Single Agent Antihypertensive Therapy and Orthostatic Blood Pressure Behaviour in Older Adults Using Beat-to-Beat Measurements: The Irish Longitudinal Study on Ageing.
Impaired blood pressure (BP) stabilisation after standing, defined using beat-to-beat measurements, has been shown to predict important health outcomes. We aimed to define the relationship between individual classes of antihypertensive agent and BP stabilisation among hypertensive older adults. Cross-sectional analysis from The Irish Longitudinal Study on Ageing, a cohort study of Irish adults aged 50 years and over. Beat-to-beat BP was recorded in participants undergoing an active stand test. We defined grade 1 hypertension according to European Society of Cardiology criteria (systolic BP [SBP] 140-159 mmHg ± diastolic BP [DBP] 90-99 mmHg). Outcomes were: (i) initial orthostatic hypotension (IOH) (SBP drop ≥40 mmHg ± DBP drop ≥20 mmHg within 15 seconds [s] of standing accompanied by symptoms); (ii) sustained OH (SBP drop ≥20 mmHg ± DBP drop ≥10 mmHg from 60 to 110 s inclusive); (iii) impaired BP stabilisation (SBP drop ≥20 mmHg ± DBP drop ≥10 mmHg at any 10 s interval during the test). Outcomes were assessed using multivariable-adjusted logistic regression. A total of 536 hypertensive participants were receiving monotherapy with a renin-angiotensin-aldosterone-system inhibitor (n = 317, 59.1%), beta-blocker (n = 89, 16.6%), calcium channel blocker (n = 89, 16.6%) or diuretic (n = 41, 7.6%). A further 783 untreated participants met criteria for grade 1 hypertension. Beta-blockers were associated with increased odds of initial OH (OR 2.05, 95% CI 1.31-3.21) and sustained OH (OR 3.36, 95% CI 1.87-6.03) versus untreated grade 1 hypertension. Multivariable adjustment did not attenuate the results. Impaired BP stabilisation was evident at 20 s (OR 2.59, 95% CI 1.58-4.25) and persisted at 110 s (OR 2.90, 95% CI 1.64-5.11). No association was found between the other agents and any study outcome. Beta-blocker monotherapy was associated with a >2-fold increased odds of initial OH and a >3-fold increased odds of sustained OH and impaired BP stabilisation, compared to untreated grade 1 hypertension. These findings support existing literature questioning the role of beta-blockers as first line agents for essential hypertension.


Iterative shrinkage approach to restoration of optical imagery.
The problem of reconstruction of digital images from their degraded measurements is regarded as a problem of central importance in various fields of engineering and imaging sciences. In such cases, the degradation is typically caused by the resolution limitations of an imaging device in use and/or by the destructive influence of measurement noise. Specifically, when the noise obeys a Poisson probability law, standard approaches to the problem of image reconstruction are based upon using fixed-point algorithms which follow the methodology first proposed by Richardson and Lucy. The practice of using these methods, however, shows that their convergence properties tend to deteriorate at relatively high noise levels. Accordingly, in the present paper, a novel method for denoising and/or deblurring of digital images corrupted by Poisson noise is introduced. The proposed method is derived under the assumption that the image of interest can be sparsely represented in the domain of a linear transform. Consequently, a shrinkage-based iterative procedure is proposed, which guarantees the solution to converge to the global maximizer of an associated maximum a posteriori criterion. It is shown in a series of computer-simulated experiments that the proposed method outperforms a number of existing alternatives in terms of stability, precision, and computational efficiency.


Super-Resolution Reconstruction of Multi-Slice T2-W FLAIR MRI Improves Multiple Sclerosis Lesion Segmentation.
Due to acquisition time constraints, T2-w FLAIR MRI of Multiple Sclerosis (MS) patients is often acquired with multi-slice 2D protocols with a low through-plane resolution rather than with high-resolution 3D protocols. Automated lesion segmentation on such low-resolution (LR) images, however, performs poorly and leads to inaccurate lesion volume estimates. Super-resolution reconstruction (SRR) methods can then be used to obtain a high-resolution (HR) image from multiple LR images to serve as input for lesion segmentation. In this work, we evaluate the effect on MS lesion segmentation of three SRR approaches: one based on interpolation, a state-of-the-art self-supervised CNN-based strategy, and a recently proposed model-based SRR method. These SRR strategies were applied to LR acquisitions simulated from 3D T2-w FLAIR MRI of MS patients. Each SRR method was evaluated in terms of image reconstruction quality and subsequent lesion segmentation performance. When compared to segmentation on LR images, the three considered SRR strategies demonstrate improved lesion segmentation. Furthermore, in some scenarios, SRR achieves a similar segmentation performance compared to segmentation of HR images.Clinical relevance- This study demonstrates the positive impact of super-resolution reconstruction from T2-w FLAIR multi-slice MRI acquisitions on segmentation performance of MS lesions.


The effects of archipelago spatial structure on island diversity and endemism: predictions from a spatially-structured neutral model.
Islands are particularly suited to testing hypotheses about the ecological and evolutionary mechanisms underpinning community assembly. Yet the complex spatial arrangements of real island systems have received little attention from both empirical studies and theoretical models. Here, we investigate the extent to which the spatial structure of archipelagos affects species diversity and endemism. We start by proposing a new spatially structured neutral model that explicitly considers archipelago structure, and then investigate its predictions under a diversity of scenarios. Our results suggest that considering the spatial structure of archipelagos is crucial to understanding their diversity and endemism, with structured island systems acting both as "museums" and "cradles" of biodiversity. These dynamics of diversification may change the traditionally expected pattern of decrease in species richness with distance from the mainland, even potentially leading to increasing patterns for taxa with high speciation rates in archipelagos off species-poor continental areas. Our results also predict that, within spatially structured archipelagos, metapopulation dynamics and evolutionary processes can generate higher diversity on islands more centrally placed than at the periphery. We derive from our results a set of theoretical predictions, potentially testable with empirical data.


Antinociceptive effects of the novel neuronal nicotinic acetylcholine receptor agonist, ABT-594, in mice.
ABT-594 [5-((2R)-azetidinylmethoxy)-2-chloropyridine], a novel neuronal nicotinic acetylcholine receptor agonist, produced significant antinociceptive effects in mice against both acute noxious thermal stimulation--the hot-plate and cold-plate tests--and persistent visceral irritation--the abdominal constriction (writhing) assay (maximally-effective dose in each test 0.62 micromol/kg, i.p.). This effect was not stereoselective since the S-enantiomer, A-98593 [5-((2S)-azetidinylmethoxy)-2-chloropyridine], produced similar antinociceptive effects in this dose range. The effect in the hot-plate test peaked at 30 min after i.p. administration and was still present 60 min, but not 120 min, after injection. ABT-594 was orally active, but 10-fold less potent by this route than after i.p. administration. The antinociceptive effect of ABT-594 was prevented, but not reversed, by the noncompetitive neuronal nicotinic acetylcholine receptor antagonist mecamylamine (5 micromol/kg, i.p.). In contrast, the antinociceptive effect of ABT-594 was not prevented by hexamethonium (10 micromol/kg, i.p.), a neuronal nicotinic acetylcholine receptor antagonist that does not readily enter the central nervous system, nor by naltrexone (0.8 micromol/kg), an opioid receptor antagonist. Thus, initiation of antinociception by ABT-594 involves activation of central nicotinic acetylcholine receptors, but does not require activation of naltrexone-sensitive opioid receptors. The antinociceptive effects of morphine and ABT-594 in the mouse hot-plate test appeared to be additive, but ABT-594 did not potentiate the respiratory depression produced by morphine when the two compounds were coadministered. ABT-594 reduced body temperature and spontaneous exploration in the antinociceptive dose range, but did not reliably impair motor coordination in the rotarod test. Thus, it is unlikely that the antinociceptive effects result simply from impaired motor function. The compound also produced an anxiolytic-like effect in the elevated plus maze (at 0.019 and 0.062 micromol/kg, i.p.). Preliminary safety testing revealed an ED50 for overt seizure production of 1.9 micromol/kg, i.p. and an LD50 of 19.1 micromol/kg i.p. in mice, values 10 and 100 times the minimum effective antinociceptive dose of the compound. ABT-594 increased the duration of ethanol-induced hypnotic effects, tended to increase pentobarbital-induced hypnotic effects (P = 0.0502), and had no effect on pentobarbital-induced lethality. These data indicate that ABT-594 is a centrally acting neuronal nicotinic acetylcholine receptor agonist with potent antinociceptive and anxiolytic-like effects in mice.


Attachment research in eating disorders.
In a recent review, disturbances in attachment have been linked with eating disorder symptomatology. However, because of the limitations of study design, few inferences could be drawn about these processes in the aetiology and maintenance of eating disorder. Since that review, there has been further development in the instruments used and the publication of several further studies of attachment processes in eating disorders. We reviewed the field, expecting that greater clarity may have emerged in the 3 years since the previous review. A review of the literature was carried out, using the computer search PsychLIT, Medline, Embase and The Cochrane Library. There have been more studies published in this area in the last 3 years than in the entire period up until then. These can broadly be divided into those carried out in clinical and non-clinical populations, with greater weight ascribed to the former. The vast majority of studies found that attachment processes, by whatever method measured, are abnormal in eating disordered populations. Attachment style (dismissing versus preoccupied) may be linked with eating disorder diagnostic subgroup. Insecure attachment is common in eating disordered populations, with implications for therapy. Further work with refined instruments may clarify whether or not there is a specific association between attachment style and eating disorder subgroup. However, such an association is likely to be complicated and it may be more fruitful to study specific aspects of attachment, rather than global attachment style, in relation to eating disorder behaviour. The transgenerational transmission of attachment is a fruitful area for further investigation in eating disordered populations.


Optimal Sensitizer Concentration in Single Upconversion Nanocrystals.
Each single upconversion nanocrystal (UCNC) usually contains thousands of photon sensitizers and hundreds of photon activators to up-convert near-infrared photons into visible and ultraviolet emissions. Though in principle further increasing the sensitizers' concentration will enhance the absorption efficiency to produce brighter nanocrystals, typically 20% of Yb3+ ions has been used to avoid the so-called "concentration quenching" effect. Here we report that the concentration quenching effect does not limit the sensitizer concentration and NaYbF4 is the most bright host matrix. Surface quenching and the large size of NaYbF4 nanocrystals are the only factors limiting this optimal concentration. Therefore, we further designed sandwich nanostructures of NaYbF4 between a small template core to allow an epitaxial growth of the size-tunable NaYbF4 shell enclosed by an inert shell to minimize surface quenching. As a result, the suspension containing 25.2 nm sandwich structure UCNCs is 1.85 times brighter than the homogeneously doped ones, and the brightness of each single 25.2 nm heterogeneous UCNC is enhanced by nearly 3 times compared to the NaYF4: 20% Yb3+, 4% Tm3+ UCNCs in similar sizes. Particularly, the blue emission intensities of the UCNCs with the sandwich structure in the size of 13.6 and 25.2 nm are 1.36 times and 3.78 times higher than that of the monolithic UCNCs in the similar sizes. Maximizing the sensitizer concentration will accelerate the development of brighter and smaller UCNCs as more efficient biomolecule probes or photon energy converters.


Location of protons in anhydrous Keggin heteropolyacids H(3)PMo(12)O(40) and H(3)PW(12)O(40) by (1)H[(31)P]/(31)P[(1)H] REDOR NMR and DFT quantum chemical calculations.
HeteroPolyAcids (HPA's) are a class of solid acids that have broad applications in many fields of science and technology, including catalysis and chemical engineering. The proton locations within the thermally stable and commonly known Keggin unit, which is the primary structure building unit/block, has remained undetermined in anhydrous HPAs, despite numerous theoretical and experimental efforts. However, Rotational Echo DOuble Resonance (REDOR) NMR and Density Functional Theory (DFT) quantum chemical calculations offer a new opportunity to determine the exact locations of protons within the Keggin unit. The crucial experimental evidence is provided for the basic and very extensively studied acidic form of H(8-n)X(n+)M(12)O(40), X = Si, P and M = Mo, W, belonging to the Keggin structure. While showing that the acidic protons are located in the bridging oxygen positions (R(P-H) = 520 +/- 20 pm) in H(3)PMo(12)O(40) and in the terminal oxygen positions (R(P-H) = 570 +/- 20 pm) in H(3)PW(12)O(40), REDOR measurements also provide for the first time the structural basis to consistently rank the acid strength for the important class of Keggin solid catalysts.


[Research Progress and Application Future of MicroRNA-36].
MicroRNA-36 (miR-36) is a recently discovered miRNA family which including at least eight members, and specifically existed in helminths compared with other miRNAs that widely exists in almost all kinds of lives. This paper reviews recent research advances about miR-36 to provide further fundamental information for helminth and miRNA study.


Resistance Training Increases Muscle Strength and Muscle Size in Patients With Liver Cirrhosis.
Cirrhosis is often complicated by reduced muscle mass and strength, which limits the ability to perform daily activities and affects quality of life. Resistance training can increase muscle strength and mass in elderly and chronically ill patients. We performed a randomized controlled trial to investigate whether resistance training increases muscle strength and size in patients with compensated cirrhosis. We performed a prospective study of 39 patients with cirrhosis (Child-Pugh class A or B) seen at an outpatient clinic in Denmark from January 2015 through March 2017. Participants protein intake and activity levels were registered daily. Participants were randomly assigned (1:1) to a group that performed 36 1-hour sessions of physical exercise (supervised progressive resistance training for 1 hour, 3 times weekly for 12 weeks) or a control group (no change in daily activity level). Maximal muscle strength was measured as the peak torque in isokinetic knee extension and muscle size was measured as the cross-sectional area of the quadriceps muscle, assessed by magnetic resonance imaging of the thigh. The exercise group increased their muscle strength by 13% (from a mean 119 Nm to 134 Nm)-an 11 Nm greater gain in mean strength than that of the control group (P = .05). The exercise group increased their quadriceps cross-sectional area by 10% (from a mean 58.5 cm2 to 64.6 cm2)-a 4.4 cm2 greater gain than that of the control group (P < .01). The exercise group had significant increases in whole-body lean mass and body cell mass, and significant increases in 6-minute walking distance and the mental component summary of the short form-36 questionnaire. Adverse events were minor and equal between groups. In a randomized trial of patients with compensated cirrhosis, we found that 12 weeks of supervised progressive resistance training increased muscle strength and size and had beneficial effects on general performance measures, compared with patients who did not change their daily activity routine (control subjects). ClinicalTrials.gov no: NCT02343653.


X-ray sterilisation.
Radiation sterilisation of medical products has traditionally been done with gamma rays from radioactive sources or with electron beams produced by accelerators. Both methods sterilise by destroying microorganisms with ionising radiation. High energy X-rays sterilise in the same way. X-ray sterilisation is still a young process, however, considerable industrial experience has been gained through its post 9/11 use for sterilising large quantities of mail.


Induced stem cell neoplasia in a cnidarian by ectopic expression of a POU domain transcription factor.
The evolutionary origin of stem cell pluripotency is an unresolved question. In mammals, pluripotency is limited to early embryos and is induced and maintained by a small number of key transcription factors, of which the POU domain protein Oct4 is considered central. Clonal invertebrates, by contrast, possess pluripotent stem cells throughout their life, but the molecular mechanisms that control their pluripotency are poorly defined. To address this problem, we analyzed the expression pattern and function of Polynem (Pln), a POU domain gene from the marine cnidarian Hydractinia echinata. We show that Pln is expressed in the embryo and adult stem cells of the animal and that ectopic expression in epithelial cells induces stem cell neoplasms and loss of epithelial tissue. Neoplasm cells downregulated the transgene but expressed the endogenous Pln gene and also Nanos, Vasa, Piwi and Myc, which are all known cnidarian stem cell markers. Retinoic acid treatment caused downregulation of Pln and the differentiation of neoplasm cells to neurosensory and epithelial cells. Pln downregulation by RNAi led to differentiation. Collectively, our results suggest an ancient role of POU proteins as key regulators of animal stem cells.


Increased rate of purine biosynthesis in rat liver after bilateral adrenalectomy.
In bilaterally adrenalectomized rat liver the increased rate of de novo purine synthesis was shown by the increased [14C]glycine incorporation into hepatic acid-soluble purines with unchanged rapidly miscible glycine pool size and its turnover rate and by the increased rate of chasing of radiolabeled purines. At 24 h after adrenalectomy, the rate of de novo purine synthesis increased by 70%, 5-phosphoribosyl-1-pyrophosphate (PRPP) content increased by 200%, the specific activity of amidophosphoribosyltransferase (EC 2.4.2. 14; ATase) did not change, ATP and GTP showed a 33 and 24% decrease, and AMP and ADP showed a 245 and 38% increase. Combined, the metabolic pool size data reflected an unchanged total inhibitory potential on ATase. Replacement with corticosterone acetate for 24 h partially restored some of these abnormalities. These results suggest that the increase in the rate of de novo purine synthesis in adrenalectomized rat liver is secondary to increased catabolism of purine ribonucleotides and mediated by increased PRPP concentrations.


Role of Metabolites of Nitric Oxide and Arginase in the Pathogenesis of Glomerulonephritis.
The aim of the study is to assess the level of nitric oxide metabolites and arginase in the urine of children with glomerulonephritis depending on clinical evolutional stages of the disease. The prospective study included 65 children with primary glomerulonephritis, 25 children with steroid-sensitive nephrotic syndrome (SSNS) and 20 children with steroid-resistant nephrotic syndrome (SRNS), 20 children with mixed form of chronic glomerulonephritis(CGN). Thus in the SRNS group, during relapse period the concentration of NO metabolites in urine was increased by 4,2 times, while in SSNS by 3,0 times in comparison with the control group. The concentration of NO metabolites in the urine increased by 4,8 times during relapse CGN mixed form in comparison to the control values. During remission, the levels of NO metabolites in the urine remain increased in both groups. In relapse of SSNS arginase levels in the urine increased by 4,5 times in comparation to SRNS, thus the concentration of arginase was reduced. During remission period arginase levels in the urine were practically reduced to the levels of the control group. In the mixed form of CGN, relapse period arginase levels in the urine were increased by 2,9 times and during remission were decreased by almost 1,9 times in comparision to the control group. Assesment of NO metabolites and arginase in urine can be used as a diagnostic method in order to monitor renal disease process, evolution and effectiveness of the applied treatment.


Glochidion zeylanicum leaf extracts exhibit lifespan extending and oxidative stress resistance properties in Caenorhabditis elegans via DAF-16/FoxO and SKN-1/Nrf-2 signaling pathways.
Glochidion zeylanicum (GZ), a common plant in Thailand and Eastern Asia, is rich in antioxidants. However, the possible anti-aging and oxidative stress resistance properties of GZ leaf extracts (hexane and methanol extracts) have not been reported. We aimed to provide the first science-based evidence of the beneficial effects of GZ on anti-aging and oxidative stress resistance in the Caenorhabditis elegans model. The phytochemical composition of the hexane and methanol extracts were analyzed using GLC-MS and LC-MS. Fingerprinting analysis of the extract was performed by RP-HPLC. We determined total phenolics, flavonoids, and antioxidant properties via DPPH and ABTS assays. Oxidative stress resistance, anti-aging and lifespan were studied in C. elegans treated with leaf extracts. GZ leaf extracts protected the worms against oxidative stress and attenuated ROS accumulation. The expression of stress-response genes, such as SOD-3, and GST-4 were up-regulated, whereas HSP-16.2 was down-regulated after GZ treatment. The oxidative stress resistance properties of GZ possibly involved the DAF-16/FoxO and SKN-1/Nrf-2 transcription factors. GZ leaf extracts improved pharyngeal pumping function and autofluorescent pigment attenuation suggesting anti-aging properties. GZ leaf extracts modulated the lifespan extension in C. elegans. This study reports novel anti-aging and antioxidant activities of GZ leaf extracts, suggesting a novel bioactivity for a medicinally important plant and supplementary drug against oxidative stress.


PACAP stimulates insulin secretion but inhibits insulin sensitivity in mice.
Although pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates insulin secretion, its net influence on glucose homeostasis in vivo has not been established. We therefore examined the action of PACAP-27 and PACAP-38 on insulin secretion, insulin sensitivity, and glucose disposal as derived from the minimal model of glucose disappearance during an intravenous glucose tolerance test in anesthetized mice. PACAP-27 and PACAP-38 markedly and equipotently potentiated glucose-stimulated insulin secretion, with a half-maximal effect at 33 pmol/kg. After PACAP-27 or PACAP-38 (1.3 nmol/kg), the acute (1-5 min) insulin response was 3.8 +/- 0.4 nmol/l (PACAP-27) and 3.3 +/- 0.3 nmol/l (PACAP-38), respectively, vs. 1.4 +/- 0.1 nmol/l after glucose alone (P < 0.001), and the total area under the curve for insulin (AUCinsulin) was potentiated by 60% (P < 0.001). In contrast, PACAP-27 and PACAP-38 reduced the insulin sensitivity index (SI) [0.23 +/- 0.04 10(-4) min-1/(pmol/l) for PACAP-27 and 0.29 +/- 0.06 10(-4) min-1/(pmol/l) for PACAP-38 vs. 0.46 +/- 0.02 10(-4) min-1/(pmol/l) for controls (P < 0.01)]. Furthermore, PACAP-27 or PACAP-38 did not affect glucose elimination determined as glucose half-time or the glucose elimination rate after glucose injection or the area under the curve for glucose. Moreover, glucose effectiveness and the global disposition index (AUCinsulin times SI) were not affected by PACAP-27 or PACAP-38. Finally, when given together with glucose, PACAP-27 did not alter plasma glucagon or norepinephrine levels but significantly increased plasma epinephrine levels. We conclude that PACAP, besides its marked stimulation of insulin secretion, also inhibits insulin sensitivity in mice, the latter possibly explained by increased epinephrine. This complex action explains why the peptide does not enhance glucose disposal.


Improved Surgical Outcomes for ACS NSQIP Hospitals Over Time: Evaluation of Hospital Cohorts With up to 8 Years of Participation.
The American College of Surgeons, National Surgical Quality Improvement Program (ACS NSQIP) surgical quality feedback models are recalibrated every 6 months, and each hospital is given risk-adjusted, hierarchical model, odds ratios that permit comparison to an estimated average NSQIP hospital at a particular point in time. This approach is appropriate for "relative" benchmarking, and for targeting quality improvement efforts, but does not permit evaluation of hospital or program-wide changes in quality over time. We report on long-term improvement in surgical outcomes associated with participation in ACS NSQIP. ACS NSQIP data (2006-2013) were used to create prediction models for mortality, morbidity (any of several distinct adverse outcomes), and surgical site infection (SSI). For each model, for each hospital, and for year of first participation (hospital cohort), hierarchical model observed/expected (O/E) ratios were computed. The primary performance metric was the within-hospital trend in logged O/E ratios over time (slope) for mortality, morbidity, and SSI. Hospital-averaged log O/E ratio slopes were generally negative, indicating improving performance over time. For all hospitals, 62%, 70%, and 65% of hospitals had negative slopes for mortality, morbidity, and any SSI, respectively. For hospitals currently in the program for at least 3 years, 69%, 79%, and 71% showed improvement in mortality, morbidity, and SSI, respectively. For these hospitals, we estimate 0.8%, 3.1%, and 2.6% annual reductions (with respect to prior year's rates) for mortality, morbidity, and SSI, respectively. Participation in ACS NSQIP is associated with reductions in adverse events after surgery. The magnitude of quality improvement increases with time in the program.


Effects of constant and fluctuating temperature on the development of the oriental fruit moth, Grapholita molesta (Lepidoptera: Tortricidae).
The oriental fruit moth, Grapholita molesta, is an important pest in many commercial orchards including apple, pear and peach orchards, and responsible for substantial economic losses every year. To help in attaining a comprehensive and thorough understanding of the ecological tolerances of G. molesta, we collected life history data of individuals reared on apples under different constant temperature regimes and compared the data with moths reared under a variable outdoor temperature environment. Because G. molesta individuals reared at a constant 25°C had the heaviest pupal weight, the highest survival rate from egg to adult, highest finite rate of increase, and greatest fecundity, 25°C was considered as the optimum developmental temperature. The G. molesta population reared at a constant 31°C had the shortest development time, lowest survival rate and fecundity, resulting in population parameters of r < 0, λ < 1, lead to negative population growth. The population parameters r and λ reared under fluctuating temperature were higher than that reared under constant temperatures, the mean generation time (T) was shorter than it was in all of the constant temperatures treatments. This would imply that the outdoor G. molesta population would have a higher population growth potential and faster growth rate than indoor populations raised at constant temperatures. G. molesta moths reared under fluctuating temperature also had a higher fertility than moths reared under constant temperatures (except at 25°C). Our findings indicated that the population raised under outdoor fluctuating temperature conditions had strong environment adaptiveness.


The worldwide COVID-19 lockdown impacts on global secondary inorganic aerosols and radiative budget.
Global lockdown measures to prevent the spread of the coronavirus disease 2019 (COVID-19) led to air pollutant emission reductions. While the COVID-19 lockdown impacts on both trace gas and total particulate pollutants have been widely investigated, secondary aerosol formation from trace gases remains unclear. To that end, we quantify the COVID-19 lockdown impacts on NOx and SO2 emissions and sulfate-nitrate-ammonium aerosols using multiconstituent satellite data assimilation and model simulations. We find that anthropogenic emissions over major polluted regions were reduced by 19 to 25% for NOx and 14 to 20% for SO2 during April 2020. These emission reductions led to 8 to 21% decreases in sulfate and nitrate aerosols over highly polluted areas, corresponding to >34% of the observed aerosol optical depth declines and a global aerosol radiative forcing of +0.14 watts per square meter relative to business-as-usual scenario. These results point to the critical importance of secondary aerosol pollutants in quantifying climate impacts of future mitigation measures.


[Anorexia and bulimia--limits and options in clinical practice].
Even though there is no convincing evidence that eating disorders in general are on the rise, there has been an enormous increase in "treated" cases of patients with eating disorders. General practitioners detect only about 12% of all bulimia nervosa cases, and about 45% of all anorexia nervosa cases. As they often serve as gatekeepers to specialized care, they should receive better training in the recognition of eating disorders. The paper covers important aspects which are essential for the diagnosis and treatment of subjects with eating disorders: early detection, medical examination, motivational interviewing, treatment with self-help manuals, and drug treatment.


On the Contribution of Target Audibility to Performance in Spatialized Speech Mixtures.
Hearing loss has been shown to reduce speech understanding in spatialized multitalker listening situations, leading to the common belief that spatial processing is disrupted by hearing loss. This paper describes related studies from three laboratories that explored the contribution of reduced target audibility to this deficit. All studies used a stimulus configuration in which a speech target presented from the front was masked by speech maskers presented symmetrically from the sides. Together these studies highlight the importance of adequate stimulus audibility for optimal performance in spatialized speech mixtures and suggest that reduced access to target speech information might explain a substantial portion of the "spatial" deficit observed in listeners with hearing loss.


Involvement of 5-HT1A receptors in behavioural effects of the cannabinoid receptor agonist CP 55,940 in male rats.
We have studied the possible interaction between the cannabinoid receptor agonist CP 55,940 (1 and 50 microg/kg) and the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg) in the modulation of plus-maze and holeboard activity in Wistar adult male rats. In the plus-maze, the higher dose of CP 55,940 induced an anxiogenic-like effect, whereas the lower dose induced anxiolytic-like responses. The 5-HT1A antagonist, which was silent in this test, attenuated the anxiogenic, but not the anxiolytic, effect of CP 55,940. In the holeboard, the higher dose of CP 55,940 significantly decreased head-dipping duration, and WAY 100635, which did not affect exploratory head-dipping when administered alone, antagonized this effect. The administration of WAY 100635 significantly increased grooming behaviour, and this effect was inhibited by the two doses of CP 55,940, which did not exert any effect, per se, on this parameter. We provide the first evidence implicating 5-HT1A receptors in anxiety-related behavioural responses to a cannabinoid agonist.


[Surgical treatment of achalasia of pharyngoesophageal sphincter].
Being a rather simple operation, cricoid-pharyngeal myotomy ensures restoration of deglutition in neurological patients. The article describes a method of the operation with plastics of the pharyngoesophageal junction. The operation was effective in 5 among 6 patients who had been subjected to it.


Quality by design aided self-nano emulsifying drug delivery systems development for the oral delivery of Benidipine: Improvement of biopharmaceutical performance.
The primary objective of the research effort is to establish efficient solid self-nanoemulsifying drug delivery systems (S-SNEDDS) for benidipine (BD) through the systematic application of a quality-by-design (QbD)-based paradigm. Utilizing Labrafil M 2125 CS, Kolliphor EL, and Transcutol P, the BD-S-SNEDDS were created. The central composite design was adopted to optimize numerous components. Zeta potential, drug concentration, resistance to dilution, pH, refractive index, viscosity, thermodynamic stability, and cloud point were further investigated in the most efficient formulation, BD14, which had a globule size of 156.20 ± 2.40 nm, PDI of 0.25, zeta potential of -17.36 ± 0.18 mV, self-emulsification time of 65.21 ± 1.95 s, % transmittance of 99.80 ± 0.70%, and drug release of 92.65 ± 1.70% at 15 min. S-SNEDDS were formulated using the adsorption process and investigated via Fourier transform infrared spectroscopy, Differential scanning calorimeter, Scanning electron microscopy, and powder X-ray diffraction. Optimized S-SNEDDS batch BD14 dramatically decreased blood pressure in rats in contrast to the pure drug and the commercial product, according to a pharmacodynamics investigation. Accelerated stability tests validated the product's stability. Therefore, the development of oral S-SNEDDS of BD may be advantageous for raising BD's water solubility and expanding their releasing capabilities, thereby boosting oral absorption.


Response Evaluation Criteria in Cancer of the liver version 6 (Response Evaluation Criteria in Cancer of the Liver 2021 revised version).
Response Evaluation Criteria in Solid Tumors (RECIST) is inappropriate to assess the direct effects of treatment on hepatocellular carcinoma (HCC) by locoregional therapies, such as radiofrequency ablation or transarterial chemoembolization. Therefore, establishment of response evaluation criteria solely devoted to HCC is needed in clinical practice, as well as in clinical trials of HCC treatment, such as systemic therapies, which cause necrosis of the tumor. Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2021 by the Liver Cancer Study Group of Japan based on the 2019 version of RECICL, which was commonly used in Japan. The major revised points of the RECICL 2021 is inclusion of RECIST version 1.1 and modified RECIST as response evaluation criteria in systemic therapy for HCC. We hope this new treatment response criteria, RECICL, proposed by the Liver Cancer Study Group of Japan will benefit the HCC treatment response evaluation in the setting of daily clinical practice and clinical trials as well, not only in Japan, but also internationally.


[Hemorrhoidal disease accompanied by anal prolapsus and its treatment methods].
The objective of this research is to evaluate specifications of the surgery, its post-operative period and complications in patients with traditional hemorrhoidectomy which is a procedure performed by using a linear stapler along with a circular resection of prolapsed mucosal and sub-mucosal layers of lower rectal ampulla with the utilization of Longo technique. The study was conducted with the participation of 398 patients with the hemorrhoidal disease accompanied by anal prolapsus of which 338 (84%) were composed of males and 65 (16%) of females. Out of 398 patients, 308 (77%) underwent stapler hemorrohidectomy using linear stapler, 74 (19%) patients had conventional hemorrhoidectomy with the utilization of electric coagulation and 16 (4%) of them received circular hemorroidopexy using Longo technique. According to the data obtained during this research linear stapler use in the treatment of hemorroidal desease, accompanied by anal prolapses is an effective and technically simple solution to the problem. This method is implemented quickly, allows to cover greater part of abnormally changed cavernous tissue and conduct persist lifting of anal canal mucosal layer. It is also a safe method without any disease relapses.


Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: computer simulation and metabolic control analysis.
This is the third of three papers [see also Mulquiney, Bubb and Kuchel (1999) Biochem. J. 342, 565-578; Mulquiney and Kuchel (1999) Biochem. J. 342, 579-594] for which the general goal was to explain the regulation and control of 2,3-bisphosphoglycerate (2,3-BPG) metabolism in human erythrocytes. 2,3-BPG is a major modulator of haemoglobin oxygen affinity and hence is vital in blood oxygen transport. A detailed mathematical model of erythrocyte metabolism was presented in the first two papers. The model was refined through an iterative loop of experiment and simulation and it was used to predict outcomes that are consistent with the metabolic behaviour of the erythrocyte under a wide variety of experimental and physiological conditions. For the present paper, the model was examined using computer simulation and Metabolic Control Analysis. The analysis yielded several new insights into the regulation and control of 2,3-BPG metabolism. Specifically it was found that: (1) the feedback inhibition of hexokinase and phosphofructokinase by 2, 3-BPG are equally as important as the product inhibition of 2,3-BPG synthase in controlling the normal in vivo steady-state concentration of 2,3-BPG; (2) H(+) and oxygen are effective regulators of 2,3-BPG concentration and that increases in 2,3-BPG concentrations are achieved with only small changes in glycolytic rate; (3) these two effectors exert most of their influence through hexokinase and phosphofructokinase; (4) flux through the 2,3-BPG shunt changes in absolute terms in response to different energy demands placed on the cell. This response of the 2,3-BPG shunt contributes an [ATP]-stabilizing effect. A 'cost' of this is that 2, 3-BPG concentrations are very sensitive to the energy demand of the cell and; (5) the flux through the 2,3-BPG shunt does not change in response to different non-glycolytic demands for NADH.


Fully automated liver segmentation using Sobolev gradient-based level set evolution.
Quantitative analysis and precise measurements on the liver have vital importance for pre-evaluation of surgical operations and require high accuracy in liver segmentation from all slices in a data set. However, automated liver segmentation from medical image data sets is more challenging than segmentation of any other organ due to various reasons such as vascular structures in the liver, high variability of liver shapes, similar intensity values, and unclear edges between liver and its adjacent organs. In this study, a variational level set-based segmentation approach is proposed to be efficient in terms of processing time and accuracy. The efficiency of this method is achieved by (1) automated initialization of a large initial contour, (2) using an adaptive signed pressure force function, and also (3) evolution of the level set with Sobolev gradient. Experimental results show that the proposed fully automated segmentation technique avoids local minima and stops evolution of the active contour at desired liver boundaries with high speed and accuracy. Copyright © 2016 John Wiley & Sons, Ltd.


Ethanol stimulates ciliary beating by dual cyclic nucleotide kinase activation in bovine bronchial epithelial cells.
Previously, we have shown that ethanol (EtOH) stimulates a rapid increase in the ciliary beat frequency (CBF) of bovine bronchial epithelial cells (BBECs) via the activation of PKA. We have also shown that inhibitors of nitric oxide synthase block EtOH-stimulated increases in CBF. We hypothesize that EtOH acutely stimulates CBF via the activation of both PKA and PKG pathways. Using chemiluminescence detection of nitric oxide (NO), we directly measured increases in NO production in BBECs treated with 100 mmol/L of EtOH beginning at 25 minutes. Pretreatment of BBECs with guanylyl cyclase inhibitors, ODQ or LY83583, resulted in the inhibition of EtOH-stimulated CBF. Low concentrations (1 nmol/L) of cyclic nucleotide analogues do not stimulate CBF increases. However, a combination of both 1 nmol/L of 8Br-cAMP and 8Br-cGMP stimulates a significant increase over baseline CBF. This effect could be blocked by pretreating BBECs with inhibitors of either PKA or PKG. Very high concentrations of either 8Br-cAMP or 8Br-cGMP (> or =100 micromol/L) were required to cross-activate both PKA and PKG. This suggests that cross-activation of PKA by cGMP is not occurring at the concentrations (1 nmol/L) capable of stimulating CBF. 8-pCPT-cGMPS, an antagonist analogue to cGMP, blocked EtOH-stimulated PKA activity increases. These data support that EtOH-stimulated increases in CBF require the dual activation of both PKA (via cAMP) and PKG (via NO).


Egg fortification with n-3 polyunsaturated fatty acids (PUFA): nutritional benefits versus high n-6 PUFA western diets, and consumer acceptance.
As high dietary n-6 polyunsaturated fatty acids and n-6:n-3 PUFA ratio may contribute to many western ailments, increasing n-3 PUFA in foods could be beneficial. The nutritional significance of n-3 PUFA-fortified egg vs. enzymatically competitive high n-6 PUFA diets is debatable. To evaluate the dietary contribution of 'field fortification' of eggs by adding n-3 PUFA to high n-6 PUFA hen feed and to assess whether it meets consumer preferences. Laying hens (n=3500) were fed n-3 PUFA-fortified (5% extruded linseed) feed or standard (control) feed for 5 weeks. Nutritional significance was evaluated for western (American, Israeli) populations. Compared to regular (control) eggs, fortified eggs yielded a 3.8-fold increase in total n-3 PUFA, 6.4-fold alpha-linolenic acid (18:3), and 2.4-fold docohexaenoic acid 22:6). N-6:n-3 PUFA ratio decreased 3.6-fold, and n-6:n-3 long chain PUFA ratio (AA:DHA) 3.0-fold (P< 0.0003). Sensory evaluations were not significantly different. Egg cost increased by 1.5-3.0%. Fortified egg n-3 PUFA content averaged 14.3% of the current intake of Americans and 15.9% of Israelis - 9.8 and 10.6% of upper Dietary Reference Intakes, respectively. Egg DHA content averaged 33.7 and 41.4% of upper DRI. Current cholesterol intakes average 281 and 263 mg/day (median 214 and 184 mg/day) including 0.7 and 0.5 egg/day; reported hypercholesterolemia rates are 17.7 and 16.5%, respectively. Effective concentration and transformation of supplemental n-3 PUFA/LCPUFA from feed to egg substantially enhanced egg n-3 PUFA %DRI, particularly of DHA, critical for health but often deficient. Such land-based n-3 PUFA/LCPUFA fortification may be applicable to high n-6 PUFA diets, fitting within cholesterol limitations and market criteria. It may contribute to general health and specific requirements (i.e., pregnancy and lactation), with possibilities of wide accessibility and standardization.


On the relationship between an Asian haplotype on chromosome 6 that reduces androstenone levels in boars and the differential expression of SULT2A1 in the testis.
Androstenone is one of the major compounds responsible for boar taint, a pronounced urine-like odor produced when cooking boar meat. Several studies have identified quantitative trait loci (QTL) for androstenone level on Sus scrofa chromosome (SSC) 6. For one of the candidate genes in the region SULT2A1, a difference in expression levels in the testis has been shown at the protein and RNA level. Haplotypes were predicted for the QTL region and their effects were estimated showing that haplotype 1 was consistently related with a lower level, and haplotype 2 with a higher level of androstenone. A recombinant haplotype allowed us to narrow down the QTL region from 3.75 Mbp to 1.94 Mbp. An RNA-seq analysis of the liver and testis revealed six genes that were differentially expressed between homozygotes of haplotypes 1 and 2. Genomic sequences of these differentially expressed genes were checked for variations within potential regulatory regions. We identified one variant located within a CpG island that could affect expression of SULT2A1 gene. An allele-specific expression analysis in the testis did not show differential expression between the alleles of SULT2A1 located on the different haplotypes in heterozygous animals. However a synonymous mutation C166T (SSC6: 49,117,861 bp in Sscrofa 10.2; C/T) was identified within the exon 2 of SULT2A1 for which the haplotype 2 only had the C allele which was higher expressed than the T allele, indicating haplotype-independent allelic-imbalanced expression between the two alleles. A phylogenetic analysis for the 1.94 Mbp region revealed that haplotype 1, associated with low androstenone level, originated from Asia. Differential expression could be observed for six genes by RNA-seq analysis. No difference in the ratio of C:T expression of SULT2A1 for the haplotypes was found by the allele-specific expression analysis, however, a difference in expression between the C over T allele was found for a variation within SULT2A1, showing that the difference in androstenone levels between the haplotypes is not caused by the SNP in exon 2.


The thermal decomposition studies of solid iron bamboo (Dendrocalamus strictus) - potential precursor for eco-materials.
Block samples of carbonized solid iron bamboo (Dendrocalamus strictus) - unique genus among bamboos, were prepared by means of slow pyrolysis. They are expected to be promising monolithic supports for various composites. The purpose of this study is to describe the thermal decomposition of rectangular shapes cut from solid stems of Dendrocalamus strictus, raw and pre-charred in a wide range of temperatures: 300, 350, 400, 500 and 600 degrees C. The DTG thermograms of carbonized solid iron bamboo (char), determined at temperatures up to 900 degrees C, exhibited minima even for samples previously pyrolysed at temperatures over 400 degrees C, at which decomposition of plant material have to be completed. For pre-charred samples, the temperature of the DTG peaks increased, while the weight loss registered in the temperature range up to 900 degrees C decreased, with increasing temperature of carbonization. It was found that extension of time of holding at final temperature of carbonization decreased a height of the DTG peaks to full reduction of it after heating along the time of 8h. It was suggested that bamboo tar remaining in vessels after carbonization reacts with the bamboo char creating new compounds that decompose in distinctly higher temperatures.


Expression of transforming growth factor-beta in the rat ventral prostate during castration-induced programmed cell death.
Castration-induced androgen deprivation leads to the activation of the programmed death of the androgen-dependent prostatic epithelial cells in the rat ventral prostate. In order to identify potential mediators of this programmed cell death, the expression of transforming growth factor-beta (TGF beta) in the rat ventral prostate was studied, after castration induced-androgen withdrawal. Steady state levels of TGF beta mRNA were determined by Northern blot analysis and compared with mRNA levels for prostatein C3, the major androgen-dependent secretory protein of ventral prostate and also with mRNA levels for TRPM-2, a gene that is specifically expressed during castration induced prostatic cell death. Within the first day after castration there was a dramatic increase in the levels of TGF beta mRNA in the ventral prostate (approximately 10-fold) and by 4 days after castration TGF beta mRNA was maximally expressed (approximately 40-fold increase), by which time the androgen-dependent C3 secretory protein mRNA transcripts have diminished to undetectable levels. Androgen administration to 4-day castrated rats led to a marked decrease in TGF beta mRNA to a level comparable to its constitutive expression obtained in the intact control animals, indicating that expression of TGF beta in the rat ventral prostate is under negative androgenic regulation. The transcript levels encoding TRPM-2 initially increased 10-fold within the first day after castration and by day 4 post castration there was a dramatic increase (approximately 50-fold) which correlated well with the maximal rate of cell death of the androgen-dependent prostatic epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Hysteroscopic Essure Inserts for Permanent Contraception: Extended Follow-Up Results of a Phase III Multicenter International Study.
To describe safety, tolerability, and effectiveness results through 5 years of follow-up of a Phase III trial with Essure inserts. Multicenter, nonrandomized, single-arm international study (Canadian Task Force classification II-3). Thirteen clinical study centers in the United States, Europe, and Australia. A total of 518 previously fertile women seeking permanent contraception. The objective of the hysteroscopic sterilization procedure was bilateral Essure insert placement (ESS205 model) and tubal occlusion. Women with satisfactory device location and tube occlusion (based on modified hysterosalpingography [HSG]) were instructed to discontinue alternative contraception and to rely on Essure inserts for permanent contraception. The primary endpoint for the Phase III study was the rate of pregnancies occurring during the first year of relying (i.e., HSG-confirmed occlusion) on the Essure inserts for permanent contraception (i.e., 12 months after HSG). For the full 5 years of follow-up (5 years total of relying on the Essure inserts for contraception), the endpoints of interest were safety, prevention of pregnancy, and satisfaction. No pregnancies were reported among women relying on the Essure inserts who completed the full 5 years of follow-up. As of December 5, 2007, 449 women with successful bilateral placement relying on the Essure inserts contributed a total 24 942 woman-months of follow-up for assessing effectiveness. Overall, the Essure inserts were generally well tolerated, with participant comfort rated as "good" to "excellent" by 99% of women (382 of 385) after 5 years of use. Similarly, overall satisfaction was rated as "somewhat" to "very satisfied" by 98% of women (376 of 384) after 5 years of use. The majority of adverse events reported during the 5 years of follow-up were rated as either "mild" or "moderate" in severity. Three severe events (abdominal pain with very heavy periods and irregular menstrual bleeding) were reported in 2 subjects during follow-up as being "possibly" related to the procedure or the inserts. The findings from extended follow-up of this Phase III trial with Essure inserts further support the effectiveness, tolerability, and satisfaction of this nonhormonal, nonincisional option for permanent contraception.


Toward a Multi-Modal Brain-Body Assessment in Parkinson's Disease: A Systematic Review in fNIRS.
Parkinson's disease (PD) causes impairments in cortical structures leading to motor and cognitive symptoms. While common disease management and treatment strategies mainly depend on the subjective assessment of clinical scales and patients' diaries, research in recent years has focused on advances in automatic and objective tools to help with diagnosing PD and determining its severity. Due to the link between brain structure deficits and physical symptoms in PD, objective brain activity and body motion assessment of patients have been studied in the literature. This study aimed to explore the relationship between brain activity and body motion measures of people with PD to look at the feasibility of diagnosis or assessment of PD using these measures. In this study, we summarised the findings of 24 selected papers from the complete literature review using the Scopus database. Selected studies used both brain activity recording using functional near-infrared spectroscopy (fNIRS) and motion assessment using sensors for people with PD in their experiments. Results include 1) the most common study protocol is a combination of single tasks. 2) Prefrontal cortex is mostly studied region of interest in the literature. 3) Oxygenated haemoglobin (HbO 2) concentration is the predominant metric utilised in fNIRS, compared to deoxygenated haemoglobin (HHb). 4) Motion assessment in people with PD is mostly done with inertial measurement units (IMUs) and electronic walkway. 5) The relationship between brain activity and body motion measures is an important factor that has been neglected in the literature.


Middle ear mechanics in subjects with rheumatoid arthritis.
The incudo-malleolar and incudo-stapedial joints are true diarthroses and therefore may be subject to the same rheumatic lesions as any other articulation in the body. The existence of this involvement in rheumatoid arthritis (RA), however, is highly controversial. The present study investigates modifications of the mechanical properties of the middle ear in a group of subjects with RA by evaluating the resonance frequency obtained with multiple-frequency tympanometry (MFT). Thirty patients with RA, aged 20 to 68 years (mean age: 45.8 +/- 12.4 years), participated in the investigation. Their data were compared with those obtained in a control group of 48 age-matched subjects. Results obtained in both ears were examined in all subjects. The two groups displayed almost equal hearing levels with mean air conduction thresholds ranging from 10 to 22 dB HL. None of the subjects displayed an air-bone gap greater than 5 dB. Normal resonance frequency, calculated at the 95th percentile from the control group, ranged from 900 to 1250 Hz. Twelve rheumatoid arthritis patients (40 per cent) displayed abnormal resonance values. These findings were monolateral in 9 patients and bilateral in 3. Eleven out of 15 ears with abnormal multiple-frequency tympanometry data were characterized by an increase in resonance and 4 by a decrease. A correlation between abnormal resonance values and more aggressive RA was established. The results of this study suggest that rheumatoid arthritis may involve the incudo-malleolar and incudo-stapedial joints, altering the ossicular mechanics in response to static air pressure modifications. This does not impair sound conduction through the middle ear, but might reduce the protective mechanisms of the middle ear towards high static pressures.


Influence of fermentation conditions on glucosinolates, ascorbigen, and ascorbic acid content in white cabbage (Brassica oleracea var. capitata cv. Taler) cultivated in different seasons.
The content of glucosinolates (GLS), ascorbigen, and ascorbic acid in white cabbage (Brassica oleracea var. capitata cv. Taler) cultivated in different seasons (summer and winter) was determined, before and after spontaneous and starter-induced fermentation. Different salt concentrations (0.5% NaCl or 1.5% NaCl) were used for sauerkraut production. Glucoiberin, sinigrin, and glucobrassicin were dominating in raw white cabbage cultivated either in winter or summer seasons. Ascorbigen precursor, glucobrassicin, was found higher in cabbage cultivated in winter (2.54 micromol/g dw) than those grown in summer (1.83 micromol/g dw). Cabbage fermented for 7 d was found to contain only traces of some GLS irrespective of the fermentation conditions used. Ascorbigen synthesis occurred during white cabbage fermentation. Brining cabbage at low salt concentration (0.5% NaCl) improved ascorbigen content in sauerkraut after 7 d of fermentation at 25 degrees C. The highest ascorbigen concentration was observed in low-sodium (0.5% NaCl) sauerkraut produced from cabbage cultivated in winter submitted to either natural (109.0 micromol/100 g dw) or starter-induced fermentation (108.3 and 104.6 micromol/100 g dw in cabbages fermented by L. plantarum and L. mesenteroides, respectively). Ascorbic acid content was found higher in cabbage cultivated in summer and fermentation process led to significant reductions. Therefore, the selection of cabbages with high glucobrassicin content and the production of low-sodium sauerkrauts may provide enhanced health benefits towards prevention of chronic diseases.


How to assess the business performance of your practice.
The objective of this article is to provide motivation and practical guidance to those general practitioners who wish to assess the performance of their practice in the business and financial sense, but who believe that they lack the necessary training and resources.


Predictive Roles of ADAM17 in Patient Survival and Immune Cell Infiltration in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is the deadliest malignant tumour worldwide. The metalloproteinase ADAM17 is associated with tumour formation and development; however, its significance in HCC is unclear. This study aimed to investigate the role of ADAM17 in HCC and the correlation between its expression and immune cell infiltration. ADAM17 expression was analysed in pan-cancer and HCC tissues using The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Kaplan-Meier survival analysis displayed a negative association between ADAM17 expression and the overall survival of patients with HCC. High ADAM17 expression was linked to poor tumour/node (T/N) stage and alpha fetoprotein (AFP) levels. Gene Set Enrichment Analysis, Gene Ontology, and Kyoto Encyclopaedia of Genes and Genomes analyses revealed the enrichment of several pathways, including epithelial-mesenchymal transition, inflammatory response, Hedgehog, and KRAS signalling, in patients with upregulated ADAM17. ADAM17 was shown to be positively correlated with immune cell infiltration and immune checkpoint expression via the Tumour Immune Estimation Resource (TIMER) database and immunohistochemistry analyses. Protein-protein interaction (PPI) network analysis revealed that ADAM17 plays a core role in cancer development and immune evasion. In vitro and in vivo experiments demonstrated that ADAM17 influences HCC growth and metastasis. In conclusion, ADAM17 is upregulated in most cancers, particularly HCC, and is critical in the development and immune evasion of HCC.


Structure, Mechanism, and Inhibition of Aspergillus fumigatus Thioredoxin Reductase.
Aspergillus fumigatus infections are associated with high mortality rates and high treatment costs. Limited available antifungals and increasing antifungal resistance highlight an urgent need for new antifungals. Thioredoxin reductase (TrxR) is essential for maintaining redox homeostasis and presents as a promising target for novel antifungals. We show that ebselen [2-phenyl-1,2-benzoselenazol-3(2H)-one] is an inhibitor of A. fumigatus TrxR (Ki = 0.22 μM) and inhibits growth of Aspergillus spp., with in vitro MIC values of 16 to 64 µg/ml. Mass spectrometry analysis demonstrates that ebselen interacts covalently with a catalytic cysteine of TrxR, Cys148. We also present the X-ray crystal structure of A. fumigatus TrxR and use in silico modeling of the enzyme-inhibitor complex to outline key molecular interactions. This provides a scaffold for future design of potent and selective antifungal drugs that target TrxR, improving the potency of ebselen toward inhbition of A. fumigatus growth.


The relationship between alcohol and individual differences variables on attitudes and behavioral skills relevant to sexual health among heterosexual young adult men.
The purpose of this experiment was to investigate the effects of alcohol, alcohol sex expectancies, and sexual sensation seeking on determinants of sexual health behavior according to the Information-Motivation-Behavioral Skills (IMB) model. The participants were 48 heterosexual young adult males who attended 2 laboratory sessions. During Session 1, participants completed a set of screening and individual differences measures, and during Session 2 they were randomly assigned to 1 of 3 beverage conditions: control, alcohol (0.65 g alcohol/kg body weight), or placebo. Following the experimental manipulation, all participants completed measures regarding attitudes toward condom use, intention to engage in risky sex, and condom use negotiation skills. The results showed that participants who consumed alcohol had poorer negotiation skills and greater intention to engage in risky sex compared to participants who did not drink alcohol. Although alcohol did not affect any dimension of attitude regarding condom use, attitude about condoms' effects on sex, as well as sexual sensation seeking, were correlated with both intention ratings and skills. Multiple regression models, including both attitudes and sensation seeking, showed that attitudes accounted for 20-25% of variance independent of beverage condition in predicting intention ratings and skills. The findings were consistent with past research showing that alcohol consumption can have detrimental effects on determinants of sexual health behavior and that individual differences factors can enhance the power of models like the IMB to predict such behavior.


Progression index and disability status in multiple sclerosis: a resurvey of 207 patients in central Poland.
The progression index (disability grade divided by the duration of the disease) and disability status are presented in multiple sclerosis (MS) patients from two hospital series in central Poland. The natural course of 207 patients showed continuously decreasing progression index (PI) from 4.15 after the first year to 0.72 and 0.23 after 10 yr. or 26 yr. respectively. Within the duration of the disease from 1 to 40 years mean PI was 1.12. Among 207 hospitalized patients 156 (75.6%) showed moderately speedy progression with PI 0.21-1.33. Mean neurologic impairment evaluated on Disability Status Scale (DSS) was 6.27 (range 4.40-8.25). Overall neurologic disability slowly increased from 5.82, 6.50, 7.04 at 5 years intervals up to 7.17 after 26 years. Out of 207 patients 127 (71.1%) demonstrated either moderate or severe impairment (4-9 grades at DSS). These figures represent rather biased hospital over-representation of grave cases than more malignant natural course of MS in Poland. It was also considered that very slow PI (0.20 or less) has at least approximately as good prognostic value as Kurtzke's "rule of 5 yr. at DSS". In the present hospital series none of MS patients with low PI - less than or equal to 0.20 - had deteriorated after 26 yr. of the disease beyond 6th grade of DSS.


[Consideration about chemistry, manufacture and control (CMC) key problems in simplified registration of classical traditional Chinese medicine excellent prescriptions].
As an outstanding representative of traditional Chinese medicine(TCM) prescriptions accumulated from famous TCM doctors' clinical experiences in past dynasties, classical TCM excellent prescriptions (cTCMeP) are the most valuable part of TCM system. To support the research and development of cTCMeP, a series of regulations and measures were issued to encourage its simplified registration. There is still a long-way to go because many key problems and puzzles about technology, registration and administration in cTCMeP R&D process are not resolved. Based on the analysis of registration and management regulations of botanical drug products in FDA of USA and Japan, and EMA of Europe, the possible key problems and countermeasures in chemistry, manufacture and control (CMC) of simplified registration of cTCMeP were analyzed on the consideration of its actual situation. The method of "reference decoction extract by traditional prescription" (RDETP) was firstly proposed as standard to evaluate the quality and preparation uniformity between the new developing product under simplified registration and traditional original usages of cTCMeP, instead of Standard Decoction method in Japan. "Totality of the evidence" approach, mass balance and bioassay/biological assay of cTCMeP were emphatically suggested to introduce to the quality uniformity evaluation system in the raw drug material, drug substance and final product between the modern product and traditional decoction.


Molecular basis for PrimPol recruitment to replication forks by RPA.
DNA damage and secondary structures can stall the replication machinery. Cells possess numerous tolerance mechanisms to complete genome duplication in the presence of such impediments. In addition to translesion synthesis (TLS) polymerases, most eukaryotic cells contain a multifunctional replicative enzyme called primase-polymerase (PrimPol) that is capable of directly bypassing DNA damage by TLS, as well as repriming replication downstream of impediments. Here, we report that PrimPol is recruited to reprime through its interaction with RPA. Using biophysical and crystallographic approaches, we identify that PrimPol possesses two RPA-binding motifs and ascertained the key residues required for these interactions. We demonstrate that one of these motifs is critical for PrimPol's recruitment to stalled replication forks in vivo. In addition, biochemical analysis reveals that RPA serves to stimulate the primase activity of PrimPol. Together, these findings provide significant molecular insights into PrimPol's mode of recruitment to stalled forks to facilitate repriming and restart.


[The characteristics of the formation of spontaneous neuronal activity in the trigeminal sensory nuclei of surviving slices of rat brain stem in postnatal ontogeny].
An attempt was made to characterize the development of neurones of sensory trigeminal nuclei--basic structure of sensory provision of alimentary behaviour at late stages of postnatal ontogenesis. The method of the brain-stem slices of rat pups [correction of ratlings] aged 2.4 and 8 weeks was applied. An increase with the age was shown of the number of neurones with spontaneous activity (44%-2 weeks; 69%-8 weeks), growth of discharges frequency, appearance of cells population with high-frequency spontaneous activity by the fourth week and an increase of such neurones number by the eighth week. Three types of background-active neurones were singled out: episodic, continuous and group; the dynamics of correlations change of these types with the age was shown. No significant changes of rest potential with the age were found, though there was a tendency to its increase between the 2-nd and 8-th weeks of postnatal development.


Osteoblastic differentiation improved by bezafibrate-induced mitochondrial biogenesis in deciduous tooth-derived pulp stem cells from a child with Leigh syndrome.
Leigh syndrome is a highly heterogeneous condition caused by pathological mutations in either nuclear or mitochondrial DNA regions encoding molecules involved in mitochondrial oxidative phosphorylation, in which many organs including the brain can be affected. Among these organs, a high incidence of poor bone health has been recognized in primary mitochondrial diseases including Leigh syndrome. However, the direct association between mitochondrial dysfunction and poor bone health has not been fully elucidated. Mitochondrial biosynthesis is a potential therapeutic target for this syndrome, as it can ameliorate the impairment of oxidative phosphorylation without altering these gene mutations. A recent study has shown the impaired osteogenesis in the dental pulp stem cells derived from the deciduous teeth of a child with Leigh syndrome, harboring the heteroplasmic mutation G13513A in the mitochondrial DNA region encoding the ND5 subunit of the respiratory chain complex I. The present study aimed to investigate whether mitochondrial biogenesis could be a therapeutic target for improving osteogenesis, using the same stem cells in a patient-specific cellular model. For this purpose, bezafibrate was used because it has been reported to induce mitochondrial biogenesis as well as to improve bone metabolism and osteoporosis. Bezafibrate clearly improved the differentiation of patient-derived stem cells into osteoblasts and the mineralization of differentiated osteoblasts. The mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1α, ATP production, and mitochondrial Ca2+ levels were all significantly increased by bezafibrate in the patient-derived cells. In addition, the increased amount and morphological shift from the fragmentary to network shape associated with DRP1 downregulation were also observed in the bezafibrate-treated patient-derived cells. These results suggest that mitochondrial biogenesis may be a potential therapeutic target for improving osteogenesis in patients with Leigh syndrome, and bezafibrate may be one of the candidate treatment agents.


Apoptosis induced by cytoskeletal disruption requires distinct domains of MEKK1.
MEKK1 is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates the MAPK JNK and is required for microtubule inhibitor-induced apoptosis in B cells. Here, we find that apoptosis induced by actin disruption via cytochalasin D and by the protein phosphatase 1/2A inhibitor okadaic acid also requires MEKK1 activation. To elucidate the functional requirements for activation of the MEKK1-dependent apoptotic pathway, we created mutations within MEKK1. MEKK1-deficient cells were complemented with MEKK1 containing mutations in either the ubiquitin interacting motif (UIM), plant homeodomain (PHD), caspase cleavage site or the kinase domain at near endogenous levels of expression and tested for their sensitivity to each drug. We found that both the kinase activity and the PHD domain of MEKK1 are required for JNK activation and efficient induction of apoptosis by drugs causing cytoskeletal disruption. Furthermore, we discovered that modification of MEKK1 and its localization depends on the integrity of the PHD.


[An evaluation of the status of natural foci of Crimean-Congo hemorrhagic fever in the Crimea].
Parasitological data, the results of virological and serological investigations of materials, collected in nature and during the study of the immune structure of the population and indicative of the circulation of CCHF, virus in the Crimea and the possibility of human infection, are presented. The data on the spontaneous CCHF virus infection of 4 tick species belonging to the genus Ixodes have been confirmed, and evidence on the participation of Dermacentor marginatus in this process obtained for the first time in this region. The study has revealed for the first time that, besides European brown hares, scilly shrews, common voles and field mice may contribute to the maintenance of the natural foci of this infection. The low activity of the Crimean focus of CCHF may be the result of the intensive use of land, the widely spread stall-feeding of cattle, as well as a sharp decrease in the number of hares on the territories of hunting preserves.


Development of medicated foams that combine incompatible hydrophilic and lipophilic drugs for psoriasis treatment.
The focus was on the development of medicated foam for incorporation of two incompatible active agents for psoriasis treatment; i.e., lipophilic cholecalciferol, and hydrophilic salicylic acid. Emphasis was given to formulation of a propellant-free foam, with sufficient foaming properties, physical and chemical stability, and low irritancy potential to maintain relevance for later translation into clinical practice. Various excipients and concentrations were examined to achieve suitable foam stability parameters, viscoelasticity, and bubble-size, which relate to foamability and spreadability. The major positive impact on these properties was through a combination of surfactants, and by inclusion of a viscosity-modifying polymer. Incorporation of the incompatible drugs was then examined, noting the instability of cholecalciferol in an acidic environment, with the design aim to separate the drug distributions among the different foam phases. Cholecalciferol was stabilized in the emulsion-based foam, with at least a 30-fold lower degradation rate constant compared to its aqueous solution. The composition of the emulsion-based foam itself protected cholecalciferol from degradation, as well as the addition of the radical-scavenging antioxidant tocopheryl acetate to the oil phase. With the patient in mind, the irritancy potential was also examined, which was below the set limit that defines a non-irritant dermal product.


CRISPR-Cas Systems in Streptococci.
Streptococci are one of the most important and common constituents of the host's microbiota and can colonize and live in the upper respiratory and urogenital tract of humans and animals. The CRISPR-Cas systems (i.e., clustered regularly interspaced short palindromic repeat, with CRISPR-associated proteins) found in bacteria and archaea provide sequence-based adaptive immunity against mobile genetic elements, especially in the streptococci. Here, recent research progress on CRISPR-Cas systems in the streptococci is reviewed, including their classification (mainly type I, type II, and type III), physiological function, defense mechanism (CRISPR adaptation, crRNA biogenesis, and target interference) and applications, which are useful for a better understanding of the functions of such systems. Finally, the advances that have been made in streptococci may help in the discovery of further novel CRISPR-Cas systems for use in new technologies and applications in other species.


False negatives in the assessment of lifetime alcohol use disorders: a serious but unappreciated problem.
Some individuals will not meet criteria for a lifetime alcohol use disorder (AUD) at a baseline assessment but will at a follow-up measurement, but not because the disorder began after the initial evaluation. Despite several research implications, this type of unreliability of lifetime AUD estimates has not been studied extensively. The present study investigated the extent of false negatives in the assessment of lifetime AUDs using longitudinal data. A prospective cohort of college freshmen (baseline N = 489) were assessed seven times between ages 18 and 34 years using the Diagnostic Interview Schedule. Individuals were categorized as false negatives at the index assessment using a retrospective (using Diagnostic and Statistical Manual of Mental Disorders, Third Edition [DSM-III], and DSM-IV data), a prospective (using DSM-III data only), and a combined approach (using DSM-III data only). For DSM-IV, of the 29 ostensible new onsets at a follow-up 5 years later (age approximately 34 years), 28 (96%) reported meeting AUD criteria before the index assessment (age approximately 29 years). For DSM-III, of the 25 ostensible new onsets, the retrospective, prospective, and combined approaches categorized 18 (72%) individuals as false negatives at the index assessment. These findings further demonstrate sensitivity issues with lifetime AUD assessments and call into question the validity of "onset" cases that rely on only two waves of data, especially when the follow-up assessment fails to reassess lifetime fully (i.e., across the entire drinking history).


Population assignment in autopolyploids.
Understanding the patterns of contemporary gene dispersal within and among populations is of critical importance to population genetics and in managing populations for conservation. In contrast to diploids, there are few studies of gene dispersal in autopolyploids, in part due to complex polysomic inheritance and genotype ambiguity. Here we develop a novel approach for population assignment for codominant markers for autotetraploids and autohexaploids. This method accounts for polysomic inheritance, unreduced gametes and unknown allele dosage. It can also utilise information regarding the origin and genotype of one parent for population assignment of maternal or paternal parents. Using simulations, we demonstrate that our approach achieves high levels of accuracy for assignment even when population divergence is low (FST~0.06) and with only 12 microsatellite loci. We also show that substantially higher accuracy is achieved when known maternal information is utilised, regardless of whether allele dosage is known. Although this novel method exhibited near identical levels of accuracy to Structure when population divergence was high, it performed substantially better for most parameters at moderate (FST=0.06) to low levels of divergence (FST=0.03). These methods fill an important gap in the toolset for autopolyploids and pave the way for investigating contemporary gene dispersal in a widespread group of organisms.


Characterization of linoleic acid (C18:2) concentration in commercial corn silage and grain hybrids.
Corn silage and high-moisture corn grain are commonly recognized as risk factors for biohydrogenation-induced milk fat depression and may be due to the high concentration of linoleic acid (C18:2) in corn. Corn silage and corn grain have a low concentration of fatty acids (FA), but due to their high inclusion rate in diets they contribute substantially to unsaturated FA intake. The first objective of this study was to characterize the contribution of individual plant parts to total FA in whole-plant chopped corn. The second objective was to characterize the variation in FA profile in commercial silage and grain hybrids and evaluate the relationship between FA profile and other nutrients. To determine the location of FA in the corn plant, 4 stalks from 4 different commercial hybrids were separated into stalk, husk and shank, leaves, cob, and kernels. On a dry matter basis, 80.5% of total FA were in the kernels, 11.8% in the leaves, 5.1% in the stalk, 1.7% in the cob, and 1.0% in the husk and shank. More than 96% of the oleic acid (C18:1) and 92.5% of the C18:2 was in the kernels, whereas 71.0% of the linolenic acid (C18:3) was in the leaves. Next, the FA composition of fresh whole-plant chopped corn from 124 silage hybrids and grain from 72 grain hybrids was determined over 2 yr from test plots in Pennsylvania. Last, to extend the characterization, FA composition of whole-plant corn silage from 45 hybrids grown in test plots in South Dakota were characterized. In the fresh whole-plant chopped corn from PA test plots, C18:2 as a percentage of total FA averaged from 48.7% in 2013 (percentiles: 10th = 45.2, 90th = 52.2) and 48.0% in 2014 (percentiles: 10th = 44.1, 90th = 49.4). Concentration of C18:2 in corn grain averaged 57.5% in the 2013 (percentiles: 10th = 53.4, 90th = 60.8) and 56.1% in 2014 (percentiles: 10th = 53.5, 90th = 59.4). In the corn silage from South Dakota, the concentration of C18:2 as percentage of total FA averaged 45.4% (percentiles: 10th = 39.4, 90th = 50.2) and C18:2 concentration as a percent of dry matter averaged 1.1% (percentiles: 10th = 0.76, 90th = 1.41). An increase in the concentration of C18:2 was associated with a decrease in C18:3 in fresh whole-plant chopped corn and with a decrease in C18:1 in corn grain. Total FA and C18:2 (as a percentage of dry matter) were positively correlated with starch and negatively correlated with neutral detergent fiber in both fresh whole-plant chopped corn and corn silage samples, whereas no correlation with these traits was observed for C18:2 as a percentage of total FA. In conclusion, FA concentration and profile of corn silage reflects to a great extent the FA composition of kernels and the proportion of grain in the silage. The variation in C18:2 across hybrids provides the opportunity to develop selection programs to decrease C18:2 in corn silage and grain. Selection based on C18:2 concentration as a percent of total FA is preferred as this trait did not correlate with other nutritional properties.


[The use of computer electronystagmography in the assessment of optokinetic nystagmic reactions].
A novel technique of computer-assisted electronystagmography (CENG) has been used in 90 patients with vertigo. Two variants of optokinetic nystagmus (cortical and subcortical) were analysed. Registration of optokinetic nystagmus (OKN) was carried out using original devices for CENG. Right- and left-directed nystagmic reactions and their quantitation were performed according to specially devised registering and analysing programs. In one-sided vestibular disorders cases of cross-over OKN asymmetry prevailed in affection of the cerebellopontine angle (neurinoma of the VIII nerve) compared to labyrinthine disturbances (one-sided Meniere's disease). In 90% of patients with vertebrobasillar deficiency OKN asymmetry was found even in a straight position of the head. OKN asymmetry was less pronounced or disappeared in the OKN test performed with the head turned right or left by 90 degrees.


Revascularization of the Posterior Inferior Cerebellar Artery Using the Occipital Artery: A Cadaveric Study Comparing the p3 and p1 Recipient Sites.
Revascularization of the posterior inferior cerebellar artery (PICA) is typically performed with the occipital artery (OA) as an extracranial donor. The p3 segment is the most accessible recipient site for OA-PICA bypass at its caudal loop inferior to the cerebellar tonsil, but this site may be absent or hidden due to a high-riding location. To test our hypothesis that freeing p1 PICA from its origin, transposing the recipient into a shallower position, and performing OA-p1 PICA bypass with an end-to-end anastomosis would facilitate this bypass. The OA was harvested, and a far lateral craniotomy was performed in 16 cadaveric specimens. PICA caliber and number of perforators were measured at p1 and p3 segments. OA-p3 PICA end-to-side and OA-p1 PICA end-to-end bypasses were compared. OA-p1 PICA bypass with end-to-end anastomosis was performed in 16 specimens; whereas, OA-p3 PICA bypass with end-to-side anastomosis was performed in 11. Mean distance from OA at the occipital groove to the anastomosis site was shorter for p1 than p3 segments (30.2 vs 48.5 mm; P < .001). Median number of perforators on p1 was 1, and on p3, it was 4 (P < .001). Although most OA-PICA bypasses can be performed using the p3 segment as the recipient site for an end-to-side anastomosis, a more feasible alternative to conventional OA-p3 PICA bypass in cases of high-riding caudal loops or aberrant anatomy is to free the p1 PICA, transpose it away from the lower cranial nerves, and perform an end-to-end OA-p1 PICA bypass instead.


Si₃N₄ ring resonator-based microwave photonic notch filter with an ultrahigh peak rejection.
We report a simple technique in microwave photonic (MWP) signal processing that allows the use of an optical filter with a shallow notch to exhibit a microwave notch filter with anomalously high rejection level. We implement this technique using a low-loss, tunable Si₃N₄ optical ring resonator as the optical filter, and achieved an MWP notch filter with an ultra-high peak rejection > 60 dB, a tunable high resolution bandwidth of 247-840 MHz, and notch frequency tuning of 2-8 GHz. To our knowledge, this is a record combined peak rejection and resolution for an integrated MWP filter.


On- versus off-responses of raccoon glabrous skin rapidly adapting cutaneous mechanoreceptors.
1. The on- and off-responses of 50 raccoon median nerve fibers associated with rapidly adapting cutaneous mechanoreceptors in glabrous skin were examined under experimental conditions designed to allow comparable opportunities for on- and off-responses to occur. Trapezoidal stimuli were utilized, providing for equal stimulus indentation and retraction velocities and equal static displacement times and intertrial intervals. Principal findings were as follows: 2. At stimulus levels well above displacement and velocity thresholds for on-responses, 80% of units yielded a more vigorous on-response than off-response (as measured by the total number of ramp impulses); in 6%, the reverse was true; while in the remaining 14%, the off-discharge was absent. 3. On and off displacement thresholds were approximately equal (on median, 43 micron; off median, 42 micron). However, on velocity thresholds were significantly lower than off velocity thresholds (on median, 1.0 micron/ms; off median, 3.8 micron/ms). 4. Exponents (b) of power functions relating discharge rate to ramp velocity (frequency = a x velocityb) were consistently greater for on-responses than for off-responses, but intercept constants (a) were consistently greater for off-responses than for on-responses. 5. Previous findings that mammalian rapidly adapting (RA) mechanoreceptors possess a "linear directionality" generally favoring on-responses were confirmed. 6. Results are discussed in relation to the role of viscoelastic properties of RA mechanoreceptors and neighboring skin. It is suggested that, when considerations is also given to the mechanical properties of surrounding tissues, the Loewenstein and Skalak (18) analysis of the mode of operation of Pacinian corpuscles might also apply, at least qualitatively, to the simple dermal (rapidly adapting) corpuscle of raccoon glabrous skin.


Solvent-free double aza-Michael under ultrasound irradiation: diastereoselective sequential one-pot synthesis of pyrrolidine Lobelia alkaloids analogues.
Novel 2,5-meso-pyrrolidines have been straightforwardly synthesized from readily available symmetrical double Michael acceptors. The key step rested on an aza-Michael addition of primary alkylamines to bis-enones. Competitive Rauhut-Currier and aza-Michael reactions have been highlighted in protic solvent. Ultrasound activation associated with solvent-free conditions led to the expected pyrrolidines in quantitative yields and excellent stereoselectivities. The optimized conditions have been extended to the sonochemical synthesis of pyrrolidine Lobelia alkaloids analogues in short sequences.


SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling.
Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of this pathology are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to trigger barrier dysfunction in vitro and vascular leak in vivo , independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Our findings suggest that S interactions with barrier cells are a contributing factor to COVID-19 disease severity and offer mechanistic insight into SARS-CoV-2 triggered vascular leak, providing a starting point for development of therapies targeting COVID-19 pathogenesis.


Frequency of Routine Testing for Coronavirus Disease 2019 (COVID-19) in High-risk Healthcare Environments to Reduce Outbreaks.
Routine asymptomatic testing strategies for COVID-19 have been proposed to prevent outbreaks in high-risk healthcare environments. We used simulation modeling to evaluate the optimal frequency of viral testing. We found that routine testing substantially reduces risk of outbreaks, but may need to be as frequent as twice weekly.


Bioinformatics Analysis Explores Potential Hub Genes in Nonalcoholic Fatty Liver Disease.
Background: Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most prevalent chronic liver disease worldwide. However, the dysregulated gene expression for NAFLD is still poorly understood. Material and methods: We analyzed two public datasets (GSE48452 and GSE89632) to identify differentially expressed genes (DEGs) in NAFLD. Then, we performed a series of bioinformatics analyses to explore potential hub genes in NAFLD. Results: This study included 26 simple steatosis (SS), 34 nonalcoholic steatohepatitis (NASH), and 13 healthy controls (HC). We observed 6 up- and 19 down-regulated genes in SS, and 13 up- and 19 down-regulated genes in NASH compared with HC. Meanwhile, the overlapping pathways between SS and NASH were PI3K-Akt signaling pathway and pathways in cancer. Then, we screened out 10 hub genes by weighted Gene Co-Expression Network Analysis (WGCNA) and protein-protein interaction (PPI) networks. Eventually, we found that CYP7A1/GINS2/PDLIM3 were associated with the prognosis of hepatocellular carcinoma (HCC) in the TCGA database. Conclusion: Although further validation is still needed, we provide useful and novel information to explore the potential candidate genes for NAFLD prognosis and therapeutic options.


Detection of medically relevant volatile organic compounds with graphene field-effect transistors and separated by low-frequency spectral and time signatures.
Exhaled human breath contains a mixture of gases including nitrogen, oxygen, carbon dioxide, water vapour and low molecular weight volatile organic compounds (VOCs). Different VOCs detected in human breath condensate have been recently related to several metabolic processes occurring inside body tissues in the pathological state, as candidate biomarkers for monitoring conditions such as lung injury, airway inflammation, immunity dysfunction, infection, and cancer. Current techniques for detecting these compounds include several types of mass spectroscopy, which are highly costly, time-consuming and dependent on trained personnel for sample analysis. The need for fast and label-free biosensors is paving the way towards the design of novel and portable electronic devices for point-of-care diagnosis with VOCs such as E-noses, and based on the measurement of signal signatures derived from their chemical composition. In this paper, we propose a device for VOC detection that was tested inside a controlled gas flow setup, resorting to graphene field-effect transistors (GFETs). Electrical measurements from graphene directly exposed to nitrogen plus VOC vapours involved cyclic measurements for the variation of graphene's resistance and low-frequency spectral noise in order to obtain distinctive signatures of the tested compounds in the time and frequency domains related, respectively, to Gutmann's theory for donor-acceptor chemical species and spectral sub-band analysis.


Unusual valyl-transfer ribonucleic acid synthetase mutant of Escherichia coli.
Escherichia coli strain NP2907 was isolated as a spontaneous mutant of strain NP29, which possesses a thermolabile valyl-transfer ribonucleic acid (tRNA) synthetase. The valyl-tRNA synthetase of the new mutant, unlike that of its immediate parent, retains enzymatic activity in vitro but differs from the wild-type enzyme in stability and apparent K(m) for adenosine triphosphate. The new mutant locus, valS-102, cotransduces with pyrB at the same frequency as does the parental locus, valS-1. Cultures of strain NP29 cease growth immediately in any medium when shifted from 30 to 40 C. The new mutant grows normally at 30 C, and upon a shift to 40 C growth quickly accelerates exactly as for normal cells. Exponential growth, however, cannot be sustained at 40 C. At a point characteristic for each medium, growth becomes linear with time. This transition occurs almost immediately in rich media and after 1.5 generations in glucose minimal medium. Net synthesis of valyl-tRNA synthetase ceases in the new mutant as soon as the temperature is raised to 40 C, irrespective of the growth medium. We conclude that it is the amount of valyl-tRNA synthetase activity that limits the rate of growth in the linear phase at 40 C. This property of the mutant makes it possible to evaluate the in vivo efficiency of this enzyme at different growth rates and thereby to determine the concentration that is necessary for a given rate of protein synthesis. The results of our measurements indicate that cells of E. coli growing in minimal medium normally possess a functional excess of valyl-tRNA synthetase with respect to protein synthesis and to repression of threonine deaminase.


Ophthalmic Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis and Relation to SCORTEN.
To evaluate the severity of ocular involvement of patients with Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap, and to investigate the relationship of the SCORTEN (a severity-of-illness score for SJS and TEN based on a minimal set of well-defined variables calculated within 24 hours of admission) with eye disease in this patient population. Retrospective observational case series. Charts of all patients admitted to the Parkland Memorial Hospital Burn Center with a preliminary diagnosis of SJS, SJS/TEN overlap, or TEN between 1998 and 2008 were reviewed. Patients were included for study if they met clinical criteria, had positive diagnostic skin biopsy, and had dermatologic and ophthalmologic consultations. Eighty-two patients with a diagnosis of SJS, SJS/TEN overlap, or TEN met inclusion criteria. Ocular manifestations were classified as mild, moderate, or severe. Admission data were used to calculate the SCORTEN. Main outcome measure was the severity of ocular involvement with respect to diagnosis and SCORTEN. Overall, 84% of patients had ocular involvement (71% SJS, 90% TEN, 100% SJS/TEN overlap). There was no difference in the severity of acute ocular complications among groups. While the SCORTEN value did correlate well with mortality rate (correlation coefficient 0.97, P = .005), there was no correlation between the SCORTEN value and severity of eye involvement in the acute setting. There was also no association of any individual diagnosis of SJS/overlap/TEN with the severity of eye involvement, although eye findings are more common in TEN (P = .03). Ocular damage in the acute setting was more frequent in patients with epidermal detachment >10% of the total body surface area. The SCORTEN value did not correlate with the severity of eye involvement in the acute setting.


Tunica propria in chronic allergic rhinitis. Electron-microscopic study. I. The nasal blood vessels.
The fine structure of human nasal blood vessels was studied in 15 chronic allergic patients. The venules showed gaping of the interendothelial junctions and lamination of the basal lamina. The capillaries displayed numerous endothelial cytoplasmic processes. The arteriolar walls showed thinning and destructive changes. A reciprocal relation between the vascular endothelium and its basal lamina was deduced.


Prognostic factors for stage I ovarian carcinoma.
Stage I ovarian carcinoma is relatively uncommon, and data on prognostic factors are conflicting. The clinical and pathologic features of 51 International Federation of Gynecology and Obstetrics stage I ovarian carcinomas were analyzed. There were 22 stage IA, 1 stage IB, and 28 stage IC cases. The mean follow-up was 6.1 years. The 5-year and 10-year disease-specific survival rates for the entire cohort were 92% and 78%, respectively. Among 51 patients, there were 6 tumor deaths, and 1 patient died of unrelated causes. All patients who died of disease were stage IC. Significant adverse prognostic factors were serous histology [relative risk (RR) 5.4, 95% confidence interval (CI) 1.3-22.0] and stage IC (RR 1.3, 95% CI 1.1-1.5). Among factors associated with stage IC, only positive washings or ascites affected survival (RR 9.25, 95% CI 1.9-44.4). The 5-year survival rates for stages IA and IC were 100% and 83%, respectively (P<0.025, log rank test). For comprehensively staged patients, the 5-year survival rate was 96% as compared with 72% for all others (P<0.025, log rank test). Tumor rupture, surface involvement, histologic grade and clear cell histology were not of adverse prognostic significance. Serous histology and positive washings or ascites are adverse prognostic factors in stage I. The prognostic importance of tumor grade, rupture, surface involvement and clear cell histology remains unclear. Patients who are International Federation of Gynecology and Obstetrics stage I on the basis of comprehensive surgical staging have an excellent prognosis.


Recent Advances in Modified Cap Analogs: Synthesis, Biochemical Properties, and mRNA Based Vaccines.
The recent FDA approval of the mRNA vaccine for severe acute respiratory syndrome coronavirus (SARS-CoV-2) emphasizes the importance of mRNA as a powerful tool for therapeutic applications. The chemically modified mRNA cap analogs contain a unique cap structure, m7 G[5']ppp[5']N (where N=G, A, C or U), present at the 5'-end of many eukaryotic cellular and viral RNAs and several non-coding RNAs. The chemical modifications on cap analog influence orientation's nature, translational efficiency, nuclear stability, and binding affinity. The recent invention of a trinucleotide cap analog provides groundbreaking research in the area of mRNA analogs. Notably, trinucleotide cap analogs outweigh dinucleotide cap analogs in terms of capping efficiency and translational properties. This review focuses on the recent development in the synthesis of various dinucleotide cap analogs such as dinucleotide containing a triazole moiety, phosphorothiolate cap, biotinylated cap, cap analog containing N1 modification, cap analog containing N2 modification, dinucleotide containing fluorescence probe and TAT, bacterial caps, and trinucleotide cap analogs. In addition, the biological applications of these novel cap analogs are delineated.