On linear variational surface deformation methods.
This survey reviews the recent advances in linear variational mesh deformation techniques. These methods were developed for editing detailed high-resolution meshes, like those produced by scanning real-world objects. The challenge of manipulating such complex surfaces is three-fold: the deformation technique has to be sufficiently fast, robust, and intuitive and easy to control to be useful for interactive applications. An intuitive, and thus predictable, deformation tool should provide physically plausible and aesthetically pleasing surface deformations, which in particular requires its geometric details to be preserved. The methods we survey generally formulate surface deformation as a global variational optimization problem that addresses the differential properties of the edited surface. Efficiency and robustness are achieved by linearizing the underlying objective functional, such that the global optimization amounts to solving a sparse linear system of equations. We review the different deformation energies and detail preservation techniques that were proposed in the recent years, together with the various techniques to rectify the linearization artifacts. Our goal is to provide the reader with a systematic classification and comparative description of the different techniques, revealing the strengths and weaknesses of each approach in common editing scenarios.


Therapeutic thoracentesis: the role of ultrasound and pleural manometry.
Therapeutic thoracentesis is one of the most commonly performed medical procedures. The availability of handheld ultrasound machines has greatly enhanced the evaluation and management of patients with pleural effusions, with advantages including the absence of radiation, ease of use, portability and real-time/dynamic imaging. Pleural manometry refers to the measurement of pleural pressure during thoracentesis. Though described more than 122 years ago, most physicians do not measure pleural pressure, or even consider the role pleural pressures plays in the development of pleural effusions. This review summarizes the relevant data behind the use of ultrasound and manometry and explores their use during therapeutic thoracentesis The use of ultrasound has been associated with a higher sensitivity for identifying pleural effusions, avoiding 'near misses' and a lower pneumothorax rate for thoracentesis. Pleural manometry can be used to distinguish patients with lung entrapment from those with trapped lung. Manometry is also able to predict the ability to pleurodesis patients with malignant effusions, and possibly minimize the risk of reexpansion pulmonary edema when large volumes of pleural fluid are removed. The use of ultrasound and pleural manometry enhances the understanding of pleural disease and is associated with clinical benefit that will lead to improved patient care.


A Biotin Biosynthesis Gene Restricted to Helicobacter.
In most bacteria the last step in synthesis of the pimelate moiety of biotin is cleavage of the ester bond of pimeloyl-acyl carrier protein (ACP) methyl ester. The paradigm cleavage enzyme is Escherichia coli BioH which together with the BioC methyltransferase allows synthesis of the pimelate moiety by a modified fatty acid biosynthetic pathway. Analyses of the extant bacterial genomes showed that bioH is absent from many bioC-containing bacteria and is replaced by other genes. Helicobacter pylori lacks a gene encoding a homologue of the known pimeloyl-ACP methyl ester cleavage enzymes suggesting that it encodes a novel enzyme that cleaves this intermediate. We isolated the H. pylori gene encoding this enzyme, bioV, by complementation of an E. coli bioH deletion strain. Purified BioV cleaved the physiological substrate, pimeloyl-ACP methyl ester to pimeloyl-ACP by use of a catalytic triad, each member of which was essential for activity. The role of BioV in biotin biosynthesis was demonstrated using a reconstituted in vitro desthiobiotin synthesis system. BioV homologues seem the sole pimeloyl-ACP methyl ester esterase present in the Helicobacter species and their occurrence only in H. pylori and close relatives provide a target for development of drugs to specifically treat Helicobacter infections.


Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.
Hyperuricemia is associated with hypertension, inflammation, renal disease progression, and cardiovascular disease. However, no data are available regarding the effect of allopurinol in patients with chronic kidney disease. We conducted a prospective, randomized trial of 113 patients with estimated GFR (eGFR) <60 ml/min. Patients were randomly assigned to treatment with allopurinol 100 mg/d (n = 57) or to continue the usual therapy (n = 56). Clinical, biochemical, and inflammatory parameters were measured at baseline and at 6, 12, and 24 months of treatment. The objectives of study were: (1) renal disease progression; (2) cardiovascular events; and (3) hospitalizations of any causes. Serum uric acid and C-reactive protein levels were significantly decreased in subjects treated with allopurinol. In the control group, eGFR decreased 3.3 +/- 1.2 ml/min per 1.73 m(2), and in the allopurinol group, eGFR increased 1.3 +/- 1.3 ml/min per 1.73 m(2) after 24 months. Allopurinol treatment slowed down renal disease progression independently of age, gender, diabetes, C-reactive protein, albuminuria, and renin-angiotensin system blockers use. After a mean follow-up time of 23.4 +/- 7.8 months, 22 patients suffered a cardiovascular event. Diabetes mellitus, previous coronary heart disease, and C-reactive protein levels increased cardiovascular risk. Allopurinol treatment reduces risk of cardiovascular events in 71% compared with standard therapy. Allopurinol decreases C-reactive protein and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects.


Extensive regional variation in the phenology of insects and their response to temperature across North America.
Climate change models often assume similar responses to temperatures across the range of a species, but local adaptation or phenotypic plasticity can lead plants and animals to respond differently to temperature in different parts of their range. To date, there have been few tests of this assumption at the scale of continents, so it is unclear if this is a large-scale problem. Here, we examined the assumption that insect taxa show similar responses to temperature at 96 sites in grassy habitats across North America. We sampled insects with Malaise traps during 2019-2021 (N = 1041 samples) and examined the biomass of insects in relation to temperature and time of season. Our samples mostly contained Diptera (33%), Lepidoptera (19%), Hymenoptera (18%), and Coleoptera (10%). We found strong regional differences in the phenology of insects and their response to temperature, even within the same taxonomic group, habitat type, and time of season. For example, the biomass of nematoceran flies increased across the season in the central part of the continent, but it only showed a small increase in the Northeast and a seasonal decline in the Southeast and West. At a smaller scale, insect biomass at different traps operating on the same days was correlated up to ~75 km apart. Large-scale geographic and phenological variation in insect biomass and abundance has not been studied well, and it is a major source of controversy in previous analyses of insect declines that have aggregated studies from different locations and time periods. Our study illustrates that large-scale predictions about changes in insect populations, and their causes, will need to incorporate regional and taxonomic differences in the response to temperature.


Association of prone position with sudden unexpected death in epilepsy.
To examine the association between prone position and sudden unexpected death in epilepsy (SUDEP). We conducted a systematic review and meta-analysis based on a literature search from databases PubMed, Web of Science, and Scopus, using keywords "SUDEP" or "sudden unexpected death in epilepsy" or "sudden unexplained death syndromes in epilepsy." Twenty-five publications met the inclusion and exclusion criteria and were enrolled in this study. Body positions were documented in 253 cases of SUDEP. Of these patients, 73.3% (95% confidence interval [CI] = 65.7%, 80.9%) died in the prone position, whereas 26.7% (95% CI = 16.3%, 37.1%) died in nonprone positions. Binary random-effects analysis showed that prone position is significantly associated with SUDEP, as compared with nonprone position (p < 0.001). In addition, the prone position was reported in all 11 cases of video-EEG-monitored SUDEP. Moreover, in a subgroup of 88 cases of SUDEP in which demographics and circumstances of death were documented, the prone position was observed in 85.7% (95% CI = 74.6%, 93.3%) of patients aged 40 years or younger, but in only 60% (95% CI = 38.7%, 78.9%) of patients older than 40 years. Statistical analysis confirmed that the prone position was significantly more prevalent in the younger patient group, as compared with the older patient group (odds ratio 3.9; 95% CI = 1.4%, 11.4%; p = 0.009). There is a significant association between prone position and SUDEP, which suggests that prone position is a major risk factor for SUDEP, particularly in patients aged 40 years and younger. As such, SUDEP may share mechanisms similar to sudden infant death syndrome.


Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank.
Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.


Motif discovery and transcription factor binding sites before and after the next-generation sequencing era.
Motif discovery has been one of the most widely studied problems in bioinformatics ever since genomic and protein sequences have been available. In particular, its application to the de novo prediction of putative over-represented transcription factor binding sites in nucleotide sequences has been, and still is, one of the most challenging flavors of the problem. Recently, novel experimental techniques like chromatin immunoprecipitation (ChIP) have been introduced, permitting the genome-wide identification of protein-DNA interactions. ChIP, applied to transcription factors and coupled with genome tiling arrays (ChIP on Chip) or next-generation sequencing technologies (ChIP-Seq) has opened new avenues in research, as well as posed new challenges to bioinformaticians developing algorithms and methods for motif discovery.


Protein engineering of toluene-o-xylene monooxygenase from Pseudomonas stutzeri OX1 for oxidizing nitrobenzene to 3-nitrocatechol, 4-nitrocatechol, and nitrohydroquinone.
Toluene-o-xylene monooxygenase (ToMO) from Pseudomonas stutzeri OX1 was found to oxidize nitrobenzene (NB) to form m-nitrophenol (m-NP, 72%) and p-NP (28%) with an initial rate of 0.098 and 0.031 nmol/(min mg protein), respectively. It was also discovered that wild-type ToMO forms 4-nitrocatechol (4-NC) from m-NP and p-NP with an initial rate of 0.15 and 0.0082 nmol/(min mg protein), respectively, and 3-NC (12%) and nitrohydroquinone (NHQ, 88%) from o-NP with an initial rate of 0.11 and 0.8 nmol/(min mg protein), respectively. To increase the oxidation rate and alter the oxidation regiospecificity of nitro aromatics as well as to study the role of the active site residues I100, Q141, T201, and F205 of the alpha hydroxylase fragment of ToMO (TouA), DNA shuffling and saturation mutagenesis were used to generate random mutants. The mutants were initially identified by screening via a rapid agar plate assay and then were further examined by high-performance liquid chromatography (HPLC) and gas chromatography (GC). Several mutants with higher rates of activities and with different regiospecificities were identified; for example, Escherichia coli TG1 cells expressing either TouA mutant M180T/E284G or E214G/D312N/M399V produce 4-NC 4.5- and 20-fold faster than wild-type ToMO (0.037 and 0.16 nmol/min mg protein from p-NP, respectively). TouA mutant A107T/E214A had the regiospecificity of NB changed significantly from 28% to 79% p-NP. From 200 microM NB, TouA variants A101T/M114T, A110T/E392D, M180T/E284G, and E214G/D312N/M399V produce 4-NC whereas wild-type ToMO does not. From m-NP, TouA mutant I100Q produces 4-NC (37%) and NHQ (63%), whereas wild-type ToMO produces only 4-NC (100%). Variant A107T/E214A acts like a para enzyme and forms p-cresol as the major product (93%) from toluene with enhanced activity (2.3-fold), whereas wild-type ToMO forms 32%, 21%, and 47% of o-, m-, and p-cresol, respectively. Hence, the non-specific ToMO was converted into a regiospecific enzyme, which rivals toluene 4-monooxygenase of P. mendocina KR1 and toluene o-monooxygenase of Burkholderia cepacia G4 in its specificity.


1-Year Outcomes of Everolimus-Eluting Bioresorbable Scaffolds Versus Everolimus-Eluting Stents: A Propensity-Matched Comparison of the GHOST-EU and XIENCE V USA Registries.
The purpose of this study was to compare the 1-year outcomes of the ABSORB everolimus-eluting bioresorbable scaffold (BRS) (Abbott Vascular, Santa Clara, California) and the XIENCE everolimus-eluting stent (EES) (Abbott Vascular) in patients undergoing percutaneous coronary intervention. Randomized studies of the ABSORB BRS have been performed in selected patient and lesion scenarios. The available registries of the ABSORB BRS reflect real-world practice more closely compared with randomized studies, but most of them are limited by the small sample size and the lack of comparative outcomes versus second-generation drug-eluting stents. A total of 1,189 consecutive patients treated with ABSORB BRS from the GHOST-EU (Gauging coronary Healing with bioresorbable Scaffolding plaTforms in EUrope) registry and 5,034 patients treated with XIENCE EES from the XIENCE V USA registry were analyzed. Clinical outcomes were compared with the use of propensity-score matching techniques and reported as Kaplan-Meier estimates and absolute risk difference (D) with 95% confidence intervals (CIs). The primary endpoint was a device-oriented composite endpoint, including cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization at 1-year follow-up. After propensity score matching was performed for the entire population (N = 6,223), there were 905 matched pairs of patients. In the matched cohort (N = 1,810), there was no significant difference between ABSORB BRS and XIENCE EES in the risk of device-oriented composite endpoint at 1 year (5.8% vs. 7.6%, D = -1.8 [95% CI: -4.1 to 0.5]; p = 0.12). Cardiac death was less likely to occur in the ABSORB BRS group (0.7% vs. 1.9%, D = -1.2 [95% CI: -2.2 to 0.2]; p = 0.03), and a trend toward a reduction in myocardial infarction was noted with ABSORB BRS compared with XIENCE EES (2.4% vs. 4.0%, D = -1.6 [95% CI: -3.2 to 0.0]; p = 0.07). Conversely, no differences in ischemia-driven target lesion revascularization (4.6% vs. 3.5%, D = 1.1 [95% CI: -0.7 to 2.9]; p = 0.22) and definite or probable device thrombosis (1.8% vs. 1.1%, D = 0.7 [95% CI: -0.4 to 1.8]; p = 0.23) were detected between ABSORB BRS and XIENCE EES. In a contemporary large cohort of patients undergoing percutaneous coronary intervention with ABSORB BRS, the combined rate of ischemic events at 1 year was low and nonsignificantly different compared with matched patients treated with XIENCE EES.


A Critical Role for DLK and LZK in Axonal Repair in the Mammalian Spinal Cord.
The limited ability for axonal repair after spinal cord injury underlies long-term functional impairment. Dual leucine-zipper kinase [DLK; MAP kinase kinase kinase 12; MAP3K12] is an evolutionarily conserved MAP3K implicated in neuronal injury signaling from Caenorhabditis elegans to mammals. However, whether DLK or its close homolog leucine zipper kinase (LZK; MAP3K13) regulates axonal repair in the mammalian spinal cord remains unknown. Here, we assess the role of endogenous DLK and LZK in the regeneration and compensatory sprouting of corticospinal tract (CST) axons in mice of both sexes with genetic analyses in a regeneration competent background provided by PTEN deletion. We found that inducible neuronal deletion of both DLK and LZK, but not either kinase alone, abolishes PTEN deletion-induced regeneration and sprouting of CST axons, and reduces naturally-occurring axon sprouting after injury. Thus, DLK/LZK-mediated injury signaling operates not only in injured neurons to regulate regeneration, but also unexpectedly in uninjured neurons to regulate sprouting. Deleting DLK and LZK does not interfere with PTEN/mTOR signaling, indicating that injury signaling and regenerative competence are independently controlled. Together with our previous study implicating LZK in astrocytic reactivity and scar formation, these data illustrate the multicellular function of this pair of MAP3Ks in both neurons and glia in the injury response of the mammalian spinal cord.SIGNIFICANCE STATEMENT Functional recovery after spinal cord injury is limited because of a lack of axonal repair in the mammalian CNS. Dual leucine-zipper kinase (DLK) and leucine zipper kinase (LZK) are two closely related protein kinases that have emerged as regulators of neuronal responses to injury. However, their role in axonal repair in the mammalian spinal cord has not been described. Here, we show that DLK and LZK together play critical roles in axonal repair in the mammalian spinal cord, validating them as potential targets to promote repair and recovery after spinal cord injury. In addition to regulating axonal regeneration from injured neurons, both kinases also regulate compensatory axonal growth from uninjured neurons, indicating a more pervasive role in CNS repair than originally anticipated.


Usefulness of perfusion index to detect the effect of brachial plexus block.
The traditional method to evaluate adequacy of the block for surgery is based on loss of sensory response to stimuli, which requires patient cooperation. Several methods have been described for objective assessment of the nerve block. The aim of the study was to investigate whether perfusion index (PI), a measure of peripheral perfusion from a pulse oximetry finger sensor, is a reliable and objective method for assessing the adequacy of infraclavicular blockade and to describe the time course of PI changes once peripheral nerve block has been achieved during surgery. The study was performed on patients scheduled for elective hand, wrist and forearm surgery under infraclavicular brachial plexus block. The pulse oximetry sensor was affixed to a finger ipsilateral to the side of the infraclavicular block for continuous measurement of PI. The average PI and the average percent change in PI from baseline, at 10, 20 and 30 min from the administration of the block were calculated. Baseline values of PI ranged from 0.6 to 4.7 % in 44 patients for whom infraclavicular block was effective and 1.8 to 2.4 % in 2 patients for whom infraclavicular block failed. Differences were not significant (p = 0.60). In the effective infraclavicular block group, PI rose continuously during the 30-min observation period. At 10 min, PI increased by (mean ± standard deviation) 120 ± 119 % from baseline. At 20 and 30 min, perfusion index increased by 133 ± 125 % and 155 ± 144 % from baseline. All changes from baseline were significant (p < 0.01). The perfusion index is a predictor of infraclavicular block success. The largest changes in PI occur 30 min after the block administration but significant changes in PI were detected 10 min after administration. Perfusion index monitoring may provide a highly valuable tool to quickly evaluate the success of regional anesthesia of the upper extremity in clinical practice.


Effect of two mouthwashes on salivary ph.
To analyze the effect of two mouthwashes on salivary pH and correlate it with age, buffer capacity and saliva flow rate in healthy volunteers, a crossover phase IV clinical study involving three age-based groups was designed. Two commercial mouthwashes (MW), Cool Mint ListerineR (MWa) and Periobacter R (MWb) were used. The unstimulated saliva of each individual was first characterized by measuring flow rate, pH, and buffer capacity. Salivary pH was evaluated before rinsing with a given MW, immediately after rinsing, 5 minutes later, and then every 10 min (at 15, 25, 35 min) until the baseline pH was recovered. Paired t-test, ANOVA with a randomized block design, and Pearson correlation tests were used. Averages were 0.63 mL/min, 7.06, and 0.87 for flow rate, pH, and buffer capacity, respectively. An immediate significant increase in salivary pH was observed after rinsing, reaching average values of 7.24 (MWb) and 7.30 (MWa), which declined to an almost stable value 15 minutes. The great increase in salivary pH, after MW use shows that saliva is a dynamic system, and that the organism is capable of responding to a stimulus with changes in its composition. It is thus evident that pH of the external agent alone is not a good indicator for its erosive potential because biological systems tend to neutralize it. The results of this study enhance the importance of in vivo measurements and reinforce the concept of the protective action of saliva.


Experimentally based sea urchin gene regulatory network and the causal explanation of developmental phenomenology.
Gene regulatory networks for development underlie cell fate specification and differentiation. Network topology, logic and dynamics can be obtained by thorough experimental analysis. Our understanding of the gene regulatory network controlling endomesoderm specification in the sea urchin embryo has attained an advanced level such that it explains developmental phenomenology. Here we review how the network explains the mechanisms utilized in development to control the formation of dynamic expression patterns of transcription factors and signaling molecules. The network represents the genomic program controlling timely activation of specification and differentiation genes in the correct embryonic lineages. It can also be used to study evolution of body plans. We demonstrate how comparing the sea urchin gene regulatory network to that of the sea star and to that of later developmental stages in the sea urchin, reveals mechanisms underlying the origin of evolutionary novelty. The experimentally based gene regulatory network for endomesoderm specification in the sea urchin embryo provides unique insights into the system level properties of cell fate specification and its evolution.


Effects of tezosentan, a dual endothelin receptor antagonist, on the cardiovascular and renal systems of neonatal piglets during endotoxic shock.
Endothelin is a potent mediator of the cardiovascular and renal systems. Studies have found that endothelin has an important role in regulating cardiac function and renal perfusion in neonates who are suffering from endotoxic shock. The authors believe that blockade of the endothelin response during endotoxemia will have a beneficial effect on neonatal cardiac and renal functions. In this study the authors have examined the effects of tezosentan, a dual endothelin-receptor antagonist, on the cardiovascular and renal systems of neonatal piglets during endotoxemia. Thirteen piglets were subjected to endotoxic shock and divided into a fluid-therapy group that received 0.9% normal saline and a group that received tezosentan (1 mg/kg/h). Mean arterial pressure (MAP), heart rate (HR), and glomerular filtration rate (GFR) were plotted at baseline, 1, 2, and 3 hours. Cardiac index (CI), renal blood flow (RBF), systemic vascular resistance (SVR), and renal vascular resistance (RVR) were obtained at baseline, 1, and 3 hours after baseline. (P <.05 for 3 hours versus baseline and tezosentan versus fluid). Although fluid therapy in endotoxemia had no significant effect on MAP and RVR, it significantly increased HR (139 plus minus 17 to 246 plus minus 17 beats/min) and SVR (0.08 plus minus 0.05 to 0.33 plus minus 0.09 mm Hg/mL/min) and decreased CI (407 plus minus 208 to 98 plus minus 13 mL/min/kg), RBF (1.84 plus minus 0.38 to 0.97 plus minus 0.34 mL/min/kg kidney), and GFR (0.20 plus minus 0.05 to 0.11 plus minus 0.04 mL/min/kg) at 3 hours. The use of tezosentan also significantly increased HR (130 plus minus 14 to 220 plus minus 31 beats/min), but unlike in the fluid therapy group, there was a significant fall in MAP (77 plus minus 10 to 54 plus minus 9 mm Hg) and RVR (1.92 plus minus 0.44 to 1.77 plus minus 0.64 mm Hg/mL/min) and a less severe decrease in CI (482 plus minus 188 to 176 plus minus 67 mL/min/kg) at 3 hours. SVR, RBF, and GFR were maintained. Endotoxic shock affected cardiac and renal functions in both treatment groups. Fluid therapy alone could not prevent a statistically significant fall in CI, RBF, and GFR or prevent the increase in HR and SVR. Endothelin antagonism with tezosentan resulted in a statistically significant fall in MAP and RVR from baseline, not seen in the fluid-therapy group. CI and RBF were significantly higher, and MAP, SVR, and RVR were significantly lower when compared with the fluid-therapy group at 3 hours. GFR also was maintained at baseline with tezosentan. During endotoxemia, endothelin antagonism maintained renal and cardiac functions better than with fluid therapy alone.


Disparities in COVID-19 vaccine uptake among health care workers.
COVID-19 vaccine uptake by healthcare workers (HCWs) is critical to protect HCWs, the patients they care for, and the healthcare infrastructure. Our study aims to examine the actual COVID-19 vaccination rate among HCWs and identify risk factors associated with vaccine nonacceptance. A retrospective analysis of COVID-19 vaccinations for HCWs at a large multi-site US academic medical center from 12/18/2020 through 05/04/2021. Comparisons between groups were performed using unpaired student t-test for continuous variables and the chi-square test for categorical variables. A logistic regression analysis was used to assess the associations between vaccine uptake and risk factor(s). Of the 65,270 HCWs included in our analysis, the overall vaccination rate was 78.6%. Male gender, older age, White and Asian race, and direct patient care were associated with higher vaccination rates (P <.0001). Significant differences were observed between different job categories. Physicians and advanced practice staff, and healthcare professionals were more likely to be vaccinated than nurses and support staff. Our data demonstrated higher initial vaccination rates among HCWs than the general population national average during the study period. We observed significant disparities among different high-risk HCWs groups, especially among different job categories, black HCWs and younger HCWs despite their high risk of contracting the infection. Interventions to address lower vaccination rate and vaccine hesitancy should be built with these disparities and differences in mind to create more targeted interventions.


Electrochemical tuning of MoS2 nanoparticles on three-dimensional substrate for efficient hydrogen evolution.
Molybdenum disulfide (MoS2) with the two-dimensional layered structure has been widely studied as an advanced catalyst for hydrogen evolution reaction (HER). Intercalating guest species into the van der Waals gaps of MoS2 has been demonstrated as an effective approach to tune the electronic structure and consequently improve the HER catalytic activity. In this work, by constructing nanostructured MoS2 particles with largely exposed edge sites on the three-dimensional substrate and subsequently conducting Li electrochemical intercalation and exfoliation processes, an ultrahigh HER performance with 200 mA/cm(2) cathodic current density at only 200 mV overpotential is achieved. We propose that both the high surface area nanostructure and the 2H semiconducting to 1T metallic phase transition of MoS2 are responsible for the outstanding catalytic activity. Electrochemical stability test further confirms the long-term operation of the catalyst.


Dominant chymotrypsin-like esterase activity in human lymphocyte granules is mediated by the serine carboxypeptidase called cathepsin A-like protective protein.
We identified a chymotrypsin-like activity in the granules of IL-2 lymphokine-activated killer (LAK) cells and a NK cell line (YT) that reacted preferentially with the oligopeptide substrate succinyl-Phe-Leu-Phe-thiobenzyl ester (Suc-Phe-Leu-Phe-SBzl). The enzyme was isolated by detergent extraction of sedimented cytotoxic granules and then by a sequence of sieve, hydrophobic, and anion exchange chromatography. On SDS-PAGE, the protein migrated at 42 kDa in nonreduced form and became two bands (31 and 19 kDa, respectively) after reduction. Amino-terminal sequencing of the reduced protein bands revealed 100% homology with cathepsin A-like protective protein (CAPP), a lysosomal enzyme that expresses serine carboxypeptidase and deamidase activities. The carboxypeptidase activity of lymphocyte CAPP was verified by showing that the protease preferred hydrophobic amino acids in the penultimate position of the C terminus (i.e., cleaved arginine from dansyl-Phe-Leu-Arg). The presence of lymphocyte CAPP in secretory lysosomes was demonstrated by showing that Suc-Phe-Leu-Phe-SBzl activity co-migrated with tryptase and Asp-ase activities on Percoll density gradients and that 95% of the Suc-Phe-Leu-Phe-SBzl activity in granule fractions of cavitated YT cells could be immunoprecipitated with an anti-CAPP antiserum. In addition, calcium ionophore-stimulated YT cells were shown to secrete immunoprecipitable CAPP. As proposed for platelets, lymphocyte CAPP may be secreted to function extracellularly by inactivating bioactive peptides.


[The effect of changes in interpersonal closeness on person perception].
The purpose of this study was to investigate changes in person perception due to changes in interpersonal closeness. Immediately after beginning the first semester, four female university freshmen belonging to a student club were asked: 1) to tell what they thought of or knew about three fellow club members (stimulus persons; SPs); and 2) to indicate liking for SPs, and rate them in terms of factors related to interpersonal attraction. The interviews, with the same interviewees and SPs, were repeated seven more times during the following six months. Content of their statements for each SP was analyzed, and results indicated: 1) Liking for SPs was positively correlated with the frequency of statements concerning SPs' disposition, but negatively with that of SP's objective information; 2) the more distant the subject-SP relationship became after initial closeness, the more the frequency of statements about SP's objective information, and the less that of SPs' disposition. It was suggested that self-other relationship had an effect on person perception.


Whole-body magnetic resonance imaging and positron emission tomography-computed tomography in oncology.
The advent of positron emission tomography-computed tomography (PET-CT) and whole-body magnetic resonance imaging (WB-MRI) has introduced tumor imaging with a systemic and functional approach compared with established sequential, multimodal diagnostic algorithms.Whole-body PET with [18F]-fluoro-2-desoxy-glucose is a useful imaging procedure for tumor staging and monitoring that can visualize active tumor tissue by detecting pathological glucose metabolism. The combination of PET with the detailed anatomical information of multislice computed tomography as dual-modality scanners has markedly increased lesion localization and diagnostic accuracy compared with both modalities as standalone applications.Hardware innovations, such as the introduction of multi-receiver channel whole-body MRI scanners at 1.5 and, recently, 3 T, combined with acquisition acceleration techniques, have made high-resolution WB-MRI clinically feasible. Now, a dedicated assessment of individual organs with various soft tissue contrast, spatial resolution, and contrast media dynamics can be combined with whole-body anatomical coverage in a multiplanar imaging approach. More flexible protocols (eg, T1-weighted turbo spin-echo and short inversion recovery imaging, dedicated lung imaging or dynamic contrast-enhanced studies of the abdomen) can be performed within 45 minutes.Whole-body magnetic resonance imaging has recently been proposed for tumor screening of asymptomatic individuals, and potentially life-changing diagnoses, such as formerly unknown malignancy, have been reported. However, larger patient cohort studies will have to show the cost efficiency and the clinical effectiveness of such an approach.For initial tumor staging, PET-CT has proved more accurate for the definition of T-stage and lymph node assessment, mainly because of the missing metabolic information in WB-MRI. However, new applications, such as magnetic resonance whole-body diffusion-weighted imaging or lymphotropic contrast agents, may significantly increase sensitivity in near future. Whole-body magnetic resonance imaging has shown advantages for the detection of distant metastatic disease, especially from tumors frequently spreading to the liver or brain and as a whole-body bone marrow screening application. Within this context, WB-MRI is highly accurate for the detection of skeletal metastases and staging of multiple myeloma. This article summarizes recent developments of CT/PET-CT and WB-MRI and highlights their performance within the scope of systemic oncological imaging.


Association of Biomarkers for Human Papillomavirus With Survival Among Adults With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma.
The presence of high-risk human papillomavirus (HPV) has been associated with a favorable outcome in Barrett high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Nevertheless, the prognostic significance of other HPV-related biomarkers (ie, retinoblastoma protein [pRb], cyclin D1 [CD1], minichromosome maintenance protein [MCM2] and Ki-67) is unknown. To examine the association between HPV-related biomarkers and survival in adult patients with Barrett HGD and EAC. This retrospective case-control study examined the hypothesis that the HPV-related cell cycle markers (pRb, CD1, and Ki-67) and the viral surrogate marker (MCM2) may be associated with a favorable prognosis in Barrett HGD and EAC. Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction and immunohistochemistry for the HPV-related biomarkers. Recruitment of patients occurred in secondary and tertiary referral centers, with 151 patients assessed for eligibility. The study period was from December 1, 2002, to November 28, 2017, and the dates of analysis were from September 9, 2011, to November 28, 2017. Disease-free survival and overall survival. Of 151 patients assessed for eligibility, 9 were excluded. Among the 142 patients with Barrett HGD or EAC (126 [88.7%] men; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. No association with disease-free survival was noted for pRb, CD1, Ki-67, and MCM2. In regard to overall survival, only low expression of CD1 had a favorable prognosis (hazard ratio [HR], 0.53; 95% CI, 0.30-0.95; adjusted P = .03). All the biomarkers stratified by HPV status showed significant associations with survival. Patients with HPV-positive, low-expression pRb esophageal tumors were associated with a significantly improved disease-free survival compared with the HPV-negative, high-expression Rb tumors (HR, 0.33; 95% CI, 0.12-0.93; adjusted P = .04). Similarly, HPV-positive, low-expression CD1 was associated with a significantly favorable disease-free survival (HR, 0.26; 95% CI, 0.09-0.76; adjusted P = .01), as was HPV-positive, high-expression MCM2 (HR, 0.27; 95% CI, 0.09-0.78; adjusted P = .02). In regard to overall survival, HPV was significantly associated only with low CD1 (HR, 0.38; 95% CI, 0.15-0.94; adjusted P = .04). This study's findings suggest that low expression of CD1 appears to be an independent prognostic marker in Barrett HGD and EAC. Human papillomavirus positivity in combination with pRb, CD1, MCM2, and Ki-67 was associated with a survival benefit in esophageal tumors. These findings suggest the possibility of personalization of therapy for Barrett HGD and EAC based on viral status.


Capture of arginine at low concentrations by a marine psychrophilic bacterium.
The cells of the marine bacterium Ant-300 were found to take up arginine when this substrate was at low concentrations. The cells possessed an uptake system(s) that specifically transported l-arginine. The kinetic parameters for uptake appeared to differ when the cells were exposed to nanomolar and micromolar concentrations of the amino acid. Uptake over this concentration range functioned in the absence of an exogenous energy source, even after the cells had been preincubated in unsupplemented artificial seawater. Respiratory activity appeared to be a more important driving force for arginine uptake than adenosine 5'-triphosphate hydrolysis. The cells also exhibited chemotaxis toward l-arginine. The minimum arginine concentration needed to elicit a chemotactic response was between 10 and 10 M. It is proposed that the capture of arginine by cells of Ant-300 in nutrient-depleted waters, which are typical of the open ocean, proceeds via high-affinity active transport, whereas in substrate-enriched seawater, capture involves chemotaxis and an active transport mechanism with reduced affinity for the substrate.


Acute rheumatic fever: is it returning to Virginia?
In summary, rheumatic fever seems to be on the rise in the United States. It remains to be seen whether this case is an example of a resurgence of ARF in adults in Virginia, but it probably does, since there are a number of cases being seen in the pediatric population.


Pentosan Polysulfate Sodium-Associated Pigmentary Retinopathy: Risk Factors and Fundus Findings.
To evaluate the risk factors and fundus findings of patients with potential PPS-associated retinopathy. A retrospective chart review was performed of patients exposed to PPS who had a dilated fundus examination at a large retina-only practice from 2018-21. Multimodal images were evaluated by masked reviewers. A total of 148 patients were included, of whom 33 (22%) had PPS-associated retinopathy, and 115 (78%) did not. The mean age was 60.3 years old, and the mean follow-up was 11.8 months. The PPS-associated retinopathy group had higher mean cumulative doses of PPS (1600g±849 vs 864g±852, P < 0.0001, Mann-Whitney test) and longer duration of PPS use (13.6 years vs 7.48, P < 0.0001). There was no statistically significant difference based on a history of kidney or liver disease or the dosage per day for the weight, body mass index, body surface area, or lean body weight. Of the patients with PPS-associated retinopathy whose genetic results were available, 15 of 16 (93%) were heterozygous for variants of uncertain significance. A longer duration of PPS use and higher cumulative dosage of PPS were associated with an increased risk of developing PPS-associated pigmentary retinopathy. The role of genetic mutations in patients exposed to PPS is still to be determined.


Age-related changes of cortical excitability in subjects with sleep-enhanced centrotemporal spikes: a somatosensory evoked potential study.
Middle-latency somatosensory evoked potentials (SEPs) of particularly large amplitude (giant) have been reported in subjects with benign childhood epilepsy with centrotemporal spikes (BECT) and in normal children, which usually show significant age-related changes. However, the mechanisms by which age modifies the appearance of centrotemporal spikes and giant SEPs in these children, are not known. The characteristics of SEPs were studied in a group of 18 subjects (10 males and 8 females, aged 7.1-17.2 years) with sleep-enhanced centrotemporal spikes, with or without BECT and the results were compared with those obtained from a group of age-matched normal controls. Giant SEPs were recorded in 6 subjects and, in 3 of these, EEG spikes evoked by hand tapping were obtained also. No subjects with giant SEPs were found in subjects older than 12 years, and an age-related decrease in amplitude of giant SEPs as this age approached was observed. Moreover, at repeated SEP recordings, a clear trend towards a more important reduction in amplitude of giant SEPs over the temporal and parietal than over the central regions was evident. The study of EEG spikes evoked by hand tapping showed a striking similarity between the averaged evoked spikes and the main negative component of giant SEPs. It was also possible to observe that the spike negative peak recorded over the central areas always preceded the same component recorded over the parietal and temporal areas by 5-15 ms. Our study seems to support the idea that giant SEPs in subjects with centrotemporal spikes are generated by a complex mechanism different from that at the basis of the normal N60 component of SEPs; they also show peculiar age-related modifications which can be interpreted in terms of maturational changes of brain excitability/inhibition and probably constitute a tool for monitoring the clinical course of BECT, when present.


Heart rate variability (HRV) in kidney failure: measurement and consequences of reduced HRV.
A common cause of death in end-stage renal disease (ESRD) patients on dialysis is sudden cardiac death (SCD). Compared to the general population, the percentage of cardiovascular deaths that are attributed to SCD is higher in patients treated by dialysis. While coronary artery disease (CAD) is the predominant cause of SCD in dialysis patients, reduced heart rate variability (HRV) may play a role in the higher risk of SCD among other risk factors. HRV refers to beat-to-beat alterations in heart rate as measured by periodic variation in the R-R interval. HRV provides a non-invasive method for investigating autonomic input into the heart. It quantifies the amount by which the R-R interval or heart rate changes from one cardiac cycle to the next. The autonomic nervous system transmits impulses from the central nervous system to peripheral organs and is responsible for controlling the heart rate, blood pressure and respiratory activity. In normal individuals, without cardiac disease, the heart rate has a high degree of beat-to-beat variability. HRV fluctuates with respiration: it increases with inspiration and decreases with expiration and is primarily mediated by parasympathetic activity. HRV has been used to evaluate and quantify the cardiac risk associated with a variety of conditions including cardiac disorders, stroke, multiple sclerosis and diabetes. In this narrative review, we will examine the association between HRV and SCD. This report explains the measurement of HRV and the consequences of reduced HRV in the general population and dialysis patients. Lastly, this review will outline the possible use of HRV as a clinical predictor for SCD in the dialysis population. The current understanding of SCD based on HRV findings among the ESRD population support the use of more aggressive treatment of CAD; greater use of angiotensin converting enzyme inhibitor (ACE-i)/angiotensin receptor blockers (ARBs) and beta-blockers and more frequent and/or nocturnal haemodialysis to improve the survival of a patient with kidney failure.


Toward a framework for systemic multi-hazard and multi-risk assessment and management.
In our increasingly interconnected world, natural hazards and their impacts spread across geographical, administrative, and sectoral boundaries. Owing to the interrelationships between multi-hazards and socio-economic dimensions, the impacts of these types of events can surmount those of multiple single hazards. The complexities involved in tackling multi-hazards and multi-risks hinder a more holistic and integrative perspective and make it difficult to identify overarching dimensions important for assessment and management purposes. We contribute to this discussion by building on systemic risk research, especially the focus on interconnectedness, and suggest ways forward for an integrated multi-hazard and multi-risk framework that should be beneficial in real-world applications. In this article, we propose a six-step framework for analyzing and managing risk across a spectrum ranging from single-to multi- and systemic risk.


Group B Streptococci Screening Before Repeat Cesarean Delivery: A Cost-Effectiveness Analysis.
To estimate the cost-effectiveness of universal group B streptococci (GBS) screening in women with a singleton pregnancy planning a repeat cesarean delivery. We conducted a decision analysis from a health care perspective to compare the cost-effectiveness of GBS screening for women planning a repeat cesarean delivery. With universal screening, all GBS-positive women who labored before a scheduled cesarean delivery received antibiotic prophylaxis. With no screening, women who presented in labor received antibiotics based on risk-based criteria. Neonates born to women colonized with GBS were at risk for early-onset GBS disease, disability, and death. We assumed a GBS prevalence of 25%, that 26.6% of women labored between 35 weeks of gestation and their scheduled time for cesarean delivery, and that 3.3% who planned a repeat cesarean delivery instead delivered vaginally. The primary outcome was cost per neonatal quality-adjusted life-year gained, with a cost-effectiveness threshold of $100,000 per quality-adjusted life-year. Neonatal quality of life was assessed using five health states (healthy, mild, moderate, or severe disability, and death) with a life expectancy of 79 years for healthy neonates. One-way sensitivity and Monte Carlo analyses were used to evaluate the results. In the base case, universal GBS screening in women planning a repeat cesarean delivery was not cost-effective compared with no screening, costing $114,445 per neonatal quality-adjusted life-year gained. The cost to prevent an adverse outcome from GBS exceeded $400,000. If greater than 28% of women were GBS-positive, greater than 29% labored before their scheduled delivery, or greater than 10% delivered vaginally, universal screening became cost effective. Universal GBS screening in women with a singleton pregnancy planning a repeat cesarean delivery may not be cost-effective in all populations. However, in populations with a high GBS prevalence, women at high risk of laboring before their scheduled cesarean delivery, or women who may ultimately opt for a vaginal delivery, GBS screening may be cost effective.


Mechanisms of heme iron absorption: current questions and controversies.
Iron is a critical micronutrient, and iron derived from heme contributes a large proportion of the total iron absorbed in a typical Western diet. Heme iron is absorbed by different mechanisms than non-heme iron, but despite considerable study over many years these mechanisms remain poorly understood. This review provides an overview of the importance of heme iron in the diet and discusses the two prevailing hypotheses of heme absorption; namely receptor mediated endocytosis of heme, and direct transport into the intestinal enterocyte by recently discovered heme transporters. A specific emphasis is placed on the questions surrounding the site of heme catabolism and the identity of the enzyme that performs this task. Additionally, we present the hypothesis that a non-heme iron transport protein may be required for heme iron absorption and discuss the experiences of our laboratory in examining this hypothesis.


A systematic review on heart-rate recovery to monitor changes in training status in athletes.
Heart-rate recovery (HRR) has been proposed as a marker of autonomic function and training status in athletes. The authors performed a systematic review of studies that examined HRR after training. Five cross-sectional studies and 8 studies investigating changes over time (longitudinal) met our criteria. Three out of 5 cross-sectional studies observed a faster HRR in trained compared with untrained subjects, while 2 articles showed no change as a result of training. Most longitudinal studies observed a corresponding increase in HRR and power output (training status). Although confounding factors such as age, ambient temperature, and the intensity and duration of the exercise period preceding HRR make it difficult to compare these studies, the available studies indicated that HRR was related to training status. Therefore, the authors conclude that HRR has the potential to become a valuable tool to monitor changes in training status in athletes and less well-trained subjects, but more studies and better standardization are required to match this potential.


Access to healthcare in Chilean prisons: an inmates' perspective.
To analyze the perception of access to Chilean prisons in a representative national sample of persons deprived of liberty as well as to examine the most important covariates of such access. This study uses secondary data from the First National Survey on the Quality of Prison Life (2014), which investigated inmates' perceptions regarding access to health services inside the prisons. To do this, it uses descriptive statistics and a logistic regression model. Descriptive results at the national level show that access to health services in prisons tends to be "difficult" (44.7% of cases in this category). Multivariate logistic regression results indicate that men (OR=0.43) and those who reported better infrastructure (OR=0.70) were less likely to report "difficult access to health services". On the other hand, prison inmates (OR=1.61) and those who had reported higher levels of mistreatment (OR=1.26) were associated with a higher probability of reporting "difficult access to health services". Our study suggests that access to health care is dynamically linked to other aspects of life within prisons such as the composition of the prison population (gender), some of the material aspects of prisons (infrastructure, type of facility), and even some relational aspects (level of mistreatment/abuse). Future studies could further extend the debate on healthcare in prisons, incorporating more complex both variables and analyses.


DRG "creep". Pitfalls and sanctions to avoid.
In 1983, with the advent of the Medicare prospective payment system, the physician's role became crucial in determining a hospital's reimbursement for treatment of a Medicare patient. The correct diagnosis-related group assignment depends upon the physician's accurate designation of the primary and secondary discharge diagnoses. Manipulation of this information can result in an inaccurate payment, and the physician is ultimately responsible for the misrepresentation. Physicians' recognition of the importance of their responsibility to designate complete and accurate diagnostic and procedural information can help avoid problems, including the potential for sanctions against physicians who unwittingly contribute to fraud and abuse.


Isolation of the biosynthetic gene cluster for tautomycetin, a linear polyketide T cell-specific immunomodulator from Streptomyces sp. CK4412.
The bacterial genus Streptomyces has long been appreciated for its ability to produce various kinds of medically important secondary metabolites, such as antibiotics, anti-tumour agents, immunosuppressants and enzyme inhibitors. Tautomycetin (TMC), which is produced by Streptomyces sp. CK4412, is a novel activated T cell-specific immunosuppressive compound with an ester bond linkage between a terminal cyclic anhydride moiety and a linear polyketide chain bearing an unusual terminal alkene. Using a Streptomyces polyketide methylmalonyl-CoA acyltransferase gene as a probe, three overlapping cosmids were isolated from the genomic library of TMC-producing Streptomyces sp. CK4412. Sequence information of an approximately 70 kb contiguous DNA region revealed two multi-modular type I polyketide synthases (PKSs), and 12 additional gene products presumably involved in TMC biosynthesis. The deduced roles for most of the TMC PKS catalytic domains were consistent with the expected functions necessary for TMC chain elongation and processing. In addition, disruption of a putative TMC acyl-CoA transferase gene, located upstream of the PKS gene locus, completely abolished TMC biosynthesis. Taken together, these data provide strong supporting evidence that the cloned gene cluster identified in this study is responsible for TMC biosynthesis in Streptomyces sp. CK4412, and set the stage for detailed genetic and biochemical studies of the biosynthesis of this important metabolite.


Model of peripheral and amblyopic hyperacuity.
Vernier thresholds rise much more rapidly in the periphery than do grating thresholds. A similar dissociation between acuity and hyperacuity has been shown to be present in strabismic but not in anisometropic amblyopia, thus leading to the suggestion that the strabismic fovea is similar to the normal periphery. Here it is shown that a quantitative model for spatial pattern discrimination, which accounts for foveal hyperacuity data, can be extended to encompass both the periphery and amblyopia if appropriate alterations are made. For the periphery it is necessary to increase the size of model receptive fields and to introduce both spatial undersampling and position irregularity (i.e. irregularity in the location of cortical filters). The strabismic fovea also requires spatial undersampling and position irregularity but no change in receptive field size. Defects in the good eye of strabismics can be explained by spatial irregularity. Finally, the anisometropic fovea requires a reduction in mechanism sensitivity but neither spatial undersampling nor position irregularity.


[The content of substances of low and medium molecular mass in biologic liquids in patients with erysipelas].
The endogenic intoxication is a metabolic response to any aggressive factor. The concentration of substances of low and medium molecular mass biologic liquids of organism w and medium molecular mass is a common indicator of intoxication syndrome. The study analyzed the role of uptake of substances of low and medium molecular mass in biologic liquids of organism in pathogenesis of erysipelas depending on period, form and ration of disease. The sampling included 76 patients with erysipelas aged from 27 to 62 years being in infection hospital for treatment. The concentration of substances of low and medium molecular mass was detected using M. Ya. Malakhova technique (1996). It is established that under erysipelas in organism occurs uptake of toxic substances in blood and gradual increase of concentration of substances of low and medium molecular mass in blood plasma and erythrocytes paralleled by corresponding changes of their concentration in urine. The altitude of increase of concentration level of substances of low and medium molecular mass and their reapportion between biologic mediums of organisms depends on period, form, ratio of course and degree of severity of pathologic process.


Rinse water for heat labile endoscopy equipment.
The increase in use of endoscopic procedures in diagnosis and surgical treatment has underlined the need for safe cleaning methods for these instruments. While decontamination has been reviewed by several Working Groups in Britain, the problems relating to the prevention of contamination of rinse water and its monitoring procedures have not been addressed previously. This report from the Joint Working Party identifies the problems, and provides guidance on the monitoring and provision of high-quality rinse water.


Bioactive lipids in schizophrenia.
Bioactive lipids, in particular arachidonic acid (AA), are vital for monoaminergic neurotransmission, brain development and synaptic plasticity. Phospholipases A2 (PLA2) are key-enzymes in AA metabolism and are activated during monoaminergic neurotransmission. Reduced membrane AA levels, and an altered activity of PLA2 have been found in peripheral membranes of drug-naïve patients with schizophrenia with some conflicting results in more chronic patient populations. Furthermore, in vivo brain phosphorus-31 magnetic resonance spectroscopy suggests reduced lipid membrane precursors (phosphomonoesters) and increased membrane breakdown products (phosphodiesters) in drug-naïve or early treated first-episode schizophrenia patients compared to age-matched controls or chronic populations and these changes were correlated with peripheral red blood cell membrane AA levels. We postulate that processes modulating membrane lipid metabolism are associated with psychotic illnesses and might partially explain the mechanism of action of antipsychotic agents, as well as experimental agents such as purified ethyl-eicosapentaenoic acid (E-EPA). Recent supplementation trials suggest that E-EPA is a modestly effective augmentation treatment resulting in reduced doses of antipsychotic medication in acutely ill patients with schizophrenia (but not in residual-type schizophrenia). This review investigates the role of bioactive lipids in schizophrenia and its treatment, as well as its potential use in prevention.


Exosomes Derived from Human Induced Pluripotent Stem Cells Ameliorate the Aging of Skin Fibroblasts.
Stem cells and their paracrine factors have emerged as a resource for regenerative medicine. Many studies have shown the beneficial effects of paracrine factors secreted from adult stem cells, such as exosomes, on skin aging. However, to date, few reports have demonstrated the use of exosomes derived from human pluripotent stem cells for the treatment of skin aging. In this study, we collected exosomes from the conditioned medium of human induced pluripotent stem cells (iPSCs) and investigated the effect on aged human dermal fibroblasts (HDFs). Cell proliferation and viability were determined by an MTT assay and cell migration capacity was shown by a scratch wound assay and a transwell migration assay. To induce photoaging and natural senescence, HDFs were irradiated by UVB (315 nm) and subcultured for over 30 passages, respectively. The expression level of certain mRNAs was evaluated by quantitative real-time PCR (qPCR). Senescence-associated-β-galactosidase (SA-β-Gal) activity was assessed as a marker of natural senescence. As a result, we found that exosomes derived from human iPSCs (iPSCs-Exo) stimulated the proliferation and migration of HDFs under normal conditions. Pretreatment with iPSCs-Exo inhibited the damages of HDFs and overexpression of matrix-degrading enzymes (MMP-1/3) caused by UVB irradiation. The iPSCs-Exo also increased the expression level of collagen type I in the photo-aged HDFs. In addition, we demonstrated that iPSCs-Exo significantly reduced the expression level of SA-β-Gal and MMP-1/3 and restored the collagen type I expression in senescent HDFs. Taken together, it is anticipated that these results suggest a therapeutic potential of iPSCs-Exo for the treatment of skin aging.


The potential for hormonal prevention trials.
Breast and prostate cancer are significant causes of morbidity and mortality and are very similar in etiology, epidemiology, and modalities of treatment. Investigational strategies in the prevention of these malignancies also have strong parallels. The National Cancer Institute is sponsoring several large scale clinical trials involving hormonal manipulation and cancer prevention. In the Breast Cancer Prevention Trial, 16,000 women at high risk for breast cancer are being randomized to receive the antiestrogen agent tamoxifen or placebo for 5 years in an effort to determine if breast cancer development can be inhibited. In a similar trial, the Prostate Cancer Prevention Trial, 18,000 men older than 55 years of age will be randomized to receive finasteride, a 5-alpha-reductase inhibitor, or placebo to determine if inhibition of dihydrotestosterone synthesis in the prostate over a prolonged period will lead to a decreased incidence of prostate cancer. Both clinical trials offer the possibility of demonstrating that a hormonal intervention can decrease an individual's risk of developing breast or prostate cancer. They also have the potential of providing critical information about cancer risk, etiology, screening, and genetics, as well as quantifying the risks and benefits of specific preventive interventions.


Companies' Responses to a Tax on Sugar-Sweetened Beverages: Implications for Research Comment on "Understanding Marketing Responses to a Tax on Sugary Drinks: A Qualitative Interview Study in the United Kingdom, 2019".
The paper by Forde et al, newly published in this journal, sheds light on how sugar-sweetened beverages (SSBs) companies may react to the introduction of a SSB tax. This commentary goes over the paper's main findings and drafts implications for research on the impacts of SSB taxes. First and foremost, future research needs to assess the actual impacts of SSB taxes on companies' actions, especially reformulation. Second, cross-country research, comparing large companies with similar beverage portfolios, could bring insights about the impacts of external factors, including different SSB taxes, on companies' decisions. Third, SSB companies' actions are potential confounders in empirical studies looking into the impacts of SSB taxes on prices, demand, or other outcomes. Researchers need to be aware of and discuss such aspects thoroughly in their studies, as the implications for the interpretation of results are evident.


Effect of comorbidity on coronary reperfusion strategy and long-term mortality after acute myocardial infarction.
Chronic comorbidity is a prognostic determinant in ST-segment elevation myocardial infarction (STEMI). This study was aimed at determining to what extent this effect is independent or derives from adoption of different therapeutic strategies. Seven hundred forty patients with STEMI hospitalized within 12 hours of symptom onset were enrolled in a population-based registry, in a health district comprising 1 teaching hospital with and 5 district hospitals without percutaneous coronary intervention (PCI) facilities. Three categories of increasing chronic comorbidity score (CS-1, n = 259; CS-2, n = 235; CS-3, n = 246) were identified from age-adjusted associations of comorbidities with 1-year survival. Higher CS was associated with lower direct admission or transferal rates to hospital with PCI. Coronary reperfusion therapy (PCI in 91.5% of 470 cases) was adopted less frequently (P < .001) in CS-3 (41.9%) than CS-2 (69.4%) or CS-1 (78.8%). Compared with conservative therapy (n = 270), reperfusion therapy reduced 1-year mortality in the whole series not significantly (P = .816) in CS-1 but significantly in CS-2 (P = .012) and CS-3 (P = .001). This trend persisted after adjusting for age, Killip class, and acute myocardial infarction location (hazard ratio [HR] = 0.63 [95% CI 0.14-2.80], HR = 0.62 [95% CI 0.31-1.25], and HR = 0.47 [95% CI 0.26-0.86] in CS-1, CS-2, and CS-3, respectively). By hypothesizing an extension of coronary reperfusion therapy utilization rate in CS-2 and CS-3 to that in CS-1, from 21 (crude analysis) to 20 (adjusted analysis) deaths were classified as potentially avoidable. Increased mortality in patients with chronic comorbidity and STEMI derives, at least in part, from underutilization of coronary reperfusion therapy, and might be reduced with a more aggressive therapeutic approach.


A lysosome-targetable fluorescent probe based on HClO-mediated cyclization reaction for imaging of hypochlorous acid.
Misplaced or excessive hypochlorous acid in lysosomes has a close association with lots of diseases, so monitoring hypochlorous acid in lysosomes is particularly necessary. In the present work, a novel lysosome-targetable fluorescent probe (Lyso-R-HClO) for hypochlorous acid based on a HClO-mediated cyclization reaction was developed. In the fluorescent probe, the morpholine unit and the site of a HClO-mediated cyclization reaction were, respectively, used as the lysosome-targetable group and the response group. The probe has high selectivity and high sensitivity to hypochlorous acid, with a linear range from 5.0 × 10-8 to 3.0 × 10-6 M and a detection limit of 15 nM; it was successfully used to image endogenous and exogenous lysosomal HClO. Finally, Lyso-R-HClO was further applied to image lysosomal HClO produced in bacteria-infected macrophage with satisfactory results, which indicate that it is an useful tool for studies of lysosomal HClO and the role of lysosome.


Secoisolariciresinol diglucoside alleviates hepatic lipid metabolic misalignment involving the endoplasmic reticulum-mitochondrial axis.
Secoisolariciresinol diglucoside (SDG) has positive effects on obesity and its complications. We investigated the effects and mechanism of SDG on high-fat and high-fructose diet (HFFD)-induced hepatic lipid metabolic disorders. Supplementation with 40 mg kg-1 d-1 SDG for 12 weeks significantly reduced the body weight and the ratio of liver and adipose tissue to body weight in HFFD-fed mice. Serum and hepatic TG, TC, HDL-C, and LDL-C levels became normalized, and hepatic lipid metabolic disorders lessened because of the downregulation of lipid synthesis genes and upregulation of lipid oxidation genes. SDG also alleviated endoplasmic reticulum (ER) stress and mitochondrial dysfunction by regulating the ER stress factors Bip, IRE1α, Xbp1, Atf6, Perk, and Chop and mitochondrial function-related genes Cox5b, Cox7a1, Cox8b, and Cycs. Results with HepG2 cells confirmed that SDG regulated lipid metabolic disorders by the ER stress-Ca2+-mitochondrial-associated pathway. Our study provides a strategy for the treatment of obesity and its related comorbidities.


Effects on growth after portal hypertension induced in young rats.
Physical growth retardation in children with hypertension portal was observed regardless of schistosomiasis. It has been suggested that the shunt of portal blood through portosystemic collateral vessels would result in metabolic consequences that would lead to the physical growth deficit observed. Study the effects of hypertension portal in the growth of young rats. The growth of 20 young rats, divided in the groups hypertension portal, n = 10, 103 +/- 3.7 g and sham operation n = 10, 102.6 +/- 3.4 g was evaluated throughout 5 weeks and the following parameters were under observation: quality of diet offered, diet ingestion, weight increase and urinary creatinine within 24 hours. At the end of the experiment, blood was taken for biochemical tests, prothrombin time and hematocrit and hypertension portal was measured. Rats with hypertension portal induced at early stages of their lives present growth delay in the first week after surgery recovering their growth rhythm in the next weeks, catching up with the sham animals. Differences related to urinary creatinine excretion, biochemical tests and hematocrit were not observed. Such results are evidence against the hypothesis that the hypertension portal induced in early stages of rats lives would cause delay in their growth.


The genus Rachicladosporium: introducing new species from sooty mould communities and excluding cold adapted species.
The fungal genus Rachicladosporium (Cladosporiales, Cladosporiaceae), typified by cladosporium-like Rachicladosporium luculiae, includes a morphologically diverse assemblage of species. The species of this genus were reported from different substrates, habitats and environments, including plant leaves and needles, twig, black mould on baobab trees, rocks and insects. In this study, four new Rachicladosporium species (R. europaeum, R. ignacyi, R. kajetanii, R. silesianum) isolated from sooty mould communities covering leaves and needles of trees and shrubs in Poland are described. The new species are delineated based on morphological characteristics and molecular phylogenetic analyses using concatenated ITS, LSU, and rpb2 sequences. All newly described species are nested in the main Rachicladosporium lineage (centred around the type species), which contains species that are able to grow at 25 °C. By contrast, four cold adapted, endolithic species known from Antarctica (R. antarcticum, R. aridum, R. mcmurdoi) and Italian Alps (R. monterosanum) form distant phylogenetic lineage and do not grow at this temperature. Therefore, they are accommodated in the new genus Cryoendolithus, typified by Cryoendolithus mcmurdoi.


A review of monochromatic light devices for the treatment of alopecia areata.
There are many laser technologies that are being tested that claim to support hair regrowth for patients with alopecia areata (AA). In this paper, we will determine whether the body of evidence supports the use of devices using monochromatic light sources to treat AA. Articles were gathered from PubMed, Embase, and the Cochrane database using these keywords: lasers, excimer laser, low-level laser therapy (LLLT), low-level light therapy, alopecia, alopecia areata, and hair loss with a category modifier of English. Ten clinical trials and seven case reports/abstracts were assessed. Eight clinical trials and two case reports demonstrated hair regrowth with the 308-nm excimer laser/light in men, women, and children. One case report demonstrated hair regrowth with the ALBA 355® laser. One clinical trial and two case reports demonstrated hair regrowth with LLLT. While two case reports demonstrated hair regrowth with fractional laser therapy, one clinical trial showed no improvement. The 308-nm excimer laser is a safe and effective treatment for men, women, and children with refractory AA of the scalp and beard. Larger, double-blinded clinical trials should be conducted to compare excimer laser therapy to standard treatments. More data is needed to determine the efficacy of LLLT and fractional laser therapy in the treatment of AA.


Pre- and postoperative MR imaging of craniopharyngiomas.
To compare the pre- and postoperative MR appearance of craniopharyngiomas with respect to lesion size, tumour morphology and identification of surrounding normal structures. MR images obtained prior to and following craniopharyngioma resection were evaluated retrospectively in 10 patients. Tumour signal characteristics, size and extension with particular reference to the optic chiasm, the pituitary gland, the pituitary stalk and the third ventricle were evaluated. Following surgery, tumour volume was reduced in all patients. In 6 patients there was further tumour volume reduction between the first and second postoperative images. Two of these patients received radiation therapy between the 2 postoperative studies, while 4 had no adjuvant treatment to the surgical intervention. There was improved visualization of the optic chiasm in 3, the pituitary stalk in one, and the third ventricle in 9 of the 10 patients. The pituitary gland was identified preoperatively only in one patient, postoperatively only in another, pre- and postoperatively in 5, and neither pre- nor postoperatively in 3 patients. In 3 patients MR imaging 0-7 days postoperatively identified tumour remnants not seen at the end of the surgical procedure. The signal intensities of solid and cystic tumour components were stable from pre- to the first postoperative MR images. Optic tract increased signal prior to surgery was gone 28 days postoperatively in one patient, but persisted on the left side for 197 days after surgery in another. Postoperative MR imaging of craniopharyngiomas demonstrated tumour volume reduction and tumour remnants not seen at surgery. Early postoperative MR imaging of craniopharyngiomas may overestimate the size of residual tumour. Improved visualization of peritumoral structures may be achieved.


The Care Span: Medicaid savings resulted when community health workers matched those with needs to home and community care.
The Affordable Care Act of 2010 builds on earlier efforts to expand home and community-based alternatives to institutional long-term care. Identifying people living in the community who have unmet long-term care needs and who may be at risk for entering nursing homes may be crucial to these efforts. The Arkansas Community Connector Program used specially trained community health workers to identify such people in three disadvantaged counties and connect them to Medicaid home and community-based services. The result was a 23.8 percent average reduction in annual Medicaid spending per participant during the period 2005-08. Net three-year savings to the Arkansas Medicaid program equaled $2.619 million. Similar interventions may help other localities achieve cost-saving and equitable access to publicly funded long-term care options other than institutional care.


LncRNA SNHG1 overexpression regulates the proliferation of acute myeloid leukemia cells through miR-488-5p/NUP205 axis.
To elucidate the function of long non-coding RNA (lncRNA) SNHG1 in acute myeloid leukemia (AML) and to explore its biological mechanism. Expression levels of lncRNA SNHG1 and miR-488-5p in AML cell lines pAML and THP-1 were determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Proliferative potential and cell cycle progression of pAML and THP-1 cells were detected after SNHG1 knockdown. Potential binding sites of SNHG1 and miR-488-5p were predicted by bioinformatics. Through RNA Binding Protein Immunoprecipitation (RIP) assay and luciferase reporter gene assay, we evaluated the binding condition between SNHG1 and miR-488-5p. MiR-488-5p expression in pAML and THP-1 cells with SNHG1 knockdown was detected by qRT-PCR to further verify their interaction. Subsequently, binding sites of NUP205 and miR-488-5p were predicted. Both mRNA and protein levels of NUP205 in pAML and THP-1 cells were examined. The regulatory effects of overexpressed NUP205 on proliferative potential and cell cycle progression of pAML and THP-1 cells transfected with si-SNHG1 were explored by gain-of-function experiments. LncRNA SNHG1 was highly expressed in pAML and THP-1 cells, while miR-488-5p was lowly expressed. SNHG1 knockdown in pAML and THP-1 cells inhibited proliferative ability and arrested cell cycle in G0/G1 phase. Knockdown of SNHG1 markedly upregulated the miR-488-5p expression in pAML and THP-1 cells. Furthermore, RIP and luciferase reporter gene assay confirmed the binding between SNHG1 and miR-488-5p. NUP205 was highly expressed in pAML and THP-1 cells at both mRNA and protein levels. Moreover, luciferase reporter gene assay indicated that NUP205 could bind to miR-488-5p. More importantly, the overexpression of NUP205 in pAML and THP-1 cells reversed the inhibitory effect of SNHG1 knockdown on proliferative ability and cell cycle progression. LncRNA SNHG1 promotes the development of AML through miR-488-5p/NUP205 axis.


A Point Mutation in IKAROS ZF1 Causes a B Cell Deficiency in Mice.
IKZF1 (IKAROS) is essential for normal lymphopoiesis in both humans and mice. Previous Ikzf1 mouse models have demonstrated the dual role for IKZF1 in both B and T cell development and have indicated differential requirements of each zinc finger. Furthermore, mutations in IKZF1 are known to cause common variable immunodeficiency in patients characterized by a loss of B cells and reduced Ab production. Through N-ethyl-N-nitrosourea mutagenesis, we have discovered a novel Ikzf1 mutant mouse with a missense mutation (L132P) in zinc finger 1 (ZF1) located in the DNA binding domain. Unlike other previously reported murine Ikzf1 mutations, this L132P point mutation (Ikzf1L132P ) conserves overall protein expression and has a B cell-specific phenotype with no effect on T cell development, indicating that ZF1 is not required for T cells. Mice have reduced Ab responses to immunization and show a progressive loss of serum Igs compared with wild-type littermates. IKZF1L132P overexpressed in NIH3T3 or HEK293T cells failed to localize to pericentromeric heterochromatin and bind target DNA sequences. Coexpression of wild-type and mutant IKZF1, however, allows for localization to pericentromeric heterochromatin and binding to DNA indicating a haploinsufficient mechanism of action for IKZF1L132P Furthermore, Ikzf1+/L132P mice have late onset defective Ig production, similar to what is observed in common variable immunodeficiency patients. RNA sequencing revealed a total loss of Hsf1 expression in follicular B cells, suggesting a possible functional link for the humoral immune response defects observed in Ikzf1L132P/L132P mice.


Optimizing antimicrobial therapy in critically ill patients.
Critically ill patients with infection in the intensive care unit (ICU) would certainly benefit from timely bacterial identification and effective antimicrobial treatment. Diagnostic techniques have clearly improved in the last years and allow earlier identification of bacterial strains in some cases, but these techniques are still quite expensive and not readily available in all institutions. Moreover, the ever increasing rates of resistance to antimicrobials, especially in Gram-negative pathogens, are threatening the outcome for such patients because of the lack of effective medical treatment; ICU physicians are therefore resorting to combination therapies to overcome resistance, with the direct consequence of promoting further resistance. A more appropriate use of available antimicrobials in the ICU should be pursued, and adjustments in doses and dosing through pharmacokinetics and pharmacodynamics have recently shown promising results in improving outcomes and reducing antimicrobial resistance. The aim of multidisciplinary antimicrobial stewardship programs is to improve antimicrobial prescription, and in this review we analyze the available experiences of such programs carried out in ICUs, with emphasis on results, challenges, and pitfalls. Any effective intervention aimed at improving antibiotic usage in ICUs must be brought about at the present time; otherwise, we will face the challenge of intractable infections in critically ill patients in the near future.


Physical activity-related health and economic benefits of building walkable neighbourhoods: a modelled comparison between brownfield and greenfield developments.
A consensus is emerging in the literature that urban form can impact health by either facilitating or deterring physical activity (PA). However, there is a lack of evidence measuring population health and the economic benefits relating to alternative urban forms. We examined the issue of housing people within two distinct types of urban development forms: a medium-density brownfield development in an established area with existing amenities (e.g. daily living destinations, transit), and a low-density suburban greenfield development. We predicted the health and economic benefits of a brownfield development compared with a greenfield development through their influence on PA. We combined a new Walkability Planning Support System (Walkability PSS) with a quantitative health impact assessment model. We used the Walkability PSS to estimate the probability of residents' transport walking, based on their exposure to urban form in the brownfield and greenfield developments. We developed the underlying algorithms of the Walkability PSS using multi-level multivariate logistic regression analysis based on self-reported data for transport walking from the Victorian Integrated Survey of Transport and Activity 2009-10 and objectively measured urban form in the developments. We derived the difference in transport walking minutes per week based on the probability of transport walking in each of the developments and the average transport walking time per week among those who reported any transport walking. We then used the well-established method of the proportional multi-cohort multi-state life table model to translate the difference in transport walking minutes per week into health and economic benefits. If adult residents living in the greenfield neighbourhood were instead exposed to the urban development form observed in a brownfield neighbourhood, the incidence and mortality of physical inactivity-related chronic diseases would decrease. Over the life course of the exposed population (21,000), we estimated 1600 health-adjusted life years gained and economic benefits of A$94 million. Our findings indicate that planning policies that create walkable neighbourhoods with access to shops, services and public transport will lead to substantial health and economic benefits associated with reduced incidence of physical inactivity related diseases and premature death.


Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus.
The association of insulin-dependent diabetes mellitus (IDDM) with certain HLA alleles is well documented in pediatric patients. Whether a similar association is found in adult-on-set IDDM is not clear, although the disease occurs after the age of 20 in 50% of cases. HLA class II DRB1, DQA1, and DQB1 alleles were studied in 402 type I diabetics and 405 healthy controls (all Caucasian) using oligonucleotide typing after gene amplification. Alleles DRB1*03, DRB1*04, DQB1*0201, DQB1*0302, DQA1*0301, and DQA1*0501 were indeed enriched in diabetics and the highest relative risk was observed in patients carrying both the DRB1*03-DQB1*0201 and the DRB1*0402 or DRB1*0405-DQB1*0302 haplotypes. However none of these alleles, or specific residues, could alone account for the susceptibility to IDDM. Furthermore, there were major differences in HLA class II gene profiles according to the age of onset. Patients with onset after 15 yr (n = 290) showed a significantly higher percentage of non-DR3/non-DR4 genotypes than those with childhood onset (n = 112) and a lower percentage of DR3/4 genotypes. These non-DR3/non-DR4 patients, although presenting clinically as IDDM type 1 patients, showed a lower frequency of islet cell antibodies at diagnosis and a significantly milder initial insulin deficiency. These subjects probably represent a particular subset of IDDM patients in whom frequency increases with age. The data confirm the genetic heterogeneity of IDDM and call for caution in extrapolating to adult patients the genetic concepts derived from childhood IDDM.


Recognition of HLA-A2 mutant and variant target cells by an HLA-A2 allospecific human cytotoxic T lymphocyte line.
HLA-A2 specific human cytotoxic T lymphocytes (CTL) cell lines have been developed using T cell growth factor and coculture of peripheral blood lymphocytes with selected allogeneic target cell lines. The CTL-8 line showed specificity for human leukocyte antigens (HLA)-A2 bearing target cells after 5 weeks in culture when tested against a panel of 14 lymphoblastoid cell lines in a 51Chromium (51Cr) release assay. Purified anti-human leukocyte antigens (HLA) monoclonal antibodies W6/32 and PA2.1 inhibited cytolysis by 85% and 60%, respectively. The CTL-8 line lysed non-HLA-A2 target cells in the presence of lectins concanavalin A (Con A) or phytohemagglutinin-P lectin (PHA-P) indicating the specificity of cytolysis was not due to nonspecific resistance of target cells to the CTL-lytic mechanism. The T5-1 HLA-A2 mutant cell series were tested as targets for the CTL-8 line. Cell clones 8.18.1, 8.21.1 and 8.6.1, which express altered HLA-A2 molecules as determined by their decreased reactivity with allospecific monoclonal antibodies, were lysed by the CTL-8 line as efficiently as the T5-1 wild type. These cell lines also acted as efficient cold target competitors for a normal HLA-A2 target cell. The 8.14.1 cell clone expressed a lower amount of HLA-A2 alloantigen and showed a corresponding decreased reactivity with CTL-8 in direct cytolytic and cold target competitive inhibition assays. In contrast, the M7 and DK1 HLA-A2 variant cell lines, which express normal HLA-A2 serological determinants, were inefficiently lysed by CTL-8 and did not act as competitive inhibitors of normal HLA-A2 target cells. These results support the concept that the alloantigenic determinant(s) recognized by T cells and antibodies occur at separate regions on the HLA-A2 molecule.


Characterization of pH-sensitive molecular switches that trigger the structural transition of vesicular stomatitis virus glycoprotein from the postfusion state toward the prefusion state.
Vesicular stomatitis virus (VSV; the prototype rhabdovirus) fusion is triggered at low pH and mediated by glycoprotein G, which undergoes a low-pH-induced structural transition. A unique feature of rhabdovirus G is that its conformational change is reversible. This allows G to recover its native prefusion state at the viral surface after its transport through the acidic Golgi compartments. The crystal structures of G pre- and postfusion states have been elucidated, leading to the identification of several acidic amino acid residues, clustered in the postfusion trimer, as potential pH-sensitive switches controlling the transition back toward the prefusion state. We mutated these residues and produced a panel of single and double mutants whose fusion properties, conformational change characteristics, and ability to pseudotype a virus lacking the glycoprotein gene were assayed. Some of these mutations were also introduced in the genome of recombinant viruses which were further characterized. We show that D268, located in the segment consisting of residues 264 to 273, which refolds into postfusion helix F during G structural transition, is the major pH sensor while D274, D395, and D393 have additional contributions. Furthermore, a single passage of recombinant virus bearing the mutation D268L (which was demonstrated to stabilize the G postfusion state) resulted in a pseudorevertant with a compensatory second mutation, L271P. This revealed that the propensity of the segment of residues 264 to 273 to refold into helix F has to be finely tuned since either an increase (mutation D268L alone) or a decrease (mutation L271P alone) of this propensity is detrimental to the virus. Vesicular stomatitis virus enters cells via endocytosis. Endosome acidification induces a structural transition of its unique glycoprotein (G), which mediates fusion between viral and endosomal membranes. G conformational change is reversible upon increases in pH. This allows G to recover its native prefusion state at the viral surface after its transport through the acidic Golgi compartments. We mutated five acidic residues, proposed to be pH-sensitive switches controlling the structural transition back toward the prefusion state. Our results indicate that residue D268 is the major pH sensor, while other acidic residues have additional contributions, and reveal that the propensity of the segment consisting of residues 264 to 273 to adopt a helical conformation is finely regulated. This segment might be a good target for antiviral compounds.


MtDNA diversity among four Portuguese autochthonous dog breeds: a fine-scale characterisation.
The picture of dog mtDNA diversity, as obtained from geographically wide samplings but from a small number of individuals per region or breed, has revealed weak geographic correlation and high degree of haplotype sharing between very distant breeds. We aimed at a more detailed picture through extensive sampling (n = 143) of four Portuguese autochthonous breeds - Castro Laboreiro Dog, Serra da Estrela Mountain Dog, Portuguese Sheepdog and Azores Cattle Dog-and comparatively reanalysing published worldwide data. Fifteen haplotypes belonging to four major haplogroups were found in these breeds, of which five are newly reported. The Castro Laboreiro Dog presented a 95% frequency of a new A haplotype, while all other breeds contained a diverse pool of existing lineages. The Serra da Estrela Mountain Dog, the most heterogeneous of the four Portuguese breeds, shared haplotypes with the other mainland breeds, while Azores Cattle Dog shared no haplotypes with the other Portuguese breeds.A review of mtDNA haplotypes in dogs across the world revealed that: (a) breeds tend to display haplotypes belonging to different haplogroups; (b) haplogroup A is present in all breeds, and even uncommon haplogroups are highly dispersed among breeds and continental areas; (c) haplotype sharing between breeds of the same region is lower than between breeds of different regions and (d) genetic distances between breeds do not correlate with geography. MtDNA haplotype sharing occurred between Serra da Estrela Mountain dogs (with putative origin in the centre of Portugal) and two breeds in the north and south of the country-with the Castro Laboreiro Dog (which behaves, at the mtDNA level, as a sub-sample of the Serra da Estrela Mountain Dog) and the southern Portuguese Sheepdog. In contrast, the Azores Cattle Dog did not share any haplotypes with the other Portuguese breeds, but with dogs sampled in Northern Europe. This suggested that the Azores Cattle Dog descended maternally from Northern European dogs rather than Portuguese mainland dogs. A review of published mtDNA haplotypes identified thirteen non-Portuguese breeds with sufficient data for comparison. Comparisons between these thirteen breeds, and the four Portuguese breeds, demonstrated widespread haplotype sharing, with the greatest diversity among Asian dogs, in accordance with the central role of Asia in canine domestication.


Electrotonic parameters of rat dentate granule cells measured using short current pulses and HRP staining.
The passive electrotonic parameters of nerve cells in the dentate gyrus of the rat were studied in vitro. Intracellular recordings from 30 granule cells and 3 pyramidal basket cells followed by intracellular injection of horseradish peroxidase (HRP), allowed calculations of input resistance (RN), membrane time constant (tau m), electrotonic length (L), ratio of dendritic to somatic conductance (rho), membrane specific capacitance and resistance (Rm, Cm), and specific axoplasmic resistance (Ri). The analysis of the voltage decays from long saturating (100 ms) and short (0.5 ms) current pulses showed that the short-pulse method gave better resolution for the measurement of the time constants and avoided some of the time-dependent nonlinearities but required larger currents than the long pulse. Morphological analysis of 49 branching points taken from the dendritic trees of granule cells showed that the branching power, n, is equal to 1.56 +/- 0.186 and was fairly constant throughout the tree. Given the fact that all dendrites have approximately the same length and number of branch points, the granule cell dendritic tree can be meaningfully collapsed into an equivalent cable. Moreover, electrophysiological data suggested that the cable had a "sealed" end or at least a high-impedance termination. Based on an equivalent cable model with a sealed end and a lumped soma impedance, a method was implemented to analyze the multiexponential decays from hyperpolarizing current pulses and to solve the equations of the model. This was done successfully in only 40% of the cells and yielded the following mean values for L = 1.13 and rho = 7.58. From the measurements of the soma surface area (S) and the equivalent cable diameter (D), the average specific membrane parameters were calculated: Rm = 2,726 alpha x cm2, Cm = 5.24 microF/cm2, Ri = 101 alpha x cm. The input resistance and time constant of the granule cells as measured from the short-pulse technique averaged to RN 58.57 M alpha and tau m = 16.21 ms. The failure of the model to fit 60% of the cells was interpreted to be due to the presence of a somatic shunt resulting from electrode injury, tonic synaptic activity, a lower somatic membrane specific resistance, or electronic coupling.(ABSTRACT TRUNCATED AT 400 WORDS)


Increased bronchial responsiveness in primary and secondary Sjögren's syndrome.
We examined one group of 33 patients with primary Sjögren's syndrome, one group of 17 patients with secondary Sjögren's syndrome, i.e. associated with other connective tissue diseases, and one group of 14 patients with connective tissue diseases but without Sjögren's syndrome. In each patient we obtained chest radiographs and measured lung volumes, carbon monoxide diffusing capacity and airway responsiveness to methacholine. We observed no difference in chest radiograph abnormalities, in lung volumes and in carbon monoxide diffusing capacity among the three groups. However, we found a slight but significant increase of bronchial responsiveness in patients with primary and secondary Sjögren's syndrome compared with patients with connective tissue disorders but without Sjögren's syndrome. Thus PD20FEV1 methacholine was 1.07 mg (1.2) (geometric mean and GSEM) in primary Sjögren's syndrome, 0.91 mg (1.4) in secondary Sjögren's syndrome (NS), and 2.24 mg (1.09) in patients with connective tissue diseases but without Sjögren's syndrome (t = 2.59 and t = 2.8, both p less than 0.05, vs primary and secondary Sjögren's syndrome, respectively). These results show that some patients with Sjögren's syndrome have mild bronchial hyperresponsiveness, which may be related to the specific airway abnormalities of this disease.


Genotoxic evaluation of two oral antidiabetic agents in the Drosophila wing spot test.
In this study, two sulfonylureas--glimepiride and glipizide--commonly used in type 2 diabetes mellitus were investigated for genotoxicity in the Drosophila wing spot test. For this purpose, three-day-old transheterozygous larvae were treated with three mutagenic compounds, and the results obtained were compared with the control group. Mutational or recombinogenic changes were recorded in two recessive genes--multiple wing hairs (mwh) and flare (flr (3)). Two recessive markers were located on the left arm of chromosome 3, mwh in map position 0.3, and flare-3 (flr3) at 38.8, while the centromere was located in position 47.7. Wing spot tests are targeted on the loss of heterozygosity, which may be grounded in different genetic mechanisms such as mutation, mitotic recombination, deletion, half-translocation, chromosome loss, or nondisjunction. Genetic changes formatting in somatic cells of the imaginal discs cause nascence different mutant cloning in different body parts of adult flies. Our in vivo experiments demonstrated that glimepiride and glipizide show the genotoxicity, which is especially dependent on homologous somatic recombination.


Stimulation of steroidogenesis in cultured rat adrenocortical cells by unsaturated fatty acids.
The hypothesis that the stimulatory action of free fatty acids (FFA) in the hypothalamic-pituitary-adrenocortical (HPA) axis occurs in part at the adrenal cortex was evaluated. Pathophysiological concentrations of oleic and linoleic acids, but not stearic or caprylic acid, stimulated steroidogenesis from cultured rat adrenocortical cells (concentrations eliciting 50% of maximal responses, approximately 60 and 120 microM, respectively), with a latency of 90 min. Maximal stimulation of steroidogenesis by both acids was < 50% of that produced by adrenocorticotropic hormone (ACTH) and was blocked by cycloheximide. The maximal steroidogenic response to ACTH was inhibited approximately 50% by oleic acid. The actions of oleic and linoleic acids were not associated with an increase in adenosine 3',5'-cyclic monophosphate (cAMP) secretion but appeared to require intracellular oxidation. None of the lipids influenced cell viability or corticosterone radioimmunoassay. The latency of the steroidogenic response, the putative requirement for intracellular oxidation, and the apparent lack of involvement of cAMP suggest a mechanism of action of FFA distinct from that of ACTH, yet still requiring protein synthesis. It is concluded that the modulation of steroidogenesis by these abundant naturally occurring lipids may be an important component of the control mechanisms within the HPA pathway in disorders of lipid homeostasis (e.g., obesity, starvation, or diabetes).


Enhancing selective CO2 adsorption via chemical reduction of a redox-active metal-organic framework.
A new microporous framework, Zn(NDC)(DPMBI) (where NDC = 2,7-naphthalene dicarboxylate and DPMBI = N,N'-di-(4-pyridylmethyl)-1,2,4,5-benzenetetracarboxydiimide), containing the redox-active benzenetetracarboxydiimide (also known as pyromellitic diimide) ligand core has been crystallographically characterised and exhibits a BET surface area of 608.2 ± 0.7 m(2) g(-1). The crystallinity of the material is retained upon chemical reduction with sodium naphthalenide (NaNp), which generates the monoradical anion of the pyromellitic diimide ligand in the framework Zn(NDC)(DPMBI)·Na(x) (where x represents the molar Na(+)/Zn(2+) ratio of 0.109, 0.233, 0.367 and 0.378 from ICP-AES), as determined by EPR, solid state Vis-NIR spectroelectrochemistry and UV-Vis-NIR spectroscopy. The CO2 uptake in the reduced materials relative to the neutral framework is enhanced up to a Na(+)/Zn(2+) molar ratio of 0.367; however, beyond this concentration the surface area and CO2 uptake decrease due to pore obstruction. The CO2 isosteric heat of adsorption (|Q(st)|) and CO2/N2 selectivity (S), obtained from pure gas adsorption isotherms and Ideal Adsorbed Solution Theory (IAST) calculations, are also maximised relative to the neutral framework at this concentration of the alkali metal counter-ion. The observed enhancement in the CO2 uptake, selectivity and isoteric heat of adsorption has been attributed to stronger interactions between CO2 and both the radical DPMBI ligand backbone and the occluded Na(+) ions.