Differential expression of two bc1 complexes in the strict acidophilic chemolithoautotrophic bacterium Acidithiobacillus ferrooxidans suggests a model for their respective roles in iron or sulfur oxidation.
Three strains of the strict acidophilic chemolithoautotrophic Acidithiobacillus ferrooxidans, including the type strain ATCC 23270, contain a petIIABC gene cluster that encodes the three proteins, cytochrome c1, cytochrome b and a Rieske protein, that constitute a bc1 electron-transfer complex. RT-PCR and Northern blotting show that the petIIABC cluster is co-transcribed with cycA, encoding a cytochrome c belonging to the c4 family, sdrA, encoding a putative short-chain dehydrogenase, and hip, encoding a high potential iron-sulfur protein, suggesting that the six genes constitute an operon, termed the petII operon. Previous results indicated that A. ferrooxidans contains a second pet operon, termed the petI operon, which contains a gene cluster that is similarly organized except that it lacks hip. Real-time PCR and Northern blot experiments demonstrate that petI is transcribed mainly in cells grown in medium containing iron, whereas petII is transcribed in cells grown in media containing sulfur or iron. Primer extension experiments revealed possible transcription initiation sites for the petI and petII operons. A model is presented in which petI is proposed to encode the bc1 complex, functioning in the uphill flow of electrons from iron to NAD(P), whereas petII is suggested to be involved in electron transfer from sulfur (or formate) to oxygen (or ferric iron). A. ferrooxidans is the only organism, to date, to exhibit two functional bc1 complexes.


Assessing physical activity in an Asian country: low energy expenditure and exercise frequency among adults in Taiwan.
Leisure-time physical activity (LTPA) has been closely related to health improvement. The under-appreciation for energy output by nutritionists stems in part from limited data expressed in caloric equivalent. We converted the frequency, duration, and intensity of LTPA, reported from 15,390 adults in the Taiwan National Health Interview Survey 2001, into kilocalories (kcal). Half of Taiwanese adults admit to no LTPA. Women, lower education or income, younger age, smokers and chewers of betel quid; exercised significantly less than their counterparts. Less than 1/5 (18.9%) of the population in Taiwan was physically active at >or=750 kcal/week, and only 1/7 (13.9%) reached a more desirable goal of >or=1,000 kcal/week, compared with 1/3 in the U.S. The most disconcerting finding was the Taiwan unique U-shaped prevalence for males, with the 25-44 age group being the least active, >or=65 age group being the most active; and S-shaped for females, lowest at age 18-24 years and highest at the two older groups (45-64 and >or=65 years). LTPA was under-appreciated, particularly among the most productive work force (25-44-year group), who exercised with a prevalence only 1/4 of their U.S. counterparts. Expressing LTPA in kcal makes direct comparison easier. Invoking a goal of >or=750 kcal/week for Asians, attainable by exercising 4 hours/week, can facilitate nutritionists in assessing LTPA adequacy. Currently, 4/5 of adults in Taiwan failed to reach this goal. Recognizing the concept of cumulative energy expenditure, in contrast to disciplined daily work for 5 or more days, will encourage the infrequent exercisers such as "weekend warriors" to continue with their activities.


Pyrolysis of waste electrical and electronic equipment: effect of antinomy trioxide on the pyrolysis of styrenic polymers.
This work has investigated the effect that antimony trioxide has on the pyrolysis of styrenic polymers and the effect that different types of brominated flame retardants used in plastics have on the composition of the pyrolysis products. Brominated high impact polystyrene (Br-HIPS) which contained either 5% or 0% antimony trioxide and either decabromodiphenyl oxide (DDO) or decabromodiphenyl ethane (DDE) was pyrolysed in a fixed bed reactor at 430 degrees C. Some experiments on the fixed bed reactor involved mixing the Br-HIPS with polystyrene. The gaseous products were analysed by GC-FID and GC-TCD and it was found that antimony trioxide caused an increase in the proportion of ethane and ethene and suppressed the proportion of butane and butene. When DDE was the flame retardant increased proportions of ethane and ethene were found in the pyrolysis gas compared to when DDO used. When polystyrene was mixed with the Br-HIPS it suppressed the trends observed in the gas composition during the pyrolysis of Br-HIPS. The pyrolysis oils were characterised using FT-IR, GC-MS, GC-FID, and GC-ECD. It was found that the plastic which did not contain antimony trioxide pyrolysed to form mainly toluene, ethylbenzene, styrene, cumene, and alpha-methylstyrene. The oils produced from the pyrolysis of the plastic that contained antimony trioxide did not contain any styrene or alpha-methylstyrene, but instead contained greater concentrations of ethylbenzene and cumene. The absence of styrene and alpha-methylstyrene from the pyrolysis oil occurred even when the Br-HIPS was mixed with polystyrene. GC-ECD analysis of the oils showed that the plastics which did not contain antimony trioxide pyrolysed to form (1-bromoethyl)benzene, which was totally absent from the pyrolysis oils when antimony trioxide was present in the plastic.


Smoking cessation after discharge among Japanese patients with established ischemic heart disease: a prospective cohort study.
In this prospective cohort study for Japanese patients with established ischemic heart disease (IHD), the authors investigated the rate of success of smoking cessation 3 months after hospital discharge and its related factors. The subjects included 90 current smokers admitted for IHD. A total of 58 subjects (64%) had quit smoking for 3 months after being discharged. In comparison with subjects with acute myocardial infarction, those with stable angina (SA) showed a significantly lower frequency of smoking cessation (relative risk of resuming smoking (95% confidence interval):2.06 (1.09, 3.92), p=0.036). This relationship remained significant even after controlling for sex, age, and scores of the Fagerstrom Test for Nicotine Dependence (adjusted odds ratio:3.39 (1.01, 11.37), p=0.048). However, it became insignificant when hospital admission followed by emergency medical service (EMS) care was additionally adjusted (adjusted odds ratio:2.48 (0.36, 16.97), p=0.356). The smoking cessation rate in this study was identical to that observed in studies conducted in Japan prior to the recent social changes with regard to tobacco use. SA still appears to be a risk factor for smoking resumption after discharge. Experiencing EMS care would be an intermediate variable in this relationship.


A comparison of Cornell and Sokolow-Lyon electrocardiographic criteria for left ventricular hypertrophy in a military male population in Taiwan: the Cardiorespiratory fitness and HospItalization Events in armed Forces study.
The Cornell and Sokolow-Lyon electrocardiography (ECG) criteria have been widely used for diagnosing left ventricular hypertrophy (LVH) in patients with hypertension. However, the correlations of these ECG criteria with LVH were rarely compared in military members who received rigorous training, particularly of the Asian male population. We compared the Cornell voltage and product criteria with the Sokolow-Lyon criteria for the echocardiographic LVH in 539 military male members, ages 18-50 years and free of hypertension in the Cardiorespiratory fitness and HospItalization Events in armed Forces (CHIEF) study in Taiwan. Pearson's correlation coefficient was used to determine the association of each ECG criterion with the index of left ventricular mass (LVM, g)/height (m)2.7. The sensitivities and specificities were estimated using a receiver-operating characteristics (ROC) curve in relation to the echocardiographic LVH which was defined as LVM index ≥49 g/m2.7. The correlations of the Cornell voltage and product criteria (r=0.24 and 0.26 respectively, both P<0.0001) were stronger than that of the Sokolow-Lyon criteria (r=0.049 and 0.095, and P=0.26 and 0.03 respectively) with the LVM index. Similarly the performances of the Cornell voltage and product criteria for the echocardiographic LVH [area under curve (AUC): 0.66 and 0.68, both P<0.0001] were superior to that of the Sokolow-Lyon criteria (AUC: 0.54 and 0.53, both P>0.1) in the area under the ROC curve analysis. The Cornell ECG criteria for the echocardiographic LVH had better performance than the Sokolow-Lyon criteria in a young military male cohort in Taiwan.


Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission.
Treatment-free remission (TFR) is an opportunity for patients with chronic myeloid leukemia (CML). Reported cumulative incidence curves of molecular recurrence (MRec) arbor a 2-phase shape with mainly early events, but also some late events (late MRec [LMRec]). Having discontinued our first patient in 2004, we have access to a prolonged follow-up, enabling us to characterize these late events. Over 15 years, 128 patients from our institution were registered in the Stop Imatinib (STIM; A Study for Tyrosine Kinase Inhibitors Discontinuation [A-STIM]) trial. MRec was defined by the loss of major molecular response (BCR-ABL1IS >0.1%). At the first TFR attempt, patients had been taking a tyrosine kinase inhibitor for a median of 7.1 years and in BCR-ABL1IS ≤0.01% (MR4) for a median of 4 years. The median follow-up of patients in TFR was 6.5 years. The TFR rate was estimated to be 45.6% after 7 years. For 9/65 (14%) patients experiencing MRec, recurrence occurred after 2 years in TFR (median, 3.6 years). The residual rate of MRec after 2 years was estimated to be 18%. The probability of remaining in TFR was 65.4% for patients having experienced fluctuations of their minimal residual disease (MRD) (at least 2 consecutive measurements BCR-ABL1IS >0.0032% or loss of MR4), whereas it was 100% for those with stable MRD (P = .003). After 2 years in TFR, we observed an 18% residual rate of LMRec. These late events represent 14% of all MRec and occur in patients with fluctuating MRD measurements. A long-term molecular follow-up therefore remains mandatory for CML patients in TFR. The A-STIM study was registered at www.clinicaltrials.gov as #NCT02897245.


Altered expression of atrial natriuretic peptide and contractile protein genes in hypertrophied ventricle of JVS mice with systemic carnitine deficiency.
To characterize cardiac hypertrophy in juvenile visceral steatosis (JVS) mice with systemic carnitine deficiency, we investigated how the hypertrophy develops and whether it is associated with altered expression of any specific genes, especially atrial natriuretic peptide (ANP) and contractile protein genes, in the hypertrophied ventricle. Cardiac hypertrophy in JVS mice became apparent at 10 days after birth and progressed during development. The hypertrophy was observed in the ventricles but not in the atria. ANP mRNA was more intensively expressed in JVS ventricles than in control even at 5 days. Carnitine administration ameliorated the cardiac hypertrophy and suppressed the augmentation of ANP mRNA in the ventricles. Isoform change of expression of alpha-actin genes from cardiac to skeletal was seen in the ventricles of JVS mice at 2 weeks. There was no difference in the ratio of beta-myosin heavy chain mRNA to alpha-myosin heavy chain mRNA between control and JVS mice at 5 days, but at 2 weeks the ratio was significantly lower in JVS mice than in control. These results suggest that the molecular characteristics of cardiac hypertrophy caused by carnitine deficiency are different from those of cardiac hypertrophy caused by aortic constriction.


An evolving approach to the laboratory assessment of COVID-19.
As the 2019 novel coronavirus disease (COVID-19) outbreak has evolved in each country, the approach to the laboratory assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has had to evolve as well. This review addresses the evolving approach to the laboratory assessment of COVID-19 and discusses how algorithms for testing have been driven, in part, by the demand for testing overwhelming the capacity to accomplish such testing. This review focused on testing in the USA, as this testing is evolving, whereas in China and other countries such as South Korea testing is widely available and includes both molecular testing for SARS-CoV-2 as well as serological testing using both enzyme-linked immunosorbent assay methodology and lateral flow immunoassay methodology. Although commercial testing systems are becoming available, there will likely be insufficient numbers of such tests due to high demand. Serological testing will be the next testing issue as the COVID-19 begins to subside. This will allow immunity testing as well as will allow the parameters of the COVID-19 outbreak to be defined.


Clinical, behavioural and neural validation of the PANSS amotivation factor.
Negative symptoms in schizophrenia have been suggested to map onto two distinct factors - amotivation and diminished expression. Only recently, two-factor solutions for measuring negative symptoms have been proposed for the Positive and Negative Symptom Scale (PANSS), the most commonly used scale to assess the psychopathology of patients with schizophrenia. We aimed to validate the PANSS two-factor structure on a clinical, behavioural and neural level. For this multi-level validation, we reanalysed several datasets with patients for whom both the Brief Negative Symptom Assessment Scale (BNSS) and PANSS data were collected. We used a clinical dataset (n = 120) as well as behavioural data from an effort-based decision making task (n = 31) and functional neuroimaging data from a monetary incentive delay task (n = 41). Both tasks have previously been shown to be associated with BNSS amotivation. On the clinical level, the PANSS amotivation and diminished expression were highly correlated with their BNSS counterparts. On the behavioural level, we found that the PANSS amotivation factor but not the diminished expression factor specifically associated with willingness to invest effort to obtain a reward. On the neural level, PANSS amotivation was specifically related to reduced ventral striatal activation during reward anticipation. Our data confirm that the PANSS clearly allows distinguishing amotivation from diminished expression, as it relates selectively to specific aspects of behaviour and brain function. Our results will allow a re-analysis and sharing of existing datasets that used the PANSS to further substantiate the distinction between the two factors in neuroscientific studies and clinical trials.


Photophysical properties of [Ru(phen)2(dppz)]2+ intercalated into DNA: an integrated Car-Parrinello and TDDFT study.
Combined Car-Parrinello and time-dependent DFT calculations performed on [Ru(phen)2dppz]2+ intercalated into an adenine-thymine tetramer reveal a remarkable influence of the base pairs in determining the electronic structure and the character of the excited states involved in the absorption and emission processes.


Epstein-Barr virus: the impact of scientific advances on clinical practice.
Epstein-Barr virus (EBV) is a tumorigenic herpes virus that infects and persists in B lymphocytes in the majority of humans, generally without causing disease. However, in a few individuals the virus is associated with significant pathology, particularly benign and malignant lymphoproliferations. Recently acquired knowledge on the mechanisms of EBV persistence, immune control of primary and persistent infection, and disease pathogenesis is now being translated into the clinic with novel methods of diagnosis, prevention and treatment contributing to improved patient care. This review concentrates on these recent advances in the field of hematology/oncology.


[Comparative anatomy of the hand].
The pentadactyl scheme is common to all tetrapods, even in case of adaptative phenomenon (five digits are observed during ontogenesis), or in case of functional convergence The carpal organization with two rows is common too, if we take into account the desappearing of the central bones in mature man. The sellar shape of the trapeziometacarpal joint of the thumb, to often attributed to Man and his only thumb, is in fact the regular shape of all carpometacarpal articulations and present in very ancient primitive primate fossils. Some discontinuous caracters in Man (entepicondylar tunnel) are present in all individuals of some species (carnivors). Rarely present in Man, it can exceptionally produce a real pathology.


[Use of average-acting nondepolarizing myorelaxants in abdominal surgery].
The efficiency and safety of use of average-acting nondepolarizing myorelaxants, such as atracurium, vecuronuim, rocuronium, and cisatracurum, during abdominal surgical interventions under general anesthesia (combined or total intravenous anesthesia) were investigated in 162 patients. There is evidence that the use of the above agents ensures a qualitative myorelaxation during different types of operations (laparoscopic and laparotomic) and no impact on hemodynamics (according to the data of continuous non-invasive monitoring) allows these myorelaxants to be used in patients with concomitant cardiovascular diseases. Rocuronium is the myorelaxant of choice for rapid tracheal intubation. The high degree of predictability of the duration of an effect produced by atracurium and cisatracurium enables these myorelaxants to be used without monitoring neuromuscular conduction. With the equally good quality of myoplegia and with virtually comparable consumed diseases, the infusion procedure of relaxation maintenance is preferable for early activation of patients. Insignificant effects on histamine release make it possible to use vecuronium, rocuronium, and cisatracurium in patients with the compromised immune system.


An assessment of bone mineral density in patients with Addison's disease and isolated ACTH deficiency treated with glucocorticoid.
Glucocorticoid replacement therapy needs to be tailored to individual patient's requirements in order to avoid risk of over or under medication. We measured bone mineral density (BMD) of lumbar spine using dual X-ray absorptiometory in 10 patients with Addison's disease and 5 patients with isolated ACTH deficiency receiving glucocorticoid replacement therapy. We also examined the effect of glucocorticoid replacement on BMD. Decreased %BMD (less than 80% of age-matched controls) was found in 2 female patients who had received hydrocortisone at a dose of 14.8 and 15.4 mg/m(2)/day. In contrast, no patient receiving a hydrocortisone dose of less than 12.4 mg/m (2)/day had decreased %BMD. There was no correlation between %BMD and hydrocortisone dose (mg/m(2)), duration of therapy, or cumulative hydrocortisone dose when treated with appropriate dose of hydrocortisone (<13.6 mg/m(2)). There was also no statistically significant difference in %BMD with age. We concluded that long-term glucocorticoid replacement therapy does not induce bone loss in patients with glucocorticoid deficiency unless an excessive dose of hydrocortisone is given.


Computer Assisted Oswestry Disability Questionnaire Evaluation Using Fuzzy Inference Systems.
This paper proposes the evaluation of the Oswestry Disability Index (ODI) using a fuzzy inference system. The ODI is used to evaluate the impact of the low back pain on the patient's quality of life. The patient grades from 0 to 5 a number of 10 questions regarding usual daily activities. At the end a mathematical formula is used to calculate the degree of the impact/disability. It has been observed that this method easily can generate false positive results due to the fact that patients purposely try to score a higher degree so that they can benefit from advantages offered by the medical system. To eliminate the false positive results a fuzzy inference system was developed which can identify the contradictory input data and warn the medical staff about a possible erroneous result.


Assessment of magnetic properties of A2B'B''O6 double perovskites by multivariate data analysis techniques.
Multivariate data analysis is a promising tool for structure-property data mining and new-material prediction in the field of inorganic materials chemistry. Here we demonstrate its usability in assessing the magnetic properties of one of the most intriguing and plural functional inorganic material families, the ordered perovskite oxides of the A2B'B''O6 type.


Strain differences in kinetic and thermal stability of two mouse brain tryptophan hydroxylase activities.
Levels of forebrain serotonin (5-HT), tryptophan, 5-hydroxyindoleacetic acid (5-HIAA) and hydroxylase cofactor (BH4) were comparable in two experimental mouse strains (A/J and C57Bl/6J) despite 2-3-fold differences in vitro in the relative activities of forebrain and midbrain tryptophan-5-monooxygenase (TPOH; EC 18.104.22.168). The enzyme activities did not differ with respect to Km for cofactor at saturating levels, but manifested different degrees of cooperativity with respect to cofactor when examined with BH4 concentrations within a physiological range. They differed also in the frequency and amplitude of kinetic variation around comparable mean velocity slopes across cofactor and time; in resistance to pre-incubation inactivation and responsiveness to its facilitation by calcium; in molecular weight heterogeneity as reflected in the distribution of molecular weight forms by gel diffusion chromatography; and in the number of peaks in power spectral analysis of kinetic variation patterns. Although the potential roles of small-molecule ligand and/or regulator proteins have not been ruled out, we hypothesize that differences in conformational stability underlie the differences in regulatory properties and make one enzyme activity more vulnerable to occlusive influences in vivo.


Randomized clinical trial of interceptive and comprehensive orthodontics.
Focusing public insurance programs on interceptive orthodontics (IO) may increase access for low-income children. This report presents outcomes from a randomized clinical trial (RCT) comparing IO with comprehensive orthodontics (CO) in Medicaid patients. One hundred seventy pre-adolescents with Medicaid-eligible malocclusions were randomized to IO (n = 86) followed by observation (OBS) or OBS followed by CO (n = 84). One hundred thirty-four completed the trial. Models at pre-treatment (baseline) and following ≤ 2 years of intervention and 2 years of OBS (48 mos) were scored by calibrated examiners using the Peer Assessment Rating (PAR) and Index of Complexity, Outcome and Need (ICON). Overall outcomes and clinically meaningful categorical ICON data on need/acceptability, complexity, and improvement were compared. At baseline, groups were balanced by age, gender, ethnicity, and PAR/ICON scores. Most were minorities. Most (77%) were rated as difficult-to-very difficult. Scores improved significantly for both groups, but CO more than IO (PAR, 18.6 [95%CI 15.1, 22.1] vs.10.1 [95%CI 6.7, 13.4]; ICON, 44.8 [95% CI 39.7, 49.9] vs. 35.2 [95%CI 29.7, 40.6], respectively). On average, IO is effective at reducing malocclusions in Medicaid patients, but less than CO. (ClinicalTrials.gov number CT00067379).


Risk factors predicting acute postoperative pain immediately after minimally invasive inguinal hernia repair.
Acute postoperative pain remains one of the most common problems, even after laparoscopic or endoscopic hernia repair. Avoiding predictive factors for acute pain after surgery or prescribing additional analgesia for a patient who has risk factors that cannot be removed can be one of the options to reduce acute postoperative pain. However, there is a lack of clinical studies that evaluate the predictive factors of postoperative pain after transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP) surgeries. To identify independent risk factors predicting pain after laparoscopic and endoscopic inguinal hernia repair. A prospective, randomized clinical trial was carried out by randomising patients into 2 groups (TAPP and TEP). Pre-operative and peri-operative findings were recorded. Postoperative pain was evaluated 3 h after the surgery using a visual analogue scale (VAS). Groups of patients who felt mild pain (VAS 0-2) and patients who felt average or severe pain (VAS 3-10) were compared. A total of 132 male patients were included in the study. Disease duration of more than 1 year, smoking, and TAPP surgery significantly increase the risk of moderate and strong pain 3 h after surgery. Conversely, shorter duration of symptoms and physical occupation decrease the risk of acute pain score greater than 3 according to the VAS. The study shows that the duration since groin hernia appearance, smoking, physical occupation, and TAPP technique are possible predictive factors for acute postoperative pain after minimally invasive inguinal hernia repair. We suggest that for patients who have those predictors, some factors can be avoided or additional analgesia can be used.


Transient Ischemic Attack Outpatient Clinic: Past Journey and Future Adventure.
A transient ischemic attack (TIA), a constellation of temporary neurological symptoms, precedes stroke in one-fifth of patients. Thus far, many clinical models have been introduced to optimize the quality, time to treatment, and cost of acute TIA care, either in an inpatient or outpatient setting. In this article, we aim to review the characteristics and outcomes of outpatient TIA clinics across the globe. In addition, we discussed the main challenges for outpatient management of TIA, including triage and diagnosis, and the system dynamics of the clinics. We further reviewed the potential developments in TIA care, such as telemedicine, predictive analytics, personalized medicine, and advanced imaging.


Real-time PCR assay targets the 23S-5S spacer for direct detection and differentiation of Legionella spp. and Legionella pneumophila.
A real-time PCR for the ABI Prism 7000 system targeting the 23S-5S spacer of Legionella spp. was developed. Simultaneous detection and differentiation of Legionella spp. and Legionella pneumophila within 90 min and without post-PCR melting-curve analysis was achieved using two TaqMan probes. In sputum samples from 23 controls and 17 patients with legionellosis, defined by positive culture, urinary antigen testing, or seroconversion, 94% sensitivity and 100% specificity were observed.


Sigma 1 Receptor antagonist potentiates the anti-cancer effect of p53 by regulating ER stress, ROS production, Bax levels, and caspase-3 activation.
Over the last years, many improvements have been made in the treatment of breast cancer; however, novel and less toxic therapies are still needed, especially for relapsing and chemo-resistant patients. Here, we analyzed the therapeutic potential of p53 and Rimcazole, a Sigma 1 Receptor antagonist. Rimcazole and p53 are being evaluated in preclinical and clinical trials, respectively. While p53 is a promising antitumor therapeutic agent, antagonists of Sigma 1 Receptor also inhibit tumor cell survival and induce apoptosis. Our current study demonstrates for the first time the synergistic effect of p53 in combination with the Sigma 1 Receptor antagonist Rimcazole. Furthermore, we show that shRNA knockdown of Sigma 1 Receptor in combination with p53, lead to a similar synergistic effect, and that this synergistic effect, in breast cancer growth suppression occurs independent of p53 status. Furthermore, this combination treatment induced ER stress, p38 MAPK activation, ROS production, and proteins involved in apoptosis (caspases-3, Bax) in breast cancer cells. Combining these therapeutic anti-cancer molecules provides an innovative approach for potentially treating human breast cancer.


Peripheral blood and granuloma CD4(+)CD28(-) T cells are a major source of interferon-gamma and tumor necrosis factor-alpha in Wegener's granulomatosis.
To elucidate whether the fraction of CD28(-) T cells within the CD4(+) T-cell population is a major source of Th1-like and proinflammatory cytokine production driving Wegener's granulomatosis (WG) granuloma formation, we analyzed the phenotype and functional characteristics of peripheral blood CD4(+)CD28(-) T cells and of T cells in granulomatous lesions of 12 patients with active WG. Surface markers and intracytoplasmic cytokine and perforin expression were assessed by flow cytometry. Cytokine secretion was measured by enzyme-linked immunosorbent assay. Immunohistological studies demonstrated interferon-gamma and tumor necrosis factor-alpha cytokine positivity attributable to CD4(+)CD28(-) T cells in granulomatous lesions. Peripheral blood CD4(+)CD28(-) T cells expressed CD57, also found on natural killer cells, and intracytoplasmic perforin. They were generally CD25 (interleukin-2 receptor)-negative. CD18 (adhesion molecule beta(2)-integrin) was strongly up-regulated on CD4(+)CD28(-) T cells, whereas only a minority of CD4(+)CD28(+) T cells expressed CD18. CD4(+)CD28(-) T cells appeared as a major source of interferon-gamma and tumor necrosis factor-alpha. In contrast, CD4(+)CD28(+) T cells were able to produce and secrete a wider variety of cytokines including interleukin-2. One-quarter of CD4(+)CD28(+) T cells expressed the activation marker CD25, but they lacked perforin. Thus, CD4(+)CD28(-) T cells appeared more differentiated than CD4(+)CD28(+) T cells. They displayed Th1-like cytokine production and features suggestive of the capability of CD4(+) T-cell-mediated cytotoxicity. CD4(+)CD28(-) T cells may be recruited into granulomatous lesions from the blood via CD18 interaction, and may subsequently promote monocyte accumulation and granuloma formation through their cytokine secretion in WG.


Transfer Learning-Motivated Intelligent Fault Diagnosis Designs: A Survey, Insights, and Perspectives.
Over the last decade, transfer learning has attracted a great deal of attention as a new learning paradigm, based on which fault diagnosis (FD) approaches have been intensively developed to improve the safety and reliability of modern automation systems. Because of inevitable factors such as the varying work environment, performance degradation of components, and heterogeneity among similar automation systems, the FD method having long-term applicabilities becomes attractive. Motivated by these facts, transfer learning has been an indispensable tool that endows the FD methods with self-learning and adaptive abilities. On the presentation of basic knowledge in this field, a comprehensive review of transfer learning-motivated FD methods, whose two subclasses are developed based on knowledge calibration and knowledge compromise, is carried out in this survey article. Finally, some open problems, potential research directions, and conclusions are highlighted. Different from the existing reviews of transfer learning, this survey focuses on how to utilize previous knowledge specifically for the FD tasks, based on which three principles and a new classification strategy of transfer learning-motivated FD techniques are also presented. We hope that this work will constitute a timely contribution to transfer learning-motivated techniques regarding the FD topic.


Interferon antagonist function of Japanese encephalitis virus NS4A and its interaction with DEAD-box RNA helicase DDX42.
The interferon (IFN) antagonists of Japanese encephalitis virus (JEV) proteins contribute to the JE pathogenesis. Most flavivirus non-structural (NS) proteins correlate with virus-induced inflammation and immune escape. NS4A proteins of West Nile virus and dengue type 2 virus have been demonstrated to inhibit IFN signaling. In this study, JEV NS4A without the C-terminal 2K domain has been demonstrated to partially block activation of an IFN-stimulated response element (ISRE)-based cis-reporter by IFN-alpha/beta. In addition, JEV NS4A significantly inhibited the phosphorylation levels of STAT1 and STAT2, but not TYK2 in the IFN-treated cells. Moreover, the N-terminus of a RNA helicase DDX42 protein identified using a phage display human brain cDNA library have been demonstrated to specifically bind to JEV NS4A in vitro using a co-immunoprecipitation assay. The interaction between JEV NS4A and RNA helicase DDX42 showed partial co-localization in human medulloblastoma TE-671 cells by confocal microscopy. Importantly, the expression of N-terminal DDX42 is able to overcome JEV-induced antagonism of IFN responses. Therefore, these results show that JEV NS4A without the C-terminal 2K domain is associated with modulation of the IFN response and the interaction of JEV NS4A with RNA helicase DDX42 could be important for JE pathogenesis.


Regional anesthesia for vascular surgery.
Vascular surgical patients are a diverse group of patients who tend to be elderly, with multiple comorbidities, while vascular procedures may involve significant blood loss and ischemia of tissues beyond the arterial obstruction. Regional anesthesia techniques may offer benefits to patients undergoing vascular surgery because of their cardiorespiratory comorbidities. However, this group of patients is commonly receiving multiple medications, including anticoagulants, so regional techniques are not without risks. This review will discuss this topic based around 3 fundamental revascularization procedures, carotid, abdominal aortic aneurysm repair, and infrainguinal surgery, discussing the clinical applications of regional techniques relevant to each key area.


Cellulose nanofiber aerogel as a promising biomaterial for customized oral drug delivery.
Cellulose nanofiber (CNF) aerogels with favorable floatability and mucoadhesive properties prepared by the freeze-drying method have been introduced as new possible carriers for oral controlled drug delivery system. Bendamustine hydrochloride is considered as the model drug. Drug loading was carried out by the physical adsorption method, and optimization of drug-loaded formulation was done using central composite design. A very lightweight-aerogel-with-matrix system was produced with drug loading of 18.98%±1.57%. The produced aerogel was characterized for morphology, tensile strength, swelling tendency in media with different pH values, floating behavior, mucoadhesive detachment force and drug release profiles under different pH conditions. The results showed that the type of matrix was porous and woven with excellent mechanical properties. The drug release was assessed by dialysis, which was fitted with suitable mathematical models. Approximately 69.205%±2.5% of the drug was released in 24 hours in medium of pH 1.2, whereas ~78%±2.28% of drug was released in medium of pH 7.4, with floating behavior for ~7.5 hours. The results of in vivo study showed a 3.25-fold increase in bioavailability. Thus, we concluded that CNF aerogels offer a great possibility for a gastroretentive drug delivery system with improved bioavailability.


Steps towards a computer-based library network: a survey of three medical libraries.
The introduction of a computerized biomedical network in three medical libraries in the State University of New York demanded a study of the various bibliographic records held by the libraries. The investigation produced figures relating to the total number of monographs held by each library and the number of unique titles owned by the network as a whole. These were broken down to identify the amount of works dating from 1962 or later, and estimates were made of the mean length of the normal bibliographic record, as well as of its traditional subareas. Thought was given to the implication of applying depth-indexing to monographs with reference to the length of the record.


Outcome of misoprostol and oxytocin in induction of labour.
Induction of labour is the process of initiating the labour by artificial means from 24 weeks of gestation. The main aim of this study is to find out the maternal and foetal outcomes after induction of labour with misoprostol and oxytocin beyond 37 weeks of gestation. This was a hospital-based observational study carried out at Paropakar Maternity and Women's Hospital, Nepal. Misoprostol of 25 µg was inserted in posterior fornix of vagina or oxytocin infusion was started from 2.5 units on whom induction was decided. Maternal and foetal/neonatal outcomes were observed. Collected data were analysed using SPSS and MS Excel. General induction rate was found to be 7.2%. In this study, post-term pregnancy was found to be the most common reason for induction of labour. Analysis of onset of labour led to the finding that mean onset of labour was much rapid in oxytocin (6.6 h) than misoprostol (13.6 h). However, there is similarity in induction-delivery interval in both groups. Overall, the rate of normal delivery and caesarean section was found to be 64.9% and 33.2%, respectively. Similarly, normal delivery within 12 h was seen in 18.4% of the patients given with misoprostol and 43.5% in oxytocin group. Foetal distress was found as the most common reason for caesarean section. The overall occurrence of maternal complication was found to be similar in misoprostol and oxytocin groups, nausea/vomiting being the most common (36.7%) complication followed by fever (24.1%). Besides this, the most common neonatal complication found in overall cases was meconium stained liquor (49.2%). It was found that misoprostol was used most frequently for induction of labour compared to oxytocin. The onset of labour was found to be rapid in oxytocin than misoprostol. However, the occurrence of side effects was found to be similar in both misoprostol and oxytocin groups.


Epidemiology and individual susceptibility to adverse drug reactions affecting the liver.
Adverse drug reactions affecting the liver represent an important challenge for safety in drug development. Drugs can reproduce practically the whole spectrum of liver diseases, but acute hepatitis is the most common syndrome. Drug hepatotoxicity is one of the most common causes of fulminant hepatitis. Most hepatic drug reactions occur in only a small proportion of individuals, making them difficult to detect at the time of drug development. Liver injury is principally recognized on the basis of spontaneous reports within the first 2 years of marketing a new drug. The prevalence of drug hepatotoxicity is poorly documented by a small number of retrospective studies. Despite the development of international analytical methods to allow standardized evaluation, the diagnosis remains indeterminate in many cases. Acquired and genetic factors influence the individual susceptibility to drug hepatotoxicity. Important directions for the future include prospective studies of the incidence of hepatic adverse drug reactions, finding specific markers that augment or replace causality assessment, and further elucidating the role of the genetic and environmental factors that contribute to individual susceptibility.


Analysis of genetic relationships among Rosa damascena plants grown in Turkey by using AFLP and microsatellite markers.
Rosa damascena Mill. is the most important rose species for rose oil production. The main rose oil producers in the world are Turkey and Bulgaria and they obtain the rose oil almost exclusively from R. damascena. In spite of coming from the same original populations, R. damascena plants grown in Turkey show some morphological differences. In this study, it was aimed to investigate the genetic relationships among R. damascena plants grown in Turkey by using microsatellite and AFLP markers. Twenty three AFLP and nine microsatellite primer pairs were used for this aim. No polymorphism could be detected among the plants, as the marker patterns obtained from different plants are identical. The conclusion from these data is that all R. damascena plants under study are derived from the same original genotype by vegetative propagation. Furthermore, the observed morphological differences originate from point mutations not detectable by molecular markers. Therefore, they are equivalent to sport mutations frequently observed in cut and garden rose varieties.


Regulation of Epithelial Cell Proliferation, Differentiation, and Plasticity by Grainyhead-Like 2 During Oral Carcinogenesis.
Grainyhead-Like 2 (GRHL2) was originally described as one of the three mammalian isoforms with sequence homology to Grainyhead (GRH) in Drosophila, which determines the cuticle formation in fruit flies. Earlier studies characterized GRHL2 as an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Using a high-throughput proteomic approach, we discovered GRHL2 as a novel trans-regulator of the hTERT gene, which codes for the catalytic subunit of the human telomerase. GRHL2 was found to be necessary and sufficient for hTERT expression and telomerase activity in human oral squamous cell carcinomas (OSCCs) and in primary normal human keratinocytes. Subsequently, we found numerous other direct transcription targets of GRHL2, including p63, microRNA (miR)-200 family genes, FoxM1, and epidermal differentiation complex (EDC) genes. These target molecules mediate the phenotypic effects of GRHL2 on epithelial cell proliferation, differentiation, and epithelial plasticity. The pro-carcinogenic role of GRHL2 was implicated by its aberrant overexpression in OSCC cells and tissues, although several other studies also suggested the tumor suppressive effects of GRHL2. Using the novel Grhl2 cKO model, we recently reported the first genetic study in which Grhl2 knockout completely abolished oral carcinogenesis induced by a potent carcinogen, 4-nitroquinoline N-oxide (NQO). In this review, we discuss the mechanistic insights underlying the phenotypic effects of GRHL2 on epithelial cell proliferation and differentiation, as well as possibly mechanisms by which GRHL2 may promote oral carcinogenesis.


Anthropometric and micronutrient status of school-children in an urban West Africa setting: a cross-sectional study in Dakar (Senegal).
Urban areas in West Africa are not immune to undernutrition with recent urbanization and high food prices being important factors. School children often have a poor nutritional status, potentially affecting their health and schooling performance. Yet, generally school children do not benefit from nutrition programs. The objective of the study was to assess the anthropometric and micronutrient status of children from state schools in the Dakar area. School children (n = 604) aged from 5 to 17 y (52.5% girls, 47.5% ≥ 10 y) were selected through a two-stage random cluster sample of children attending urban primary state schools in the Dakar area (30 schools × 20 children). The prevalence of stunting (height-for-age<-2 z-scores) and thinness (BMI-for-age<-2 z-scores, WHO 2006, and three grades of thinness corresponding to BMI of 18.5, 17.0 and 16.0 kg/m2 in adults) were calculated from weight and height. Hemoglobin, plasma concentrations of ferritin (FER), transferrin receptors (TfR), retinol binding protein (RBP), and zinc, and urinary iodine concentrations were measured. Correction factors were used for FER and RBP in subjects with inflammation determined with C-reactive protein and α1-acid-glycoprotein. 4.9% of children were stunted, 18.4% were thin, 5.6% had severe thinness (BMI-for-age<-3 z-scores). Only one child had a BMI-for-age>2 z-scores. Prevalence of anemia, iron deficiency and iron deficiency anemia was 14.4%, 39.1% and 10.6% respectively. 3.0% had vitamin A deficiency, 35.9% a marginal vitamin A status, and 25.9% zinc deficiency. Urinary iodine was <50 µg/L in 7.3% of children and ≥ 200 µg/L in 22.3%. The prevalence of marginal vitamin A, zinc deficiency, high TfR was significantly higher in boys than in girls (P<0.05). Height-for-age and retinol were significantly lower in participants ≥ 10 y and <10 y respectively. Undernutrition, especially thinness, iron and zinc deficiencies in school children in the Dakar area requires special targeted nutrition interventions.


Cefdinir: an advanced-generation, broad-spectrum oral cephalosporin.
Cefdinir is an advanced-generation, broad-spectrum cephalosporin antimicrobial agent that has been approved for the treatment of community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, acute maxillary sinusitis, pharyngitis/tonsillitis, acute bacterial otitis media, and uncomplicated skin and skin-structure infections in adult and pediatric patients. The purpose of this article was to review the in vitro antimicrobial activity, pharmacokinetics, clinical efficacy, safety, and potential role of cefdinir. Studies were identified by a MEDLINE search (January 1983-September 2001) of the English-language medical literature, a review of identified articles and their bibliographies, and a review of data on file with the manufacturer. Clinical efficacy data were selected from all published trials mentioning cefdinir. Information concerning in vitro susceptibility, safety, chemistry, and the pharmacokinetic profile of cefdinir also was reviewed. Cefdinir has a broad spectrum of activity against many gram-negative and gram-positive aerobic organisms, including Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Cefdinir is stable to hydrolysis by 13 of the common beta-lactamases. It is rapidly absorbed from the gastrointestinal tract (mean time to peak plasma concentration, 3 hours) and is almost entirely eliminated via renal clearance of unchanged drug. The terminal disposition half-life of cefdinir is approximately 1.5 hours. Efficacy has been demonstrated in 19 clinical trials in adults and children with upper and lower respiratory tract infections (eg, pharyngitis, sinusitis, acute otitis media, acute bronchitis, acute bacterial exacerbation of chronic bronchitis, community-acquired pneumonia), and skin and skin-structure infections. The adverse-event profile is similar to that of comparator agents, although in 4 adult and adolescent studies and 1 adult study, diarrhea occurred significantly more frequently in cefdinir recipients than in recipients of penicillin V, cephalexin, cefaclor, and cefprozil. Cefdinir is an alternative to other antimicrobial agents and can be dosed once or twice daily for the treatment of upper and lower respiratory tract infections and skin and skin-structure infections. Similar to other oral expanded-spectrum cephalosporins, cefdinir has activity against common pathogens of the respiratory tract and skin and is stable in the presence of selected beta-lactamases. The clinical choice of an oral expanded-spectrum cephalosporin will be based on patient acceptance, frequency of administration, and cost.


Incidence of myocardial infarction and vascular death in elderly patients with atrial fibrillation taking anticoagulants: relation to atherosclerotic risk factors.
Recent findings suggest that patients with atrial fibrillation (AF), in addition being at thromboembolic risk, are at risk of myocardial infarction (MI). Our aim was to investigate predictors of MI and cardiovascular death in a cohort of patients with AF who were taking anticoagulants. We prospectively followed up 1,019 patients with AF for a median of 33.7 months (3,223 person-years). All patients were treated with oral vitamin K antagonists. Primary outcome was a composite end point of cardiovascular events (CVEs) including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death. The mean age of the patients was 73.2 years, and 43.8% were women. At follow-up, 111 CVEs (3.43%/y) had occurred: 47 fatal-nonfatal MI/revascularization and 64 cardiovascular deaths. In addition, 31 stroke/transient ischemic attacks (0.96%/y) were recorded. Patients experiencing CVEs were older (P < .001) and had a higher prevalence of metabolic syndrome (MetS) (P = .005), heart failure (P = .001), and prior cardiac (P < .001) and cerebrovascular events (P < .001). On a Cox proportional hazard analysis, age (hazard ratio [HR], 1.083; 95% CI, 1.053-1.113; P < .001), smoking (HR, 2.158; 95% CI, 1.193-3.901; P = .011), history of cerebrovascular (HR, 1.704; 95% CI, 1.119-2.597; P = .013) and cardiac (HR, 1.658; 95% CI, 1.105-2.489; P = .015) events, MetS (HR, 1.663; 95% CI, 1.107-2.499; P = .014), heart failure (HR, 1.584; 95% CI, 1.021-2.456; P = .040), and male sex (HR, 1.499; 95% CI, 1.010-2.223; P = .044) predicted CVEs. Patients with AF still experience a high rate of CVEs despite receiving anticoagulant treatment. MetS is a common clinical feature in patients with AF, which increases the risk of CVEs. A holistic approach is needed to reduce the cardiovascular risk in patients with AF. ClinicalTrials.gov; No.: NCT01882114; URL: www.clinicaltrials.gov.


[A 46-year-old man with cardiac failure and statues epileptics].
We report a 46-year-old man with bacterial endocarditis and cardiac failure, who developed status epileptics. The patient was apparently well until July of 1991 when there was a gradual onset of fever and general fatigue. He was hospitalized to the cardiology service of our hospital where diagnosis of bacterial endocarditis and aortic insufficiency was made. On October 9, 1991, he suddenly developed cardiogenic shock, and emergency replacement of the aortic valve was made; at the operation, the main trunk of the left coronary artery showed embolic occlusion, and the myocardial movement was markedly diminished; serum creatine kinase was 3.150 IU/l. His cardiac failure did not resolve, and renal failure developed in December 1991, for which peritoneal dialysis was necessary. On February 2, 1992, he suddenly developed a clonic seizure which started from his face with a transient post-ictal left hemiparesis; a cranial CT scan was unremarkable. He was treated with phenytoin and glycerol, however, he developed status epileptics on February 3; he developed cardiac arrest after the injection of phenytoin 750 mg. He was resuscitated, however, his status did not resolve. Neurological consultation was asked on February 4. On physical examination, his blood pressure was 80/40 mmHg heart rate 77/min and regular, and body temperature 39.1 degrees C. The palpebral conjunctiva were slightly anemic, however, the bulbar conjunctiva were not icteric. No cervical adenopathy was noted. Glade II systolic murmur was heard in the apex; the lungs were clear. The abdomen was flat and soft without organomegaly. No edema was present in the legs. On neurologic examination, he was comatose without response to painful stimuli. He repeatedly had convulsion lasting for 30 seconds every 2 to 3 minutes; his convulsions started with the conjugate deviation of the eyes to the left followed by turning of the head toward left, and then clonic convulsions started in this left upper limb extending to other extremities. The optic fundi were unable to visualize because of corneal clouding; light reflex was sluggish on the right side; no oculocephalic response was elicited; corneal reflex was also lost bilaterally. Extremities were hypotonic, and no automatic movement was seen. The triceps brachii reflex was diminished, but all the other deep reflexes were lost; no plantar response was elicited. Meningeal sign was absent. He was treated with intravenous diazepam; the interval of convulsions prolonged, however, blood pressure dropped to 40 to 40 mmHg. On February 4, intravenous thiopental anesthesia was instituted, and assisted respiration was started.(ABSTRACT TRUNCATED AT 400 WORDS)


Lactoferrin stimulates the production of leucocyte migration inhibitory factor by human peripheral mononuclear leucocytes.
The effect of lactoferrin on the migration of human polymorphonuclear cells was investigated. High concentrations of lactoferrin (greater than 250 micrograms/ml) markedly inhibited the migration of granulocytes under agarose. This migration inhibition could not be neutralized by an antibody against leucocyte migration inhibitory factor (LIF), suggesting a direct effect of lactoferrin on the granulocytes. Low concentrations of lactoferrin were, however, indirectly capable of inhibiting neutrophil migration. The overnight culture of mononuclear leucocytes with low concentrations of lactoferrin (10 micrograms/ml) resulted in the release of granulocyte migration inhibiting factors in the cell free culture supernatant. Strong evidence indicating that the migration inhibiting factors were due to LIF, was obtained in experiments whereby the inhibitory activity could be completely neutralized by anti-LIF antibodies. The lactoferrin-mediated stimulation of LIF release by mononuclear leucocytes could be neutralized by an anti-lactoferrin serum, but not by an anti-albumin serum, whereas PPD-induced LIF release was not affected by either antiserum. These findings suggest that lactoferrin besides its well known anti-microbial properties, may also play a regulatory role in the migratory response of polymorphonuclear cells during inflammatory conditions.


[PI-RADS score of prostate multi-parametric magnetic resonance imaging predicts pathological features of prostate cancer: An imaging to whole-mount pathology matching study].
To explore the value of the prostate imaging reporting and data system (PI-RADS) score of prostate multi-parametric magnetic resonance imaging (mpMRI) in predicting the pathological features of PCa based on matching images and whole-mount pathology images. This retrospective study included 318 cases of PCa treated by radical prostatectomy in our hospital from August 2016 to December 2018, with preoperative mpMRI images and complete whole-mount pathological sections. We obtained PI-RADS scores on the mpMRI lesions corresponding to the cancer lesions, evaluated the Gleason scores, pT stages, pN stages and cribriform structure, and compared them between different groups using Chi-square test or Fisher's exact test. We evaluated the efficiency of the PI-RADS score in distinguishing different pathological features by ROC curve analysis, and obtained the corresponding area under the curve (AUC) and 95% confidence interval (CI). The 318 patients averaged 69 years of age, with a median preoperative PSA level of 11.0 μg/L and a median tumor diameter of 1.8 cm. The PI-RADS score was significantly correlated with the Gleason score, pT stage, pN stage and cribriform structure (all P < 0.01), with AUCs of 0.773 (95% CI: 0.704-0.843) for distinguishing Gleason scores (3+3 vs >3+3), 0.748 (95% CI: 0.694-0.803) for distinguishing pT stages (T2 vs >T2), 0.700 (95% CI: 0.598-0.802) for distinguishing pN stages (N0 vs N1), and 0.831 (95% CI: 0.786-0.876) for distinguishing the cribriform structure (negative vs positive). The preoperative PI-RADS score of mpMRI in PCa patients is significantly correlated with postoperative pathological features, and therefore can be used for risk stratification of the malignancy.


Rodent Brain Microinjection to Study Molecular Substrates of Motivated Behavior.
Brain microinjection can aid elucidation of the molecular substrates of complex behaviors, such as motivation. For this purpose rodents can serve as appropriate models, partly because the response to behaviorally relevant stimuli and the circuitry parsing stimulus-action outcomes is astonishingly similar between humans and rodents. In studying molecular substrates of complex behaviors, the microinjection of reagents that modify, augment, or silence specific systems is an invaluable technique. However, it is crucial that the microinjection site is precisely targeted in order to aid interpretation of the results. We present a method for the manufacture of surgical implements and microinjection needles that enables accurate microinjection and unlimited customizability with minimal cost. Importantly, this technique can be successfully completed in awake rodents if conducted in conjunction with other JoVE articles that covered requisite surgical procedures. Additionally, there are many behavioral paradigms that are well suited for measuring motivation. The progressive ratio is a commonly used method that quantifies the efficacy of a reinforcer to maintain responding despite an (often exponentially) increasing work requirement. This assay is sensitive to reinforcer magnitude and pharmacological manipulations, which allows reinforcing efficacy and/ or motivation to be determined. We also present a straightforward approach to program operant software to accommodate a progressive ratio reinforcement schedule.


Insight into c-di-GMP Regulation in Anammox Aggregation in Response to Alternating Feed Loadings.
Substrate concentrations generally fluctuate in wastewaters. However, how anammox biomass behaves to overcome the stress of alternating feed loadings remains unclear. Here, we combined long-term reactor operation, batch tests, 16S rRNA transcript sequencing, and metabolomics analysis to investigate the aggregation of anammox biomass under the regulation of c-di-GMP, a key second messenger, in response to alternating feed loadings. We demonstrated that the aggregation process was significantly faster under alternating loadings and was significantly correlated with higher levels of c-di-GMP and extracellular polymeric substances (EPS) production. The increase in c-di-GMP was positively correlated with a higher relative transcript expression level in the c-di-GMP pathway-dependent community. The targeted metabolomics results indicated that the increased production of fructose 6-phosphate and UDP-N-acetyl-d-glucosamine, the precursor substances for the synthesis of exopolysaccharides, was induced by higher levels of c-di-GMP. Consequently, the granulation process was accelerated via EPS production. Higher levels of intracellular hydrophobic amino acids were also positively correlated with increased extracellular protein levels, considering the significant increase in peptides under alternating loadings. On the basis of our findings, we believe that c-di-GMP regulation and EPS production of the anammox biomass are important mechanisms to enhance its tolerance against unfavorable feed stress. These results highlight the role of c-di-GMP in anammox biomass as it works to survive in unfavorable niches.


Ambroxol suppresses influenza-virus proliferation in the mouse airway by increasing antiviral factor levels.
The protective effect of ambroxol, a mucolytic agent which has antioxidant properties and stimulates the release of pulmonary surfactant, against influenza-virus proliferation in the airway was investigated in mice. Ambroxol or the vehicle was administered intraperitoneally twice a day for 5-7 days to mice shortly after intranasal infection with a lethal dose of influenza A/Aichi/68 (H3N2) virus, and the survival rate, virus titre and levels of factors regulating virus proliferation in the airway fluid were analysed. Ambroxol significantly suppressed virus multiplication and improved the survival rate of mice. The effect of ambroxol reached a peak at 10 mg x kg(-1) x day(-1), higher doses being less effective. Ambroxol stimulated the release of suppressors of influenza-virus multiplication, such as pulmonary surfactant, mucus protease inhibitor, immunoglobulin (Ig)-A and IgG, although it stimulated the release of a trypsin-type protease that potentiates virus proliferation. In addition, ambroxol transiently suppressed release of the cytokines, tumour necrosis factor-alpha, interferon-gamma and interleukin-12, into airway fluid. Although ambroxol had several negative effects on the host defence system, overall it strikingly increased the concentrations of suppressors of influenza-virus multiplication in the airway.


Modelling of oxygen vacancy aggregates in monoclinic HfO2: can they contribute to conductive filament formation?
Formation of metal rich conductive filaments and their rearrangements determine the switching characteristics in HfO2 based resistive random access memory (RRAM) devices. The initiation of a filament formation process may occur either via aggregation of pre-existing vacancies randomly distributed in the oxide or via generation of new oxygen vacancies close to the pre-existing ones. We evaluate the feasibility of vacancy aggregation processes by calculating the structures and binding energies of oxygen vacancy aggregates consisting of 2, 3 and 4 vacancies in bulk monoclinic (m)-HfO2 using density functional theory (DFT). We demonstrate that formation of neutral oxygen vacancy aggregates is accompanied by small energy gain, which depends on the size and shape of the aggregate. In the most strongly bound configurations, vacancies are unscreened by Hf cations and form voids within the crystal, with the larger aggregates having larger binding energy per vacancy (-0.11 to -0.18 eV). The negatively charged di-vacancy was found to have similar binding energies to the neutral one, while the positively charged di-vacancy was found to be unstable. Thus aggregation process of either neutral or negatively charged oxygen vacancies is energetically feasible.


Tool-use for drinking water by immature chimpanzees of Mahale: prevalence of an unessential behavior.
Use of leaves or sticks for drinking water has only rarely been observed during long-term study of wild chimpanzees (Pan troglodytes schweinfurthii) at Mahale. Recently, however, we observed 42 episodes of tool-use for drinking water (73 tools and two cases of using "tool-sets") between 1999 and 2004. Interestingly, all of the performers were immature chimpanzees aged from 2 to 10 years. Immature chimpanzees sometimes observed the tool-using performance of others and subsequently reproduced the behavior, while adults usually paid no attention to the performance. This tool-use did not seem to occur out of necessity: (1) chimpanzees often used tools along streams where they could drink water without tools, (2) they used tools for drinking water from tree holes during the wet season when they could easily obtain water from many streams, and (3) the tool-using performance sometimes contained playful aspects. Between-site comparisons revealed that chimpanzees at drier habitats used tools for drinking water more frequently and in a more "conventional" manner. However, some variations could not be explained by ecological conditions. Such variations and the increase in this tool-use in recent years at Mahale strongly suggest that social learning plays an important role in the process of acquiring the behavior. We should note here that such behaviors that lack obvious benefits or necessity can be prevalent in a group.


Nutritional profile of patients in a multidisciplinary treatment program for severe obesity and preoperative bariatric surgery.
Along with the augmentation in obesity rates in recent years, the demand for bariatric surgery has startlingly increased. Nutritional counseling in the preoperative period is very important because it contributes to higher success rate in the post-operative period. To assess the nutritional status of patients in a multidisciplinary program for the treatment of severe obesity and pre-operatively for bariatric surgery, characterizing the consumption of healthy nutrients. A retrospective analysis of 30 patients was conducted. Personal information, anthropometric data and dietary assessment by 24-hour food record were collected. The analysis of energy intake was performed in Dietpro 5.1 Professional(r) program. The statistical treatment of the caloric intake was performed by an ANOVA test with Bonferroni's post hoc and for anthropometric data the paired t test was used. From the total, 73% of the patients were women and 27% male, mean age was 48.4+12.9 and 49.8+8.1, respectively. A lower weight in the 5th appointment was observed when compared with the 1st one. There was a reduction in caloric intake in the 2nd, 3rd, 4th and 5th appointments when compared with the 1st. It was observed that in the 5th appointment more than 50% of the patients underwent six meals a day. There was an increase in the consumption of fruit along the appointments and 72.2% of patients consumed 1-2 servings of fruit a day. Vegetables intake was high in all appointments in the pre-operative period and, although low, the whole grain products consumption has increased during the pre-operative period achieving 30% of the study population. There was a decrease in body weight, a trend in the decrease of the body mass index and waist circumference and quantitative and qualitative improvement of food consumption.


BES1 and BZR1 Redundantly Promote Phloem and Xylem Differentiation.
Vascular development is a good model for studying cell differentiation in plants. Two conductive tissues, the xylem and phloem, are derived from common stem cells known as procambial/cambial cells. Glycogen synthase kinase 3 proteins (GSK3s) play crucial roles in maintaining procambial/cambial cells by suppressing their differentiation into xylem or phloem cells. We previously designed an in vitro culture system for analyzing vascular cell differentiation named VISUAL (Vascular cell Induction culture System Using Arabidopsis Leaves). Using this system, we found that the transcription factor BRI1-EMS-SUPPRESSOR 1 (BES1) functions as a downstream target of GSK3s during xylem differentiation. However, the function of BES1 in vascular development remains largely unknown. Here, we found that, in addition to xylem differentiation, BES1 positively regulates phloem differentiation downstream of GSK3s. Transcriptome analysis using VISUAL confirmed that BES1 promotes bi-directional differentiation of procambial cells into xylem and phloem cells. Genetic analysis of loss-of-function mutants newly generated using the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system revealed that BRASSINAZOLE RESISTANT 1 (BZR1), the closest homolog of BES1, functions in vascular development redundantly with BES1. Notably, BZR1 has a weaker impact on vascular cell differentiation than BES1, suggesting that they contribute differentially to this process. In conclusion, our findings indicate that BES1 and BZR1 are key regulators of both xylem and phloem cell differentiation from vascular stem cells.


Genotype variation of ACE and ACE2 genes affects the severity of COVID-19 patients.
Genetic polymorphisms in ACE and ACE2 genes are involved in the RAS regulation of blood pressure and their activity may confer susceptibility to hypertension. In addition, they may play a role in SARS-CoV-2 pathogenesis and the severity of COVID-19. This study aims to determine the effect of genetic variations in the ACE (rs4331) and ACE2 (rs2074192) genes with hypertension comorbidity on the severity of COVID-19 in the Indonesian population. 186 patients were enrolled and assigned into the COVID-19 group (n = 95) and non-COVID-19 group (n = 91) in this cross-sectional study. GG genotype frequency was dominant in ACE gene, but there were no significant differences between the groups (p = 0.163). The two groups had a significant difference (p = 0.000) for the CC genotype frequency (0,37 vs. 0.01) in the ACE2 gene. The proportion of women with COVID-19 is higher (51%), but men with hypertension had more severe symptoms (44%). Men with hypertension comorbidity, GG (ACE), and TT (ACE2) genotypes tended to have moderate-to-severe symptoms (25%). Similarly, women with hypertension as well as GG and CT genotypes tended to have moderate-to-severe symptoms (21%). We conclude that hypertension and mutations in the ACE (rs4331) and ACE2 (rs2074192) genes affect the severity of COVID-19.


Hispanic mortality paradox: a systematic review and meta-analysis of the longitudinal literature.
To investigate the possibility of a Hispanic mortality advantage, we conducted a systematic review and meta-analysis of the published longitudinal literature reporting Hispanic individuals' mortality from any cause compared with any other race/ethnicity. We searched MEDLINE, PubMed, EMBASE, HealthSTAR, and PsycINFO for published literature from January 1990 to July 2010. Across 58 studies (4 615 747 participants), Hispanic populations had a 17.5% lower risk of mortality compared with other racial groups (odds ratio = 0.825; P < .001; 95% confidence interval = 0.75, 0.91). The difference in mortality risk was greater among older populations and varied by preexisting health conditions, with effects apparent for initially healthy samples and those with cardiovascular diseases. The results also differed by racial group: Hispanics had lower overall risk of mortality than did non-Hispanic Whites and non-Hispanic Blacks, but overall higher risk of mortality than did Asian Americans. These findings provided strong evidence of a Hispanic mortality advantage, with implications for conceptualizing and addressing racial/ethnic health disparities.


Equilibrating immigration and anthracene-maleimide-based Diels-Alder-trapping of octylmaleimide in mixed photo-cross-linked polymer micelles.
It is possible that the hydrophobic guest within amphiphilic polymer micelles may leak out and be captured by other species before polymer micelles adhere to the desired focus because of the complexity in an actual release procedure, rendering the reduced efficiency of the nanocarrier system. To describe such a scenario, two water-soluble fluorescent amphiphilic random copolymers of PAV and PAA with photo-cross-linkable coumarin and anthracene pendants, respectively, were chosen to investigate the equilibrating immigration and maleimide-anthracene-based Diels-Alder-trapping of hydrophobic octylmaleimide guest from one type of photo-cross-linked polymer micelles of PAV85% to another of PAA66% in aqueous solution using the emission and absorption spectra techniques.


Retroviral vectors containing chimeric promoter/enhancer elements exhibit cell-type-specific gene expression.
Retroviral vectors were constructed in which the U3 promoter/enhancer of Moloney murine leukemia (Mo-MLV) was replaced by the corresponding region from five related murine retroviruses--AKR murine leukemia virus (AKV), Harvey murine sarcoma virus (HaMSV), myeloproliferative sarcoma virus (MPSV), SL3-3, and the NZB-xenotropic virus (Xeno). In these vectors the chimeric long terminal repeat (chLTR) drives the expression of the chloramphenicol acetyl transferase (CAT) reporter gene that is followed by an internal SV40 virus early region promoter linked to the neomycin phosphotransferase II (NEO) gene. As an initial measure of the relative promoter/enhancer strength of the chLTR vectors, the murine NIH-3T3 cell line and the human JURKAT cell lines were transfected and assayed for CAT reporter activity. Relative to the MoMLV vector, the HaMSV construct was the most active in NIH-3T3 cells whereas the SL3-3 vector displayed the greatest activity in JURKAT cells. Retroviral vector producer cell populations and cell clones were established for each chLTR vector, and all were capable of yielding high vector titers (> 10(5) G418R cfu/ml on NIH-3T3). Supernatant from these cells was used to transduce both mouse and human cell lines and primary cells. In NIH-3T3 cells and two murine fibrosarcoma cell lines, the HaMSV chLTR vector was slightly more active than the MoMLV chLTR vector. In the human HepG2 and HeLa cell lines, the MPSV chLTR vector was the most active. Data from the human JURKAT T-cell line and a T cell line derived from an ADA-deficient severe combined immunodeficiency (SCID) patient demonstrate that the SL3-3 chLTR is the most active in these lymphoid cell lines. The greatest difference in the comparison of the different chLTR vectors was observed in primary human umbilical vein endothelial cells, where the MoMLV vector produced up to 100 times more CAT activity than the SL3-3 vector. These data suggest that the use of specific promoter/enhancer elements may lead to higher levels of gene expression following retroviral-mediated gene transfer into specific cell types and these observations may be useful in the design of human gene therapy experiments.


Associations Between Ross River Virus Infection in Humans and Vector-Vertebrate Community Ecology in Brisbane, Australia.
Transmission of vector-borne pathogens can vary in complexity from single-vector, single-host systems through to multivector, multihost vertebrate systems. Understanding the dynamics of transmission is important for disease prevention efforts, but is dependent on disentangling complex interactions within coupled natural systems. Ross River virus (RRV) is a multivector multihost pathogen responsible for the greatest number of notified vector-borne pathogen infections in humans in Australia. Current evidence suggests that nonhuman vertebrates are critical for the maintenance and spillover of RRV into mosquito populations. Yet, there is a limited knowledge of which mosquito vector species and amplifying vertebrate host species are most important for transmission of RRV to humans. We conducted field surveys of nonhuman vertebrates and mosquitoes in the RRV endemic city of Brisbane, Australia, to assess the effect of vector and host community structure on human RRV notifications. Six suburbs were selected across a gradient of human disease notification rates. Differences in vertebrate and mosquito compositions were observed across all suburbs. Suburbs with higher RRV notification rates contained greater vertebrate biomass (dominated by the presence of horses) and higher mosquito abundances. This study suggests that horse-mosquito interactions should be considered in more detail and that vertebrate biomass and mosquito abundance be incorporated into future RRV modeling studies and considered in public health strategies for RRV management.


[Bone metabolic markers for evaluation of bone metastases].
Bone metabolic markers consist of bone formation markers, which are secreted from osteoblasts (BAP, OC, P1CP, P1NP) , and bone resorption markers, which are metabolites of bone type 1 collagen or secreted from osteoclasts (PYD, DPD, NTX, CTX, 1CTP, TRACP) . Those bone metabolic markers are useful for : (1) diagnosis of bone metastases, (2) follow-up during treatment of bone metastases, and (3)predicting prognosis of bone metastases.


Roadmap to Value Driven Health Care.
Uncertainty over future health care costs is a major concern to business and acts as a throttle, limiting new investment. This article discusses how the North Carolina Chamber is committed to making North Carolina a top-10 state for health care value, thus creating a robust business environment across the state.


Combined Inhibition of the TGF-β1/Smad Pathway by Prevotella copri and Lactobacillus murinus to Reduce Inflammation and Fibrosis in Primary Sclerosing Cholangitis.
Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease characterized by inflammation and fibrosis of the bile ducts. Cholestasis may lead to hepatic inflammation and fibrosis, and amelioration of cholestasis may allow recovery from inflammatory and fibrotic pathological damage. Prevotella copri (P. copri) interventions have been reported to significantly improve cholestasis and liver fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced PSC mouse models. Even though P. copri treatment alone cannot bring about recovery from DDC-induced inflammation, it increases the abundance of Lactobacillus murinus (L. murinus) compared with DDC treatment, which has been reported to have anti-inflammatory effects. The abundance of L. murinus still not recovering to a normal level may underlie hepatic inflammation in P. copri + DDC mice. Separate or combined interventions of P. copri and L. murinus were used to investigate the molecular mechanism underlying the improvement in PSC inflammation and fibrosis. P. copri and L. murinus significantly reduced the hepatic inflammatory cell aggregation and inflammatory factor expression as well as the hepatic collagen content and fibrin factor expression in the PSC mice. Further analysis of phosphorylation and dephosphorylation levels revealed that treating the PSC mice with the P. copri and L. murinus combined intervention inhibited the activity of the DDC-activated TGF-β1/Smad pathway, thereby reducing liver inflammation and fibrosis. The combination of P. copri and L. murinus inhibits the TGF-β1/Smad pathway and reduces inflammation and fibrosis in PSC.


A logical model of HIV-1 interactions with the T-cell activation signalling pathway.
Human immunodeficiency virus type 1 (HIV-1) hijacks host cellular processes to replicate within its host. Through interactions with host proteins, it perturbs and interrupts signaling pathways that alter key cellular functions. Although networks of viral-host interactions have been relatively well characterized, the dynamics of the perturbation process is poorly understood. Dynamic models of infection have the potential to provide insights into the HIV-1 host interaction. We employed a logical signal flow network to model the dynamic interactions between HIV-1 proteins and key human signal transduction pathways necessary for activation of CD4+ T lymphocytes. We integrated viral-host interaction and host signal transduction data into a dynamic logical model comprised of 137 nodes (16 HIV-1 and 121 human proteins) and 336 interactions collected from the HIV-1 Human Interaction Database. The model reproduced expected patterns of T-cell activation, co-stimulation and co-inhibition. After simulations, we identified 26 host cell factors, including MAPK1&3, Ikkb-Ikky-Ikka and PKA, which contribute to the net activation or inhibition of viral proteins. Through in silico knockouts, the model identified a further nine host cell factors, including members of the PI3K signalling pathway that are essential to viral replication. Simulation results intersected with the findings of three siRNA gene knockout studies and identified potential drug targets. Our results demonstrate how viral infection causes the cell to lose control of its signalling system. Logical Boolean modelling therefore provides a useful approach for analysing the dynamics of host-viral interactions with potential applications for drug discovery. Supplementary data are available at Bioinformatics online.


Real-time polymerase chain reaction for the diagnosis of necrotizing herpes stromal keratitis.
To design, optimize and validate a rapid, internally controlled real-time polymerase chain reaction (RT-PCR) test for herpes simplex virus (HSV) in the diagnosis of necrotizing herpes stromal keratitis. Tears alone or together with corneal epithelium scrapings from 30 patients (30 eyes) suspected of necrotizing herpes stromal keratitis were tested for HSV DNA by RT-PCR. The samples were collected during the first visit and then on the subsequent 7, 14, 28, 42, and 56d. The symptoms of the patients were scored before treatment to determine the correlation between HSV concentration in the corneal epithelium scrapings and clinical scores. The positive rate (46.4%) in the corneal epithelium group before the therapy was significantly higher than that (13.3%) in the tears group (P=0.006). There were 13 positive HSV patients before the therapy, the concentration of HSV DNA in corneal epithelium scrapings group was significantly higher than that in the tears group (paired t-test, P=0.0397). Multilevel mixed-effects model analysis showed that the difference between the corneal epithelium scrapings group and the tears group was statistically significant (P=0.0049). The Spearman rank correlation analysis indicated a positive correlation between the HSV concentration in the corneal epithelium scrapings and clinical scores before the treatment (r=0.844, P<0.0001). RT-PCR appears to be a powerful molecular tool for the diagnosis of necrotizing herpes stromal keratitis.


Co-operative ionisation of aspartic-acid-158 and histidine-159 in papain. Evidence from 19F nuclear-magnetic-resonance and fluorescence spectroscopy.
The chemical shift of the single resonance in the 19F nuclear magnetic resonance spectrum of papain which has been irreversibly inhibited by 3-bromo-1,1,1-trifluoropropanone, exhibits pH-dependence. The fluorescence intensity of this papain derivative shows pH-dependence on two groups which exhibit co-operative ionisation. This co-operative behaviour is probably a function of the probe since the fluorescence intensity of S-ethane-thio-papain is dependent on a single ionisation constant, whereas that of S-(2-hydroxyethane)-thio-papain is dependent on two ionisable groups again acting co-operatively. The 1,1,1-trifluoroketone probe will be hydrated in aqueous solution and would be capable of hydrogen bonding with the protein. The two groups detected are considered to be aspartic-acid-158 and histidine-159. The co-operative ionisation of these groups in substrate hydrolysis is discussed.


The influence of music on mental effort and driving performance.
The current research examined the influence of loud music on driving performance, and whether mental effort mediated this effect. Participants (N=69) drove in a driving simulator either with or without listening to music. In order to test whether music would have similar effects on driving performance in different situations, we manipulated the simulated traffic environment such that the driving context consisted of both complex and monotonous driving situations. In addition, we systematically kept track of drivers' mental load by making the participants verbally report their mental effort at certain moments while driving. We found that listening to music increased mental effort while driving, irrespective of the driving situation being complex or monotonous, providing support to the general assumption that music can be a distracting auditory stimulus while driving. However, drivers who listened to music performed as well as the drivers who did not listen to music, indicating that music did not impair their driving performance. Importantly, the increases in mental effort while listening to music pointed out that drivers try to regulate their mental effort as a cognitive compensatory strategy to deal with task demands. Interestingly, we observed significant improvements in driving performance in two of the driving situations. It seems like mental effort might mediate the effect of music on driving performance in situations requiring sustained attention. Other process variables, such as arousal and boredom, should also be incorporated to study designs in order to reveal more on the nature of how music affects driving.


Adductor-related groin pain in competitive athletes. Role of adductor enthesis, magnetic resonance imaging, and entheseal pubic cleft injections.
Adductor dysfunction is a condition that can cause groin pain in competitive athletes, but the source of the pain has not been established and no specific interventions have been evaluated. We previously defined a magnetic resonance imaging protocol to visualize adductor enthesopathy. The aim of this study was to elucidate, in the context of adductor-related groin pain in the competitive athlete, the role of the adductor enthesis (origin), the relevance of adductor enthesopathy diagnosed with magnetic resonance imaging, and the efficacy of entheseal pubic cleft injections of local anesthetic and steroids. We reviewed the findings in a consecutive series of twenty-four competitive athletes who had presented to our sports medicine clinic with groin pain secondary to adductor longus dysfunction. Magnetic resonance imaging was performed to assess the adductor longus origin for the presence or absence of enthesopathy. Seven patients (Group 1) had no evidence of enthesopathy on magnetic resonance imaging, and seventeen patients (Group 2) had enthesopathy confirmed on magnetic resonance imaging. All patients were treated with a single pubic cleft injection of local anesthetic and steroid into the adductor enthesis. At one year after this treatment, the patients were assessed for recurrence of symptoms. On clinical reassessment five minutes after the injection, all twenty-four athletes reported resolution of the groin pain. At one year, none of the seven patients in Group 1 had experienced a recurrence. Sixteen of the seventeen patients in Group 2 had a recurrence of the symptoms (p < 0.001) at a mean of five weeks (range, one to sixteen weeks) after the injection. A single entheseal pubic cleft injection can be expected to afford at least one year of relief of adductor-related groin pain in a competitive athlete with normal findings on a magnetic resonance imaging scan; however, it should be employed only as a diagnostic test or short-term treatment for a competitive athlete with evidence of enthesopathy on magnetic resonance imaging.


Scale of VO(2peak) in obese and non-obese adolescents by different methods.
Peak oxygen uptake (VO(2peak)) can be defined as the highest oxygen rate consumed during exhaustive or maximal exercise. The evaluation of the aerobic fitness can be expressed as relative to body mass, but this procedure may not fully remove differences when heavy subjects are assessed. Thus, the allometric scaling procedure is an attractive strategy to compare individuals with large differences in body mass. Investigate VO(2peak) in obese and non-obese individuals using body mass correction (conventional) and allometric scaling (allometric) methods and how these methods apply when subjects of different genders exercise on a treadmill. VO(2peak) relative to body weight and measured by the allometric method were compared in 54 obese and 33 non-obese adolescents (10 a 16 years). Indirect calorimetry was used to assess VO(2peak) during a maximal test. The allometric exponent was calculated taking into account individual body mass. Then, VO(2peak) was corrected by the allometric exponent. The comparisons were performed using a repeated measures two-way ANOVA (p<0.05). The absolute VO(2peak) was higher (p<0.05) in the obese girls (2.80+/-0.69) compared to non-obese ones (2.00+/-0.24), but this association was not observed for the male subjects (p>0.05). However, VO(2peak) calculated by the conventional method was higher (p<0.05) among non-obese individuals in both genders (girls: 41.45+/-3.85; boys: 49.81+/-7.12) in comparison to the obese subjects (girls: 32.11+/-4.48; boys: 37.54+/-6.06). The allometric VO(2peak) was similar (p>0.05) between the groups. The obese showed lower VO(2peak) values than non-obese individuals when assessed by the conventional method. However, when the allometric scaling method was applied, differences disappeared.


Mechanical overtone frequency combs.
Mechanical frequency combs are poised to bring the applications and utility of optical frequency combs into the mechanical domain. So far, their main challenge has been strict requirements on drive frequencies and power, which complicate operation. We demonstrate a straightforward mechanism to create a frequency comb consisting of mechanical overtones (integer multiples) of a single eigenfrequency, by monolithically integrating a suspended dielectric membrane with a counter-propagating optical trap. The periodic optical field modulates the dielectrophoretic force on the membrane at the overtones of a membrane's motion. These overtones share a fixed frequency and phase relation, and constitute a mechanical frequency comb. The periodic optical field also creates an optothermal parametric drive that requires no additional power or external frequency reference. This combination of effects results in an easy-to-use mechanical frequency comb platform that requires no precise alignment, no additional feedback or control electronics, and only uses a single, mW continuous wave laser beam. This highlights the overtone frequency comb as the straightforward future for applications in sensing, metrology and quantum acoustics.


Characterization of the Lipidomic Profile of Human Coronavirus-Infected Cells: Implications for Lipid Metabolism Remodeling upon Coronavirus Replication.
Lipids play numerous indispensable cellular functions and are involved in multiple steps in the replication cycle of viruses. Infections by human-pathogenic coronaviruses result in diverse clinical outcomes, ranging from self-limiting flu-like symptoms to severe pneumonia with extrapulmonary manifestations. Understanding how cellular lipids may modulate the pathogenicity of human-pathogenic coronaviruses remains poor. To this end, we utilized the human coronavirus 229E (HCoV-229E) as a model coronavirus to comprehensively characterize the host cell lipid response upon coronavirus infection with an ultra-high performance liquid chromatography-mass spectrometry (UPLC⁻MS)-based lipidomics approach. Our results revealed that glycerophospholipids and fatty acids (FAs) were significantly elevated in the HCoV-229E-infected cells and the linoleic acid (LA) to arachidonic acid (AA) metabolism axis was markedly perturbed upon HCoV-229E infection. Interestingly, exogenous supplement of LA or AA in HCoV-229E-infected cells significantly suppressed HCoV-229E virus replication. Importantly, the inhibitory effect of LA and AA on virus replication was also conserved for the highly pathogenic Middle East respiratory syndrome coronavirus (MERS-CoV). Taken together, our study demonstrated that host lipid metabolic remodeling was significantly associated with human-pathogenic coronavirus propagation. Our data further suggested that lipid metabolism regulation would be a common and druggable target for coronavirus infections.


Grain number and grain yield distribution along the spike remain stable despite breeding for high yield in winter wheat.
Two winter wheat (Triticum aestivum L.) populations, i.e. 180 genetic resources and 210 elite varieties, were compared in a field trial to analyse how grain number and grain yield distribution along the spike changed during the breeding process and how this associates to yield-related traits. Elites showed in average 38% more yield compared to resources. This breeding improvement mainly derived from an increase in grains and yield per spike in addition to grains and yield per spikelet. These increments corresponded to 19, 23, 21 and 25%, respectively. Not much gain in thousand grain weight (4%) was observed in elites as compared to resources. The number of spikelets per spike was not, or even negatively, correlated with most traits, except of grains per spike, which suggests that this trait was not favoured during breeding. The grain number and grain yield distributions along the spike (GDAS and GYDAS) were measured and compared by using a novel mathematical tool. GDAS and GYDAS measure the deviation of a spike of interest from the architecture of a model spike with even grain and yield distribution along all spikelets, respectively. Both traits were positively correlated. Elites showed in average only a 1% improvement in GDAS and GYDAS values compared to resources. This comparison revealed that breeding increased grain number and yield uniformly along the spike without changing relative yield input of individual spikelets, thereby, maintaining the general spike architecture.


Effect of heart rate on regional coronary blood flow.
The effect of tachycardia on the distribution of coronary blood flow was studied in the dog using the radioactive microsphere technique. Increasing heart rate from 1.7 to 3.0 Hz produced an increment of flow to the inner and outer layer of both ventricular walls. However, the flow ratio, inner layer to outer layer, increased in the right ventricular wall and decreased in the left wall. Measurements performed in ventricular regions with previous vasodilatation and during right ventricular hypertension revealed that the comparatively larger vasodilatation reserve of the right ventricular subendocardium is due to the lower pressure this ventricle develops normally.


Cross-Linked Gold-Nanoparticle Membrane Resonators as Microelectromechanical Vapor Sensors.
We report a novel approach for the detection of volatile compounds employing electrostatically driven drumhead resonators as sensing elements. The resonators are based on freestanding membranes of alkanedithiol cross-linked gold nanoparticles (GNPs), which are able to sorb analytes from the gas phase. Under reduced pressure, the fundamental resonance frequency of a resonator is continuously monitored while the device is exposed to varying partial pressures of toluene, 4-methylpentan-2-one, 1-propanol, and water. The measurements reveal a strong, reversible frequency shift of up to ∼10 kHz, i.e., ∼5% of the fundamental resonance frequency, when exposing the sensor to toluene vapor with a partial pressure of ∼20 Pa. As this strong shift cannot be explained exclusively by the mass uptake in the membrane, our results suggest a significant impact of analyte sorption on the pre-stress of the freestanding GNP membrane. Thus, our findings point to the possibility of designing highly sensitive resonators, which utilize sorption induced changes in the membrane's pre-stress as primary transduction mechanism.


[The relationship between intrapartum fetal heart rate disturbances, electrocardiographic changes and umbilical venous troponin-I (T-I)].
To analyse the relationship between intrapartum fetal heart rate disturbances and electrocardiographic changes and umbilical venous troponin-I (T-I), concentrations as well. 14 fetuses were continuously surveyed by CTG and ECG recordings in the first and second stage of labor, using STAN S-21 analyser. After birth, umbilical venous blood samples were collected for determination of acid-base balance, base excess and troponin-I concentrations. From among monitored fetuses, in 8 cases the CTG and FECG patterns were correct. Vaginally delivered neonates were born in good clinical status, with normal acid-base balance, base excess and T-I < 0.3 ng/ml. In 3 cases abnormal CTG patterns were observed with early decelerations but FECG patterns were correct. Vaginally delivered neonates were born in good clinical status, with normal acid-base balance, base excess and T-I < 0.3 ng/ml. In 2 cases abnormal CTG patterns were observed with variable decelerations but FECG patterns were correct. Vaginally delivered neonates were born in good clinical status, with normal acid-base balance, base excess and T-I < 0.3 ng/ml. In one case abnormal CTG pattern were observed with late decelerations but FECG patterns was correct. The pregnancy was terminated by caesarean section because of fetal distress. The neonate was born in good clinical status with normal acid-base balance and base excess but T-I concentration was increased (1.5 ng/ml).


Wound infection with Neisseria weaveri and a novel subspecies of pasteurella multocida in a child who sustained a tiger bite.
A 7-year-old girl developed a wound infection as a result of a tiger bite she sustained. DNA sequence analysis revealed that the causative organisms were Neisseria weaveri and what is, to our knowledge, a previously undescribed subspecies of Pasteurella multocida, for which we propose the designation "Pasteurella multocida subspecies tigris subspecies nov."


Antiviral Efficacy of Pralatrexate against SARS-CoV-2.
Novel coronavirus (SARS-CoV-2) has caused more than 100 million confirmed cases of human infectious disease (COVID-19) since December 2019 to paralyze our global community. However, only limited access has been allowed to COVID-19 vaccines and antiviral treatment options. Here, we report the efficacy of the anticancer drug pralatrexate against SARS-CoV-2. In Vero and human lung epithelial Calu-3 cells, pralatrexate reduced viral RNA copies of SARS-CoV-2 without detectable cytotoxicity, and viral replication was successfully inhibited in a dose-dependent manner. In a time-to-addition assay, pralatrexate treatment at almost half a day after infection also exhibited inhibitory effects on the replication of SARS-CoV-2 in Calu-3 cells. Taken together, these results suggest the potential of pralatrexate as a drug repurposing COVID-19 remedy.


NOS antagonism using viral vectors as an experimental strategy: implications for in vivo studies of cardiovascular control and peripheral neuropathies.
Nitric oxide, a free gaseous signalling molecule, has attracted the attention of numerous biologists and has been implicated in the regulation of the cardiovascular, nervous and immune system. However, the cellular mechanisms mediating nitric oxide modulation remain unclear. Upregulation by gene over-expression or down-regulation by gene inactivation of nitric oxide synthase has generated quantitative changes in abundance thereby permitting functional insights. We have tested and proved that genetic nitric oxide synthase antagonism using viral vectors, particularly with dominant negative mutants and microRNA 30-based short hairpin RNA, is an efficient and effective experimental approach to manipulate nitric oxide synthase expression both in vitro and in vivo.


Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case-control study protocol for dimethyl fumarate-induced lymphopenia.
Adverse drug reactions (ADRs) are a global public health issue. The potential for pharmacogenomic biomarkers has been demonstrated in several therapeutical areas, including HIV infection and oncology. Dimethyl fumarate (DMF) is a licensed disease-modifying therapy for the treatment of multiple sclerosis (MS). The use of DMF in MS has been associated with a severe reduction in lymphocyte counts and reports of progressive multifocal leukoencephalopathy. Here, we outline the protocol for a case-control study designed to discover genomic variants associated with DMF-induced lymphopenia. The ultimate goal is to replicate these findings and create an efficient and adaptable approach towards the identification of genomic markers that could assist in mitigating adverse drug reactions in MS. The population sample will comprise DMF-exposed patients with MS, with cases representing those who developed lymphopenia and controls who did not. DNA genotyping will take place using a high-throughput genome-wide array. Fine mapping and imputation will be performed to focus in on the potentially causal variants associated with lymphopenia. Multivariable logistic regression will be used to compare genotype and allele frequencies between the cases and the controls, with consideration of potential confounders. The association threshold will be set at p<1.0×10-5 for the discovery of genomic association analyses to select variants for replication. Ethics approval has been obtained from the respective research ethics board, which includes written informed consent. Findings will be disseminated widely, including at scientific conferences, via podcasts (targeted at both healthcare professionals as well as patients and the wider community), through patient engagement and other outreach community events, written lay summaries for all participants and formal publication in peer-reviewed scientific journals.