Novel polymer-supported coupling/dehydrating reagents for use in organic synthesis.
Two novel dehydrating reagents and, based on a phosphonium anhydride and an oxyphosphonium triflate respectively, were prepared by reaction of the corresponding polymer-supported phosphine oxides with triflic anhydride. Reagent, based on the novel phosphorus heterocycle 1,1,3,3-tetraphenyl-2-oxa-1,3-diphospholanium bis(trifluoromethanesulfonate), was found to be a useful reagent for ester and amide formation. A wide range of coupling/dehydration-type reactions, such as ester, amide, anhydride, peptide, ether and nitrile formation, were performed in high yield using the more readily prepared polymer-supported triphenylphosphine ditriflate, which was easily recovered and re-used several times without loss of efficiency. With primary alcohols, both reagents and provide an alternative to the Mitsunobu reaction, where the use of azodicarboxylates and chromatography to remove the phosphine oxide by-product can be avoided. The use of 4-dimethylaminopyridine allowed the esterification of secondary alcohols with to proceed in high yield but with retention of configuration.


Using a Mediator's Toolbox: Reducing Clinical Conflict by Learning to Reconceive the "Difficult" Patient or Family.
Given the prevalence of conflict between physicians and patients and families, it is crucial that trainees build the skills to manage clinical conflict. Mediators employ an approach that can be applied to clinical encounters to prevent conflicts from escalating. This workshop introduced trainees to techniques commonly used by mediators to manage disputes. Medical students in a virtual workshop (cohort A) and clinical fellows in an in-person workshop (cohort B) were presented with a mediator's approach to interpreting patient and family behavior viewed as challenging. Trainees were introduced to two specific techniques designed to facilitate the resolution of clinical conflict. After an interactive large-group discussion of each method, small groups practiced applying the technique to a sample clinical case. Finally, participants completed an assessment of their perception of the workshop's effectiveness. In early 2022, 15 medical students (cohort A) participated in a virtual workshop and 10 clinical fellows (cohort B) participated in an in-person workshop on clinical conflict management. Eight medical students from cohort A completed the postworkshop assessment (response rate: 53%); six clinical fellows from cohort B completed the assessment (response rate: 60%). Cohort A gave the workshop an overall evaluation of 4.6 out of 5.0; cohort B gave the workshop an overall score of 4.7 out of 5.0. In both the virtual platform and the traditional in-person format, this workshop introduces a set of tools for navigating bedside conflicts with patients and their families that participants believed would better prepare them for such challenging interactions.


Prevalent and incident HIV diagnoses among Entamoeba histolytica-infected adult males: a changing epidemiology associated with sexual transmission--Taiwan, 2006-2013.
Sexually transmitted Entamoeba histolytica infection (EHI) has been increasingly recognized among men who have sex with men (MSM). We used the National Disease Surveillance Systems (NDSS) to identify prevalent and incident HIV diagnoses among adults with EHI and to determine the associated factors. The NDSS collect demographic, clinical, and behavioral characteristics of case patients through physician reports and public health interviews. EHI was confirmed by polymerase-chain-reaction assays, histopathology, or serology with documented liver abscess. We linked NDSS databases to identify prevalent and incident HIV diagnoses among noninstitutionalized Taiwanese adults with confirmed EHI during 2006-2013. Cox proportional-hazards analysis was used to determine associated factors. Of noninstitutionalized adults with EHI, we identified prevalent HIV diagnosis in 210 (40%) of 524 males and one (1.7%) of 59 females, and incident HIV diagnosis in 71 (23%) of 314 males. MSM accounted for 183 (87%) and 64 (90%) of prevalent and incident HIV diagnoses in males, respectively. From 2006-2009 to 2010-2013, the prevalence of HIV diagnosis increased from 32% to 45% (P = 0.001) while the incidence of HIV diagnosis increased from 5.4 to 11.3 per 100 person-years (P = 0.001) among males with EHI. Incident HIV diagnosis was independently associated with a younger age, residing in metropolitan areas, hospitalization, previous syphilis, and engagement in oral, anal, or oral-anal sex before illness onset. Prevalent and incident HIV diagnoses were increasingly identified among adult males in Taiwan, preferentially affecting younger urban MSM. Surveillance and risk-reduction interventions are recommended against the interplay of HIV epidemic and sexually transmitted EHI.


Quality improvement, patient safety, and continuing education: a qualitative study of the current boundaries and opportunities for collaboration between these domains.
Quality improvement/patient safety (QI/PS) and continuing education (CE) efforts have a common aim to improve health care outcomes. Yet, minimal collaboration occurs between them. This lack of integration can be problematic given the finite resources available and the potential value of approaching health care challenges from different perspectives. The authors conducted an exploratory study to understand Canadian leaders' perceptions and experiences with both their own and the other domain, with the aim of increasing their understanding of the boundaries and opportunities for collaborative approaches to improving health care. The authors conducted this study in 2011-2012 using a qualitative interpretivist framework to guide the collection and analysis of data from semistructured interviews. They used criterion-based, maximum variation, and snowball sampling to select 15 leaders from the domains of QI/PS and CE to interview. They transcribed verbatim the interviews and coded the transcripts using a directed content analysis approach. Participants described the relationship between QI/PS and CE in four ways: (1) the separation of QI/PS and CE as distinct interventions, (2) (re)positioning CE in QI/PS activities, (3) (re)positioning QI/PS in CE activities, and (4) further integrating QI/PS and CE. These findings have important implications for how leaders in QI/PS and CE should mindfully and strategically negotiate their relationship to ensure the relevance and effectiveness of their domain's activities.


Molecular evolution of Turnip mosaic virus: evidence of host adaptation, genetic recombination and geographical spread.
Turnip mosaic virus (TuMV), a species of the genus Potyvirus, occurs worldwide. Seventy-six isolates of TuMV were collected from around the world, mostly from Brassica and Raphanus crops, but also from several non-brassica species. Host tests grouped the isolates into one or other of two pathotypes; Brassica (B) and Brassica-Raphanus (BR). The nucleotide sequences of the first protein (P1) and coat protein (CP) genes of the isolates were determined. One-tenth of the isolates were found to have anomalous and variable phylogenetic relationships as a result of recombination. The 5'-terminal 300 nt of the P1 gene of many isolates was also variable and phylogenetically anomalous, whereas the 380 nt 3' terminus of the CP gene was mostly conserved. Trees calculated from the remaining informative parts of the two genes of the non-recombinant sequences by neighbour-joining, maximum-likelihood and maximum-parsimony methods were closely similar, and so these parts of the sequences were concatenated and trees calculated from the resulting 1150 nt. The isolates fell into four consistent groups; only the relationships of these groups with one another and with the outgroup differed. The "basal-B" cluster of eight B-pathotype isolates was most variable, was not monophyletic, and came from both brassicas and non-brassicas from southwest and central Eurasia. Closest to it, and forming a monophyletic subgroup of it in most trees, and similarly variable, was the "basal-BR" group of eight BR pathotype Eurasian isolates. The third and least variable group, the "Asian-BR" group, was of 22 BR-pathotype isolates, all from brassicas, mostly Raphanus, and all from east Asia mostly Japan. The fourth group of 36 isolates, the "world-B" group, was from all continents, most were isolated from brassicas and most were of the B-pathotype. The simplest of several possible interpretations of the trees is that TuMV originated, like its brassica hosts, in Europe and spread to the other parts of the world, and that the BR pathotype has recently evolved in east Asia.


Pattern of recurrence of trachomatous trichiasis after surgery surgical technique as an explanation.
To evaluate the pattern of recurrence of trachomatous trichiasis (TT) after bilamellar tarsal rotation surgery for trachoma. Observational cohort. Three hundred eighty-four participants having at least 1 eye that had undergone a single TT surgery a minimum of 18 months before June 2001. The 630 study eyes were divided equally between left (311) and right (319) eyes. Patients living in Central Tanzania were identified from surgical lists. Participants were screened for recurrence of TT, including evidence of epilation, after surgery. Detailed information on the location of recurrence was collected, including number of lashes touching the globe and location of trichiatic lashes (nasal, central, or temporal). One hundred seventy-six eyes had evidence of TT recurrence (28%), including 23 eyes having recently undergone epilation. In eyes without epilation, left eyes had a higher rate of recurrence than right eyes (32% vs. 25%; P = 0.05). Among eyes with recurrence originating from 1 location, recurrence was highest centrally (40%). Right eyes had nasal recurrence more often than temporal recurrence (33% vs. 20%). Left eyes had temporal recurrence more often than nasal recurrence (41% vs. 24%). Recurrence of TT after surgery is more common in the left eye and on the left side of the eyelid. The surgical procedure is more difficult to perform on the right side of the eyelid by a right-handed surgeon. This difficulty may lead to an unintentional change in surgical technique on the right, which may result in lower recurrence on that side.


An overview of bioinformatics methods for modeling biological pathways in yeast.
The advent of high-throughput genomics techniques, along with the completion of genome sequencing projects, identification of protein-protein interactions and reconstruction of genome-scale pathways, has accelerated the development of systems biology research in the yeast organism Saccharomyces cerevisiae In particular, discovery of biological pathways in yeast has become an important forefront in systems biology, which aims to understand the interactions among molecules within a cell leading to certain cellular processes in response to a specific environment. While the existing theoretical and experimental approaches enable the investigation of well-known pathways involved in metabolism, gene regulation and signal transduction, bioinformatics methods offer new insights into computational modeling of biological pathways. A wide range of computational approaches has been proposed in the past for reconstructing biological pathways from high-throughput datasets. Here we review selected bioinformatics approaches for modeling biological pathways inS. cerevisiae, including metabolic pathways, gene-regulatory pathways and signaling pathways. We start with reviewing the research on biological pathways followed by discussing key biological databases. In addition, several representative computational approaches for modeling biological pathways in yeast are discussed.


Immune profiles and clinical outcomes between sepsis patients with or without active cancer requiring admission to intensive care units.
Immunoparalysis was observed in both patients with cancer and sepsis. In cancer patients, Cytotoxic T lymphocyte antigen-4 and programmed cell death protein 1/programmed death-ligand 1 axis are two key components of immunoparalysis. Several emerging therapies against these two axes gained significant clinical benefit. In severe sepsis patients, immunoparalysis was known as compensatory anti-inflammatory response syndrome and this has been suggested as an important cause of death in patients with sepsis. It would be interesting to see if immune status was different in severe sepsis patients with or without active cancer. The aim of this study was to assess the differences in immune profiles, and clinical outcomes between severe sepsis patients with or without cancer admitted to ICU. A combined retrospective and prospective observational study from a cohort of adult sepsis patients admitted to three medical ICUs at Kaohsiung Chang Gung Memorial Hospital in Taiwan between August 2013 and June 2016. Of the 2744 patients admitted to the ICU, 532 patients with sepsis were included. Patients were divided into those with or without active cancer according to their medical history. Of the 532 patients, 95 (17.9%) patients had active cancer, and 437 (82.1%) patients had no active cancer history. Patients with active cancer were younger (p = 0.001) and were less likely to have diabetes mellitus (p < 0.001), hypertension (p < 0.001), coronary artery disease (p = 0.004), chronic obstructive pulmonary disease (p = 0.002) or stroke (p = 0.002) compared to patients without active cancer. Patients with active cancer also exhibited higher baseline lactate levels (p = 0.038), and higher baseline plasma interleukin (IL)-10 levels (p = 0.040), higher trend of granulocyte colony-stimulating factor (G-CSF) (p = 0.004) compared to patients without active cancer. The 14-day, 28-day and 90-day mortality rates were higher for patients with active cancer than those without active cancer (P < 0.001 for all intervals). Among patients admitted to the ICU with sepsis, those with underling active cancer had higher baseline levels of plasma IL-10, higher trend of G-CSF and higher mortality rate than those without active cancer.


The role of growth hormone in alpha 2u globulin synthesis: a reexamination.
Hypophysectomy of adult male rats abolishes alpha 2u globulin synthesis; synthesis can be fully restored by daily administration of androgen, thyroid hormone, glucocorticoid and growth hormone for 12 days. It has been previously reported that growth hormone is not required to maintain alpha 2u globulin mRNA levels, and that growth hormone functions only translationally. We have reexamined the role of growth hormone in alpha 2u globulin synthesis using a cloned alpha 2u globulin cDNA probe. Measurement of alpha 2u globulin mRNA levels by hybridization and cell-free translation, and of alpha 2u globulin synthesis by pulse-labeling in vivo, demonstrates that growth hormone is required to maintain full, steady state hepatic levels of both alpha 2u globulin and its mRNA. Furthermore, the small amount of hepatic alpha 2u globulin mRNA that accumulates in the absence of growth hormone is efficiently translated in vivo. Thus we now find no evidence for growth-hormone-mediated translational control. We have also found that rats hypophysectomized prepubescently respond to the multihormonal restoration therapy to only 10% of the alpha 2u globulin mRNA levels observed in rats hypophysectomized as adults. This finding suggests that some unidentified pituitary factor(s) is required during puberty to potentiate normal alpha 2u globulin gene expression.


Advances in quantification and analysis of the celiac-related immunogenic potential of gluten.
Gluten-free products have emerged in response to the increasing prevalence of gluten-related disorders, namely celiac disease. Therefore, the quantification of gluten in products intended for consumption by individuals who may suffer from these pathologies must be accurate and reproducible, in a way that allows their proper labeling and protects the health of consumers. Immunochemical methods have been the methods of choice for quantifying gluten, and several kits are commercially available. Nevertheless, they still face problems such as the initial extraction of gluten in complex matrices or the use of a standardized reference material to validate the results. Lately, other methodologies relying mostly on mass spectrometry-based techniques have been explored, and that may allow, in addition to quantitative analysis, the characterizationof gluten proteins. On the other hand, although the level of 20 mg/kg of gluten detected by these methods is sufficient for a product to be considered gluten-free, its immunogenic potential for celiac patients has not been clinically validated. In this sense, in vitro and in vivo models, such as the organoid technology applied in gut-on-chip devices and the transgenic humanized mouse models, respectively, are being developed for investigating both the gluten-induced pathogenesis and the treatment of celiac disease. Due to the ubiquitous nature of gluten in the food industry, as well as the increased prevalence of gluten-related disorders, here we intend to summarize the available methods for gluten quantification in food matrices and for the evaluation of its immunogenic potential concerning the development of novel therapies for celiac disease to highlight active research and discuss knowledge gaps and current challenges in this field.


Low doses of 17β-estradiol rapidly improve learning and increase hippocampal dendritic spines.
While a great deal of research has been performed on the long-term genomic actions of estrogens, their rapid effects and implications for learning and memory are less well characterized. The often conflicting results of estrogenic effects on learning and memory may be due to complex and little understood interactions between genomic and rapid effects. Here, we investigated the effects of low, physiologically relevant, doses of 17β-estradiol on three different learning paradigms that assess social and non-social aspects of recognition memory and spatial memory, during a transcription independent period of memory maintenance. Ovariectomized female CD1 mice were subcutaneously administered vehicle, 1.5 μg/kg, 2 μg/kg, or 3 μg/kg of 17β-estradiol 15 minutes before social recognition, object recognition, or object placement learning. These paradigms were designed to allow the testing of learning effects within 40 min of hormone administration. In addition, using a different set of ovariectomized mice, we examined the rapid effects of 1.5 μg/kg, 2 μg/kg, or 3 μg/kg of 17β-estradiol on CA1 hippocampal dendritic spines. All 17β-estradiol doses tested impacted learning, memory, and CA1 hippocampal spines. 17β-Estradiol improved both social and object recognition, and may facilitate object placement learning and memory. In addition, 17β-estradiol increased dendritic spine density in the stratum radiatum subregion of the CA1 hippocampus, but did not affect dendritic spines in the lacunosum-moleculare, within 40 min of administration. These results demonstrate that the rapid actions of 17β-estradiol have important implications for general learning and memory processes that are not specific for a particular type of learning paradigm. These effects may be mediated by the rapid formation of new dendritic spines in the hippocampus.


Ctenopharyngodon idella IRF2 and ATF4 down-regulate the transcriptional level of PRKRA.
PRKRA (interferon-inducible double-stranded RNA-dependent protein kinase activator A) is a protective protein which regulates the adaptation of cells to ER stress and virus-stimulated signaling pathways by activating PKR. In the present study, a grass carp (Ctenopharyngodon idella) PRKRA full-length cDNA (named CiPRKRA, KT891991) was cloned and identified. The full-length cDNA is comprised of a 5' UTR (36 bp), a 3' UTR (350 bp) and the longest ORF (882 bp) encoding a polypeptide of 293 amino acids. The deduced amino acid sequence of CiPRKRA contains three typical dsRNA binding motifs (dsRBM). Phylogenetic tree analysis revealed a closer evolutionary relationship of CiPRKRA with other fish PRKRA, especially with Danio rerio PRKRA. qRT-PCR showed that CiPRKRA was significantly up-regulated after stimulation with tunicamycin (Tm) and Poly I:C in C. idella kidney (CIK) cells. To further study its transcriptional regulation, the partial promoter sequence of CiPRKRA (1463 bp) containing one ISRE and one CARE was cloned by Tail-PCR. Subsequently, grass carp IRF2 (CiIRF2) and ATF4 (CiATF4) were expressed in Escherichia coli BL21 and purified by affinity chromatography with the Ni-NTA His-Bind Resin. In vitro, both CiIRF2 and CiATF4 bound to CiPRKRA promoter with high affinity by gel mobility shift assays, revealing that IRF2 and ATF4 might be potential transcriptional regulatory factors for CiPRKRA. Dual-luciferase reporter assays were applied to further investigate the transcriptional regulation of CiPRKRA in vivo. Recombinant plasmid of pGL3-PRKRAPro was constructed and transiently co-transfected into CIK cells with pcDNA3.1-CiIRF2 and pcDNA3.1-CiATF4, respectively. The results showed that both CiIRF2 and CiATF4 significantly decreased the luciferase activity of pGL3-PRKRAPro, suggesting that they play a negative role in CiPRKRA transcription.


Nurse, Patient, and Care Partner Perceptions of a Personalized Safety Plan Screensaver.
A patient safety plan dashboard was developed that captures disparate data from the electronic health record that is then displayed as a personalized bedside screensaver. The dashboard aligns all care team members, including patients and families, in the safety plan. The screensaver content includes icons that pertain to common geriatric syndromes. In two phases, interviews were conducted with nurses, nursing assistants, patients, and informal caregivers in a large, tertiary care center. End user perceptions of the content and interface of the personalized safety plan screensavers were identified and strategies to overcome the barriers to use for future iterations were defined. Many themes were identified, ranging from appreciation of the clinical decision support provided by the screensavers to the value of the safety-centric content. Differences emerged stemming from each group of end users' role on the care team. All feedback will inform requirements for improvements to the personalized safety plan screensaver. [Journal of Gerontological Nursing, 43(4), 15-22.].


Mental health and quality of life across 6 years of medical training: A year-by-year analysis.
Despite growing evidence on medical students' mental health deterioration, studies have primarily used short follow-up periods and not followed the students throughout their medical training. To assess mental health (stress, anxiety, and depression) and quality of life changes throughout their medical program, we followed up with the same cohort of students for 6 years. This longitudinal prospective study followed up with the same group of medical students at a Brazilian public medical school from 2014 to 2020. The study analyzed sociodemographic data, mental health (including depression, anxiety, and stress [DASS-21]), quality of life (WHOQOL-BREF), satisfaction from studying to be a physician, and happiness with life. General linear mixed models were used for the analyses. The cohort included 80 Brazilian medical students (63.7% women; mean age = 19.6 years [SD = 2.21]). A high prevalence of depressive symptoms, anxiety, and stress was found throughout medical training, with more than 50% of students having significant symptoms. Mental health, happiness, and quality of life levels tended to be better in the first and last semesters, being worse in the middle of the program. However, satisfaction from studying to become a doctor decreased in the second semester, remained low throughout the program, and never returned to baseline levels. Mental health and quality of life levels remained high throughout the medical program, with better levels in the first and last semesters and falling in the middle of the program. These data can help managers and educators understand how psychological distress affects medical students.


Comparison of volumetric bone mineral density in the tibial region of interest for ACL reconstruction.
Adequate tibial bone mineral density (BMD) is essential to soft tissue graft fixation during anterior cruciate ligament (ACL) reconstruction. The purpose of this study was to compare volumetric bone plug density measurements at the tibial region of interest for ACL reconstruction using a standardized immersion technique and Archimedes' principle. Cancellous bone cores were harvested from the proximal, middle, and distal metaphyseal regions of the lateral tibia and from the standard tibial tunnel location used for ACL reconstruction of 18 cadaveric specimens. Proximal tibial cores displayed 32.6% greater BMD than middle tibial cores and 31.8% greater BMD than distal tibial cores, but did not differ from the BMD of the tibial tunnel cores. Correlational analysis confirmed that the cancellous BMD in the tibial tunnel related to the cancellous BMD of the proximal and distal lateral tibial metaphysis. In conjunction with its adjacent cortical bone, the cancellous BMD of the region used for standard tibial tunnel placement provides an effective foundation for ACL graft fixation. In tibia with poor BMD, bicortical fixation that incorporates cortical bone from the distal tibial tunnel region is recommended.


The demonstration of candidal pseudohyphae in salivary smears as a method of early diagnosis of oral candidiasis in patients with acute myeloid leukemia.
To investigate the oral coloniation of candidal pseudohyphae, a salivary smear method was tested against the use of mucosal smears in 10 patients with acute myeloid leukemia. The salivary smears showed to be reproducible and more sensitive than mucosal smears for the demonstration of Candida organisms. The salivary smear method was applied to another group of 10 patients with acute myeloid leukemia during a 28-day period. According to swab cultures, 8 patients were colonized with Candida spp. on day 0, whereas 2 patients were unclonized on day 0, and remained so. All colonized patients developed acute oral candidiasis. According to the salivary smear method, 5 patients were colonized with pseudohyphae as early as on day 0, whereas 3 patients became colonized with pseudohyphae within the first 7 days. Pseudohyphae were detected with a median of 4 days prior to the emergence of acute oral candidiasis, and the detection of acute oral candidiasis was associated with an increase in the quantity of pseudohyphoae. The study suggests that the demonstration of candidal pseudohyphae in salivary smears is an early indicator of subsequent development of acute oral candidiasis. Further studies are neded to clairfy whether early treatment based on this finding will reduce the occurrence of acute oral candidiasis and disseminated candidiasis in these patients.


Evaluating the capabilities of aerosol-to-liquid particle extraction system (ALPXS)/ICP-MS for monitoring trace metals in indoor air.
This study investigates the application of the Aerosol-to-Liquid Particle Extraction System (ALPXS), which uses wet electrostatic precipitation to collect airborne particles, for multi-element indoor stationary monitoring. Optimum conditions are determined for capturing airborne particles for metal determination by inductively coupled plasma-mass spectrometry (ICP-MS), for measuring field blanks, and for calculating limits of detection (LOD) and quantification (LOQ). Due to the relatively high flow rate (300 L min(-1)), a sampling duration of 1 hr to 2 hr was adequate to capture airborne particle-bound metals under the investigated experimental conditions. The performance of the ALPXS during a building renovation demonstrated signal-to-noise ratios appropriate for sampling airborne particles in environments with elevated metal concentrations, such as workplace settings. The ALPXS shows promise as a research tool for providing useful information on short-term variations (transient signals) and for trapping particles into aqueous solutions where needed for subsequent characterization. As the ALPXS does not provide size-specific samples, and its efficiency at different flow rates has yet to be quantified, the ALPXS would not replace standard filter-based protocols accepted for regulatory applications (e.g., exposure measurements), but rather would provide additional information if used in conjunction with filter based methods. Implications: This study investigates the capability of the Aerosol-to-Liquid Particle Extraction System (ALPXS) for stationary sampling of airborne metals in indoor workplace environments, with subsequent analysis by ICP-MS. The high flow rate (300 L/min) permits a short sampling duration (< 2 hr). Results indicated that the ALPXS was capable of monitoring short-term changes in metal emissions during a renovation activity. This portable instrument may prove to be advantageous in occupational settings as a qualitative indicator of elevated concentrations of airborne metals at short time scales.


New insights into structural alteration of enamel apatite induced by citric acid and sodium fluoride solutions.
Attenuated total reflectance infrared spectroscopy and complementary scanning electron microscopy were applied to analyze the surface structure of enamel apatite exposed to citric acid and to investigate the protective potential of fluorine-containing reagents against citric acid-induced erosion. Enamel and, for comparison, geological hydroxylapatite samples were treated with aqueous solutions of citric acid and sodium fluoride of different concentrations, ranging from 0.01 to 0.5 mol/L for citric acid solutions and from 0.5 to 2.0% for fluoride solutions. The two solutions were applied either simultaneously or consecutively. The citric acid-induced structural modification of apatite increases with the increase in the citric acid concentration and the number of treatments. The application of sodium fluoride alone does not suppress the atomic level changes in apatite exposed to acidic agents. The addition of sodium fluoride to citric acid solutions leads to formation of surface CaF2 and considerably reduces the changes in the apatite P-O-Ca framework. However, the CaF2 globules deposited on the enamel surface seem to be insufficient to prevent the alteration of the apatite structure upon further exposure to acidic agents. No evidence for fluorine-induced recovery of the apatite structure was found.


Preliminary investigation into the Rorschach response patterns of children with documented learning disabilities.
Since the introduction of the Rorschach Inkblot Test, no normative data have been obtained on learning-disabled (LD) children. Indeed, there is little or no mention in the Rorschach literature on differences in perceptual accuracy, Self-concept and reaction to emotion-laden stimuli of LD children as compared with non-patient, withdrawn, and behavior-problem children. This study with a relatively small N of 20 compares the LD child with Exner (1978) norms on non-patient, withdrawn, and behavior-problem children. The findings show clearly differences in perceptual accuracy, affective ratio, egocentricity index, and reaction to emotion-laden stimuli.


The ICE family of cysteine proteases as effectors of cell death.
Programmed cellular suicide follows a set of distinct morphological events involving profound cytoplasmic and nuclear changes. The recent discovery of a family of mammalian homologues of the Caenorhabditis elegans cell death protein CED-3 is now providing insight into how these events might be brought about. These mammalian proteins encode cysteine proteases with homology to the interleukin-1beta converting enzyme (ICE). CED-3 and seven of its currently known mammalian homologues cleave their substrates after an aspartate residue, a property shared only by the cytotoxic T cell (CTL) protease granzyme B which is necessary for the CTL-mediated killing of target cells. A number of proteins previously known to be cleaved in cells undergoing apoptosis have now been shown to be targeted by ICE-like proteases. Although many questions remain, it is becoming increasingly clear that this unique group of proteases play a central effector role in the process of physiological cell death. This article reviews various aspects of the ICE family of proteases.


The triazole linked galactose substituted dicyano compound can induce autophagy in NSCLC cell lines.
As seen in other types of cancer, development of drug resistance in NSCLC treatment causes adverse effects on disease fighting process. Recent studies have shown that one of the drug resistance development mechanisms is that cancer cells may acquire the ability to escape from cell death. Therefore, development of anticancer drugs which have the strategy to redirect cancer cells to any cell death pathways may provide positive results for cancer treatments. Autophagy may be a target mechanism of alternative cancer treatment strategy in cases of blocked apoptosis. There is also a complex molecular link between autophagy and apoptosis, has not been fully understood yet. The dicyano compound which we used in our study caused cell death in NSCLC cell lines. When we analyzed the cells which were treated with dicyano compound by transmission electron microscope, we observed autophagosome structures. Upon this result, we investigated expression levels of autophagic proteins in the dicyano compound-treated cells by immunoblotting and observed that expression levels of autophagic proteins were increased significantly. The TUNEL assay and qRT-PCR for pro-apoptotic and anti-apoptotic gene expression, which we performed to assess apoptosis in the dicyano compound-treated cells, showed that the cell death does not occur through apoptotic pathway. We showed that the dicyano compound, which was developed in our laboratories, may play a role in molecular link between apoptosis and autophagy and may shed light on development of new anticancer treatment strategies.


Use of calculated cation-pi binding energies to predict relative strengths of nicotinic acetylcholine receptor agonists.
Agonists and antagonists of the nicotinic acetylcholine receptor (nAChR) are used to treat nicotine addiction, neuromuscular disorders, and neurological diseases. In designing small molecule therapeutics with the nAChR as a target, it is useful to identify chemical parameters that correlate with ability to activate the receptor. Previous studies have shown that cation-pi interactions at the transmitter binding sites of the nAChR are important for receptor activation by strong agonists such as acetylcholine. We hypothesized that a calculated estimate of cation-pi binding ability could be used to predict the efficiency for channel opening (i.e., the gating efficiency) associated with activation of the acetylcholine receptor by a series of structurally related organic cations. We demonstrate that the calculated cation-pi energy is strongly correlated with gating efficiency but only weakly correlated with closed-state binding affinity. Our results suggest that cation-pi interactions contribute significantly to the open-state affinity of these cations and that the calculated cation-pi energy will be a useful parameter for designing nAChR agonists and antagonists.


[Effect of neurohormone C and hexapeptide on incorporation of labeled amino acids into the proteins of different organs].
The influence of two coronarodilatatory substances (neurohormone "C" and hexapeptide) on the rate of protein synthesis was investigated. The stimulation of incorporation of labelled (14C- and 3H-) leucine into proteins of rat brain, heart and liver tissues characterized the hormonal regulation of the protein synthesis in these organs in vivo. Activation of the protein synthesis depended on the dose of the hormone administered. 5 mg of hexapeptide markedly inhibited the amino acid incorporation into proteins, while 0.5 mg produced the effect, which was contrary to the effect caused by 5 mg of the hormone. The data obtained suggest that hypothalamic neurohormonal preparations exhibit an important effect on protein metabolism in different organs.


Eliminating the requirement of an essential gene product in an already very small virus: scaffolding protein B-free øX174, B-free.
Unlike most viral assembly systems, two scaffolding proteins, B and D, mediate bacteriophage øX174 morphogenesis. The external scaffolding protein D is highly ordered in the atomic structure and proper function is very sensitive to mutation. In contrast, the internal scaffolding protein B is relatively unordered and extensive alterations do not eliminate function. Despite this genetic laxity, protein B is absolutely required for virus assembly. Thus, this system, with its complex arrangements of overlapping reading frames, can be regarded as an example of "irreducible complexity." To address the biochemical functions of a dual scaffolding protein system and the evolution of complexity, progressive and targeted genetic selections were employed to lessen and finally eliminate B protein-dependence. The biochemical and genetic bases of adaptation were characterized throughout the analysis that led to the sextuple mutant with a B-independent phenotype, as evaluated by plaque formation in wild-type cells. The primary adaptation appears to be the over-expression of a mutant external scaffolding protein. Progeny production was followed in lysis-resistant cells. The ability to produce infectious virions does not require all six mutations. However, the lag phase before progeny production is shortened as mutations accumulate. The results suggest that the primary function of the internal scaffolding protein may be to lower the critical concentration of the external scaffolding protein needed to nucleate procapsid formation. Moreover, they demonstrate a novel mechanism by which a stringently required gene product can be bypassed, even in a system encoding only eight strictly essential proteins.


Unexpected efficacy of rituximab in multirelapsing minimal change nephrotic syndrome in the adult: first case report and pathophysiological considerations.
Nephrotic syndrome secondary to minimal change disease (MCNS) usually is considered to have a good renal prognosis, but frequency of relapses and steroid dependency are therapeutic challenges to physicians. Treatment of patients with multiple relapses remains controversial because few control studies are available. We report the case of a 23-year-old woman of Malian origin who experienced more than 30 relapses of MCNS. Long-term remission was observed only with rituximab (anti-CD20 antibody) treatment after step-by-step use of all currently available medications for MCNS were unsuccessful. Our observation is the first report of efficacy of rituximab during multirelapsing MCNS in an adult patient with a significant follow-up and no adjuvant therapy. This case suggests a role of B cells in MCNS, possibly by regulating T-cell function.


The incidence of the adult respiratory distress syndrome.
Although adult respiratory distress syndrome (ARDS) has been a recognized entity for over 20 years, estimates of its incidence have been very controversial. The most quoted figure is from a 1972 National Heart and Lung Institute Task Force, which estimated 150,000 cases/year in the United States, an incidence of about 75 cases/100,000 population. No experimental study, however, has adequately addressed this issue. We were in a unique position to answer this controversy because the hospital of one of the investigators is located on an island (Las Palmas, Canary Islands, population 700,000). All patients who required mechanical ventilation (other than during anesthesia and immediate postoperative care) were admitted to the same adult intensive care unit. A prospective study to determine the incidence of ARDS was carried out over a 3-yr period. Inclusion criteria were: (1) a known predisposing illness for ARDS; (2) PaO2 less than or equal to 55 mm Hg with FIO2 greater than 0.5 with 5 cm H2O PEEP, without improvement in 24 h; (3) bilateral pulmonary infiltrates; (4) no evidence of left ventricular failure. An average of ten patients per year, representing an incidence of 1.5 cases/100,000 population, were diagnosed as having ARDS and the mortality rate was 70%. Using a more liberal clinical criterion of PaO2 less than or equal to 75 mm Hg with FIO2 greater than or equal to 0.5, 44 more patients with ARDS, representing a total incidence of 3.5 cases/100,000 population, were identified. In conclusion, the overall incidence of ARDS was 1.5 to 3.5 cases/100,000 population, an incidence that is much lower than most previously published estimates.


So You Want to be an Author: A Primer on Writing for Publication in the Medical Literature Part I: Manuscript Preparation.
Writing a manuscript on a topic in the medical sciences that gets accepted for publication is not always a guaranteed process. The goal of this article is to provide a description of some key points associated with preparing a manuscript. It has been written primarily for less experienced or aspiring authors, but it addresses points that are important for even well-established authors to consider. Although there may not be a direct path from scientific observation to published work, possessing the desire to publish and persevering throughout the process can ultimately lead to one's findings being both preserved in and contributing to the scientific literature. Although challenging, and at times frustrating, it is a rewarding endeavor.


Hydroxyl radical mediated demethylenation of (methylenedioxy)phenyl compounds.
The oxidative demethylenation reactions of (methylendioxy)phenyl compounds (MDPs), (methylenedioxy)benzene (MDB), (methylenedioxy)amphetamine (MDA), and (methylenedioxy)methamphetamine (MDMA), were evaluated by using two hydroxyl radical generating systems, the autoxidation of ascorbate in the presence of iron-EDTA and the iron-catalyzed Haber-Weiss reaction conducted by xanthine/xanthine oxidase with iron-EDTA. Reaction products generated when MDB, MDA, and MDMA were incubated with the ascorbate or xanthine oxidase system were catechol, dihydroxyamphetamine (DHA), and dihydroxymethamphetamine (DHMA), respectively. The reaction required the presence of either ascorbic acid or xanthine oxidase. Levels of each catechol increased in proportion to ferric ion concentration and were suppressed by desferrioxamine B methanesulfonate (desferal). Catalase (CAT) inhibited the oxidation by the ascorbate system whereas superoxide dismutase (SOD) had little effect. The addition of hydrogen peroxide to the reaction mixture stimulated the oxidation, but the reaction was not initiated by hydrogen peroxide alone, suggesting that hydrogen peroxide acts as a precursor of hydroxyl radical. SOD and CAT suppressed the demethylenation reactions in the xanthine oxidase system. Hydroxyl radical scavenging agents such as ethanol, benzoate, DMSO, and thiourea effectively inhibited the oxidation by both systems. Urea, which has little effect on hydroxyl radical, was without any effect. These results indicated that hydroxyl radical can effect the cleavage of methylenedioxy group on MDPs.


Hepatitis B virus vaccine: identification of HBsAg/a and HBsAg/d but not HBsAg/y subtype antigenic determinants on a synthetic immunogenic peptide.
On the basis of theoretical considerations, a peptide (H peptide) was synthesized by Hopp and Woods [Hopp, T. P. & Woods, K. R. (1981) Proc. Natl. Acad. Sci. USA 78, 3824---3828]. This peptide contains a sequence of six amino acids postulated to represent the major epitope, or antibody-combining site, of hepatitis B virus surface antigen (HBsAg). We have used passive hemagglutination inhibition with monospecific antibodies against the a, d, and y subdeterminants of this antigen and against human serum albumin to investigate the antigenic specificities on this peptide, and we have found it to contain the HBsAg/a and HBsAg/d but not HBsAg/y or human serum albumin subdeterminants. When the peptide was conjugated onto human erythrocytes and injected into mice, it induced the formation of anti-HBsAg with and without the use of Freund's adjuvant. If anti-HBsAg/a confers immunity to infection with hepatitis B virus, as is generally thought, these findings may permit the development of a synthetic vaccine lacking all unnecessary antigenic determinants.


Recurrence of fidelity in nearly integrable systems.
Within the framework of simple perturbation theory, recurrence time of quantum fidelity is related to the period of the classical motion. This indicates the possibility of recurrence in nearly integrable systems. We have studied such possibility in detail with the kicked rotor as an example. In accordance with the correspondence principle, recurrence is observed when the underlying classical dynamics is well approximated by the harmonic oscillator. Quantum revival of fidelity is noted in the interior of resonances, while classical-quantum correspondence of fidelity is seen to be very short for states initially in the rotational Kolmogorov-Arnold-Moser region.


Threshold of cerebral perfusion pressure as a prognostic factor in hydrocephalus during infancy.
An analysis of the intracranial pressure (ICP) was done on 30 hydrocephalic infants using a newly devised computerized analyzing system. As a cerebrovascularly compromised index of the ICP, the transmission ratio of systemic arterial pulse pressure (SABP) to ICP as defined by Ikeyama [eta HB (PP of ICP/PP of SABP)] was used. Cerebral perfusion pressure (CPP) versus eta HB showed significant bilinear relationship. From this correlation the threshold of CPP in relation to ICP level was calculated. A reduction of CPP below this level abruptly reduced the correlation with ICP. Thus, the CPP threshold showed an increase related to age (from 20 mm Hg in preterm babies at birth to 80 mm Hg at 12 months of age) and is correlated with the psychomotor development evaluated 6-36 months after shunting. The abnormal waves that appear when there is a high level of eta HB and that also appear below the threshold level of CPP can be defined as pressure waves, based on the physiological findings. It was shown that in hydrocephalus during infancy, a prolonged ICP below the threshold of CPP is one of the cerebrohemodynamic factors that can adversely affect the outcome of psychomotor development.


Airway wall thickening on CT: Relation to smoking status and severity of COPD.
Airway wall thickening in cigarette smokers is thought to be a result of inflammatory changes and airway remodeling. This study investigates if CT-derived airway wall thickening associates to disease severity in smokers with and without COPD and if airway wall thickening is reversible by smoking cessation. We examined 2000 smokers and 46 never-smokers who returned for a 5-year follow-up visit in the COPDGene-study. Multivariable regression analyses were performed at visit 1 to associate airway wall thickness (expressed as Pi10) with percent predicted forced expiratory volume in 1 s (FEV1%-predicted), 6-min walking distance (6MWD), and St. George Respiratory Questionnaire (SGRQ). Longitudinal analyses were performed to assess the effect of smoking cessation on Pi10 using linear mixed models. A higher Pi10 was significantly associated with worse FEV1%-predicted, 6MWD, and SGRQ in all GOLD-stages. Longitudinal analyses showed that subjects that quit smoking significantly decreased in Pi10 (ΔPi10 = -0.18 mm, p < 0.001). Subjects that started smoking had a significant increase in Pi10 (ΔPi10 = 0.14 mm, p < 0.001). Pi10 is a clinically relevant biomarker of smoking-related airway injury in smokers with and without COPD. The change in Pi10 with change in smoking status suggests that it can quantify a reversible component of smoking-related airway inflammation.


Comparative Investigation of Anti-Inflammatory Effect of Platelet-Rich Fibrin after Mandibular Wisdom Tooth Surgery: A Randomized Controlled Study.
This study evaluated the anti-inflammatory effect of platelet-rich fibrin (PRF) applied to the extraction socket after impacted mandibular third molar surgery with subjective and objective parameters. Forty-eight patients with impacted wisdom teeth in bilateral and similar positions were included in the study. The control group was formed with the standard surgery and the PRF group was formed with local PRF application in addition to standard procedure (n = 96). The anti-inflammatory activity of PRF on postoperative 2nd and 7th days was evaluated subjectively by clinical parameters and objectively by biochemical parameters. Postoperative 2nd- and 7th-day follow-up data of pain, edema, and trismus in the PRF group were found to be statistically significantly lower. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were found to be statistically significantly lower in the PRF group than the control in the postoperative 2nd-day follow-up period (p < 0.001). There was no statistically significant difference in interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) parameters when the PRF group and the control group were compared in both follow-up periods (p > 0.05). The study has demonstrated the effectiveness of locally applied PRF after ITM surgery via clinical parameters and objective data. The quantitative analysis of CRP and ERS can be an effective parameter in determining the amount of inflammation after ITM surgery.


The ethics of pornography in the era of AIDS.
Since the inception of sexology as an academic discipline a century ago, the boundary between sexology, the science, and sexosophy, the philosophy of sex, has been poorly demarcated, especially with respect to the principles of sex-reform movements. Several early 20th centruy sexologists overtly espoused the principles of eugenics reform, which, in the 1930s, Hitler used against them. A large proportion of today's sex therapists, researchers, and educators are among "those who cannot remember the past" and are, therefore, according to Santayana, "condemned to repeat it." That is to say, they follow the example of eugenics reformers by adhering to explanatory principles as if they were apolictically indisputable; whereas, they are, in fact, dangerously political professional platitudes for the criminalization of sex. One such platitude is that pornography is dehumanizing and a socially contagious criminal offense. Social-contagion theory had its origin in Tissot's 18th century revival of semen-conservation theory. In America, Tissot's antisexual health-reform ideas were transmitted by Graham to Kellogg and Comstock. The Comstock Laws of 1873 are still extant and are the basis of contemporary judicial, academic, and public misconceptions regarding the social contagiousness of pornography. These misconceptions render the nation incapable of using pornography constructively in a program of sex-safety to prevent AIDS infection, especially among newly pubertal adolescents and young adults. The model to follow has already been provided by gay JACK and JO masturbation clubs.


Mitochondria DNA 4977 bp common deletion in peripheral whole blood from healthy donors.
To investigate the distribution of mitochondria DNA 4 977 bp deletion, a common deletion (CD), in normal populations of Chinese, human peripheral blood samples from sixty healthy donors were collected, and levels of the CD in genomic DNA from the samples were detected using real-time PCR. The results showed that the CD was found in 27 health donors, with its positive rate being 45% (27/60). The CD ratio was between 0 and 0.00308%, and not affected by age and gender in sixty healthy donors. Our studies indicate that the CD ratio is low, and do not show the age-dependent accumulation and any gender difference in peripheral whole blood from the normal Chinese population.


Postpartum aggression in mice: the role of ovarian hormones.
The development of aggression during the immediate postpartum period was investigated in Rockland-Swiss albino female mice. Aggression was low immediately following delivery and increased with advancing lactation. The majority of females delivered during the dark cycle, however, whether females delivered or were tested during the light or dark cycle did not influence aggression. Females ovariectomized on Gestation Day 18 displayed aggression sooner than sham-operated controls. Estrogen treatment restored typical postpartum docility in prepartum ovariectomized females. Ovariectomy also increased the number of nursing bouts, but not total nursing time, when compared to sham-operated females. These findings suggest that peripartum estrogen stimulation, directly or through influencing nursing activity, prevents aggression in females immediately postpartum.


A U.S. isolate of Theileria orientalis, Ikeda genotype, is transmitted to cattle by the invasive Asian longhorned tick, Haemaphysalis longicornis.
Theileria orientalis is a tick-borne hemoparasite that causes anemia, ill thrift, and death in cattle globally. The Ikeda strain of T. orientalis is more virulent than other strains, leading to severe clinical signs and death of up to 5% of affected animals. Within the Asia-Pacific region, where it affects 25% of Australian cattle, T. orientalis Ikeda has a significant economic impact on the cattle industry. In 2017, T. orientalis Ikeda was detected in a cattle herd in Albermarle County, Virginia, United States. Months earlier, the U.S. was alerted to the invasion of the Asian longhorned tick, Haemaphysalis longicornis, throughout the eastern U.S. Abundant H. longicornis ticks were identified on cattle in the T. orientalis-affected herd in VA, and a subset of ticks from the environment were PCR-positive for T. orientalis Ikeda. A strain of T. orientalis from a previous U.S. outbreak was not transmissible by H. longicornis; however, H. longicornis is the primary tick vector of T. orientalis Ikeda in other regions of the world. Thus, the objective of this study was to determine whether invasive H. longicornis ticks in the U.S. are competent vectors of T. orientalis Ikeda. Nymphal H. longicornis ticks were fed on a splenectomized calf infected with the VA-U.S.-T. orientalis Ikeda strain. After molting, a subset of adult ticks from this cohort were dissected, and salivary glands assayed for T. orientalis Ikeda via qPCR. The remaining adult ticks from the group were allowed to feed on three calves. Calves were subsequently monitored for T. orientalis Ikeda infection via blood smear cytology and PCR. After acquisition feeding on a VA-U.S.-T. orientalis Ikeda-infected calf as nymphs, a subset of molted adult tick salivary glands tested positive by qPCR for T. orientalis Ikeda. Adult ticks from the same cohort successfully transmitted T. orientalis Ikeda to 3/3 naïve calves, each of which developed parasitemia reaching 0.4-0.9%. Our findings demonstrate that U.S. H. longicornis ticks are competent vectors of the VA-U.S.-T. orientalis Ikeda strain. This data provides important information for the U.S. cattle industry regarding the potential spread of this parasite and the necessity of enhanced surveillance and control measures.


Inhibitory effects of transcription factor Ikaros on the expression of liver cancer stem cell marker CD133 in hepatocellular carcinoma.
CD133 is a cellular surface glycoprotein that has been reported as a marker for the enrichment of cancer stem cells (CSCs). However, the regulatory mechanism of CD133 remains unknown. CSCs have been proposed to contribute to radioresistance and multi-drug resistance. The elucidation of key regulators of CD133 and CSCs is critical for the development of CSC-targeted therapy. In this study, we showed that Ikarosinhibited the expression of CD133 via direct binding to the CD133 P1 promoter and repressed the tumorigenic and self-renewal capacity of CD133(+) cancer stem-like cells in hepatocellular carcinoma (HCC). We found that Ikaros interacted with CtBP as a transcription repressor complex, which inhibited CD133 expression in HCC. We also demonstrated that Ikaros expression was up-regulated by ETS1 which activity was regulated by MAPKs pathway. Furthermore, decreased expression of Ikaroswas significantly associated with poor survival in HCC patients. Overall, our study identifies that Ikaros plays a role as a transcription repressor in HCC and is a new reactivated therapeutic target for the treatment of HCC. Meanwhile, our findings provide evidence that Ikaros could be an attractive inhibitor of the target gene CD133, which reactivates anticancer mechanisms in targeted CSC therapy.


The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis.
and Aims; To investigate the association between use of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) and outcomes of hypertensive COVID-19 patients, a systematic review and meta-analysis were performed. We systematically searched PubMed, EuropePMC, ProQuest, and Cochrane Central Databases using the terms "(COVID-19 OR SARS-CoV-2) AND (angiotensin converting enzyme OR angiotensin receptor blocker)". The primary and second outcomes were mortality (non-survivor) and severe COVID-19, respectively. Totally, 7410 patients were included from 15 studies. Pooled analysis showed that the use of ACEI/ARB was not associated with mortality (OR 0.73 [0.38, 1.40], p = 0.34; I2: 81%) and severity (OR 1.03 [0.73, 1.45], p = 0.87; I2: 65%). Pooled adjusted OR showed no risk/benefit associated with ACEI/ARB use in terms of mortality (OR 0.83 [0.54, 1.27], p = 0.38; I2: 0%). Subgroup analysis showed that the use of ARB was associated with reduced mortality (OR 0.51 [0.29, 0.90], p = 0.02; I2: 22%) but not ACEI subgroup (OR 0.68 [0.39, 1.17], p = 0.16; I2: 0%). Meta-regression showed that the association between ACEI/ARB use and mortality in patients with COVID-19 do not varies by gender (p = 0.104). GRADE showed a very low certainty of evidence for effect of ACEI/ARB on mortality and severity. The certainty of evidence was very low for both ACEI and ARB subgroups. Administration of a renin angiotensin system (RAS) inhibitor, was not associated with increased mortality or severity of COVID-19 in patients with hypertension. Specifically, ARB and not ACEI use, was associated with lower mortality.


Angiopoietin-like-2: a multifaceted protein with physiological and pathophysiological properties.
Angptl2 is a multifaceted protein, displaying both physiological and pathological functions, in which scientific and clinical interest is growing exponentially within the past few years. Its physiological functions are not well understood, but angptl2 was first acknowledged for its pro-angiogenic and antiapoptotic capacities. In addition, angptl2 can be considered a growth factor, since it increases survival and expansion of hematopoietic stem cells and may promote vasculogenesis. Finally, angptl2 has an important, but largely unrecognised, physiological role: in the cytosol, angptl2 binds to type 1A angiotensin II receptors and induces their recycling, with recovery of the receptor signal functions. Despite these important physiological properties, angptl2 is better acknowledged for its deleterious pro-inflammatory properties and its contribution in multiple chronic diseases such as cancer, diabetes, atherosclerosis, metabolic disorders and many other chronic diseases. This review aims at presenting an updated description of both the beneficial and deleterious biological properties of angptl2, in addition to its molecular signalling pathways and transcriptional regulation. The multiplicity of diseases in which angptl2 contributes makes it a new highly relevant clinical therapeutic target.


Respiratory Sinus Arrhythmia Mediates Links Between Borderline Personality Disorder Symptoms and Both Aggressive and Violent Behavior.
Although emotion dysregulation (ED) is a core symptom of borderline personality disorder (BPD), tests of associations between ED and aggression and violence-which are common to BPD-are sparse. The authors evaluated mediating effects of an autonomic vulnerability to ED on links between BPD symptoms and (a) reactive aggression, (b) proactive aggression, and (c) histories of interpersonal violence in a sample of young adults (N = 104), ages 18-22 years. Low baseline respiratory sinus arrhythmia (RSA) mediated the association between BPD symptoms and reactive aggression. In contrast, although BPD symptoms were correlated with proactive aggression, no mediational effect was found. In addition, low RSA mediated the association between BPD symptoms and histories of interpersonal violence. Collectively, these findings add evidence that neurobiological vulnerability to ED contributes to aggressive and violent behavior among those with BPD.


Is Five Percent Too Small? Analysis of the Overlaps between Disorder, Coiled Coil and Collagen Predictions in Complete Proteomes.
Identification of intrinsic disorder in proteins and proteomes has revealed important novel aspects of protein function and interactions. However, it has been pointed out that several oligomeric fibrillar protein motifs such as coiled coils and collagen triple helical segments can also identified as intrinsically disordered. This feature has not yet been investigated in more detail at the proteome level. The present work aims at the identification and quantification of such overlaps in full proteomes to assess their significance in large-scale studies of protein disorder. It was found that the percentage of cross-predicted residues is around 5% in the human proteome and is generally near that value in other metazoan ones but shows remarkable variation in different organisms. In particular, smaller proteomes are increasingly prone to such cross-predictions, thus, especially the analysis of viral proteomes requires the use of specific prediction tools.


Diaphragm thickness on computed tomography for nutritional assessment and hospital stay prediction in critical COVID-19.
To evaluate the significance of diaphragm thickness (DT) in assessing the nutritional status and predicting the length of hospital stay (LOS) of patients with COVID-19. The data of 212 patients with severe and critical COVID-19 in Wuhan, China, were retrospectively analyzed. Computed tomography (CT)-obtained DT was measured in cross-sectional images of the mediastinal window at the level of the outlet of the celiac trunk at admission and at 2 weeks, then the rate of change in DT(RCDT) at 2 weeks was calculated. Nutritional risk and malnutrition were evaluated at admission. A total of 91 patients were involved in the study. The mean DT was 3.06±0.58 mm (3.15±0.63 mm in male and 2.93±0.50 mm in female). DT was significantly negatively correlated with malnutrition based on Global Leadership Initiative on Malnutrition (GLIM) criteria (r=-0.324, p=0.002), Nutritional Risk Screening 2002 (NRS-2002) score (r=-0.364, p=0.000) and the Malnutrition Universal Screening Tool (MUST) score (r=-0.326, p=0.002) at admission. For the prediction of LOS ≥4 weeks in patients with COVID-19, the area under the ROC curve (AUC) of the RCDT at 2 weeks was 0.772, while the AUCs of DT, NRS-2002, MUST and Nutrition Risk in Critically Ill scores at admission were 0.751, 0.676, 0.638 and 0.699 respectively. According to the model of multiple linear regression analysis, the DT at admission (β=-0.377, p=0.000), RCDT at 2 weeks (β =-0.323, p=0.001), and mechanical ventilation (β=0.192, p=0.031) were independent risk factors contributed to LOS. CT-obtained DT can be used as a dynamic assessment tool for evaluating the nutritional status of patients in isolation wards for COVID-19.


Management of expanding aortic arch aneurysm after hybrid endovascular and debranching repair.
Hybrid procedures are used to treat aneurysms of the transverse aortic arch (TAA), combining debranching of the brachiocephalic vessels with endovascular approaches. Continued enlargement of the aneurysmal sac is a late complication. A 60-year-old man presented with an expanding transverse aortic arch aneurysm after prior hybrid repair and underwent left posterolateral thoracotomy, partial excision of the previous stent graft and replacement with an interposition graft.


Dynamic chemical communication between plants and bacteria through airborne signals: induced resistance by bacterial volatiles.
Certain plant growth-promoting rhizobacteria (PGPR) elicit induced systemic resistance (ISR) and plant growth promotion in the absence of physical contact with plants via volatile organic compound (VOC) emissions. In this article, we review the recent progess made by research into the interactions between PGPR VOCs and plants, focusing on VOC emission by PGPR strains in plants. Particular attention is given to the mechanisms by which these bacterial VOCs elicit ISR. We provide an overview of recent progress in the elucidation of PGPR VOC interactions from studies utilizing transcriptome, metabolome, and proteome analyses. By monitoring defense gene expression patterns, performing 2-dimensional electrophoresis, and studying defense signaling null mutants, salicylic acid and ethylene have been found to be key players in plant signaling pathways involved in the ISR response. Bacterial VOCs also confer induced systemic tolerance to abiotic stresses, such as drought and heavy metals. A review of current analytical approaches for PGPR volatile profiling is also provided with needed future developments emphasized. To assess potential utilization of PGPR VOCs for crop plants, volatile suspensions have been applied to pepper and cucumber roots and found to be effective at protecting plants against plant pathogens and insect pests in the field. Taken together, these studies provide further insight into the biological and ecological potential of PGPR VOCs for enhancing plant self-immunity and/or adaptation to biotic and abiotic stresses in modern agriculture.


Low Titer Pneumocystis jirovecii Infections: More than Just Colonization?
Non-pneumonia Pneumocystis jirovecii colonization is thought to occur frequently in immunocompetent individuals. The aim was to analyze if P. jirovecii low-titer detections have more impact than just colonization. From our total cohort of patients for which P. jirovecii testing by qPCR was requested, we selected exclusively those that were fully immunocompetent. Patients were defined as fully immunocompetent if they did not receive immunosuppressive therapy, displayed regular antibody titers, and did not suffer from acquired, inherited or autoimmune diseases. Only those patients with complete medical records available were included. A retrospective analysis identified patients with P. jirovecii colonization and successful antibiotic therapy in response to laboratory pathogen detection. We identified 30 fully immunocompetent patients with P. jirovecii colonization suspected to suffer from infection with the pathogen, but with milder symptoms than pneumonia. All patients were successfully treated with cotrimoxazole against P. jirovecii and resolved from chronic cough and recurrent pulmonary infections. The fact that all patients displayed recovery from their clinical symptoms gives raise to the hypothesis that P. jirovecii infections may also occur in immunocompetent patients but with milder symptoms.


Capsid proteins from human immunodeficiency virus type 1 and simian immunodeficiency virus SIVmac can coassemble into mature cores of infectious viruses.
We have recently shown that the Gag polyproteins from human immunodeficiency virus type 1 (HIV-1) and HIV-2 can coassemble and functionally complement each other. During virion maturation, the Gag polyproteins undergo proteolytic cleavage to release mature proteins including capsid (CA), which refolds and forms the outer shell of a cone-shaped mature core. Less than one-half of the CA proteins present within the HIV-1 virion are required to form the mature core. Therefore, it is unclear whether the mature core in virions containing both HIV-1 and HIV-2 Gag consists of CA proteins from a single virus or from both viruses. To determine whether CA proteins from two different viruses can coassemble into mature cores of infectious viruses, we exploited the specificity of the tripartite motif 5alpha protein from the rhesus monkey (rhTRIM5alpha) for cores containing HIV-1 CA (hCA) but not the simian immunodeficiency virus SIV(mac) CA protein (sCA). If hCA and sCA cannot coassemble into the same core when equal amounts of sCA and hCA are coexpressed, the infectivities of such virus preparations in cells should be inhibited less than twofold by rhTRIM5alpha. However, if hCA and sCA can coassemble into the same core structure to form a mixed core, rhTRIM5alpha would be able to recognize such cores and significantly restrict virus infectivity. We examined the restriction phenotypes of viruses containing both hCA and sCA. Our results indicate that hCA and sCA can coassemble into the same mature core to produce infectious virus. To our knowledge, this is the first demonstration of functional coassembly of heterologous CA protein into the retroviral core.


Protein profiling in the habenula after chronic (-)-menthol exposure in mice.
The identification of proteins that are altered following nicotine/tobacco exposure can facilitate and positively impact the investigation of related diseases. In this report, we investigated the effects of chronic (-)-menthol exposure in 14 murine brain regions for changes in total β2 subunit protein levels and changes in epibatidine binding levels using immunoblotting and radioligand binding assays. We identified the habenula as a region of interest due to the region's marked decreases in β2 subunit and nAChR levels in response to chronic (-)-menthol alone. Thus, we further examined the habenula, a brain region associated with both the reward and withdrawal components of addiction, for additional protein level alterations using mass spectrometry. A total of 552 proteins with altered levels were identified after chronic (-)-menthol exposure. Enriched in the proteins with altered levels after (-)-menthol exposure were proteins associated with signaling, immune systems, RNA regulation, and protein transport. The continuation and expansion of the brain region-specific protein profiling in response to (-)-menthol will provide a better understanding of how this common flavorant in tobacco and e-liquid products may affect addiction and general health.


Mobile device for disease diagnosis and data tracking in resource-limited settings.
Collection of epidemiological data and care of patients are hampered by lack of access to laboratory diagnostic equipment and patients' health records in resource-limited settings. We engineered a low-cost mobile device that combines cell-phone and satellite communication technologies with fluid miniaturization techniques for performing all essential ELISA functions. We assessed the device's ability to perform HIV serodiagnostic testing in Rwanda and synchronize results in real time with electronic health records. We tested serum, plasma, and whole blood samples collected in Rwanda and on a commercially available sample panel made of mixed antibody titers. HIV testing on 167 Rwandan patients evaluated for HIV, viral hepatitis, and sexually transmitted infections yielded diagnostic sensitivity and specificity of 100% and 99%, respectively. Testing on 40 Rwandan whole-blood samples-using 1 μL of sample per patient-resulted in diagnostic sensitivity and specificity of 100% and 100%. The mobile device also successfully transmitted all whole-blood test results from a Rwandan clinic to a medical records database stored on the cloud. For all samples in the commercial panel, the device produced results in agreement with a leading ELISA test, including detection of weakly positive samples that were missed by existing rapid tests. The device operated autonomously with minimal user input, produced each result 10 times faster than benchtop ELISA, and consumed as little power as a mobile phone. A low-cost mobile device can perform a blood-based HIV serodiagnostic test with laboratory-level accuracy and real-time synchronization of patient health record data.


Ultra high energy density nanocomposite capacitors with fast discharge using Ba0.2Sr0.8TiO3 nanowires.
Nanocomposites combining a high breakdown strength polymer and high dielectric permittivity ceramic filler have shown great potential for pulsed power applications. However, while current nanocomposites improve the dielectric permittivity of the capacitor, the gains come at the expense of the breakdown strength, which limits the ultimate performance of the capacitor. Here, we develop a new synthesis method for the growth of barium strontium titanate nanowires and demonstrate their use in ultra high energy density nanocomposites. This new synthesis process provides a facile approach to the growth of high aspect ratio nanowires with high yield and control over the stoichiometry of the solid solution. The nanowires are grown in the cubic phase with a Ba0.2Sr0.8TiO3 composition and have not been demonstrated prior to this report. The poly(vinylidene fluoride) nanocomposites resulting from this approach have high breakdown strength and high dielectric permittivity which results from the use of high aspect ratio fillers rather than equiaxial particles. The nanocomposites are shown to have an ultra high energy density of 14.86 J/cc at 450 MV/m and provide microsecond discharge time quicker than commercial biaxial oriented polypropylene capacitors. The energy density of our nanocomposites exceeds those reported in the literature for ceramic/polymer composites and is 1138% greater than the reported commercial capacitor with energy density of 1.2 J/cc at 640 MV/m for the current state of the art biaxial oriented polypropylene.


A synthetic ionophore for Ca2+: studies with model and biological systems.
We show that the relatively simple beta-diketone, 184.108.40.206.2.3.3-heptafluoro-7,7-dimethyloctane-4,6-dione, known as "fod", will solvate Ca2+ ions in an organic phase. In consequence it will transport Ca2+ across phospholipid bilayers. It acts as predicted for a Ca2+-transporting ionophore in two biological systems: it will stimulate Ca2+-dependent K+ efflux from human red blood cells, and Ca2+-dependent histamine secretion from rat peritoneal mast cells.


Neuromuscular system of piglets with splayleg: the synthesis of acetylcholine and the myelinization and ultrastructure of peripheral nerve fibres.
No difference has been found between the activity of choline acetyltransferase in the sciatic nerve of one-day-old piglets with the syndrome of splayleg and in the sciatic nerve of apparently healthy piglets from the same breed. The maximum rates of total synthesis of acetylcholine in the homogenates of the sartorius, tibialis ant. and peroneus tertius muscles and the bromoacetylcholine -inhibitable portions of the acetylcholine-synthesizing capacity (corresponding to the activity of choline acetyltransferase in intramuscular branches and terminals of the motor nerves) were also the same in both groups of one-day-old animals. The number of myelinated fibres in the peroneal nerve of piglets with splayleg did not differ from that in the control group; it increased by 33% between the first and the seventh day of postnatal life in both groups. The only difference revealed by electron microscopy of the peroneal nerves between the animals with splayleg (or on the 7th day after birth, the animals that had recovered from the condition of splayleg) and the unaffected animals was a higher accumulation of glycogen granules in the axons of animals with splayleg. Biochemical and morphological data obtained in the present study thus support the view that an impairment of the function of peripheral nerves is unlikely to be responsible for the development of the splayleg syndrome.


Expression of thymic stromal lymphopoietin in canine atopic dermatitis.
In humans, thymic stromal lymphopoietin (TSLP) plays a central role in the development of allergic inflammation, such as atopic dermatitis (AD), but it is unknown whether it is involved in the pathogenesis of canine AD (CAD). Our aim was to characterize canine TSLP and to assess its expression in CAD. Canine TSLP was identified based on sequence homology with human TSLP and the complementary DNA (cDNA) cloned by RT-PCR. Real-time quantitative RT-PCR was established to assess the expression of canine TSLP in cultured canine keratinocytes and in skin biopsy specimens from lesional and nonlesional skin of 12 dogs with CAD and eight healthy control dogs. Partial canine TSLP cDNA was cloned and characterized. It contained four exons that shared 70 and 73% nucleotide identity with human and equine TSLP, respectively, encoding the signal peptide and full-length secreted protein. We found significantly increased TSLP expression in lesional and nonlesional skin of dogs with CAD compared with healthy control dogs (P < 0.05), whereas no difference was measured between lesional and nonlesional samples. In cultured primary canine keratinocytes, we found increased TSLP expression after stimulation with house dust mite allergen extract or Toll-like receptor ligands lipopolysaccharide and poly I:C. Increased TSLP expression in the skin of dogs with CAD supports an involvement of TSLP in the pathogenesis of CAD similar to that in humans. Further studies should elucidate the function and therapeutic potential of TSLP in CAD.


Characterization of florfenicol resistance among calf pathogenic Escherichia coli.
Three floR genes were cloned from calf pathogenic Escherichia coli strains, and the efflux-mediated accumulation of florfenicol in the floR gene-JM109 E. coli system was determined by HPLC. The floR genes resulted in a 1356-bp fragment covering the ORF in region 66-1280 coding for 404 amino acids. The common motifs of 12-transmembrane segments efflux pumps family were conserved in the deduced floR amino acid sequences. HPLC results indicated a significant difference in florfenicol accumulation between florfenicol-resistant strains and the susceptible strains, which was almost reversed by the addition of a proton motive force blocker. These results suggest that the florfenicol resistance mediated by the floR gene involves active efflux of florfenicol.


Evidence for a defective platelet L-tryptophan transport in depressed patients.
The kinetic characteristics of platelet L-tryptophan uptake were investigated in 23 untreated depressed patients and 18 healthy volunteers. A significant increase of 50% in the apparent Michaelis constant (Km) was observed in depressed patients compared with controls, without significant change in the maximal velocity (Vmax). After 1 month of successful antidepressant treatment the mean Km value decreased significantly and reached the control value. This result raises the possibility that the decrease in platelet tryptophan uptake affinity is a state-dependent marker for depression. It is likely that the transport alteration results in a decrease in platelet tryptophan accumulation. The effect of this peripheral membrane defect on brain serotonin function is discussed.


Proteomic analysis of middle and late stages of bread wheat (Triticum aestivum L.) grain development.
Proteomic approaches were applied in four grain developmental stages of the Chinese bread wheat Yunong 201 and its ethyl methanesulfonate (EMS) mutant line Yunong 3114. 2-DE and tandem MALDI-TOF/TOF-MS analyzed proteome characteristics during middle and late grain development of the Chinese bread wheat Yunong 201 and its EMS mutant line Yunong 3114 with larger grain sizes. We identified 130 differentially accumulated protein spots representing 88 unique proteins, and four main expression patterns displayed a dynamic description of middle and late grain formation. Those identified protein species participated in eight biochemical processes: stress/defense, carbohydrate metabolism, protein synthesis/assembly/degradation, storage proteins, energy production and transportation, photosynthesis, transcription/translation, signal transduction. Comparative proteomic characterization demonstrated 12 protein spots that co-accumulated in the two wheat cultivars with different expression patterns, and six cultivar-specific protein spots including serpin, small heat shock protein, β-amylase, α-amylase inhibitor, dimeric α-amylase inhibitor precursor, and cold regulated protein. These cultivar-specific protein spots possibly resulted in differential yield-related traits of the two wheat cultivars. Our results provide valuable information for dissection of molecular and genetics basis of yield-related traits in bread wheat and the proteomic characterization in this study could also provide insights in the biology of middle and late grain development.


Analysis of regulatory mechanisms of an insulin-inducible SHARP-2 gene by (S)-Equol.
Small compounds that activate the insulin-dependent signaling pathway have potential therapeutic applications in controlling type 2 diabetes mellitus. The rat enhancer of split- and hairy-related protein-2 (SHARP-2) is an insulin-inducible transcription factor that decreases expression of the phosphoenolpyruvate carboxykinase gene, a gluconeogenic enzyme gene. In this study, we screened for soybean isoflavones that can induce the rat SHARP-2 gene expression and analyzed their mechanism(s). Genistein and (S)-Equol, a metabolite of daidzein, induced rat SHARP-2 gene expression in H4IIE rat hepatoma cells. The (S)-Equol induction was mediated by both the phosphoinositide 3-kinase- and protein kinase C (PKC)-pathways. When a dominant negative form of atypical PKC lambda (aPKCλ) was expressed, the induction of SHARP-2 mRNA level by (S)-Equol was inhibited. In addition, Western blot analyses showed that (S)-Equol rapidly activated both aPKCλ and classical PKC alpha. Furthermore, the (S)-Equol induction was inhibited by treatment with a RNA polymerase inhibitor or a protein synthesis inhibitor. Finally, a reporter gene assay revealed that the transcriptional stimulation by (S)-Equol was mediated by nucleotide sequences located between -4687 and -4133 of the rat SHARP-2 gene. Thus, we conclude that (S)-Equol is an useful dietary supplement to control type 2 diabetes mellitus.


Effect of the degree of head elevation on the incidence and severity of venous air embolism in cranial neurosurgical procedures with patients in the semisitting position.
OBJECTIVE The semisitting position of a patient confers numerous advantages in various neurosurgical procedures, but venous air embolism is one of the associated complications of this position. To date, no prospective studies of the relationship between the degree of head elevation and the rate and severity of venous air embolism for patients undergoing a procedure in this position have been performed. In this study, the authors compared changes in the severity of venous air embolism according to the degree of head elevation (30° or 45°) in patients undergoing an elective cranial neurosurgical procedure in the semisitting position. METHODS One hundred patients undergoing an elective infratentorial craniotomy in the semisitting position were included, and each patient was assigned to 1 of 2 groups. In Group 1, each patient's head was elevated 30° during surgery, and in Group 2, each patient's head elevation was 45°. Patients were assigned to their group according to the location of their lesion. During surgery, the standard anesthetic protocol was used with total intravenous anesthesia, and transesophageal echocardiography was used to detect air in the blood circulation. Any air embolism seen on the echocardiography screen was classified as Grade 0 to 4. If multiple events occurred, the worst graded attack was used for statistical analysis. During hemodynamic changes caused by emboli, fluid and vasopressor requirements were recorded. Surgical and anesthetic complications were recorded also. All results were compared statistically, and a p value of < 0.05 was considered statistically significant. RESULTS There was a statistically significant difference between groups for the total rates of venous air emboli detected on transesophageal echocardiography (22.0% [n = 11] in Group 1 and 62.5% [n = 30] in Group 2; p < 0.0001). The rate and severity of air embolism were significantly lower in Group 1 than in Group 2 (p < 0.001). The rates of clinically important venous air embolism (Grade 2, 3, or 4, venous air embolism with decreased end-tidal carbon dioxide levels and/or hemodynamic changes) were 8.0% (n = 4) in Group 1 and 50.0% (n = 24) in Group 2 (p < 0.0001). There was no association between the rate and severity of venous air embolism with patient demographics (p > 0.05). An association was found, however, between the rate of venous air embolism and the type of surgical pathology (p < 0.001); venous embolism occurred more frequently in patients with a meningioma. There were no major surgical or anesthetic complications related to patient position during the postoperative period. CONCLUSIONS For patients in the semisitting position, an increase in the degree of head elevation is related directly to a higher rate of venous air embolism. With a 30° head elevation and our standardized technique of positioning, the semisitting position can be used safely in neurosurgical practice.


Study on the signalling pathway of inhibitory effect of adreno-medullin on the growth of cultured glomerular mesangial cells.
Adrenomedullin (ADM), a potent hypotensive small peptide, was recently found to inhibit the proliferation of glomerular mesangial cells (MsC) in vitro and to attenuate glomerular lesions in vivo, however the mechanisms remain poorly understood. In this study, we attempted to elucidate them using molecular signal transduction. Cultured rat MsC were treated with ADM and several inhibitors of signalling molecules. Methyl thiazoleterazolium (MTT) assay and BrdU incorporation method were employed for examining MsC proliferation. Western blot analysis was used for detecting total mitogen activated protein kinases (t-MAPKs) and phosphorylated MAPKs (p-MAPKs) proteins. ADM suppressed MsC proliferation in a concentration- and time-dependent fashion. This response was inhibited by ADM receptor antagonist CGRP8-37 and a potent protein kinase-A (PKA) inhibitor, H89. Forskolin, a direct adenylate cyclase activator, also significantly inhibited MsC proliferation. SB203580, a P38MAPK inhibitor, and U0126, a MEK inhibitor, both completely blocked ADM mediated responses in MsC. However, curcumin, a SAPK/JNK inhibitor, and GF109203X, a potent protein kinase-C (PKC) inhibitor, had no effect on MsC growth. Western blot analysis showed that ADM did not change the expression of t-MAPKs but increased p-SAPK/JNK and p-P38MAPK levels and decreased p-ERK level. These responses were inhibited by CGRP8-37. All these kinase phosphorylations, except for the increase in p-SAPK/JNK, could be stimulated using forskolin. In addition, only ADM mediated changes in ERK and P38MAPK phosphorylations were inhibited by H89. GF109203X did not affect ADM induced changes in three p-MAPKs expressions. ADM inhibits MsC proliferation possibly through cAMP-PKA pathway. Both phosphorylations of ERK and P38MAPK pathways were necessary in mediating the antiproliferative response of ADM. It does not preclude the involvement of cAMP independent pathways in the ADM mediated responses.


Melatonin and its metabolites as copper chelating agents and their role in inhibiting oxidative stress: a physicochemical analysis.
The copper sequestering ability of melatonin and its metabolites cyclic 3-hydroxymelatonin (3OHM), N(1) -acetyl-N(2) -formyl-5-methoxykynuramine (AFMK), and N(1) -acetyl-5-methoxykynuramine (AMK) was investigated within the frame of the Density Functional Theory. It was demonstrated that these compounds are capable of chelating copper ions, yielding stable complexes. The most likely chelation sites were identified. Two different mechanisms were modeled, the direct-chelation mechanism (DCM) and the coupled-deprotonation-chelation mechanism (CDCM). It is proposed that, under physiological conditions, CDCM would be the main chelation route for Cu(II). It was found that melatonin and its metabolites fully inhibited the oxidative stress induced by Cu(II)-ascorbate mixtures, via Cu(II) chelation. In the same way, melatonin, AFMK, and 3OHM also prevented the first step of the Haber-Weiss reaction, consequently turning off the ˙OH production via the Fenton reaction. Therefore, it is proposed that, in addition to the previously reported free radical scavenging cascade, melatonin is also involved in a concurrent 'chelating cascade', thereby contributing to a reduction in oxidative stress. 3OHM was identified as the most efficient of the studied compounds for that purpose, supporting the important role of this metabolite in the beneficial effects of melatonin against oxidative stress.


Death associated protein kinases: molecular structure and brain injury.
Perinatal brain damage underlies an important share of motor and neurodevelopmental disabilities, such as cerebral palsy, cognitive impairment, visual dysfunction and epilepsy. Clinical, epidemiological, and experimental studies have revealed that factors such as inflammation, excitotoxicity and oxidative stress contribute considerably to both white and grey matter injury in the immature brain. A member of the death associated protein kinase (DAPk) family, DAPk1, has been implicated in cerebral ischemic damage, whereby DAPk1 potentiates NMDA receptor-mediated excitotoxicity through interaction with the NR2BR subunit. DAPk1 also mediate a range of activities from autophagy, membrane blebbing and DNA fragmentation ultimately leading to cell death. DAPk mRNA levels are particularly highly expressed in the developing brain and thus, we hypothesize that DAPk1 may play a role in perinatal brain injury. In addition to reviewing current knowledge, we present new aspects of the molecular structure of DAPk domains, and relate these findings to interacting partners of DAPk1, DAPk-regulation in NMDA-induced cerebral injury and novel approaches to blocking the injurious effects of DAPk1.


Effects of bedrest on deltoideus muscle morphology and enzymes.
To examine the effects of unweighting on the structural and metabolic adaptations of a non-postural muscle, deltoideus muscle biopsies were taken in seven male healthy subjects, before and after a 37 day bedrest. Myofibrillar ATPase histochemistry demonstrated no change in fibre type distributions (I, IIA, IIB), in fibre cross-sectional areas nor in capillary supply. No difference was noted in enzyme activities of oxidative metabolism (citrate synthase, 3-hydroxy-acyl-CoA dehydrogenase), and glycolysis (hexokinase, lactate dehydrogenase). Electron microscopy showed a decrease in the volume density of lipids but no change in mitochondrial volume density and distribution. The results indicate that bedrest induces no major morphological and biochemical changes in deltoideus muscle, contrary to what was previously reported in vastus lateralis muscle. This lack of changes is probably related to an unaltered deltoideus muscle use.


Model-Based Network Meta-Analysis: A Framework for Evidence Synthesis of Clinical Trial Data.
Model-based meta-analysis (MBMA) is increasingly used in drug development to inform decision-making and future trial designs, through the use of complex dose and/or time course models. Network meta-analysis (NMA) is increasingly being used by reimbursement agencies to estimate a set of coherent relative treatment effects for multiple treatments that respect the randomization within the trials. However, NMAs typically either consider different doses completely independently or lump them together, with few examples of models for dose. We propose a framework, model-based network meta-analysis (MBNMA), that combines both approaches, that respects randomization, and allows estimation and prediction for multiple agents and a range of doses, using plausible physiological dose-response models. We illustrate our approach with an example comparing the efficacies of triptans for migraine relief. This uses a binary endpoint, although we note that the model can be easily modified for other outcome types.


Purification of a recombinant human respiratory syncytial virus chimeric glycoprotein using reversed-phase chromatography and protein refolding in guanidine hydrochloride.
FG glycoprotein is a recombinant chimeric protein consisting of the extracellular portions of human respiratory syncytial virus (RSV) F and G glycoproteins. In theory, highly purified FG glycoprotein may be effective as a RSV vaccine. Recombinant FG glycoprotein was expressed using the baculovirus/insect cell system. FG glycoprotein was isolated from cell culture supernatants using S Sepharose ion-exchange chromatography, Cu(2+)-immobilized metal affinity chromatography, preparative reversed-phase high-performance liquid chromatography, denaturation with 6 M guanidine hydrochloride, and protein refolding in Tween 80 detergent. The purified FG glycoprotein was concentrated on a S Sepharose column and exchanged into an appropriate buffer for vaccine formulation. Five batches of FG glycoprotein with protein purity of 92-99% were produced using this purification process. FG glycoprotein produced using reversed-phase chromatography and protein refolding was compared with nondenatured FG glycoprotein using a panel of 14 monoclonal antibodies directed against conformational and linear epitopes on RSV F and G glycoproteins. The results of these studies indicated that refolded FG glycoprotein had the same three-dimensional structure as nondenatured FG glycoprotein.


Ritonavir-boosted lopinavir as maintenance monotherapy in HIV-infected patients who achieved viral suppression during a second-line protease inhibitor-based regimen: a pilot randomized trial (BIDI-MONO).
Eligibility criteria were (I) having previously failed first-line nonnucleoside reverse transcriptase inhibitor-based regimens and (2) having achieved virologic suppression >6 months while receiving a protease inhibitor (PI)-based regimen as second-line treatment. Eligible participants were randomized to receive either (I) ritonavir-boosted lopinavir (LPV/r) monotherapy (n = 29) or (2) LPV/r with optimized background regimens (OBRs; n = 31). Median duration of viral suppression before randomization was 45 months. At week 48, viral suppression during LPV/r monotherapy was 86.2% and did not differ from the suppression achieved with LPV/r with OBRs (87.1%, P = 1.000). However, persistent viremia during LPV/r monotherapy tended to be higher than during LPV/r with OBRs (10.3% versus 3.2%, P = .346). History of viral blip during virologic suppression with second-line PI-based regimen is a predictor of achieving viral suppression at all visits (adjusted relative risk 0.255 [95% confidence interval 0.080-0.821], P = .022). Use of LPV/r monotherapy as maintenance regimen in this study produced persistent viremia that tended to be higher than LPV/r monotherapy with OBRs.


[Evaluation of sperm mitochondrial function using Rh123/PI dual fluorescent staining].
To investigate the feasibility and clinical significance of detecting sperm mitochondrial function by using Rh123/PI dual fluorescent staining and flow cytometry analysis, and to explore the relationship between the results of Rh123/PI dual fluorescent staining and seminal parameters. Sixty-three semen samples were classified as normal (n=31) and abnormal (n=32) according to the World Health Organization guidelines. Rh123/PI dual fluorescent staining was then carried out to evaluate sperm mitochondrial function by flow cytometry analysis. Significant differences in Rh123+ PI-, Rh123- /PI+ and Rh123- /PI- were detected between the normal and abnormal semen samples (P < 0.05). There was a significant positive correlation between the Rh123+ PI- sperm and sperm motility and a significant inverse correlation between Rh123+ PI- and immotile sperm. But the Rh123- PI+ sperm showed a contrary relationship with Rh123+ PI-. A significant inverse correlation was also observed between the Rhl23- /PI- sperm and sperm concentration in the abnormal group. Rh123/PI dual fluorescent staining and flow cytometry analysis can readily and quickly detect sperm mitochondrial function and be used to evaluate semen quality.


Accurate Identification of Cancerlectins through Hybrid Machine Learning Technology.
Cancerlectins are cancer-related proteins that function as lectins. They have been identified through computational identification techniques, but these techniques have sometimes failed to identify proteins because of sequence diversity among the cancerlectins. Advanced machine learning identification methods, such as support vector machine and basic sequence features (n-gram), have also been used to identify cancerlectins. In this study, various protein fingerprint features and advanced classifiers, including ensemble learning techniques, were utilized to identify this group of proteins. We improved the prediction accuracy of the original feature extraction methods and classification algorithms by more than 10% on average. Our work provides a basis for the computational identification of cancerlectins and reveals the power of hybrid machine learning techniques in computational proteomics.


Differing roles for short chain fatty acids and GPR43 agonism in the regulation of intestinal barrier function and immune responses.
Inflammatory bowel disease (IBD) is associated with a loss of intestinal barrier function and dysregulated immune responses. It has been shown that short chain fatty acids (SCFAs) are protective in IBD and that GPR43 mediates the protective effects of SCFAs. In this study, we investigated the effects of SCFAs in comparison to highly specific GPR43 agonists on human intestinal epithelial and immune cells. Our results confirm that SCFAs are enhancers of barrier function in intestinal epithelial cells. Additionally, SCFAs also displayed potent immunoregulatory properties based upon the ability to inhibit LPS-induced cytokine production in PBMC, and human T cell proliferation and cytokine production. Unexpectedly, and in contrast to the current belief, specific GPR43 agonists failed to exhibit similar barrier enhancing and anti-inflammatory properties. These findings demonstrate that SCFA possess broad protective functions in IBD and agonizing GPR43 alone is unlikely to be beneficial in patients.