A New Kinetic Modeling Approach for Predicting the Lifetime of ATH-Filled Silane Cross-Linked Polyethylene in a Nuclear Environment.
This study focuses on the degradation of a silane cross-linked polyethylene (Si-XLPE) matrix filled with three different contents of aluminum tri-hydrate (ATH): 0, 25, and 50 phr. These three materials were subjected to radiochemical ageing at three different dose rates (8.5, 77.8, and 400 Gy·h-1) in air at low temperatures close to ambient (47, 47, and 21 °C, respectively). Changes due to radio-thermal ageing were investigated according to both a multi-scale and a multi-technique approach. In particular, the changes in the chemical composition, the macromolecular network structure, and the crystallinity of the Si-XLPE matrix were monitored by FTIR spectroscopy, swelling measurements in xylene, differential scanning calorimetry, and density measurements. A more pronounced degradation of the Si-XLPE matrix located in the immediate vicinity of the ATH fillers was clearly highlighted by the swelling measurements. A very fast radiolytic decomposition of the covalent bonds initially formed at the ATH/Si-XLPE interface was proposed to explain the higher concentration of chain scissions. If, as expected, the changes in the elastic properties of the three materials under study are mainly driven by the crystallinity of the Si-XLPE matrix, in contrast, the changes in their fracture properties are also significantly impacted by the degradation of the interfacial region. As an example, the lifetime was found to be approximately halved for the two composite materials compared to the unfilled Si-XLPE matrix under the harshest ageing conditions (i.e., under 400 Gy·h-1 at 21 °C). The radio-thermal oxidation kinetic model previously developed for the unfilled Si-XLPE matrix was extended to the two composite materials by taking into account both the diluting effect of the ATH fillers (i.e., the ATH content) and the interfacial degradation.


Microneedling Monotherapy for Acne Scar: Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Acne scarring, formed by the deposition of collagen following inflammatory acne, not only represents a cosmetic problem but also poses a psychological health risk to patients. As microneedling has become a common treatment for acne scarring, an increasing number of studies have compared the efficacy and safety of microneedling. In this study, we conducted a meta-analysis of randomized controlled trials (RCTs) comparing microneedling with other treatments. Three databases, namely Embase, PubMED, and Cochrane library, were searched until June 20, 2021, for RCTs only. Studies using microneedling in both treatments were excluded. Twelve studies, totaling 414 participants, were included in our meta-analysis. For objective scar improvement, the pooled estimate analysis of the first group, treated with microneedling without radiofrequency, yielded a mean difference of 0.42 (95% CI-0.12-0.73%) with a significant difference at the 5% significance level. The second group, treated with fractional radiofrequency microneedling, exhibited no significance at the 5% significance level. Regarding subjective satisfaction, most results exhibited no significant difference between microneedling and other treatments. Although no case of secondary scarring or infection was reported in our study, the pooled result of postinflammatory hyperpigmentation was significant at the 5% significance level and preferred microneedling treatment. Microneedling without radiofrequency achieved superior results in terms of scar improvement. No form of microneedling caused postinflammatory hyperpigmentation-an advantage in acne scar treatment. Thus, microneedling is a favorable choice for the treatment of acne scarring. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Estradiol-mediated inhibition of Sp1 decreases miR-3194-5p expression to enhance CD44 expression during lung cancer progression.
Sp1, an important transcription factor, is involved in the progression of various cancers. Our previous studies have indicated that Sp1 levels are increased in the early stage of lung cancer progression but decrease during the late stage, leading to poor prognosis. In addition, estrogen has been shown to be involved in lung cancer progression. According to previous studies, Sp1 can interact with the estrogen receptor (ER) to coregulate gene expression. The role of interaction between Sp1 and ER in lung cancer progression is still unknown and will be clarified in this study. The clinical relevance between Sp1 levels and survival rates in young women with lung cancer was studied by immunohistochemistry. We validated the sex dependence of lung cancer progression in EGFRL858R-induced lung cancer mice. Wound healing assays, chamber assays and sphere formation assays in A549 cells, Taxol-induced drug-resistant A549 (A549-T24) and estradiol (E2)-treated A549 (E2-A549) cells were performed to investigate the roles of Taxol and E2 in lung cancer progression. Luciferase reporter assays, immunoblot and q-PCR were performed to evaluate the interaction between Sp1, microRNAs and CD44. Tail vein-injected xenograft experiments were performed to study lung metastasis. Samples obtained from lung cancer patients were used to study the mRNA level of CD44 by q-PCR and the protein levels of Sp1 and CD44 by immunoblot and immunohistochemistry. In this study, we found that Sp1 expression was decreased in premenopausal women with late-stage lung cancer, resulting in a poor prognosis. Tumor formation was more substantial in female EGFRL858R mice than in male mice and ovariectomized female mice, indicating that E2 might be involved in the poor prognosis of lung cancer. We herein report that Sp1 negatively regulates metastasis and cancer stemness in E2-A549 and A549-T24 cells. Furthermore, E2 increases the mRNA and protein levels of RING finger protein 4 (RNF4), which is the E3-ligase of Sp1, and thereby decreases Sp1 levels by promoting Sp1 degradation. Sp1 can be recruited to the promoter of miR-3194-5p, and positively regulate its expression. Furthermore, there was a strong inverse correlation between Sp1 and CD44 levels in clinical lung cancer specimens. Sp1 inhibited CD44 expression by increasing the expression of miR-3194-5p, miR-218-5p, miR-193-5p, miR-182-5p and miR-135-5p, ultimately resulting in lung cancer malignancy. Premenopausal women with lung cancer and decreased Sp1 levels have a poor prognosis. E2 increases RNF4 expression to repress Sp1 levels in premenopausal women with lung cancer, thus decreasing the expression of several miRNAs that can target CD44 and ultimately leading to cancer malignancy.


Effects of aromatherapy on patient satisfaction with procedural abortion at less than 10 weeks' gestation: A randomized controlled trial.
This study aimed to compare satisfaction with procedural abortion prior to 10 weeks' gestation in patients randomized to lavender essential oil aromatherapy vs placebo (jojoba oil). This randomized trial compared lavender aromatherapy vs placebo in patients undergoing procedural abortion <10 weeks' gestation. Participants self-administered and inhaled oil during their procedures. Our primary outcome was composite mean score on the Iowa Satisfaction with Anesthesia Scale. Participants completed the State-Trait Anxiety Inventory, a visual analog scale reporting maximum procedural pain, and reported postprocedure aromatherapy acceptability. We analyzed 112 participants randomized to aromatherapy (n = 57) vs placebo (n = 55). Baseline characteristics were similar between groups. We found no difference in overall satisfaction (mean Iowa Satisfaction with Anesthesia Scale scores aromatherapy: 0.72 ± 0.96 vs placebo: 0.46 ± 0.98, p = 0.17) or maximum procedural pain (median visual analog scale score aromatherapy: 65 [range: 4-95] vs placebo: 63 [range: 7-97], p = 0.91). Independent predictors of satisfaction included the use of oral sedation (B: 0.36; 95% CI: 0.04-0.69), state anxiety (B: -0.45; 95% CI: -0.79 to -0.10), and maximum procedural pain (B: -0.17; 95% CI: -0.25 to -0.09). The aromatherapy participants were significantly more likely to have found inhaling scented oil helpful during their procedure (71.9% vs 45.5%; p = 0.005) and would recommend it to a friend who needed a procedural abortion (86.0% vs 56.4%; p = 0.0005) compared to those in the placebo group. Additionally, patients in the aromatherapy group were significantly more likely to agree with the statement, "If I need another procedural abortion, I would want to inhale scented oil during my procedure" (87.7% vs 70.9%; p = 0.03). The adjunctive use of lavender aromatherapy during first-trimester procedural abortion does not improve satisfaction with anesthesia but is highly valued by patients. Oral opioids as an adjunct to standard analgesics during procedural abortion (ibuprofen and paracervical block) do not decrease pain, and nonopioid options are lacking. Given current limited anesthesia options, aromatherapy could serve as an affordable and acceptable nonopioid adjunct to current standard of care during procedural abortion. NCT04969900.


Minimum adequate levels of personal health care: history and justification.
By giving everyone paper rights to health care, Americans may end up doing little better, at much greater cost, and feeling worse about it. The key to providing greater equity may be to find a way of defining the minimum that all should have. Most countries somehow define these limits for publicly provided services from education to cash assistance. But for health care benefits there are no simple limiting criteria--especially when professionals have the exceptional luxury of using whatever resources they choose. A realistic floor requires toughly maintained ceilings.


Pulmonary Langerhans' cells in patients with fibrotic lung disorders.
Langerhans' cells were found in lung biopsies in one of nine control patients and in 20 of 160 patients with fibrotic lung disorders, including 13 of 56 patients with idiopathic pulmonary fibrosis, two of nine patients with collagen vascular diseases, two of seven patients with hypersensitivity pneumonitis, and each of three patients with end stage fibrosis of uncertain cause. Langerhans' cells were not found in any of the 41 patients with sarcoidosis, the 35 patients with interstitial lung diseases associated with inhalation of inorganic dusts, the seven patients with pulmonary lymphangioleiomyomatosis, or the two patients with chronic eosinophilic pneumonia. In the control patient, Langerhans' cells were found between epithelial cells in bronchioles. In patients with fibrotic lung disorders, Langerhans' cells were found in the epithelial layer of bronchioles and alveoli containing proliferating epithelial cells, i.e., either cuboidal epithelial cells of bronchiolar origin or type II alveolar epithelial cells. Severe fibrosis or squamous metaplasia were not prerequisites for the presence of Langerhans' cells. The motility of Langerhans' cells apparently was restricted, as they were not found in the air spaces in any of the biopsies, and they were not recovered from bronchoalveolar lavage fluid of any of the 97 patients studied, even though some of these patients had relatively numerous Langerhans' cells in lung biopsies. These observations are in sharp contrast to those in pulmonary histiocytosis X, in which histiocytosis X cells (HX cells) occur in granulomas, in alveolar interstitium, and between epithelial cells of the lower respiratory system. HX cells also migrate into air spaces, as shown by their occurrence in bronchoalveolar lavage fluid. The HX bodies in HX cells are morphologically similar to Langerhans' cell granules, but are more numerous and pleomorphic. HX cells are considered to be reactive or activated Langerhans' cells.


Abdominal aortic calcification quantified by the Morphological Atherosclerotic Calcification Distribution (MACD) index is associated with features of the metabolic syndrome.
Abdominal aortic calcifications (AAC) predict cardiovascular mortality. A new scoring model for AAC, the Morphological Atherosclerotic Calcification Distribution (MACD) index may contribute with additional information to the commonly used Aortic Calcification Severity (AC24) score, when predicting death from cardiovascular disease (CVD). In this study we investigated associations of MACD and AC24 with traditional metabolic-syndrome associated risk factors at baseline and after 8.3 years follow-up, to identify biological parameters that may account for the differential performance of these indices. Three hundred and eight healthy women aged 48 to 76 years, were followed for 8.3 ± 0.3 years. AAC was quantified using lumbar radiographs. Baseline data included age, weight, blood pressure, blood lipids, and glucose levels. Pearson correlation coefficients were used to test for relationships. At baseline and across all patients, MACD correlated with blood glucose (r(2) = 0.1, P< 0.001) and to a lesser, but significant extent with traditional risk factors (p < 0.01) of CVD. In the longitudinal analysis of correlations between baseline biological parameters and the follow-up calcification assessment using radiographs we found LDL-cholesterol, HDL/LDL, and the ApoB/ApoA ratio significantly associated with the MACD (P< 0.01). In a subset of patients presenting with calcification at both baseline and at follow-up, all cholesterol levels were significantly associated with the MACD (P< 0.01) index. AC24 index was not correlated with blood parameters. Patterns of calcification identified by the MACD, but not the AC24 index, appear to contain useful biological information perhaps explaining part of the improved identification of risk of cardiovascular death of the MACD index. Correlations of MACD but not the AC24 with glucose levels at baseline suggest that hyperglycemia may contribute to unique patterns of calcification indicated by the MACD.


Differences in the processing of anaphoric reference between closely related languages: neurophysiological evidence.
The present study examines the involvement of syntactic and semantic/conceptual processes in the comprehension of pronouns in Dutch using the technique of event-related brain potentials (ERPs) replicating and extending an earlier study in German. Dutch and German are closely related and share the same logic in referring to non-diminutive and diminutive NPs (i.e. adding an affix which changes the syntactic gender into neutral). Both languages separate male (hij/er (he)) and female pronouns (zij/sie (she)), as well as a pronoun that refers to an entity of neutral gender, (het/es (it)). However, the neutral pronoun het in Dutch is not only a pronoun, it also is the article of a neutral noun. To investigate the influence of this word class ambiguity on pronoun resolution, as well as to establish the generality of the finding of the German study we manipulated syntactic and biological gender congruency between a personal pronoun and its antecedent in Dutch. In Dutch, sentences with the word-class (pronoun/article) ambiguous pronoun het elicited an early negative shift (150-280 ms) which continued in the time frame of the N400. For sentences with a syntactically and biologically incongruent pronoun a P600 (in absence of an N400) was obtained, which was independent of the morphological form of the referent. The neurophysiological pattern found for Dutch stimuli was clearly different from the German study, indicating that the processing of pronouns in these two languages differs. This can be explained in terms of language specific characteristics concerning the word class ambiguous neutral pronoun het. Moreover, in contrast to the findings in the German study, there was no clear effect caused by the morphological form of the referent. Additionally, in Dutch, the pronoun resolution in sentences with a non-diminutive antecedent seems to reflect processes of revision (P600 in absence of an N400), whereas for German evidence was found for clear involvement of conceptual/semantic processes as well as structure building processes (N400/P600 complex).


Neonatal Section of the Optic Chiasm Changes the Interhemispheric Transfer of Visual Information in Cats.
Recent studies in adult split-chiasm cats show that the contrast gain of the visual callosal pathway is considerably lower than the gain of the direct geniculocortical system and that high spatial and temporal frequencies are strongly attenuated in the process of callosal transfer. We recorded visual evoked potentials (VEPs) and single unit activities from visual cortical areas 17 and 18 in cats which had the optic chiasm sectioned at 3 weeks of age. Our results show that, unlike the animals sectioned as adults, the contrast gain and the spatial and temporal acuities of the callosal pathway of young split-chiasm cats were as good as the direct retinogeniculocortical pathway. Thus, under the present experimental conditions all the spatial and temporal information processed in areas 17 and 18 of one hemicortex is transferred to the other hemicortex via the callosal connections. These animals have also been tested behaviourally for the interocular (interhemispheric) transfer of learning of patterns of high spatial frequency and low contrast. In agreement with the electrophysiological results, we find a complete interocular transfer for this behavioural task. We conclude that the functional development of the interhemispheric connections can be modified by an early section of the optic chiasm and therefore the loss in binocular convergence can be partially compensated.


The antimicrobial activity of cephalexin against old and new pathogens.
The present report reviews the significant in vitro characteristics of cephalexin based on data published since 1967 (Wick, 1967). Whenever possible, current data on the action spectrum of cephalexin are compared with previous results, and the significance of in vitro activity to therapeutic efficacy is evaluated in the light of current clinical reports. Recent observations are presented on the in vitro action of cephalexin against newly recognized bacterial pathogens, such as beta-lactamase-producing Haemophilus influenzae and Branhamella catarrhalis (formerly Neisseria catarrhalis). Data are presented on the stability of cephalexin to various beta-lactamases. Current information on the types of penicillin-binding proteins that interact with cephalexin is briefly noted. Finally, consideration is given to the effects of inoculum density on the minimum inhibitory and bactericidal concentrations of cephalexin. The continued utility of the 30 micrograms cephalothin-class disc to predict cephalexin susceptibility is emphasized.


A 33nW Fully Autonomous SoC with Distributed Cooperative Energy Harvesting and Multi-Chip Power Management for mm-scale System-in-Fiber.
This paper presents a fully autonomous system-on-chip (SoC) that can be distributed along a fiber strand, capable of simultaneously harvesting energy, cooperatively scaling performance, sharing power, and booting-up with other in-fiber SoCs for ultra-low-power (ULP) sensing applications. Utilizing a custom switched capacitor energy harvesting and power management unit (EHPMU), the SoC can efficiently redistribute and reuse harvested energy along the fiber. Integrated on-chip, the ULP RISC-V digital core and temperature sensor enable energy-efficient sensing and computation at nanowatt power levels. A dedicated ripple boot-up and cooperative dynamic voltage and frequency scaling (DVFS) further optimize the operation and physical size of the system. Fabricated in 65 nm, measurement results show that the proposed SoC achieves 33 nW power consumption for the whole chip under 92 Lux lighting condition and can reduce control power down to 2.7 nW for the EHPMU. With the proposed power sharing and cooperative DVFS techniques, the SoC reduces the illuminance needed to stay alive by >7× down to 12 Lux. Integrated into a mm-scale polymer fiber, our SoC demonstrates the feasibility of fully autonomous and ULP on-body sensing systems in resource-constrained fiber environments.


[THE TRUTH ABOUT THE RINGWORM AFFAIR].
Ringworm of the scalp (Tinea Capitis), a fungal skin ailment that appears on the scalp, was treated until the early sixties by radiation therapy. It was discovered during the seventies that radiation treatment for ringworm may be associated with a higher risk of cancerous and benign tumors in the head and neck area for patients undergoing treatment. In 1995, Israel enacted a law to compensate ringworm irradiation patients which provided monetary compensation for those who were treated between 1946 and 1960. "The Ringworm Affair" focuses on the issue of radiation treatment for ringworm and the social perceptions surrounding the ethnic identity of the patients. Common opinion in Israel holds that the target population for these treatments was limited to the children of North African immigrants, and that the treatment was intentionally administered despite knowledge of its health hazards. Furthermore, according to these beliefs, over 100,000 children of immigrants were treated. This paper examines these common arguments in light of historical and research-based data regarding the ethnic background and total number of patients treated. Moreover, this paper will examine the argument that a mass operation took place to cure those children only in Israel between 1946 and 1960. As evidence will show, these arguments are unfounded. Notably, radiation therapy was used worldwide; other populations in Israel as well as other Jewish communities in Europe and North Africa were exposed to the same treatment since the 20's. The total number of patients in Israel is less than 100,000.


Genetic and viral etiology of glioblastoma--a unifying hypothesis.
Growing body of evidence implicates human cytomegalovirus (HCMV) in the etiology of glioblastoma (GBM). Although HCMV is a ubiquitous herpesvirus, only a minority of those infected develop GBM, suggesting the involvement of host genetic factors in susceptibility to HCMV-induced/spurred GBM. HCMV has evolved a large repertoire of strategies for decreasing the efficacy of the host immune response and interfering with viral clearance. One strategy involves the generation of proteins that have functional properties of the Fcgamma receptor (FcγR), which may enable the virus to evade host immunosurveillance by avoiding the effector consequences of antibody binding, such as antibody-dependent cellular cytotoxicity. Results of binding studies involving HCMV-encoded FcγR and genetically different immunoglobulin G proteins suggest that GM genes--genetic determinants of immunoglobulin γ chains--could modulate this viral strategy and thus serve as functional risk factors for the development of GBM, potentially unifying its seemingly disparate infectious, immune, and genetic etiologies.


Adherence to the Healthy Eating Index-2015 across Generations Is Associated with Birth Outcomes and Weight Status at Age 5 in the Lifeways Cross-Generation Cohort Study.
Maternal dietary quality during pregnancy is associated with offspring outcomes. These associations have not been examined in three-generation families. We investigated associations between parental and grandparental dietary quality, determined by healthy eating index (HEI)-2015, and offspring birth outcomes and weight status at age 5. The Lifeways cohort study in the Republic of Ireland comprises 1082 index-child's mothers, 333 index-child's fathers, and 707 grandparents. HEI-2015 scores were generated for all adults from prenatal dietary information collected using a validated food frequency questionnaire. In an adjusted model, greater adherence to the maternal HEI was associated with lower likelihood of low birth weight (LBW) (OR: 0.72, 95% CI: 0.50-0.99, p = 0.04). Similarly, maternal grandmothers (MGM) with higher HEI scores were less likely to have grandchildren with LBW (OR: 0.87, 95% CI: 0.61-0.96, p = 0.04) and more likely to have macrosomia (OR: 1.10, 95% CI: 1.01-1.22, p = 0.03). Higher paternal and paternal grandmothers (PGM) HEI scores were associated with lower likelihood of childhood obesity (OR: 0.89, 95% CI: 0.30-0.94, p = 0.03) and overweight (OR: 0.83, 95% CI: 0.22-0.99, p = 0.04), respectively. Mediation analysis showed significant direct relationship of MGM and PGM HEI scores on grandchildren's birthweight and obesity, respectively. In conclusion, maternal line dietary quality appears to influence fetal growth whereas paternal line dietary quality appears to influence postnatal growth.


The Management of Oligoprogression in the Landscape of New Therapies for Metastatic Melanoma.
Background: A limited degree of progression after a response to treatment is labelled as oligoprogression and is a hot topic of metastatic melanoma (MM) management. Rogue progressive metastases could benefit from local treatment, which could allow the continuation of ongoing systemic therapy, also known as treatment beyond progression (TBP). Methods: We retrospectively reviewed 214 selected MM patients who developed oligoprogression during treatment with v-Raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen-activated-extracellular signal-regulated kinase (MEK) or programmed cell death protein 1 (PD-1) inhibitors and received a local treatment continuing TBP. We performed univariate and multivariable analyses to assess the association between therapy outcomes and a series of clinical and biological features. Results: We identified 27 (10%) oligoprogressed patients treated locally with surgery (14), radiosurgery (11), and electrochemotherapy (2). TBP included PD-1 inhibitors (13) and BRAF/MEK inhibitors (14). The median progression-free survival post oligoprogression (PFSPO) was 14 months (5-19 95% confidence interval (C.I.)). In the univariate analysis, a significantly longer PFSPO was associated with complete response (CR), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, neutrophils/lymphocytes ratio (N/L) <2, and progression-free survival (PFS) at oligoprogression >11 months. Nevertheless, in the multivariable analysis, only CR and N/L <2 were found to be associated with longer PFSPO. Conclusions: In selected patients, local treatments contribute to controlling oligoprogression for a long time, allowing the continuation of systemic treatment and prolongation of overall survival (OS). Increasing biological and clinical knowledge is improving the accuracy in identifying patients to apply for local ablative therapies.


Perceptions of barriers and benefits to physical activity among outpatients in psychiatric rehabilitation.
To explore perceived barriers and benefits to physical activity in people with serious and persistent mental illness (SPMI) who were enrolled in community-based psychiatric rehabilitation. Four focus groups, two for men and two for women, were held with a total of 34 outpatients from two program sites. The investigators used a semistructured interview guide to facilitate the discussions. Audiotapes of the discussions were transcribed and analyzed for concepts and themes. Significant barriers to physical activity were: mental illness symptoms, medications, weight gain from medications, fear of discrimination, and safety concerns. Being in a psychiatric rehabilitation program offered comfort and belonging, but it also had the effect of leaving activity initiation up to the program staff, which some participants perceived was part of required program compliance. However, participants viewed physical activity positively, and they linked being active to improved mental health. Outpatients in psychiatric rehabilitation valued physical activity, but mental illness symptoms, medication sedation, weight gain, fear of unsafe conditions, fear of discrimination, and interpretations of program compliance were barriers. Confronting how attitudes and barriers specific to this population can affect activity and reframing program compliance to include the independent initiation of activity as part of improving health might help clients of mental health services to become more active.


Structural insights into the exquisite selectivity of neurexin/neuroligin synaptic interactions.
The extracellular domains of neuroligins and neurexins interact through Ca(2+) to form flexible trans-synaptic associations characterized by selectivity for neuroligin or neurexin subtypes. This heterophilic interaction, essential for synaptic maturation and differentiation, is regulated by gene selection, alternative mRNA splicing and post-translational modifications. A new, 2.6 A-resolution crystal structure of a soluble neurexin-1beta-neuroligin-4 (Nrx1beta-NL4) complex permits a detailed description of the Ca(2+)-coordinated interface and unveils concerted positional rearrangements of several residues of NL4, not observed in neuroligin-1, associated with Nrx1beta binding. Surface plasmon resonance analysis of the binding of structure-guided Nrx1beta mutants towards NL4 and neuroligin-1 shows that flexibility of the Nrx1beta-binding site in NL4 is reflected in a greater dissociation constant of the complex and higher sensitivity to ionic strength and pH variations. Analysis of neuroligin mutants points to critical functions for two respective residues in neuroligin-1 and neuroligin-2 in governing the affinity of the complexes. Although neuroligin-1 and neuroligin-2 have pre-determined conformations that respectively promote and prevent Nrx1beta association, unique conformational reshaping of the NL4 surface is required to permit Nrx1beta association.


Common-path optical coherence tomography guided vertical pneumodissection for DALK.
We reported a design and evaluation of an optical coherence tomography (OCT) sensor-integrated 27 gauge vertically inserted razor edge cannula (VIREC) for pneumatic dissection of Descemet's membrane (DM) from the stromal layer. The VIREC was inserted vertically at the apex of the cornea to the desired depth near DM. The study was performed using ex vivo bovine corneas (N = 5) and rabbit corneas (N = 5). A clean penumodissection of a stromal layer was successfully performed using VIREC without any stomal blanching on bovine eyes. The "big bubble" was generated in all five tests without perforation. Only micro bubbles were observed on rabbit eyes. The results proved that VIREC can be an effective surgical option for "big bubble" DALK.


[Spin probe mobility in the whole blood of white rats].
By means of ESR-method the rotary mobility of a tanol spin probe is studied in the whole blood of white rats at the temperatures 5.20 and 37 degrees C. It is shown that at all the temperatures the spin probe is localized in the blood plasma and has a value HFS a = (17.1 +/- 0.1) G. By means of linear anamorphism method it is shown on the example of the spectrum central line that the contour is lorenz, i. e. the superposition of the spectra of different sample regions is absent. The spin probe rotation frequency v is a stable blood parameter, the same for 11 rats investigated and dependent only on the blood temperature. For T = 5.20 and 37 degrees C the values have been received v = (86 +/- 2) x 10(8) s-1, (98 +/- 2) x 10(8) s-1 and (107 +/- 3) x 10(8) s-1, subsequently, which compared to v value in water-glycerin system (1:1) (WGS) allow one to calculate the blood microviscosity values (7.2 +/- 0.4), (6.3 +/- 0.4) and (5.8 +/- 0.4) mPds, subsequently. For the mentioned temperatures the non-sphericity parameter epsilon of the spin probe rotation has the values 0.19 +/- 0.03, 0.22 +/- 0.04 and 0.21 +/- 0.05, subsequently that is close to this parameter value for WCS (epsilon = 0.21 +/- 0.02; v = (6 divided by 20) x 10(9) s-1).


ProteomicsDB.
ProteomicsDB (https://www.ProteomicsDB.org) is a protein-centric in-memory database for the exploration of large collections of quantitative mass spectrometry-based proteomics data. ProteomicsDB was first released in 2014 to enable the interactive exploration of the first draft of the human proteome. To date, it contains quantitative data from 78 projects totalling over 19k LC-MS/MS experiments. A standardized analysis pipeline enables comparisons between multiple datasets to facilitate the exploration of protein expression across hundreds of tissues, body fluids and cell lines. We recently extended the data model to enable the storage and integrated visualization of other quantitative omics data. This includes transcriptomics data from e.g. NCBI GEO, protein-protein interaction information from STRING, functional annotations from KEGG, drug-sensitivity/selectivity data from several public sources and reference mass spectra from the ProteomeTools project. The extended functionality transforms ProteomicsDB into a multi-purpose resource connecting quantification and meta-data for each protein. The rich user interface helps researchers to navigate all data sources in either a protein-centric or multi-protein-centric manner. Several options are available to download data manually, while our application programming interface enables accessing quantitative data systematically.


EVOLUTION: Parasites Make Scaredy-Rats Foolhardy.
In the 7 August issue of the Proceedings of the Royal Society of London B, researchers offer a striking demonstration of the ability of some parasites to alter the behavior of their hosts for their own benefit. Rats, the intermediate hosts of the protozoan Toxoplasma gondii, appear to lose their fear of cats, Toxoplasma's final host, when the parasite infects them. By precisely altering rat brains, the parasite potentially increases its chances of completing its life cycle.


Identification and Analysis of Genes Underlying Bone Mineral Density by Integrating Microarray Data of Osteoporosis.
Osteoporosis is a kind of brittle bone disease, which is characterized by a reduction in bone mineral density (BMD). In recent years, a number of genes and pathophysiological mechanisms have been identified for osteoporosis. However, the genes associated with BMD remain to be explored. Toward this end, we integrated multiple osteoporosis microarray datasets to identify and systematically characterize BMD-related genes. By integrating the differentially expressed genes from three osteoporosis microarray datasets, 152 genes show differentially expressed between high and low BMD osteoporosis samples in at least two of the three datasets. Among them, 88 were up-regulated in high BMD samples and 64 were up-regulated in low BMD samples. The expression of ZFP36, JUNB and TMEM8A were increased at high BMD samples in all three datasets. Hub genes were further identified by co-expression network analysis. Functional enrichment analysis showed that the gene up-regulated in high BMD were enriched in immune-related functions, suggesting that the immune system plays an important role in osteoporosis. Our study explored BMD-related genes based on the integration of osteoporosis microarray data, providing guidance to other researchers from a new perspective.


Predicting Memory Score Using Paralinguistic Features.
An automated method of assessing short term memory can act as a dementia risk predictor, as poor short-term memory is strongly linked to early signs of dementia. While previous works show the feasibility of using speech to predict healthy and diagnosed dementia participants, there are still gaps in predicting 'dementia risk' and clear difficulties distinguishing early dementia with regular ageing. We extracted paralinguistic features from audio of individuals completing an over the phone episodic memory test, LOGOS. These paralinguistic features were used to discriminate between those with strong and poor short term memory performance. This work also explored various feature selection methods and tested this method across multiple datasets. Our best result was achieved using a Support Vector Machine (SVM) classifier, obtaining accuracy of 84% per audio recording.Clinical relevance- This work establishes the efficacy of using speech from older participants completing the LOGOS episodic memory test to estimate risk of dementia.


NK cells are primed by ANRS MVA(HIV)-infected DCs, via a mechanism involving NKG2D and membrane-bound IL-15, to control HIV-1 infection in CD4+ T cells.
Natural killer (NK) cells are the major antiviral effector cell population of the innate immune system. It has been demonstrated that NK-cell activity can be modulated by the interaction with dendritic cells (DCs). The HIV-1 vaccine candidate Modified Vaccinia Ankara encoding an HIV polypeptide (MVA(HIV)), developed by the French National Agency for Research on AIDS (ANRS), has the ability to prime NK cells to control HIV-1 infection in DCs. However, whether or not MVA(HIV)-primed NK cells are able to better control HIV-1 infection in CD4(+) T cells, and the mechanism underlying the specific priming, remain undetermined. In this study, we show that MVA(HIV)-primed NK cells display a greater capacity to control HIV-1 infection in autologous CD4(+) T cells. We also highlight the importance of NKG2D engagement on NK cells and DC-produced IL-15 to achieve the anti-HIV-1 specific priming, as blockade of either NKG2D or IL-15 during MVA(HIV)-priming lead to a subsequent decreased control of HIV-1 infection in autologous CD4(+) T cells. Furthermore, we show that the decreased control of HIV-1 infection in CD4(+) T cells might be due, at least in part, to the decreased expression of membrane-bound IL-15 (mbIL-15) on DCs when NKG2D is blocked during MVA(HIV)-priming of NK cells.


Background noise levels and reverberation times in unoccupied classrooms: predictions and measurements.
Classrooms are often filled with deterrents that hamper a child's ability to listen and learn. It is evident that the acoustical environment in classrooms can be one such deterrent. Excessive background noise and reverberation can affect the achievement and educational performance of children with sensorineural hearing loss (SNHL) and children with normal hearing sensitivity who have other auditory learning difficulties, as well as elementary school children with no verbal or hearing disabilities. The purpose of this study was to evaluate the extent of the problem of noise and reverberation in schools. To that end, we measured reverberation times and background noise levels in 32 different unoccupied elementary classrooms in eight public school buildings in central Ohio. The results were compared with the limits recommended in the American National Standards Institute standard for acoustical characteristics of classrooms in the United States (ANSI S12.60-2002). These measurements were also compared to the external and internal criteria variables developed by Crandell, Smaldino, & Flexer (1995) to determine if a simple checklist can accurately predict unwanted classroom background noise levels and reverberation. Results indicated that most classrooms were not in compliance with ANSI noise and reverberation standards. Further, our results suggested that a checklist was not a good predictor of the noisier and more reverberant rooms.


Endothelial progenitor cell homing: prominent role of the IGF2-IGF2R-PLCbeta2 axis.
Homing of endothelial progenitor cells (EPCs) to the neovascular zone is now considered to be an essential step in the formation of vascular networks during embryonic development and also for neovascularization in postnatal life. We report here the prominent role of the insulin-like growth factor 2 (IGF2)/IGF2 receptor (IGF2R) system in promoting EPC homing. With high-level expression of IGF2R in EPCs, IGF2-induced hypoxic conditions stimulated multiple steps of EPC homing in vitro and promoted both EPC recruitment and incorporation into the neovascular area, resulting in enhanced angiogenesis in vivo. Remarkably, all IGF2 actions were exerted predominantly through IGF2R-linked G(i) protein signaling and required intracellular Ca(2+) mobilization induced by the beta2 isoform of phospholipase C. Together, these findings indicate that locally generated IGF2 at either ischemic or tumor sites may contribute to postnatal vasculogenesis by augmenting the recruitment of EPCs. The utilization of the IGF2/IGF2R system may therefore be useful for the development of novel means to treat angiogenesis-dependent diseases.


A comparison of the main structures of N-glycans of porcine islets with those from humans.
After producing α1-3-galactosyltransferase knockout (GKO) pigs, most of the organs of these pigs showed less antigenicity to the human body. However, wild-type adult pig islets (API) that originally contained negligible levels of α-galactosidase now showed a clear antigenicity to human serum. In this study, N-glycans were isolated from both APIs and human islets. Their structures were then analyzed by a mapping technique based on their high-performance liquid chromatography elution positions and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometric data. Both preparations contained substantial amounts of high-mannose structures. The N-glycans from human islets were separated into 17 neutral, 8 mono-sialyl and 4 di-sialyl glycans, and the API glycans were comprised of 11 neutral, 8 mono-sialyl, 3 di-sialyl, 2 mono-sulfated, 3 mono-sialyl-mono-sulfated and 1 di-sulfated glycans. Among them, the API preparation contained one neutral, five mono-sialyl glycans and six sulfated glycans that were not detected in human islets. The structures of 9 of these 12 could be clearly determined. In addition, a study of the sulfate-depleted API suggests that sulfate residues could be antigenic to humans. The data herein will be helpful for future studies of the antigenicity associated with API.


Obesity and hypoalbuminaemia are independent risk factors for readmission and reoperation following primary total knee arthroplasty.
Rates of readmission and reoperation following primary total knee arthroplasty (TKA) are under scrutiny due to new payment models, which penalize these negative outcomes. Some risk factors are more modifiable than others, and some conditions considered modifiable such as obesity may not be as modifiable in the setting of advanced arthritis as many propose. We sought to determine whether controlling for hypoalbuminaemia would mitigate the effect that prior authors had identified in patients with obesity. We reviewed the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database for the period of January 2008 to December 2016 to evaluate the rates of reoperation and readmission within 30 days following primary TKA. Multivariate logistic regression modelling controlled for preoperative albumin, age, sex, and comorbidity status. Readmission rates only differed significantly between patients with Normal Weight and Obesity Class II, with a decreased rate of readmission in this group (odds ratio (OR) 0.82; 95% confidence interval (CI) 0.71 to 0.96; p = 0.010). The only group demonstrating association with increased risk of reoperation within 30 days was the Obesity Class III group (OR 1.38; 95% CI 1.05 to 1.82; p = 0.022). Hypoalbuminaemia (preoperative albumin < 35 g/L) was significantly associated with readmission (OR 1.62; 95% CI 1.41 to 1.86; p < 0.001) and reoperation (OR 1.52; 95% CI 1.18 to 1.96; p = 0.001) within 30 days. In this study, hypoalbuminaemia appears to be a more significant risk factor for readmission and reoperation than even the highest obesity categories. Future studies may assess whether preoperative albumin restoration or weight loss may improve outcomes for patients with hypoalbuminaemia. The implications of this study may allow surgeons to discuss risk of surgery with obese patients planning to undergo primary TKA procedures if other comorbidities are adequately controlled. Cite this article: Bone Joint J 2020;102-B(6 Supple A):31-35.


Genome sequence of the temperate bacteriophage PH10 from Streptococcus oralis.
Exponential growing cultures of Streptococcus oralis strain OMZ 1038, isolated from human supragingival dental plaque, were found to release a bacteriophage (designated PH10) upon treatment with mitomycin C. The complete genome sequence of phage PH10 was determined. The genome was 31276 bp in size and contained 54 open reading frames. The module encoding structural proteins was highly similar to that of Streptococcus pneumoniae prophage PhiSpn_3. The most abundant phage structural protein was encoded by ORF35 and was likely processed by proteolytic cleavage. The putative endolysin from PH10, which contained a muramidase domain and a choline-binding domain, was purified and shown to have lytic activity with S. oralis, S. pneumoniae and Streptococcus mitis, but not with other streptococcal species.


Evaluation of a hypervariable octameric oligonucleotide fingerprints assay for identification of and discrimination between wild-type and vaccine strains of Brucella melitensis.
OBJECTIVE To evaluate a hypervariable octameric oligonucleotide fingerprints (HOOF-Prints) assay for identification of and discrimination between wild-type and vaccine strains of Brucella melitensis. SAMPLE Brucella melitensis vaccine strain M5 and wild-type strain M43. PROCEDURES 8 pairs of primers (alterable, octameric nucleotides) were designed on the basis of a biological analysis of 8 flanking sequences in the DNA of B melitensis. The HOOF-Prints technique was used to identify wild-type and vaccine strains of B melitensis. Phylogenetic analysis of short, polymorphic fragments of DNA from B melitensis strains M5 and M43 was performed. RESULTS Variable-number tandem repeat DNA segments of B melitensis vaccine strain M5 and wild-type strain M43 were successfully amplified by means of PCR assay. All target gene fragments ranged in size from 100 to 300 bp. Separate phylogenetic analysis of each Brucella strain revealed considerable differences between the vaccine and wild-type strains. CONCLUSIONS AND CLINICAL RELEVANCE The results of this study suggested the HOOF-Prints assay may be useful for discriminating vaccine strains of B melitensis from wild-type strains. This ability could allow discrimination between animals that are seropositive because of vaccination against B melitensis and those that are seropositive because of B melitensis infection and could decrease the likelihood of importing Brucella-infected animals.


The role of natural killer cells in the pathogenesis of sepsis: the ongoing enigma.
The study by Souza-Fonseca-Guimaraes and colleagues in the previous issue of Critical Care shows several alterations in blood natural killer (NK) characteristics during human sepsis and systemic inflammatory response syndrome, including changes in NK cell numbers, Toll-like receptor (TLR) expression, and responsiveness to TLR agonists. This paper advances our knowledge of NK cell biology during sepsis and provides the background for future investigations.


Tobacco Marketing and Subsequent Use of Cigarettes, E-Cigarettes, and Hookah in Adolescents.
Tobacco marketing has expanded from cigarettes to other tobacco products through many promotional channels. Marketing exposure is associated with use of that tobacco product. However, it is unclear if marketing for one product leads to subsequent use of other tobacco products. This prospective cohort study assessed self-reported marketing exposure for six tobacco products across five marketing channels in 11th and 12th grade students in 2014. Approximately 16 months later, a follow-up survey was conducted online (N = 1553) to assess initiation of cigarettes, electronic cigarettes (e-cigarettes), and hookah. Adolescent never-smokers with frequent exposure to cigarette marketing on the Internet and in stores are more than two times as likely to begin smoking as young adults (Internet OR = 2.98 [95% CI = 1.56 to 5.66]; stores OR = 2.83 [95% CI = 1.23 to 6.50]). Never users of e-cigarettes were significantly more likely to initiate use, if exposed to Internet, store, and outdoor e-cigarette marketing. Never users of hookah were more likely to use hookah after seeing it marketed in stores. Youth exposed to marketing of e-cigarettes, hookah, cigars, smokeless tobacco, and pipe tobacco in stores were two to three times more likely to begin smoking cigarettes even though the marketed products were not cigarettes. Adolescent exposure to marketing of tobacco products is associated with initiation of those products as young adults. Exposure to marketing for non-cigarette tobacco products is associated with subsequent cigarette smoking, even when the promoted products are not cigarettes. Future research and interventions should consider the influence of marketing from multiple tobacco products on adolescent tobacco use. Adolescents grow up in a rich media environment with exposure to tobacco marketing in both their homes (eg, through the Internet and television) and their communities (eg, stores and billboards). This prospective study provides evidence that adolescents exposed to tobacco marketing for multiple tobacco products are more likely to subsequently begin using those products and to begin smoking cigarettes even when the marketing they recall is for different tobacco products. Adolescent exposure to tobacco marketing can increase likelihood of cigarette smoking, e-cigarette, and hookah use with potential lifelong health effects.


Quantification of 108 illicit drugs and metabolites in bile matrix by LC-MS/MS for the toxicological testing of sudden death cases.
Sudden death could occur after assumption of illicit drugs for recreational purposes in adults or after intoxication in children, and toxicological testing would help identify the cause of the death. Analytical methods sensitive and specific for the quantification of a great number of drugs and metabolites in at least 2 matrices should be used. Bile, collected postmortem, may be considered a specimen alternative to blood and urine to perform toxicological testing because of its extended detection window. The present study proposed a LC-MS/MS method to quantify 108 drugs and metabolites in bile. Compounds belonging to the drugs of abuse classes of amphetamines, benzodiazepines, cocaine derivatives, barbiturates, opioids, z-drugs, and psychedelics were analyzed. The sample preparation is simple and does not require solid-phase extraction. The proposed method showed an appropriate selectivity, specificity, accuracy, and precision of the calibrators and quality controls tested (precision < 15%; accuracy < 100 ± 15%). The sensitivity allowed to identify low amounts of drugs (e.g., morphine limit of detection = 0.2 µg/L; limit of quantification = 1.1 µg/L). There is no significant matrix effect, except for buprenorphine and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol. Carry-over was not present. Analytes were stable at least for 1 month at - 20 °C. Analyzing 13 postmortem specimens, methadone (50%), and cocaine (37.5%) resulted to be the most prevalent consumed substances; the concentrations quantified in bile resulted to be higher than the ones in blood suggesting bile as a potential new matrix for identifying illicit drugs and their metabolites.


Postmenopausal hormone replacement: effects on autonomic, neuroendocrine, and immune reactivity to brief psychological stressors.
Postmenopausal status increases some aspects of women's physiological responses to psychological stress; however, the influences of chronic hormone replacement with estrogen and progestogen on these responses are not known. We investigated possible effects of long-term estrogen replacement therapy (ERT), both with and without progestogen, on physiological reactivity to brief laboratory stressors. We studied three groups of postmenopausal women: 16 on estrogen alone, 14 on estrogen and progestogen, and 25 control participants receiving no replacement therapy. Cardiovascular, neuroendocrine, and immune data were collected at baseline and after speech and math tasks. In all groups, the stressors reduced vagal cardiac control (indexed by respiratory sinus arrhythmia); increased heart rate and plasma epinephrine, adrenocorticotropic hormone, and cortisol levels; and altered T lymphocyte response (measured by mitogen-induced cell proliferation), natural killer cell lysis, and circulating leukocyte subsets. Women on either type of ERT had higher total cortisol levels (reflecting an estrogen effect on cortisol binding globulin) and greater mitogen-induced blastogenesis across measurement periods than controls. They also showed greater vagal withdrawal and less decline in mitogen-stimulated blastogenesis in response to the stressors. Combined estrogen and progestogen was associated with higher epinephrine and lower circulating total lymphocytes, T cells, and CD4+ T cells across measurement periods, and with intermediate levels of vagal withdrawal in response to the stressors. Long-term ERT was associated with enhanced parasympathetic responsiveness to stress, suggesting possible reduced demand for potentially detrimental sympathetic activation; and with higher overall levels and smaller stress-induced reductions of mitogen-stimulated blastogenesis, suggesting up-regulated T cell function.


Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin.
Patients with chronic hepatitis C virus (HCV) infections are treated with pegylated interferon and ribavirin (PEG-IFN/RBV), which is effective in less than 50% of those infected with HCV genotype 1. Genome-wide association studies have linked response to PEG-IFN/RBV with common single nucleotide polymorphisms in the vicinity of interferon (IFN)-lambda genes on chromosome 19. We investigated the association between the polymorphism rs12979860 and treatment response in a diverse cohort of chronic HCV patients. A cross-sectional study of 1021 consecutive patients enrolled in the Duke Hepatology Clinic Research Database and Biorepository. We analyzed DNA, clinical and demographic data, along with validated data of the response of 231 subjects to PEG-IFN/RBV. The study included Caucasians (n = 178), African Americans (n = 53), and HCV genotypes 1 (n = 186) and 2/3 (n = 45). The rs12979860 genotype was tested for an association with sustained virologic response, defined as undetectable levels of HCV RNA 24 weeks after treatment ended. The rs12979860 CC genotype (found in approximately 40% of Caucasians) predicted a sustained virologic response to therapy among Caucasians (odds ratio, 5.79; 95% confidence interval, 2.67-12.57; P = 9.0 x 10(-6)), independent of HCV genotype and other covariates. Rs12979860 CC predicted a sustained response with 78% specificity and 65% sensitivity in patients infected with HCV genotype 1). rs12979860 genotype is a significant independent predictor of response to PEG-IFN/RBV in patients with chronic HCV infection; tests for this genotype might be used to determine the best course of treatment for patients considering antiviral therapy.


Transition: the experiences of support workers caring for people with learning disabilities towards the end of life.
This research aims to provide a better understanding of the experience of support workers, as paid carers, caring for adults with learning disabilities (LDs) nearing the end of life in residential settings. In the past 100 years, people with LDs (also referred to as 'learning difficulty', 'mental retardation' and 'intellectual disability' internationally) are living longer with life expectancy approaching the population norm and more likely to die from diseases such as cancer, respiratory and vascular diseases. Community-based supported accommodation has become the foremost provider for people with LDs in their late 30 s or over in the UK. In the midst of the transition from living to dying for people with LDs, and even postdeath, the needs of support workers are often neglected against a background where most are unqualified, often with little experience of death and dying event, and with limited access to clinical supervision and education. 3 focus groups involving 13 support workers were conducted at 3 independent service provider settings for people with LDs in London. In recounting the experiences of these groups of support workers, 6 themes are described: strong emotional bond and identification; collaboration with other services; training issues around the extended role; support within the organisation; relationship with family/other residents; and grieving the 'loss'. Although support workers play a key role in meeting the end-of-life care needs of people with LDs in residential settings, their own needs are often neglected. There are still significant gaps in understanding these needs and practice development in this area.


Expression and function of the equine herpesvirus 1 virion-associated host shutoff homolog.
The ability of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2, respectively) to repress host cell protein synthesis early in infection has been studied extensively and found to involve the activities of the UL41 gene product, the virion-associated host shutoff (vhs) protein. To date, UL41 homologs have been identified in the genomes of three other alphaherpesviruses: equine herpesvirus 1 (EHV-1), varicella-zoster virus, and pseudorabies virus, but very little is known about the putative products of these homologous genes. Our earlier observations that no rapid early host protein shutoff occurred in EHV-1-infected cells led us to test EHV-1 vhs activity more thoroughly and to examine the expression and function of the EHV-1 UL41 homolog, ORF19. In the present study, the effects of EHV-1 and HSV-1 infections on cellular protein synthesis and mRNA degradation were compared at various multiplicities of infection in several cell types under an actinomycin D block. No virion-associated inhibition of cellular protein synthesis or vhs-induced cellular mRNA degradation was detected in cells infected with any of three EHV-1 strains (Ab4, KyA, and KyD) at multiplicities of infection at which HSV-1 strain F exhibited maximal vhs activity. However, further analyses revealed that (i) the EHV-1 vhs homolog gene, ORF19, was transcribed and translated into a 58-kDa protein in infected cells; (ii) the ORF19 protein was packaged into viral particles in amounts detectable in Western blots (immunoblots) with monoclonal antibodies; (iii) in cotransfection vhs activity assays, transiently-expressed ORF19 protein had intrinsic vhs activity comparable to that of wild-type HSV-1 vhs; and (iv) this intrinsic vhs activity was ablated by in vitro site-directed mutations in which either the functionally inactive HSV-1 vhs1 UL41 mutation (Thr at position 214 replaced by Ile [Thr-214-->Ile]) was recreated within ORF19 or two conserved residues within the putative poly(A) binding region of the ORF19 sequence were altered (Tyr-190, 192-->Phe). From these results we conclude that EHV-1's low vhs activity in infected cells is not a reflection of the ORF19 protein's intrinsic vhs activity but may be due instead to the amount of ORF19 protein associated with viral particles or to modulation of ORF19 protein's intrinsic activity by another viral component(s).


Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients.
Lipoprotein lipase-deficient (LPLD) individuals display marked chylomicronemia and hypertriglyceridemia associated with increased pancreatitis risk. The aim of this study was to determine the effect of i.m. administration of an adeno-associated viral vector (AAV1) for expression of LPL(S447X) in muscle (alipogene tiparvovec, AAV1-LPL(S447X)) on postprandial chylomicron metabolism and on nonesterified fatty acid (NEFA) and glycerol metabolism in LPLD individuals. In an open-label clinical trial (CT-AMT-011-02), LPLD subjects were administered alipogene tiparvovec at a dose of 1 × 10(12) genome copies per kilogram. Two weeks before and 14 wk after administration, chylomicron metabolism and plasma palmitate and glycerol appearance rates were determined after ingestion of a low-fat meal containing (3)H-palmitate, combined with (continuous) iv infusion of [U-(13)C]palmitate and [1,1,2,3,3-(2)H]glycerol. After administration of alipogene tiparvovec, the triglyceride (TG) content of the chylomicron fraction and the chylomicron-TG/total plasma TG ratio were reduced throughout the postprandial period. The postprandial peak chylomicron (3)H level and chylomicron (3)H area under the curve were greatly reduced (by 79 and 93%, 6 and 24 h after the test meal, respectively). There were no significant changes in plasma NEFA and glycerol appearance rates. Plasma glucose, insulin, and C-peptide also did not change. Intramuscular administration of alipogene tiparvovec resulted in a significant improvement of postprandial chylomicron metabolism in LPLD patients, without inducing large postprandial NEFA spillover.


[HIV infection in Mexican children].
To review the experience of the Immunodeficiency Clinic of the Department of Infectious Diseases at Hospital Infantile de México "Federico Gómez", in the management of children with HIV infection and AIDS. the medical records of 130 patients with a clinical and laboratory diagnosis of HIV/AIDS seen between September 1985 and June 1994 were reviewed. Data was obtained regarding diagnosis, epidemiological risk factors, clinical features, types and numbers of bacterial and opportunistic infections, malignancies, hospitalizations, general and specific treatment and outcome. The diagnosis followed CDC guidelines and was established in all 130 patients serologically with ELISA and Western Blot. In infants < 18 months, diagnosis was made by detection of p24 and/or viral culture in two separate occasions. Data from 130 subjects was obtained; 74 were male and 56 female for a M:F ratio of 1.3:1. With regards to mode of transmission, 62.3% was vertical, 20.8% post transfusion, 8.5% hemophiliacs (the latter two males were cases before occurred 1987), 6.2% sexual and 2.2% unknown. With regards to additional risk factors, in 35 cases the parents were heterosexual, in 18 one parent had a history of transfusion, and in eight the father was bisexual. According to the CDC classification; 16 had indeterminate infection or PO; nine were asymptomatic or P1; and 105 were symptomatic or P2. Eighty two patients had nonspecific findings, 60 had neurologic manifestations, 18 had lymphocytic interstitial pneumonia and four had secondary malignancies. It was possible to document 296 episodes of secondary infections: 154 bacterial, 58 opportunistic, and 84 with other pathogens. in Mexico, as in other Western countries, vertical transmission has become the dominant form of acquiring HIV infection in children, reflecting a change in the epidemiology of infection in women of child bearing age. Moreover, since IV drug use is a very limited phenomenon in Mexico, heterosexual transmission is the major form of transmission in women.


Ambient assisted living technology-mediated interventions for older people and their informal carers in the context of healthy ageing: A scoping review.
There is a growing demand for health and social care services to provide technology-mediated interventions that promote the health and well-being of older people with health or care needs and of their informal carers. The objectives of this study were to scope and review the nature and extent of prior intervention studies involving ambient assisted living technology-mediated interventions for older people and their informal carers, and how and in what ways (if any) the goals and aims of these interventions reflected the domains of the World Health Organization framework for healthy ageing. We conducted a scoping review. Data were collected between June and October 2018 with an updated search in October 2020. A total of 85 articles were eligible for inclusion. Nine categories described the aims and content of the included studies. The healthy ageing domain "Ability to meet basic needs" was mirrored in four categories, whereas "Ability to contribute to society" was not addressed at all. The ways in which domains of healthy ageing are mirrored suggest that there is an emphasis on individual factors and individual responsibility, and a lack of attention given to broader, environmental factors affecting healthy ageing. Only a few of the studies used a dyadic approach when assessing health outcomes concerning older people and their informal carers.


Intensive lifestyle intervention improves physical function among obese adults with knee pain: findings from the Look AHEAD trial.
Lifestyle interventions have resulted in weight loss or improved physical fitness among individuals with obesity, which may lead to improved physical function. This prospective investigation involved participants in the Action for Health in Diabetes (Look AHEAD) trial who reported knee pain at baseline (n = 2,203). The purposes of this investigation were to determine whether an Intensive Lifestyle Intervention (ILI) condition resulted in improvement in self-reported physical function from baseline to 12 months vs. a Diabetes Support and Education (DSE) condition, and whether changes in weight or fitness mediated the effect of the ILI. Outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and physical function subscales, and WOMAC summary score. ILI participants exhibited greater adjusted mean weight loss (s.e.) vs. DSE participants (-9.02 kg (0.48) vs. -0.78 kg (0.49); P < 0.001)). ILI participants also demonstrated more favorable change in WOMAC summary scores vs. DSE participants (β (s.e.) = -1.81 (0.63); P = 0.004). Multiple regression mediation analyses revealed that weight loss was a mediator of the effect of the ILI intervention on change in WOMAC pain, function, and summary scores (P < 0.001). In separate analyses, increased fitness also mediated the effect of the ILI intervention upon WOMAC summary score (P < 0.001). The ILI condition resulted in significant improvement in physical function among overweight and obese adults with diabetes and knee pain. The ILI condition also resulted in significant weight loss and improved fitness, which are possible mechanisms through which the ILI condition improved physical function.


Engineering proximal vs. distal heme-NO coordination via dinitrosyl dynamics: implications for NO sensor design.
Proximal vs. distal heme-NO coordination is a novel strategy for selective gas response in heme-based NO-sensors. In the case of Alcaligenes xylosoxidans cytochrome c' (AXCP), formation of a transient distal 6cNO complex is followed by scission of the trans Fe-His bond and conversion to a proximal 5cNO product via a putative dinitrosyl species. Here we show that replacement of the AXCP distal Leu16 residue with smaller or similar sized residues (Ala, Val or Ile) traps the distal 6cNO complex, whereas Leu or Phe residues lead to a proximal 5cNO product with a transient or non-detectable distal 6cNO precursor. Crystallographic, spectroscopic, and kinetic measurements of 6cNO AXCP complexes show that increased distal steric hindrance leads to distortion of the Fe-N-O angle and flipping of the heme 7-propionate. However, it is the kinetic parameters of the distal NO ligand that determine whether 6cNO or proximal 5cNO end products are formed. Our data support a 'balance of affinities' mechanism in which proximal 5cNO coordination depends on relatively rapid release of the distal NO from the dinitrosyl precursor. This mechanism, which is applicable to other proteins that form transient dinitrosyls, represents a novel strategy for 5cNO formation that does not rely on an inherently weak Fe-His bond. Our data suggest a general means of engineering selective gas response into biologically-derived gas sensors in synthetic biology.


[A clinical case of diagnosis of left ventricular noncompaction myocardium in a patient with infectious myocarditis].
The paper describes a rare clinical case involving primary cardiomyopathy (noncompaction of the left ventricular myocardium (NCLVM), infectious myocarditis, and, possibly, hypertrophic cardiomyopathy (HCM). Objective, laboratory instrumental, invasive examination (coronarography with right ventricular endomyocardial biopsy) of the patient and histological study of his heart biopsy revealed acute infectious myocarditis concurrent with NCLVM and, possibly, HCM. The detection of a rare abnormality as NCLVM necessitates a meticulous additional examination to identify other primary cardiomyopathies (including HCM).


Multifunctional roles for the protein translocation machinery in RNA anchoring to the endoplasmic reticulum.
Signal sequence-encoding mRNAs undergo translation-dependent localization to the endoplasmic reticulum (ER) and at the ER are anchored via translation on Sec61-bound ribosomes. Recent investigations into the composition and membrane association characteristics of ER-associated mRNAs have, however, revealed both ribosome-dependent (indirect) and ribosome-independent (direct) modes of mRNA association with the ER. These findings raise important questions regarding our understanding of how mRNAs are selected, localized, and anchored to the ER. Using semi-intact tissue culture cells, we performed a polysome solubilization screen and identified conditions that distinguish polysomes engaged in the translation of distinct cohorts of mRNAs. To gain insight into the molecular basis of direct mRNA anchoring to the ER, we performed RNA-protein UV photocross-linking studies in rough microsomes and demonstrate that numerous ER integral membrane proteins display RNA binding activity. Quantitative proteomic analyses of HeLa cytosolic and ER-bound polysome fractions identified translocon components as selective polysome-interacting proteins. Notably, the Sec61 complex was highly enriched in polysomes engaged in the translation of endomembrane organelle proteins, whereas translocon accessory proteins, such as ribophorin I, were present in all subpopulations of ER-associated polysomes. Analyses of the protein composition of oligo(dT)-selected UV photocross-linked ER protein-RNA adducts identified Sec61α,β and ribophorin I as ER-poly(A) mRNA-binding proteins, suggesting unexpected roles for the protein translocation and modification machinery in mRNA anchoring to the ER. In summary, we propose that multiple mechanisms of mRNA and ribosome association with ER operate to enable an mRNA transcriptome-wide function for the ER in protein synthesis.


Metabolomics of plant root exudates: From sample preparation to data analysis.
Plants release a set of chemical compounds, called exudates, into the rhizosphere, under normal conditions and in response to environmental stimuli and surrounding soil organisms. Plant root exudates play indispensable roles in inhibiting the growth of harmful microorganisms, while also promoting the growth of beneficial microbes and attracting symbiotic partners. Root exudates contain a complex array of primary and specialized metabolites. Some of these chemicals are only found in certain plant species for shaping the microbial community in the rhizosphere. Comprehensive understanding of plant root exudates has numerous applications from basic sciences to enhancing crop yield, production of stress-tolerant crops, and phytoremediation. This review summarizes the metabolomics workflow for determining the composition of root exudates, from sample preparation to data acquisition and analysis. We also discuss recent advances in the existing analytical methods and future perspectives of metabolite analysis.


Methylation of the gamma-catenin gene is associated with poor prognosis of renal cell carcinoma.
Gamma-catenin is a cell adhesion protein, and its functional loss is associated with tumor invasion and metastasis. We hypothesize that (1) promoter CpG methylation regulates the expression and function of the gamma-catenin gene in renal cell carcinoma (RCC) and (2) methylation of the gamma-catenin gene is associated with poor prognosis of RCC. To test these hypotheses, we analyzed the CpG methylation status of the gamma-catenin gene and its correlation with clinical outcome in RCC. Genomic DNA and total RNA were extracted from three renal cancer cell lines (A498, Caki-1, and Caki-2) and 54 RCC tissue samples with their corresponding normal kidney tissue samples. Expression of gamma-catenin gene was analyzed by reverse transcription-PCR and immunostaining. Promoter methylation was analyzed by two different methylation-specific PCR (MSP-A and MSP-B), and the results were verified by DNA sequencing. The demethylating agent (5-aza-2'-deoxycytidine) increased levels of mRNA transcript of the gamma-catenin gene in three renal cancer cell lines. Gamma-catenin mRNA and protein expression were significantly reduced in RCC samples compared with normal kidney samples, respectively (P < 0.05). MSP-A and MSP-B bands were detected in 45 of 54 (83.3%) and 49 of 54 (90.7%) RCC samples, respectively. In normal kidney, weak products of MSP-A and MSP-B were detected in 5 of 54 (9.3%) and 6 of 54 (11.1%) samples, respectively. Likewise, both MSP-A and MSP-B ratios were significantly higher in RCC samples compared with normal kidney samples, respectively (P < 0.01). Multivariate analysis revealed that the MSP-B ratio was a powerful and independent predictor superior to nuclear grade and Robson stage with respect to survival and disease progression (P = 0.029 and 0.0071, respectively). No mutations in the NH(2)-terminal region of gamma-catenin were found in this study. Expression of gamma-catenin is regulated by promoter CpG methylation, and the balance between methylated and unmethylated RCC cell populations could determine its functional role. Because the conventional nuclear grade and/or staging system have some limitations to predict precise clinical outcome, this is the first report demonstrating that promoter CpG methylation of gamma-catenin can be an independent and superior predictor for survival and disease progression.


Inhibition of breast cancer growth and invasion by single-minded 2s.
Single-minded 2 (SIM2) is a member of the bHLH-PAS family of transcription factors. SIM2 was initially identified by positional cloning on chromosome 21 and is thought to contribute to the etiology of trisomy-21 [Down syndrome (DS)]. In addition to the physical and mental deficiencies associated with this genetic disease, it has become apparent that women with DS are 10-25 times less likely to die from breast cancer in comparison with age-matched normal populations. This is thought to be a result of gene dosage effect of tumor suppressor genes on chromosome 21. Here, we report that a splice variant of SIM2, SIM2 short (SIM2s), is differentially expressed in normal breast and breast cancer-derived cell lines and is downregulated in human breast cancer samples. Re-establishment of SIM2s in MDA-MB-435 breast cancer cells significantly reduced proliferation, anchorage-independent growth and invasive potential. Consistent with its role as a transcriptional repressor, SIM2s directly decreased expression of matrix metalloprotease-3, a known mediator of breast cancer metastasis. These results suggest that SIM2s has breast tumor suppressive activity.


New insight into bacterial social communication in natural host: Evidence for interplay of heterogeneous and unison quorum response.
Many microbes exhibit quorum sensing (QS) to cooperate, share and perform a social task in unison. Recent studies have shown the emergence of reversible phenotypic heterogeneity in the QS-responding pathogenic microbial population under laboratory conditions as a possible bet-hedging survival strategy. However, very little is known about the dynamics of QS-response and the nature of phenotypic heterogeneity in an actual host-pathogen interaction environment. Here, we investigated the dynamics of QS-response of a Gram-negative phytopathogen Xanthomonas pv. campestris (Xcc) inside its natural host cabbage, that communicate through a fatty acid signal molecule called DSF (diffusible signal factor) for coordination of several social traits including virulence functions. In this study, we engineered a novel DSF responsive whole-cell QS dual-bioreporter to measure the DSF mediated QS-response in Xcc at the single cell level inside its natural host plant in vivo. Employing the dual-bioreporter strain of Xcc, we show that QS non-responsive cells coexist with responsive cells in microcolonies at the early stage of the disease; whereas in the late stages, the QS-response is more homogeneous as the QS non-responders exhibit reduced fitness and are out competed by the wild-type. Furthermore, using the wild-type Xcc and its QS mutants in single and mixed infection studies, we show that QS mutants get benefit to some extend at the early stage of disease and contribute to localized colonization. However, the QS-responding cells contribute to spread along xylem vessel. These results contrast with the earlier studies describing that expected cross-induction and cooperative sharing at high cell density in vivo may lead to synchronize QS-response. Our findings suggest that the transition from heterogeneity to homogeneity in QS-response within a bacterial population contributes to its overall virulence efficiency to cause disease in the host plant under natural environment.


Margaritaella gracilis gen. n. et sp. n. (Eucestoda: Proteocephalidea), a parasite of Callichthys callichthys (Pisces: Siluriformes) from the Paraná River basin, Argentina.
Margaritaella gracilis gen. n. et sp. n. (Proteocephalidea: Proteocephalinae) found in the intestine of Callichthys callichthys (Linnaeus) from the Paraná River basin is described. The new genus is placed in the Proteocephalinae because of the medullary position of the genital organs. It differs from all known genera included in the Proteocephalinae by the following combination of characters: 1) scolex with a conspicuous cluster of drop-shaped gland cells posterior to suckers; 2) strobila with a low number of proglottides, all much longer than wide; 3) testes arranged in one field, composed of two parallel rows of testes separated by the uterus; 4) ovary delicate, H-shaped, with branches slender and deeply folliculate at the edges, located at 25-35% from the posterior end; 5) uterus largely extended posterior to the ovary but not reaching the end of proglottis; and 6) vitelline follicles in two narrow lateral bands, largely extended posterior to the ovary. Scanning electron microscopy revealed three types of microtriches on the tegument surface: acicular and capiliform filitriches and gladiate spinitriches. The relative size of the ovary, a character recently used in the systematics of the proteocephalidean cestodes, was calculated for the new species and compared with other species of the group. M. gracilis is the first record of a proteocephalidean cestode parasitizing a callichthyid catfish.


A Comparison of Four Computerized Neurocognitive Assessment Tools to a Traditional Neuropsychological Test Battery in Service Members with and without Mild Traumatic Brain Injury.
Computerized neurocognitive assessment tools (NCATS) are often used as a screening tool to identify cognitive deficits after mild traumatic brain injury (mTBI). However, differing methodology across studies renders it difficult to identify a consensus regarding the validity of NCATs. Thus, studies where multiple NCATs are administered in the same sample using the same methodology are warranted. We investigated the validity of four NCATs: the ANAM4, CNS-VS, CogState, and ImPACT. Two NCATs were randomly assigned and a battery of traditional neuropsychological (NP) tests administered to healthy control active duty service members (n = 272) and to service members within 7 days of an mTBI (n = 231). Analyses included correlations between NCAT and the NP test scores to investigate convergent and discriminant validity, and regression analyses to identify the unique variance in NCAT and NP scores attributed to group status. Effect sizes (Cohen's f2) were calculated to guide interpretation of data. Only 37 (0.6%) of the 5,655 correlations calculated between NCATs and NP tests are large (i.e. r ≥ 0.50). The majority of correlations are small (i.e. 0.30 > r ≥ 0.10), with no clear patterns suggestive of convergent or discriminant validity between the NCATs and NP tests. Though there are statistically significant group differences across most NCAT and NP test scores, the unique variance accounted for by group status is minimal (i.e. semipartial R2 ≤ 0.033, 0.024, 0.062, and 0.011 for ANAM4, CNS-VS, CogState, and ImPACT, respectively), with effect sizes indicating small to no meaningful effect. Though the results are not overly promising for the validity of the four NCATs we investigated, traditional methods of investigating psychometric properties may not be appropriate for computerized tests. We offer several conceptual and methodological considerations for future studies regarding the validity of NCATs.


Infectious complications after orthotopic liver transplantation.
Advances in surgical technique, critical care, immunosuppression, donor and recipient screening, and prophylactic strategies have contributed to the evolving microbiology and epidemiology of infectious complications after liver transplantation. Although decreased overall, infections continue to be a major contributor to graft loss and patient morbidity. Bacterial and candidal infections are less frequent, but antimicrobial resistance has become more common and can potentially limit successful treatment of health care-acquired and surgical site infections. As the transplant population grows, intensivists and pulmonologists are more likely to evaluate liver transplant recipients with infections. Presentations of opportunistic respiratory infections may be atypical in the setting of immunosuppression. Although novel noninvasive diagnostic tools are available for some pathogens, bronchoscopic evaluation may be increasingly helpful in differentiating between certain respiratory pathogens when empirical therapy is plagued by drug interactions and drug toxicities. Knowledge about common postoperative infections and opportunistic respiratory pathogens such as cytomegalovirus and fungi is essential to improving the global care of the liver transplant recipient.


Diversity and evolution of cerebellar folding in mammals.
The process of brain folding is thought to play an important role in the development and organisation of the cerebrum and the cerebellum. The study of cerebellar folding is challenging due to the small size and abundance of its folia. In consequence, little is known about its anatomical diversity and evolution. We constituted an open collection of histological data from 56 mammalian species and manually segmented the cerebrum and the cerebellum. We developed methods to measure the geometry of cerebellar folia and to estimate the thickness of the molecular layer. We used phylogenetic comparative methods to study the diversity and evolution of cerebellar folding and its relationship with the anatomy of the cerebrum. Our results show that the evolution of cerebellar and cerebral anatomy follows a stabilising selection process. We observed two groups of phenotypes changing concertedly through evolution: a group of 'diverse' phenotypes - varying over several orders of magnitude together with body size, and a group of 'stable' phenotypes varying over less than 1 order of magnitude across species. Our analyses confirmed the strong correlation between cerebral and cerebellar volumes across species, and showed in addition that large cerebella are disproportionately more folded than smaller ones. Compared with the extreme variations in cerebellar surface area, folial anatomy and molecular layer thickness varied only slightly, showing a much smaller increase in the larger cerebella. We discuss how these findings could provide new insights into the diversity and evolution of cerebellar folding, the mechanisms of cerebellar and cerebral folding, and their potential influence on the organisation of the brain across species.


A comprehensive review of histopathological findings of infections induced by COVID-19.
The severe acute respiratory syndrome (SARS)-Coronavirus (CoV2) virus, first identified in Wuhan, China, caused the coronavirus disease 2019 (COVID-19) which soon became a global pandemic, as labelled by the World Health Organization (WHO). The transmission method of the infection is primarily through droplets of various sizes. The SARS-CoV2 virus leads to a severe respiratory illness which in the first place causes the simulation of the acute respiratory syndrome. In order to diagnose of COVID-19 efficiently, samples with infection probability need to be examined through histopathological methods. Survival chances of the infected can remarkably increase if the virus is diagnosed timely by reverse transcription-polymerase chain reaction (RT-PCR) or computed tomography (CT) scan of the chest. One of the destructive effects of COVID-19 is the formation of ground-glass opacity (GGO) in the lungs which might be regarded to be equivalent to high-altitude pulmonary edema (HAPE). COVID-19 acts very similarly to SARS and Middle East Respiratory Syndrome (MERS) which can be inactivated by the chemical compounds of ethanol and sodium hypochlorite. Epidemiologic characteristics of COVID-19 have been indicated by numerous studies; however, there is still a lack of details of pathologic changes in the lung. The present comprehensive review is an attempt to assess and cover the current state of knowledge on COVID-19 disease based on the histopathologic studies conducted before May 2020.


Differentiation of sigma ligand-activated receptor subtypes that modulate NMDA-evoked [3H]-noradrenaline release in rat hippocampal slices.
1. It is now widely accepted that there are two classes of sigma (sigma) binding sites, denoted sigma(1) and sigma(2), and recently sigma(3) subtype has been proposed. Selective sigma(1) and sigma(2) receptor agonists are known to modulate the neuronal response to N-methyl-D-aspartate (NMDA) in vivo and in vitro. To identify the site of action of a series of recently synthesised high affinity sigma ligands, the present in vitro series of experiments was carried out on NMDA-evoked [3H]-noradrenaline ([3H]-NA) overflow from preloaded hippocampal slices of the rat. 2. The ligands (+)-cis-N-methyl-N-[2,(3,4-dichlorophenyl) ethyl]-2-(1-pyrrolidinyl) cyclohexylamine (BD-737) and (+)-pentazocine, considered as the prototypic sigma(1) agonists, potentiated the NMDA response from 10 nM to 100 nM. This potentiation faded between 100 nM and 1 microM ligand concentrations. On the other hand, 1,3-di(2-tolyl)guanidine (DTG), a mixed sigma(1)/sigma(2) agonist, at concentrations greater than 100 nM inhibited the NMDA-evoked [3H]-NA release. Spiperone, considered as active on putative sigma(3) receptors, was without effect on the NMDA response, or on the potentiating effect of BD-737. 3. The high affinity sigma antagonists haloperidol and 1[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD-1063), inactive by themselves on the NMDA-induced response, at concentrations above 30 nM totally prevented the potentiating effect of (+)-pentazocine (100 nM) as well as the inhibitory effect of DTG (300 nM) on NMDA-evoked [3H]-NA release. Whereas haloperidol and BD-1063, at concentrations < 1 microM, were inactive on the potentiating effect of BD-737 (100 nM). 4. 4-(4-Chlorophenyl)-alpha-4-fluorophenyl-4-hydroxy-1-piperidinebutanol (reduced haloperidol), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD-1008), inactive by themselves on the NMDA-evoked [3H]-NA release, failed to reverse the effects of (+)-pentazocine and DTG, but at concentrations of 30 nM to 1 microM antagonised the BD-737-induced potentiation of the NMDA response. Conversely, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) blocked the effects of (+)-pentazocine as well as those of BD-737, but not those of DTG. 5. The present results provide in vitro functional evidence for a sigma receptor type preferentially sensitive to BD-737, reduced haloperidol, BD-1008 and also to NE-100, that differs from the already identified sigma(1), sigma(2) and sigma(3) sites.


Chemical enhancement in embryo development and stem cell derivation from single blastomeres.
Several chemicals targeting the mitogen-activated protein (MAP) kinase signaling pathway, which play an important role in regulating cell growth and differentiation, have shown enhancing effects on the development of the inner cell mass (ICM) and the derivation of ES cells. However, investigation of such chemicals on early embryonic development and the establishment of ES cell lines has not been elucidated. This study was aimed to determine if ACTH, MAP2K1 inhibitor [MAP2K1 (I)], and MAPK14 inhibitor [MAPK14 (I)] could enhance the development of the ICM in preimplantation mouse embryos and blastocyst outgrowths, and the establishment of ES cell lines from blastomeres of early embryos. We have demonstrated that both MAP2K1 (I) and MAPK14 (I) delay early embryo development and inhibit the development of embryos from early blastomeres. On the other hand, ACTH had a positive effect on embryos derived from early blastomeres. As a result, 17 ES cell lines were established. Among these ES cell lines, nine and five ES cell lines were established from single blastomeres of two-cell embryos with and without the supplement of ACTH, respectively. In addition to two-cell isolated blastomeres, three ES cell lines were established from blastomeres of four-cell embryos only with the supplement of ACTH. Our results suggest that ACTH can enhance the derivation of ES cells from single blastomere-derived embryos.


High-resolution distributed shape sensing using phase-sensitive optical time-domain reflectometry and multicore fibers.
In this paper, a highly-sensitive distributed shape sensor based on a multicore fiber (MCF) and phase-sensitive optical time-domain reflectometry (φ-OTDR) is proposed and experimentally demonstrated. The implemented system features a high strain sensitivity (down to ∼0.3 µɛ) over a 24 m-long MCF with a spatial resolution of 10 cm. The results demonstrate good repeatability of the relative fiber curvature and bend orientation measurements. Changes in the fiber shape are successfully retrieved, showing detectable displacements of the free moving fiber end as small as 50 µm over a 60 cm-long fiber. In addition, the proposed technique overcomes cross-sensitivity issues between strain and temperature. To the best of our knowledge, the results presented in this work provide the first demonstration of distributed shape sensing based on φ-OTDR using MCFs. This high-sensitivity technique proves to be a promising approach for a wide range of new applications such as dynamic, long distance and three-dimensional distributed shape sensing.


Successful strategies implemented towards the elimination of canine rabies in the Western Hemisphere.
Almost all cases of human rabies result from dog bites, making the elimination of canine rabies a global priority. During recent decades, many countries in the Western Hemisphere have carried out large-scale dog vaccination campaigns, controlled their free-ranging dog populations and enforced legislation for responsible pet ownership. This article reviews progress in eliminating canine rabies from the Western Hemisphere. After briefly summarizing the history of control efforts and describing the approaches listed above, we note that programs in some countries have been hindered by societal attitudes and severe economic disparities, which underlines the need to discuss measures that will be required to complete the elimination of canine rabies throughout the region. We also note that there is a constant threat for dog-maintained epizootics to re-occur, so as long as dog-maintained rabies "hot spots" are still present, free-roaming dog populations remain large, herd immunity becomes low and dog-derived rabies lyssavirus (RABLV) variants continue to circulate in close proximity to rabies-naïve dog populations. The elimination of dog-maintained rabies will be only feasible if both dog-maintained and dog-derived RABLV lineages and variants are permanently eliminated. This may be possible by keeping dog herd immunity above 70% at all times, fostering sustained laboratory-based surveillance through reliable rabies diagnosis and RABLV genetic typing in dogs, domestic animals and wildlife, as well as continuing to educate the population on the risk of rabies transmission, prevention and responsible pet ownership. Complete elimination of canine rabies requires permanent funding, with governments and people committed to make it a reality. An accompanying article reviews the history and epidemiology of canine rabies in the Western Hemisphere, beginning with its introduction during the period of European colonization, and discusses how spillovers of viruses between dogs and various wild carnivores will affect future eradication efforts (Velasco-Villa et al., 2017).


Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression.
Activated platelets can express CD40 ligand (CD40L) and trigger inflammatory response and tissue factor (TF) expression in endothelial cells through interaction with CD40. This pathway is also important for T cell-induced monocyte and endothelial cell procoagulant activity. We have studied the potential role of the CD40-CD40L pathway in platelet-induced TF expression in a monocytic cell line and in whole-blood monocytes. In vitamin D(3)-differentiated U-937 cells, thrombin-stimulated platelets increased TF expression as measured by mRNA quantification, flow cytometry, and procoagulant activity. Maximum antigen expression occurred after 2 hours. Neutralizing anti-P-selectin antibody yielded a 50% suppression of procoagulant activity, whereas antibody to CD40L had no effect. In thrombin receptor activator-stimulated citrated blood, monocytes were up to 77% TF-positive, with peak expression after only 15 minutes. However, no TF mRNA was detectable at that time. Anti-P-selectin antibody reduced TF by 50%, whereas antibody to CD40L gave a 17% reduction. Thus, we conclude that P-selectin exposed on activated platelets induces the expression of TF in both U-937 cells and whole-blood monocytes but by different mechanisms. Platelet CD40L does not display any significant effect on U-937 cells but may be of some importance on whole-blood monocytes. This suggests a possible functional difference between U-937 and monocyte CD40. Another important finding in this study is the rapid appearance of surface TF on monocytes without detectable mRNA formation. This indicates that TF may be stored intracellularly in these cells and can be exposed on the surface independent of de novo protein synthesis.


Identification of CFDD (common regulatory factor for DNA replication and DREF genes) and role of its binding site in regulation of the proliferating cell nuclear antigen gene promoter.
The Drosophila proliferating cell nuclear antigen (PCNA) gene promoter contains at least three transcriptional regulatory elements, the URE (upstream regulatory element), DRE (DNA replication-related element), and E2F recognition sites. In nuclear extracts of Drosophila Kc cells, we detected a novel protein factor(s), CFDD (common regulatory factor for DNA replication and DREF genes) that appeared to recognize two unique nucleotide sequences (5'-CGATA and 5'-CAATCA) and bind to three sites in the PCNA gene promoter. These sites were located at positions -84 to -77 (site 1), -100 to -93 (site 2) and -134 to -127 (site 3) with respect to the transcription initiation sites. Sites 2 and 3 overlapped with DRE and URE, respectively, and the 5'-CGATA matched with the reported recognition sequence of BEAF-32 (boundary element-associated factor of 32 kDa). Detailed analyses of CFDD recognition sequences and experiments with specific antibodies to DREF (DRE-binding factor) and BEAF-32 suggest that CFDD is different from DREF, UREF (URE-binding factor) and BEAF-32. A UV cross-linking experiment revealed that polypeptides of approximately 76 kDa in the nuclear extract interact directly with the CFDD site 1 sequence. Transient expression assays of chloramphenicol acetyltransferase (CAT) in Kc cells transfected with PCNA promoter-CAT fusion genes carrying mutations in CFDD site 1 and examination of lacZ expression from PCNA promoter-lacZ fusion genes carrying mutations in site 1, introduced into flies by germ line transformation, revealed that CFDD site 1 plays an important role for the promoter activity both in cultured cells and in living flies. In addition to the PCNA gene, multiple CFDD sites were found in promoters of the DNA polymerase alpha and DREF genes, and CFDD binding to the DREF promoter was confirmed. Therefore, CFDD may play important roles in regulation of Drosophila DNA replication-related genes.


[The role of pharmacogenomics in the tuberculosis treatment regime].
Tuberculosis is a health problem worldwide with one-third of the population infected with the Mycobacterium tuberculosis bacilli. The first-line of treatment for tuberculosis includes the drugs Isoniazid (INH) and Rifampicin (RIF) metabolized in the liver. Drug metabolism is directly related to the genetic variation of NAT2 and CYP2E1 (associated with INH metabolism) and AADAC (associated with RIF metabolism), and the effects produced in an individual may be a fast, intermediate or slow metobolizer. Polymorphisms in genes of people in standard tuberculosis treatment can cause effects on drug metabolism with consequences of hepatotoxicity and even drug resistance. Countries have began clinical trials focused on personalization of tuberculosis treatment to reduce the consequences for patients in treatment. In countries like Peru, where high rates of tuberculosis are recorded and therefore more people in treatment, the pharmacogenomic of individuals becomes a crucial tool for an optimum tuberculosis treatment. This review highlights the importance of having pharmacogenomic studies and having the identification of polymorphisms associated to the metabolism of the anti-tuberculosis drugs in our Peruvian population.