Characteristics Analysis, Clinical Outcome and Risk Factors for Fungal Peritonitis in Peritoneal Dialysis Patients: A 10-Year Case-Control Study.
Background: Fungal peritonitis (FP) is a rare but severe complication that can appear in patients receiving peritoneal dialysis (PD). This study aimed to investigate the incidence rate and clinical characteristics of FP, evaluate clinical outcomes between FP and bacterial peritonitis (BP) patients on PD, and especially estimate the risk factors for FP outbreak. Methods: All episodes of FP diagnosed in our hospital from January 1, 2011, to December 31, 2020, were reviewed in this single-center study. FP cases were analyzed and compared with patients diagnosed with BP in a 1:6 ratio matching for case-control study. Patient information, including clinical information, biochemical analysis, and outcomes, was recorded. Univariate and multivariate logistic regression model were used to analyze the risk factors for FP. Results: A total of 15 FP episodes were observed in 15 PD patients, with an FP rate of 0.0071 episodes per patient-year. Seventeen strains of fungi were isolated and identified. Candida was the most common pathogen (15 strains, 88.2%), followed by Aspergillus fumigatus (2 strains, 11.8%). Between the groups, FP group showed a higher rate of HD transfer and catheter removal, and a lower rate of PD resumption in the short-term outcome (all P < 0.01), while no significant difference in the mortality was noted during the whole study period. The multivariate logistic regression analysis showed that longer PD duration (odds ratio [OR] 1.042, 95% confidence interval [CI] 1.012-1.073, P < 0.01), higher serum potassium (OR 3.373, 95% CI 1.068-10.649, P < 0.05), elevated estimated glomerular filtration rate (eGFR) (OR 1.845, 95% CI 1.151-2.955, P < 0.05), reduced serum albumin level (OR 0.820, 95% CI 0.695-0.968, P < 0.05) and peritoneal effluent polymorphonuclear (PMN) count (OR 0.940, 95%CI 0.900-0.981, P < 0.01) were significantly increased the risk for FP. Conclusion: These results suggested that FP leads to higher rate of catheter removal and HD transfer, and a lower rate of PD resumption than BP, and that additional attention should be paid to hypoalbuminemia, increased serum potassium, long PD duration, and low peritoneal effluent PMN in PD patients.


Acclimation to Cu in fathead minnows: does age influence the response?
This study had two primary objectives. The first was to determine if the length of exposure necessary for acclimation to Cu to develop in larval fathead minnows (Pimephales promelas) is different than that for juveniles. The second objective was to determine whether the acclimatory response, as determined by organism survival, is consistent with acclimation as determined by whole-body Na+. Six experiments were conducted: four using larval (<20-d-old) and two using juvenile (<60-d-old) fathead minnows. Within each experiment, fish were allocated to one of four groups: unexposed, continuously exposed, episodically exposed or naïvely exposed. The continuous group was exposed to a sublethal Cu exposure (125 microg/L) for 8, 12, 16 or 20 d and then subjected to a survival test at a lethal dose (375 microg/L). Fish in the episodic group were exposed to the sublethal dose for either 4 or 8 d, given a depuration period of varying lengths (4-16 d) then subjected to a survival test. Naïve minnows were maintained in clean water then given the survival challenge. Results from survival tests show that the larvae acclimate after only a 4-d sublethal exposure to Cu. In contrast, juveniles require a 16-d exposure to acclimate. Once acclimation had developed, there was a strong relationship between larval survival and whole-body Na+. Acclimated larvae maintained whole-body Na+ relative to unexposed fish, while unacclimated larvae did not. Interestingly, this was not the case for juveniles, as acclimated and unacclimated groups did not differ with respect to whole-body Na+ concentrations. The results of this study show that age influences the time course and possibly the mechanisms of acclimation in fathead minnows exposed to Cu.


Confidence intervals for fMRI activation maps.
Neuroimaging activation maps typically color voxels to indicate whether the blood oxygen level-dependent (BOLD) signals measured among two or more experimental conditions differ significantly at that location. This data presentation, however, omits information critical for interpretation of experimental results. First, no information is represented about trends at voxels that do not pass the statistical test. Second, no information is given about the range of probable effect sizes at voxels that do pass the statistical test. This leads to a fundamental error in interpreting activation maps by naïve viewers, where it is assumed that colored, "active" voxels are reliably different from uncolored "inactive" voxels. In other domains, confidence intervals have been added to data graphics to reduce such errors. Here, we first document the prevalence of the fundamental error of interpretation, and then present a method for solving it by depicting confidence intervals in fMRI activation maps. Presenting images where the bounds of confidence intervals at each voxel are coded as color allows readers to visually test for differences between "active" and "inactive" voxels, and permits for more proper interpretation of neuroimaging data. Our specific graphical methods are intended as initial proposals to spur broader discussion of how to present confidence intervals for fMRI data.


The role of metabonomics as a tool for augmenting nutritional information in epidemiological studies.
Most chronic diseases have been demonstrated to have a link to nutrition. Within food and nutritional research there is a major driver to understand the relationship between diet and disease in order to improve health of individuals. However, the lack of accurate dietary intake assessment in free-living populations, makes accurate estimation of how diet is associated with disease risk difficulty. Thus, there is a pressing need to find solutions to the inaccuracy of dietary reporting. Metabolic profiling of urine or plasma can provide an unbiased approach to characterizing dietary intake and various high-throughput analytical platforms have been used in order to implement targeted and nontargeted assays in nutritional clinical trials and nutritional epidemiology studies. This review describes first the challenges presented in interpreting the relationship between diet and health within individual and epidemiological frameworks. Second, we aim to explore how metabonomics can benefit different types of nutritional studies and discuss the critical importance of selecting appropriate analytical techniques in these studies. Third, we propose a strategy capable of providing accurate assessment of food intake within an epidemiological framework in order establish accurate associations between diet and health.


Clinical experience of patients undergoing photodynamic therapy for Barrett's dysplasia or cancer.
Barrett's oesophagus is the most important risk factor in the increase in incidence of oesophageal adenocarcinoma. Photodynamic therapy using porfimer sodium is the only approved endoscopic treatment for use in patients with Barrett's high-grade dysplasia. To determine clinical characteristics, endoscopic findings and treatment complications in Barrett's high-grade dysplasia patients undergoing photodynamic therapy. We reviewed our experience using porfimer sodium photodynamic therapy to treat patients with Barrett's oesophagus and high-grade dysplasia or mucosal carcinoma. Data collected included patients characteristics, presentation symptoms, endoscopic findings, subsequent use of surveillance endoscopy and outcome after photodynamic therapy. Since 1997, 102 patients with Barrett's high-grade dysplasia (69 patients) or mucosal adenocarcinoma (33 patients) have been treated with photodynamic therapy using porfimer sodium as an alternative to oesophagectomy (median series follow-up time = 1.6 years). Almost half (46%) of patients had high-grade dysplasia or carcinoma detected on their first endoscopy and the remainder (54%) were found during surveillance of known Barrett's oesophagus. Symptoms typically associated with oesophageal disease were only found in 29 of 47 (62%) patients in whom dysplasia/carcinoma was detected on the initial endoscopy - chest pain in 13 patients, dysphagia in nine patients and chronic gastro-oesophageal disease in seven patients. Comparison of endoscopic characteristics found the median Barrett's glandular segment length was significantly shorter in adenocarcinoma patients (median 3 cm; range: 1-12) vs. Barrett's high-grade dysplasia patients (median 5 cm; range: 1-16, P < 0.001). Overall treatment results found complete ablation of glandular epithelium with one course of photodynamic therapy in most patients (56%). Stricture requiring dilation occurred in 20 patients (20%) was the most common serious adverse event. Photodynamic therapy failed to ablate dysplasia or carcinoma in four patients and subsequent oesophagectomy was curative in three of these patients. Approximately 40% of newly diagnosed patients with Barrett's associated dysplasia or carcinoma had no oesophageal symptoms and had carcinoma associated with short segment (3 cm or less). Photodynamic therapy is a highly effective, safe and minimally invasive first-line treatment for patients with Barrett's dysplasia and mucosal adenocarcinoma.


The Arabidopsis COMATOSE locus regulates germination potential.
Mutation of the COMATOSE locus in Arabidopsis results in a marked reduction in germination potential. Whilst the morphology of comatose (cts) embryos is not altered, physiological analysis reveals that mature cts seeds do not respond to gibberellin. Prolonged chilling of imbibed seeds only partially restores germination potential, and seeds do not after ripen. Genetic analysis shows that the cts phenotype is expressed in the embryo and phenotypic differences between wild-type and mutant plants were not observed during other stages of plant growth and development. Therefore cts represents a new class of mutant, with a specific lesion that results in severely impaired germination potential. Genetic interactions were analysed between cts and loci that regulate embryo maturation, and abscisic acid biosynthesis and perception. Results from these studies showed that the cts mutant phenotype required the wild-type action of these loci, and suggested that CTS exerts a repressive function on these loci. A model is presented postulating that CTS promotes increased germination potential, and represses embryo dormancy. These functions of CTS may result in the removal of embryo dormancy as a prerequisite to germination.


Comparison of the Amplitudes of the H-reflex of Post-stroke Hemiplegia Patients and Normal Adults during Walking.
[Purpose] The purpose of this study was to compare H-reflex characteristics during gait of hemiplegic stroke patients. [Subjects] Twenty-five patients and age-matched twenty-five volunteers in good health were studied. All the subjects could walk independently. [Methods] An MP150 (BIOPAC Systems, Inc., Goleta, CA, USA) was used to record the electromyography (EMG) data collected with Ag-Ag/Cl measurement electrodes (BIOPAC, diameter of 2 cm). [Results] The comparison showed significant differences of Hmax/Mmax ratio (%) in all gait cycles between the stroke group and the control group. [Conclusion] In conclusion, this study furnished basic reference data for gait strategies and functional training programs for hemiplegic stroke patients.


Assessing the Food Safety Risk Posed by Birds Entering Leafy Greens Fields in the US Southwest.
In the US Southwest, it is common to observe birds in leafy green fields, though the risk they contribute to foodborne outbreaks remains unclear. In this study, we investigated and recorded the relationship between birds near leafy green fields and the risk for contaminated irrigation water or leafy green plants. We monitored the presence of birds for over two years and performed cloacal swab analysis for non-pathogenic Escherichia coli, E. coli O157:H7 and Salmonellaenterica, while also monitoring the incidence of other microbial indicators. We also assessed the risks from bird feces by performing observations in a commercial field reported with Salmonella positive samples and by analyzing the survival of foodborne pathogens in bird feces. Our results showed that most of the birds near the crop fields were resident small birds. We did not observe a correlation between the number of birds in sites and the incidence of indicator bacteria (e.g., coliforms, E. coli) in irrigation canal water, with the exception of one out of four sites where water flow was low or stagnant. Using walk-in-traps, 305 birds were captured and placed in short-term captivity to determine the presence of various bacteria. None of the birds tested positive for E. coli O157:H7 or Salmonella. However, nearly 40% of the birds captured were confirmed positive for non-pathogenic E. coli. We found no correlation between age (young, adult, unknown), gender (male, female, unknown) and the incidence of E. coli positive birds, but we observed significantly higher probability of incidence during October-December. The role of relative humidity and temperature on bacterial survival appeared to play a key role in the survival of Salmonella on the leaves of spinach plants in a commercial field. This was also confirmed in laboratory conditions where Salmonella inoculated in bird feces and exposed to 15 °C and 80% RH(Relative humidity) survived beyond 133 days, while at 26 °C and 40% RH, the organism was undetectable after 63 days. Our results suggest that local birds associated with leafy green fields likely pose a minimal impact of risk for food contamination, but also points out the need for increased analysis specifically for E. coli O157:H7. Furthermore, our study suggests the need for expanding research that addresses risks associated with large migratory birds, especially in areas where stagnated water sources would be used for overhead sprinkle irrigation.


Circadian rhythms in microorganisms: new complexities.
Recent advances in understanding circadian (daily) rhythms in the genera Neurospora, Gonyaulax, and Synechococcus are reviewed and new complexities in their circadian systems are described. The previous model, consisting of a unidirectional flow of information from input to oscillator to output, has now expanded to include multiple input pathways, multiple oscillators, multiple outputs; and feedback from oscillator to input and output to oscillator. New posttranscriptional features of the frq/white-collar oscillator (FWC) of Neurospora are described, including protein phosphorylation and degradation, dimerization, and complex formation. Experimental evidence is presented for frq-less oscillator(s) (FLO) downstream of the FWC. Mathematical models of the Neurospora system are also discussed.


Implementation of an automated medication/supply distribution system.
In the summer of 1992, Carraway Methodist Medical Center implemented a computerized medication and supply distribution system from the pharmacy and central supply to the patient care units. Improved efficiency was achieved in the form of automatic billing, inventory control, decreased worked hours per patient day, and improved documentation. Regulatory requirements relating to narcotic distribution were simplified through technology eliminating manual counting, handwritten signatures, and manual record keeping. The impact from this change was cost effective, allowed more time at the bedside, provided easier access to pharmacy and central supply items, facilitated inventory control, and increased nursing productivity as well as increasing nursing satisfaction.


Towards quantitative condition assessment of biodiversity outcomes: Insights from Australian marine protected areas.
Protected area management effectiveness (PAME) evaluation is increasingly undertaken to evaluate governance, assess conservation outcomes and inform evidence-based management of protected areas (PAs). Within PAME, quantitative approaches to assess biodiversity outcomes are now emerging, where biological monitoring data are directly assessed against quantitative (numerically defined) condition categories (termed quantitative condition assessments). However, more commonly qualitative condition assessments are employed in PAME, which use descriptive condition categories and are evaluated largely with expert judgement that can be subject to a range of biases, such as linguistic uncertainty and overconfidence. Despite the benefits of increased transparency and repeatability of evaluations, quantitative condition assessments are rarely used in PAME. To understand why, we interviewed practitioners from all Australian marine protected area (MPA) networks, which have access to long-term biological monitoring data and are developing or conducting PAME evaluations. Our research revealed that there is a desire within management agencies to implement quantitative condition assessment of biodiversity outcomes in Australian MPAs. However, practitioners report many challenges in transitioning from undertaking qualitative to quantitative condition assessments of biodiversity outcomes, which are hampering progress. Challenges include a lack of agency capacity (staff numbers and money), knowledge gaps, and diminishing public and political support for PAs. We point to opportunities to target strategies that will assist agencies overcome these challenges, including new decision support tools, approaches to better finance conservation efforts, and to promote more management relevant science. While a single solution is unlikely to achieve full evidence-based conservation, we suggest ways for agencies to target strategies and advance PAME evaluations toward best practice.


Results From a Virtual Clinic for the Follow-up of Patients Using the Advanced Hybrid Closed-Loop System.
Evidence regarding the implementation of medium-term strategies in advanced hybrid closed-loop (AHCL) system users is limited. Therefore, this study aimed to describe the efficacy and safety of the AHCL system in patients with type 1 diabetes (T1D) on a six-month follow-up in a virtual diabetes clinic (VDC). A prospective cohort of adult patients with T1D treated using the AHCL system (Mini Med 780G; Medtronic, Northridge, California) in a VDC follow-up. Standardized training and follow-up were conducted virtually. Clinical data and metabolic control outcomes were reported at baseline, and at three and six months. Sixty-four patients (mean age = 42 ± 14.6 years, 65% men, 54% with graduate education) were included. Percentage time in range (%TIR) increased significantly regardless of prior therapy with intermittently scanned continuous glucose monitoring + multiple daily injections and sensor-augmented pump therapy with predictive low-glucose management after starting AHCL and persisted during the follow-up period with no hypoglycemic events. The %TIR 70 to 180 mg/dL according to socioeconomic strata was 73.4% ± 5.3%, 78.1% ± 8.1%, and 84.2% ± 7.5% for the lower, middle, and upper strata, respectively. The sensor was used more frequently in the population with a higher education level. Adherence to sensor use and SmartGuard retention were higher in patients who underwent the VDC follow-up. Medium-term follow-up of users of AHCL systems in a VDC contributes to safely achieving %TIR goals. Virtual diabetes clinic follow-up favored adherence to sensor use and continuous SmartGuard use. Socioeconomic strata were associated with a better glycemic profile and education level was associated with better adherence to sensor use.


Functional analyses of vertebrate TCF proteins in C. elegans embryos.
In the canonical Wnt pathway, signaling results in the stabilization and increased levels of β-catenin in responding cells. β-catenin then enters the nucleus, functioning as a coactivator for the Wnt effector, TCF/LEF protein. In the absence of Wnt signaling, TCF is complexed with corepressors, together repressing Wnt target genes. In C. elegans, Wnt signaling specifies the E blastomere to become the endoderm precursor. Activation of endoderm genes in E requires not only an increase in β-catenin level, but a concomitant decrease in the nuclear level of POP-1, the sole C. elegans TCF. A decrease in nuclear POP-1 levels requires Wnt-induced phosphorylation of POP-1 and 14-3-3 protein-mediated nuclear export. Nuclear POP-1 levels remain high in the sister cell of E, MS, where POP-1 represses the expression of endoderm genes. Here we express three vertebrate TCF proteins (human TCF4, mouse LEF1 and Xenopus TCF3) in C. elegans embryos and compare their localization, repression and activation functions to POP-1. All three TCFs are localized to the nucleus in C. elegans embryos, but none undergoes Wnt-induced nuclear export. Although unable to undergo Wnt-induced nuclear export, human TCF4, but not mouse LEF1 or Xenopus TCF3, can repress endoderm genes in MS, in a manner very similar to POP-1. This repressive activity requires that human TCF4 recognizes specific promoter sequences upstream of endoderm genes and interacts with C. elegans corepressors. Domain swapping identified two regions of POP-1 that are sufficient to confer nuclear asymmetry to human TCF4 when swapped with its corresponding domains. Despite undergoing Wnt-induced nuclear export, the human TCF4/POP-1 chimeric protein continues to function as a repressor for endoderm genes in E, a result we attribute to the inability of hTCF4 to bind to C. elegans β-catenin. Our results reveal a higher degree of species specificity among TCF proteins for coactivator interactions than for corepressor interactions, and uncover a basic difference between how POP-1 and human TCF4 steady state nuclear levels are regulated.


[Development of PCR methods and their applications in oncological research and practice].
Since its discovery, PCR has become a conventional method of molecular biology research laboratories and an indispensable tool in diagnostic medicine. Multiple variants of the PCR technique were developed, which enable the analysis of different bio-logical materials at different amounts and reaction conditions. This article briefly summarizes the PCR approaches and points out their applications in oncological research and practice.


The middle interhemispheric variant of holoprosencephaly: magnetic resonance and diffusion tensor imaging findings.
The middle interhemispheric (MIH) variant of holoprosencephaly (HPE) is the incomplete separation of midline cerebral hemispheres with the absence of callosal body. We aimed to describe the additional knowledge of diffusion tensor imaging (DTI) over conventional MRI in the evaluation of patients with MIH variant of HPE. Conventional MRI and DTI data of five patients were retrospectively evaluated. The parenchymal anomalies as well as changes at white matter tracts were systematically reviewed. Except the callosal body and central cingulum fibres, which were missing in all patients, all other major white matter tracts (superior and inferior longitudinal, superior and inferior fronto-occipital, subcallosal and uncinate fasciculi and anterior commissure) had a normal course, thickness and integrity on diffusion tensor images. The genial and splenial callosal fibres were altered and rarefied on tractography. All patients had a central ventricular notch extending into the non-cleaved heterotopic grey matter involving the body of the corpus callosum, which is very typical for the MIH variant of HPE. The remnant traversing white matter fibres above the non-cleaved heterotopic grey matter and incomplete partition of the interhemispheric fissure were also identified. No Probst bundles were detected. A single common ventricle without the septum pellucidum was noted in all patients. One patient had incomplete partition of the thalami, and two patients had abnormally oriented thalami without any prominent interthalamic connection. Vertically oriented hippocampi were detected in four out of five patients. Three patients had relatively flat and vertically oriented Sylvian fissures and in two patients, fissures were abnormally connected over the vertex. Additional DTI findings can not only clearly reveal the white matter alterations better than conventional MRI but also provide a better understanding of the aetiological changes that cause the MIH variant of HPE. DTI can provide a better analysis of cerebral white matter connectivity and promotes understanding of the underlying microstructural changes that occur in patients with the MIH variant of HPE.


Lower cost strategies for triage of human papillomavirus DNA-positive women.
Using human papillomavirus (HPV) testing for cervical cancer screening in lower-resource settings (LRS) will result in a significant number of screen-positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV-positive women in LRS. This was a population-based study of women aged 25-65 years living in China (n = 7,541). Each woman provided a self-collected and two clinician-collected specimens. The self-collected and one clinician-collected specimen were tested by two HPV DNA tests-careHPV™ and Hybrid Capture 2; the other clinician-collected specimen was tested for HPV16/18/45 E6 protein. CareHPV™-positive specimens were tested for HPV16/18/45 DNA. HPV DNA-positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA-positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8-17.4% for VIA, 17.8-20.9% for an abnormal colposcopic impression; 7.9-10.5% for HPV16/18/45 E6; 23.4-28.4% for HPV16/18/45 DNA; and 48.0-62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA-positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.


Cytochrome P-450 ligands: metyrapone revisited.
Expressing metyrapone interactions with ferrous cytochrome P-450 as ligand saturation by cytochrome, rather than the more conventional cytochrome saturation by ligand, an extinction coefficient of 68.5 +/- 1.8 mM-1 cm-1 for the metyrapone complex of dithionite-reduced rat hepatic microsomal cytochrome P-450 was derived. Utilizing this new extinction coefficient, the increased cytochrome P-450 present after phenobarbital induction was almost exclusively that which is able to both bind to metyrapone and form a metabolic-intermediate complex from norbenzphetamine. However, it was not the only subpopulation present in microsomes that was able to bind metyrapone, nor the only one capable of forming a metabolic intermediate complex from norbenzphetamine. Thus, neither technique alone can be used to quantitate the "phenobarbital-induced form" of cytochrome P-450.


Preparation and properties of a coated slow-release and water-retention biuret phosphoramide fertilizer with superabsorbent.
In this investigation, a novel water-insoluble slow-release fertilizer, biuret polyphosphoramide (BPAM), was formulated and synthesized from urea, phosphoric acid (H(3)PO(4)), and ferric oxide (Fe(2)O(3)). The structure of BPAM was characterized by Fourier transform infrared (FTIR) spectroscopy. Subsequently, a coated slow-release BPAM fertilizer with superabsorbent was prepared by ionic cross-linked carboxymethylchitosan (the core), acrylic acid, acrylamide, and active carbon (the coating). The variable influences on the water absorbency were investigated and optimized. Component analysis results showed that the coated slow-release BPAM contained 5.66% nitrogen and 11.7% phosphorus. The property of water retention, the behavior of slow release of phosphorus, and the capacity of adsorption of cations were evaluated, and the results revealed that the product not only had good slow-release property and excellent water retention capacity but also higher adsorption capacities of cations in saline soil.


Bacteriological survey of fresh pork sausage produced at establishments under Federal inspection.
At the time of manufacture, 75% of 67 sets of finished fresh pork sausage collected in 44 plants had aerobic plate counts in the range of 500,000 or fewer/g; 88% contained 100 or fewer E. coli/g; and 75% contained 100 or fewer S. aureus/g (geometric means of 10 samples). Salmonellae were isolated from 28% of 529 samples of pork trimmings used for sausage, and from 28% of 560 finished sausage samples. Semiquantitative analysis revealed that salmonellae were at low levels; more than 80% of the salmonellae-positive samples were positive only in 25-g portions (negative in 1.0- and 0.1-g portions).


Glycogen-fuelled metabolism supports rapid mucosal-associated invariant T cell responses.
Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells which recognize a limited repertoire of ligands presented by the MHC class-I like molecule MR1. In addition to their key role in host protection against bacterial and viral pathogens, MAIT cells are emerging as potent anti-cancer effectors. With their abundance in human, unrestricted properties, and rapid effector functions MAIT cells are emerging as attractive candidates for immunotherapy. In the current study, we demonstrate that MAIT cells are potent cytotoxic cells, rapidly degranulating and inducing target cell death. Previous work from our group and others has highlighted glucose metabolism as a critical process for MAIT cell cytokine responses at 18 h. However, the metabolic processes supporting rapid MAIT cell cytotoxic responses are currently unknown. Here, we show that glucose metabolism is dispensable for both MAIT cell cytotoxicity and early (<3 h) cytokine production, as is oxidative phosphorylation. We show that MAIT cells have the machinery required to make (GYS-1) and metabolize (PYGB) glycogen and further demonstrate that that MAIT cell cytotoxicity and rapid cytokine responses are dependent on glycogen metabolism. In summary, we show that glycogen-fueled metabolism supports rapid MAIT cell effector functions (cytotoxicity and cytokine production) which may have implications for their use as an immunotherapeutic agent.


A dynamic mathematical model to clarify signaling circuitry underlying programmed cell death control in Arabidopsis disease resistance.
Plant cells undergo programmed cell death in response to invading pathogens. This cell death limits the spread of the infection and triggers whole plant antimicrobial and immune responses. The signaling network connecting molecular recognition of pathogens to these responses is a prime target for manipulation in genetic engineering strategies designed to improve crop plant disease resistance. Moreover, as alterations to metabolism can be misinterpreted as pathogen infection, successful plant metabolic engineering will ultimately depend on controlling these signaling pathways to avoid inadvertent activation of cell death. Programmed cell death resulting from infection of Arabidopsis thaliana with Pseudomonas syringae bacterial pathogens was chosen as a model system. Signaling circuitry hypotheses in this model system were tested by construction of a differential-equations-based mathematical model. Model-based simulations of time evolution of signaling components matched experimental measurements of programmed cell death and associated signaling components obtained in a companion study. Simulation of systems-level consequences of mutations used in laboratory studies led to two major improvements in understanding of signaling circuitry: (1) Simulations supported experimental evidence that a negative feedback loop in salicylic acid biosynthesis postulated by others does not exist. (2) Simulations showed that a second negative regulatory circuit for which there was strong experimental support did not affect one of two pathways leading to programmed cell death. Simulations also generated testable predictions to guide future experiments. Additional testable hypotheses were generated by results of individually varying each model parameter over 2 orders of magnitude that predicted biologically important changes to system dynamics. These predictions will be tested in future laboratory studies designed to further elucidate the signaling network control structure.


Social context has differential effects on acquisition of nicotine self-administration in male and female rats.
Smoking typically begins during adolescence or early adulthood in a social context, yet the role of social context in animal models is poorly understood. The present study examined the effect of social context on acquisition of nicotine self-administration. Sixty-day-old male and female Sprague-Dawley rats were trained to press a lever for nicotine (0.015 mg/kg, IV) or saline infusions (males only) on a fixed ratio (FR1) schedule of reinforcement across nine sessions in duplex chambers that were conjoined with either a solid wall or a wall containing wire mesh creating a social context between rat dyads (social visual, auditory, and olfactory cues). In a subsequent experiment, sex differences and dose-dependent effects of nicotine [0 (saline), 0.015 or 0.03 mg/kg, IV] were directly compared in rats trained in the isolated or social context on a schedule progressing from FR1 to FR3. These rats were given 20 sessions followed by 3 extinction sessions. We consistently found transient social facilitation of low-dose nicotine self-administration in males during the first session. However, across training overall, we found social suppression of nicotine intake that was most prominent in females during later sessions. Collectively, these findings suggest that at the age of transition from adolescence to adulthood, a social context enhances the initial reinforcing effects of nicotine in males, but protects against nicotine intake during later sessions especially in females. These findings highlight the importance of sex and social context in studying neural mechanisms involved in initiation of nicotine use.


[Interaction of oligonucleotides and ATP with preparations of sIgA possessing protein kinase activity].
Interaction of secretory immunoglobulins A of a varying degree of purity with oligonucleotides and ATP has been studied by the method of affinity modification. For this aim we used reactive derivatives of 32P-labeled deoxyoligonucleotide (ClRCH2NHp(T)14) and [gamma-32P]ATP (ClR-32PppA) or ATP (ClR-pppA) bearing a 4-[(N-2-chloroethyl-N-methyl)amino]benzylamine residue. Preparations of sIgA were obtained from human milk by sequential chromatography on protein A-sepharose (P1), DEAE-fractogel (P2) and by gel-filtration in 50 mM NaOH (P3). It was revealed, that the H- and L-chains of sIgA P1; H-, L-chains and secretory component (SC) in sIgA P2 and only SC in sIgA P3 were exposed to modification after incubation with ClRCH2NHp(T)14. LPS, DNA, tRNA, heparin, sufficiently inhibited the modification of chains of sIgA P1. These competitors did not influence the modification of H- and L-chains of sIgA P2, but DNA, tRNA, heparin, inhibited binding of SC with the modifier. Suppressing affect of binding of ClRCH2NHp(T)14 with secretory component of sIgA P3 by d(T)14 has been observed as well. The research of ClR-32PppA interaction with sIgA P3 has shown that H- and L-chains of sIgA are exposed to modification. ATP inhibited the reaction. Study of the influence of modification on the protein kinase activity of sIgA P3 has revealed, that the preliminary incubation of sIgA P3 with ClR-pppA leads to inhibition of protein kinase activity. We suggest that sIgA, possessing the protein kinase activity (sIgA-abzymes) has an ATP-binding center (catalytic center) and has an oligonucleotide-binding center as well.


The fbpABC locus of Neisseria gonorrhoeae functions in the periplasm-to-cytosol transport of iron.
We have determined that the DNA sequence downstream of the well-characterized gonococcal fbp gene contains two open reading frames: one designated fbpB, which encodes a protein proposed to function as a cytoplasmic permease, and one designated fbpC, which encodes a protein proposed to function as a nucleotide-binding protein. The fpbABC operon composes an iron transport system that is homologous to the sfu and hit operons previously reported for Serratia marcescens and Haemophilus influenzae, respectively, and displays elements characteristic of ATP binding cassette transporters. The fpbABC operon differs from these loci in that it is lethal when overexpressed in Escherichia coli.


Real-Time Genomics for Tracking Severe Acute Respiratory Syndrome Coronavirus 2 Border Incursions after Virus Elimination, New Zealand.
Since severe acute respiratory syndrome coronavirus 2 was first eliminated in New Zealand in May 2020, a total of 13 known coronavirus disease (COVID-19) community outbreaks have occurred, 2 of which led health officials to issue stay-at-home orders. These outbreaks originated at the border via isolating returnees, airline workers, and cargo vessels. Because a public health system was informed by real-time viral genomic sequencing and complete genomes typically were available within 12 hours of community-based positive COVID-19 test results, every outbreak was well-contained. A total of 225 community cases resulted in 3 deaths. Real-time genomics were essential for establishing links between cases when epidemiologic data could not do so and for identifying when concurrent outbreaks had different origins.


Personality and substance use disorders in young adults.
There have been no studies of the co-occurrence of personality and substance use disorders in young community-dwelling adults. To examine the association between DSM-IV personality disorders and substance use disorders in a large representative sample of young community-dwelling participants. Young Australian adults (n=1520, mean age=24.1 years) were interviewed to determine the prevalence of substance use disorders; 1145 also had an assessment for personality disorder. The prevalence of personality disorder was 18.6% (95% CI 16.5-20.7). Personality disorder was associated with indices of social disadvantage and the likely presence of common mental disorders. Independent associations were found between cluster B personality disorders and substance use disorders. There was little evidence for strong confounding or mediating effects of these associations. In young adults, there are independent associations between cluster B personality disorders and substance use disorders.


Inverted Regulation of Multidrug Efflux Pumps, Acid Resistance, and Porins in Benzoate-Evolved Escherichia coli K-12.
Benzoic acid, a partial uncoupler of the proton motive force (PMF), selects for sensitivity to chloramphenicol and tetracycline during the experimental evolution of Escherichia coli K-12. Transcriptomes of E. coli isolates evolved with benzoate showed the reversal of benzoate-dependent regulation, including the downregulation of multidrug efflux pump genes, the gene for the Gad acid resistance regulon, the nitrate reductase genes narHJ, and the gene for the acid-consuming hydrogenase Hyd-3. However, the benzoate-evolved strains had increased expression of OmpF and other large-hole porins that admit fermentable substrates and antibiotics. Candidate genes identified from benzoate-evolved strains were tested for their roles in benzoate tolerance and in chloramphenicol sensitivity. Benzoate or salicylate tolerance was increased by deletion of the Gad activator ariR or of the acid fitness island from slp to the end of the gadX gene encoding Gad regulators and the multidrug pump genes mdtEF Benzoate tolerance was also increased by deletion of multidrug component gene emrA, RpoS posttranscriptional regulator gene cspC, adenosine deaminase gene add, hydrogenase gene hyc (Hyd-3), and the RNA chaperone/DNA-binding regulator gene hfq Chloramphenicol resistance was decreased by mutations in genes for global regulators, such as RNA polymerase alpha subunit gene rpoA, the Mar activator gene rob, and hfq Deletion of lipopolysaccharide biosynthetic kinase gene rfaY decreased the rate of growth in chloramphenicol. Isolates from experimental evolution with benzoate had many mutations affecting aromatic biosynthesis and catabolism, such as aroF (encoding tyrosine biosynthesis) and apt (encoding adenine phosphoribosyltransferase). Overall, benzoate or salicylate exposure selects for the loss of multidrug efflux pumps and of hydrogenases that generate a futile cycle of PMF and upregulates porins that admit fermentable nutrients and antibiotics.IMPORTANCE Benzoic acid is a common food preservative, and salicylic acid (2-hydroxybenzoic acid) is the active form of aspirin. At high concentrations, benzoic acid conducts a proton across the membrane, depleting the proton motive force. In the absence of antibiotics, benzoate exposure selects against proton-driven multidrug efflux pumps and upregulates porins that admit fermentable substrates but that also allow the entry of antibiotics. Thus, evolution with benzoate and related molecules, such as salicylates, requires a trade-off for antibiotic sensitivity, a trade-off that could help define a stable gut microbiome. Benzoate and salicylate are naturally occurring plant signal molecules that may modulate the microbiomes of plants and animal digestive tracts so as to favor fermenters and exclude drug-resistant pathogens.


Skeletal effects of long-term caloric restriction in rhesus monkeys.
Age-related bone loss is well established in humans and is known to occur in nonhuman primates. There is little information, however, on the effect of dietary interventions, such as caloric restriction (CR), on age-related bone loss. This study examined the effects of long-term, moderate CR on skeletal parameters in rhesus monkeys. Thirty adult male rhesus monkeys were subjected to either a restricted (R, n = 15) or control (C, n = 15) diet for 20 years and examined throughout for body composition and biochemical markers of bone turnover. Total body, spine, and radius bone mass and density were assessed by dual-energy X-ray absorptiometry. Assessment of biochemical markers of bone turnover included circulating serum levels of osteocalcin, carboxyterminal telopeptide of type I collagen, cross-linked aminoterminal telopeptide of type I collagen, parathyroid hormone, and 25(OH)vitamin D. Overall, we found that bone mass and density declined over time with generally higher levels in C compared to R animals. Circulating serum markers of bone turnover were not different between C and R with nonsignficant diet-by-time interactions. We believe the lower bone mass in R animals reflects the smaller body size and not pathological osteopenia.


Phytosulfokine peptide optimizes plant growth and defense via glutamine synthetase GS2 phosphorylation in tomato.
Phytosulfokine (PSK) is a plant pentapeptide hormone that fulfills a wide range of functions. Although PSK has frequently been reported to function in the inverse regulation of growth and defense in response to (hemi)biotrophic pathogens, the mechanisms involved remain largely unknown. Using the tomato (Solanum lycopersicum) and Pseudomonas syringae pv. tomato (Pst) DC3000 pathogen system, we present compelling evidence that the PSK receptor PSKR1 interacts with the calcium-dependent protein kinase CPK28, which in turn phosphorylates the key enzyme of nitrogen assimilation glutamine synthetase GS2 at two sites (Serine-334 and Serine-360). GS2 phosphorylation at S334 specifically regulates plant defense, whereas S360 regulates growth, uncoupling the PSK-induced effects on defense responses and growth regulation. The discovery of these sites will inform breeding strategies designed to optimize the growth-defense balance in a compatible manner.


[Immunologic aspects to the prevention of infection cardiac surgery (author's transl)].
1. The humoral immunosystem is impaired in those cases of catabolic metabolism in which quantitative and qualitative insufficient alimentation is expected after operation. 2. We showed that after cardiac surgery with extracorporal circulation as well as after other operations a reasonably balanced parenteral nutrition composed of carbohydrates and amino acids could considerably inhibit the changes in the humoral immunity, which is a valuable contribution to the prevention of infection. 3. In our experiments on transformation of lymphocytes after mitogenic stimulation, the depressive effects of operation on the cellular immunity were found to be etiologically more complex than was previously assumed in publications.


Comparison of enhancement quantification from virtual unenhanced images to true unenhanced images in multiphase renal Dual-Energy computed tomography: A phantom study.
Multiphase computed tomography (CT) exams are a commonly used imaging technique for the diagnosis of renal lesions and involve the acquisition of a true unenhanced (TUE) series followed by one or more postcontrast series. The difference in CT number of the mass in pre- and postcontrast images is used to quantify enhancement, which is an important criterion used for diagnosis. This study sought to assess the feasibility of replacing TUE images with virtual unenhanced (VUE) images derived from Dual-Energy CT datasets in renal CT exams. Eliminating TUE image acquisition could reduce patient dose and improve clinical efficiency. A rapid kVp-switching CT scanner was used to assess enhancement accuracy when using VUE compared to TUE images as the baseline for enhancement calculations across a wide range of clinical scenarios simulated in a phantom study. Three phantoms were constructed to simulate small, medium, and large patients, each with varying lesion size and location. Nonenhancing cystic lesions were simulated using distilled water. Intermediate (10-20 HU [Hounsfield units]) and positively enhancing masses (≥20 HU) were simulated by filling the spherical inserts in each phantom with varied levels of iodinated contrast mixed with a blood surrogate. The results were analyzed using Bayesian hierarchical models. Posterior probabilities were used to classify enhancement measured using VUE compared to TUE images as significantly less, not significantly different, or significantly higher. Enhancement measured using TUE images was considered the ground truth in this study. For simulation of nonenhancing renal lesions, enhancement values were not significantly different when using VUE versus TUE images, with posterior probabilities ranging from 0.23-0.56 across all phantom sizes and an associated specificity of 100%. However, for simulation of intermediate and positively enhancing lesions significant differences were observed, with posterior probabilities < 0.05, indicating significantly lower measured enhancement when using VUE versus TUE images. Positively enhancing masses were categorized accurately, with a sensitivity of 91.2%, when using VUE images as the baseline. For all scenarios where iodine was present, VUE-based enhancement measurements classified lesions with a sensitivity of 43.2%, a specificity of 100%, and an accuracy of 78.1%. Enhancement calculated using VUE images proved to be feasible for classifying nonenhancing and highly enhancing lesions. However, differences in measured enhancement for simulation of intermediately enhancing lesions demonstrated that replacement of TUE with VUE images may not be advisable for renal CT exams.


Survey of renewable chemicals produced from lignocellulosic biomass during ionic liquid pretreatment.
Lignin is often overlooked in the valorization of lignocellulosic biomass, but lignin-based materials and chemicals represent potential value-added products for biorefineries that could significantly improve the economics of a biorefinery. Fluctuating crude oil prices and changing fuel specifications are some of the driving factors to develop new technologies that could be used to convert polymeric lignin into low molecular weight lignin and or monomeric aromatic feedstocks to assist in the displacement of the current products associated with the conversion of a whole barrel of oil. We present an approach to produce these chemicals based on the selective breakdown of lignin during ionic liquid pretreatment. The lignin breakdown products generated are found to be dependent on the starting biomass, and significant levels were generated on dissolution at 160°C for 6 hrs. Guaiacol was produced on dissolution of biomass and technical lignins. Vanillin was produced on dissolution of kraft lignin and eucalytpus. Syringol and allyl guaiacol were the major products observed on dissolution of switchgrass and pine, respectively, whereas syringol and allyl syringol were obtained by dissolution of eucalyptus. Furthermore, it was observed that different lignin-derived products could be generated by tuning the process conditions. We have developed an ionic liquid based process that depolymerizes lignin and converts the low molecular weight lignin fractions into a variety of renewable chemicals from biomass. The generated chemicals (phenols, guaiacols, syringols, eugenol, catechols), their oxidized products (vanillin, vanillic acid, syringaldehyde) and their easily derivatized hydrocarbons (benzene, toluene, xylene, styrene, biphenyls and cyclohexane) already have relatively high market value as commodity and specialty chemicals, green building materials, nylons, and resins.


[Spanish adaptation of the disease-specific questionnaire MSQOL-54 in multiple sclerosis patients].
The Multiple Sclerosis Quality of Life 54 (MSQOL-54) is a health-related quality of life specific questionnaire for multiple sclerosis (MS) patients. The objective of this study was to develop the Spanish version of the MSQOL-54 and to obtain a conceptually equivalent version to the original one for its use in patients with MS in the first phase of the project. A transcultural adaptation procedure was designed according to the following phases: a) two independent translations made by bilingual native Spanish speaking translators (forward translation); b) a revision of the items by an expert panel; c) a back translation by a bilingual native English speaking person; d) comparison with the original version (expert panel and advise by the original authors), and e) cognitive debriefing (interviews with subjects with MS) to test the comprehension and feasibility of the instrument. Ten interviews were carried out with 5 men and 5 women with MS, aged 21 to 54 years, with different education levels and EDSS scores ranging from 1,0 to 8,0. Most of the patients found the questionnaire easy to fill out and the understanding favorable. Only one item (item 51) was modified after the cognitive debriefing to improve its comprehension. Finally, a final pretest version was obtained. The procedure carried out maximizes the conceptual equivalence between the original MSQOL-54 and the translated version and shows that the Spanish pre-test version is comprehensible and its administration feasible in patients with MS. The psychometric properties must be evaluated in the next phase of the project.


Distributive justice in American healthcare: institutions, power, and the equitable care of patients.
The authors argue that the American healthcare system has developed in a fashion that permits and may support ongoing, widespread inequities based on poverty, race, gender, and ethnicity. Institutional structures also contribute to this problem. Analysis is based on (1) discussions of a group of experts convened by the Office of Minority Health, US Department of Health and Human Services at a conference to address healthcare disparities; and (2) review of documentation and scientific literature focused on health, health-related news, language, healthcare financing, and the law. Institutional factors contributing to inequity include the cost and financing of American healthcare, healthcare insurance principles such as mutual aid versus actuarial fairness, and institutional power. Additional causes for inequity are bias in decision making by healthcare practitioners, clinical training environments linked to abuse of patients and coworkers, healthcare provider ethnicity, and politics. Recommendations include establishment of core attributes of trust, relationship and advocacy in health systems; universal healthcare; and insurance systems based on mutual aid. In addition, monitoring of equity in health services and the development of a set of ethical principles to guide systems change and rule setting would provide a foundation for distributive justice in healthcare. Additionally, training centers should model the behaviors they seek to foster and be accountable to the communities they serve.


Thiazide diuretics in the treatment of hypertension: an update.
Thiazide diuretics were the first tolerated efficient antihypertensive drugs that significantly reduced cardiovascular morbidity and mortality in placebo-controlled clinical studies. Although these drugs today still are considered a fundamental therapeutic tool for the treatment of hypertensive patients, the following considerations should be taken into account. Although there are some indications that chlorthalidone can offer additional advantages as compared with other compounds, a recent meta-analysis of placebo-controlled trials suggested that the beneficial effects of thiazide diuretics could be a class effect. Thiazide diuretics must be used at appropriate and/or optimal doses to achieve the optimal antihypertensive effect with the smallest occurrence of side effects, including alterations in glucose and lipid profiles and hypokalemia. Moreover, because thiazide diuretics can increase the incidence of new-onset diabetes, especially when combined with beta blockers, caution is advised in using these drugs above all in patients who are at high risk for developing diabetes, in whom thiazide diuretics should be used at the lowest active dose and possibly in combination with drugs that block the renin-angiotensin system. Finally, the current debate on whether thiazide diuretics are the first-choice drug for most patients with uncomplicated hypertension, as stated in the Seventh Joint National Committee Report, or are included in the major classes of antihypertensive agents that are suitable for initiation and maintenance of therapy, as reported in the European Society of Hypertension-European Society of Cardiology Guidelines, derives from different interpretations of controlled clinical trial data on drug class comparison and of cost-benefit analyses. However, considering that the benefit of antihypertensive drugs seems to be due principally to BP lowering per se without definitive evidence of the superiority of a particular drug class and that there is no cost-benefit analysis showing the superiority of thiazide diuretics, it is believed that these drugs should not be considered as the only first-choice drug but included among first-choice drugs.


Calibrated variability of muscle sympathetic nerve activity during graded head-up tilt in humans and its link with noradrenaline data and cardiovascular rhythms.
Muscle sympathetic nerve activity (MSNA) variability is traditionally computed through a low-pass filtering procedure that requires normalization. We proposed a new beat-to-beat MSNA variability computation that preserves dimensionality typical of an integrated neural discharge (i.e., bursts per unit of time). The calibrated MSNA (cMSNA) variability technique is contrasted with the traditional uncalibrated MSNA (ucMSNA) version. The powers of cMSNA and ucMSNA variabilities in the low-frequency (LF, from 0.04 to 0.15 Hz) band were computed with those of the heart period (HP) of systolic and diastolic arterial pressure (SAP and DAP, respectively) in seven healthy subjects (age, 20-28 years; median, 22 years; 5 women) during a graded head-up tilt. Subjects were sequentially tilted at 0°, 20°, 30°, 40°, and 60° table inclinations. The LF powers of ucMSNA and HP variabilities were expressed in normalized units (LFnu), whereas all remaining spectral markers were expressed in absolute units. We found that 1) the LF power of cMSNA variability was positively correlated with tilt angle, whereas the LFnu power of the ucMSNA series was uncorrelated; 2) the LF power of cMSNA variability was correlated with LF powers of SAP and DAP, LFnu power of HP and noradrenaline concentration, whereas the relationship of the LFnu power of ucMSNA variability to LF powers of SAP and DAP was weaker and that to LFnu power of HP was absent; and 3) the stronger relationship of cMSNA variability to SAP and DAP spectral markers compared with the ucMSNA series was confirmed individually. The cMSNA variability appears to be more suitable in describing sympathetic control in humans than traditional ucMSNA variability.


Characterization of the mouse lysosomal sialidase promoter.
Lysosomal sialidase is required for the catabolism of sialoglycoconjugates such as gangliosides and deficiency in this enzyme results in the autosomal recessive disease sialidosis. Furthermore, we have shown that overexpression of human sialidase is sufficient to clear accumulated ganglioside in Tay-Sachs neuroglia [Hum. Mol. Genet. 8 (1999) 1111]. In this paper, we have characterized the 5' regulatory region of the mouse lysosomal sialidase gene in order to understand the molecular mechanisms regulating its expression. We used bioinformatic approaches to identify a transcriptional initiation site at -45 bp relative to the ATG and significant sequence homology with the rat and human promoters. Expression by the promoter was found to be cell-type restricted and required at least 750 bp upstream of the ATG for high-level expression. DNAse I footprinting analysis and reporter gene assays indicated that the promoter is responsive to Sp-1. We discovered a CCAAT box and four E-boxes within the mouse upstream region and demonstrated that CCAAT displacement protein as well as the muscle regulatory factors MyoD and Myf-5 influence sialidase expression. Taken together, these results identify cis- and trans-acting factors involved in the regulation of sialidase and point to mechanisms of gene upregulation.


Human Leukocyte Antigen (HLA) A*1101-Restricted Epstein-Barr Virus-Specific T-cell Receptor Gene Transfer to Target Nasopharyngeal Carcinoma.
Infusing virus-specific T cells is effective treatment for rare Epstein-Barr virus (EBV)-associated posttransplant lymphomas, and more limited success has been reported using this approach to treat a far more common EBV-associated malignancy, nasopharyngeal carcinoma (NPC). However, current approaches using EBV-transformed lymphoblastoid cell lines to reactivate EBV-specific T cells for infusion take 2 to 3 months of in vitro culture and favor outgrowth of T cells targeting viral antigens expressed within EBV(+) lymphomas, but not in NPC. Here, we explore T-cell receptor (TCR) gene transfer to rapidly and reliably generate T cells specific for the NPC-associated viral protein LMP2. We cloned a human leukocyte antigen (HLA) A*1101-restricted TCR, which would be widely applicable because 40% of NPC patients carry this HLA allele. Studying both the wild-type and modified forms, we have optimized expression of the TCR and demonstrated high-avidity antigen-specific function (proliferation, cytotoxicity, and cytokine release) in both CD8(+) and CD4(+) T cells. The engineered T cells also inhibited LMP2(+) epithelial tumor growth in a mouse model. Furthermore, transduced T cells from patients with advanced NPC lysed LMP2-expressing NPC cell lines. Using this approach, within a few days large numbers of high-avidity LMP2-specific T cells can be generated reliably to treat NPC, thus providing an ideal clinical setting to test TCR gene transfer without the risk of autoimmunity through targeting self-antigens.


HPTLC based approach for bioassay-guided evaluation of antidiabetic and neuroprotective effects of eight essential oils of the Lamiaceae family plants.
A high-performance thin-layer chromatography (HPTLC) method combined with effect-directed-analysis (EDA) was developed to screen the antioxidant, neuroprotective and antidiabetic effects in essential oils derived from lavender flower, lemon myrtle, oregano, peppermint, sage, and rosemary leaves (Lamiaceae family). HPTLC hyphenated with microchemical (DPPH•, p-anisaldehyde, and ferric chloride) derivatizations, was used to evaluate antioxidant activity, presence of phytosterols and terpenoids, and polyphenolic content, while the combination with biochemical (α-amylase and acetylcholine esterase (AChE) enzymatic) derivatizations was used to asses α-amylase and AChE inhibitory activities. The superior antioxidant activity of oregano leaf extract is attributed to the presence of high levels of aromatic compounds, like polyphenolic acids. The strongest α-amylase inhibition was observed in lemon myrtle and rosemary plus extracts due to the presence of monoterpenes. Rosemary and sage extracts exhibit the highest AChE inhibition activity, with 1 μL essential oils being more potent than the recommended daily dose of donepezil. This superior neuroprotection was attributed to the presences of di- and triterpenes that displayed strong AChE inhibition and antioxidant potential in DPPH• free radical assay. Antioxidant activity was related to phenolic content (R = 0.49), while α-amylase inhibitory activity was positively related to antioxidant activity (R = 0.20) and terpenoid/sterol content (R = 0.31). AChE inhibitory activity was correlated (R = 0.80) to the combined effect of phenolics and terpenoids. Thus, the superior AChE inhibitory and neuroprotection potential of rosemary and sage essential oils could be attributed to joint effects of main phenolic and terpene constituents. The hyphenated HPTLC method provided rapid bioanalytical profiling of highly complex essential oil samples.


Nano-engineered electro-responsive drug delivery systems.
Stimuli-responsive drug delivery systems can release therapeutic agents when actuated by an appropriate stimulus, whether endogenous or exogenous. Interestingly, exogenous stimuli are completely dissociated from the patient's physiology and can be precisely controlled externally in magnitude, in space, and in time. They can therefore constitute more reproducible means of controlling the release of therapeutics from appropriately responsive delivery systems. One stimulus which has long attracted attention is the application of an electric potential, and most electro-responsive drug delivery systems reported to date have been based on intrinsically conducting polymers. These systems, however, are limited by slow drug release and low drug loading. These challenges are currently driving the development of new electro-responsive delivery systems with higher responsiveness and drug loading, by implementing concepts of nano-engineering into their structure. This review will focus on this exciting and most recent direction taken in this field by first discussing drug delivery from electro-responsive films containing nano-scaled features, and then nanoscale dispersed/colloidal electro-responsive drug delivery systems, such as nanoparticles, micelles, and vesicular structures.


The Diagnostic Utility of RAS Q61R Mutation-specific Immunohistochemistry in Epithelial-Myoepithelial Carcinoma.
Epithelial-myoepithelial carcinoma (EMC) is a rare salivary gland cancer characterized by biphasic tubular structures composed of inner ductal and outer clear myoepithelial cells. Because of its histologic variety and overlap of histologic features with other salivary gland tumors, there are broad differential diagnoses. The HRAS Q61R mutation has been reported to be frequent in and specific to EMC. We evaluated the usefulness of RAS Q61R mutant-specific immunohistochemical (IHC) staining for detecting this genetic alteration in EMC. We investigated 83 EMC cases and 66 cases of salivary gland tumors with an EMC-like component, including pleomorphic adenoma, adenoid cystic carcinoma, basal cell adenoma/adenocarcinoma, and myoepithelial carcinoma. Sanger sequencing was performed for HRAS, KRAS, and NRAS. The diffuse and membranous/cytoplasmic RAS Q61R IHC expression was observed in 65% of EMC cases, in which all cases harbored the HRAS Q61R mutation. IHC-positive cases were present only in de novo EMCs (54/76 cases, 71%) but not in EMCs ex pleomorphic adenoma. The immunoreactivity was almost always restricted to the myoepithelial cells. Conversely, all EMC cases lacking the HRAS Q61R mutation were negative on IHC. In addition, only 3% of EMC-like tumors showed the abovementioned immunopositivity. None of the cases examined carried KRAS or NRAS mutations. IHC for RAS Q61R is highly sensitive and specific for detecting the HRAS Q61R mutation in EMC. Since significant immunopositivity was almost exclusively identified in nearly two thirds of EMCs but seldom in the histologic mimics, the IHC of RAS Q61R is a useful tool for diagnosing EMC in general pathology laboratories.


Metabolic profiles and lipoprotein lipid concentrations in non-obese and obese patients with polycystic ovarian disease.
Clinical parameters, androgen status and lipoprotein lipid profiles were assessed in 10 non-obese and 10 obese patients with polycystic ovarian disease (PCOD) and reference subjects matched for age, height and weight. Both obese and non-obese women with PCOD had significantly higher androgen levels when compared to the reference groups. When comparison of lipoprotein lipid profiles were made between groups, non-obese women with PCOD had significantly higher total cholesterol, triglycerides and LDL-cholesterol levels than non-obese reference subjects. Obese PCOD women manifested significantly higher total cholesterol, LDL-cholesterol, cholesterol/HDL, and LDL/HDL values than did obese reference subjects. Correlations between serum androgens and lipoprotein lipid concentrations in PCOD and normal women were unhelpful. Both non-obese and obese patients with PCOD had significantly higher systolic and diastolic blood pressures (BPs) than the reference groups. Thus, both non-obese and obese women with PCOD manifest hyperandrogenaemia which may result in a male pattern of lipoprotein lipid concentrations.


Public Health Regulations and Policies Dealing with Preparedness and Emergency Management: The Experience of the COVID-19 Pandemic in Italy.
Worldwide, the management of health emergencies requires a high degree of preparedness and resilience on the part of governments and health systems. Indeed, disasters are becoming increasingly common, with significant health, social, and economic impacts. Living in a globalized world also means that emergencies that occur in one country often have an international, in some cases global, spread: the COVID-19 pandemic is a cogent example. The key elements in emergency management are central governance, coordination, investment of resources before the emergency occurs, and preparedness to deal with it at all levels. However, several factors might condition the response to the emergency, highlighting, as for Italy, strengths and weaknesses. In this context, policies and regulation of actions to be implemented at international and national level must be up-to-date, clear, transparent and, above all, feasible and implementable. Likewise, the allocation of resources to develop adequate preparedness plans is critical. Due to COVID-19 pandemic, the European Commission proposed the temporary recovery instrument NextGenerationEU, as well as a targeted reinforcement of the European Union's long-term budget for the period 2021-2027. The pandemic highlighted that it is necessary to interrupt the continuous defunding of the health sector, allocating funds especially in prevention, training and information activities: indeed, a greater and more aware public attention on health risks and on the impacts of emergencies can help to promote virtuous changes, sharing contents and information that act as a guide for the population.


Electrographic predictors of successful weaning from anaesthetics in refractory status epilepticus.
Intravenous third-line anaesthetic agents are typically titrated in refractory status epilepticus to achieve either seizure suppression or burst suppression on continuous EEG. However, the optimum treatment paradigm is unknown and little data exist to guide the withdrawal of anaesthetics in refractory status epilepticus. Premature withdrawal of anaesthetics risks the recurrence of seizures, whereas the prolonged use of anaesthetics increases the risk of treatment-associated adverse effects. This study sought to measure the accuracy of features of EEG activity during anaesthetic weaning in refractory status epilepticus as predictors of successful weaning from intravenous anaesthetics. We prespecified a successful anaesthetic wean as the discontinuation of intravenous anaesthesia without developing recurrent status epilepticus, and a wean failure as either recurrent status epilepticus or the resumption of anaesthesia for the purpose of treating an EEG pattern concerning for incipient status epilepticus. We evaluated two types of features as predictors of successful weaning: spectral components of the EEG signal, and spatial-correlation-based measures of functional connectivity. The results of these analyses were used to train a classifier to predict wean outcome. Forty-seven consecutive anaesthetic weans (23 successes, 24 failures) were identified from a single-centre cohort of patients admitted with refractory status epilepticus from 2016 to 2019. Spectral components of the EEG revealed no significant differences between successful and unsuccessful weans. Analysis of functional connectivity measures revealed that successful anaesthetic weans were characterized by the emergence of larger, more densely connected, and more highly clustered spatial functional networks, yielding 75.5% (95% confidence interval: 73.1-77.8%) testing accuracy in a bootstrap analysis using a hold-out sample of 20% of data for testing and 74.6% (95% confidence interval 73.2-75.9%) testing accuracy in a secondary external validation cohort, with an area under the curve of 83.3%. Distinct signatures in the spatial networks of functional connectivity emerge during successful anaesthetic liberation in status epilepticus; these findings are absent in patients with anaesthetic wean failure. Identifying features that emerge during successful anaesthetic weaning may allow faster and more successful anaesthetic liberation after refractory status epilepticus.


Brain oscillations and Parkinson disease.
Brain oscillations have been associated with Parkinson's disease (PD) for a long time mainly due to the fundamental oscillatory nature of parkinsonian rest tremor. Over the years, this association has been extended to frequencies well above that of tremor, largely owing to the opportunities offered by deep brain stimulation (DBS) to record electrical activity directly from the patients' basal ganglia. This chapter reviews the results of research on brain oscillations in PD focusing on theta (4-7Hz), beta (13-35Hz), gamma (70-80Hz) and high-frequency oscillations (200-400Hz). For each of these oscillations, we describe localization and interaction with brain structures and between frequencies, changes due to dopamine intake, task-related modulation, and clinical relevance. The study of brain oscillations will also help to dissect the mechanisms of action of DBS. Overall, the chapter tentatively depicts PD in terms of "oscillopathy."


Air stable and highly efficient Bi3+-doped Cs2SnCl6 for blue light-emitting diodes.
Cs2SnCl6 perovskite has recently attracted attention as a promising optoelectronic material owing to its better stability and reduced toxicity than its lead counterparts. However, its luminescence performance hardly satisfies the requirements. Hence, a series of Bi3+-doped Cs2SnCl6 (Cs2SnCl6:Bi3+) with enhanced luminescence were synthesized by a solution-phase route. The results show that the initial concentration of Sn2+ can adjust the nucleation density and the quality of the crystal nucleus growth, which will affect the Bi3+ doping amount, crystal morphology, and photophysical properties of Cs2SnCl6:Bi3+. Cs2SnCl6:Bi3+ shows excellent stability in the atmosphere with a photoluminescence (PL) of around 456 nm and a photoluminescence quantum yield (PLQY) of 31%. The luminescence performance results from [BiSn4+ 3+ + VCl] defects caused by the Bi3+ doping. The blue LED based on the Cs2SnCl6:Bi3+ phosphor exhibits a long life of about 120 h and a Commission Internationale de L'Eclairage (CIE) color coordinates of (0.14, 0.11). This work demonstrates a strategy for Bi-doped perovskites with good stability. This investigation will facilitate the development of Cs2SnCl6:Bi3+ for blue LED applications.


Dissecting the association between migraine and stroke.
Migraine is a common disabling neurological disorder resulting from excessive cortical excitation and trigeminovascular afferent sensitization. In addition to aberrant neuronal processing, migraineurs are also at significant risk of vascular disease. Consequently, the impact of migraine extends well beyond the ictal headache and includes a well-documented association with acute ischemic stroke, particularly in young women with a history of migraine with aura. The association between migraine and stroke has been acknowledged for 40 years or more. However, examining the pathobiology of this association has become a more recent and critically important undertaking. The diversity of mechanisms underlying the association between migraine and stroke likely reflects the heterogenous nature of this disorder. Vasospasm, endothelial injury, platelet aggregation and prothrombotic states, cortical spreading depression, carotid dissection, genetic variants, and traditional vascular risk factors have been offered as putative mechanisms involved in migraine-related stroke risk. Assimilating these seemingly divergent pathomechanisms into a cogent understanding of migraine-related stroke will inform future studies and the development of new strategies for the prevention and treatment of migraine and stroke.


[Stereotactic radiosurgery of cerebral arteriovenous malformations].
Different treatment modalities are being used for cerebral arteriovenous malformations. We have evaluated the results of stereotactic radiosurgery on 85 patients (48 females) with median age 34.5 years (range 4-70 years) treated at Haukeland University Hospital in Norway in 1989-96. Median follow-up time was 7 years 3 months (range 51-144 months). Data were obtained retrospectively from patient files. Haemorrhage was the initial symptom in 72 patients. The majority of lesions were located deep within the brain parenchyma or near critical structures. The minimum dose to the periphery of the malformation was 15 to 33.3 Gy in 30-70% isodose line according to the volume and location of the malformation. Complete obliteration was obtained in 65 of 85 malformations (77%) and in two of five patients who were retreated. 85% of the malformations smaller than 4 cm3; 50% of those larger than 4 cm3 were obliterated after the treatment. The majority of the malformations were obliterated between two and three years after radiation. Radiation-related side effects were observed in six patients. Five patients experienced new bleeding during follow-up. Small and medium-sized arteriovenous malformations are successfully treated with stereotactic radiosurgery with an acceptable rate of radiation-related side effects and latency bleeding.


Conserved repeat motifs and glucan binding by glucansucrases of oral streptococci and Leuconostoc mesenteroides.
Glucansucrases of oral streptococci and Leuconostoc mesenteroides have a common pattern of structural organization and characteristically contain a domain with a series of tandem amino acid repeats in which certain residues are highly conserved, particularly aromatic amino acids and glycine. In some glucosyltransferases (GTFs) the repeat region has been identified as a glucan binding domain (GBD). Such GBDs are also found in several glucan binding proteins (GBP) of oral streptococci that do not have glucansucrase activity. Alignment of the amino acid sequences of 20 glucansucrases and GBP showed the widespread conservation of the 33-residue A repeat first identified in GtfI of Streptococcus downei. Site-directed mutagenesis of individual highly conserved residues in recombinant GBD of GtfI demonstrated the importance of the first tryptophan and the tyrosine-phenylalanine pair in the binding of dextran, as well as the essential contribution of a basic residue (arginine or lysine). A microplate binding assay was developed to measure the binding affinity of recombinant GBDs. GBD of GtfI was shown to be capable of binding glucans with predominantly alpha-1,3 or alpha-1,6 links, as well as alternating alpha-1,3 and alpha-1,6 links (alternan). Western blot experiments using biotinylated dextran or alternan as probes demonstrated a difference between the binding of streptococcal GTF and GBP and that of Leuconostoc glucansucrases. Experimental data and bioinformatics analysis showed that the A repeat motif is distinct from the 20-residue CW motif, which also has conserved aromatic amino acids and glycine and which occurs in the choline-binding proteins of Streptococcus pneumoniae and other organisms.


Identification and characterization of [6]-shogaol from ginger as inhibitor of vascular smooth muscle cell proliferation.
Vascular smooth muscle cell (VSMC) proliferation is involved in the pathogenesis of cardiovascular disease, making the identification of new counteracting agents and their mechanisms of action relevant. Ginger and its constituents have been reported to improve cardiovascular health, but no studies exist addressing a potential interference with VSMC proliferation. The dichloromethane extract of ginger inhibited VSMC proliferation when monitored by resazurin metabolic conversion (IC50 = 2.5 μg/mL). The examination of major constituents from ginger yielded [6]-shogaol as the most active compound (IC50 = 2.7 μM). In the tested concentration range [6]-shogaol did not exhibit cytotoxicity toward VSMC and did not interfere with endothelial cell proliferation. [6]-shogaol inhibited DNA synthesis and induced accumulation of the VSMC in the G0 /G1 cell-cycle phase accompanied with activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2)/HO-1 pathway. Since [6]-shogaol lost its antiproliferative activity in the presence of the heme oxygenase-1 (HO-1) inhibitor tin protoporphyrin IX, HO-1 induction appears to contribute to the antiproliferative effect. This study demonstrates for the first time inhibitory potential of ginger constituents on VSMC proliferation. The presented data suggest that [6]-shogaol exerts its antiproliferative effect through accumulation of cells in the G0 /G1 cell-cycle phase associated with activation of the Nrf2/HO-1 pathway.


The inhibition of Src kinase suppresses the production of matrix metalloproteinases in from synovial fibroblasts and inhibits MAPK and STATs pathways
The purpose of this study was to investigate the antiarthritic potentials of the inhibition of Src kinase in vivo and in vitro settings. Arthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund's adjuvant (collagen induced arthritis [CIA] model) in Wistar albino rats. One day after the onset of arthritis, dasatinib, a potent Src kinase inhibitor, (5 mg/kg/day) was given via oral gavage. Tissue Src, Fyn, MAPK and STAT mRNA expressions were determined by real-time polymerase chain reaction. On the other hand, fibroblast like synoviocytes (FLSs) were harvested patients with rheumatoid arthritis (RA) undergoing surgical knee joint replacement. FLSs were stimulated with cytokines and dasatinib was added in different concentrations. MMP –1, –3, and –13 levels in FLSs culture were determined by ELISA. The tissue mRNA expressions of Src, Fyn, MAPK and STATs were increased in the arthritis CIA group compared to the control group. Their mRNA expressions in the CIA + dasatinib group were decreased and similar in the control group. In in vitro setting, MMP –1, –3, and –13 expressions from FLSs induced by IL-1β and TNF-α were increased, while dasatinib suppressed their productions from FLSs. The present study shows that the inhibition of Src kinase has antiarthritic potentials in both in vivo and in vitro settings. Src kinase inhibition may be candidate to further research in human RA.


The non-coding genome in genetic brain disorders: new targets for therapy?
The non-coding genome, consisting of more than 98% of all genetic information in humans and once judged as 'Junk DNA', is increasingly moving into the spotlight in the field of human genetics. Non-coding regulatory elements (NCREs) are crucial to ensure correct spatio-temporal gene expression. Technological advancements have allowed to identify NCREs on a large scale, and mechanistic studies have helped to understand the biological mechanisms underlying their function. It is increasingly becoming clear that genetic alterations of NCREs can cause genetic disorders, including brain diseases. In this review, we concisely discuss mechanisms of gene regulation and how to investigate them, and give examples of non-coding alterations of NCREs that give rise to human brain disorders. The cross-talk between basic and clinical studies enhances the understanding of normal and pathological function of NCREs, allowing better interpretation of already existing and novel data. Improved functional annotation of NCREs will not only benefit diagnostics for patients, but might also lead to novel areas of investigations for targeted therapies, applicable to a wide panel of genetic disorders. The intrinsic complexity and precision of the gene regulation process can be turned to the advantage of highly specific treatments. We further discuss this exciting new field of 'enhancer therapy' based on recent examples.


Morbid prognostic features in patients with chronic liver failure undergoing nonhepatic surgery.
Although the risk of portal decompression surgery is accurately predicted by objective scoring systems (Child classification and Pugh score), few useful prognostic criteria exist regarding nonhepatic surgery in patients with chronic liver failure. To evaluate the clinical findings associated with perioperative mortality in patients with chronic liver failure undergoing nonhepatic surgery. A retrospective cohort study. University teaching hospitals. Forty consecutive patients with an International Classification of Diseases, Ninth Revision (ICD-9), diagnosis of chronic liver failure and one or more of the following: jaundice, cirrhosis, chronic hepatitis, or alcoholism. Forty operations, including 28 abdominal procedures, 2 coronary artery bypass grafts, 5 orthopedic procedures, and 5 miscellaneous procedures. Thirty-day mortality as related to 19 preoperative clinical and laboratory variables. Eleven (28%) of the patients died within 30 days of surgery. By univariate analysis, the following variables were significantly (P < .05, pearson chi 2 test for categorical data or Mann-Whitney U test for continuous data) associated with nonsurvival: encephalopathy, congestive heart failure, the need for emergent surgery, infection, hyperbilirubinemia, international normalized ratio greater than 1.6, hypoalbuminemia, and an elevated creatinine level. By multiple logistic regression analysis, an international normalized ratio greater than 1.6 and encephalopathy were associated with a greater than 10- and 35-fold increased mortality risk, respectively. Child classification and Pugh score failed to predict 30-day mortality. We identified 8 clinical and laboratory variables associated with death within 30 days in patients with chronic liver failure undergoing nonhepatic surgery. Two factors-international normalized ratio greater than 1.6 and encephalopathy-independently predicted mortality by multivariate analysis. Neither Child classification nor Pugh score was prognostically helpful. Nonhepatic surgery confers a substantial mortality risk in patients with chronic liver failure.


Luminal-apposing stents for benign intraluminal strictures: a large United States multicenter study of clinical outcomes.
The use of fully covered lumen-apposing metal stents (LAMS) for benign short gastrointestinal (GI) strictures has been reported. This study aimed to evaluate the safety and efficacy of LAMS for refractory GI strictures. A retrospective analysis was performed of patients who underwent LAMS placement for benign GI strictures in 8 United States centers. The primary outcomes were technical success and initial clinical response. Secondary outcomes were reintervention rate and adverse events. A total of 51 patients underwent 61 LAMS placement procedures; 33 (64.7%) had failed previous treatments. The most common stricture location was the pylorus (n=17 patients). Various sizes of stents were used, with 15-mm LAMS placed in 45 procedures, 20-mm LAMS in 14 procedures, and 10-mm LAMS in 2 procedures. The overall technical success, short-term clinical response and reintervention rate after stent removal were 100%, 91.8% and 31.1%, respectively. Adverse events were reported in 17 (27.9%) procedures, with stent migration being the most common (13.1%). In subgroup analysis, both 15 mm and 20 mm stents had comparable short-term clinical response and adverse event rates. However, stent migration (15.6%) was the most common adverse event with 15-mm LAMS while pain (14.3%) was the most common with 20-mm LAMS. The reintervention rate was 80% at 200-day follow up after stent removal. Using LAMS for treatment of short benign GI strictures is safe and effective. Larger LAMS, such as the new 20 mm in diameter, may have a lower stent migration rate compared to smaller diameter LAMS.


Opsonophagocytosis of Chlamydia pneumoniae by Human Monocytes and Neutrophils.
The human respiratory tract pathogen Chlamydia pneumoniae, which causes mild to severe infections, has been associated with the development of chronic inflammatory diseases. To understand the biology of C. pneumoniae infections, several studies have investigated the interaction between C. pneumoniae and professional phagocytes. However, these studies have been conducted under nonopsonizing conditions, making the role of opsonization in C. pneumoniae infections elusive. Thus, we analyzed complement and antibody opsonization of C. pneumoniae and evaluated how opsonization affects chlamydial infectivity and phagocytosis in human monocytes and neutrophils. We demonstrated that IgG antibodies and activation products of complement C3 and C4 are deposited on the surface of C. pneumoniae elementary bodies when incubated in human serum. Complement activation limits C. pneumoniae infectivity in vitro and has the potential to induce bacterial lysis by the formation of the membrane attack complex. Coculture of C. pneumoniae and freshly isolated human leukocytes showed that complement opsonization is superior to IgG opsonization for efficient opsonophagocytosis of C. pneumoniae in monocytes and neutrophils. Neutrophil-mediated phagocytosis of C. pneumoniae was crucially dependent on opsonization, while monocytes retained minor phagocytic potential under nonopsonizing conditions. Complement opsonization significantly enhanced the intracellular neutralization of C. pneumoniae in peripheral blood mononuclear cells and neutrophils and almost abrogated the infectious potential of C. pneumoniae In conclusion, we demonstrated that complements limit C. pneumoniae infection in vitro by interfering with C. pneumoniae entry into permissive cells by direct complement-induced lysis and by tagging bacteria for efficient phagocytosis in both monocytes and neutrophils.


The time-course of alcohol impairment of general aviation pilot performance in a Frasca 141 simulator.
This study examined the time-course of alcohol impairment of general aviation pilot simulator performance. We tested 14 young (mean age 25.8 years) and 14 older (mean age 37.9 years) pilots in a Frasca 141 simulator during alcohol and placebo conditions. In the alcohol condition, pilots drank alcohol and were tested after reaching 0.10% BAL, and then 2, 4, 8, 24, and 48 h after they had stopped drinking. They were tested at the same times in the placebo condition. Alcohol impaired overall performance. Alcohol impairment also depended on the order in which subjects participated in the alcohol and placebo sessions, with larger decrements for the alcohol-placebo order than for the opposite order. To examine the influence of alcohol independent of session order effects, we compared performance in the first alcohol session with performance in the first placebo session. This analysis showed that alcohol significantly reduced mean performance in the alcohol condition at 0.10% BAL and at 2 h. In addition, alcohol increased variability in performance in the alcohol session from 0.10% BAL to 8 h, suggesting that some subjects were more susceptible to alcohol than others. Older pilots tended to perform some radio communication tasks less accurately than younger pilots.


[Microcirculatory bed of the heart during peripheral arteriovenous shunting].
In the experiment performed on 108 test and 28 control dogs, by means of injection and histological methods, the effect of arteriovenous fistula on the cardiac microcirculatory bed has been studied. The arteriovenous blood shunting results in plethora and stasis in the cardiac microcirculatory bed, in dilatation of all its links, in aggregation and adhesion of the blood formed elements, in increased permeability of microvessels, in diapedesis of erythrocytes and in myocardial edema, in winding microvessels, in development of the venoarterial reaction, in hypertrophy of myocytes, recalibration and sclerosis of the microvascular walls.


More Reliable Neighborhood Contrastive Learning for Novel Class Discovery in Sensor-Based Human Activity Recognition.
Human Activity Recognition (HAR) systems have made significant progress in recognizing and classifying human activities using sensor data from a variety of sensors. Nevertheless, they have struggled to automatically discover novel activity classes within massive amounts of unlabeled sensor data without external supervision. This restricts their ability to classify new activities of unlabeled sensor data in real-world deployments where fully supervised settings are not applicable. To address this limitation, this paper presents the Novel Class Discovery (NCD) problem, which aims to classify new class activities of unlabeled sensor data by fully utilizing existing activities of labeled data. To address this problem, we propose a new end-to-end framework called More Reliable Neighborhood Contrastive Learning (MRNCL), which is a variant of the Neighborhood Contrastive Learning (NCL) framework commonly used in visual domain. Compared to NCL, our proposed MRNCL framework is more lightweight and introduces an effective similarity measure that can find more reliable k-nearest neighbors of an unlabeled query sample in the embedding space. These neighbors contribute to contrastive learning to facilitate the model. Extensive experiments on three public sensor datasets demonstrate that the proposed model outperforms existing methods in the NCD task in sensor-based HAR, as indicated by the fact that our model performs better in clustering performance of new activity class instances.


A comprehensive and quantitative comparison of text-mining in 15 million full-text articles versus their corresponding abstracts.
Across academia and industry, text mining has become a popular strategy for keeping up with the rapid growth of the scientific literature. Text mining of the scientific literature has mostly been carried out on collections of abstracts, due to their availability. Here we present an analysis of 15 million English scientific full-text articles published during the period 1823-2016. We describe the development in article length and publication sub-topics during these nearly 250 years. We showcase the potential of text mining by extracting published protein-protein, disease-gene, and protein subcellular associations using a named entity recognition system, and quantitatively report on their accuracy using gold standard benchmark data sets. We subsequently compare the findings to corresponding results obtained on 16.5 million abstracts included in MEDLINE and show that text mining of full-text articles consistently outperforms using abstracts only.


Acculturation and cigarette smoking among Korean American men.
This study examined the prevalence and correlated factors of cigarette smoking in a cross-sectional, epidemiological survey of Korean American men living in Maryland (n=333). In this sample, 26.1% were current smokers and 42.3% were former smokers. The older age group (> or = 40 years) was more likely to have quit smoking than the younger age group (< 40 years). In multiple logistic regression analysis, acculturation was associated with smoking status; those who stayed more than 20 years in the U.S. were less likely to be current smokers (OR=0.32, 95% CI 0.13-0.77) than those who stayed less than 10 years. Alcohol use was associated with smoking status; those who consumed alcohol were more likely to be current smokers (OR=5.24, 95% CI 2.33-11.79) or former smokers (OR=5.45, 95% CI=2.69-11.04) than those did not. Those with hypertension were more likely to have quit smoking (OR=3.11, 95% CI=1.33-7.24). The results suggest that the role of acculturation in smoking status among Korean American men deserves further attention by researchers as well as by health professionals who develop smoking prevention and cessation programs.


An automated method for studying drug effects on problem solving by small laboratory animals.
The design and construction details of a method for studying problem solving by small animals is described. The form of motivation is escape from water in a T-shaped apparatus, thus eliminating possible confounding effects involved when food or water intake is restricted below normal. The arm of the T in which escape is possible is alternated from trial to trial. Two levels of problem solving are evaluated: an animal can minimize escape time during a series of trials by alternating its responses, i.e., 100% reinforcement; alternatively, it may choose the same alley on each trial, which results in only 50% reinforcement. The time to make the decision and the total time are automatically recorded. We have demonstrated the sensitivity of the method to hypofunctioning of the cholinergic neurotransmitter system, an analogy to behavioral changes accompanying progressive degenerative dementia. Two effects of the hypocholinergic state were especially notable: animals in this state have significantly greater difficulty in shifting from the "primitive" position habit to the more complex alternation solution, and preliminary experiments suggest that certain pharmacological treatments may be effective in overcoming this deficiency.


Ubiquitination of Major Histocompatibility Complex II Changes Its Immunological Recognition Structure.
Ubiquitination is a process that dictates the lifespan of major histocompatibility complex class II (MHC II)/peptide complexes on antigen-presenting cells. This process is tightly controlled by the levels of ubiquitin ligases, and disruptions in the turnover of MHC II can lead to the improper development of CD4+ T cells within the thymus and hinder the formation of regulatory T cells in the peripheral tissue. To investigate the underlying mechanisms, we utilized dendritic cells lacking the Membrane-associated RING-CH (MARCH) I ubiquitin ligase. We discovered that the overexpression of MARCH I decreases the interaction with LAG-3. Moreover, the MHC II molecules tethered with ubiquitin also showed diminished binding to LAG-3. We employed Diffracted X-ray Blinking (DXB), a technique used for single-molecule X-ray imaging, to observe the protein movements on live cells in real time. Our observations indicated that the normal MHC II molecules moved more rapidly across the cell surface compared to those on the MARCH I-deficient dendritic cells or MHC II KR mutants, which is likely a result of ubiquitination. These findings suggest that the signaling from ubiquitinated MHC II to the T cell receptor differs from the non-ubiquitinated forms. It appears that ubiquitinated MHC II might not be quickly internalized, but rather presents antigens to the T cells, leading to a range of significant immunological responses.