would impact the child (e.g., pain or discomfort, cognitive and physical abilities) and their family (e.g., care for other children, marriage, and career). Parents reported inconsistent communication of options by clinicians and challenges related to time constraints for making a decision and difficulty in processing information when distressed. This study offers important insights that can be used to design interventions to improve decision support and family-centred care in clinical practice.


Jorge Lobo's disease with restricted labial presentation.
Jorge Lobo's Disease (JLD) is a chronic granulomatous cutaneous mycosis caused by Lacazia loboi. The most typical lesions are keloid-like growths preferentially located on limbs and ears. To the best of the authors' knowledge, only one labial case has previously been reported. We describe the case of a man who presented with a left-sided papulonodular lesion of 10 years' duration on the vermillion border of the upper lip. A successful surgical resection of the lesion was performed and there was no recurrence in eight years of follow-up.


Challenges and perspectives in anti-doping testing.
In less than 10 years after the implementation of the World Anti-Doping Code and of the International Standard for Laboratories and its related Technical Documents, the analysis of human samples for the purpose of anti-doping testing has undergone a noticeable evolution. The research programs developed by the anti-doping organizations, and in particular the World Anti-Doping Agency (WADA), have created an unprecedented momentum in anti-doping science to strengthen the existing analytical methods, as well as to support the development and implementation of new and more sophisticated methodologies by the WADA-accredited laboratories. The integration of technical novelties into the analytical menus has been stimulated by the never-ending challenges posed by the adoption of more complex doping regimens by some athletes and their entourage. This increased sophistication of doping practices has also been reflected in the addition of new doping substances or methods on the WADA Prohibited Substances and Methods List. The integration of new anti-doping scientific paradigms with the development of the Athlete Biological Passport or the foreseen implementation of genomic- and proteomic-based tests constantly reshapes the environment of anti-doping analysis. This article provides a multiangle perspective on some of the key analytical challenges that anti-doping analytical science will face in 2012 and beyond.


TbMgNi4-xCox-(H,D)2 System. II: Correlation between Structural and Magnetic Properties.
The magnetic properties of TbMgNi4-xCox intermetallic compounds and selected hydrides and deuterides of this system have been studied by various techniques, including magnetic measurements, in situ X-ray and neutron powder diffraction. The intermetallic compounds crystallize in a SnMgCu4-type structure and magnetically order below a Curie temperature (TC), which increases exponentially with the Co content. This can be due to the ordering of the Co sublattice. On the other hand, the insertion of D or H in TbMgNiCo3 strongly decreases TC. The X-ray diffraction measurements versus temperature reveal cell volume minima at TC for the compounds with x = 1-3 without any hints of the structure change. The analysis of the neutron diffraction patterns for the intermetallics with x = 2 and 3 indicates a slightly canted ferrimagnetic structure below TC. The Tb moments refined at 16 K are 4.1(2) μB/Tb for x = 2, and 6.2(1) μB/Tb for x = 3, which are smaller than the free ion value (9.5 μB/Tb). This reduction can be due to the influence of temperature but also reveals the crystal field effect. As Ni and Co occupy statistically the same Wyckoff site, an average Ni/Co moment was refined, leading to 1.7(2) μB/atom for x = 2 and 1.8(1) μB/atom for x = 3 at 16 K. This moment is slightly canted compared to the Tb moment.


[Allelic variants of the CYP2D6: *4, *6 and *10 in a sample of resident from the Aragua state, Venezuela].
The aim of this study was to determine the CYP2D6: * 4, * 6 and * 10 gene variants frequency and to predict the metabolizer phenotype in a sample of 145 unrelated apparently healthy individuals residing in the state of Aragua, Venezuela. Genotypes were determined by Polymerase chain reaction assays followed by restriction endonucleases digestion. The metabolizer phenotype prediction was made based on the activity score system. The frequencies of CYP2D6 * 4, * 6 and * 10 allelic variants were 14.5%, 0.3% and 1%. A significant percentage of individuals were categorized as heterozygote-extensive/intermediate (23.5%) and poor metabolizers (4.1%), this information has potential clinical impact, because the CYP2D6 protein is involved in the metabolism of drugs frequently prescribed as: carvedilol, captopril, chloroquine, codeine, fluoxetine, fluvastatin, haloperidol, idarubicin, indinavir, imatinib, loperamide, nifedipine, ondansetron and tamoxifen.


A three-year study of the effect of a sodium fluoride-silica abrasive dentifrice on dental caries.
The purpose of this study was to determine if a 0.243% sodium fluoride-silica abrasive dentifrice provides greater anticaries efficacy than a 0.4% stannous fluoride-calcium pyrophosphate abrasive dentifrice. A sample of 1,824 schoolchildren was randomly assigned to either the sodium fluoride dentifrice or the stannous fluoride dentifrice and examined clinically and radiographically for dental caries initially and after one, two, and three years of dentifrice usage. Two examiners independently examined each of the subjects for dental caries. After three years of ad libitum dentifrice usage, the results for both examiners showed that the group brushing with the sodium fluoride dentifrice had significantly lower DMF tooth and DMF surface increments than the group brushing with the stannous fluoride dentifrice. The percent reductions for DMF teeth were 14.8% and 10.5%, and for DMF surfaces 16.4% and 13.1% for the two examiners, respectively.


A catalog of microbial genes from the bovine rumen unveils a specialized and diverse biomass-degrading environment.
The rumen microbiota provides essential services to its host and, through its role in ruminant production, contributes to human nutrition and food security. A thorough knowledge of the genetic potential of rumen microbes will provide opportunities for improving the sustainability of ruminant production systems. The availability of gene reference catalogs from gut microbiomes has advanced the understanding of the role of the microbiota in health and disease in humans and other mammals. In this work, we established a catalog of reference prokaryote genes from the bovine rumen. Using deep metagenome sequencing we identified 13,825,880 non-redundant prokaryote genes from the bovine rumen. Compared to human, pig, and mouse gut metagenome catalogs, the rumen is larger and richer in functions and microbial species associated with the degradation of plant cell wall material and production of methane. Genes encoding enzymes catalyzing the breakdown of plant polysaccharides showed a particularly high richness that is otherwise impossible to infer from available genomes or shallow metagenomics sequencing. The catalog expands the dataset of carbohydrate-degrading enzymes described in the rumen. Using an independent dataset from a group of 77 cattle fed 4 common dietary regimes, we found that only <0.1% of genes were shared by all animals, which contrast with a large overlap for functions, i.e., 63% for KEGG functions. Different diets induced differences in the relative abundance rather than the presence or absence of genes, which explains the great adaptability of cattle to rapidly adjust to dietary changes. These data bring new insights into functions, carbohydrate-degrading enzymes, and microbes of the rumen to complement the available information on microbial genomes. The catalog is a significant biological resource enabling deeper understanding of phenotypes and biological processes and will be expanded as new data are made available.


Magnetic support of the optical emission line filaments in NGC 1275.
The giant elliptical galaxy NGC 1275, at the centre of the Perseus cluster, is surrounded by a well-known giant nebulosity of emission-line filaments, which are plausibly in excess of 10(8) years old. The filaments are dragged out from the centre of the galaxy by radio-emitting 'bubbles' rising buoyantly in the hot intracluster gas, before later falling back. They act as markers of the feedback process by which energy is transferred from the central massive black hole to the surrounding gas. The mechanism by which the filaments are stabilized against tidal shear and dissipation into the surrounding extremely hot (4 x 10(7) K) gas has been unclear. Here we report observations that resolve thread-like structures in the filaments. Some threads extend over 6 kpc, yet are only 70 pc wide. We conclude that magnetic fields in the threads, in pressure balance with the surrounding gas, stabilize the filaments, so allowing a large mass of cold gas to accumulate and delay star formation.


Freestanding and Supported MoS2 Monolayers under Cluster Irradiation: Insights from Molecular Dynamics Simulations.
Two-dimensional (2D) materials with nanometer-size holes are promising systems for DNA sequencing, water purification, and molecule selection/separation. However, controllable creation of holes with uniform sizes and shapes is still a challenge, especially when the 2D material consists of several atomic layers as, e.g., MoS2, the archetypical transition metal dichalcogenide. We use analytical potential molecular dynamics simulations to study the response of 2D MoS2 to cluster irradiation. We model both freestanding and supported sheets and assess the amount of damage created in MoS2 by the impacts of noble gas clusters in a wide range of cluster energies and incident angles. We show that cluster irradiation can be used to produce uniform holes in 2D MoS2 with the diameter being dependent on cluster size and energy. Energetic clusters can also be used to displace sulfur atoms preferentially from either top or bottom layers of S atoms in MoS2 and also clean the surface of MoS2 sheets from adsorbents. Our results for MoS2, which should be relevant to other 2D transition metal dichalcogenides, suggest new routes toward cluster beam engineering of devices based on 2D inorganic materials.


Ulnar collateral ligament injuries of the elbow in female division I collegiate gymnasts: a report of five cases.
Elbow ulnar collateral ligament (UCL) injuries in gymnastics have not been well documented in the literature, in comparison to UCL injuries in baseball. Few studies have examined the mechanism and nonoperative management of this injury, and no studies to date have been published on incidence of injury and return to play recommendations in gymnastics. A literature search was performed using PubMed to review articles from 1980 to 2016 that addressed the biomechanics of UCL injury in baseball and gymnastics, the anatomy of the elbow, injury rates, surgical vs non-surgical management, rehabilitation, and return to play recommendations for the sport of gymnastics. Five female collegiate gymnasts sustained UCL injury over a 3-year period. Electronic medical records for each case were thoroughly reviewed including imaging, surgical and non-surgical management, rehabilitation, and the progressive return to gymnastics. Four UCL injuries were confirmed by MRI to be avulsions at the distal insertion of the UCL and one was an avulsion at the proximal origin. While less than half of baseball players can return to competition with conservative management of these types of injuries, four out of five gymnasts were able to return to competition with nonoperative management. One gymnast opted to have reconstruction after a successful competition season. Time to return to play varied seemingly dependent on the severity of UCL injury and event. In our case series, collegiate female gymnasts were able to return to participation with nonoperative treatment of the UCL. Their success in returning to competitive gymnastics may also depend on the event(s) in which they are trying to participate. C.


Binaural summation of amplitude modulation involves weak interaural suppression.
The brain combines sounds from the two ears, but what is the algorithm used to achieve this summation of signals? Here we combine psychophysical amplitude modulation discrimination and steady-state electroencephalography (EEG) data to investigate the architecture of binaural combination for amplitude-modulated tones. Discrimination thresholds followed a 'dipper' shaped function of pedestal modulation depth, and were consistently lower for binaural than monaural presentation of modulated tones. The EEG responses were greater for binaural than monaural presentation of modulated tones, and when a masker was presented to one ear, it produced only weak suppression of the response to a signal presented to the other ear. Both data sets were well-fit by a computational model originally derived for visual signal combination, but with suppression between the two channels (ears) being much weaker than in binocular vision. We suggest that the distinct ecological constraints on vision and hearing can explain this difference, if it is assumed that the brain avoids over-representing sensory signals originating from a single object. These findings position our understanding of binaural summation in a broader context of work on sensory signal combination in the brain, and delineate the similarities and differences between vision and hearing.


Origin of structural difference in metabolic networks with respect to temperature.
Metabolism is believed to adaptively shape-shift with changing environment. In recent years, a structural difference with respect to temperature, which is an environmental factor, has been revealed in metabolic networks, implying that metabolic networks transit with temperature. Subsequently, elucidatation of the origin of these structural differences due to temperature is important for understanding the evolution of life. However, the origin has yet to be clarified due to the complexity of metabolic networks. Consequently, we propose a simple model with a few parameters to explain the transitions. We first present mathematical solutions of this model using mean-field approximation, and demonstrate that this model can reproduce structural properties, such as heterogeneous connectivity and hierarchical modularity, in real metabolic networks both qualitatively and quantitatively. We next show that the model parameters correlate with optimal growth temperature. In addition, we present a relationship between multiple cyclic properties and optimal growth temperature in metabolic networks. From the proposed model, we find that such structural properties are determined by the emergence of a short-cut path, which reduces the minimum distance between two nodes on a graph. Furthermore, we investigate correlations between model parameters and growth temperature; as a result, we find that the emergence of the short-cut path tends to be inhibited with increasing temperature. In addition, we also find that the short-cut path bypasses a relatively long path at high temperature when the emergence of the new path is not inhibited. Even further, additional network analysis provides convincing evidence of the reliability of the proposed model and its conclusions on the possible origins of differences in metabolic network structure.


Risk association between scleroderma disease characteristics, periodontitis, and tooth loss.
Systemic sclerosis (SSc) is a multi-system disorder that can have significant adverse effects on the health of the mouth. The aim of this study was to investigate the associations between the disease characteristics of SSc, periodontal disease (PD), and tooth loss. Fifty-four patients affected by SSc and 55 non-diseased controls were matched for age and gender. SSc was characterized in subtypes and with the mean duration of disease and the Modified Rodnan Skin Score [mRSS]. Patients were surveyed and examined through the evaluation of the periodontal parameters and the number of teeth. A logistic regression analysis showed that patients with SSc presented a higher number of missing teeth (p = 0.001) and a significant median increased odds 2.95 (95% CI 1.26 to 6.84) of PD (defined as clinical attachment loss, CAL) compared to nondiseased controls (6.83, 95% CI 1.94 to 24.36). Moreover, the fewer values of PD was correlated with mRSS in the total SSc group and with the mean duration of disease in patients with limited SSc (p = 0.007), even after adjusting this correlation with the presence of the major organ involvement. This study showed that patients with SSc presented increased odds of PD and tooth loss compared to non-diseased controls. In SSc patients, the magnitude of PD was strongly associated with the mRSS and with the mean duration of the disease. The clinicians should be aware of the potential systemic health problems related to PD.


Methamphetamine-associated psychosis: links to drug use characteristics and similarity to primary psychosis.
Objectives: Despite the prevalence of methamphetamine-associated psychosis, how characteristics of drug use affect the severity and clinical course, and its optimal treatments have not been established. We addressed these questions, assessing clinical features of methamphetamine-associated psychosis, and compared it with primary psychosis.Methods: Hospitalised patients with methamphetamine-associated (n = 70) or primary schizophrenic psychosis (n = 70) were matched on sex, age and duration of psychosis. Association of drug use variables (age at initiation, duration of methamphetamine use) with the Brief Psychiatric Rating Scale (BPRS) scores and psychosis duration were examined for patients with methamphetamine-associated psychosis, and the groups were compared on the BPRS scores.Results: Methamphetamine use initiation age correlated negatively with the BPRS total score and the Activation subscale score; methamphetamine use duration correlated positively with psychosis duration. Methamphetamine-associated psychosis group scored lower on the Hostility-Suspiciousness and Anergia subscales of the BPRS (adjusted p values < .05).Conclusions: Association of early initiation of methamphetamine with psychosis severity may suggest a lasting effect on brain development. Correlation of drug use and psychosis durations may suggest a cumulative effect of methamphetamine exposure. Less severe paranoia and negative symptoms in the methamphetamine-using group could implicate better social functioning of these patients. Further mechanistic studies are warranted.Key pointsEarly initiation of methamphetamine use is associated with psychosis severity.Methamphetamine use duration associates with psychosis duration.Methamphetamine-associated and primary schizophrenic psychoses were similar in symptoms.Methamphetamine psychosis patients were less severe in paranoia and negative symptoms.


Effects of pituitary adenylate cyclase-activating polypeptide, vasoactive intestinal polypeptide, and somatostatin on the release of thyrotropin from the bullfrog pituitary.
The recent development of a specific radioimmunoassay for amphibian (bullfrog, Rana catesbeiana) thyrotropin (TSH) has made it possible to study the effects of various neuropeptides on the release of TSH from the pituitary in vitro. Up to now, corticotropin-releasing factor of bullfrog origin has been shown to have a potent TSH-releasing activity, whereas gonadotropin-releasing hormone and TSH-releasing hormone exhibit a moderate TSH-releasing effect on the adult, but not larval, pituitary. In the present study, the effects of pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP), and somatostatin (SS) on the in vitro release of TSH from the bullfrog pituitary were investigated. Both frog (R. ridibunda) PACAP-38 and PACAP-27 caused a concentration-dependent stimulation of the release of TSH from dispersed pituitary cells during a 24-h culture. The PACAP-38- and PACAP-27-induced TSH release was suppressed by a simultaneous application of PACAP6-38. Application of high concentrations of PACAP6-38 alone caused a slight but significant stimulatory effect on the release of TSH. Frog VIP also stimulated TSH release from pituitary cells concentration-dependently. Frog SS1 (homologous to mammalian somatostatin-14) and SS2 (homologous to mammalian cortistatin) did not affect the basal release of TSH but caused a concentration-dependent suppression of the PACAP-38-induced release of TSH. These results suggest the involvement of multiple neuropeptides in the regulation of the release of TSH from the amphibian pituitary.


B-cell differentiation in EBV-positive Burkitt lymphoma is impaired at posttranscriptional level by miRNA-altered expression.
Endemic, sporadic and HIV-associated Burkitt lymphoma (BL) all have a B-cell phenotype and a MYC translocation, but a variable association with the Epstein-Barr virus (EBV). However, there is still no satisfactory explanation of how EBV participates in the pathogenesis of BL. A recent investigation suggested that EBV-positive and EBV-negative BL have different cells of origin. In particular, according to immunoglobulin gene mutation analysis, EBV-negative BLs may originate from early centroblasts, whereas EBV-positive BLs seem to arise from postgerminal center B cells or memory B cells. The appearance of a germinal center phenotype in EBV-positive cells might thus derive from a block in B-cell differentiation. The exit from the germinal center involves a complex series of events, which require the activation of BLIMP-1, and the consequent downregulation of several target genes. Here, we investigated the expression of specific miRNAs predicted to be involved in B-cell differentiation and found that hsa-miR-127 is differentially expressed between EBV-positive and EBV-negative BLs. In particular, it was strongly upregulated only in EBV-positive BL samples, whereas EBV-negative cases showed levels of expression similar to normal controls, including microdissected germinal centers (GC) cells. In addition, we found evidence that hsa-miR-127 is involved in B-cell differentiation process through posttranscriptional regulation of BLIMP1 and XBP1. The overexpression of this miRNA may thus represent a key event in the lymphomagenesis of EBV positive BL, by blocking the B-cell differentiation process.


Magnetic field generation through angular momentum exchange between circularly polarized radiation and charged particles.
The interaction between circularly polarized radiation and charged particles can lead to generation of magnetic field through an inverse Faraday effect. The spin of the circularly polarized electromagnetic wave can be converted into the angular momentum of the charged particles so long as there is dissipation. We demonstrate this by considering two mechanisms of angular momentum absorption relevant for laser-plasma interactions: electron-ion collisions and ionization. The precise dissipative mechanism, however, plays a role in determining the efficiency of the magnetic-field generation.


Theoretical study of molecular vibrations in electron momentum spectroscopy experiments on furan: an analytical versus a molecular dynamical approach.
The influence of thermally induced nuclear dynamics (molecular vibrations) in the initial electronic ground state on the valence orbital momentum profiles of furan has been theoretically investigated using two different approaches. The first of these approaches employs the principles of Born-Oppenheimer molecular dynamics, whereas the so-called harmonic analytical quantum mechanical approach resorts to an analytical decomposition of contributions arising from quantized harmonic vibrational eigenstates. In spite of their intrinsic differences, the two approaches enable consistent insights into the electron momentum distributions inferred from new measurements employing electron momentum spectroscopy and an electron impact energy of 1.2 keV. Both approaches point out in particular an appreciable influence of a few specific molecular vibrations of A1 symmetry on the 9a1 momentum profile, which can be unravelled from considerations on the symmetry characteristics of orbitals and their energy spacing.


Prevalence and Epidemiology of Non-O157 Escherichia coli Serogroups O26, O103, O111, and O145 and Shiga Toxin Gene Carriage in Scottish Cattle, 2014-2015.
Cattle are a reservoir for Shiga toxin-producing Escherichia coli (STEC), zoonotic pathogens that cause serious clinical disease. Scotland has a higher incidence of STEC infection in the human population than the European average. The aim of this study was to investigate the prevalence and epidemiology of non-O157 serogroups O26, O103, O111, and O145 and Shiga toxin gene carriage in Scottish cattle. Fecal samples (n = 2783) were collected from 110 herds in 2014 and 2015 and screened by real-time PCR. Herd-level prevalence (95% confidence interval [CI]) for O103, O26, and O145 was estimated as 0.71 (0.62, 0.79), 0.43 (0.34, 0.52), and 0.23 (0.16, 0.32), respectively. Only two herds were positive for O111. Shiga toxin prevalence was high in both herds and pats, particularly for stx2 (herd level: 0.99; 95% CI: 0.94, 1.0). O26 bacterial strains were isolated from 36 herds on culture. Fifteen herds yielded O26 stx-positive isolates that additionally harbored the intimin gene; six of these herds shed highly pathogenic stx2-positive strains. Multiple serogroups were detected in herds and pats, with only 25 herds negative for all serogroups. Despite overlap in detection, regional and seasonal effects were observed. Higher herd prevalence for O26, O103, and stx1 occurred in the South West, and this region was significant for stx2 at the pat level (P = 0.015). Significant seasonal variation was observed for O145 prevalence, with the highest prevalence in autumn (P = 0.032). Negative herds were associated with Central Scotland and winter. Herds positive for all serogroups were associated with autumn and larger herd size and were not housed at sampling.IMPORTANCE Cattle are reservoirs for Shiga toxin-producing Escherichia coli (STEC), bacteria shed in animal feces. Humans are infected through consumption of contaminated food or water and by direct contact, resulting in serious disease and kidney failure in the most vulnerable. The contribution of non-O157 serogroups to STEC illness was underestimated for many years due to the lack of specific tests. Recently, non-O157 human cases have increased, with O26 STEC of particular note. It is therefore vital to investigate the level and composition of non-O157 in the cattle reservoir and to compare them historically and by the clinical situation. In this study, we found cattle prevalence high for toxin, as well as for O103 and O26 serogroups. Pathogenic O26 STEC were isolated from 14% of study herds, with toxin subtypes similar to those seen in Scottish clinical cases. This study highlights the current risk to public health from non-O157 STEC in Scottish cattle.


The implication of life style on codon usage patterns and predicted highly expressed genes for three Frankia genomes.
Frankia are nitrogen-fixing actinomycetes that form a symbiotic association with over 200 species of woody dicotyledonous plants. Recently, three Frankia genomes were completely sequenced. In this study, the synonymous codon usage patterns of three Frankia genomes (strains CcI3, ACN14a, and EAN1pec) were determined and compared to each other and to other actinobacteria. As expected for a high G+C organism, codon usage by Frankia was highly biased, but differences were observed among the three strains. Using the codon adaptation index (CAI) as a numerical estimator of gene expression level, highly expressed genes in Frankia were predicted with ribosomal protein genes as a reference. The analysis of the predicted highly expressed genes showed that Frankia strain CcI3 had a different profile from the other two strains. Strain CcI3 had fewer predicted highly expressed genes in several COG categories including lipid transport and metabolism, secondary metabolites biosynthesis, inorganic ion transport and metabolism, and general function prediction only than Frankia strains EAN1pec and ACN14a. Interestingly, Frankia EAN1pec had more predicted highly expressed genes in transcription and signal transduction mechanisms than the other two strains. These differences were not just a reflection in total gene numbers, but also based on percentage of genes within a category. These results support the hypothesis that strain CcI3 is becoming a symbiotic specialist and the other two facultative symbiotic strains are maintaining their capacity to exist as free-living soil dwellers.


2008 - a year of three anniversaries: 125th anniversary of the Club for Natural Sciences in Fiume (Rijeka), 160th anniversary of the birth and 80th anniversary of the death of Professor Peter Salcher.
The Natural Science Club was founded in Fiume/Rijeka (Naturwissentschaflichen Club in Fiume/Club di scienze naturali in Fiume) on November 28th 1883. The foundation charter stipulated no restriction on language use, and lectures could be held in any language. Right from the start, the Club had active women members, and one of them, Rosa Fatour, the headmistress of the municipal school, held a lecture entitled "Development of anthropology" as early as in 1889. The Club started to publish a bilingual bulletin in German and Italian in 1896 (Mittheilungen des Naturwissenshaftlichen Clubs in Fiume/Bolletino del Club di scienze naturali in Fiume), bringing not only reports on lectures held in the Club, but also important scientific and professional papers. In 1896, several sections were founded within the Club, as follows: 1. The Committee for Röntgen, whose aim was to purchase the Röntgen apparatus. This task was completed in 1897. The apparatus was ceded to the municipal hospital in 1899, and the Committee was disbanded. 2. The Photography Section, lead initially by A. Riegler. The section organized several photo exhibitions in which women often took part.3. The Prehistoric Research Section was founded subsequent to the discovery of the remains of an old fortification in the town. This section collaborated closely with the municipal museum. Since founding and until 1902, Prof Peter Salcher held important positions in the Club; he founded the Röntgen Committee and the Photography Section; he himself gave 31 lectures and was editor of the German part of the Bulletin.


[Rehospitalization of elderly patients in a hospital in Lima, Perú].
In order to determine the frequency and factors associated to rehospitalization among elderly patients in a general hospital in Lima (Peru), a longitudinal study was conducted. An interview was administered to patients or care providers during their hospitalization, and data were collected from their medical records. After they were discharged from the hospital, they were followed up for 30 days through phone calls to become aware of their condition and if they were hospitalized at some health center during this period of time. 276 elderly patients were included, 14% of which were rehospitalized. It was found that rehospitalization was associated to functional dependency (p=0,003), pneumonia diagnosis upon admission (p=0,045) and lack of outpatient control (p<0,001); the latter having had RRa 2.22 (95% CI: 1,23-3,22). In conclusion, the most important associated factor in the rehospitalization of the elderly is the lack of control visits after being discharged.


Buildup of laser oscillations from quantum noise.
Buildup of laser oscillation is expressed in terms of the probabilities p(n)(t) that there are n photons in the laser cavity. These probabilities obey a coupled set of difference-differential equations of motion. The method and results of numerical integration of these equations are given here for the initial condition that no photons exist (radiation field vacuum). Corresponding equations of motion for the moments of the photon distribution are derived, and their time dependences are given. A movie showing the time development of the p(n) from an initial vacuum is given on the corners of the November 1970 issue of Applied Optics and can be seen by flipping through the pages.


Cause of death in 1144 patients with diabetes mellitus: an autopsy study.
The pathological reports for all patients over 13 years of age who had had an autopsy at one of three university-affiliated hospitals between 1967 and 1976 were reviewed to determine the principal cause of death. The clinical records of the patients with diabetes were reviewed to verify the diagnosis and to determine the known duration of diabetes. There were 1144 patients with diabetes mellitus and 5674 without. The sex distribution was similar in the two groups. The patients with diabetes were slightly older, males by 2.2 years and females by 3.2 years. Disease of the circulatory system was the principal cause of death in males (53.7%) and females (58.9%) with diabetes. The rates in the corresponding patients without diabetes were 37.6% and 35.2%. Neoplasms accounted for 18.9% of deaths in males with diabetes, compared with 35.7% in males without diabetes; the corresponding figures in females were 16.0% and 39.4%. Renal disease accounted for 5.9% of deaths in patients with diabetes.


Comparative expression of hepatitis B virus antigens in several cell model systems.
In this paper the kinetics of hepatitis B virus (HBV) gene expression were investigated in natural and experimentally transfected cell systems. These systems included four human hepatocellular carcinoma cell lines containing HBV DNA (TONG/PHC, HEp 3B2, PLC/PRF/5 and HA22T/VGH) as well as a mouse and a rat cell line both experimentally transfected with HBV DNA. Comparative results on the kinetics of hepatitis B surface antigen in these cell systems suggested that the S gene in the integrated state is expressed at different levels. No human cell line derived from HBV-associated hepatocellular carcinoma produced hepatitis B e antigen (HBeAg) when medium was concentrated by ultrafiltration. In distinct contrast, the two experimentally transfected cell systems produced e antigen at different levels. When all HBV-containing cell lines were grown as tumours in nude mice, no HBeAg was detected in the serum of these mice inoculated with human hepatocellular carcinoma cell lines, in the tumour homogenates, or in the tumour-derived lines, whereas e antigen was expressed both in vivo and in vitro in the experimentally transfected cell lines. These observations indicate that C gene expression is restricted to transfected cell cultures and this suggests a distinct difference in the mechanisms of HBV gene expression between the two types of in vitro model systems.


Association of inflammatory biomarkers with subsequent clinical course in suspected late onset sepsis in preterm neonates.
Sepsis is a major health issue in preterm infants. Biomarkers are used to diagnose and monitor patients with sepsis, but C-reactive protein (CRP) is proven not predictive at onset of late onset neonatal sepsis (LONS) diagnosis. The aim of this study was to evaluate the association of interleukin-6(IL-6), procalcitonin (PCT) and CRP with subsequent sepsis severity and mortality in preterm infants suspected of late onset neonatal sepsis. The study was conducted at the Erasmus University Medical Center-Sophia Children's Hospital Rotterdam. Patient data from January 2018 until October 2019 were reviewed for all preterm neonates born with a gestational age below 32 weeks with signs and symptoms suggestive of systemic infection, in whom blood was taken for blood culture and for inflammatory biomarkers determinations. Plasma IL-6 and PCT were assessed next to CRP at the moment of suspicion. We assessed the association with 7-day mortality and sepsis severity (neonatal sequential organ failure assessment (nSOFA) score, need for inotropic support, invasive ventilation and thrombocytopenia). A total of 480 suspected late onset neonatal sepsis episodes in 208 preterm neonates (gestational age < 32 weeks) were retrospectively analyzed, of which 143 episodes were classified as sepsis (29.8%), with 56 (11.7%) cases of culture negative, 63 (13.1%) cases of gram-positive and 24(5.0%) cases of gram-negative sepsis. A total of 24 (5.0%) sepsis episodes resulted in death within 7 days after suspicion of LONS. Both IL-6 (adjusted hazard ratio (aHR): 2.28; 95% CI 1.64-3.16; p < 0.001) and PCT (aHR: 2.91; 95% CI 1.70-5.00; p < 0.001) levels were associated with 7-day mortality; however, CRP levels were not significantly correlated with 7-day mortality (aHR: 1.16; 95% CI (0.68-2.00; p = 0.56). Log IL-6, log PCT and log CRP levels were all significantly correlated with the need for inotropic support. Our findings show that serum IL-6 and PCT levels at moment of suspected late onset neonatal sepsis offer valuable information about sepsis severity and mortality risk in infants born below 32 weeks of gestation. The discriminative value was superior to that of CRP. Determining these biomarkers in suspected sepsis may help identify patients with imminent severe sepsis, who may require more intensive monitoring and therapy.


Insomnia Symptoms Among Female Veterans: Prevalence, Risk Factors, and the Impact on Psychosocial Functioning and Health Care Utilization.
To examine the prevalence of self-reported insomnia symptoms, identify subgroups of female veterans with clinically significant insomnia symptoms, and examine the effect on psychosocial functioning and health care utilization. Cross-sectional analysis of insomnia symptoms and associated characteristics among a stratified random sample of female veterans using Department of Veterans Affairs primary care facilities between October 1, 2010 and September 30, 2011 (n = 6,261) throughout the United States. The primary outcome was reported presence of insomnia symptoms. Other variables included psychological disorders, chronic conditions, chronic pain, and demographic variables. Overall, 47.39% of female veterans screened positively for insomnia symptoms. They differed demographically from those without insomnia symptoms and reported more substance use, chronic physical conditions, and psychological conditions. Receiver operating characteristic analysis indicated the primary factor that differentiated those with versus those without insomnia symptoms was depression. Individuals were further differentiated based on presence of pain and posttraumatic stress disorder. Results yielded eight homogenous subgroups of women at low and high risk of experiencing insomnia symptoms. Sleep problems are common among female veterans (47.39%) despite limited diagnosis of sleep disorders (0.90%). Eight unique subgroups of female veterans with both low and high insomnia symptoms were observed. These subgroups differed in terms of psychosocial functioning and health care utilization, with those with depression, posttraumatic stress disorder, and pain having the poorest outcomes. These results shed light on the prevalence of insomnia symptoms experienced among female veterans and the effect on psychosocial functioning and health care utilization. Results can inform targeted detection and customized treatment among female veterans.


ENDOSCOPIC CHARACTERISTICS OF PATIENTS WITH COMPLETE PATHOLOGICAL RESPONSE AFTER NEOADJUVANT CHEMOTHERAPY FOR GASTRIC AND ESOPHAGOGASTRIC JUNCTION ADENOCARCINOMAS.
Gastric and esophagogastric junction adenocarcinoma are responsible for approximately 13.5% of cancer-related deaths. Given the fact that these tumors are not typically detected until they are already in the advanced stages, neoadjuvancy plays a fundamental role in improving long-term survival. Identification of those with complete pathological response (pCR) after neoadjuvant chemotherapy (NAC) is a major challenge, with effects on organ preservation, extent of resection, and additional surgery. There is little or no information in the literature about which endoscopic signs should be evaluated after NAC, or even when such re-evaluation should occur. To describe the endoscopic aspects of patients with gastric and esophagogastric junction adenocarcinomas who underwent NAC and achieved pCR, and to determine the accuracy of esophagogastroduodenoscopy (EGD) in predicting the pCR. A survey was conducted of the medical records of patients with these tumors who were submitted to gastrectomy after NAC, with anatomopathological result of pCR. Twenty-nine patients were identified who achieved pCR after NAC within the study period. Endoscopic responses were used to classify patients into two groups: G1-endoscopic findings consistent with pCR and G2-endoscopic findings not consistent with pCR. Endoscopic evaluation in G1 was present in an equal percentage (47.4%; p=0.28) in Borrmann classification II and III. In this group, the predominance was in the gastric body (57.9%; p=0.14), intestinal subtype with 42.1% (p=0.75), undifferentiated degree, 62.5% (p=0.78), Herb+ in 73.3% (p=0.68). The most significant finding, however, was that the time interval between NAC and EGD was longer for G1 than G2 (24.4 vs. 10.2 days, p=0.008). EGD after NAC seems to be a useful tool for predicting pCR, and it may be possible to use it to create a reliable response classification. In addition, the time interval between NAC and EGD appears to significantly influence the predictive power of endoscopy for pCR.


Cancer-testis antigens: the current status on antigen regulation and potential clinical use.
Immunotherapy is theoretically an attractive therapeutic option for patients with hematological malignancies. Various laboratory studies suggested the importance of the choice of tumor antigen for successful immunotherapy. Cancer-testis antigens (CTAs) are potentially suitable molecules for tumor vaccines of hematological malignancies because of their high immunogenicity in vivo, even in cancer-bearing patients, and their relatively restricted normal tissue distribution. Tumor cell kill using a CTA-based immunotherapy will, therefore, be more specific and associated with less toxicities when compared to chemotherapy. Many CTAs have been identified in various hematologic malignancies. In this review, we will take the readers through the journey of hopes and the disappointments arisen from the discovery of CTAs. We will describe the features of CTAs and their expression in hematologic malignancies. We will also discuss the mechanisms regulating the expression of these CTAs, from a primary regulatory mechanism involving DNA methylation to secondary controls by cytokines. Finally, we will address the potential obstacles that will prevent the successful use of CTAs as targets for tumor immunotherapy.


Functional brain network organization measured with magnetoencephalography predicts cognitive decline in multiple sclerosis.
Cognitive decline remains difficult to predict as structural brain damage cannot fully explain the extensive heterogeneity found between MS patients. To investigate whether functional brain network organization measured with magnetoencephalography (MEG) predicts cognitive decline in MS patients after 5 years and to explore its value beyond structural pathology. Resting-state MEG recordings, structural MRI, and neuropsychological assessments were analyzed of 146 MS patients, and 100 patients had a 5-year follow-up neuropsychological assessment. Network properties of the minimum spanning tree (i.e. backbone of the functional brain network) indicating network integration and overload were related to baseline and longitudinal cognition, correcting for structural damage. A more integrated beta band network (i.e. smaller diameter) and a less integrated delta band network (i.e. lower leaf fraction) predicted cognitive decline after 5 years (Radj2=15%), independent of structural damage. Cross-sectional analyses showed that a less integrated network (e.g. lower tree hierarchy) related to worse cognition, independent of frequency band. The level of functional brain network integration was an independent predictive marker of cognitive decline, in addition to the severity of structural damage. This work thereby indicates the promise of MEG-derived network measures in predicting disease progression in MS.


"This policy sucks and it's stupid:" Mapping maternity care for First Nations women on reserves in Manitoba, Canada.
First Nations women who live on rural and remote reserves in Canada leave their communities between 36 and 38 weeks gestational age to receive labor and birthing services in large urban centers. The process and administrative details of this process are undocumented despite decades of relocation as a routine component of maternity care. Using data from 32 semistructured interviews and information from peer-reviewed literature, grey literature, and public documents, I constructed a descriptive map and a visual representation of the policy. I present new and detailed information about Canada's health policy as well as recommendations to address the health care gaps identified.


Rocket-borne twin-channel photoelectric stellar photometer suitable for use in the 1400-3000-a region.
A description is given of a rugged compact twin-channel stellar photometer developed for low resolution observations of stars in the wavelength region 1400-3000 A. The photometer employs two parallel Newtonian telescopes of large collecting area and incorporates photoelectric detection. Various methods of nondispersive wavelength isolation are described including what may be regarded as the state of the art in reflectance filter technology. The instrument has been successfully flown on six separate occasions under the auspices of the European Space Research Organization's program of collaborative research and yielded what are believed to be the first photoelectric stellar observations in Europe from above the earth's atmosphere.


Intracytoplasmic membrane formation and increased oxidation of glycerol growth of Gluconobacter oxydans.
Gluconobacter oxydans is well known for the limited oxidation of compounds and rapid excretion of industrially important oxidation products. The dehydrogenases responsible for these oxidations are reportedly bound to the cell's plasma membrane. This report demonstrates that fully viable G. oxydans differentiates at the end of exponential growth by forming dense regions at the end of each cell observed with the light microscope. When these cells were thin sectioned, their polar regions contained accumulations of intracytoplasmic membranes and ribosomes not found in undifferentiated exponentially growing cells. Both freeze-fracture-etched whole cells and thin sections through broken-cell envelopes of differentiated cells demonstrate that intracytoplasmic membranes occur as a polar accumulation of vesicles that are attached to the plasma membrane. When cells were tested for the activity of the plasma membrane-associated glycerol dehydrogenase, those containing intracytoplasmic membranes were 100% more active than cells lacking these membranes. These results suggest that intracytoplasmic membranes are formed by continued plasma membrane synthesis at the end of active cell division.


The use of recently described ionisation techniques for the rapid analysis of some common drugs and samples of biological origin.
Three ionisation techniques that require no sample preparation or extraction prior to mass analysis have been used for the rapid analysis of pharmaceutical tablets and ointments. These methods were (i) the novel direct analysis in real time (DART), (ii) desorption electrospray ionisation (DESI), and (iii) desorption atmospheric pressure chemical ionisation (DAPCI). The performance of the three techniques was investigated for a number of common drugs. Significant differences between these approaches were observed. For compounds of moderate to low polarity DAPCI produced more effective ionisation. Accurate DESI and DAPCI tandem mass spectra were obtained and these greatly enhance the selectivity and information content of the experiment. The detection from human skin of the active ingredients from ointments is reported together with the detection of ibuprofen metabolites in human urine.


An extracellular serine protease produced by Vibrio vulnificus NCIMB 2137, a metalloprotease-gene negative strain isolated from a diseased eel.
Vibrio vulnificus is a ubiquitous estuarine microorganism but causes fatal systemic infections in immunocompromised humans, cultured eels or shrimps. An extracellular metalloprotease VVP/VvpE has been reported to be a potential virulence factor of the bacterium; however, a few strains isolated from a diseased eel or shrimp were recently found to produce a serine protease termed VvsA, but not VVP/VvpE. In the present study, we found that these strains had lost the 80 kb genomic region including the gene encoding VVP/VvpE. We also purified VvsA from the culture supernatant through ammonium sulfate fractionation, gel filtration and ion-exchange column chromatography, and the enzyme was demonstrated to be a chymotrypsin-like protease, as well as those from some vibrios. The gene vvsA was shown to constitute an operon with a downstream gene vvsB, and several Vibrio species were found to have orthologues of vvsAB. These findings indicate that the genes vvp/vvpE and vvsAB might be mobile genetic elements.


Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis.
Growth factor receptor bound (Grb)10 and Grb14 are closely related adaptor proteins that bind directly to the insulin receptor (IR) and regulate insulin-induced IR tyrosine phosphorylation and signaling to IRS-1 and Akt. Grb10- and Grb14-deficient mice both exhibit improved whole-body glucose homeostasis as a consequence of enhanced insulin signaling and, in the case of the former, altered body composition. However, the combined physiological role of these adaptors has remained undefined. In this study we utilize compound gene knockout mice to demonstrate that although deficiency in one adaptor can enhance insulin-induced IRS-1 phosphorylation and Akt activation, insulin signaling is not increased further upon dual ablation of Grb10 and Grb14. Context-dependent limiting mechanisms appear to include IR hypophosphorylation and decreased IRS-1 expression. In addition, the compound knockouts exhibit an increase in lean mass comparable to Grb10-deficient mice, indicating that this reflects a regulatory function specific to Grb10. However, despite the absence of additive effects on insulin signaling and body composition, the double-knockout mice are protected from the impaired glucose tolerance that results from high-fat feeding, whereas protection is not observed with animals deficient for individual adaptors. These results indicate that, in addition to their described effects on IRS-1/Akt, Grb10 and Grb14 may regulate whole-body glucose homeostasis by additional mechanisms and highlight these adaptors as potential therapeutic targets for amelioration of the insulin resistance associated with type 2 diabetes.


The Impact of Family Environment on Language Development of Children With Cochlear Implants: A Systematic Review and Meta-Analysis.
The authors conducted a systematic review of the literature and meta-analyses to assess the influence of family environment on language development in children with cochlear implants. The Pubmed, excerpta medica dataBASE (EMBASE), Education Research Information Center, cumulative index to nursing and allied health literature (CINAHL), Healthcare Literature Information Network, PubPsych, and Social SciSearch databases were searched. The search strategy included terms describing family environment, child characteristics, and language development. Studies were included that (a) assessed distal family variables (such as parental income level, parental education, family size, and parental stress) with child language outcomes, and/or more proximal correlates that directly affect the child (such as family engagement and participation in intervention, parenting style, and more specifically, the quantity and quality of parental linguistic input) on child language; (b) included children implanted before the age of 5 years; (c) measured child language before the age of 21 years with standardized instruments; (d) were published between 1995 and February 2018; and (e) were published as peer-reviewed articles. The methodological quality was assessed with an adaptation of a previously validated checklist. Meta-analyses were conducted assuming a random-effects model. A total of 22 study populations reported in 27 publications were included. Methodological quality was highly variable. Ten studies had a longitudinal design. Three meta-analyses on the correlations between family variables and child language development could be performed. A strong effect of the quality and quantity of parental linguistic input in the first 4½ years postimplantation on the child's language was found, r = 0.564, p ≤ 0.001, 95% confidence interval (CI) = 0.449 to 0.660, accounting for 31.7% of the variance in child language outcomes. Results demonstrated high homogeneity, Q(3) = 1.823, p = 0.61, I = 0. Higher-level facilitative language techniques, such as parental expansions of the child's utterances or the use of open-ended questions, predicted child language skills. Risk of publication bias was not detected. The results on the impact of family involvement/participation in intervention on child language development were more heterogeneous. The meta-analysis included mainly cross-sectional studies and identified low to moderate benefits, r = 0.380, p ≤ 0.052, 95% CI = -0.004 to 0.667, that almost attained significance level. Socioeconomic status, mainly operationalized by parental level of education, showed a positive correlation with child language development in most studies. The meta-analysis confirmed an overall low and nonsignificant average correlation coefficient, r = 0.117, p = 0.262, 95% CI = -0.087 to 0.312. A limitation of the study was the lack of some potentially relevant variables, such as multilingualism or family screen time. These data support the hypothesis that parental linguistic input during the first years after cochlear implantation strongly predicts later child language outcomes. Effects of parental involvement in intervention and parental education are comparatively weaker and more heterogeneous. These findings underscore the need for early-intervention programs for children with cochlear implants focusing on providing support to parents for them to increase their children's exposure to high-quality conversation.


"Pastoral crisis intervention": toward a definition.
The pastoral community represents a large and often untapped resource in times of crisis. It possesses a unique aggregation of characteristics that makes it uniquely valuable amidst the turmoil of a psychological crisis. In critical incidents such as terrorism, mass disasters, violence, the loss of loved ones, and any events wherein human actions result in injury, destruction, and/or death, the pastoral community may possess especially powerful restorative attributes. Unfortunately, heretofore, there has existed no generally recognized and accepted manner in which the healing factors inherent in pastoral care have been functionally integrated with the well-formulated principles of crisis intervention. This paper represents an initial effort to elucidate how the principles of pastoral care may be functionally integrated with those of crisis intervention. The amalgam shall heretofore be referred to as "pastoral crisis intervention" and is defined herein.


The relationship of the hyperspherical harmonics to SO(3), SO(4) and orientation distribution functions.
The expansion of an orientation distribution function as a linear combination of the hyperspherical harmonics suggests that the analysis of crystallographic orientation information may be performed entirely in the axis-angle parameterization. Practical implementation of this requires an understanding of the properties of the hyperspherical harmonics. An addition theorem for the hyperspherical harmonics and an explicit formula for the relevant irreducible representatives of SO(4) are provided. The addition theorem is useful for performing convolutions of orientation distribution functions, while the irreducible representatives enable the construction of symmetric hyperspherical harmonics consistent with the crystal and sample symmetries.


Practice patterns in pediatric chronic rhinosinusitis: A survey of the American Rhinologic Society.
The management of pediatric chronic rhinosinusitis (PCRS) is evolving. To assess current practice patterns of members of the American Rhinologic Society (ARS) in managing PCRS. A 27-item Web-based survey on treatment of PCRS was electronically distributed to the ARS membership. The survey was completed by 67 members, 40% of whom had completed a rhinology fellowship. The most frequently used medical therapies as part of initial treatment for PCRS were nasal saline solution irrigation, (90%), topical nasal steroids (93%), oral antibiotics (52%), and oral steroids (20%). For initial surgical therapy, 90% performed adenoidectomy; in addition, 31% also performed sinus lavage, 17% performed balloon catheter dilation (BCD), and 17% performed endoscopic sinus surgery (ESS). Sixty percent performed adenoidectomy before obtaining computed tomography imaging. When initial surgical treatment failed, 85% performed traditional ESS. In patients with pansinusitis, 50% of the respondents performed frontal sinusotomy and 70% performed sphenoidotomy. BCD was not frequently used; overall, 66% never or rarely used it, 20% sometimes used it, 12% usually used it, and 3% always or almost always used BCD. Most aspects of PCRS management among ARS members were aligned with published consensus statements. Adenoidectomy was almost always included as part of first-line surgical treatment but was also combined with adjunctive surgical procedures with moderate frequency. ESS was performed by a minority of rhinologists as a primary procedure for medically refractory PCRS but was favored when previous surgery failed. BCD was uncommonly used in PCRS.


Activated PAK4 regulates cell adhesion and anchorage-independent growth.
The serine/threonine kinase PAK4 is an effector molecule for the Rho GTPase Cdc42. PAK4 differs from other members of the PAK family in both sequence and function. Previously we have shown that an important function of this kinase is to mediate the induction of filopodia in response to activated Cdc42. Since previous characterization of PAK4 was carried out only with the wild-type kinase, we have generated a constitutively active mutant of the kinase to determine whether it has other functions. Expression of activated PAK4 in fibroblasts led to a transient induction of filopodia, which is consistent with its role as an effector for Cdc42. In addition, use of the activated mutant revealed a number of other important functions of this kinase that were not revealed by studying the wild-type kinase. For example, activated PAK4 led to the dissolution of stress fibers and loss of focal adhesions. Consequently, cells expressing activated PAK4 had a defect in cell spreading onto fibronectin-coated surfaces. Most importantly, fibroblasts expressing activated PAK4 had a morphology that was characteristic of oncogenic transformation. These cells were anchorage independent and formed colonies in soft agar, similar to what has been observed previously in cells expressing activated Cdc42. Consistent with this, dominant-negative PAK4 mutants inhibited focus formation by oncogenic Dbl, an exchange factor for Rho family GTPases. These results provide the first demonstration that a PAK family member can transform cells and indicate that PAK4 may play an essential role in oncogenic transformation by the GTPases. We propose that the morphological changes and changes in cell adhesion induced by PAK4 may play a direct role in oncogenic transformation by Rho family GTPases and their exchange factors.


Treatment considerations in facial paralysis.
Facial nerve paralysis and its sequelae are devastating to patients. For the reconstructive surgeon, the management of the patient with facial paralysis is challenging. There is a lack of consensus regarding the initial management. Then, there is the dizzying array of treatment options for each patient, including nonoperative observation, nerve transfers, static slings, dynamic muscle transfers, and chemodenervation. The appropriate timing of any intervention is often not clear. In this article, we will briefly outline some important considerations for the facial plastic surgeon in the management of facial paralysis. This includes the relevant anatomy and the initial evaluation. An overview of treatment options, with suggestions for the appropriate use of each option, is then provided.


Robust adaptive estimator for filtering noise in images.
Provides three new methods for storing images corrupted by additive noise. One is the adaptive mean median filter for preserving the details of images when restored from additive Gaussian noise. Another is the minimum-maximum method for moving outlier noise. The third method, the robust adaptive mean p-median filter, is based on a combination of the previous two methods. In the past, proposed restoration methods have generally proven to be inadequate for both detail preservation and noise suppression, but the new adaptive mean p-median filter is shown to be good at both of these tasks, while the robust adaptive mean p-median filter can give good performance even in the presence of outliers. Degraded images are processed by the proposed algorithms, with the results compared with a selection of other median-based algorithms that have been proposed in the literature.


Distinct subunit-specific α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking mechanisms in cultured cortical and hippocampal neurons in response to oxygen and glucose deprivation.
Brain ischemia occurs when the blood supply to the brain is interrupted, leading to oxygen and glucose deprivation (OGD). This triggers a cascade of events causing a synaptic accumulation of glutamate. Excessive activation of glutamate receptors results in excitotoxicity and delayed cell death in vulnerable neurons. Following global cerebral ischemia, hippocampal CA1 pyramidal neurons are more vulnerable to injury than their cortical counterparts. The mechanisms that underlie this difference are unclear. Cultured hippocampal neurons respond to OGD with a rapid internalization of AMPA receptor (AMPAR) subunit GluA2, resulting in a switch from GluA2-containing Ca(2+)-impermeable receptors to GluA2-lacking Ca(2+)-permeable subtypes (CP-AMPARs). GluA2 internalization is a critical component of OGD-induced cell death in hippocampal neurons. It is unknown how AMPAR trafficking is affected in cortical neurons following OGD. Here, we show that cultured cortical neurons are resistant to an OGD insult that causes cell death in hippocampal neurons. GluA1 is inserted at the plasma membrane in both cortical and hippocampal neurons in response to OGD. In contrast, OGD causes a rapid endocytosis of GluA2 in hippocampal neurons, which is absent in cortical neurons. These data demonstrate that populations of neurons with different vulnerabilities to OGD recruit distinct cell biological mechanisms in response to insult, and that a crucial aspect of the mechanism leading to OGD-induced cell death is absent in cortical neurons. This strongly suggests that the absence of OGD-induced GluA2 trafficking contributes to the relatively low vulnerability of cortical neurons to ischemia.


Genome-Wide Association Study Identified Candidate Genes for Alkalinity Tolerance in Rice.
Alkalinity stress is a major hindrance to enhancing rice production globally due to its damaging effect on plants' growth and development compared with salinity stress. However, understanding of the physiological and molecular mechanisms of alkalinity tolerance is limited. Therefore, a panel of indica and japonica rice genotypes was evaluated for alkalinity tolerance at the seedling stage in a genome-wide association study to identify tolerant genotypes and candidate genes. Principal component analysis revealed that traits such as alkalinity tolerance score, shoot dry weight, and shoot fresh weight had the highest contribution to variations in tolerance, while shoot Na+ concentration, shoot Na+:K+ ratio, and root-to-shoot ratio had moderate contributions. Phenotypic clustering and population structure analysis grouped the genotypes into five subgroups. Several salt-susceptible genotypes such as IR29, Cocodrie, and Cheniere placed in the highly tolerant cluster suggesting different underlying tolerance mechanisms for salinity and alkalinity tolerance. Twenty-nine significant SNPs associated with alkalinity tolerance were identified. In addition to three alkalinity tolerance QTLs, qSNK4, qSNC9, and qSKC10, which co-localized with the earlier reported QTLs, a novel QTL, qSNC7, was identified. Six candidate genes that were differentially expressed between tolerant and susceptible genotypes were selected: LOC_Os04g50090 (Helix-loop-helix DNA-binding protein), LOC_Os08g23440 (amino acid permease family protein), LOC_Os09g32972 (MYB protein), LOC_Os08g25480 (Cytochrome P450), LOC_Os08g25390 (Bifunctional homoserine dehydrogenase), and LOC_Os09g38340 (C2H2 zinc finger protein). The genomic and genetic resources such as tolerant genotypes and candidate genes would be valuable for investigating the alkalinity tolerance mechanisms and for marker-assisted pyramiding of the favorable alleles for improving alkalinity tolerance at the seedling stage in rice.


Effects of methylphenidate on sensitivity to reinforcement in children diagnosed with attention deficit hyperactivity disorder: an application of the matching law.
The behavior of children diagnosed with attention deficit hyperactivity disorder (ADHD) has been hypothesized to be the result of decreased sensitivity to consequences compared to typical children. The present study examined sensitivity to reinforcement in 2 boys diagnosed with ADHD using the matching law to provide more precise and quantitative measurement of this construct. This experiment also evaluated the effects of methylphenidate (MPH) on sensitivity to reinforcement of children with ADHD. Subjects completed math problems to earn tokens under four different variable-interval (VI) schedules of reinforcement presented in random order under both medicated and nonmedicated conditions. Results showed that, in the medicated condition, the matching functions for both subjects resulted in higher asymptotic values, indicating an overall elevation of behavior rate under these conditions. The variance accounted for by the matching law was also higher under the medicated conditions, suggesting that their behavior more closely tracked the changing rates of reinforcement while taking MPH compared to placebo. Under medicated conditions, the reinforcing efficacy of response-contingent tokens decreased. Results are discussed with respect to quantifying behavioral changes and the extent to which the drug interacts with prevailing contingencies (i.e., schedule values) to influence behavioral variability.


Design, engineering, and construction of photosynthetic microbial cell factories for renewable solar fuel production.
There is an urgent need to develop sustainable solutions to convert solar energy into energy carriers used in the society. In addition to solar cells generating electricity, there are several options to generate solar fuels. This paper outlines and discusses the design and engineering of photosynthetic microbial systems for the generation of renewable solar fuels, with a focus on cyanobacteria. Cyanobacteria are prokaryotic microorganisms with the same type of photosynthesis as higher plants. Native and engineered cyanobacteria have been used by us and others as model systems to examine, demonstrate, and develop photobiological H(2) production. More recently, the production of carbon-containing solar fuels like ethanol, butanol, and isoprene have been demonstrated. We are using a synthetic biology approach to develop efficient photosynthetic microbial cell factories for direct generation of biofuels from solar energy. Present progress and advances in the design, engineering, and construction of such cyanobacterial cells for the generation of a portfolio of solar fuels, e.g., hydrogen, alcohols, and isoprene, are presented and discussed. Possibilities and challenges when introducing and using synthetic biology are highlighted.


Associations Between Food Insecurity and Neighborhood Safety, Social Cohesion, Social Control, and Crime Among Mothers of Preschool-Aged Children.
Food insecurity has myriad associations with poor health, and low-income communities have higher than average prevalence of food insecurity. Living in a supportive neighborhood social environment may protect against food insecurity, while adverse neighborhood social conditions, such as crime, may increase the likelihood of food insecurity. To examine associations between food insecurity and neighborhood social factors among families with young children, we administered a cross-sectional survey to 300 mothers and female caregivers of Medicaid-enrolled two- to four-year-old children in Philadelphia. We used multivariable regression to examine associations between food insecurity and perceived neighborhood safety, social cohesion, informal social control, and crime, adjusted for demographics, socioeconomic status, and neighborhood characteristics. Lower food insecurity prevalence was associated with higher perceived neighborhood safety and social cohesion, and lower police-recorded violent crime rates. Future work to increase food security among low-income households may benefit from targeting the neighborhood social environment.


Three-dimensional localization microscopy using deep learning.
Single molecule localization microscopy (SMLM) is one of the fastest evolving and most broadly used super-resolving imaging techniques in the biosciences. While image recordings could take up to hours only ten years ago, scientists are now reaching for real-time imaging in order to follow the dynamics of biology. To this end, it is crucial to have data processing strategies available that are capable of handling the vast amounts of data produced by the microscope. In this article, we report on the use of a deep convolutional neural network (CNN) for localizing particles in three dimensions on the basis of single images. In test experiments conducted on fluorescent microbeads, we show that the precision obtained with a CNN can be comparable to that of maximum likelihood estimation (MLE), which is the accepted gold standard. Regarding speed, the CNN performs with about 22k localizations per second more than three orders of magnitude faster than the MLE algorithm of ThunderSTORM. If only five parameters are estimated (3D position, signal and background), our CNN implementation is currently slower than the fastest, recently published GPU-based MLE algorithm. However, in this comparison the CNN catches up with every additional parameter, with only a few percent extra time required per additional dimension. Thus it may become feasible to estimate further variables such as molecule orientation, aberration functions or color. We experimentally demonstrate that jointly estimating Zernike mode magnitudes for aberration modeling can significantly improve the accuracy of the estimates.


Ingredients of Vicks VapoRub inhibit rhinovirus-induced ATP release.
Over-the-counter therapies, such as Vicks VapoRub, are frequently used in the management of upper respiratory tract infection symptoms. Of these, acute cough is the most bothersome; however, the mechanisms involved have not been fully elucidated. The temperature-sensitive transient receptor potential (TRP) channels, including TRPA1, TRPV1, TRPM8 and TRPV4, are potential candidates. TRPV4 is also thought to be involved in cough through the TRPV4-ATP-P2X3 pathway. Here, we hypothesise that Vicks VapoRub ingredients (VVRIs) modulate the TRP cough channels. Stably transfected HEK cells expressing TRP channels were challenged with VVRIs, individually or in combination, and the agonist and antagonist effects were measured using calcium signalling responses. In addition, rhinovirus serotype-16 (RV16)-infected A549 airway epithelial cells were pre-incubated with individual or combinations of VVRIs prior to hypotonic challenge and extracellular ATP release analysis. Calcium signalling reconfirmed some previously defined activation of TRP channels by specific VVRIs. The combined VVRIs containing menthol, camphor and eucalyptus oil activated TRPV1, TRPV4, TRPM8 and untransfected wild-type HEK293 cells. However, pre-incubation with VVRIs did not significantly inhibit any of the channels compared with the standard agonist responses. Pre-incubation of RV16-infected A549 cells with individual or combined VVRIs, except menthol, resulted in a 0.45-0.55-fold reduction in total ATP release following hypotonic stimulation, compared with infected cells not treated with VVRIs. These findings suggest that some VVRIs may reduce symptoms associated with upper respiratory tract infection by modulating specific TRP receptors and by reducing RV16-induced ATP release.


Effect of photodynamic therapy on clinical isolates of Staphylococcus spp.
Staphylococcus spp. are opportunistic microorganisms known for their capacity to develop resistance against antimicrobial agents. The objective of this study was to evaluate the effect of photodynamic therapy (PDT) on 20 Staphylococcus strains isolated from the human oral cavity, including S. aureus, S. schleiferi, S. epidermidis, S. capitis, S. haemolyticus, and S. lentus. A suspension of each Staphylococcus strain (10(6) cells/mL) was submitted to PDT using methylene blue and a low power laser. The isolated effects of methylene blue, laser treatment and ciprofloxacin were also evaluated. After the experimental treatments, 0.1 mL aliquots of the suspensions were seeded onto BHI agar for determination of the number of colony-forming units (CFU/mL). The results were analyzed by analysis of variance and Tukey's test (p < 0.05). The mean reduction in bacterial counts of the strains submitted to PDT ranged from 4.89 to 6.83 CFU (log10)/mL, with the observation of a decreasing susceptibility to treatment of S. schleiferi, S. haemolyticus, S. epidermidis, S. capitis, S. aureus, and S. lentus. The results showed that PDT was effective in reducing the number of viable cells of all clinical Staphylococcus isolates studied.


Withdrawal of cardiac medications and devices.
Withdrawal of life-sustaining therapies such as cardiac medications, pacemakers, internal cardioverter defibrillators, and ventricular assist devices occurs in patients with advanced cardiac disease as goals of treatment transition from active to less aggressive. This article defines life-sustaining therapies and describes ethical and legal considerations related to withdrawal of cardiac medications and cardiac devices. Healthcare providers need to anticipate clinical situations in which implantable cardiac devices and medications are no longer desired by patients and/or are no longer medically appropriate. Discussions are important between patients, families, and healthcare providers that focus on each patient's condition, prognosis, advance directives, goals of care, and treatment options. Critical care nurses support each patient and his or her family and work with other members of the healthcare team to achieve a peaceful death.


Wnt signaling enhances macrophage responses to IL-4 and promotes resolution of atherosclerosis.
Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.


Injuries in Austrian football players: Are they an issue?
With its load characteristics, the team sport of football places high physical demands on players and thus is associated with a high risk of injury. Therefore, the purpose of this study was to collect information about injuries suffered by football players in Austria during training or matches to enable participating clubs to learn about injuries. One hundred and forty-five players from seven teams with age ranging from 16 to 38 years participated in this prospective study during the 2015/16 season. Injury surveillance was conducted according to the consensus statement of Fuller et al. (2006). During the period of study, a total of 83 injuries were recorded, which represents an overall incidence of 4.5 injuries/1000 hours (2.3 injuries/1000 hours in training and 14.2 injuries/1000 hours of match play). There was a significant difference for older age in injured players compared to non-injured players (p = 0.019). No differences in BMI were detected (p = 0.427). Ninety-four percent of all injuries occurred in the lower extremity, with the thigh (25.8 %), ankle (19.3 %) and knee (13.3 %) being the major locations of injuries. Muscle tendon injuries were the most common non-contact injuries (78.9 %). Lower extremity injuries are the most common injury in Austrian football. The incidence of muscle injuries is high, especially injuries of the posterior thigh. There are promising preventive strategies for the most common injury types. The implementation of these strategies is essential in order to reduce the incidence or recurrence of these football injuries.


[Assessment of a version adapted and translated into Spanish of the Quality of Life Bipolar Disorder Questionnaire].
The Quality of life Bipolar Disorder (QoL.BD) Questionnaire specifically measures quality of life in patients with bipolar disorder. To adapt a version translated into Spanish of the questionnaire and assess its validity in Chilean patients. The QoL. BD was adapted to the Chilean population through the back-translation method and then administered to 32 adult patients with a bipolar disorder and 31 subjects without the disease, both groups with similar socioeconomic status. To confirm the diagnosis, the International Neuropsychiatric Interview (MINI), Young (YMRS) and Hamilton (HAM-D) scales were applied. Quality of life was assessed using the SF-36v.2 survey. We determined internal consistency, reliability, convergent validity, the cut-off point, and the sensibility and specificity of the scale. The Chilean version of the Questionnaire [QoL. BD-CL] had a high reliability (α = 0.95) and a high validity in reference to external criteria (correlation coefficients with SF-36 ranging from 0.453 and 0.819; p < 0.01). A cut-off point of 170, with sensitivity of 87.9% and specificity of 80% was determined. QoL.BD-CL has adequate psychometric properties, as well as an adequate sensitivity and specificity to distinguish between negative and positive perceptions of life quality in Chilean patients with bipolar disorders.


Higher levels of salivary alpha-amylase predict failure of cessation efforts in male smokers.
The ability to predict the success or failure of smoking cessation efforts will be useful for clinical practice. Stress response is regulated by two primary neuroendocrine systems. Salivary cortisol has been used as a marker for the hypothalamus-pituitary-adrenocortical axis and salivary alpha-amylase as a marker for the sympathetic adrenomedullary system. We studied 62 chronic smokers (34 women and 28 men with an average age of 45.2+/-12.9 years). The levels of salivary cortisol and salivary alpha-amylase were measured during the period of active smoking, and 6 weeks and 24 weeks after quitting. We analyzed the men separately from the women. The men who were unsuccessful in cessation showed significantly higher levels of salivary alpha-amylase over the entire course of the cessation attempt. Before stopping smoking, salivary cortisol levels were higher among the men who were unsuccessful in smoking cessation. After quitting, there were no differences between this group and the men who were successful in cessation. In women we found no differences between groups of successful and unsuccessful ex-smokers during cessation. In conclusions, increased levels of salivary alpha-amylase before and during smoking cessation may predict failure to quit in men. On the other hand, no advantage was found in predicting the failure to quit in women. The results of our study support previously described gender differences in smoking cessation.


Food supply modifies the trade-off between past and future reproduction in a sexual parasite-host system (Rana esculenta, Rana lessonae).
Life history theory is concerned with the costs of survival, growth and reproduction under different ecological conditions and the allocation of resources to meet these costs. Typical approaches used to address these topics include manipulation of food resources, followed by measures of subsequent reproductive traits, and measures of the relationship between current and future reproductive investment. Rarely, however, do studies test for the interaction of past investment, present resource availability and future investment simultaneously. Here, we investigate this interaction in females of a sexual parasite-host system consisting of the hybridogenetic frog Rana esculenta (E) and one of its parental species Rana lessonae (L). We kept females from each of two groups (with or without previous reproduction) under two food treatments (low or high) and regularly recorded their growth as well as their body condition and hormone titres as measures of future reproductive condition. After keeping them in hibernation until the following spring, we exposed the females to males, recorded whether they spawned or not and related this response to their condition in the previous autumn. Past reproduction negatively affected growth during summer and condition during autumn which, in turn, reduced the following year's reproductive output. These costs of previous reproduction were less pronounced under the high than under the low food treatment and lower in R. lessonae than in R. esculenta. Increasing food supply improved reproductive condition more in L than in E females. These species differences in reproductive costs and food requirements provide a mechanistic explanation for why E females skip annual reproduction almost twice as often as L females. Since R. esculenta is a sexual parasite that depends on R. lessonae for successful reproduction, these species-specific life history patterns not only affect individual fitness but also the spatial structure and temporal dynamics of mixed LE populations.


Correlation of the HER-2 protein expression and other clinicopathological features of ductal infiltrative breast cancer.
The aim of the study was to investigate the relationship between the expression of the HER-2 membrane protein and other clinical-pathological parameters such as: histological size of the tumor, degree of the tumor's differentiation, presence of vascular invasion and presence of metastases in regional lymph nodes, in cases of ductal infiltrative breast cancer. We have investigated 56 cases of ductal infiltrative breast cancer. In all patients a mastectomy with a dissection of axillary lymph nodes has been performed. All tissue samples, taken by biopsy, were embedded in the paraffin, stained by hematoxylin-eosin technique and screened, and evaluation was performed by using a semiquantitative method of the immunohistochemical expression of the HER-2 protein. A decrease of the protein HER-2 expression was noticed in cases of an increase of the tumor's diameter above 50 mm. Increased expression of the HER-2 protein was noticed in cases of moderate (grade II) and poor (grade III) differentiation of carcinoma, as well as in cases where there was no metastases in the regional lymph nodes. No relationship has been observed between the expression of HER-2 and occurrence of vascular invasion. In cases of ductal infiltrative breast cancer the expression of HER-2 protein is in correlation with the size and degree of tumor's differentiation, as well as with the presence of metastases in regional lymph nodes.


Testicular distribution and toxicity of a novel LTA4H inhibitor in rats.
JNJ 40929837, a novel leukotriene A4 hydrolase inhibitor in drug development, was reported to induce testicular toxicity in rats. The mechanism of toxicity was considered to be rodent specific and not relevant to humans. To further investigate this finding in rats, the distribution and toxicokinetics of JNJ 40929837 and its two metabolites, M1 and M2, were investigated. A quantitative whole body autoradiography study showed preferential distribution and retention of JNJ 40929837-derived radioactivity in the testes consistent with the observed site of toxicity. Subsequent studies with unlabeled JNJ 40929837 showed different metabolite profiles between the plasma and testes. Following a single oral 50mg/kg dose of JNJ 40929837, M2 was the primary metabolite in plasma whereas M1 was the primary metabolite in testes. The exposure of M1 was 386-fold higher in the testes compared to plasma whereas M2 had limited exposure in testes. Furthermore, the Tmax of M1 was 48h in testes suggesting a large accumulation potential of this metabolite in testes compared to plasma. Following six months of repeated daily oral dosing, M1 accumulated approximately five-fold in the testes whereas the parent did not accumulate. These results indicate that the toxicokinetic profiles of JNJ 40929837 and its two metabolites in testes are markedly different compared to plasma and support the importance of understanding the toxicokinetic profiles of compounds and their metabolites in organs/tissues where toxicity is observed.


Replication of adeno-associated virus in synchronized cells without the addition of a helper virus.
We investigated the helper-independent replication of adeno-associated virus (AAV) in cells synchronized by pretreatment with hydroxyurea, reversal of polyamine depletion, or physical mitotic detachment. In Chinese hamster cells (OD4 line) treated with hydroxyurea prior to infection. AAV underwent a complete cycle of replication. Transfection of such cells with plasmid-cloned AAV DNAs also gave rise to infectious viral progeny. Synchronization of OD4 cells by reversal of polyamine depletion or mitotic detachment led to independent AAV DNA synthesis (and infectious viral progeny in the case of the former procedure), but these procedures were not as effective as hydroxyurea pretreatment. Independent AAV DNA synthesis was also detected in some other cell lines of Chinese hamster, human, and monkey origin treated with hydroxyurea prior to infection. The results demonstrate that, in contrast to previous notions, the AAV infectious process is not absolutely dependent upon the addition of a coinfecting helper virus.


[Carcinogenesis-modifying properties of aniline, carbon tetrachloride, benzene and ethanol].
Aniline and ethanol properties modifying carcinogenesis were revealed in chronic 12-month experiment with 500 females of hybrid CBAXC57Bl/6 mice. The drugs were administered with water in combination with nitrosodiethylamine. The absence of a modifying effect in groups with carbon tetrachloride and benzene is attributed to the fact that concentrations of these chemicals used in the experiment were similar to those in the environment.


Human papillomavirus vaccines in plants.
Human papillomaviruses are the etiological agents of cervical cancer, one of the two most prevalent cancers in women in developing countries. Currently available prophylactic vaccines are based on the L1 major capsid protein, which forms virus-like particles when expressed in yeast and insect cell lines. Despite their recognized efficacy, there are significant shortcomings: the vaccines are expensive, include only two oncogenic virus types, are delivered via intramuscular injection and require a cold chain. Plant expression systems may provide ways of overcoming some of these problems, in particular the expense. In this article, we report recent promising advances in the production of prophylactic and therapeutic vaccines against human papillomavirus by expression of the relevant antigens in plants, and discuss future prospects for the use of such vaccines.


Ionic conductances underlying the activity of interneurons that control heartbeat in the medicinal leech.
Electrical properties of interneurons that control heartbeat in the leech (HN cells) were studied using intracellular recording and stimulation in isolated ganglia bathed by salines of various ionic compositions. Substitution of Na+ ions in the bath by Tris stopped the spontaneous firing of HN cells and led to their gradual hyperpolarization by 15-20 mV. In the absence of Na+, HN neurons produced long-lasting regenerative plateau potentials with thresholds near -55 mV and peaks near -30 mV that were accompanied by an increase in membrane conductance. Elevation of Ca2+ concentration enhanced plateaus, as did replacement of Ca2+ by Ba2+. Plateaus were formed when Sr2+ replaced Ca2+, but were blocked by addition of Mg2+ or Co2+ to the bath, Co2+ being effective at lower concentrations than Mg2+. Hyperpolarization of HN neurons with injected currents revealed a time-dependent change in membrane potential, whereby initial maximum hyperpolarization was followed by a "sag" in potential towards more depolarized values. The sag showed dual voltage dependence, being diminished when HN neurons were hyperpolarized or depolarized outside the normal range of oscillation. The sag was found to depend on the presence of Na+ ions and to be blocked by Cs+ but not by Ba2+. This time-dependent change in membrane potential counters hyperpolarizations of HN neuron membrane potential and may contribute to the escape of these neurons from synaptic inhibition.


Search for Gamma-ray Emission from p-wave Dark Matter Annihilation in the Galactic Center.
Indirect searches for dark matter through Standard Model products of its annihilation generally assume a cross-section which is dominated by a term independent of velocity (s-wave annihilation). However, in many DM models an s-wave annihilation cross-section is absent or helicity suppressed. To reproduce the correct DM relic density in these models, the leading term in the cross section is proportional to the DM velocity squared (p-wave annihilation). Indirect detection of such p-wave DM is difficult because the average velocities of DM in galaxies today are orders of magnitude slower than the DM velocity at the time of decoupling from the primordial thermal plasma, thus suppressing the annihilation cross-section today by some five orders of magnitude relative to its value at freeze out. Thus p-wave DM is out of reach of traditional searches for DM annihilations in the Galactic halo. Near the region of influence of a central supermassive black hole, such as Sgr A*, however, DM can form a localized over-density known as a "spike". In such spikes the DM is predicted to be both concentrated in space and accelerated to higher velocities, thereby allowing the γ-ray signature from its annihilation to potentially be detectable above the background. We use the Fermi Large Area Telescope to search for the γ-ray signature of p-wave annihilating DM from a spike around Sgr A* in the energy range 10 GeV-600 GeV. Such a signal would appear as a point source and would have a sharp line or box-like spectral features difficult to mimic with standard astrophysical processes, indicating a DM origin. We find no significant excess of γ rays in this range, and we place upper limits on the flux in γ-ray boxes originating from the Galactic Center. This result, the first of its kind, is interpreted in the context of different models of the DM density near Sgr A*.


Burden of moderate visual impairment in an urban population in southern India.
To assess the prevalence and causes of moderate visual impairment in an urban population in southern India. Population-based, cross-sectional study. A total of 2522 (85.4% of the eligible) persons of all ages, including 1399 persons 30 years of age or older, from 24 clusters representative of the population of Hyderabad city. The eligible subjects underwent a detailed ocular evaluation, including logarithm of the minimum angle of resolution (logMAR) visual acuity, refraction, slit-lamp biomicroscopy, applanation tonometry, gonioscopy, cataract grading, and stereoscopic dilated fundus evaluation. Automated threshold visual fields and slit-lamp and fundus photography were done when indicated by standardized criteria. Moderate visual impairment was defined as presenting distance visual acuity less than 20/40 to 20/200 or visual field loss by predefined standardized conservative criteria in the better eye. In addition to the 1% prevalence of blindness in this sample reported earlier, moderate visual impairment was present in 303 subjects, an age-gender-adjusted prevalence of 7.2% (95% confidence interval [CI], 4.5%-9.9%; design effect, 2.7). The major cause of moderate visual impairment was refractive error (59.4%, 95% CI, 52.3%-66.5%) followed by cataract (25.3%, 95% CI, 19%-31.6%). Multivariate analysis showed that the prevalence of moderate visual impairment was significantly higher in those 40 years of age or older (odds ratio, 10.9; 95% CI, 8-15) and females (odds ratio, 1.89; 95% CI, 1.41-2.53) and lower in those belonging to the highest socioeconomic status (odds ratio, 0.27; 95% CI, 0.14-0.51). However, because of the pyramidal age distribution of the population, 38.1% of the total moderate visual impairment was present in those younger than 40 years of age. The proportion of moderate visual impairment caused by refractive error was higher in the younger than in the older age groups (P < 0.0001). Projecting the results to the 26.5% urban population of India, there would be 18.4 million (95% CI, 11.5-25.2 million) persons with moderate visual impairment in urban India alone. Refractive error was the major cause of moderate visual impairment in the population studied. The absolute proportion of moderate visual impairment in those younger than 40 years of age was considerable. The eyecare policy of India, apart from dealing with blindness, should address the issue of the relatively easily treatable uncorrected refractive error as the cause of moderate visual impairment in an estimated 10.9 million persons in urban India.