Weekly variations in feelings of trust predict incident STI within a prospective cohort of adolescent women from a US city.
Feelings of intimacy, perceptions of partner concurrency (PPC) and perceptions of risk for an STD (PRSTD) are meaningful and dynamic attributes of adolescent sexual relationships. Our objective was to examine whether variations in these STI-associated feelings and perceptions predicted incident Chlamydia trachomatis and/or Neisseriagonorrhoeae infection within a prospective cohort of urban adolescent women. A cohort of clinic-recruited women aged 16-19 completed daily surveys on feelings and risk perceptions about each current sex partner on a smartphone continuously for up to 18 months. Urine was tested for C. trachomatis and N. gonorrhoeae every 3 months. Daily responses were averaged across the week. As overall means for trust, closeness and commitment were high, data were coded to indicate any decrease in feelings from the previous week. PRSTD and PPC were reverse coded to indicate any increase from the previous week. An index was created to examine the cumulative effect of variation in these feelings and perceptions. Generalised linear models were used to account for correlation among repeated measures within relationships. For each week that there was a decrease in trust, there was a 45% increase in the risk of being infected with an STI at follow-up (relative risk (RR) 1.45, 95% CI 1.18 to 1.78, P=0.004). Neither a decrease in closeness or commitment, nor an increase in PRSTD or PPC was associated with an STI outcome. Cumulatively, the index measure indicated that a change in an additional feeling or perception over the week increased the odds of an STI by 14% (RR 1.14, 95% CI 1.02 to 1.29, P=0.026). A decrease in feelings of trust towards a main partner may be a more sensitive indicator of STI risk than PRSTD, PPC or commitment. The next generation of behavioural interventions for youth will need strategies to address feelings of intimacy within adolescent romantic relationships.


Platelet activity and selective beta-blockade in migraine prophylaxis.
Migraine is associated with increased platelet activity and an incidence of cerebrovascular ischemic events. Because cerebrovascular events might result from platelet aggregation, enhancing platelet activity further in the treatment of migraine is not desirable. beta-Adrenoceptor blockers effective in migraine prophylaxis include propranolol (nonselective) and metoprolol (beta 1-selective), but it is uncertain how beta-receptor subtype selectivity might influence platelet behavior in migraine. In 29 patients, comparable clinical responses were obtained with therapeutic doses during 1 month of treatment with propranolol, metoprolol, and the beta 2-selective Li 32-468. Propranolol increased and metoprolol decreased platelet aggregation and ATP release, and the effect of Li 32-468 could be related to that of propranolol. These actions can be largely explained in terms of what is known of platelet beta-receptors and therefore can be generalized to other effective beta-blockers. Since altered platelet activity does not account for the efficacy of these agents in migraine, the actions of beta-blockers on platelets should be considered as side effects. Those beta-blockers inhibiting platelet activity should be preferred in migraine treatment, assuming equal efficacy, which implies the use of beta 1-selective blockers.


Alpha-2 agonists for sedation in mechanically ventilated neurocritical care patients: a systematic review protocol.
Sedation is an important consideration in the care of the neurocritically ill patient. It provides anxiety and relief, facilitates procedures and nursing tasks, and minimizes intolerance of mechanical ventilation. Alpha-2 agonists such as dexmedetomidine and clonidine have been shown to be an effective alternative in the general critical care population by reducing duration of mechanical ventilation and length of stay in the intensive care unit (ICU), as compared to traditional sedative agents such as propofol or benzodiazepines. However, there is a paucity of literature detailing their utility and safety in neurocritical care, a population that presents unique considerations for management of global and cerebral hemodynamics, agitation, and facilitation of neurological assessments. The objective of this review is to assess the efficacy and safety of alpha-2 agonists for non-procedural sedation in mechanically ventilated brain-injured patients. We will search the Embase and MEDLINE databases for all randomized controlled trials, prospective and retrospective cohort studies examining neurocritically ill adult patients aged 18 years and older who are on mechanical ventilation and receiving alpha-2 agonists for non-procedural sedation. Primary outcomes of interest include effect on mean arterial pressure (MAP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP). Secondary outcomes include adverse events, duration of mechanical ventilation, 30-day mortality, ICU length of stay, incidence of delirium, and quality of sedation. Continuous outcomes will be presented as means and mean differences and discrete counting events will be presented as event rates. Pre-defined criteria for heterogeneity are provided for determination of pooling eligibility. Where appropriate, we will pool estimates for individual outcomes. Planned subgroup analyses include specific alpha-2 agonist agent, study design, clinical diagnosis, dosing regimen, and use of adjunctive agents. Quality of evidence for the recommendation will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach where appropriate. This systematic review will summarize the evidence on the efficacy and safety for the use of alpha-2 agonists as sedative agents in the neurocritical care population. PROSPERO CRD42016037045.


Respiratory health effects of e-cigarette substitution for tobacco cigarettes: a systematic review.
E-cigarettes (electronic nicotine delivery system, ENDS) have been presented as a harm reduction strategy for people who smoke tobacco cigarettes but who cannot achieve abstinence, or for those who wish to continue to enjoy nicotine and the habit of smoking. What are the health effects of the substitution of ENDS for tobacco cigarettes? This systematic review evaluates the evidence of human clinical tests on the respiratory effects of ENDS use in participants who smoke tobacco cigarettes. A registered and published protocol was developed conforming to PRISMA 2020 and AMSTAR2 standards. The literature search was conducted in PubMed, Scopus, and the CENTRAL Cochrane Library and updated to May 2022. Three supplementary searches and a grey literature search were performed. Studies were evaluated with the JBI quality tools and the Oxford Catalogue of Bias. Due to the heterogeneity (diversity) of the studies, a narrative data synthesis was performed on the test findings plus three sub-group analyses. The review consists of sixteen studies and twenty publications. Spirometry tests comprised the majority of the data. In total, 66 respiratory test measurements were reported, out of which 43 (65%) were not significant. Statistically significant findings were mixed, with 9 tests showing improvements and 14 measuring declines, none of which was clinically relevant. Ten studies were rated at a high risk of bias, and six had some concerns primarily due to inadequate research designs and the conduct of the studies. Reporting bias was documented in thirteen studies. Most of the studies showed no difference in respiratory parameters. This indicates that ENDS substitution for smoking likely does not result in additional harm to respiratory health. Due to the low quality of the studies, confidence in the conclusions is rated as low. Robust studies with a longer duration and sufficient power are required to validate any potential benefits or possible harms of ENDS substitution. Registration PROSPERO #CRD42021239094, International Registered Report Identifier (IRRID): DERR1-10.2196/29084.


The developmental expression of three mammalian lens fiber cell membrane proteins.
The expression of the lens fiber cell integral membrane proteins MP20, the alpha 3 gap junction protein (connexin 46), and MP26 (MIP) was determined both during development of the bovine fetal lens and in different animal species. The relative levels of the mRNA species coding for these proteins was determined by Northern blotting; this was correlated with the amounts of these proteins as determined by Western immunoblotting. RNA extracted from fetal calf lenses at 3-4, 5-6, and 7-8 mo gestation, and from postnatal calf lenses, showed a progressive decrease of the mRNA species coding for MP20 (20-fold), alpha 3 gap junction protein (22-fold), and MP26 (12-fold) with development. This compared with a 6-fold decrease in total RNA and a 15-fold decrease in poly-A(+) RNA over the same period. In contrast to these significant changes in the levels of mRNA, there were no significant changes in the concentrations of these proteins over the same period. Whereas the mRNA coding for each of these proteins were concentrated in the lens cortical regions. MP20 and MP26 protein concentrations in cortical and nuclear regions were very similar. Both protein and mRNA coding for MP20, alpha 3 gap junction, and MP26 were detected in calf, sheep, pig, and rat lenses. These results indicate that the expression of the mRNA coding for the lens fiber cell integral membrane proteins MP20, alpha 3 gap junction, and MP26 is regulated and may be coordinated. That the decrease in mRNA concentrations is not correlated with changes in the concentrations of these lens membrane proteins indicates their unique stability.


Are IgE levels to foods other than rosaceae predictive of allergy in lipid transfer protein-hypersensitive patients?
Lipid transfer protein (LTP), the most frequent cause of primary food allergy in Italy, is a cross-reacting plant pan-allergen. Markers able to predict whether a patient sensitized to a certain food but not yet clinically allergic will develop allergy would be extremely helpful. It was the aim of this study to investigate the relevance of IgE levels to some plant foods other than Rosaceae as predictors of either local or systemic allergic reaction in LTP-allergic subjects. One hundred (40 males, 60 females , mean age 29 years) peach-allergic patients monosensitized to LTP seen at 14 Italian centres in 2009 were studied. Walnut, hazelnut, peanut, tomato, rice and/or maize allergy was ascertained by interview and confirmed by positive skin prick test. IgE levels to these foods and to rPru p 3 were measured. Higher levels of IgE to Pru p 3 were associated with a higher prevalence of allergy to hazelnut, peanut and walnut. For all study foods, except rice, median IgE levels in allergic subjects significantly exceeded those in tolerant subjects, though within single allergic groups, the differences between patients reporting systemic or local (oral) symptoms were not significant. Ninety-five percent cut-off IgE levels predictive of clinical allergy were established for study foods although the marked overlaps between allergic and tolerant subjects made them of limited usefulness. Specific IgE levels are only partially predictive of clinical allergy. The reasons why some individuals showing low specific IgE levels develop clinical allergy whereas others showing high IgE levels do not, despite similar exposure to the allergen, remain unclear.


mTOR and the health benefits of exercise.
Exercise is the greatest physiological stress that our bodies experience. For example, during maximal endurance exercise in elite athlete's cardiac output can increase up to 8-fold and the working muscles receive 21-times more blood each minute than at rest. Given the physiological stress associated with exercise and the adaptations that occur to handle this stress, it is not surprising that exercise training is known to prevent or effectively treat a multitude of degenerative conditions including cardiovascular disease, cancer, diabetes, depression, Alzheimer's disease, Parkinson's disease, and many others. Many of the health benefits of exercise are mediated by the mammalian/mechanistic target of rapamycin (mTOR), either in complex 1 or 2, not only within the working muscle, but also in distant tissues such as fat, liver, and brain. This review will discuss how exercise activates mTOR in diverse tissues and the ways that mTOR is important in the adaptive response that makes us bigger, stronger, and healthier as a result of exercise.


Impact of DNA Sequencing and Analysis Methods on 16S rRNA Gene Bacterial Community Analysis of Dairy Products.
DNA sequencing and analysis methods were compared for 16S rRNA V4 PCR amplicon and genomic DNA (gDNA) mock communities encompassing nine bacterial species commonly found in milk and dairy products. The two communities comprised strain-specific DNA that was pooled before (gDNA) or after (PCR amplicon) the PCR step. The communities were sequenced on the Illumina MiSeq and Ion Torrent PGM platforms and then analyzed using the QIIME 1 (UCLUST) and Divisive Amplicon Denoising Algorithm 2 (DADA2) analysis pipelines with taxonomic comparisons to the Greengenes and Ribosomal Database Project (RDP) databases. Examination of the PCR amplicon mock community with these methods resulted in operational taxonomic units (OTUs) and amplicon sequence variants (ASVs) that ranged from 13 to 118 and were dependent on the DNA sequencing method and read assembly steps. The additional 4 to 109 OTUs/ASVs (from 9 OTUs/ASVs) included assignments to spurious taxa and sequence variants of the 9 species included in the mock community. Comparisons between the gDNA and PCR amplicon mock communities showed that combining gDNAs from the different strains prior to PCR resulted in up to 8.9-fold greater numbers of spurious OTUs/ASVs. However, the DNA sequencing method and paired-end read assembly steps conferred the largest effects on predictions of bacterial diversity, with effect sizes of 0.88 (Bray-Curtis) and 0.32 (weighted Unifrac), independent of the mock community type. Overall, DNA sequencing performed with the Ion Torrent PGM and analyzed with DADA2 and the Greengenes database resulted in the most accurate predictions of the mock community phylogeny, taxonomy, and diversity.IMPORTANCE Validated methods are urgently needed to improve DNA sequence-based assessments of complex bacterial communities. In this study, we used 16S rRNA PCR amplicon and gDNA mock community standards, consisting of nine, dairy-associated bacterial species, to evaluate the most commonly applied 16S rRNA marker gene DNA sequencing and analysis platforms used in evaluating dairy and other bacterial habitats. Our results show that bacterial metataxonomic assessments are largely dependent on the DNA sequencing platform and read curation method used. DADA2 improved sequence annotation compared with QIIME 1, and when combined with the Ion Torrent PGM DNA sequencing platform and the Greengenes database for taxonomic assignment, the most accurate representation of the dairy mock community standards was reached. This approach will be useful for validating sample collection and DNA extraction methods and ultimately investigating bacterial population dynamics in milk- and dairy-associated environments.


Restraint of B cell activation by Foxj1-mediated antagonism of NF-kappa B and IL-6.
The forkhead transcription factor Foxj1 inhibits spontaneous autoimmunity, in part by antagonizing NF-kappaB activation in T cells. We demonstrate here that Foxj1 also inhibits humoral immune responses intrinsically in B cells; Foxj1 deficiency in B cells results in spontaneous and accentuated germinal center formation, associated with the development of pathogenic autoantibodies and accentuated responses to immunizations-all reflecting excessive activity of NF-kappaB and its target gene IL-6, and correlating with a requirement for Foxj1 to regulate the inhibitory NF-kappaB component IkappaBbeta. Thus, Foxj1 restrains B cell activation and the maturation of humoral responses, demonstrating a critical role for at least this forkhead transcription factor in the regulation of B lymphocyte homeostasis.


The expression of nuclear genes encoding plastid ribosomal proteins precedes the expression of chloroplast genes during early phases of chloroplast development.
The development of different plant organs (root, hypocotyl, and cotyledons) during seed germination is connected with the transformation of proplastids, which are found in embryonic and meristematic tissues, into amyloplasts in root tissues and into chloroplasts in cotyledons. We have analyzed the expression of nuclear and plastid genes coding for the plastid translational apparatus during the first 7 d of Spinacia oleracea development. Results show that the nuclear genes (rps1, rps22, rpI21, and rpI40) are expressed from the 1st d of seed imbibition and precede transcription of the chloroplast-encoded genes (photosynthetic and nonphotosynthetic), which starts the 3rd d after the beginning of imbibition. Transcription from the leaf-/cotyledon-specific P1 promoter of the rpI21 gene starts on the first imbibition day. Inhibition of chloroplast biogenesis by bleaching in the presence of norflurazon has no influence on the expression from this P1 promoter, suggesting that the onset of transcription of nuclear gene rpI21 is independent of a plastid signal.


The binding of ferric iron by ferritin.
Equilibrium-dialysis experiments with 59Fe-labelled Fe(III) chelate solutions show that ferritin is capable of binding a limited number of Fe(III) atoms. Some of this Fe(III) is readily removed, but up to about 200 Fe(III) atoms/molecule remain bound after extensive washing. Some exchange of labelled Fe(III) with endogenous unlabelled ferritin Fe occurs during prolonged dialysis against 59Fe(III)-citrate, but there is a net binding of Fe(III). Bound Fe(III) resembles endogenous Fe(III) in several respects. It appears to be attached to the micelle and not to the protein component of ferritin. Although the physiological mechanism of Fe incorporation into ferritin is unknown, our experiments suggest the possibility that some iron finds its way into ferritin as Fe(III) chelate.


Predictors of reversible severe functional tricuspid regurgitation in patients with atrial fibrillation.
Atrial remodeling associated with atrial fibrillation (AF) is known to be a risk factor for significant tricuspid regurgitation (TR), but the predictor of reversible TR in patients with severe functional TR and AF has been poorly studied. The aim of this study was to investigate the predictors of reversible TR in patients with severe functional TR and AF. Among 232 patients with severe TR, a total of 71 patients with severe functional TR and AF were enrolled and divided into 2 groups: reversible TR group (n=16, 70.1±15.5 years, 7 males) vs. non-reversible TR group (n=55, 72.3±11.8 years, 20 males). Improvement of TR to moderate or lesser degree on follow-up (FU) echocardiography was considered as reversible TR in the present study. During 38.9±26.7 months of FU period, reversible TR was observed in 16 patients (22.5%). The presence of left ventricular (LV) systolic dysfunction was significantly prevalent (43.8% vs. 20.0%, p=0.03) and the improvement in LV ejection fraction (EF) more than 10% on FU echocardiography was more significantly frequent (62.5% vs. 23.3%, p=0.003) in the reversible TR group than in the non-reversible TR group. However, the other echocardiographic parameters, including right ventricular function were not different between the groups. In multivariate analysis using Cox proportional hazard model, the improvement of LVEF more than 10% was the only independent predictor of reversible TR (HR=7.39, 95%CI 1.80-30.28, p=0.005). Nine patients died only in patients with non-reversible TR (12.7%), but the reversibility of TR was not associated with mortality. The improvement of LV systolic function was the only independent predictor of reversible TR. Appropriate medical therapy including management for heart failure should be considered before performing surgery in patients with severe functional TR and AF, especially in patients with LV dysfunction.


Statistical optimization of waste molasses-based exopolysaccharides and self-sustainable bioelectricity production for dual chamber microbial fuel cell by Bacillus piscis.
The application of exopolysaccharide-producing bacteria (EPS) in dual chamber microbial fuel cells (DCMFC) is critical which can minimize the chemical oxygen demand (COD) of molasses with bioelectricity production. Hence, our study aimed to evaluate the EPS production by the novel strain Bacillus piscis by using molasses waste. Therefore, statistical modeling was used to optimize the EPS production. Its structure was characterized by UV, FTIR, NMR, and monosaccharides compositions. Eventually, to highlight B. piscis' adaptability in energy applications, bioelectricity production by this organism was studied in the BCMFC fed by an optimized molasses medium. B. piscis OK324045 characterized by 16S rRNA is a potent EPS-forming organism and yielded a 6.42-fold increase upon supplementation of molasses (5%), MgSO4 (0.05%), and inoculum size (4%). The novel exopolysaccharide produced by Bacillus sp. (EPS-BP5M) was confirmed by the structural analysis. The findings indicated that the MFC's maximum close circuit voltage (CCV) was 265 mV. The strain enhanced the performance of DCMFC achieving maximum power density (PD) of 31.98 mW m-2, COD removal rate of 90.91%, and color removal of 27.68%. Furthermore, cyclic voltammetry (CV) revealed that anodic biofilms may directly transfer electrons to anodes without the use of external redox mediators. Additionally, CV measurements made at various sweep scan rates to evaluate the kinetic studies showed that the electron charge transfer was irreversible. The SEM images showed the biofilm growth distributed over the electrode's surface. This study offers a novel B. piscis strain for EPS-BP5M production, COD removal, decolorization, and electricity generation of the optimized molasses medium in MFCs. The biosynthesis of EPS-BP5M by a Bacillus piscis strain and its electrochemical activity has never been documented before. The approach adopted will provide significant benefits to sugar industries by generating bioelectricity using molasses as fuel and providing a viable way to improve molasses wastewater treatment.


Effects on Bacillus subtilis of a conditional lethal mutation in the essential GTP-binding protein Obg.
The obg gene is part of the spo0B sporulation operon and codes for a GTP-binding protein which is essential for growth. A temperature-sensitive mutant in the obg gene was isolated and found to be the result of two closely linked missense mutations in the amino domain of Obg. Temperature shift experiments revealed that the mutant was able to continue cell division for 2 to 3 generations at the nonpermissive temperature. Such experiments carried out during sporulation showed that Obg was necessary for the transition from vegetative growth to stage 0 or stage II of sporulation, but sporulation subsequent to these stages was unaffected at the nonpermissive temperature. Spores of the temperature-sensitive mutant germinated normally at the nonpermissive temperature but failed to outgrow. The primary consequence of the obg mutation may be an alteration in initiation of chromosome replication.


Compositional changes in trypsin inhibitors, phytic acid, saponins and isoflavones related to soybean processing.
Soybeans are high in protein but also contain a number of minor constituents traditionally considered to be antinutritional factors. These include trypsin inhibitors, phytic acid, saponins and isoflavones. These compounds are now thought to have beneficial biological effects in the diet, such as lowering blood cholesterol or preventing cancer. Soybean processing changes the content of these minor constituents in various ways. This review discusses the changes in content of trypsin inhibitors, phytic acid, saponins and isoflavones as soybeans are processed into the conventional protein ingredients, flours, concentrates and isolates, as well as some of the traditional Oriental soybean foods.


Inhibition of platelet adhesion to fibronectin, fibrinogen, and von Willebrand factor substrates by complex gangliosides.
Gangliosides, which are complex glycosphingolipids containing sialic acid, are found in cell membranes and have been implicated in a variety of cell surface events including cellular adhesion. Complex gangliosides were observed to inhibit the adhesion of thrombin-activated platelets to substrates of fibronectin, von Willebrand factor, and fibrinogen. This adhesion, which is mediated by the glycoprotein IIb-IIIa complex, was differentially inhibited by gangliosides depending on the number of sialic acid residues present within the ganglioside. The observed order of effectiveness was GT1b greater than GD1a greater than GM1 greater than asialo-GM1. Another structurally related glycosphingolipid, globoside, exhibited little inhibitory activity. In contrast to the inhibition of platelet adhesion to von Willebrand factor mediated by the glycoprotein IIb-IIIa complex, gangliosides had no detectable effect on the ristocetin-dependent adhesion of platelets to von Willebrand factor mediated by glycoprotein Ib. These results suggest that the function of the glycoprotein IIb-IIIa complex may be modulated by gangliosides in a manner similar to that previously described for the closely related vitronectin receptor.


Narrowband Bragg filters based on subwavelength grating waveguides for silicon photonic sensing.
Subwavelength grating (SWG) waveguides have been shown to provide enhanced light-matter interaction resulting in superior sensitivity in integrated photonics sensors. Narrowband integrated optical filters can be made by combining SWG waveguides with evanescently coupled Bragg gratings. In this paper, we assess the sensing capabilities of this novel filtering component with rigorous electromagnetic simulations. Our design is optimized for an operating wavelength of 1310 nm to benefit from lower water absorption and achieve narrower bandwidths than at the conventional wavelength of 1550 nm. Results show that the sensor achieves a sensitivity of 507 nm/RIU and a quality factor of 4.9 × 104, over a large dynamic range circumventing the free spectral range limit of conventional devices. Furthermore, the intrinsic limit of detection, 5.1 × 10-5 RIU constitutes a 10-fold enhancement compared to state-of-the-art resonant waveguide sensors.


Advances in sarcoma diagnostics and treatment.
The heterogeneity of sarcomas with regard to molecular genesis, histology, clinical characteristics, and response to treatment makes management of these rare yet diverse neoplasms particularly challenging. This review encompasses recent developments in sarcoma diagnostics and treatment, including cytotoxic, targeted, epigenetic, and immune therapy agents. In the past year, groups internationally explored the impact of adding mandatory molecular testing to histological diagnosis, reporting some changes in diagnosis and/or management; however, the impact on outcomes could not be adequately assessed. Transcriptome sequencing techniques have brought forward new diagnostic tools for identifying fusions and/or characterizing unclassified entities. Next-generation sequencing and advanced molecular techniques were also applied to identify potential targets for directed and epigenetic therapy, where preclinical studies reported results for agents active within the receptor tyrosine kinase, mTOR, Notch, Wnt, Hedgehog, Hsp90, and MDM2 signaling networks. At the level of clinical practice, modest developments were seen for some sarcoma subtypes in conventional chemotherapy and in therapies targeting the pathways activated by various receptor tyrosine kinases. In the burgeoning field of immune therapy, sarcoma work is in its infancy; however, elaborate protocols for immune stimulation are being explored, and checkpoint blockade agents advance from preclinical models to clinical studies.


The need to belong as motive for (cyber)bullying and aggressive behavior among immigrant adolescents in Cyprus.
Peer group integration is a crucial acculturative goal for immigrant adolescents who, in order to reach this goal, may use bullying and/or aggressive behavior. The present study aims to explore the underlying aggression motives by investigating the importance of three motives (anger, power, and affiliation) for five different forms of aggressive behavior (bullying, cyberbullying, physical, verbal, and relational aggression) in three groups of adolescents (non-immigrants, first-generation and second-generation immigrants) in Cyprus. The sample consists of 507 non-immigrant Greek Cypriots, 149 first-generation and 93 second-generation immigrants (age M = 16.1, SD = 0.39; range 15-19; 52% female). Data was collected via validated self-report scales. In line with our hypotheses, latent means and covariances structure (MACS) models revealed that the affiliation motive was a stronger predictor for all five forms of aggressive behavior among first-generation immigrant adolescents indicating that the need to belong is especially important for their acculturation. The practical importance of these findings for better integrating newcomer immigrants in schools and aggression prevention are discussed.


The three waves: Rethinking the structure of the first Upper Paleolithic in Western Eurasia.
The Neronian is a lithic tradition recognized in the Middle Rhône Valley of Mediterranean France now directly linked to Homo sapiens and securely dated to 54,000 years ago (ka), pushing back the arrival of modern humans in Europe by 10 ka. This incursion of modern humans into Neandertal territory and the relationships evoked between the Neronian and the Levantine Initial Upper Paleolithic (IUP) question the validity of concepts that define the first H. sapiens migrations and the very nature of the first Upper Paleolithic in western Eurasia. Direct comparative analyses between lithic technology from Grotte Mandrin and East Mediterranean archeological sequences, especially Ksar Akil, suggest that the three key phases of the earliest Levantine Upper Paleolithic have very precise technical and chronological counterparts in Western Europe, recognized from the Rhône Valley to Franco-Cantabria. These trans-Mediterranean technical connections suggest three distinct waves of H. sapiens expansion into Europe between 55-42 ka. These elements support an original thesis on the origin, structure, and evolution of the first moments of the Upper Paleolithic in Europe tracing parallel archaeological changes in the East Mediterranean region and Europe.


Molecular mechanisms of apoptosis induced by magnolol in colon and liver cancer cells.
Magnolol has been reported to have anticancer activity. In this study we found that treatment with 100 microm magnolol induced apoptosis in cultured human hepatoma (Hep G2) and colon cancer (COLO 205) cell lines but not in human untransformed gingival fibroblasts and human umbilical vein endothelial cells. Our investigation of apoptosis in Hep G2 cells showed a sequence of associated intracellular events that included (a) increased cytosolic free Ca(2+); (b) increased translocation of cytochrome c (Cyto c) from mitochondria to cytosol; (c) activation of caspase 3, caspase 8, and caspase 9; and (d) downregulation of bcl-2 protein. Pretreatment of the cells with the phospholipase C inhibitor 1-[6-[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1 H-pyrrole-2,5-dione (U73122) or the intracellular chelator of Ca(2+) 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA/AM) inhibited the subsequent magnolol augmentation of [Ca(2+)](i) and also the activation of caspase-8 and caspase-9, so that the occurrence of apoptosis in those cells was greatly reduced. Pretreatment of the cells with ZB4 (which disrupts the Fas response mechanism) also decreased the subsequent magnolol-induced caspase-8 activation and reduced the occurrence of apoptosis. We interpreted these findings to indicate that the above-listed sequence of intracellular events led to the apoptosis seen in Hep G2 cells and that [Ca(2+)](i), Cyto c, and Fas function as intracellular signals to coordinate those events.


A condensing enzyme from the seeds of Lesquerella fendleri that specifically elongates hydroxy fatty acids.
Lesquerella fendleri seed oil contains up to 60% hydroxy fatty acids, nearly all of which is the 20-carbon hydroxy fatty acid lesquerolic acid (D-14-hydroxyeicos-cis-11-enoic acid). Previous work suggested that lesquerolic acid in L. fendleri was formed by the elongation of the 18-carbon hydroxy fatty acid, ricinoleic acid. To identify a gene encoding the enzyme involved in hydroxy fatty acid elongation, an L. fendleri genomic DNA library was screened using the coding region of the Arabidopsis Fatty Acid Elongation1 gene as a probe. A gene, LfKCS3, with a high sequence similarity to known very long-chain fatty acid condensing enzymes, was isolated. LfKCS3 has a 2,062-bp open reading frame interrupted by two introns, which encodes a polypeptide of 496 amino acids. LfKCS3 transcripts accumulated only in the embryos of L. fendleri and first appeared in the early stages of development. Fusion of the LfKCS3 promoter to the uidA reporter gene and expression in transgenic Arabidopsis resulted in a high level of beta-glucuronidase activity exclusively in developing embryos. Seeds of Arabidopsis plants transformed with LfKCS3 showed no change in their very long-chain fatty acid content. However, when these Arabidopsis plants were crossed with the transgenic plants expressing the castor oleate 12-hydroxylase, significant amounts of 20-carbon hydroxy fatty acids accumulated in the seed, indicating that the LfKCS3 condensing enzyme specifically catalyzes elongation of 18-carbon hydroxy fatty acids.


A randomised controlled trial of fluid restriction compared to oesophageal Doppler-guided goal-directed fluid therapy in elective major colorectal surgery within an Enhanced Recovery After Surgery program.
There is continued controversy regarding the benefits of goal-directed fluid therapy, with earlier studies showing marked improvement in morbidity and length-of-stay that have not been replicated more recently. The aim of this study was to compare patient outcomes in elective colorectal surgery patients having goal-directed versus restrictive fluid therapy. Inclusion criteria included suitability for an Enhanced Recovery After Surgery care pathway and patients with an American Society of Anesthesiologists Physical Status score of 1 to 3. Patients were intraoperatively randomised to either restrictive or Doppler-guided goal-directed fluid therapy. The primary outcome was length-of-stay; secondary outcomes included complication rate, change in haemodynamic variables and fluid volumes. Compared to restrictive therapy, goal-directed therapy resulted in a greater volume of intraoperative fluid, 2115 (interquartile range 1350 to 2560) ml versus 1500 (1200 to 2000) ml, P=0.008, and was associated with an increase in Doppler-derived stroke volume index from beginning to end of surgery, 43.7 (16.3) to 54.2 (21.1) ml/m(2), P <0.001, in the latter group. Length-of-stay was similar, 6.5 (5 to 9) versus 6 (4 to 9) days, P=0.421. The number of patients with any complication (minor or major) was similar; 0% (30) versus 52% (26), P=0.42, or major complications, 1 (2%) versus 4 (8%), P=0.36, respectively. The increased perioperative fluid volumes and increased stroke volumes at the end of surgery in patients receiving goal-directed therapy did not translate to a significant difference in length-of-stay and we did not observe a difference in the number of patients experiencing minor or major complications.


[The new thrombolytic agents].
Among the new thrombolytic agents, two are or will be available in the near future: plasminogen tissue activator and antistreplase or anysoiled plasminogen-streptokinase activator complex (APSAC). The repermeabilization rate provided by these two thrombolytic agents administered intravenously, is practically identical, close to 70 p. cent, i.e. comparable to that obtained by intracoronary administration of streptokinase. The rate of secondary reobstruction is estimated near 17 p. cent for the tissue plasminogen activator and 10 p. cent for APSAC. Secondary reobstruction would be more frequently observed with thrombolytics with a short half-life (5 to 8 minutes of the tissue plasminogen activator whether it has one or two chains, versus 90 minutes with APSAC). Other factors influence it: persistence of a thrombogenic stimulus at the site of the stenosis, presence of thrombin, platelet activation... Both products have been found to be effective in limiting the size of the myocardial infarction and preservation of the left ventricular function. Finally, both have been shown to be effective on the reduction of the immediate and long-term mortality during extensive multicentric trials. The tissue plasminogen activator, although specific for fibrin, results in haemorrhagic complications which are as frequent as those cause by anistreplase which does not present this specificity for fibrin. The fibrin of pathological thrombi and the fibrin of the haemostatic centrifugate are identical. It is therefore lysed in the same fashion by all thrombolytic agents, whether or not specific of fibrin.


Electrostatic effects and calcium ion concentration as modulators of acid phosphatase bound to plant cell walls.
At 'low' ionic strength, acid phosphatase bound to plant cell walls exhibits an apparent negative co-operativity, whereas it displays classic Michaelis-Menten kinetics in free solution. Conversely, at 'high' ionic strength, the bound enzyme and the soluble enzyme behave identically. This apparent negative co-operativity is explained by the existence of an electrostatic partition of the charged substrate by the fixed negative charges of the cell wall. Raising the ionic strength suppresses these electrostatic repulsion effects. Calcium may be removed from the cell walls by acid treatment and the acid phosphatase is apparently strongly inhibited. This inhibition occurs together with an increased apparent negative co-operativity of the enzyme. Incubating cell wall fragments previously depleted of calcium with CaCl2 restores the initial behaviour of the enzyme. Calcium, which tightly binds to cell wall pectic compounds, has by itself no effect on the enzyme in free solution. It affects the net charge of the cell wall and therefore the amplitude of electrostatic repulsion effects. Non-linear least-square fitting methods make it possible to estimate the density of fixed negative charges as well as the electrostatic partition coefficient, for both the 'native' and 'calcium-deprived' cell wall fragments. It may be shown directly that calcium loading and unloading in the cell wall controls the electrostatic effects, by monitoring proton extrusion from cell wall fragments upon raising the ionic strength. Proton outflux in the bulk phase is considerably enhanced upon removal of calcium from the cell walls. The main conclusion is that loading and unloading of calcium during cell elongation and division may regulate the activity of cell wall enzymes.


Combining host plant defence with targeted nutrition: key to durable control of hemiparasitic Striga in cereals in sub-Saharan Africa?
Host plant defence mechanisms (resistance and tolerance) and plant nutrition are two of the most widely proposed components for the control of hemiparasitic weeds of the genus Striga in tropical cereal production systems. Neither of the two components alone is effective enough to prevent parasitism and concomitant crop losses. This review explores the potential of improved plant nutrition, being the chemical constituent of soil fertility, to fortify the expression of plant inherent resistance and tolerance against Striga. Beyond reviewing advances in parasitic plant research, we assess relevant insights from phytopathology and plant physiology in the broader sense to identify opportunities and knowledge gaps and to develop the way forward regarding research and development of combining genetics and plant nutrition for the durable control of Striga.


Prospective study on embolization of intracranial aneurysms with the pipeline device (PREMIER study): 3-year results with the application of a flow diverter specific occlusion classification.
The pipeline embolization device (PED; Medtronic) has presented as a safe and efficacious treatment for small- and medium-sized intracranial aneurysms. Independently adjudicated long-term results of the device in treating these lesions are still indeterminate. We present 3-year results, with additional application of a flow diverter specific occlusion scale. PREMIER (prospective study on embolization of intracranial aneurysms with pipeline embolization device) is a prospective, single-arm trial. Inclusion criteria were patients with unruptured wide-necked intracranial aneurysms ≤12 mm. Primary effectiveness (complete aneurysm occlusion) and safety (major neurologic event) endpoints were independently monitored and adjudicated. As per the protocol, of 141 patients treated with a PED, 25 (17.7%) required angiographic follow-up after the first year due to incomplete aneurysm occlusion. According to the Core Radiology Laboratory review, three (12%) of these patients progressed to complete occlusion, with an overall rate of complete aneurysm occlusion at 3 years of 83.3% (115/138). Further angiographic evaluation using the modified Cekirge-Saatci classification demonstrated that complete occlusion, neck residual, or aneurysm size reduction occurred in 97.1%. The overall combined safety endpoint at 3 years was 2.8% (4/141), with only one non-debilitating major event occurring after the first year. There was one case of aneurysm recurrence but no cases of delayed rupture in this series. The PED device presents as a safe and effective modality in treating small- and medium-sized intracranial aneurysms. The application of a flow diverter specific occlusion classification attested the long-term durability with higher rate of successful aneurysm occlusion and no documented aneurysm rupture. NCT02186561.


[Massive hemorrhage caused by colonic diverticulosis].
Massive hemorrhage from diverticular disease of the colon is a very difficult problem in abdominal emergency surgery. The pathogenesis of bleeding colonic diverticulosis is strictly correlated to the angioarchitecture of the colonic diverticular wall. Here the vasa recta penetrate the colonic wall from the serosa to the submucosa through connective tissue septa. Injurious factors arising from the colonic or diverticular lumen can produce an eccentric damage to the luminal side with intimal thickening, segmental weakening of the artery and its rupture with massive bleeding. Conventional barium enema is not able to show the source of the hemorrhage in the majority of the bleeding patients; colonoscopy, as primary emergency procedure, has significant positive findings in 41.5%-83.7% of patients. Radionuclide bleeding scans have a sensitivity rate of 86%-94%. Emergency arteriography localizes the bleeding source in higher rates ranging from 58% to 86% and is successful after intraarterial infusion of vasopressin or embolization in 47%-92% of patients. Surgical treatment for continued bleeding from diverticular disease is controversy. Segmental resection should be performed on patients with localized bleeding sources (positive arteriogram). Laparotomy, anterograde irrigation and intraoperative colonoscopy are indicated in patients with multiple bleeding sites and negative arteriography. Because the right colon is the most common site of bleeding in same cases is necessary to perform a subtotal colectomy with ileorectal anastomosis. Blind resections particularly in the elderly patients present high rebleeding rate (> 60%) and high mortality (30%) with sepsis accounting for the majority of deaths.


Factors affecting production and effectiveness, performance improvement and mechanisms of action of bacteriocins as food preservative.
Modern society is increasingly attracted with safe, natural, and additive-free food products, that gives preference to bacteriocins produced by General Recognized as Safe bacteria as a food preservative. Bacteriocins have been reported to be effective in extending shelf life of diverse foods such as meats, dairy products, wine, juice, and fruits and vegetables, whereas commercialized bacteriocins remain only nisin, pediocin, and Micocin. It is important that commercialized preservatives undergo an easy-to-handle manufacturing while maintaining high efficacy. Limited application of bacteriocins is most often caused by the absence of legislatives for use, low production, high cost and complicated purification process, reduced efficiency in the complex food matrix and insufficiently defined mechanism of action. Accordingly, this review provides an overview of bacteriocins, in relation to production stimulation, general purification scheme, impact of food matrix on bacteriocin effectiveness, and collaborative technology to improve bacteriocin performances. It is worth to note that purification and performance improvement technology remain the two challenging tasks in promoting bacteriocins as a widely used bio-preservative. Furthermore, this review for the first time divides bacteriocin receptors into specific classes (class I, II, III) and nonspecific class, to provide a basis for an in-depth understanding of the mechanism of action.


Artificially and sugar-sweetened carbonated beverage consumption is not associated with risk of lymphoid neoplasms in older men and women.
Concern about the carcinogenic potential of aspartame was raised after an increase in lymphomas and leukemia was reported in an animal study at doses similar to human exposure. Two prospective cohort studies published after the report found inconsistent results for estimated aspartame intake, artificially sweetened beverage consumption, and risk of lymphoid neoplasms. The objective of this study was to examine associations of artificially and sugar-sweetened carbonated beverage consumption (for comparison) and aspartame intake with risk of non-Hodgkin lymphoma (NHL) overall and by major histologic subtype in the Cancer Prevention Study-II Nutrition Cohort. Among 100,442 adult men and women who provided information on diet and lifestyle factors in 1999, 1196 NHL cases were verified during a 10-y follow-up period. Cox proportional hazards regression was used to estimate multivariable-adjusted RRs and 95% CIs. In women and men combined, there were no associations of consumption of ≥1 (355 mL) servings/d of artificially (RR: 0.92; 95% CI: 0.73, 1.17; P-trend: 0.14) or sugar- (RR: 1.10; 95% CI: 0.77, 1.58; P-trend: 0.62) sweetened carbonated beverages with NHL risk, compared to no consumption (P-heterogeneity by gender: 0.11-1.00). Similarly, aspartame intake was not associated with NHL risk (RR: 1.02; 95% CI: 0.84, 1.24; P-trend: 0.69, top vs. bottom quintile). Associations with NHL subtype (multiple myeloma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and follicular and other B-cell lymphoma) were generally null. These findings do not support associations of daily consumption of artificially or sugar-sweetened carbonated beverages, or aspartame, with NHL risk.


Astronomical imaging with infrared array detectors.
History shows that progress in astronomy often stems directly from technological innovation and that each portion of the electromagnetic spectrum offers unique insights into the nature of the universe. Most recently, the widespread availability of infrared-sensitive two-dimensional array detectors has led to dramatic improvements in the capabilities of conventional ground-based observatories. The impact of this new technology on our understanding of a wide variety of phenomena is illustrated here by infrared pictures of star-forming regions, of nebulae produced by the late stages of stellar evolution, of the nucleus of our own galaxy(the Milky Way), and of activity in other galaxies.


Crimean-Congo haemorrhagic fever virus replication in adult Hyalomma truncatum and Amblyomma variegatum ticks.
The kinetics of the replication of the Crimean-Congo haemorrhagic fever virus (CCHFV) was studied in intra-anally inoculated adult Hyalomma truncatum and Amblyomma variegatum ticks. The virus was re-isolated by suckling mouse inoculation and revealed by antigen capture with ground ticks and indirect immunofluorescence of haemolymph. The virus was detected in ticks in the first hours post-inoculation (p.i.) and its replication was observed from 36 h p.i. onwards. Virus titre reached a maximum within 3-5 days then decreased slowly to a level of at 2 log LD50/ml for several months until the end of observations. Several specific, non-identified factors seem to favour CCHFV replication in H. truncatum. Long-term virus persistence seems to occur in CCHFV-infected adult ticks.


On the origin of the liver.
While it has been well established that the fetal liver originates from foregut endoderm, the identity of the mechanisms that maintain liver mass under both basal and injury conditions remains controversial. Dramatically different models have been proposed based on the experimental design employed. In this issue of the JCI, Malato and colleagues report their elegant new model for genetic lineage tracing of mature mouse hepatocytes using an adenoassociated virus-driven Cre recombinase. They show convincingly that maintenance of liver mass during normal turnover or in response to mild injury is achieved by mature hepatocytes, rather than cholangiocytes or specialized progenitor cells, as has been suggested by others.


Cycling G1 CD34+/CD38+ cells potentiate the motility and engraftment of quiescent G0 CD34+/CD38-/low severe combined immunodeficiency repopulating cells.
The mechanism of human stem cell expansion ex vivo is not fully understood. Furthermore, little is known about the mechanisms of human stem cell homing/repopulation and the role that differentiating progenitor cells may play in these processes. We report that 2- to 3-day in vitro cytokine stimulation of human cord blood CD34(+)-enriched cells induces the production of short-term repopulating, cycling G1 CD34(+)/CD38(+) cells with increased matrix metalloproteinase (MMP)-9 secretion as well as increased migration capacity to the chemokine stromal cell-derived factor-1 (SDF-1) and homing to the bone marrow of irradiated nonobese diabetic severe/combined immunodeficiency (NOD/SCID) mice. These cycling G1 cells enhance SDF-1-mediated in vitro migration and in vivo homing of quiescent G0 CD34(+) cells, which is partially abrogated after inhibition of MMP-2/-9 activity. Moreover, the engraftment potential of quiescent G0 SCID repopulating cells (SRCs) is also increased by the cycling G1 CD34(+)/CD38(+) cells. This effect is significantly abrogated after incubation of cycling G1 cells with a neutralizing anti-CXCR4 antibody. Our data suggest synergistic interactions between accessory cycling G1 CD34(+)/CD38(+) committed progenitor cells and quiescent, primitive G0 CD34(+)/CD38(-/low) SRC/stem cells, the former increasing the motility and engraftment potential of the latter, partly via secretion of MMP-9.


[Hepatopulmonary syndrome].
Hepatopulmonary Syndrome is an uncommon clinical situation of unknown cause. It remains the focus of intense investigation and ongoing debate. The authors present a case of a 77 year old man with chronic liver disease known for 5 years, who developed central cyanoses, digital clubbing and hypoxemia. On searching for the cause of these clinical features, the diagnosis of Hepatopulmonary Syndrome was admitted and confirmed by contrast enhanced echocardiography using agitated saline, and also by technetium 99m-labelled macroaggregated albumin scanning.


[Large- scale prospective clinical study on prophylactic intervention of COVID-19 in community population using Huoxiang Zhengqi Oral Liquid and Jinhao Jiere Granules].
To scientifically evaluate the intervention effect of Chinese medicine preventive administration(combined use of Huo-xiang Zhengqi Oral Liquid and Jinhao Jiere Granules) on community population in the case of coronavirus disease 2019(COVID-19), a large cohort, prospective, randomized, and parallel-controlled clinical study was conducted. Total 22 065 subjects were included and randomly divided into 2 groups. The non-intervention group was given health guidance only, while the traditional Chinese medicine(TCM) intervention group was given two coordinated TCM in addition to health guidance. The medical instructions were as follows. Huoxiang Zhengqi Oral Liquid: oral before meals, 10 mL/time, 2 times/day, a course of 5 days. Jinhao Jiere Granules: dissolve in boiling water and take after meals, 8 g/time, 2 times/day, a course of 5 days, followed up for 14 days, respectively. The study found that with the intake of medication, the incidence rate of TCM intervention group was basically maintained at a low and continuous stable level(0.01%-0.02%), while the non-intervention group showed an overall trend of continuous growth(0.02%-0.18%) from 3 to 14 days. No suspected or confirmed COVID-19 case occurred in either group. There were 2 cases of colds in the TCM intervention group and 26 cases in the non-intervention group. The incidence of colds in the TCM intervention group was significantly lower(P<0.05) than that in the non-intervention group. In the population of 16-60 years old, the incidence rate of non-intervention and intervention groups were 0.01% and 0.25%, respectively. The difference of colds incidence between the two groups was statistically significant(P<0.05). In the population older than 60 years old, they were 0.04% and 0.21%, respectively. The incidence of colds in the non-intervention group was higher than that in the intervention group, but not reaching statistical difference. The protection rate of TCM for the whole population was 91.8%, especially for the population of age 16-60(95.0%). It was suggested that TCM intervention(combined use of Huoxiang Zhengqi Oral Liquid and Jinhao Jiere Granules) could effectively protect community residents against respiratory diseases, such as colds, which was worthy of promotion in the community. In addition, in terms of safety, the incidence of adverse events and adverse reactions in the TCM intervention group was relatively low, which was basically consistent with the drug instructions.


Oxytocin enhances the recovery of eye-contact induced autonomic arousal: A treatment mechanism study with placebo-controlled design.
The neuropeptide oxytocin (OT) is suggested to exert a pivotal role in a variety of complex human behaviors, including trust, attachment, social perception and fear regulation. Previous studies have demonstrated that intranasal administration of OT reduces subjective and neuroendocrine stress responses and dampens amygdala reactivity. OT has also been proposed to modulate activity of the autonomic nervous system. Here, a randomized double-blind, placebo-controlled study (with parallel design) was conducted with 56 healthy adult men to investigate whether a single-dose of OT (24 IU) modulates sympathetic autonomic arousal upon live dyadic gaze interactions. To do so, electrodermal recordings of skin conductance were performed during the engagement of eye contact with a live model in a two-person social context. In accordance to prior research, direct eye gaze elicited a significant enhancement in skin conductance responses, but OT did not specifically enhance or dampen the overall magnitude (amplitude) of the skin conductance response. Administration of OT did facilitate the recovery of skin conductance responses back to baseline (reduced recovery time), indicating a role of OT in restoring homeostatic balance. Notably, the treatment-effect on autonomic recovery was most prominent in participants with low self-reported social responsiveness, indicating that person-dependent factors play an important role in determining OT treatment-responses. Exploratory, it was shown that OT also significantly reduced self-reported feelings of tension and (at trend-level) worrying about how one presents oneself. Together, these observations add further evidence to a role of OT in modulating activity of the autonomic nervous system, primarily by facilitating a restoration of homeostatic balance after stimulus-induced increases in sympathetically-driven autonomic arousal.


Bullosis Diabeticorum: A Neglected Bullous Dermatosis.
A 75-year-old African-American man presented with a 3-year history of painless, fluid-filled blisters, for which his primary care physician had treated him with doxycycline, cephalexin, and topical corticosteroids, with no significant improvement. The blisters had ruptured spontaneously and healed with scarring. He denied antecedent trauma. His medical history was remarkable for insulin-dependent type 2 diabetes mellitus, hypertension, hypercholesterolemia, primary cutaneous melanoma status-post excision, and breast cancer status-post mastectomy and chemotherapy. Physical examination revealed nontender bullae, measuring up to 4 cm × 3 cm and containing serous fluid, on the anterior portion of both tibias (Figure 1). The Nikolsky sign was negative. There was no evidence of surrounding inflammation. A biopsy revealed subepidermal bullae formation with sparse inflammatory infiltrate (Figure 2). Direct and indirect immunofluorescence studies were negative for immunoglobulin (Ig) G, IgA, IgM, complement C3, C5b-9, and fibrinogen deposition. Culture of the bullous fluid was negative.


Identification of the human mitochondrial S-adenosylmethionine transporter: bacterial expression, reconstitution, functional characterization and tissue distribution.
The mitochondrial carriers are a family of transport proteins that, with a few exceptions, are found in the inner membranes of mitochondria. They shuttle metabolites and cofactors through this membrane, and connect cytoplasmic functions with others in the matrix. SAM (S-adenosylmethionine) has to be transported into the mitochondria where it is converted into S-adenosylhomocysteine in methylation reactions of DNA, RNA and proteins. The transport of SAM has been investigated in rat liver mitochondria, but no protein has ever been associated with this activity. By using information derived from the phylogenetically distant yeast mitochondrial carrier for SAM and from related human expressed sequence tags, a human cDNA sequence was completed. This sequence was overexpressed in bacteria, and its product was purified, reconstituted into phospholipid vesicles and identified from its transport properties as the human mitochondrial SAM carrier (SAMC). Unlike the yeast orthologue, SAMC catalysed virtually only countertransport, exhibited a higher transport affinity for SAM and was strongly inhibited by tannic acid and Bromocresol Purple. SAMC was found to be expressed in all human tissues examined and was localized to the mitochondria. The physiological role of SAMC is probably to exchange cytosolic SAM for mitochondrial S-adenosylhomocysteine. This is the first report describing the identification and characterization of the human SAMC and its gene.


Effects of conjugated linoleic acid on myogenic and inflammatory responses in a human primary muscle and tumor coculture model.
The antiproliferative and anti-inflammatory properties of conjugated linoleic acid (CLA) make it a potentially novel treatment in chronic inflammatory muscle wasting disease, particularly cancer cachexia. Human primary muscle cells were grown in coculture with MIA PaCa-2 pancreatic tumor cells and exposed to varying concentrations of c9,t11 and t10,c12 CLA. Expression of myogenic (Myf5, MyoD, myogenin, and myostatin) and inflammatory genes (CCL-2, COX-2, IL-8, and TNF-alpha) were measured by real-time PCR. The t10,c12 CLA isomer, but not the c9,t11 isomer, significantly decreased MIA PaCa-2 proliferation by between 15% and 19%. There was a marked decrease in muscle MyoD and myogenin expression (78% and 62%, respectively), but no change in either Myf5 or myostatin, in myotubes grown in coculture with MIA PaCa-2 cells. CLA had limited influence on these responses. A similar pattern of myogenic gene expression changes was observed in myotubes treated with TNF-alpha alone. Several-fold significant increases in CCL-2, COX-2, IL-8, and TNF-alpha expression in myotubes were observed with MIA PaCa-2 coculture. The c9,t11 CLA isomer significantly decreased basal expression of TNF-alpha in myotubes and could ameliorate its tumor-induced rise. The study provides insight into the anti-inflammatory and antiproliferative actions of CLA and its application as a therapeutic agent in inflammatory disease states.


Possible involvement of hyperinsulinemia and adrenergic activation in the pathogenesis of indomethacin-induced antral ulcers in nonfasted hamsters and refed rats.
Subcutaneous doses of indomethacin (IND) produced mainly antral ulcers in refed rats, almost exclusively corpus erosions in fasted rats, but no antral or corpus mucosal insult in nonfasted rats. In contrast, IND-treatment in nonfasted hamsters caused antral ulcers but minimal corpus erosions. Mild and severe hyperinsulinemia were observed in refed rats and nonfasted hamsters, respectively. The hyperinsulinemia and antral ulcers in the animals were significantly attenuated by a pretreatment (80 mg/kg, i.v., in rats, 60 mg/kg, i.p., in hamsters) of streptozotocin. Furthermore, the antral ulcers were dose-dependently attenuated by prazosin, an adrenergic alpha-1 antagonist, and yohimbine, an adrenergic alpha-2 antagonist, but not by propranolol, an adrenergic beta antagonist. The large doses of atropine (3.2-10 mg/kg, p.o.) also attenuated the ulcers. The histamine H2 receptor antagonist, famotidine (1-10 mg/kg, p.o.), significantly attenuated the antral ulcers in nonfasted hamsters, but not in refed rats. The latter two drugs exhibited greater inhibition of the corpus erosions in fasted rats compared with the antral ulcers in refed rats and nonfasted hamsters. The corpus erosions were more extensive after streptozotocin treatment (80 mg/kg, i.v.) and were aggravated significantly by yohimbine, whereas they were hardly affected by prazosin or propranolol. It is thus concluded that hyperinsulinemia and adrenergic activation are commonly involved in the etiology of the IND-induced antral ulcers in refed rats and nonfasted hamsters. Vagal activity, which plays a crucial role in the etiology of the corpus erosions in fasted rats, may play a part in the antral ulcer formation in nonfasted hamsters, but not in refed rats.


Changes in 137Cs concentrations in soil and vegetation on the floodplain of the Savannah River over a 30 year period.
(137)Cs released during 1954-1974 from nuclear production reactors on the Savannah River Site, a US Department of Energy nuclear materials production site in South Carolina, contaminated a portion of the Savannah River floodplain known as Creek Plantation. (137)Cs activity concentrations have been measured in Creek Plantation since 1974 making it possible to calculate effective half-lives for (137)Cs in soil and vegetation and assess the spatial distribution of contaminants on the floodplain. Activity concentrations in soil and vegetation were higher near the center of the floodplain than near the edges as a result of frequent inundation coupled with the presence of low areas that trapped contaminated sediments. (137)Cs activity was highest near the soil surface, but depth related differences diminished with time as a likely result of downward diffusion or leaching. Activity concentrations in vegetation were significantly related to concentrations in soil. The plant to soil concentration ratio (dry weight) averaged 0.49 and exhibited a slight but significant tendency to decrease with time. The effective half-lives for (137)Cs in shallow (0-7.6 cm) soil and in vegetation were 14.9 (95% CI=12.5-17.3) years and 11.6 (95% CI=9.1-14.1) years, respectively, and rates of (137)Cs removal from shallow soil and vegetation did not differ significantly among sampling locations. Potential health risks on the Creek Plantation floodplain have declined more rapidly than expected on the basis of radioactive decay alone because of the relatively short effective half-life of (137)Cs.


Phytophthora effector targets a novel component of small RNA pathway in plants to promote infection.
A broad range of parasites rely on the functions of effector proteins to subvert host immune response and facilitate disease development. The notorious Phytophthora pathogens evolved effectors with RNA silencing suppression activity to promote infection in plant hosts. Here we report that the Phytophthora Suppressor of RNA Silencing 1 (PSR1) can bind to an evolutionarily conserved nuclear protein containing the aspartate-glutamate-alanine-histidine-box RNA helicase domain in plants. This protein, designated PSR1-Interacting Protein 1 (PINP1), regulates the accumulation of both microRNAs and endogenous small interfering RNAs in Arabidopsis. A null mutation of PINP1 causes embryonic lethality, and silencing of PINP1 leads to developmental defects and hypersusceptibility to Phytophthora infection. These phenotypes are reminiscent of transgenic plants expressing PSR1, supporting PINP1 as a direct virulence target of PSR1. We further demonstrate that the localization of the Dicer-like 1 protein complex is impaired in the nucleus of PINP1-silenced or PSR1-expressing cells, indicating that PINP1 may facilitate small RNA processing by affecting the assembly of dicing complexes. A similar function of PINP1 homologous genes in development and immunity was also observed in Nicotiana benthamiana. These findings highlight PINP1 as a previously unidentified component of RNA silencing that regulates distinct classes of small RNAs in plants. Importantly, Phytophthora has evolved effectors to target PINP1 in order to promote infection.


Indomethacin is a potent inhibitor of pristane and plastic disc induced plasmacytomagenesis in a hypersusceptible BALB/c congenic strain.
Continuous indomethacin (INDO) administration in the drinking water (10 to 20 microg/mL) profoundly inhibited plasmacytoma (PCT) development initiated by three 0.2- or 0.5-mL intraperitoneal (i.p.) injections of pristane in hypersusceptible BALB/c.DBA/2-Idh1-Pep3 congenic mice. The most effective inhibitions were obtained with continuous INDO treatment. When treatment was delayed until 50 to 60 days after the first pristane injection, there was approximately a 50% reduction in PCT incidence. The primary action of pristane is the induction of a chronic inflammation in the peritoneal connective tissues and the formation of a microenvironment where PCTs develop. INDO, a powerful inhibitor of prostaglandin synthases (cyclooxygenases 1 and 2), did not inhibit the formation of mesenteric oil granuloma nor the appearance of cells in this chronic inflammatory tissue carrying c-myc illegitimately joined to an Ig heavy chain switch region, ie, the t(12;15) chromosomal translocation. INDO inhibited PCT induction by the i.p. implantation of 21 x 2 mm polycarbonate discs. These solid objects predominantly induce the formation of a patchy fibroplastic tissue on contacting peritoneal surfaces. These and previous data indicate that indomethacin inhibits an intermediate stage in PCT development after the arrival of cells bearing the T(12;15) translocation in the oil granuloma and before these cells acquire transplantability to a pristane-conditioned host. The biological mechanism that explains how INDO inhibits PCT development is not yet established but appears to result from decreased production of prostaglandins in chronic inflammatory tissues (oil granuloma, fibroplasia), suggesting that prostaglandins play an active role in oil and solid plastic induced PCT formation.


Bio-inspired graphene-derived membranes with strain-controlled interlayer spacing.
The precisely controlled size of nanoscale fluidic channels plays a critical role in resolving the permeation-selectivity trade-off in separation and filtration applications, where highly efficient gas separation and water desalination are targeted. Inspired by natural nacre where the spacing between mineral platelets changes upon applying tension as fractured mineral bridges climb over each other, bio-inspired graphene-derived membranes with sheets cross-linked by aligned covalent bonds are proposed in design, to ensure a controlled interlayer spacing ranging from 4 Å to 14 Å while preserving structural and mechanical stabilities by prohibiting swelling. The underlying mechanism is that the tension applied to the membrane is transferred between finite-sized graphene sheets through interlayer shear of the cross-links, which expands the interlayer gallery. First-principles calculations and continuum mechanics based model analysis are combined to explore the feasibility of this protocol, by considering the microstructures of graphene-derived membranes that have recently been demonstrated to offer exceptional performance in selective mass transport. The results show that the critical size range in molecular sieving is covered by this synergetic interface- and strain-engineering approach.


Olfactory receptors in aquatic and terrestrial vertebrates.
In species representing different levels of vertebrate evolution, olfactory receptor genes have been identified by molecular cloning techniques. Comparing the deduced amino-acid sequences revealed that the olfactory receptor gene family of Rana esculenta resembles that of Xenopus laevis, indicating that amphibians in general may comprise two classes of olfactory receptors. Whereas teleost fish, including the goldfish Carassius auratus, possess only class I receptors, the 'living fossil' Latimeria chalumnae is endowed with both receptor classes; interestingly, most of the class II genes turned out to be pseudogenes. Exploring receptor genes in aquatic mammals led to the discovery of a large array of only class II receptor genes in the dolphin Stenella Coeruleoalba; however, all of these genes were found to be non-functional pseudogenes. These results support the notion that class I receptors may be specialized for detecting water-soluble odorants and class II receptors for recognizing volatile odorants. Comparing the structural features of both receptor classes from various species revealed that they differ mainly in their extracellular loop 3, which may contribute to ligand specificity. Comparing the number and diversity of olfactory receptor genes in different species provides insight into the origin and the evolution of this unique gene family.


Skin rash following Administration of Apalutamide in Japanese patients with Advanced Prostate Cancer: an integrated analysis of the phase 3 SPARTAN and TITAN studies and a phase 1 open-label study.
A higher incidence of apalutamide-related skin rash has been observed in Japanese patients with prostate cancer (PC). This integrated analysis of data of Japanese patients from 2 global Phase 3 studies, SPARTAN ( NCT01946204 ; patients with non-metastatic castration-resistant PC [nmCRPC]) and TITAN ( NCT02489318 ; patients with metastatic castration-sensitive PC [mCSPC]), and the Phase 1 study 56021927PCR1008 ( NCT02162836 ; patients with metastatic CRPC [mCRPC]), assessed clinical risk factors of apalutamide-related skin rash as well as the potential correlation with plasma exposure to apalutamide. Kaplan-Meier method was used for time-to-event analyses. Clinical risk factors for skin rash were assessed using odds ratio. Data from 68 patients (SPARTAN: n = 34, TITAN: n = 28, 56021927PCR1008: n = 6) receiving apalutamide 240 mg orally once-daily were analyzed. Rash (13 [19.1%]) and maculo-papular rash (11 [16.2%]) were the most frequently reported skin rash. All Grade and Grade 3 skin rash occurred in 35 (51.5%) and 10 (14.7%) patients, respectively. Most (85.7%) skin rash occurred within 4 months of apalutamide initiation and resolved in a median time of 1 month following the use of antihistamines, topical or systemic corticosteroids, with/without apalutamide dose interruptions/reductions. Median time-to-remission of first incidence of rash and maximum grade incidence of rash were 1.0 month (IQR: 0.36-1.81) and 1.0 month (IQR: 0.30-2.43), respectively. No significant clinical risk factors for the incidence of skin rash were observed. Areas under the curve (0-24 h) (AUC0-24, ss) at steady-state of plasma apalutamide concentration were numerically slightly higher in patients with skin rash than those without. No clinical risk factors for rash could be detected. There is a potential correlation between incidence of skin rash and plasma exposure to apalutamide. In general, apalutamide-related skin rash is easily managed, with appropriate treatment with or without dose adjustment. Retrospective pooled analysis of NCT01946204 , NCT02489318 , and NCT02162836 .


[Cell differentiation of the head ectoderm in mouse embryos in vitro].
Cell differentiation has been studied in the explants of head ectoderm of 8, 9 and 10 day old mouse (CBA) embryos and of head epidermis of 13 day old embryos. Pieces of ectoderm were taken from the temporal region. It was established by indirect immunofluorescence that within 10, 15 and 20 days of cultivation spheroids with keratins or crystallins in some groups of fibres formed in the head ectoderm explants from 9 and 10 day old embryos. When cultivating the regions of head epidermis from 13 day old embryos, spheroids formed with keratin only in their cells. The data obtained suggest that there appear to be two clones of cells determined to the synthesis of keratins or crystallins in the head ectoderm of early mouse embryos. During embryogenesis, the number of cells determined to the synthesis of keratins appears to increase in the regions not related to the eye area. At the same time, the clone of cells determined to the synthesis of crystallins appears to be eliminated.


Prognostic factors and outcome of reirradiation for locally recurrent small cell lung cancer-a multicenter study.
The prognosis of patients with recurrent small cell lung cancer (SCLC) remains poor and treatment options are limited. We performed a multi-institution retrospective cohort study to evaluate the outcome of thoracic reirradiation, identify prognostic factors and assess treatment-related toxicity. Data of 33 patients re-irradiated for recurrent SCLC at 4 international university hospitals, were analysed. Overall survival (OS) acute and late toxicities were evaluated and prognostic factors for reirradiation were identified. Reirradiation (Re-RT) was performed at a median interval time of 24 months after the first thoracic radiotherapy series. Median survival after reirradiation was 7 months (range, 1-54 months). The Re-RT dose in EQD2 ranged from 20 to 87.50 Gy with a median of 32.50 Gy. The 1- and 2-year OS were 33% and 17%, respectively. Patients with a good performance status (KPS >70%), absence of extrathoracic disease, reirradiation dose (EQD2) of >40 Gy and a cumulative dose of first plus second series of radiotherapy (EQD2) >90 Gy were associated with improved OS. Acute pulmonary Grade 1-2 toxicity from re-irradiation was recorded in 11 patients (33%) and grade 3 acute toxicity was encountered 1 patient (3%). Reirradiation for locoregionally recurrent SCLC is safe and shows promising outcomes. Patients reirradiated with doses >40 Gy experienced more favourable survival rates. In contrast, patients with a poor performance status or extrathoracic disease have a poor prognosis and Re-RT should be considered only for symptom control in this group.


Quantitative assessment of graded burn wounds in a porcine model using spatial frequency domain imaging (SFDI) and laser speckle imaging (LSI).
Accurate and timely assessment of burn wound severity is a critical component of wound management and has implications related to course of treatment. While most superficial burns and full thickness burns are easily diagnosed through visual inspection, burns that fall between these extremes are challenging to classify based on clinical appearance. Because of this, appropriate burn management may be delayed, increasing the risk of scarring and infection. Here we present an investigation that employs spatial frequency domain imaging (SFDI) and laser speckle imaging (LSI) as non-invasive technologies to characterize in-vivo burn severity. We used SFDI and LSI to investigate controlled burn wounds of graded severity in a Yorkshire pig model. Burn wounds were imaged starting at one hour after the initial injury and daily at approximately 24, 48 and 72 hours post burn. Biopsies were taken on each day in order to correlate the imaging data to the extent of burn damage as indicated via histological analysis. Changes in reduced scattering coefficient and blood flow could be used to categorize burn severity as soon as one hour after the burn injury. The results of this study suggest that SFDI and LSI information have the potential to provide useful metrics for quantifying the extent and severity of burn injuries.


Bacterial community structure is indicative of chemical inputs in the Upper Mississippi River.
Local and regional associations between bacterial communities and nutrient and chemical concentrations were assessed in the Upper Mississippi River in Minnesota to determine if community structure was associated with discrete types of chemical inputs associated with different land cover. Bacterial communities were characterized by Illumina sequencing of the V6 region of 16S rDNA and compared to >40 chemical and nutrient concentrations. Local bacterial community structure was shaped primarily by associations among bacterial orders. However, order abundances were correlated regionally with nutrient and chemical concentrations, and were also related to major land coverage types. Total organic carbon and total dissolved solids were among the primary abiotic factors associated with local community composition and co-varied with land cover. Escherichia coli concentration was poorly related to community composition or nutrient concentrations. Abundances of 14 bacterial orders were related to land coverage type, and seven showed significant differences in abundance (P ≤ 0.046) between forested or anthropogenically-impacted sites. This study identifies specific bacterial orders that were associated with chemicals and nutrients derived from specific land cover types and may be useful in assessing water quality. Results of this study reveal the need to investigate community dynamics at both the local and regional scales and to identify shifts in taxonomic community structure that may be useful in determining sources of pollution in the Upper Mississippi River.


Analeptic use in clinical toxicology: a historical appraisal.
The introduction and increasing popularity of the barbiturates during the first two decades of the 20th century was associated with a new life threatening toxicological problem: the barbiturate overdose. This paper reviews the four major phases of analeptic use. As interest in the principles of physiologic antagonism between stimulants and depressants grew, analeptic agents were increasingly used to treat the obtundation and respiratory depression of barbiturate overdose. At first, naturally occurring stimulants such as camphor, strychnine, picrotoxin, and caffeine were used in desperate attempts to awaken patients. During the 1930s, and continuing at some centers into the 1960s, an increasing number of synthetic analeptics agents such as nikethamide, pentylenetetrazol, bemegride, amphetamine, and methylphenidate were enthusiastically recommended as barbiturate antidotes, often at very high doses. Unfortunately, utilizing generous amounts of multiple convulsants was not without its share of complications. Using this analeptic strategy the mortality rate after moderate to severe barbiturate overdose remained as high as 45%. Beginning in the mid-1940s a group of Scandinavian physicians pioneered a revolutionary approach to sedativehypnotic overdose that rejected the use of analeptics and relied on respiratory ventilation and supportive care. Although barbiturate overdose mortality decreased to less than 1% using this strategy, it would take another 20 years before this technique was universally adapted. While analeptic therapies for the treatment of drug overdose have now been abandoned, one of these analeptics, methylphenidate, currently enjoys wide use in the treatment of attention deficit hyperactivity disorder.


Size-Controlled Preparation of Microsized Perfluorocarbon Emulsions as Oxygen Carriers via the Shirasu Porous Glass Membrane Emulsification Technique.
We have developed microsized perfluorocarbon (PFC) emulsions with different sizes as artificial oxygen carriers (OCs) via Shirasu porous glass membrane emulsification. Monodispersed PFC emulsions with narrow size distribution were obtained. By changing the membrane pore size, we were able to precisely control the size of emulsions and fabricate emulsions similar in size to human red blood cells. Behaviors of Pluronics with different physiochemical properties (F127, F68, P85, and P103) as surfactants were also investigated, which evidenced that the type and concentration of Pluronics have a major impact on the size of emulsions and the response to different thermal conditions. The F127-stabilized microsized PFC emulsions were stable even during autoclave sterilization. The emulsions were loaded with Ru(ddp)-an oxygen-sensitive probe-on their surfaces to indicate oxygen concentration. Finally, incubations with HeLa cells that show fluorescence in response to hypoxia cultured in 2D and 3D suggested promising potential of our emulsions for OCs.


Linear and Symmetric Li-Based Composite Memristors for Efficient Supervised Learning.
Emerging energy-efficient neuromorphic circuits are based on hardware implementation of artificial neural networks (ANNs) that employ the biomimetic functions of memristors. Specifically, crossbar array memristive architectures are able to perform ANN vector-matrix multiplication more efficiently than conventional CMOS hardware. Memristors with specific characteristics, such as ohmic behavior in all resistance states in addition to symmetric and linear long-term potentiation/depression (LTP/LTD), are required in order to fully realize these benefits. Here, we demonstrate a Li-based composite memristor (LCM) that achieves these objectives. The LCM consists of three phases: Li-doped TiO2 as a Li reservoir, Li4Ti5O12 as the insulating phase, and Li7Ti5O12 as the metallic phase, where resistive switching correlates with the change in the relative fraction of the metallic and insulating phases. The LCM exhibits a symmetric and gradual resistive switching behavior for both set and reset operations during a full bias sweep cycle. This symmetric and linear weight update is uniquely enabled by the symmetric bidirectional migration of Li ions, which leads to gradual changes in the relative fraction of the metallic phase in the film. The optimized LCM in ANN simulation showed that exceptionally high accuracy in image classification is realized in fewer training steps compared to the nonlinear behavior of conventional memristors.


DNA methylation-based forensic tissue identification.
Identifying the source tissue of biological material found at crime scenes can be very informative in a number of cases. Despite their usefulness, current visual, catalytic, enzymatic, and immunologic tests for presumptive and confirmatory tissue identification are applicable only to a subset of samples, might suffer limitations such as low specificity, lack of sensitivity, and are substantially impacted by environmental insults. Moreover these assays are incompatible and thus cannot be multiplexed. Thus they are less amenable to automation. In addition their results are operator-dependent. A better alternative approach is tissue identification based on messenger RNA (mRNA) or microRNA (miRNA); however, RNA is not as stable as DNA, and requires the use of non-standard procedures by forensic laboratories. Herein a DNA-based assay is described that enables tissue identification based on detection of tissue-specific methylation patterns. DNA samples are subjected to digestion by a methylation-sensitive restriction endonuclease followed by multiplex amplification of specific genomic targets with fluorescent-labeled primers, capillary electrophoresis of amplification products, and automatic signal analysis by dedicated software, yielding the source tissue of the sample. The single tube assay was designed for easy integration by forensic laboratories (as the assay utilizes the same platforms as current forensic STR profiling). The system is fully automatable, provides operator-independent results, and allows combining tissue identification with profiling in a single procedure. The assay was tested on 50 DNA samples from blood, saliva, semen, and skin epidermis, and the source tissue was successfully identified in all cases. Detection of semen and DNA profiling were combined into one assay and the ability to detect mixtures of semen and saliva in various ratios was demonstrated. The assay correctly detected semen in all samples where it was present, and the calculated percentage of semen was comparable to the fraction of semen in the samples. The results demonstrate that methylation-based tissue identification is more than a proof-of-concept. The methodology holds promise as another viable forensic DNA analysis tool for characterization of biological materials.


Antiproliferative activity of ruthenium(ii) arene complexes with mono- and bidentate pyridine-based ligands.
A series of Ru(II) arene complexes of mono- and bidentate N-donor ligands with carboxyl or ester groups and chlorido ancillary ligands were synthesised and structurally characterised. The complexes have a distorted tetrahedral piano-stool geometry. The binding interaction was studied with calf thymus DNA (CT-DNA) by absorption titration, viscosity measurement, thermal melting, circular dichroism, ethidium bromide displacement assay and DNA cleavage of plasmid DNA (pBR322), investigated by gel electrophoresis. The dichlorido complexes bind covalently to DNA in the dark, similar to cisplatin, while the monochlorido complexes bind covalently on irradiation, similar to cisplatin analogues. The compounds are selectively cytotoxic against several tumour cell lines and show specific nonlinear correlation between dose and activity. This phenomenon is closely related to their potential to act preferentially as inhibitors of cell division.


[A case of severe tsutsugamushi disease without eruption].
A 64-year-old male was admitted to our division because of fever. After admission, the patient was given beta-lactam antibiotics intravenously because he had no eruption and eschar. However, the fever continued, and he became unconsciousness and DIC appeared. We diagnosed the patient as Tsutsugamushi disease from indirect fluorescent antibody technique. Minocycline was excellently effective. Several reports of Tsutsugamushi disease without eruption have been given, so we must always be careful of Tsutsugamushi disease.


Method of obtaining wavefront slope data from through-focus point spread function measurements.
A method is described for analyzing point source imagery collected with various amounts of defocus to obtain wavefront slope data at the exit pupil of an imaging system. Integration of this slope data yields the system wavefront aberration function. The method is based on a geometric optics interpretation of intensity point spread function measurements in the caustic region near focus. Algorithm performance is examined through Monte Carlo simulations. Application of the method to segmented-aperture systems is also explored. The proposed method is used to generate initial wavefront estimates for an iterative phase retrieval algorithm, significantly improving the capture range over a blind phase retrieval approach when segment tilt errors are large.


Asthma Mortality Among Persons Aged 15-64 Years, by Industry and Occupation - United States, 1999-2016.
In 2015, an estimated 18.4 million U.S. adults had current asthma, and 3,396 adult asthma deaths were reported (1). An estimated 11%-21% of asthma deaths might be attributable to occupational exposures (2). To describe asthma mortality among persons aged 15-64 years,* CDC analyzed multiple cause-of-death data† for 1999-2016 and industry and occupation information collected from 26 states§ for the years 1999, 2003, 2004, and 2007-2012. Proportionate mortality ratios (PMRs)¶ for asthma among persons aged 15-64 years were calculated. During 1999-2016, a total of 14,296 (42.9%) asthma deaths occurred among males and 19,011 (57.1%) occurred among females. Based on an estimate that 11%-21% of asthma deaths might be related to occupational exposures, during this 18-year period, 1,573-3,002 asthma deaths in males and 2,091-3,992 deaths in females might have resulted from occupational exposures. Some of these deaths might have been averted by instituting measures to prevent potential workplace exposures. The annual age-adjusted asthma death rate** per 1 million persons aged 15-64 years declined from 13.59 in 1999 to 9.34 in 2016 (p<0.001) among females, and from 9.14 (1999) to 7.78 (2016) (p<0.05) among males. The highest significantly elevated asthma PMRs for males were for those in the food, beverage, and tobacco products manufacturing industry (1.82) and for females were for those in the social assistance industry (1.35) and those in community and social services occupations (1.46). Elevated asthma mortality among workers in certain industries and occupations underscores the importance of optimal asthma management and identification and prevention of potential workplace exposures.


Mass determination and sensitivity based on resonance frequency changes of the higher flexural modes of cantilever sensors.
Micro- and nanocantilevers are increasingly employed as mass sensors. Most studies consider the first flexural mode and adsorbed masses that are either discretely attached or homogeneously distributed along the entire length of the cantilever. We derive general expressions that allow for the determination of the total attached mass with any mass distribution along the cantilever length and all flexural modes. The expressions are valid for all cantilevers whose flexural deflection can be described by a one-dimensional function. This approach includes the most common types of microcantilevers, namely, rectangular, picket, and V-shaped. The theoretical results are compared with experimental data up to the fourth flexural mode obtained from thermal noise spectra of rectangular and V-shaped cantilevers.


Bovine parvovirus DNA-binding proteins: identification by a combined DNA hybridization and immunodetection assay.
We have investigated the interaction between bovine parvovirus (BPV) capsid and non-capsid proteins and restriction fragments of the BPV genome by a combined DNA hybridization and immunodetection assay. 32P-labelled DNA was bound to nitrocellulose membranes bearing lysates of mock-infected and virus-infected cells whose proteins had been separated by SDS-polyacrylamide gel electrophoresis. The position of bound DNA was determined by autoradiography. The proteins on the membrane were still accessible to specific antibodies, allowing confirmation of the DNA-binding species by an immunodetection reaction. In 0.2 M-NaCl, BPV capsid proteins VP2 (72,000 daltons) and VP3 (62,000 daltons) bound the 0 to 16 map unit EcoRI fragment of BPV DNA which contained label in either the minus or plus strand. At higher salt concentration (0.5 M), only VP2 still bound DNA. Within this fragment, the capsid protein binding was restricted to those nucleotides between map units 0 and 4. No binding to capsid proteins was seen with the fragment spanning the middle of the genome and minor binding to VP3 was seen with the 5' end. Binding to the BPV non-capsid protein NP-1 was observed with the 0 to 16 map unit fragment when label was in the virion strand and to other possibly BPV-coded proteins when label was in the plus strand. The NP-1 binding was localized to map units 4 to 16. We did not detect binding to the BPV homologue(s) of the autonomous parvovirus non-capsid protein NS1, due in part to its low concentration in the cell lysates used. Points of the parvovirus replication cycle at which DNA-binding proteins may serve controlling functions are discussed.


Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP).
This report compiles and summarizes all recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) regarding prevention and control of tetanus, diphtheria, and pertussis in the United States. As a comprehensive summary of previously published recommendations, this report does not contain any new recommendations and replaces all previously published reports and policy notes; it is intended for use by clinicians and public health providers as a resource. ACIP recommends routine vaccination for tetanus, diphtheria, and pertussis. Infants and young children are recommended to receive a 5-dose series of diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines, with one adolescent booster dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. Adults who have never received Tdap also are recommended to receive a booster dose of Tdap. Women are recommended to receive a dose of Tdap during each pregnancy, which should be administered from 27 through 36 weeks' gestation, regardless of previous receipt of Tdap. After receipt of Tdap, adolescents and adults are recommended to receive a booster tetanus and diphtheria toxoids (Td) vaccine every 10 years to assure ongoing protection against tetanus and diphtheria.


Monkeypox: a review of epidemiological modelling studies and how modelling has led to mechanistic insight.
Human monkeypox (mpox) virus is a viral zoonosis that belongs to the Orthopoxvirus genus of the Poxviridae family, which presents with similar symptoms as those seen in human smallpox patients. Mpox is an increasing concern globally, with over 80,000 cases in non-endemic countries as of December 2022. In this review, we provide a brief history and ecology of mpox, its basic virology, and the key differences in mpox viral fitness traits before and after 2022. We summarize and critique current knowledge from epidemiological mathematical models, within-host models, and between-host transmission models using the One Health approach, where we distinguish between models that focus on immunity from vaccination, geography, climatic variables, as well as animal models. We report various epidemiological parameters, such as the reproduction number, R0, in a condensed format to facilitate comparison between studies. We focus on how mathematical modelling studies have led to novel mechanistic insight into mpox transmission and pathogenesis. As mpox is predicted to lead to further infection peaks in many historically non-endemic countries, mathematical modelling studies of mpox can provide rapid actionable insights into viral dynamics to guide public health measures and mitigation strategies.


Manganese antagonizes iron blocking mitochondrial aconitase expression in human prostate carcinoma cells.
To investigate the possible role of manganese in the regulation of mitochondrial aconitase (mACON) activity human prostate carcinoma cell line PC-3 cells. The mACON enzymatic activities of human prostate carcinoma cell line PC-3 cells were determined using a reduced nicotinamide adenine dinucleotide-coupled assay. Immunoblot and transient gene expression assays were used to study gene expression of the mACON. The putative response element for gene expression was identified using reporter assays with site-directed mutagenesis and electrophoretic mobility-shift assays. In vitro study revealed that manganese chloride (MnCl2) treatment for 16 h inhibited the enzymatic activity of mACON, which induced the inhibition of citrate utility and cell proliferation of PC-3 cells. Although results from transient gene expression assays showed that MnCl2 treatment upregulated gene translation by approximately 5-fold through the iron response element pathway, immunoblot and reporter assays showed that MnCl2 treatments inhibited protein and gene expression of mACON. This effect was reversed by co-treatment with ferric ammonium citrate. Additional reporter assays with site-directed mutagenesis and electrophoretic mobility-shift assays suggested that a putative metal response element in the promoter of the mACON gene was involved in the regulation of MnCl2 on the gene expression of mACON. These findings suggest that manganese acts as an antagonist of iron, disrupting the enzymatic activity and gene expression of mACON and citrate metabolism in the prostate.


Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II.
Heterozygous deletion of chromosome 17p (17p) is one of the most frequent genomic events in human cancers. Beyond the tumor suppressor TP53, the POLR2A gene encoding the catalytic subunit of RNA polymerase II (RNAP2) is also included in a ~20-megabase deletion region of 17p in 63% of metastatic castration-resistant prostate cancer (CRPC). Using a focused CRISPR-Cas9 screen, we discovered that heterozygous loss of 17p confers a selective dependence of CRPC cells on the ubiquitin E3 ligase Ring-Box 1 (RBX1). RBX1 activates POLR2A by the K63-linked ubiquitination and thus elevates the RNAP2-mediated mRNA synthesis. Combined inhibition of RNAP2 and RBX1 profoundly suppress the growth of CRPC in a synergistic manner, which potentiates the therapeutic effectivity of the RNAP2 inhibitor, α-amanitin-based antibody drug conjugate (ADC). Given the limited therapeutic options for CRPC, our findings identify RBX1 as a potentially therapeutic target for treating human CRPC harboring heterozygous deletion of 17p.