Variability in Reproduction of Four Populations of Meloidogyne incognita on Six Cultivars of Cotton.
A range of virulence levels was found in four populations of Meloidogyne incognita collected from cotton fields of the Punjab region of Pakistan. The most virulent population was associated with development of larger gall size, larger giant cell formation and improved success of juveniles transitioning into reproducing adults. The most virulent nematode population, MI-78, emanated from cotton cultivar NIAB-78. This cotton cultivar also possessed the greatest level of resistance to the three other nematode populations evaluated in this study. The source of plant resistance was not evident during root penetration by second-stage juveniles (J2), but became apparent as nematode feeding was attempted. Although one other cotton cultivar, CIM-506, could also be designated as showing a level of resistance, none of the other cultivars reduced any nematode stage by more than 75% of that achieved on the best host. These data provide an example of a single cotton cultivar that could have short-term utility in field settings. The data also provide insight for future cotton breeding programs.


Descemet's membrane endothelial keratoplasty (DMEK): first UK prospective study of 1-year visual outcomes, graft survival and endothelial cell count.
To evaluate the clinical outcomes of Descemet's membrane endothelial keratoplasty (DMEK) in the treatment of patients with Fuchs' endothelial dystrophy. This prospective study involved 16 consecutive patients who had DMEK done and who were evaluated over a year. Measurements included best corrected visual acuity (BCVA), endothelial cell count, and central corneal thickness. Two patients had failed grafts. Of the remaining 14 patients with successful grafts, after 12 months, 79% had BCVA of 6/6 or better, and all patients had a BCVA of 6/9 or better. Median endothelial cell count was 1567 cells per mm(2) (range=900-2359) representing a 40% reduction compared with preoperative counts. Median central corneal thickness was 498 µm (range 445-567 µm) compared with a median of 649 µm (range 548-740 µm) preoperatively. All patients attained total visual rehabilitation without further surgical intervention. In our experience, DMEK has the potential to become the primary procedure for treating Fuchs' endothelial dystrophy and endothelial disease as it produces rapid total visual rehabilitation with few complications, and an easy follow-up and management regimen. Donor preparation and graft insertion, however, remain important challenges.


Feminization and marginalization? Women Ayurvedic doctors and modernizing health care in Nepal.
The important diversity of indigenous medical systems around the world suggests that gender issues, well understood for Western science, may differ in significant ways for non-Western science practices and are an important component in understanding how social dimensions of women's health care are being transformed by global biomedicine. Based on ethnographic research conducted with formally trained women Ayurvedic doctors in Nepal, I identify important features of medical knowledge and practice beneficial to women patients, and I discuss these features as potentially transformed by modernizing health care development. The article explores the indirect link between Ayurveda's feminization and its marginalization, in relation to modern biomedicine, which may evolve to become more direct and consequential for women's health in the country.


Soil bacterial diversity is positively associated with air temperature in the maritime Antarctic.
Terrestrial ecosystems in the maritime Antarctic experienced rapid warming during the latter half of the 20th century. While warming ceased at the turn of the millennium, significant increases in air temperature are expected later this century, with predicted positive effects on soil fungal diversity, plant growth and ecosystem productivity. Here, by sequencing 16S ribosomal RNA genes in 40 soils sampled from along a 1,650 km climatic gradient through the maritime Antarctic, we determine whether rising air temperatures might similarly influence the diversity of soil bacteria. Of 22 environmental factors, mean annual surface air temperature was the strongest and most consistent predictor of soil bacterial diversity. Significant, but weaker, associations between bacterial diversity and soil moisture content, C:N ratio, and Ca, Mg, PO43- and dissolved organic C concentrations were also detected. These findings indicate that further rises in air temperature in the maritime Antarctic may enhance terrestrial ecosystem productivity through positive effects on soil bacterial diversity.


Assessing crucial stress on life cycle of fish in suburban streams.
To assess crucial stresses to fish survival in suburban streams, a Life Cycle Risk Assessment (LCRA) was developed and verified by comparing with field survey results. In LCRA, 8 stresses produced by human activities were taken into consideration, referring to the literature. Field survey was conducted over 2 years to identify the present existence and distributions of fishes in 3 streams, which have different pollution levels and morphologies. Field survey results demonstrated that species of fishes and their populations were different in 3 streams and varied with location. Crucial stresses frequently identified by the LCRA were depletion of dissolved oxygen (DO), disappearances of habitats (e.g. deep and shallow), disappearance of spawning area, and existence of obstructions in the streams. Furthermore, most LCRA results regarding existence or non-existence of 15 fishes at 7 different sites were fairly in good agreement with field survey results. From these results, we concluded the present LCRA would be a useful tool in assessing crucial stress as well as in predicting fish species that are able to survive in streams.


Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis.
Irritable bowel syndrome (IBS) is a chronic functional disorder. 5-Hydroxytryptamine (5-HT) is a key modulator of gastrointestinal sensorimotor function. Many patients have IBS that can be difficult to treat, which has led to the development of newer agents, such as 5-HT(3) antagonists and 5-HT(4) agonists. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to estimate the efficacy of all available 5-HT agents in IBS. MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to June 2008). Trials recruiting adults with IBS in primary, secondary, or tertiary care comparing 5-HT(3) antagonists or 5-HT(4) agonists with placebo were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference. The strategic search identified 1,593 citations. A total of 29 RCTs were eligible for inclusion; placebo was compared with 5-HT(3) antagonists in 11 RCTs, with tegaserod in 11, and with mixed 5-HT(3) antagonists/5-HT(4) agonists in 7. The study quality was generally high. The RR of IBS symptoms persisting with 5-HT(3) antagonists vs. placebo was 0.78 (95% CI: 0.71-0.86), with a similar benefit for both alosetron and cilansetron. Tegaserod was also superior to placebo (RR=0.85; 95% CI: 0.80-0.90). Renzapride and cisapride had no benefit in IBS. Alosetron, cilansetron, and tegaserod are all effective in the treatment of IBS. Serious adverse events were rare in the eligible RCTs included in this systematic review.


DDGni: dynamic delay gene-network inference from high-temporal data using gapped local alignment.
Inferring gene-regulatory networks is very crucial in decoding various complex mechanisms in biological systems. Synthesis of a fully functional transcriptional factor/protein from DNA involves series of reactions, leading to a delay in gene regulation. The complexity increases with the dynamic delay induced by other small molecules involved in gene regulation, and noisy cellular environment. The dynamic delay in gene regulation is quite evident in high-temporal live cell lineage-imaging data. Although a number of gene-network-inference methods are proposed, most of them ignore the associated dynamic time delay. Here, we propose DDGni (dynamic delay gene-network inference), a novel gene-network-inference algorithm based on the gapped local alignment of gene-expression profiles. The local alignment can detect short-term gene regulations, that are usually overlooked by traditional correlation and mutual Information based methods. DDGni uses 'gaps' to handle the dynamic delay and non-uniform sampling frequency in high-temporal data, like live cell imaging data. Our algorithm is evaluated on synthetic and yeast cell cycle data, and Caenorhabditis elegans live cell imaging data against other prominent methods. The area under the curve of our method is significantly higher when compared to other methods on all three datasets. The program, datasets and supplementary files are available at http://www.jjwanglab.org/DDGni/.


The reflexive self and culture: a critique.
This article attempts to engage with a tendency in the theorization of social change and self-identity, evident in the work of a number of contemporary social theorists, to place an extended process of reflexivity at the heart of modern identity. As symptomatic of 'neo-modern' accounts of selfhood, critical readings of Giddens, Beck, Castells and some aspects of social theory more generally, and their account of modern reflexivity's relationship to culture, are assessed. In light of these criticisms, ways in which culture might still play an important part in the shaping of identity are considered. The relationship between language, culture and reflexivity, drawing from philosophy, sociology and G. H. Mead's own brand of social psychology, are all utilized in establishing a critique of the role Giddens and others designate for culture in the constitution of the contemporary self. By potentially repositioning self-identity in its connection to culture, the overall bearing of reflexivity upon the processes of self-identity is thus questioned. It is argued that a culturally-situated, yet fluid and multifarious account of self-identity is a necessary analytical and normative alternative.


Experimental demonstration of phase correction with a 32 x 32 microelectromechanical systems mirror and a spatially filtered wavefront sensor.
A 32 x 32 microelectromechanical systems deformable mirror is controlled in closed loop with a spatially filtered Shack-Hartmann wavefront sensor and a Fourier-transform wavefront reconstruction algorithm. A phase plate based on atmospheric turbulence statistics is used to generate a 1 microm peak-valley static phase aberration. Far-field images and direct phase measurements of the residual are used to compare performance with and without the spatial filter. Use of the spatial filter reduces error in the controllable band from 20 to 6 nm rms. Residual phase power is reduced by more than a factor of 5 for all spatial frequencies up to 0.85 x 1/2d, with a maximum attenuation factor of 37.


Comparison of transport and attachment behaviors of Cryptosporidium parvum oocysts and oocyst-sized microspheres being advected through three minerologically different granular porous media.
In order to gain more information about the fate of Cryptosporidium parvum oocysts in tropical volcanic soils, the transport and attachment behaviors of oocysts and oocyst-sized polystyrene microspheres were studied in the presence of two soils. These soils were chosen because of their differing chemical and physical properties, i.e., an organic-rich (43-46% by mass) volcanic ash-derived soil from the island of Hawaii, and a red, iron (22-29% by mass), aluminum (29-45% by mass), and clay-rich (68-76% by mass) volcanic soil from the island of Oahu. A third agricultural soil, an organic- (13% by mass) and quartz-rich (40% by mass) soil from Illinois, was included for reference. In 10-cm long flow-through columns, oocysts and microspheres advecting through the red volcanic soil were almost completely (98% and 99%) immobilized. The modest breakthrough resulted from preferential flow-path structure inadvertently created by soil-particle aggregation during the re-wetting process. Although a high (99%) removal of oocysts and microsphere within the volcanic ash soil occurred initially, further examination revealed that transport was merely retarded because of highly reversible interactions with grain surfaces. Judging from the slope of the substantive and protracted tail of the breakthrough curve for the 1.8-μm microspheres, almost all (>99%) predictably would be recovered within ∼4000 pore volumes. This suggests that once contaminated, the volcanic ash soil could serve as a reservoir for subsequent contamination of groundwater, at least for pathogens of similar size or smaller. Because of the highly reversible nature of organic colloid immobilization in this soil type, C. parvum could contaminate surface water should overland flow during heavy precipitation events pick up near-surface grains to which they are attached. Surprisingly, oocyst and microsphere attachment to the reference soil from Illinois appeared to be at least as sensitive to changes in pH as was observed for the red, metal-oxide rich soil from Oahu. In contrast, colloidal attachment in the organic-rich, volcanic ash soil was relatively insensitive to changes in pH in spite of the high iron content. Given the fundamental differences in transport behavior of oocyst-sized colloids within the two volcanic soils of similar origin, agricultural practices modified to lessen C. parvum contamination of ground or surface water would necessitate taking the individual soil properties into account.


Design, Multigram Synthesis, and in Vitro and in Vivo Evaluation of Propylamycin: A Semisynthetic 4,5-Deoxystreptamine Class Aminoglycoside for the Treatment of Drug-Resistant Enterobacteriaceae and Other Gram-Negative Pathogens.
Infectious diseases due to multidrug-resistant pathogens, particularly carbapenem-resistant Enterobacteriaceae (CREs), present a major and growing threat to human health and society, providing an urgent need for the development of improved potent antibiotics for their treatment. We describe the design and development of a new class of aminoglycoside antibiotics culminating in the discovery of propylamycin. Propylamycin is a 4'-deoxy-4'-alkyl paromomycin whose alkyl substituent conveys excellent activity against a broad spectrum of ESKAPE pathogens and other Gram-negative infections, including CREs, in the presence of numerous common resistance determinants, be they aminoglycoside modifying enzymes or rRNA methyl transferases. Importantly, propylamycin is demonstrated not to be susceptible to the action of the ArmA resistance determinant whose presence severely compromises the action of plazomicin and all other 4,6-disubstituted 2-deoxystreptamine aminoglycosides. The lack of susceptibility to ArmA, which is frequently encoded on the same plasmid as carbapenemase genes, ensures that propylamycin will not suffer from problems of cross-resistance when used in combination with carbapenems. Cell-free translation assays, quantitative ribosome footprinting, and X-ray crystallography support a model in which propylamycin functions by interference with bacterial protein synthesis. Cell-free translation assays with humanized bacterial ribosomes were used to optimize the selectivity of propylamycin, resulting in reduced ototoxicity in guinea pigs. In mouse thigh and septicemia models of Escherichia coli, propylamycin shows excellent efficacy, which is better than paromomycin. Overall, a simple novel deoxy alkyl modification of a readily available aminoglycoside antibiotic increases the inherent antibacterial activity, effectively combats multiple mechanisms of aminoglycoside resistance, and minimizes one of the major side effects of aminoglycoside therapy.


The Comparative Advantage of Medicare Advantage.
We ascertain the degree of service-level selection in Medicare Advantage (MA) using individual level data on the 100 most frequent HCC's or combination of HCC's from two national insurers in 2012-2013. We find differences in the distribution of beneficiaries across HCC's between TM and MA, principally in the smaller share of MA enrollees with no coded HCC, consistent with greater coding intensity in MA. Among those with an HCC code, absolute differences between MA and TM shares of beneficiaries are small, consistent with little service-level selection. Variation in HCC margins does not predict differences between an HCC's share of MA and TM enrollees, although one cannot a priori sign a relationship between margin and service-level selection. Margins are negatively associated with the importance of post-acute care in the HCC. Margins among common chronic disease classes amenable to medical management and typically managed by primary care physicians are larger than among diseases typically managed by specialists. These margin differences by disease are robust against a test for coding effects and suggest that the average technical efficiency of MA relative to TM may vary by diagnosis. If so, service-level selection on the basis of relative technical efficiency could be welfare enhancing.


Determinants of human apolipoprotein [a] secretion from mouse hepatocyte cultures.
Efforts to develop an in vitro model system to analyze apolipoprotein [a] (apo[a]) gene transcription, mRNA translation, and protein secretion have been complicated by the limited tissue and species distribution of apo[a] and the presence of regulatory DNA sequences remote from the apo[a] transcription start site. In the current study we examined primary hepatocytes cultured from apo[a] transgenic mice as a model system for analyzing apo[a] biogenesis. Hepatocytes from mice transgenic for a yeast artificial chromosome (YAC) encoding the entire apo[a] gene in its own genomic context (YAC-apo[a] hepatocytes) were unable to maintain apo[a] expression beyond 48 h of culture. This suggests that the apo[a] promoter was not active in cultured YAC-apo[a] hepatocytes. In contrast, apo[a] expression was maintained for at least 7 days in hepatocytes cultured from mice transgenic for an apo[a] cDNA under control of the mouse transferrin promoter (transferrin-apo[a] hepatocytes). Pulse-chase experiments established that more than 80% of apo[a] synthesized by both transferrin-apo[a] and YAC-apo[a] hepatocytes was degraded prior to secretion, independently of the coexpression of human apoB.Thus, low secretion efficiency appears to be a general characteristic of human apo[a] proteins in mouse liver. Apo[a] secretion was increased somewhat (from 18% to 32%) in the presence of lipoprotein-containing serum. Transformed cell lines derived from transferrin apo[a] hepatocytes retained characteristics of apo[a] secretion similar to those observed in primary cells. Primary and transformed apo[a] transgenic hepatocytes may provide valuable additional models with which to study posttranslational mechanisms regulating apo[a] secretion. - Wang, J., J. Boedeker, H. H. Hobbs, and A. L. White. Determinants of human apolipoprotein [a] secretion from mouse hepatocyte cultures. J. Lipid Res. 2001. 42: 60;-69.


A novel approach to evaluate the effect of medicaments used in endodontic regeneration on root canal surface indentation.
The aim of this study was to investigate the capability of a novel reference point indentation apparatus to test the indentation properties of root canal surface dentine treated with three intracanal medicaments used in endodontic regeneration. Immature human premolars were selected (n = 22). Four specimens were obtained from each root and randomly assigned to three treatment groups and a control group. Each specimen was exposed to one of the three treatment pastes (triple antibiotic (TAP), double antibiotic (DAP), or calcium hydroxide (Ca(OH)2)) or neutral deionized water (control) for 1 or 4 weeks. After each time interval, the indentation properties of the root canal dentine surfaces were measured using a BioDent reference point indenter. Two-way ANOVA and Fisher's protected least significant differences were used for statistical analyses. Significant differences in indentation parameters and estimated hardness between all groups at both time points were found. TAP-treated dentine had the highest significant indentation parameters, followed by DAP-treated dentine, untreated control dentine, and Ca(OH)2-treated dentine, respectively. Furthermore, TAP-treated dentine had the lowest significant estimated hardness, followed by DAP-treated dentine, untreated control dentine, and Ca(OH)2-treated dentine, respectively. BioDent reference point indenter was able to detect significant differences in indentation properties of root canal dentine treated with various medicaments. The use of a reference point indenter is a promising approach to characterize the indentation properties of root canal surfaces without any surface modification. This might provide an in vitro mechanical measurement that is more representative of the actual clinical situation.


Cool-temperature-induced chlorosis in rice plants.
We have established an experimental system for mimicking the phenomenon of cool-temperature-induced chlorosis (CTIC) in rice plants (Oryza sativa L.). Rice seedlings were initially grown in darkness under cool-temperature conditions and then exposed to light and warm conditions to follow the expression of CTIC. Induction of CTIC in the sensitive cultivar (cv Surjamukhi) was bimodally dependent on the temperatures experienced during the initial growth in darkness. CTIC was maximally induced between 15 and 17 degrees C. A positive correlation was demonstrated between induction of CTIC and the growth activity of shoots during growth in darkness. Electrophoretic and immunoblot analysis revealed that accumulation of NADPH-protochlorophyllide oxidoreductase in plastids was also bimodally dependent on the temperatures during the growth in darkness with minimum accumulation between 15 and 17 degrees C, suggesting that the reduction of NADPH-protochlorophyllide oxidoreductase accumulation in plastids might be closely linked to a disturbance in transformations of plastids to etioplasts during the dark growth under the critical temperatures and thereby to the CTIC phenomenon. This was corroborated by electron microscopic observations. These results suggest that growth is one of the determining factors for the expression of CTIC phenotype in rice under cool temperature.


Vyacheslav (Slava) Klimov (1945-2017): A scientist par excellence, a great human being, a friend, and a Renaissance man.
Vyacheslav Vasilevich (V.V.) Klimov (or Slava, as most of us called him) was born on January 12, 1945 and passed away on May 9, 2017. He began his scientific career at the Bach Institute of Biochemistry of the USSR Academy of Sciences (Akademy Nauk (AN) SSSR), Moscow, Russia, and then, he was associated with the Institute of Photosynthesis, Pushchino, Moscow Region, for about 50 years. He worked in the field of biochemistry and biophysics of photosynthesis. He is known for his studies on the molecular organization of photosystem II (PSII). He was an eminent scientist in the field of photobiology, a well-respected professor, and, above all, an outstanding researcher. Further, he was one of the founding members of the Institute of Photosynthesis in Pushchino, Russia. To most, Slava Klimov was a great human being. He was one of the pioneers of research on the understanding of the mechanism of light energy conversion and of water oxidation in photosynthesis. Slava had many collaborations all over the world, and he is (and will be) very much missed by the scientific community and friends in Russia as well as around the World. We present here a brief biography and some comments on his research in photosynthesis. We remember him as a friendly and enthusiastic person who had an unflagging curiosity and energy to conduct outstanding research in many aspects of photosynthesis, especially that related to PSII.


Do patients and carers agree on symptom burden in advanced COPD?
Accurate informal carer assessment of patient symptoms is likely to be valuable for decision making in managing the high symptom burden of COPD in the home setting. Few studies have investigated agreement between patients and carers in COPD. We aimed to assess agreement between patients and carers on symptoms, and factors associated with disagreement in a population-based sample of patients with advanced COPD. This was a prospective, cross-sectional analysis of data from 119 advanced COPD patients and their carers. Patients and carers separately rated symptoms on a 4-point scale. Wilcoxon signed-rank tests and weighted Cohen's kappa determined differences in patient and carer scores and patient-carer agreement, respectively. We identified characteristics associated with incongruence using Spearman's rank correlation and Mann-Whitney U tests. There were no significant differences between group-level patient and carer scores for any symptom. Patient-carer individual-level agreement was moderate for constipation (k=0.423), just below moderate for diarrhea (k=0.393) and fair for depression (k=0.341), fatigue (k=0.294), anxiety (k=0.289) and breathlessness (k=0.210). Estimation of greater patient symptom burden by carers relative to patients themselves was associated with non-spousal patient-carer relationship, non-cohabitating patients and carers, carer symptoms of anxiety and depression and more carer unmet support needs. Greater symptom burden estimation by the patient relative to the carer was associated with younger patients and longer duration of COPD. Overall, agreement between patients and carers was fair to moderate and was poorer for more subjective symptoms. There is a need to encourage open dialogue between patients and carers to promote shared understanding, help patients express themselves and encourage carers to draw attention to symptoms that patients do not report. The findings suggest a need to screen for and address both the psychological morbidities in patients with advanced COPD and their carers and unmet support needs in carers.


Efficient Transgenesis in Caenorhabditis elegans Using Flp Recombinase-Mediated Cassette Exchange.
The application of CRISPR technology has greatly facilitated the creation of transgenic Caenorhabditis elegans lines. However, methods to insert multi-kilobase DNA constructs remain laborious even with these advances. Here, I describe a new approach for introducing large DNA constructs into the C. elegans genome at specific sites using a combination of Flp and Cre recombinases. The system utilizes specialized integrated landing sites that express GFP ubiquitously flanked by single loxP, FRT, and FRT3 sites. DNA sequences of interest are inserted into an integration vector that contains a sqt-1 self-excising cassette and FRT and FRT3 sites. Plasmid DNA is injected into the germline of landing site animals. Transgenic animals are identified as Rol progeny, and the sqt-1 marker is subsequently excised with heat shock Cre expression. Integration events were obtained at a rate of approximately one integration per three injected F0 animals-a rate substantially higher than any current approach. To demonstrate the robustness of the approach, I compared the efficiency of the Gal4/UAS, QF (and QF2)/QUAS, tetR(and rtetR)/tetO, and LexA/lexO bipartite expression systems by assessing expression levels in combinations of driver and reporter GFP constructs and a direct promoter GFP fusion each integrated at multiple sites in the genome. My data demonstrate that all four bipartite systems are functional in C. elegans Although the new integration system has several limitations, it greatly reduces the effort required to create single-copy insertions at defined sites in the C. elegans genome.


Role of sarcoplasmic/endoplasmic-reticulum Ca2+-ATPases in mediating Ca2+ waves and local Ca2+-release microdomains in cultured glia.
We have characterized the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) pumps in cultured rat cortical type-1 astrocytes, type-2 astrocytes and oligodendrocytes. Perfusion with 10 microM cyclopiazonic acid (CPA) or 1 microM thapsigargin evoked a large and persistent elevation in cytosolic [Ca2+] in normal Ca2+-containing medium and a small and transient increase in nominally Ca2+-free medium. Subtraction of the response in Ca2+-free medium from that in the control revealed a slow-onset Ca2+-entry response to SERCA inhibition, which began after most of the store depletion had occurred. Thapsigargin- and CPA-induced responses propagated as Ca2+ waves, which began in several distinct cellular sites and travelled throughout the cell and through nearby cells, in confluent cultures. Propagation was supported by specialized Ca2+-release sites where the amplitude of the response was significantly higher and the rate of rise steeper. Such higher Ca2+-release kinetics were observed at these sites during Ins(1,4,5)P3-mediated Ca2+ waves in the same cells. Fluorescently tagged thapsigargin labelled SERCA pumps throughout glial cell bodies and processes. In oligodendrocyte processes, multiple domains with elevated SERCA staining were always associated with mitochondria. Our results are consistent with a model in which only a single Ca2+ store, expressing Ins(1,4,5)P3 receptors and SERCAs sensitive to both thapsigargin and CPA, is present in rat cortical glia, and indicate that inhibition of SERCA activates both Ca2+ release as a wavefront and Ca2+ entry via store-operated channels. The spatial relationship between SERCAs and mitochondria is likely to be important for regulating microdomains of elevated Ca2+-release kinetics.


Occupational exposure to anesthetic gases residue.
Although the absence of negative effects of prolonged exposure to anesthetic gases residue has been reported, controversies on the subject still linger. Contradictory data on the variability in individual response to different agents can be found in the literature. The objective of this report was to present a review of occupational exposure to anesthetic gases residue. The results of the main articles on the subject, as well as the causes of contamination of the surgical environment, ventilation, exhaust system, monitoring, and dosage of anesthetic gases residues are discussed. Recommendations to minimize the supposed effects of inhalational agents are emphasized. Even in task-forces studies of renowned international regulating institutions, there are some controversies on the risks of occupational exposure to anesthetic gases residue. Minimal values for occupational exposure are stipulated, but acknowledging the lack of epidemiological evidence of any type of damage caused by said exposure in places where standard measures of ventilation and exhaust systems and the use of anesthetic equipment are observed. In our country, most of the time those measures are not implemented and, when they are, they are not supervised properly. Besides, differences in techniques and working conditions have to be considered. Taking into consideration the multifactorial nature of the exposure of health care professionals, measures should be undertaken to minimize occupational exposure to agents with known or probable toxic potential. The demand for better equipped operating rooms, with adequate ventilation and exhaust systems as well as their maintenance should be stimulated.


A systematic review of the biomechanical research methods used in strongman studies.
As the sport of strongman is becoming increasingly popular, and such exercises are being commonly used by strength and conditioning coaches for a wide range of athletic groups, a greater understanding of the biomechanics of strongman exercises is warranted. To improve the quality of research, this systematic review summarised the research methodology used in biomechanical studies of strongman exercises and identified potential improvements to current approaches. A search of 5 databases found 10 articles adherent to the pre-defined inclusion criteria. The studies assessed 8 strongman exercises and included male participants of relatively similar body mass but varying training backgrounds. Due to the complexity of strongman exercises and the challenges in collecting advanced biomechanical data in the field, most studies used simplified measurement/analysis methods (e.g., 2D motion capture). Future strongman biomechanical studies should: assess under/un-researched strongman exercises; include a greater number of experienced and female strongman athletes; utilise more advanced (e.g., 3D motion capture and/or inertial sensor) technology so to provide a broader range and greater quality of data. Such approaches will provide strength and conditioning coaches, strongman coaches and athletes with a greater understanding of strongman exercises, thereby further improving exercise prescription, athlete performance and minimising risk of injury.


Crowdsourced Traffic Event Detection and Source Reputation Assessment Using Smart Contracts.
Real-time data about various traffic events and conditions-offences, accidents, dangerous driving, or dangerous road conditions-is crucial for safe and efficient transportation. Unlike roadside infrastructure data which are often limited in scope and quantity, crowdsensing approaches promise much broader and comprehensive coverage of traffic events. However, to ensure safe and efficient traffic operation, assessing trustworthiness of crowdsourced data is of crucial importance; this also includes detection of intentional or unintentional manipulation, deception, and spamming. In this paper, we design and demonstrate a road traffic event detection and source reputation assessment system for unreliable data sources. Special care is taken to adapt the system for operation in decentralized mode, using smart contracts on a Turing-complete blockchain platform, eliminating single authority over such systems and increasing resilience to institutional data manipulation. The proposed solution was evaluated using both a synthetic traffic event dataset and a dataset gathered from real users, using a traffic event reporting mobile application in a professional driving simulator used for driver training. The results show the proposed system can accurately detect a range of manipulative and misreporting behaviors, and quickly converges to the final trust score even in a resource-constrained environment of a blockchain platform virtual machine.


GeoSentinel surveillance of illness in returned travelers, 2007-2011.
International travel continues to increase, particularly to Asia and Africa. Clinicians are increasingly likely to be consulted for advice before travel or by ill returned travelers. To describe typical diseases in returned travelers according to region, travel reason, and patient demographic characteristics; describe the pattern of low-frequency travel-associated diseases; and refine key messages for care before and after travel. Descriptive, using GeoSentinel records. 53 tropical or travel disease units in 24 countries. 42 173 ill returned travelers seen between 2007 and 2011. Frequencies of demographic characteristics, regions visited, and illnesses reported. Asia (32.6%) and sub-Saharan Africa (26.7%) were the most common regions where illnesses were acquired. Three quarters of travel-related illness was due to gastrointestinal (34.0%), febrile (23.3%), and dermatologic (19.5%) diseases. Only 40.5% of all ill travelers reported pretravel medical visits. The relative frequency of many diseases varied with both travel destination and reason for travel, with travelers visiting friends and relatives in their country of origin having both a disproportionately high burden of serious febrile illness and very low rates of advice before travel (18.3%). Life-threatening diseases, such as Plasmodium falciparum malaria, melioidosis, and African trypanosomiasis, were reported. Sentinel surveillance data collected by specialist clinics do not reflect healthy returning travelers or those with mild or self-limited illness. Data cannot be used to infer quantitative risk for illness. Many illnesses may have been preventable with appropriate advice, chemoprophylaxis, or vaccination. Clinicians can use these 5-year GeoSentinel data to help tailor more efficient pretravel preparation strategies and evaluate possible differential diagnoses of ill returned travelers according to destination and reason for travel. Centers for Disease Control and Prevention.


New treatment options in COPD.
To review the role of long-acting bronchodilators in the treatment of chronic obstructive pulmonary disease (COPD), including the importance of treatment adherence. Overall, clinical trials show that compared with placebo and ipratropium, tiotropium significantly improves spirometric measures, increases quality-of-life scores, and is associated with fewer exacerbations. In addition, compared with salmeterol, tiotropium is associated with greater improvements in spirometric measures and clinically meaningful increases in quality-of-life measures. In comparison with either fluticasone or salmeterol alone, the fluticasone/salmeterol combination is associated with statistically greater improvement in spirometric and dyspnea measures; however, the combination is not associated with fewer exacerbations than either fluticasone or salmeterol used by itself. The 2003 update to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommends regular treatment with long-acting bronchodilators for maintenance COPD therapy because of superior effectiveness and convenience compared with short-acting bronchodilators. The results from trials presented in this article demonstrate that inhaled tiotropium is effective in treating COPD and might be considered as a first-line agent for maintenance therapy in view of its outcomes data. The convenience of once-daily administration would probably contribute to patient adherence and thus to the overall efficacy of this agent.


Histological Evaluation of Periodontal Ligament in Response to Orthodontic Mechanical Stress in Mice.
The purpose of the study was to determine the cell dynamics in periodontal ligament in response to mechanical stress during orthodontic movement. Following Waldo's method, a square sheet of rubber dam was inserted in between the first and second maxillary molars in 10 ddY mice leaving the stress load for 3 hours. After 3 days and at 1 week, cell count on pressure and tension sides of the periodontal ligament was determined. Furthermore, the type of cell present after mechanical stress was identified using GFP bone marrow transplantation mouse model. Immunohistochemistry was carried out at 0 min (immediately after mechanical stress), 24 hours, 1 week, 2 weeks and 6 months. Temporal changes in the expression of GFP-positive bone marrow derived cells were examined. Moreover, double immunofluorescent staining was performed to determine the type of cell in the periodontal ligament. Cell count on the tension side tremendously increased 3 days after mechanical stress. At 1 week, spindle and round cell count increased compared to the control group. These changes were observed on both tension and pressure sides. Cell count on pressure side at 3 days (22.11+/-13.98) and at 1 week (33.23+/-11.39) was higher compared to the control group (15.26+/-8.29). On the tension side, there was a significantly increased at 3 days (35.46+/-11.85), but decreased at 1 week (29.23+/-13.89) although it is still higher compared to the control group (AD+/-SD: 10.37+/-8.69). Using GFP bone marrow transplantation mouse model, GFP positive cell count increased gradually over time in 6 months. GFP positive cells were also positive to CD31, CD68 and Runx2 suggesting that fibroblasts differentiated into osteoclasts and tissue macrophages. In conclusion, mechanical stress during orthodontic movement promoted the increase in the number of cells in the periodontal ligament on both tension and pressure sides. The increase in the number of cells in the periodontal ligament is believed to be due to the migration and cell division of undifferentiated mesenchymal cells.


Human leukemia cell lines with comparable receptor binding characteristics but different phenotypic responses to phorbol diesters.
Phorbol diester (PDE) tumor promoters have differing effects on normal and neoplastic hematopoietic cells in vitro. The effects of PDEs on cells are apparently mediated by specific cellular receptors for these ligands. The purpose of this study was to determine if the different phenotypic responses of cells of different human leukemia cell lines were due to differences in the PDE receptors in these cells. All cells of the different lines studied [HL-60 (promyelocytic), HL-60Bll (undifferentiated blastic), U-937 (monoblastic), H-SB2 (T-lymphoblastoid), and SB (B-lymphoblastoid) bound the [20-3H]phorbol-12,13-dibutyrate in a specific manner. The ligand bound to the cells rapidly, reaching a maximum by 10 to 20 min at 37 degrees or by 60 min at 4 degrees. The bound [20-3H]phorbol-12,13-dibutyrate could be fully dissociated from the cells by adding unlabeled phorbol-12,13-dibutyrate; the kinetics of this dissociation paralleled association kinetics. Scatchard analysis of the binding data, derived from experiments done at 4 degrees, revealed linear plots, indicating, most likely, that only single classes of receptors existed on all of these lines. The dissociation constants for binding were all comparable (46 to 152 nM), and the calculated numbers of binding sites were comparable (4.8 to 8.1 X 10(5)/cell). None of the cells could degrade [20-3H]phorbol-12-myristate-13-acetate or [20-3H]phorbol-12,13-dibutyrate as determined by thin-layer chromatographic analysis of cells or supernatants of the cell cultures. PDEs inhibited the proliferation of U-937 and HL-60 cells but not that of the HL-60Bll, SB, or H-SB2 cells. The incorporation of tritiated thymidine into HL-60 cells (but not HL-60Bll cells) was dramatically inhibited by various PDEs, and the potency in causing this inhibition paralleled that known for the potency of the phorbol analogues to cause tumor promotion in vivo or to elicit other in vitro responses from hematopoietic cells. [20-3H]Phorbol-12-myristate-13-acetate caused the HL-60 and U-937 cells to adhere to the plastic, spread, and develop vacuoles, but the other cells displayed no changes. These results suggest that the differing phenotypic responses to PDEs are most likely related to postreceptor factors.


Efficacy of Obcordata A from Aspidopterys obcordata on Kidney Stones by Inhibiting NOX4 Expression.
Obcordata A (OA) is a polyoxypregnane glycoside derived from the Dai medicine Aspidopterys obcordata vines. This study aims to investigate the efficacy of OA on renal tubular epithelial cells exposed to calcium oxalate crystals. We incubated renal tubular cells with 28 μg·cm2 calcium oxalate crystals for 24 h with and without OA, GKT137831, phorbol-12-myristate-13-acetate (PMA), and tocopherol. The MTT [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, microscopic examination, flow cytometry, and immunofluorescence staining revealed that calcium oxalate crystals decreased cell viability and elevated reactive oxygen species (ROS) levels. OA, GKT137831, and tocopherol protected cells and decreased ROS levels. However, OA did not exhibit direct DPPH scavenging ability. In addition, immunoblotting illustrated that OA inhibited the NOX4 (nicotinamide adenine dinucleotide phosphate oxidases 4) expression and downregulated the protein expression in the NOX4/ROS/p38 MAPK (p38 mitogen-activated protein kinase) pathway. The findings suggest that the cytoprotective and antioxidant effects of OA can be blocked by the NOX4 agonist PMA. In conclusion, OA could be used as a NOX4 inhibitor to prevent kidney stones.


Multiomics and spatial mapping characterizes human CD8+ T cell states in cancer.
Clinically relevant immunological biomarkers that discriminate between diverse hypofunctional states of tumor-associated CD8+ T cells remain disputed. Using multiomics analysis of CD8+ T cell features across multiple patient cohorts and tumor types, we identified tumor niche-dependent exhausted and other types of hypofunctional CD8+ T cell states. CD8+ T cells in "supportive" niches, like melanoma or lung cancer, exhibited features of tumor reactivity-driven exhaustion (CD8+ TEX). These included a proficient effector memory phenotype, an expanded T cell receptor (TCR) repertoire linked to effector exhaustion signaling, and a cancer-relevant T cell-activating immunopeptidome composed of largely shared cancer antigens or neoantigens. In contrast, "nonsupportive" niches, like glioblastoma, were enriched for features of hypofunctionality distinct from canonical exhaustion. This included immature or insufficiently activated T cell states, high wound healing signatures, nonexpanded TCR repertoires linked to anti-inflammatory signaling, high T cell-recognizable self-epitopes, and an antiproliferative state linked to stress or prodeath responses. In situ spatial mapping of glioblastoma highlighted the prevalence of dysfunctional CD4+:CD8+ T cell interactions, whereas ex vivo single-cell secretome mapping of glioblastoma CD8+ T cells confirmed negligible effector functionality and a promyeloid, wound healing-like chemokine profile. Within immuno-oncology clinical trials, anti-programmed cell death protein 1 (PD-1) immunotherapy facilitated glioblastoma's tolerogenic disparities, whereas dendritic cell (DC) vaccines partly corrected them. Accordingly, recipients of a DC vaccine for glioblastoma had high effector memory CD8+ T cells and evidence of antigen-specific immunity. Collectively, we provide an atlas for assessing different CD8+ T cell hypofunctional states in immunogenic versus nonimmunogenic cancers.


The International Academy of Health Sciences Informatics (IAHSI): 2020 Report.
To summarize the major activities of the International Academy of Health Sciences Informatics (IAHSI) in the 2020 time period and to welcome its 2020 Class of Fellows. Report from the members of the Academy's Board. Due to the SARS-CoV-2 pandemic, both Plenary meetings in 2020 had to be organized as virtual meetings. Scientific discussions, focusing on mobilizing computable biomedical knowledge and on data standards and interoperability formed major parts of these meetings. A statement on the use of informatics in pandemic situations was elaborated and sent to the World Health Organization. A panel on data standards and interoperability started its work. 34 Fellows were welcomed in the 2020 Class of Fellows so that the Academy now consists of 179 members. There was a shift from supporting to strategic activities in the Academy's work. After having achieved organizational stability, the Academy can now focus on its strategic work and so on its main objective.


Beta2-adrenoceptor agonists for dysmenorrhoea.
Dysmenorrhoea is a common gynaecological complaint that can affect as many as 50% of premenopausal women, 10% of whom suffer severely enough to be rendered incapacitated for one to three days during each menstrual cycle. Primary dysmenorrhoea is where women suffer from menstrual pain but lack any pathology in their pelvic anatomy. Beta2-adrenoceptor agonists have been used in the treatment of women with primary dysmenorrhoea but their effects are unclear. To determine the effectiveness and safety of beta2-adrenoceptor agonists in the treatment of primary dysmenorrhoea. We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register; CENTRAL (The Cochrane Library 2011, Issue 8); MEDLINE; EMBASE; PsycINFO and the EBM Reviews databases. The last search was on 22 August 2011. Randomised controlled trials comparing beta2-adrenoceptor agonists with placebo or no treatment, each other or any other conventional treatment in women of reproductive age with primary dysmenorrhoea. Two review authors independently assessed trial quality and extracted the data. Five trials involving 187 women with an age range of 15 to 40 years were included. Oral isoxsuprine was compared with placebo in two trials; terbutaline oral spray, ritodrine chloride and oral hydroxyphenyl-orciprenalin were compared with placebo in a further three trials. Clinical diversity in the studies in terms of the interventions being evaluated, assessments at different time points and the use of different assessment tools mitigated against pooling of outcome data across studies in order to provide a summary estimate of effect for any of the comparisons. Only one study, with unclear risk of bias, reported pain relief with a combination of isoxsuprine, acetaminophen and caffeine. None of the other studies reported any significant clinical difference in effectiveness between the intervention and placebo. Adverse effects were reported with all of these medications in up to a quarter of the total number of participants. They included nausea, vomiting, dizziness, quivering, tremor and palpitations. The evidence presented in this review was based on a few relatively small-sized studies that were categorised to have unclear to high risk of bias, which does not allow confident decision-making at present about the use of beta2-adrenoceptor agonists for dysmenorrhoea. The benefits as reported in one study should be balanced against the wide array of unacceptable side effects documented with this class of medication. We have emphasised the lack of precision and limitations in the reported data where appropriate.


Moving toward reclaiming life: lived experiences of being physically active among persons with psychiatric disabilities.
There is abundant documentation in research about the significant relationship between physical activity and mental health, but there is still more to be learned about what can enhance motivation to become more physically active. Fourteen persons with psychiatric disabilities were interviewed about their experiences of being physically active, and data was analyzed using a phenomenological-hermeneutic method. Five themes emerged: Capability for Living, Liberation from a Heavy Mind, Companionship in Being in Motion, Longing for Living One's Life, and Struggling with Limitations. The interpreted meaning of being physically active was to be moving toward reclaiming one's life.


Clarifying the role of the mental health peer specialist in Massachusetts, USA: insights from peer specialists, supervisors and clients.
Mental health peer specialists develop peer-to-peer relationships of trust with clients to improve their health and well-being, functioning in ways similar to community health workers. Although the number of peer specialists in use has been increasing, their role in care teams is less defined than that of the community health worker. This qualitative study explored how the peer specialist role is defined across different stakeholder groups, the expectations for this role and how the peer specialist is utilised and integrated across different types of mental health services. Data were collected through interviews and focus groups conducted in Massachusetts with peer specialists (N = 44), their supervisors (N = 14) and clients (N = 10) between September 2009 and January 2011. A consensus coding approach was used and all data outputs were reviewed by the entire team to identify themes. Peer specialists reported that their most important role is to develop relationships with clients and that having lived mental health experience is a key element in creating that bond. They also indicated that educating staff about the recovery model and peer role is another important function. However, they often felt a lack of clarity about their role within their organisation and care team. Supervisors valued the unique experience that peer specialists bring to an organisation. However, without a defined set of expectations for this role, they struggled with training, guiding and evaluating their peer specialist staff. Clients reported that the shared lived experience is important for the relationship and that working with a peer specialist has improved their mental health. With increasing support for person-centred integrated healthcare delivery models, the demand for mental health peer specialist services will probably increase. Therefore, clearer role definition, as well as workforce development focused on team orientation, is necessary for peer specialists to be fully integrated and supported in care teams.


Rewiring bacterial two-component systems by modular DNA-binding domain swapping.
Two-component systems (TCSs) are the largest family of multi-step signal transduction pathways and valuable sensors for synthetic biology. However, most TCSs remain uncharacterized or difficult to harness for applications. Major challenges are that many TCS output promoters are unknown, subject to cross-regulation, or silent in heterologous hosts. Here, we demonstrate that the two largest families of response regulator DNA-binding domains can be interchanged with remarkable flexibility, enabling the corresponding TCSs to be rewired to synthetic output promoters. We exploit this plasticity to eliminate cross-regulation, un-silence a gram-negative TCS in a gram-positive host, and engineer a system with over 1,300-fold activation. Finally, we apply DNA-binding domain swapping to screen uncharacterized Shewanella oneidensis TCSs in Escherichia coli, leading to the discovery of a previously uncharacterized pH sensor. This work should accelerate fundamental TCS studies and enable the engineering of a large family of genetically encoded sensors with diverse applications.


High levels of green-tree retention are required to preserve ground beetle biodiversity in boreal mixedwood forests.
Recovery of biodiversity and other ecosystem functions to pre-disturbance levels is a central goal of natural disturbance-based approaches to ecosystem management. In boreal mixedwood forests, green-tree retention has been proposed as an alternative approach to traditional clearcutting that may minimize initial displacement of species assemblages and speed recovery of the biota. Here we evaluated the effectiveness of six levels of dispersed greentree retention for conservation of ground beetle biodiversity in four boreal mixedwood cover types that span a gradient of stand development following wildfire. Each cover type X treatment combination was replicated three times in an operational scale experiment using 10-ha compartments. Ground beetle assemblages (59 species and 45 419 individuals) responded to increasing levels of dispersed, green-tree retention, but even relatively high levels of retention (up to 50% retention) did not retain species assemblages characteristic of uncut forest stands. This latter effect was most pronounced in compartments in later successional stages; i.e., those with developing conifer understories, or mixed and/or conifer-dominated overstories. Beetle assemblages in high levels of retention (50-75%) were statistically similar across all cover types, although we detected modest differences among the 5-year recovery of assemblages, based on initial cover type differences. Thus, recovery to initial conditions likely will be slower in mixed and conifer stands than in deciduous stands. We suggest that recovery of beetle assemblages is strongly linked to stand reinitiation through deciduous "suckering" post-harvest. Increasing levels of harvest appear to homogenize carabid assemblages across the four dominant cover types, and thus higher levels of retention (>50%) will be required to preserve assemblages of later successional stages. Regional renewal of assemblages, however, will require landscape-level planning.


Physical activity counteracts increased whole-body protein breakdown in chronic obstructive pulmonary disease patients.
Chronic obstructive pulmonary disease (COPD) is associated with increased whole body protein breakdown and low-grade systemic inflammation. We aimed to determine if physical training of patients with COPD induces anti-inflammatory effects and decreases whole-body protein breakdown. Nineteen subjects with severe (FEV(1)=31+/-1) COPD were randomized into a training group (n=9) and a control group (n=10). Twenty healthy subjects were studied for baseline comparison. The "COPD training" group participated in an outpatient rehabilitation program consisting of endurance training (walking at 85% of VO(2max)) twice weekly for 7 weeks plus daily home-based training. Maximum walking distance increased by almost 70% in the training group after 7 weeks of training. At baseline, the concentrations of C-reactive protein (CRP) and IL-18 in plasma were increased in subjects with COPD compared with healthy subjects (P<0.05) and leucine rate of appearance (R(a)) was approximately 15% greater (P<0.05) in subjects with COPD. Training had no effect on the plasma concentration of inflammatory markers but decreased leucine R(a) in subjects with COPD by approximately 10% (P<0.05). In conclusion, 7 weeks of physical training markedly improved endurance in patients with COPD and accelerated whole-body protein breakdown in patients with COPD was attenuated by physical training independent of changes in inflammatory markers.


Match Situations Leading to Head Injuries in Professional Male Football (Soccer)-A Video-Based Analysis Over 12 Years.
To identify risk situations promoting head injuries in professional male football (soccer) and to investigate the impact of a rule change in 2006 punishing elbow-head contacts. Analysis of video sequences of head events leading to head injury. Professional football players of the first male German Bundesliga. Observational criteria of head impacts on video recordings (players' actions preceding head injuries, foul play-referee's decision and assessment of rater, ball possession, on-pitch medical treatment, and consequences of head impact). Three hundred thirty-four head injuries were reported in kicker Sportmagazin corresponding to an incidence rate of 2.25 (95% confidence interval 2.01-2.51) per 1000 player match hours. The injured player predominantly jumped (60%), headed the ball (36%), or ran forwards (20%); the noninjured players mainly jumped (64%), headed the ball (27%), or raised the elbow to the head (23%). Free ball situations (2 players challenge for the ball) caused most of the head injuries (81%). The players' action "raising the elbow" during a head injury seemed to be lower after the rule change. Jumping for the ball with the intention of heading is the predominant action associated with head injury risk. Head injuries occur most often when players challenge for the ball in a header duel. As head injuries bear the potential risk of long-term health sequelae, the identification of situational circumstances is essential to develop preventative means in the future.


Stress associated with road transportation in desert sheep and goats, and the effect of pretreatment with xylazine or sodium betaine.
The present work investigates some clinical, endocrinological, biochemical and haematological variables in desert sheep and goats stressed in the course of individual road transportation, and the influence thereon of pretreatment with an established anti-stressor drug, xylazine HCl, and a test compound, sodium betaine (trimethylglycine). Road transportation for 2h resulted in variable and statistically insignificant increases in heart, pulse and respiratory rates in both control and experimental animals. Transportation stress significantly increased the concentrations of plasma cortisol, and glucose, and decreased that of magnesium. The endogenous thiocyanate concentration was unaffected. The stress also insignificantly decreased the haematocrit (PCV), and the number of lymphocytes, and increased the concentration of haemoglobin. Pretreatment of sheep and goats with xylazine at a single dose of 0.01 mg/kg by the intravenous route significantly ameliorated the effects induced by the stressful stimulus. The effects of pretreatment of the two species with sodium betaine (10 mg/kg) produced variable and insignificant effects.


BCL6 Inhibitor-Mediated Downregulation of Phosphorylated SAMHD1 and T Cell Activation Are Associated with Decreased HIV Infection and Reactivation.
Clearance of HIV-infected germinal center (GC) CD4+ follicular helper T cells (Tfh) after combination antiretroviral therapy (ART) is essential to an HIV cure. Blocking B cell lymphoma 6 (BCL6; the master transcription factor for Tfh cells) represses HIV infection of tonsillar CD4+ Tfh ex vivo, reduces GC formation, and limits immune activation in vivo We assessed the anti-HIV activity of a novel BCL6 inhibitor, FX1, in Tfh/non-Tfh CD4+ T cells and its impact on T cell activation and SAMHD1 phosphorylation (Thr592). FX1 repressed HIV-1 infection of peripheral CD4+ T cells and tonsillar Tfh/non-Tfh CD4+ T cells (P < 0.05) and total elongated and multispliced HIV-1 RNA production during the first round of viral life cycle (P < 0.01). Using purified circulating CD4+ T cells from uninfected donors, we demonstrate that FX1 treatment resulted in downregulation pSAMHD1 expression (P < 0.05) and T cell activation (HLA-DR, CD25, and Ki67; P < 0.01) ex vivo corresponding with inhibition of HIV-1 and HIV-2 replication. Ex vivo HIV-1 reactivation using purified peripheral CD4+ T cells from HIV-infected ART-suppressed donors was also blocked by FX1 treatment (P < 0.01). Our results indicate that BCL6 function contributes to Tfh/non-Tfh CD4+ T cell activation and cellular susceptibility to HIV infection. BCL6 inhibition represents a novel therapeutic strategy to potentiate HIV suppression in Tfh/non-Tfh CD4+ T cells without reactivation of latent virus.IMPORTANCE The expansion and accumulation of HIV-infected BCL6+ Tfh CD4+ T cells are thought to contribute to the persistence of viral reservoirs in infected subjects undergoing ART. Two mechanisms have been raised for the preferential retention of HIV within Tfh CD4+ T cells: (i) antiretroviral drugs have limited tissue distribution, resulting in insufficient tissue concentration and lower efficacy in controlling HIV replication in lymphoid tissues, and (ii) cytotoxic CD8+ T cells within lymphoid tissues express low levels of chemokine receptor (CXCR5), thus limiting their ability to enter the GCs to control/eliminate HIV-infected Tfh cells. Our results indicate that the BCL6 inhibitor FX1 can not only repress HIV infection of tonsillar Tfh ex vivo but also suppress HIV infection and reactivation in primary, non-Tfh CD4+ T cells. Our study provides a rationale for targeting BCL6 protein to extend ART-mediated reduction of persistent HIV and/or support strategies toward HIV remission beyond ART cessation.


Vitamin C supplementation in kidney failure: effect on uraemic symptoms.
Vitamin C (ascorbate) deficiency and symptoms consistent with deficiency (fatigue, myalgia, dyspnoea, gingivitis, cardiovascular instability and depression) are common in patients with renal failure. This study aimed to determine if supplementation with ascorbate in patients with severe renal failure improved symptoms or cardiovascular stability, or was associated with adverse effects. The study was a 3-month, double-blind, randomized trial of ascorbic acid 250 mg or matching placebo given thrice weekly. Subjects were clinically stable and either received conventional dialysis or had an estimated glomerular filtration rate of <20 mL/min. Symptoms were measured using the Kidney Dialysis Quality of Life-Short Form (KDQOL-SF™) symptom subscale, and the study was 80% powered to detect a change of 10 in the KDQOL-SF™. Ninety-nine subjects were randomized, and ascorbate deficiency was present in 40% at baseline. Mean symptom scores at follow-up were similar in the two groups (P-value=0.19). There was a trend to slightly worse nausea scores in the ascorbate group after controlling for the level of baseline nausea (P=0.09), and there was no impact on cardiovascular stability. Compliance appeared adequate at 91%, and deficiency was corrected in most (85%) of the subjects in the active treatment group. This study indicates that ascorbate supplementation does not improve symptoms or cardiovascular stability in those with severe renal impairment, but is associated with a trend towards worse nausea.


Range-wide spatial mapping reveals convergent character displacement of bird song.
A long-held view in evolutionary biology is that character displacement generates divergent phenotypes in closely related coexisting species to avoid the costs of hybridization or ecological competition, whereas an alternative possibility is that signals of dominance or aggression may instead converge to facilitate coexistence among ecological competitors. Although this counterintuitive process-termed convergent agonistic character displacement-is supported by recent theoretical and empirical studies, the extent to which it drives spatial patterns of trait evolution at continental scales remains unclear. By modelling the variation in song structure of two ecologically similar species of Hypocnemis antbird across western Amazonia, we show that their territorial signals converge such that trait similarity peaks in the sympatric zone, where intense interspecific territoriality between these taxa has previously been demonstrated. We also use remote sensing data to show that signal convergence is not explained by environmental gradients and is thus unlikely to evolve by sensory drive (i.e. acoustic adaptation to the sound transmission properties of habitats). Our results suggest that agonistic character displacement driven by interspecific competition can generate spatial patterns opposite to those predicted by classic character displacement theory, and highlight the potential role of social selection in shaping geographical variation in signal phenotypes of ecological competitors.


Pheromone signal transduction in humans: what can be learned from olfactory loss.
Because humans seem to lack neuronal elements in the vomeronasal organ (VNO), many scientists believe that humans are unable to detect pheromones. This view is challenged by the observations that pheromone-like compounds, 4,16-androstadien-3-one (AND) and oestra-1,3,5(10),16-tetraen-3-ol (EST), activate the human hypothalamus. Whether these activations are mediated via VNO, venous blood or olfactory mucosa is presently unknown. To disentangle between the three alternatives, we conducted activation studies in 12 heterosexual males with chronic anosmia because of nasal polyps. Polyposis hampers signal transduction via the olfactory mucosa without interfering with the VNO or the pheromone transport via venous blood. Twelve healthy men served as controls. Subjects were investigated with (15)O-H(2)O PET during smelling of odorless air (base line), AND, EST, vanillin, and acetone. Smelling of EST activated the anterior hypothalamus in controls, but not anosmics. Neither did the anosmics display cerebral activations with AND or vanillin. Clusters were detected only with the trigeminal odorant acetone, and only in the thalamus, brainstem, the anterior cingulate, and parts of the sensorimotor cortex. Direct comparisons with controls (controls-anosmics) showed clusters in the olfactory cortex (amygdala and piriform cortex) with AND, vanillin, and acetone, and in the anterior hypothalamus with EST. The observed absence of olfactory and presence of trigeminal activations in anosmics indicates that polyposis primarily affected signal processing via the olfactory mucosa. The anosmics inability to activate the hypothalamus with EST, therefore, suggests that in healthy men EST signals were primarily transmitted via the olfactory system.


Toll-like receptor 4 contributes to small intestine allograft rejection.
Although outcomes for small intestine transplantation (SIT) have improved in recent years, allograft rejection rates remain among the highest of solid organ grafts. The high load of commensal bacteria in the small intestine may contribute through activation of the toll-like receptor (TLR) pathway. In this study, we examine the participation of TLR4 in acute allograft rejection in an orthotopic mouse model of SIT. Wild-type C57Bl/6 (H-2b) or TLR49(-/-) (H-2b) mice were transplanted with syngeneic (C57Bl/6), allogeneic (BALB/c; H-2d), or F1 (BALB/cxC57Bl/6; H-2d/b) vascularized, orthotopic small intestine grafts. Graft recipients were killed on days 2 to 6 posttransplant. Serum cytokines were measured by Luminex, and tissue was obtained for histology and quantitative real-time polymerase chain reaction. BALB/c grafts transplanted into C57Bl/6 recipients exhibited mixed inflammatory infiltrates, destruction of the mucosa, and significant apoptosis. TLR2 and TLR4 transcripts were modestly increased in syngeneic grafts on days 2 and 6 compared with native bowel, whereas TLR2 and TLR4 were significantly increased on days 2 and 6 in allogeneic grafts. Although fully mismatched and F1 grafts were rejected by C57Bl/6 recipients (mean survival time=8.2 and 9.3 days, respectively), graft survival was significantly prolonged in TLR4(-/-) recipients (mean survival time=10.6 and 14.3 days, respectively). Proinflammatory cytokines were markedly reduced in TLR4(-/-) graft recipients. Small intestine graft survival is prolonged in the absence of TLR4, suggesting that gut flora associated with the graft may augment alloimmune responses through TLR4. Thus, the TLR pathway may be a novel therapeutic target for improving SIT allograft survival.


The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway.
The FMS-like receptor tyrosine kinase 3 (FLT3) plays an important role in controlling differentiation and proliferation of hematopoietic cells. Activating mutations in FLT3 occur in patients with acute myeloid leukemia (AML; 15%-35%), resulting in abnormal cell proliferation. Furthermore, both adult and pediatric patients with AML harboring the FLT3 internal tandem duplication (ITD) mutation have a poor prognosis. Several inhibitors have been developed to target mutant FLT3 for the treatment of AML, yet the molecular pathways affected by drug inhibition of the mutated FLT3 receptor alone have not been characterized as yet. Linifanib (ABT-869) is a multitargeted tyrosine kinase receptor inhibitor that suppresses FLT3 signaling. In this article, we show that treatment with linifanib inhibits proliferation and induces apoptosis in ITD mutant cells in vitro and in vivo. We show that treatment with linifanib reduces phosphorylation of Akt and glycogen synthase kinase 3β (GSK3β). In addition, we show that inhibition of GSK3β decreases linifanib-induced apoptosis. This study shows the importance of GSK3 as a potential target for AML therapy, particularly in patients with FLT3 ITD mutations.


Structure of the N-terminal ankyrin repeat domain of the TRPV2 ion channel.
The TRPV ion channels mediate responses to many sensory stimuli including heat, low pH, neuropeptides, and chemical ligands. All TRPV subfamily members contain an intracellular N-terminal ankyrin repeat domain (ARD), a prevalent protein interaction motif. The 1.6-A crystal structure of the TRPV2-ARD, with six ankyrin repeats, reveals several atypical structural features. Repeats one through three display unusually long and flexible fingers with a large number of exposed aromatic residues, whereas repeats five and six have unusually long outer helices. Furthermore, a large counterclockwise twist observed in the stacking of repeats four and five breaks the regularity of the domain, altering the shape of surfaces available for interactions with proteins or other cellular ligands. Both solution studies and crystal packing interactions indicate that the TRPV2-ARD does not form homo-oligomers, suggesting that the ARD of TRPV ion channels may be used for interactions with regulatory factors rather than in promoting tetrameric assembly of the ion channels.


A One Health approach to managing the applications and implications of nanotechnologies in agriculture.
The need for appropriate science and regulation to underpin nanosafety is greater than ever as ongoing advances in nanotechnology are rapidly translated into new industrial applications and nano-enabled commercial products. Nevertheless, a disconnect persists between those examining risks to human and environmental health from nanomaterials. This disconnect is not atypical in research and risk assessment and has been perpetuated in the case of engineered nanomaterials by the relatively limited overlap in human and environmental exposure pathways. The advent of agri-nanotechnologies brings both increased need and opportunity to change this status quo as it introduces significant issues of intersectionality that cannot adequately be addressed by current discipline-specific approaches alone. Here, focusing on the specific case of nanoparticles, we propose that a transdisciplinary approach, underpinned by the One Health concept, is needed to support the sustainable development of these technologies.


The influence of low-barrier and voluntary service policies on survivor empowerment in a domestic violence housing organization.
The purpose of community-based domestic violence crisis housing programs (e.g., shelters) is to provide a safe setting that promotes empowerment for survivors of intimate partner violence. For staff to reach this aim, the program must have formal structures and processes in place to support such efforts. This study explored how low-barrier and voluntary service policies influenced staff practices and survivor empowerment. Low-barrier policies require that programs remove barriers that prevent survivors, particularly those who have mental health concerns and/or addictions, from being able to access services. A voluntary service policy states that survivors have the right to choose which services, if any, they would like to engage in during their stay at the program. Survivors' ability to stay at the housing program is not contingent on their participation in program services. This exploratory-sequential (QUAL→ quan) mixed-method study examined how low-barrier and voluntary service policies influenced staff behavior and how these behaviors then related to survivor empowerment. Qualitative results revealed that low-barrier and voluntary service were guided by cultural values of justice and access, encouraged survivor-centered practices among staff, and were believed to promote survivor autonomy. Quantitative results suggested that when survivors perceived they had a choice to engage in program services or meet with an advocate, their empowerment increased. This study has implications for domestic violence organizational practice and provides evidence about the contextual factors that support individual empowerment. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection.
Cytomegalovirus establishes a lifelong latent infection following primary infection that can periodically reactivate with shedding of infectious virus. Primary infection, reactivation and reinfection during pregnancy can all lead to in utero transmission to the developing fetus. Congenital CMV infections are a major cause of permanent hearing loss and neurological impairment. In this literature review, we found that CMV infection was relatively common among women of reproductive age, with seroprevalence ranging from 45 to 100%. CMV seroprevalence tended to be highest in South America, Africa and Asia and lowest in Western Europe and United States. Within the United States, CMV seroprevalence showed substantial geographic variation as well, differing by as much as 30 percentage points between states, though differences might be explained by variation in the types of populations sampled. Worldwide, seroprevalence among non-whites tended to be 20-30 percentage points higher than that of whites (summary prevalence ratio (PR) = 1.59, 95% confidence interval (CI) = 1.57-1.61). Females generally had higher seroprevalences than males, although in most studies the differences were small (summary PR = 1.13, 95% CI = 1.11-1.14). Persons of lower socioeconomic status were more likely to be CMV seropositive (summary PR = 1.33, 95% CI = 1.32-1.35). Despite high seroprevalences in some populations, a substantial percentage of women of reproductive age are CMV seronegative and thus at risk of primary CMV infection during pregnancy. Future vaccine or educational campaigns to prevent primary infection in pregnant women may need to be tailored to suit the needs of different populations.


Polymer pen lithography.
We report a low-cost, high-throughput scanning probe lithography method that uses a soft elastomeric tip array, rather than tips mounted on individual cantilevers, to deliver inks to a surface in a "direct write" manner. Polymer pen lithography merges the feature size control of dip-pen nanolithography with the large-area capability of contact printing. Because ink delivery is time and force dependent, features on the nanometer, micrometer, and macroscopic length scales can be formed with the same tip array. Arrays with as many as about 11 million pyramid-shaped pens can be brought into contact with substrates and readily leveled optically to ensure uniform pattern development.


Optimal nonsurgical treatment of hemorrhoids: a comparative analysis of infrared coagulation, rubber band ligation, and injection sclerotherapy.
Despite an abundance of nonsurgical hemorrhoid therapies, none has been consistently more efficacious. By combining data from multiple clinical trials in a meta-analysis, the present study compared the efficacy and complications of infrared coagulation, injection sclerotherapy, and rubber band ligation to determine the optimal nonoperative hemorrhoid treatment. All published clinical trials comparing the three methods were identified by computer search and review of appropriate English language journals. Five trials studying 863 patients satisfied all inclusion criteria. Results demonstrated that similar numbers of patients were asymptomatic 12 months after treatment, regardless of initial therapy. However, significantly fewer patients undergoing rubber band ligation required additional treatment because symptoms had recurred. Although rubber band ligation demonstrated greater long-term efficacy, it was associated with a significantly higher incidence of posttreatment pain. In contrast, infrared coagulation was associated with both fewer and less severe complications. Thus, when all factors are considered, infrared coagulation may in fact be the optimal nonoperative hemorrhoid treatment.


Increased fructose associates with elevated blood pressure.
The recent increase in fructose consumption in industrialized nations mirrors the rise in the prevalence of hypertension, but epidemiologic studies have inconsistently linked these observations. We investigated whether increased fructose intake from added sugars associates with an increased risk for higher BP levels in US adults without a history of hypertension. We conducted a cross-sectional analysis using the data collected from the National Health and Nutrition Examination Survey (NHANES 2003 to 2006) involving 4528 adults without a history of hypertension. Median fructose intake was 74 g/d, corresponding to 2.5 sugary soft drinks each day. After adjustment for demographics; comorbidities; physical activity; total kilocalorie intake; and dietary confounders such as total carbohydrate, alcohol, salt, and vitamin C intake, an increased fructose intake of > or =74 g/d independently and significantly associated with higher odds of elevated BP levels: It led to a 26, 30, and 77% higher risk for BP cutoffs of > or =135/85, > or =140/90, and > or =160/100 mmHg, respectively. These results suggest that high fructose intake, in the form of added sugar, independently associates with higher BP levels among US adults without a history of hypertension.


Custom CGH array profiling of copy number variations (CNVs) on chromosome 6p21.32 (HLA locus) in patients with venous malformations associated with multiple sclerosis.
Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance. In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999 bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate. In total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r = 0.6590, p = 0.0104; linear regression analysis r = 0.6577, p = 0.0106). The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype. The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.


Dual-mode optical projection tomography microscope using gold nanorods and hematoxylin-stained cancer cells.
An optical projection tomography microscope (OPTM) can improve axial resolution by viewing a sample from different perspectives. Here, we report a dual-mode OPTM that can generate 3D images of single cancer cells in both absorption mode and polarization mode. Cancer cells were labeled with hematoxylin for absorption imaging and nanorods for polarization imaging. Absorption images can provide morphologic information, and polarization images can provide molecular information. The combination of molecular detection and 3D cytological cell analysis may help with early cancer diagnosis.


Prenatal exposure to valproic acid leads to reduced expression of synaptic adhesion molecule neuroligin 3 in mice.
In rodents, a single administration of valproic acid (VPA) in utero leads to developmental delays and lifelong deficits in motor performance, social behavior, and anxiety-like behavior in the offspring. Recently, we have demonstrated that VPA mice show alterations in postnatal growth and development, and deficits in olfactory discrimination and social behavior early in development. Based on behavioral and molecular parallels between VPA rodents and individuals with autism, maternal challenge with VPA has been suggested to be a good animal model of autism. Neuroligins (NLGN) are a family of postsynaptic cell-adhesion molecules that play a role in synaptic maturation through association with their presynaptic partners, the neurexins (NRXN). Both NLGNs and NRXN members have been implicated in genetic studies of autism. In the present study, we examined changes at the level of expression of NLGN and NRXN mRNAs in the adult brain from mice exposed in utero to VPA. Mouse brain tissue was processed using in situ hybridization and analyzed with densitometry to examine expression of three NLGN genes (NLGN1, NLGN2, and NLGN3) and three NRXN genes (NRXN1, NRXN2, and NRXN3). Expression levels of NLGN1, NLGN2, NRXN1, NRXN2, and NRXN3 were observed to be similar in VPA and control mice. NLGN3 mRNA expression was found to be significantly lower in the VPA mice relative to control animals in hippocampal subregions, cornu ammonis (CA1) and dentate gyrus, and somatosensory cortex. This lowered expression may be linked to autistic-like behavioral phenotype observed in the VPA mice.


Documenting your career as an educator electronically.
Academic radiologists on the clinician-educator track are required to provide a teaching portfolio as well as a curriculum vitae (CV) for academic promotion. The specific components of a teaching portfolio vary slightly depending on the institution. Traditionally academicians have collected the necessary documentation in paper format, often stuffing them in a binder or a desk drawer. However in the digital age most academic works are readily available in electronic format and can be accessed online. An electronic portfolio is the ideal method to efficiently organize this digital material. In this article, we describe the specific advantages of an online academic portfolio, explain how to set one up and review many options available to build an online electronic portfolio.


Abundance of bacterial Type VI secretion system components measured by targeted proteomics.
The Type VI secretion system (T6SS) is important for bacterial competition as well as virulence in many Gram-negative bacteria and its dynamics and regulation varies significantly between species. To gain insights into the mechanisms regulating T6SS assembly, we apply targeted proteomics to determine the abundance of the key T6SS components in Vibrio cholerae, Pseudomonas aeruginosa and Acinetobacter baylyi. We show that while there are species specific exceptions, the abundance of most components is similar in all three bacteria and ranges from less than hundred to tens of thousands of copies per cell. The comparison of T6SS dynamics and protein abundance in V. cholerae grown under various conditions suggests that the critical component TssE and the secreted protein VasX are unstable and this diminishes T6SS assembly when protein synthesis is limited. Our quantitative analysis opens possibilities to build realistic models of T6SS assembly and to identify principles of T6SS regulation in various species.


Mechanisms and evolutionary patterns of mammalian and avian dosage compensation.
As a result of sex chromosome differentiation from ancestral autosomes, male mammalian cells only contain one X chromosome. It has long been hypothesized that X-linked gene expression levels have become doubled in males to restore the original transcriptional output, and that the resulting X overexpression in females then drove the evolution of X inactivation (XCI). However, this model has never been directly tested and patterns and mechanisms of dosage compensation across different mammals and birds generally remain little understood. Here we trace the evolution of dosage compensation using extensive transcriptome data from males and females representing all major mammalian lineages and birds. Our analyses suggest that the X has become globally upregulated in marsupials, whereas we do not detect a global upregulation of this chromosome in placental mammals. However, we find that a subset of autosomal genes interacting with X-linked genes have become downregulated in placentals upon the emergence of sex chromosomes. Thus, different driving forces may underlie the evolution of XCI and the highly efficient equilibration of X expression levels between the sexes observed for both of these lineages. In the egg-laying monotremes and birds, which have partially homologous sex chromosome systems, partial upregulation of the X (Z in birds) evolved but is largely restricted to the heterogametic sex, which provides an explanation for the partially sex-biased X (Z) expression and lack of global inactivation mechanisms in these lineages. Our findings suggest that dosage reductions imposed by sex chromosome differentiation events in amniotes were resolved in strikingly different ways.


Acupuncture for the treatment of vulvodynia: a randomized wait-list controlled pilot study.
The incidence of vulvodynia in American women has been reported to be between 8.3% and 16%. However, there is no consistently effective standardized treatment for vulvodynia. To determine the feasibility and potential effects of using a standardized acupuncture protocol for the treatment of women with vulvodynia. The primary outcome was vulvar pain, and sexual function was the secondary outcome. Pain was assessed by the Short-Form McGill Pain Questionnaire, and function was measured by the Female Sexual Function Index (FSFI). Thirty-six women with vulvodynia met inclusion criteria. The women were randomly assigned either to the acupuncture group or to the wait-list control group. The 18 subjects assigned to the acupuncture group received acupuncture two times per week for 5 weeks for a total of 10 sessions. Reports of vulvar pain and dyspareunia were significantly reduced, whereas changes in the aggregate FSFI scores suggest significant improvement in sexual functioning in those receiving acupuncture vs. those who did not. Acupuncture did not significantly increase sexual desire, sexual arousal, lubrication, ability to orgasm or sexual satisfaction in women with vulvodynia. This was the first randomized controlled pilot study to examine the use of acupuncture for the treatment of vulvodynia. The acupuncture protocol was feasible and in this small sample appeared to reduce vulvar pain and dyspareunia with an increase in overall sexual function for women with vulvodynia. This study should be replicated in a larger double-blinded randomized controlled trial.


Bovine filensin possesses primary and secondary structure similarity to intermediate filament proteins.
The cDNA coding for calf filensin, a membrane-associated protein of the lens fiber cells, has been cloned and sequenced. The predicted 755-amino acid-long open reading frame shows primary and secondary structure similarity to intermediate filament (IF) proteins. Filensin can be divided into an NH2-terminal domain (head) of 38 amino acids, a middle domain (rod) of 279 amino acids, and a COOH-terminal domain (tail) of 438 amino acids. The head domain contains a di-arginine/aromatic amino acid motif which is also found in the head domains of various intermediate filament proteins and includes a potential protein kinase A phosphorylation site. By multiple alignment to all known IF protein sequences, the filensin rod, which is the shortest among IF proteins, can be subdivided into three subdomains (coils 1a, 1b, and 2). A 29 amino acid truncation in the coil 2 region accounts for the smaller size of this domain. The filensin tail contains 6 1/2 tandem repeats which match analogous motifs of mammalian neurofilament M and H proteins. We suggest that filensin is a novel IF protein which does not conform to any of the previously described classes. Purified filensin fails to form regular filaments in vitro (Merdes, A., M. Brunkener, H. Horstmann, and S. D. Georgatos. 1991. J. Cell Biol. 115:397-410), probably due to the missing segment in the coil 2 region. Participation of filensin in a filamentous network in vivo may be facilitated by an assembly partner.


Drugs and toxins-associated pulmonary arterial hypertension: lessons learned and challenges ahead.
Since the identification of the link between pulmonary arterial hypertension (PAH) and exposure to certain drugs and toxins nearly fifty years ago, the expanding landscape of available pharmaceuticals and illicit drugs is further fueling this association. While some causative agents in drugs and toxins associated PAH (D&T-APAH) have been identified, little is known about the exact biology and clinical implications of the disease. In this review, we discuss the historical evidence that links PAH with exposure to anorexinogens, cocaine, and methamphetamines and concentrate on what is known about potential pathogenesis, clinical manifestations, and current management. We conclude that future research should focus on studies looking at clinical outcome and susceptibility factors.


Prevalence and outcomes of recycling NNRTIs despite documented NNRTI resistance in HIV-infected children and youth.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are commonly used in pediatric patients; however, rapid development of resistance, due to non-adherence and cross-resistance, results in their discontinuation and limits their recycling. We evaluated the clinical experience of recycling NNRTIs despite documented NNRTI resistance (NNRTI-R), and examined virologic and CD4 cell count outcomes among participants enrolled in Longitudinal Epidemiologic Study to Gain Insight into HIV/AIDS in Children and Youth (LEGACY), a national HIV-infected pediatric cohort. We conducted a retrospective analysis of LEGACY participants with major NNRTI-R. Using chi-square analyses and logistic regression, we examined demographic and clinical factors associated with prescription of NNRTIs despite documented NNRTI-R, and associated changes in plasma HIV RNA viral load and CD4 cell counts. Sixteen of 133 (12%) participants with documented NNRTI-R re-started NNRTIs for a median of 370 days (IQR 105-919) with a median 402 days (IQR 70-841) between documentation of NNRTI-R to NNRTI recycling. Participants recycling NNRTIs were less likely to have documented past non-adherence (40.0% vs. 69.2%; p = 0.02). Among twelve patients with virologic data at 24 (± 8) weeks; seven (58.3%) experienced virologic suppression while on the recycled NNRTI-based regimens. Of the five who failed to suppress, three with subsequent genotyping developed additional NNRTI-R mutations compromising higher generation NNRTIs. While NNRTI's were recycled in only a small fraction of LEGACY participants harboring NNRTI-R mutations, such recycling increased the risk of inducing further resistance mutations that compromised use of higher generation NNRTIs.


Pneumococcus-specific immunoglobulin E in cigarette smokers.
A relationship between elevated serum immunoglobulin E levels and smoking has been demonstrated in epidemiological studies. Allergy skin test data suggest that the excess immunoglobulin E of smokers is not specific for aeroallergens. It is possible that the excess immunoglobulin E is specific for microorganisms that often infect the lower respiratory tract of smokers. To investigate this possibility we utilized a radioallergosorbent test assay for detecting serum immunoglobulin E specific for Streptococcus pneumoniae, an organism commonly isolated from the respiratory tract of smokers with chronic bronchitis. We assayed sera of thirty smokers and thirty nonsmokers for immunoglobulin E specific for Streptococcus pneumoniae. Individual sera were considered positive for pneumococcus-specific immunoglobulin E if the binding was at least twice the non-specific binding at the total immunoglobulin E concentration of the particular serum. Eleven of the thirty sera of smokers and two of the thirty nonsmokers were positive for pneumococcus-specific immunoglobulin E. By chi-square analysis of these data, the prevalence of pneumococcus-specific immunoglobulin E was significantly greater in the smoking group compared with the non-smoking group (P less than 0.02). These results suggest that the excess immunoglobulin E of smokers is, at least in part, specific for microorganisms that infect the airways.


Novel anti-melanogenic hexapeptoids, PAL-10 and PAL-12.
Diverse compound sources are being explored for de-pigmentation activities to develop novel therapeutic agents or functional cosmetic ingredients for hyper-pigmentation disorders. Peptoids are a class of peptidomimetics whose side chains are appended to the nitrogen atom of the peptide backbone, instead of α-carbon. Peptoids are more durable against proteolysis and are being actively investigated in drug discovery, but rarely studied as cosmetic ingredients. Here, we demonstrated that new hexa-peptoids, PAL-10 and PAL-12, can inhibit melanogenesis in B16F10 melanoma cells, a 3D pigmented human skin model (Neoderm(®)-ME, Tegoscience Co) and zebrafish. Anti-melanogenic effects of PAL-10 or PAL-12 as compared with arbutin, a positive control in B16F10 cells, Neoderm(®)-ME and zebrafish were statistically significant and concentration-dependent anti-melanogenic effects were manifested as determined by image, histology, and melanin contents. Anti-melanogenic effects of PAL-10 appeared to be from enzymatic inhibition of tyrosinase while mRNA expression of melanogenic enzymes was not affected. In conclusion, we demonstrated that PAL-10 and PAL-12 can be used as a new cosmetic ingredient with strong brightening efficacies.