Potential therapeutic use of plant flavonoids in AD and PD.
Millions of people suffer from Alzheimer's disease (AD) and Parkinson's disease (PD) worldwide. Due to their complex pathology, no effective pharmacological treatment has been found to date, despite extensive research. Developing new, effective therapeutic agents to cure these disease remains a major challenge. Although the cause of AD and PD remains illusive, numerous studies indicates that oxidative stress and neuro-inflammation lead to neurodegeneration in the central nervous system and play vital role in AD and PD morbidity and progression. Flavonoids, which are found widely in nature, exhibit anti-oxidative, anti-inflammatory, anti-mutative, anti-microbial, and neuroprotective properties, so have potential to treat these two kinds of diseases. In this review, we focus on the anti-oxidative and neuroprotective action of flavonoids in attenuating Alzheimer's and Parkinson's disease, and how they might be harnessed in the development of new pharmacological agents to treat these two diseases. Some flavonoid compounds, like hesperidin, naringin, naringenin, tangeretin, nobiletin, silibinin, Epigallocatechin-3-gallate, displayed to be effective in both AD and PD. Considerable studies have demonstrated the anti-AD and anti-PD effects of flavonoids through various in vitro and in vivo models. However, more rigorous studies are needed to be done for flavonoids to develop into effective drugs and apply them to clinical practice.


Green-adapted spectrophotometric determination of fostemsavir based on selective bromophenol blue extraction; reduction of hazardous consumption using computational calculations.
A computationally-assisted and green spectrophotometric method has been developed for the determination of fostemsavir, a recently FDA-approved drug used in combination with antiretroviral drugs to treat multidrug-resistant HIV-1 infection. The method was developed using computational studies and solvent selection based on green chemistry principles. The density functional theory method was employed to identify bromophenol blue as the preferred acid dye for efficient extraction of fostemsavir. The solvent selection process involved a careful evaluation of the green ranking of solvents, which led to the use of water as the solvent. The method involved the extraction of fostemsavir with bromophenol blue to form a yellow ion-pair complex, which exhibited maximally sharp peaks at 418 nm, enabling sensitive visible spectrophotometric determination of fostemsavir in bulk and pharmaceutical preparations. The extraction procedures were optimized, and the method was demonstrated to be sensitive over the concentration range of 2-12 μg/mL fostemsavir. Furthermore, the method was evaluated with respect to green chemistry principles using the analytical eco-scale, the green analytical method index, and analytical greenness metric approach, all of which confirmed that the data obtained by the proposed method were environmentally acceptable.


Fluctuations in rat liver alanine-amino-transferase activity during experimental nippostrongylosis.
The activity of the gluconeogenic enzyme, alanine-amino-transferase (ALT), in a preparation from the liver of rats was studied by means of an in vitro assay throughout the course of a primary infection of Nippostrongylus brasiliensis, established by a subcutaneous injection of approximately 4000 3rd-stage larvae. The activity was measured on days 1-14 p.i. in both uninfected and infected rats and a marked pattern in the enzyme's activity was observed. In infected rats, the activity increased from 1.46 +/- 0.19 U/g liver on day 1 p.i. to a peak on day 4 p.i. of 10.75 +/- 1.62 U/g liver, then decreased to a trough of 0.44 +/- 0.18 U/g liver on day 10 p.i. before returning to original levels by day 14 p.i., by which time the infection had been largely eliminated. In uninfected rats the activity of the liver enzyme remained constant throughout this period with a value of 2.54 +/- 0.12 U/g liver. The activity of the enzyme in vitro was found to be related to the size of the inoculum on days 4 and 10 p.i. It was proposed that these observations could be due to either (1) a direct effect of the parasite, or (2) a consequence of the host immune response to the infection. In order to investigate the second proposition more fully, liver ALT activity was investigated by in vitro assay on selected days p.i. in rats experiencing a secondary N. brasiliensis infection.(ABSTRACT TRUNCATED AT 250 WORDS)


Discovery of Dual FGFR4 and EGFR Inhibitors by Machine Learning and Biological Evaluation.
Kinase inhibitors are widely used in antitumor research, but there are still many problems such as drug resistance and off-target toxicity. A more suitable solution is to design a multitarget inhibitor with certain selectivity. Herein, computational and experimental studies were applied to the discovery of dual inhibitors against FGFR4 and EGFR. A quantitative structure-property relationship (QSPR) study was carried out to predict the FGFR4 and EGFR activity of a data set consisting of 843 and 5088 compounds, respectively. Four different machine learning methods including support vector machine (SVM), random forest (RF), gradient boost regression tree (GBRT), and XGBoost (XGB) were built using the most suitable features selected by the mutual information algorithm. As for FGFR4 and EGFR, SVM showed the best performance with R2test-FGFR4 = 0.80 and R2test-EGFR = 0.75, demonstrating excellent model stability, which was used to predict the activity of some compounds from an in-house database. Finally, compound 1 was selected, which exhibits inhibitory activity against FGFR4 (IC50 = 86.2 nM) and EGFR (IC50 = 83.9 nM) kinase, respectively. Furthermore, molecular docking and molecular dynamics simulations were performed to identify key amino acids for the interaction of compound 1 with FGFR4 and EGFR. In this paper, the machine-learning-based QSAR models were established and effectively applied to the discovery of dual-target inhibitors against FGFR4 and EGFR, demonstrating the great potential of machine learning strategies in dual inhibitor discovery.


Antihypertensive effects of Nigella sativa supplementation: An updated systematic review and meta-analysis of randomized controlled trials.
Clinical studies have suggested that Nigella Sativa (N. sativa) supplementation may effectively reduce blood pressure, but the findings are controversial. Therefore, this study aimed to examine the effects of N. sativa on blood pressure in adults. PubMed, Cochrane Library, Web of Science, Scopus, Embase databases, and Google Scholar were searched till August 2022. To analyze weighted mean differences (WMDs), a random-effects model was utilized. Nonlinear dose-response analysis and a meta-regression were conducted. N. sativa supplementation was effective in reducing both systolic (WMD: -3.06 mmHg; 95% CI: -3.89 to -2.22, p < 0.001; I2 = 84.7%, p < 0.001) and diastolic blood pressure (WMD = -2.69 mmHg; 95% CI: -3.72, -1.66, p < 0.001; I2 = 97.3%, p < 0.001). The current meta-analysis suggests that N. sativa supplementation can improve blood pressure and claims that N. sativa could be used as an effective approach to blood pressure management.


Angiotensinogen, angiotensine converting enzyme and plasminogen activator inhibitor-1 gene polymorphism in chronic allograft dysfunction.
Despite dramatic improvements in first-year patient and graft survival rates, chronic allograft dysfunction (CAD) remains the leading cause of late renal allograft loss, while current immunologic strategies have little effect on this condition. The renin-angiotensin system (RAS) plays an important role in progression of chronic renal disease. It was shown that plasminogen activator inhibitor-1 (PAI-1) functions in the RAS. This study investigates the possible links between angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE) and PAI-1 genotypes with CAD. Assessments of polymorphism were performed in 127 renal allograft recipients (77 with CAD and 50 with normal renal function). Fifty healthy subjects were also considered for comparison. Genotypes were determined using polymerase chain reaction (PCR) sequence-specific primers and PCR followed by restriction fragment length polymorphism analysis. Kidney recipients with CAD had significantly higher frequencies of the TT than the recipients without CAD (P < 0.05). The transplant recipients with CAD also had significantly higher frequencies of the DD genotype than those without CAD (P < 0.05). No significant differences were observed between the allelic and genotypic distributions of PAI-1 polymorphisms. Therefore, determination of AGT M235T and ACE genotypes prior to transplantation may be useful to identify patients who are at risk for chronic renal transplant dysfunction.


Practical approaches to eating disorders in adolescence. Primer for family physicians.
Primary care physicians have an important role in assessing and managing adolescents who present with low weight. Initial diagnosis should be based on current understanding of adolescents' eating behaviours and be followed by obtaining supportive evidence. A practical developmental approach to management should be emphasized. Criteria for hospitalization, a three-step approach to management, and indications for expanding from a primary care to a team approach are discussed.


Randomized Controlled Trials Comparing Bone-Patellar Tendon-Bone Versus Hamstring Tendon Autografts in Anterior Cruciate Ligament Reconstruction Surgery Are Statistically Fragile: A Systematic Review.
To assess the statistical fragility of recently published randomized controlled trials (RCTs) comparing the use of hamstring tendon autograft with bone-patellar tendon-bone autograft for anterior cruciate ligament (ACL) reconstruction. The PubMed, Embase, and MEDLINE databases were queried for RCTs published since 2010 comparing autograft type (bone-patellar tendon-bone vs hamstring tendon) in ACL reconstruction surgery. The fragility index (FI) and reverse FI (rFI) were determined for significant and nonsignificant outcomes, respectively, as the number of outcome reversals required to change statistical significance. The fragility quotient (FQ) and reverse FQ, representing fragility as a proportion of the study population, were calculated by dividing the FI and rFI, respectively, by the sample size. We identified 19 RCTs reporting 55 total dichotomous outcomes. The median FI of the 55 total outcomes was 5 (interquartile range [IQR], 4-7), meaning a median of 5 outcome event reversals would alter the outcomes' significance. Five outcomes were reported as statistically significant with a median FI of 4 (IQR, 2-6), meaning a median of 4 outcome event reversals would change outcomes to be nonsignificant. Fifty outcomes were reported as nonsignificant with a median rFI of 5 (IQR, 4-7), meaning a median of 5 outcome event reversals would change outcomes to be significant. The FQ and reverse FQ for significant and nonsignificant outcomes were 0.025 (IQR, 0.018-0.045) and 0.082 (IQR, 0.041-0.106), respectively. For 61.8% of outcomes, patients lost to follow-up exceeded the corresponding FI or rFI. There is substantial statistical fragility in recent RCTs on autograft choice in ACL reconstruction surgery given that altering a few outcome events is sufficient to reverse study findings. For over half of outcomes, maintaining patients lost to follow-up may have been sufficient to reverse study conclusions. We recommend co-reporting FIs and P values to provide a more comprehensive representation of a study's conclusions when conducting an RCT.


Can Superoxide Anions Predict the Malignant Potential of Carotid body Tumor? - A Pilot Study.
Currently, there is no consensus on estimating the malignant potential of Carotid Body Tumor (CBT) and the only way to predict a metastatic CBT is through DOTANOC Positron Emission Tomography (PET) scan. There is a well-established correlation between CBT and superoxide anions inside tumor cells. The purpose of this pilot study was to measure superoxide anions inside CBT cells and find if these can be used as marker to predict malignant potential of CBT. The results were also co-related with findings of DOTANOC PET scan retrospectively. The CBT tissue from 10 patients was stained using a fluorogenic dye and superoxide anions were measured by analysis of fluorescent image. The patients were divided into two groups - First group with four patients having potentially malignant CBT based upon clinico-surgical characteristics and second group with the rest of the six patients. It was seen that the superoxide anions were highest in the first group which included patients with metastatic carotid body tumor, patients with multiple paragangliomas and patient with positive family history (p = 0.011). The same patients also had metastasis and multiple tumors detected on DOTANOC PET scan. It was concluded that measuring superoxide anions in excised tumor tissue can be used to estimate malignant potential of CBT and can identify patients who truly require DOTANOC PET scan; without affecting the treatment, as it is an expensive investigation involving ionizing radiation and may not be available in all centres. The online version contains supplementary material available at 10.1007/s12070-023-03623-6.


Gibberellic acid, a plant growth regulator, increases mast cell recruitment and alters Substance P levels.
Gibberellic acid (GA3), a plant growth regulator, is used commonly in agriculture. Its potential hazardous effects on human health, however, were relatively unexplored. Several studies demonstrated that in animals chronic GA3 consumption increased tumor formation and oxidative stress. Mast cells and Substance P (SP) play an important role in inflammation. Because chronic inflammation triggers serious conditions, including tumor formation, we examined changes in mast cell recruitment and activation as well as SP levels in skin and urinary bladder. Wistar Albino rats were treated with either a single GA3 dose or multiple GA3 doses for 30 days. Sub-chronic exposure to GA3 markedly increased mast cell recruitment and activation in both tissues. Treatment with 2mg/kg GA3 dose for 30 days decreased SP levels in skin and bladder. SP levels returned to control values in bladder and further increased in skin following 30-day treatment with the 20mg/kg GA3 dose. There was marked urothelial loss and inflammatory cell infiltration in bladder of 30-day GA3 treated groups. In skin, single GA3 doses also decreased SP levels and enhanced mast cell activation and recruitment. Since both SP and mast cell activation elicit inflammatory responses, these results demonstrate that exposure to plant growth regulators may increase inflammatory skin and bladder disease and that use of GA3 should be clearly monitored.


Altered NaCl concentration of airway surface liquid in cystic fibrosis.
A novel isotopic technique suggests that the [Na] and [Cl] of airway surface liquid are both normally approximately 50 mM. In cystic fibrosis, lack of the functional cystic fibrosis transmembrane conductance regulator (CFTR) causes failure of transcellular Cl absorption, resulting in an elevation of [Na] and [Cl] of airway surface liquid to approximately 100 mM.


Analysis of higher plant N-degron pathway components and substrates via expression in S. cerevisiae.
Heterologous expression of enzymes can generate a background-free environment that facilitates investigation of enzyme properties, for instance to focus on particular isoforms in case of gene families, or on individual splicing variants. If a proper host can be found, in vivo assays are often simpler than overexpression and purification, followed by in vitro measurements, would be. We expressed plant ubiquitin ligase PRT6 in the budding yeast Saccharomyces cerevisiae for studies on activity and substrate preferences. Expression of this large enzyme profits from the eukaryotic folding catalysis provided by budding yeast, and from the presence of endogenous ubiquitin activating enzyme. While yeast encodes a ubiquitin ligase, Ubr1, that is functionally related to PRT6, a strain with deletion of the UBR1 gene offers a background-free host. Two different substrates were analyzed. One was a model substate, and the other one a natural substrate fused to a reporter. Two different methods were compared for assessment of protein stability. A method based on internal standardization via tandem fluorescent timer measurement turned out to be complementary to standardization based on cell culture density.


Effects of high pressure homogenisation of raw bovine milk on alkaline phosphatase and microbial inactivation. A comparison with continuous short-time thermal treatments.
Raw whole milk of high microbial quality (<or=4 x 104 cfu/ml) was processed using a approximately 15 l/h homogeniser with a high pressure (HP) valve immediately followed by cooling heat exchangers. The effects of homogenisation between 100 and 300 MPa (HP valve) with an initial milk temperature Tin=4 degrees C or 24 degrees C was investigated on the inactivation of: (i) endogenous alkaline phosphatase (ALP); (ii) endogenous milk flora and (iii) two Gram positive (Listeria innocua and Micrococcus luteus) and one Gram negative (Pseudomonas fluorescens) strains inoculated into milk. Temperatures T1 and T2 measured before and immediately after the HP valve, and fat globule size distributions were also determined. ALP activity slightly decreased after homogenisation above 250 MPa when Tin=4 degrees C (corresponding T2>58 degrees C), but markedly decreased above 200 MPa when Tin=24 degrees C (T2>60 degrees C). In contrast to inactivation induced by continuous short-time thermal treatments, ALP inactivation induced by HP homogenisation was clearly due to mechanical forces (shear, cavitation and/or impact) in the HP valve and not to the short (<<1 s) residence time at temperature T2 in the same valve. Inactivation of the three exogenous microorganisms led to similar conclusions. Homogenisation at 250 MPa or 300 MPa (Tin=24 degrees C) induced a 2-3 log cycle reduction of the total endogenous milk flora and a 1.5-1.8 log cycle reduction of inoculated List. innocua. Higher reduction ratios (2-4 log cycles) were obtained for the two other microorganisms. The highest levels of ALP inactivation corresponded to the highest extents of microbial reduction. Running the milk twice or three times through the homogeniser (recycling), keeping temperature T1 approximately 29 degrees C and pressure=200 MPa, increased homogenisation efficiency.


Cerebral blood flow and sleep state in the normal newborn infant.
The cerebral blood flow (CBF) index measured by venous occlusion plethysmography in 12 normal newborn infants was found to vary significantly with sleep state. Criteria for definition of sleep state are described. The cerebral blood flow index in active sleep was 23% higher than in quiet sleep, and there were smaller, but consistent and significant, differences between intermediate and active or quiet sleep.


Association of Nitric Oxide Synthase2 gene polymorphisms with leprosy reactions in northern Indian population.
The pathogen Mycobacterium leprae causes leprosy that affects mainly skin and nerves. Polymorphisms of certain genes are substantiated to be associated with the susceptibility/resistance to leprosy. The present investigation addressed the association of Nitric Oxide Synthase2 gene polymorphisms and leprosy in a population from northern part of India. A total of 323 leprosy cases and 288 healthy controls were genotyped for four NOS2 promoter variants (rs1800482, rs2779249, rs8078340 and rs2301369) using FRET technology in Real Time PCR. None of these SNPs in promoter sites was associated with susceptibility/resistance to leprosy. NOS2 rs1800482 was found to be monomorphic with GG genotype. However, NOS2-1026T allele was observed to be in higher frequency with leprosy cases (BL and LL) who were not suffering from any reactional episodes compared to cases with ENL reaction {OR=0.30, 95% CI (0.10-0.86), p=0.024}. NOS2-1026GT genotype was more prevalent in cases without reaction (BT, BB and BL) compared to RR reactional patients {OR=0.38, 95% CI (0.17-0.86), p=0.02}. Although haplotype analysis revealed that no haplotype was associated with leprosy susceptibility/resistance with statistical significance, GTG haplotype was noted to be more frequent in healthy controls. These SNPs are observed to be in linkage disequilibrium. Although, these SNPs are not likely to influence leprosy vulnerability, -1026G>T SNP was indicated to have noteworthy role in leprosy reactions.


Folate utilisation by Leishmania species and the identification of intracellular derivatives and folate-metabolising enzymes.
The use and metabolism of folates by leishmanias have been studied by assessing the growth of promastigotes in defined media with different folates and the cell content of folate-metabolising enzymes. The folates present in Leishmania mexicana mexicana have been determined using HPLC. Folic acid, 5-formyltetrahydrofolate (THF) and 5-methyl-THF each supported growth of L. m. mexicana promastigotes in defined medium, whereas the parasites did not survive in the absence of folates; p-aminobenzoic acid could not replace the folate requirement. The only folate present at detectable levels in L. m. mexicana promastigotes was 5-methyl-THF. Dihydrofolate reductase (EC 126.96.36.199), methylene-THF reductase (EC 184.108.40.206), serine hydroxymethyltransferase (EC 22.214.171.124) and thymidylate synthetase (EC 220.127.116.11) were all detected in extracts of promastigotes of L. m. mexicana, L. donovani and L. major. Some of these activities were also found in extracts of amastigotes of the former two species. The enzymes of L. m. mexicana have been partially characterised. Methylene-THF reductase may be involved in the conversion in vivo of 5-methyl-THF to 5,10-methylene-THF.


Getting a grip on the CTD of Pol II.
The first structure of a pre-mRNA processing factor bound to heptad repeats from the C-terminal domain of RNA polymerase II is revealed in a crystal of capping guanylyltransferase complexed with a four-repeat phosphopeptide.


Progressive thrombosis of cervical and intracranial arteries related to Ponatinib treatment for Chronic Myeloid Leukemia.
Ponatinib is a third-generation Tyrosine Kinase Inhibitor (TKI), approved as first-line treatment for Chronic Myeloid Leukaemia (CML) chronic phase. Here we describe a CML patient with a history of subsequent TIAs and an ischemic stroke during Ponatinib treatment. Patient was admitted for a 3-day history of sudden onset left hemiparesis due to an acute ischemic stroke. MRI showed bilaterally the almost total absence of signal in the intracranial tract of anterior circulation and low signal of cerebral posterior circulation. Digital Subtraction Angiography showed multiple steno-occlusions of both anterior and posterior circulation large vessels. The association between cerebrovascular events and TKIs of second and third-generation has been widely described. So Ponatinib was stopped. To our knowledge, this is the first case of multiple ischemic strokes and recurrent TIAs during treatment with Ponatinib, pointing out the importance of accurate quantification of cardiovascular risk before starting Ponatinib.


Production of hepatitis B virus surface antigen containing pre-S1 and pre-S2 domains by Chinese hamster ovary cells.
We have established transformed Chinese hamster ovary cells, which secrete hepatitis B virus surface antigen containing both pre-S1 and pre-S2 domains into culture medium, by using the autologous S gene promoter.


Isolation, localization, and physical mapping of a highly polymorphic locus on human chromosome 11q13.
A highly polymorphic repetitive sequence, D11S533, was isolated by oligonucleotide hybridization from an arrayed chromosome 11q-specific cosmid library. The DNA sequence of this element was determined and found to consist of a repetitive degenerate hexanucleotide sequence [T(Pu)T(Pu)T(Pu)]n extending over 438 bp. Southern blot analysis demonstrated that this element is relatively unique in the human genome. This sequence can be detected by amplification using the polymerase chain reaction (PCR) with oligonucleotide primers complementary to unique sequences flanking the repetitive element. This sequence displays a high degree of polymorphism, and analysis of 15 individuals demonstrated at least 10 alleles ranging in size from 300 to 900 bp. Fluorescence in situ hybridization was used to localize this sequence to 11q13 (FLpter 0.60 +/- 0.02). Pulsed-field gel electrophoresis and the isolation of yeast artificial chromosomes established the long-range physical map surrounding the locus. Because various alleles of this polymorphic sequence can be easily detected by PCR amplification, this probe has potential usefulness in genetic linkage mapping as well as identity testing.


Viral infections.
In summary, viral infections of the skin that occur at adolescence include those typical of childhood and those associated with sexual maturity. Herpes simplex Type II, molluscum contagiosum, and venereal warts, diseases that have shown a marked increase, are in the latter group. Certain diseases, such as rubella, herpes simplex, varicella, and condylomata acuminata, which may lead to laryngeal papillomas, are particularly important because of their effects on the newborn infant. The epidemiological pattern of viral infections changes, and new viruses gain prominence while others fade in importance as causes of disease. Because of this, we can expect new viral entities and changes in earlier ones.


Influence of race/ethnicity on cardiovascular risk factors in polycystic ovary syndrome, the Dallas Heart Study.
Polycystic ovarian syndrome (PCOS) is estimated to affect up to 20% of women. PCOS is associated with insulin resistance and cardiovascular (CV) risk factors. We aimed to evaluate the impact of race/ethnicity on the prevalence of CV risk factors and subclinical predictors of CV events. Cross-sectional analysis of data collected by the Dallas Heart Study, an urban, population-based cohort oversampled for blacks. A previously described cohort of women with PCOS and control subjects of the same racial/ethnic group, matched for age and body mass index. Hormonal and clinical measures associated with PCOS and CV risk factors. The study included 117 women with PCOS and 204 controls. Women with PCOS had significant differences across racial/ethnic groups in the prevalence of hypertension, hypercholesterolaemia, hypertriglyceridaemia and impaired fasting glucose (P < 0·05). Controls showed significant racial/ethnic differences in the prevalence of hypertension and impaired fasting glucose (P < 0·05). The odds of hypertension were significantly greater among women with PCOS than controls after adjusting for race/ethnicity (odds ratio, 1·50 [95% CI, 1·03-2·30]; P = 0·04). However, we did not see an interaction of race/ethnicity that significantly changed CV risk factor prevalence between PCOS and controls. In addition, subclinical measures of CV disease were not different between women with PCOS vs controls, even among hypertensive women. Race/ethnicity affects the prevalence of CV risk factors for women with and without PCOS. However, race/ethnicity does not interact with PCOS to additionally increase CV risk factor prevalence or subclinical CV disease.


Methylation-associated silencing of miR-193b improves the radiotherapy sensitivity of esophageal cancer cells by targeting cyclin D1 in areas with zinc deficiency.
Although radiotherapy is an important treatment mode for esophageal cancer (EC), the outcome remains unsatisfactory due to radioresistance, and the key cause of radiotherapy resistance is a change in the cell cycle. Zinc deficiency (ZD) has a significant influence on the cell cycle, and this effect is a common phenomenon in areas with a high incidence of esophageal cancer. Radioresistant sub-cell lines were established by exposing esophageal cancer cells to nine rounds of X-ray irradiation at a dose of 2 Gy. The cells were treated with a range of different concentrations of zinc and overexpression of miR-193b. And proliferation, colony formation, cell cycle and apoptosis assays were then conducted. Luciferase reporter assays were performed to confirm direct interactions between miR-193b and ZRT/IRT-like protein 5 (ZIP5) and between miR-193b and Cyclin D1. Analysis of clinical and follow-up data was performed using data obtained from 75 patients from Cixian, a well-known high incidence area of esophageal cancer. All these patients are unable to tolerate surgery due to their advanced age or advanced stage, and serum specimens were obtained before the patients received therapy. The cell cycle of radioresistant cells is blocked in G0/G1 phase (from 50% to 68%). The expression level of Cyclin D1 was decreased and miR-193b was increased in radioresistant cells (P < 0.001). ZD decreased the proportion of cells in G0/G1 phase both in EC (from 50% to 32%) and radioresistant (from 68% to 47%) cells. And the radioresistance of these two cells were decreased. ZD increased the expression of Cyclin D1 (P < 0.001) and inhibited the level of miR-193b (P < 0.001). Up-regulation of miR-193b recovered the proportion of cells in G0/G1 phase and the radioresistance, meanwhile, recovered the altered expression levels of Cyclin D1 and miR-193b of these two cells by ZD. ZD enhanced DNMT activity both in EC (32%) and radioresistant (26%). And miR-193b was hypermethylated both in EC and radioresistant cells. MiR-193b supp ressed Cyclin D1 expression by targeting the 3'UTR of Cyclin D1 mRNA. The expression level of miR-193b in the serum of patients was correlated with the disease control rate (DCR) and had a good diagnostic value for distinguishing DCR of EC patients (AUC = 0.710, 95%CI: 0.580-0.839, P = 0.003). And the level of miR-193b was correlated with overall survival (OS) (HR = 0.208, 95%CI: 0.094-0.464). The methylation-mediated silencing of miR-193b in EC cells due to ZD increased the expression of ZIP5, and the overexpression of ZIP5 increased the intracellular zinc levels to maintain zinc homeostasis. Meanwhile, the silencing of miR-193b increased the sensitivity of radiotherapy by promoting the expression of Cyclin D1.


Electrochemical modulation enhances the selectivity of peripheral neurostimulation in vivo.
Electrical nerve stimulation serves an expanding list of clinical applications, but it faces persistent challenges in selectively activating bundled nerve fibers. In this study, we investigated electrochemical modulation with an ion-selective membrane (ISM) and whether it, used together with electrical stimulation, may provide an approach for selective control of peripheral nerves. Guided by theoretical transport modeling and direct concentration measurements, we developed an implantable, multimodal ISM cuff capable of simultaneous electrical stimulation and focused Ca2+ depletion. Acutely implanting it on the sciatic nerve of a rat in vivo, we demonstrated that Ca2+ depletion could increase the sensitivity of the nerve to electrical stimulation. Furthermore, we found evidence that the effect of ion modulation would selectively influence functional components of the nerve, allowing selective activation by electrical current. Our results raise possibilities for improving functional selectivity of new and existing bioelectronic therapies, such as vagus nerve stimulation.


Adaptive phenology of desert and Mediterranean populations of annual plants grown with and without water stress.
The dynamics of vegetative and reproductive growth were compared in matched pairs of Mediteranean and desert populations of three unrelated annual species, Erucaria hispanica (L.) Druce, Brachypodium distachyon (L.) Beauv. and Bromus fasciculatus C. Presl., under high and low levels of water availability in a common-environment experiment. Plants of all desert populations showed earlier switches to reproductive development and to subsequent phenophases, and the transition to flowering occurred at smaller plant sizes. Water stress had no effect (E. hispanica) or slightly accelerated the transition to flowering in B. fasciculatus (by 1-2 days) and in B. distachyon (by 4-6 days). Plant senescence was strongly enhanced by water stress, and this enhancement was greater in desert populations than in corresponding Mediterranean ones. Duration of life cycle was greatly shortened by water stress in all three species. Desert and Mediterranean populations of the three species exhibited small differences in their relative response, i.e. phenotypic plasticity, to water stress for phenological and plant size parameters. In E. hispanica and B. fasciculatus the population x water regime interaction amounted to less than 3% of total variance. By contrast, the Mediterranean population of B. distachyon was much more plastic in its response to water stress than the desert population in its transition to plant senescence. Plants from the desert populations appeared to be adapted to shorter, more compact growth cycles, culminating in earlier dates of seed maturation and plant senescence. In addition, they showed larger phenotypic plasticity in the transition to plant senescence, which trait was enhanced or magnified by sustained or repeated lack of water. By contrast, plants from Mediterranean populations delayed switchover from one phenophase to the next, seeming thus to "bet" on more water being forthcoming.


Cyclosporin A suppresses cisplatin-induced c-fos gene expression in ovarian carcinoma cells.
Cisplatin-resistant A2780DDP human ovarian carcinoma cells, 1 and 3 h following cisplatin treatment, display 3.2-6.1-fold enhancement of mRNA expression for oncogenes c-fos and c-H-ras and for enzymes necessary for DNA synthesis and repair. In contrast, c-myc mRNA was partially decreased. Increased transcription for the aforementioned genes accounts for the higher levels of mRNA since the enhancement is susceptible to actinomycin D pretreatment. Cyclosporin A (CSA) has been shown to reverse resistance to a variety of antineoplastic agents. An 18-h treatment with CSA yielded a 6-fold improved sensitivity to cisplatin in A2780DDP cells. When A2780DDP cells are pretreated with CSA followed by cisplatin, there is no increase in mRNA for c-fos and c-H-ras and the genes for thymidine synthesis and DNA repair. Their expression approaches the levels demonstrated in A2780S cells. In contrast, c-myc mRNA was elevated 7.4-fold in the presence of CSA in A2780DDP cells. Long term weekly exposures of A2780DDP cells to CSA resulted in the evolution of a revertant cell line, A2780DDP/CSA, with decreased c-fos and dTMP synthase mRNA. Thus, cisplatin treatment in A2780DDP cells differentially induces expression of certain nuclear oncogenes (c-fos/c-myc), as well as genes possibly involved in the repair of cisplatin-mediated DNA damage, an induction suppressed by CSA treatment.


Selective processing of pain-related word stimuli in subclinical depression as indicated by event-related brain potentials.
An intense discussion still exists as to whether pain and depression are causally related or independent of each other. To investigate processing of pain-related word stimuli in subclinically depressed individuals, we designed an event-related potentials study in a group control design. Pain words and neutral words were presented to 16 subclinically depressed and 16 control participants. Behavioral and electrophysiological measures were taken during lexical decision and recognition tasks. Depressive compared to control participants showed enhanced P300 amplitudes at parietal electrodes triggered by pain-related words during the lexical decision task, which presumably is a sign of enhanced recollection processes for these word stimuli. In line with these electrophysiological findings, depressed participants also tended to better recall the pain-related words in the later recognition task than control participants. We conclude that subclinically depressed individuals selectively process pain-related stimuli, and this processing bias could enhance their vulnerability to develop pain symptoms.


A critical appraisal of tools for delivery room assessment of the newborn infant.
Assessment of an infant's condition in the delivery room represents a prerequisite to adequately initiate medical support. In her seminal paper, Virginia Apgar described five parameters to be used for such an assessment. However, since that time maternal and neonatal care has changed; interventions were improved and infants are even more premature. Nevertheless, the Apgar score is assigned to infants worldwide but there are concerns about low interobserver reliability, especially in preterm infants. Also, resuscitative interventions may preclude the interpretation of the score, which is of concern when used as an outcome parameter in delivery room intervention studies. Within the context of these changes, we performed a critical appraisal on how to assess postnatal condition of the newborn including the clinical parameters of the Apgar score, as well as selected additional parameters and a proposed new scoring system. The development of a new scoring system that guide clinicians in assessing infants and help to decide how to support postnatal adaptation is discussed. IMPACT: This critical paper discusses the reliability of the Apgar score, as well as additional parameters, in order to improve assessment of a newborn's postnatal condition. A revised neonatal scoring system should account for infant maturity and the interventions administered. Delivery room assessment should be directed toward determining how much medical support is needed and how the infant responds to these interventions.


A machine-learning approach for predicting B-cell epitopes.
The immune activity of an antibody is directed against a specific region on its target antigen known as the epitope. Numerous immunodetection and immunotheraputics applications are based on the ability of antibodies to recognize epitopes. The detection of immunogenic regions is often an essential step in these applications. The experimental approaches used for detecting immunogenic regions are often laborious and resource-intensive. Thus, computational methods for the prediction of immunogenic regions alleviate this drawback by guiding the experimental procedures. In this work we developed a computational method for the prediction of immunogenic regions from either the protein three-dimensional structure or sequence when the structure is unavailable. The method implements a machine-learning algorithm that was trained to recognize immunogenic patterns based on a large benchmark dataset of validated epitopes derived from antigen structures and sequences. We compare our method to other available tools that perform the same task and show that it outperforms them.


Polyoxometalate embedding of a tetraruthenium(IV)-oxo-core by template-directed metalation of [gamma-SiW10O36]8-: a totally inorganic oxygen-evolving catalyst.
Solid state and solution evidence confirms the embedding of an adamantane-like, Ru4O6 fragment by the divacant, gamma-decatungstosilicate ligand. The resulting complex catalyzes water oxidation to oxygen with TON up to 500 and TOF > 450 h-1.


Environmental status of the NE Adriatic Sea, Istria, Croatia: Insights from mussel Mytilus galloprovincialis condition indices, stable isotopes and metal(loid)s.
The environmental status of the marine environment in the NE Adriatic Sea was assessed, using as a bioindicator species the Mediterranean mussel Mytilus galloprovincialis Lamarck, 1819. Samples were collected seasonally from mariculture sites and from major Istrian ports between the years 2010 and 2013. The condition indices of mussels ranged from 13.3 to 20.9% at mariculture sites and from 14.3 to 23.3% at port locations. The seasonally δ13CDIC values of seawater varied between -10.9 to 0.7‰. Pollution by sewage sludge (based on δ15N values) was confirmed only in two ports. Tissue concentrations of Mn, Co, Ni, Cu, Zn, Se, Cd, and Pb were significantly higher in the tissue of the mussels collected from the ports (polluted sites). Arsenobetaine was the major As compound present in the samples and there was no significant difference in the levels of total As in mussel tissues from mariculture and port sites.


Chronic restraint stress promotes the tumorigenic potential of oral squamous cell carcinoma cells by reprogramming fatty acid metabolism via CXCL3 mediated Wnt/β-catenin pathway.
Chronic stress promotes tumor progression and may harm homeostasis of energy metabolism by disrupting key metabolic processes. Recently, emerging evidence that chemokines CXCL3 as a novel adipokine plays a new role in lipid metabolism and various human malignancies. However, the role and mechanism of the CXCL3 in oral squamous cell carcinoma (OSCC) progression and reprogramming lipid metabolism induced by chronic restraint stress is unclear. The analysis of transcriptome sequencing, LC-MS, GC-MS, CCK8, cell apoptosis assays, cell cycle analysis, qRT-PCR, ELISA, western blotting, immunofluorescence, immunohistochemistry, RNA interference and lentivirus transfection and a xenograft tumor growth and chronic restraint stress model were used to investigate the role of CXCL3 in the regulation of lipid metabolism and OSCC and explore the underlying molecular mechanisms. We showed that CXCL3 plays a critical role in in fatty acid de novo synthesis and tumor growth induced by chronic restraint stress. We demonstrated that chronic restraint stress promoted lipid accumulation, OSCC growth and metastasis in a mouse xenograft model. CXCL3 knockdown and FH535, an inhibitor of Wnt/β-catenin pathway, could attenuate fatty acid de novo synthesis, cell proliferation and epithelial-mesenchymal transition induced by chronic restraint stress in OSCC cells. Our findings demonstrate that chronic restraint stress promotes the proliferation and metastasis of OSCC by reprogramming fatty acid metabolism via CXCL3 mediated Wnt/β-catenin pathway. Our study provides novel insights to help understand the underlying mechanisms of CXCL3 in OSCC progression induced by chronic restraint stress.


Novel alternative splicing in the 5' exon of the neurotrophin-3 gene.
The neurotrophin-3 (NT-3) gene has previously been reported to consist of three exons including two 5' short untranslated exons and a 3' long exon encoding the entire protein, and to give rise to two classes of transcripts by alternative splicing of the 5' exons to the 3' coding exon. In the present study, we demonstrated the presence of at least four new classes of transcripts of the NT-3 gene, in addition to the two known transcripts. The present finding proposes the further complexity of the regulational mechanism for NT-3 expression.


Depth and orientational dependencies of MRI T(2) and T(1ρ) sensitivities towards trypsin degradation and Gd-DTPA(2-) presence in articular cartilage at microscopic resolution.
Depth and orientational dependencies of microscopic magnetic resonance imaging (MRI) T(2) and T(1ρ) sensitivities were studied in native and trypsin-degraded articular cartilage before and after being soaked in 1 mM Gd-DTPA(2-) solution. When the cartilage surface was perpendicular to B(0), a typical laminar appearance was visible in T(2)-weighted images but not in T(1ρ)-weighted images, especially when the spin-lock field was high (2 kHz). At the magic angle (55°) orientation, neither T(2)- nor T(1ρ)-weighted image had a laminar appearance. Trypsin degradation caused a depth- and orientational-dependent T(2) increase (4%-64%) and a more uniform T(1ρ) increase at a sufficiently high spin-lock field (55%-81%). The presence of the Gd ions caused both T(2) and T(1ρ) to decrease significantly in the degraded tissue (6%-38% and 44%-49%, respectively) but less notably in the native tissue (5%-10% and 16%-28%, respectively). A quantity Sensitivity was introduced that combined both the percentage change and the absolute change in the relaxation analysis. An MRI experimental protocol based on two T(1ρ) measurements (without and with the presence of the Gd ions) was proposed to be a new imaging marker for cartilage degradation.


Attention and repetition priming in the verb generation task.
Transfer-appropriate processing (TAP) and identification-production frameworks predict that repetition priming will be reduced by encoding-phase divided attention (DA) in implicit memory tasks that involve conceptual analysis of test stimuli and require responses that go beyond the identification of the test cue. This prediction was tested using the verb generation task. Verb generation priming was weakly affected by a number classification distracting task at encoding that impacted recognition, was affected more by a more demanding mental arithmetic task, and was abolished entirely by a selective attention manipulation. Priming originating largely from a process unique to the verb generation task was also found to be attention-sensitive. DA affected priming equivalently for high-competition and low-competition items, against the identification-production framework which predicts greater DA effects on priming in high-competition conditions. The results fit comfortably within the TAP framework.


Clinical evaluation of a newly developed endoscopic resection device (Rotoresect): physical principle and first clinical results.
Endoscopic resection techniques on benign prostatic tissue aim at a high ablation rate and a minimal bleeding rate. Although commercial resection electrodes are effective, they either cause high blood loss (loop electrode) or reduce the bleeding rate with a compromised ablation rate (electrovaporization electrode). To resolve these problems, a new electrosurgical resection device, The Rotoresect, has been developed. The Rotoresect incorporates a specially designed working element. The resection electrode is driven by a micromotor with a high-frequency current that enables simultaneous coagulation and vaporization during rotoresection. To date, 40 patients with benign prostatic hyperplasia have undergone transurethral rotoresection of the prostate with this new device. The actively rotating resection electrode enables tissue coagulation and vaporization as well as mechanical tissue ablation. Only slight bleeding was observed during the entire resection procedure. Postoperatively, no significant changes in hemoglobin and sodium concentration were detected. The deobstructive effect of the Rotoresect was comparable to that of the standard loop. The simultaneous tissue vaporization, coagulation, and mechanical removal by the Rotoresect enables a high ablation rate combined with minimal blood loss. Initial clinical results gained in the transurethral resection of benign prostatic tissue are promising.


Hypertension in headache patients? A clinical study.
The aim of the present study was to assess the prevalence of hypertension in patients with headache, coming to the observation of an Headache Center. A total of 1486 consecutive outpatients were examined, and blood pressure was determined in all patients. Migraine without aura (MO) was the most common diagnosis, followed by migraine associated with tension-type headache, migraine with aura (MA), episodic tension-type headache (ETTH), chronic tension-type headache (CTTH), cluster headache (CH), and medication-overuse headache (MOH). Hypertension was present in 28% of the patients, and it was particularly common in MOH (60.6%), CTTH (55.3%), CH (35%), ETTH (31.4%), less common in MO (23%) and MA (16.9%). In all headache groups, the prevalence of hypertension was higher than in the general population, within all age groups. After adjustment for age and gender, hypertension was found to be more common in tension-type, and especially in CTTH, than in migraine. These findings could be affected by 'Berkson's bias': and should not be extrapolated to the general population, but apply only to the subpopulation of patients who come to the observation of an Headache Center, and who may have more disabling symptoms. Hypertension could be one of the factors leading to exacerbation of the frequency and severity of attacks, both in migraine and tension-type headache. Hypertension has important therapeutic implications and should be actively sought in headache patients, and more thoroughly investigated, with ad-hoc surveys in the general population.


Macro-fungal (Agaricus bisporus) wastes as an adsorbent in the removal of the acid red 97 and crystal violet dyes from ideal colored effluents.
The wastes from the macro-fungus Agaricus bisporus were used as an eco-friendly and low-cost adsorbent for the treatment of colored effluents containing the recalcitrant dyes, acid red 97 (AR97) and crystal violet (CV). The macro-fungal waste presented an amorphous structure, composed of particles with different sizes and shapes. Also, it presents typical functional chemical groups of proteins and carbohydrates with a point of zero charge of 4.6. The optimum conditions for the dosage were found to be as follows: 0.5 g L-1 with an initial pH at 2.0 for the AR97 and 8.0 for the CV. From the kinetic test, it was found that it took 210 min and an adsorption capacity of 165 mg g-1 for the AR97. Concerning the CV kinetics, it took 120 min to reach the equilibrium and it achieved an adsorption capacity of 165.9 mg g-1. The Elovich model was the most proper model for describing the experimental data, achieving an R2 ≥ 0.997 and MSE ≤ 36.98 (mg g-1)2. The isotherm curves were best represented by the Langmuir model, predicting maximum adsorption capacity of 372.69 and 228.74 mg g-1 for the AR97 and CV, respectively. The process was spontaneous and favorable for both dyes. The ∆H0 values were 9.53 and 10.69 kJ mol-1 for AR97 and CV, respectively, indicating physical and endothermic adsorption. Overall, the wastes from Agaricus bisporus have the potential to adsorb cationic and anionic dyes, thus solving environmental problems related to water quality and residue disposal.


Comparative analysis of ultrasonic elastosonography and contrast-enhanced ultrasonography in the diagnosis of benign and malignant intraocular tumors.
To compare the diagnostic value of ultrasonic elastosonography (UE) and contrast-enhanced ultrasonography (CEUS) for benign and malignant intraocular tumors. This retrospective study enrolled patients with intraocular tumors at Beijing Tongren Hospital, Capital Medical University (August 2016 to January 2020). The strain rate ratio (strain rate of tumor tissue divided by strain rate of surrounding normal tissue) was measured by UE. CEUS was performed using SonoVue® contrast agent. The performance of each method at differentiating benign from malignant intraocular tumors was evaluated by receiver operating characteristic curve analysis. The analysis included 147 eyes in 145 patients (45.6 ± 13.4 years-old; 66 males): 117 patients (119 eyes) with malignant tumors and 28 patients (28 eyes) with benign tumors. At an optimal cutoff of 22.67 for the strain rate ratio, UE distinguished benign from malignant tumors with a sensitivity of 86.6% and a specificity of 96.4%. CEUS showed that 117 eyes with malignant tumors had a fast-in, fast-out time-intensity curve, and only two eyes with malignant tumors had a fast-in, slow-out curve, while all 28 eyes with benign tumors had a fast-in, slow-out curve. CEUS differentiated benign from malignant tumors with a sensitivity of 98.3% and a specificity of 100%. The diagnostic results differed significantly between the two methods (P = 0.004, McNemar test). The diagnostic performances of the two tests were moderately consistent (κ = 0.657, P < 0.001). Both CEUS and UE have good diagnostic value in the differentiation of benign intraocular tumors from malignant intraocular tumors.


Transcription attenuation is the major mechanism by which the leu operon of Salmonella typhimurium is controlled.
Three mutations, each causing constitutive expression of the Salmonella typhimurium leu operon, were cloned into phage vector lambda gt4 on EcoRI DNA fragments carrying all of that operon except for part of the promoter-distal last gene. Sequence analysis of DNA from these phage demonstrated that each contains a single base change in the leu attenuator. Transcription of mutant DNA in vitro resulted in transcription beyond the usual site of termination. The level of beta-IPM dehydrogenase, the leuB enzyme, was elevated 40-fold in a strain carrying one of these mutations, and starvation of this strain for leucine had little effect on the amount of activity expressed. Using a strain with a wild-type promoter-leader region of the leu operon, the rates of synthesis and degradation of leu leader RNA and readthrough RNA (leu mRNA) were measured by DNA-RNA hybridizations with specific DNA probes. The rate of synthesis of the leu leader was about the same in cells grown with excess or with limiting leucine. On the other hand, the rate of synthesis of leu mRNA was 12-fold higher for cells grown in limiting leucine as opposed to excess leucine. The rate of degradation of these RNA species was the same under both conditions of growth. Thus, the variation in expression of the leu operon observed for cells grown in minimal medium is, for the most part, not caused by control over the frequency of initiation or by the differential stability of these RNA species. Rather, the variation is a direct result of the frequency of transcription termination at an attenuator site. These results taken together suggest that transcription attenuation is the major mechanism by which leucine regulates expression of the leu operon of S. typhimurium for cells growing in a minimal medium.


Advances and research needs for disinfection byproducts control strategies in swimming pools.
The control of disinfection byproducts (DBPs) in swimming pools is of great significance due to the non-negligible toxicity and widespread existence of DBPs. However, the management of DBPs remains challenging as the removal and regulation of DBPs is a multifactorial phenomenon in pools. This study summarized recent studies on the removal and regulation of DBPs, and further proposed some research needs. Specifically, the removal of DBPs was divided into the direct removal of the generated DBPs and the indirect removal by inhibiting DBP formation. Inhibiting DBP formation seems to be the more effective and economically practical strategy, which can be achieved mainly by reducing precursors, improving disinfection technology, and optimizing water quality parameters. Alternative disinfection technologies to chlorine disinfection have attracted increasing attention, while their applicability in pools requires further investigation. The regulation of DBPs was discussed in terms of improving the standards on DBPs and their preccursors. The development of online monitoring technology for DBPs is essential for implementing the standard. Overall, this study makes a significant contribution to the control of DBPs in pool water by updating the latest research advances and providing detailed perspectives.


Nucleotide sequence analysis of Vietnamese highly pathogenic porcine reproductive and respiratory syndrome virus from 2013 to 2014 based on the NSP2 and ORF5 coding regions.
A total of 34 highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) strains isolated from Vietnam during 2013-2014 were sequenced and analyzed. A partial sequence of ORF1a corresponding to the nonstructural protein 2 (Nsp2) coding region and the full sequence of open reading frame 5 (ORF5) gene was used for the analysis. The HP-PRRSV strains were isolated from pig herds that had never been vaccinated for PRRSV. Nucleotide sequence identities in the portions of ORF1a corresponding to the nonstructural protein 2 (Nsp2) coding region and ORF5 ranged from 96.4 to 100 % and 83.2 to 100 %, respectively. All of the 34 Vietnamese HP-PRRSV strains showed two discontinuous 30-amino-acid deletions in the Nsp2 coding region as a genetic marker of prototypic Chinese HP-PRRSV. The amino acid arginine (R) was present at positions 13 and 151 in ORF5 in 29 out of 34 Vietnamese HP-PRRSV isolates, as well as in the prototypic Chinese HP-PRRSV. Sequence analysis of the ORF5 genes of all Vietnamese HP-PRRSVs revealed six subgroups: Viet 1 to 4, JAX1-like, and VR-2332-like. Nucleotide and amino acid sequence analysis of 34 Vietnamese HP-PRRSV isolates from 2013-2014 indicated that Vietnamese HP-PRRSV has undergone rapid evolutionary changes in recent years when compared with Vietnamese HP-PRRSV isolated before 2012.


GTP enhances inositol trisphosphate-stimulated Ca2+ release from rat liver microsomes.
Low concentrations of GTP (10-50 microM) greatly enhance the inositol 1,4,5-trisphosphate stimulated Ca2+ release from rat liver microsomal vesicles. The effect of GTP depends on the presence of low concentrations of polyethylene glycol in the incubation medium. Guanylyl imidodiphosphate is ineffective at mimicking the GTP effect and inhibits the action of GTP added subsequently.


Search for extraterrestrial point sources of neutrinos with AMANDA-II.
We present the results of a search for point sources of high-energy neutrinos in the northern hemisphere using AMANDA-II data collected in the year 2000. Included are flux limits on several active-galactic-nuclei blazars, microquasars, magnetars, and other candidate neutrino sources. A search for excesses above a random background of cosmic-ray-induced atmospheric neutrinos and misreconstructed downgoing cosmic-ray muons reveals no statistically significant neutrino point sources. We show that AMANDA-II has achieved the sensitivity required to probe known TeV gamma-ray sources such as the blazar Markarian 501 in its 1997 flaring state at a level where neutrino and gamma-ray fluxes are equal.


Incremental benefits of novel pharmaceuticals in the UK: a cross-sectional analysis of NICE technology appraisals from 2010 to 2020.
To evaluate the incremental value of new drugs across disease areas receiving favourable coverage decisions by the UK's National Institute for Health and Care Excellence (NICE) over the past decade. This cross-sectional study assessed favourable appraisal decisions of drugs between 1 January 2010 and 31 December 2020. Estimates of incremental benefit were extracted from NICE's evidence review groups reports. Incremental benefit of novel drugs relative to the best alternative therapeutic option, expressed in quality-adjusted life-years (QALYs). 184 appraisals of 129 drugs provided QALYs. The median incremental value was 0.27 QALY (IQR: 0.07-0.73). Benefits varied across drug-indication pairs (range: -0.49 to 5.22 QALY). The highest median benefits were found in haematology (0.70, IQR: 0.55-1.22) and oncology (0.46, IQR: 0.20-0.88), the lowest in ophthalmology (0.09, IQR: 0.04-0.22) and endocrinology (0.02, IQR: 0.01-0.06). Eight appraisals (4.3%) found contributions of more than two QALYs, but one in four (50/184) drug-indication pairs provided less than the equivalent of 1 month in perfect health compared to existing treatments. In our review period, the median incremental value of novel drugs approved for use within the English National Health System, relative to the best alternative therapeutic option, was equivalent to 3-4 months of life in perfect health, but data were heterogeneous. Objective evaluations of therapeutic value helps patients and physicians to develop reasonable expectations of drugs and delivers insights into disease areas where medicinal therapeutic progress has had the most and least impact.


The relationship between CO2-assimilation rate, Rubisco carbamylation and Rubisco activase content in activase-deficient transgenic tobacco suggests a simple model of activase action.
Transgenic tobacco (Nicotiana tabacum L. cv. W38) plants with an antisense gene directed against the mRNA of ribulose-1,5-bisphosphate carboxylase/ oxygenase (Rubisco) activase were used to examine the relationship between CO2-assimilation rate, Rubisco carbamylation and activase content. Plants used were those members of the r1 progeny of a primary transformant with two independent T-DNA inserts that could be grown without CO2 supplementation. These plants had from < 1% to 20% of the activase content of control plants. Severe suppression of activase to amounts below 5% of those present in the controls was required before reductions in CO2-assimilation rate and Rubisco carbamylation were observed, indicating that one activase tetramer is able to service as many as 200 Rubisco hexadecamers and maintain wild-type carbamylation levels in vivo. The reduction in CO2-assimilation rate was correlated with the reduction in Rubisco carbamylation. The anti-activase plants had similar ribulose-1,5-bisphosphate pool sizes but reduced 3-phosphoglycerate pool sizes compared to those of control plants. Stomatal conductance was not affected by reduced activase content or CO2-assimilation rate. A mathematical model of activase action is used to explain the observed hyperbolic dependence of Rubisco carbamylation on activase content.


BODIPY-based rapid response fluorescence probe for sensing and bioimaging endogenous superoxide anion in living cells.
The superoxide anion radical (O2-), a pernicious ROS in living cells, has long been recognized as an important cell signaling molecule involved in numerous physiological and pathological processes, including innate immunity and metabolic homeostasis. Here, we developed a new bodipy-based fluorescent probe for monitoring O2- based on the selective cleavage of phosphate bond in BODIPY-T by O2-, producing a high-brightness fluorescent BODIPY-COOH. The probe exhibits excellent selectivity for O2- with little interference from other ROS species. Fluorescence imaging of RAW264.7 cells also demonstrated successful detection of endogenous O2- changes in living cells, indicating that BODIPY-T is a potential probe for the diagnosis and study of the corresponding diseases.


Considerations to address missing data when deriving clinical trial endpoints from digital health technologies.
Digital health technologies (DHTs) enable us to measure human physiology and behavior remotely, objectively and continuously. With the accelerated adoption of DHTs in clinical trials, there is an unmet need to identify statistical approaches to address missing data to ensure that the derived endpoints are valid, accurate, and reliable. It is not obvious how commonly used statistical methods to handle missing data in clinical trials can be directly applied to the complex data collected by DHTs. Meanwhile, current approaches used to address missing data from DHTs are of limited sophistication and focus on the exclusion of data where the quantity of missing data exceeds a given threshold. High-frequency time series data collected by DHTs are often summarized to derive epoch-level data, which are then processed to compute daily summary measures. In this article, we discuss characteristics of missing data collected by DHT, review emerging statistical approaches for addressing missingness in epoch-level data including within-patient imputations across common time periods, functional data analysis, and deep learning methods, as well as imputation approaches and robust modeling appropriate for handling missing data in daily summary measures. We discuss strategies for minimizing missing data by optimizing DHT deployment and by including the patients' perspectives in the study design. We believe that these approaches provide more insight into preventing missing data when deriving digital endpoints. We hope this article can serve as a starting point for further discussion among clinical trial stakeholders.


Rapid behavioural and biochemical effects of tetanus toxin microinjected into the substantia nigra: a dual role for GABA?
Tetanus toxin (200--250 mouse lethal doses) microinjected unilaterally into the substantia nigra produced rapid behavioural and biochemical effects. If the toxin was injected into the rostral part of the substantia nigra (SN), contralateral turning was observed. Raised ipsilateral striatal levels of the dopamine (DA) metabolite, homovanillic acid (HVA), indicated that this turning was due to activation of the nigro-striatal dopamine system. Caudal nigral injections of tetanus toxin produced ipsilateral turning. Biochemical estimations suggest that this behaviour change was mediated by a non-dopamine (non-DA) pathway.


Embryotoxicity of sixteen industrial amines to the chicken embryo.
Sixteen amine compounds that are used in the rubber industry, and sodium nitrite, were tested on three-day chicken embryos for embryotoxicity. The parameters measured were: early deaths recorded within two days of injection, late deaths of malformed embryos, late deaths of non-malformed embryos and malformed survivors. The most embryotoxic chemicals were N-phenyl-N'-isopropyl-p-phenylenediamine, N,N,N-triethylethylenediamine, N,N'-dicyclohexyl-p-phenyleneamine and triethylamine, with total effect ED50 values, including deaths and malformations, between 0.11 and 0.90 mumol per egg. The ED50 values for triethylenetetramine, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine, triethanolamine, N-phenyl-2-naphtylamine, aniline and N-nitrosodiphenylamine ranged from 1.1 to 7.0 mumol per egg. Sodium nitrite was the least potent, with an ED50 of 22 mumol per egg. Six chemicals produced no effects. They probably did not reach the embryo. The four most potent chemicals, together with aniline, caused the highest frequencies of malformations.


Structured approach to the elicitation of expert beliefs for a Bayesian-designed clinical trial: a case study.
To quantify uncertainty in a formal manner, statisticians play a vital role in identifying a prior distribution for a Bayesian-designed clinical trial. However, when expert beliefs are to be used to form the prior, the literature is sparse on how feasible and how reliable it is to elicit beliefs from experts. For late-stage clinical trials, high importance is placed on reliability; however, feasibility may be equally important in early-stage trials. This article describes a case study to assess how feasible it is to conduct an elicitation session in a structured manner and to form a probability distribution that would be used in a hypothetical early-stage trial. The case study revealed that by using a structured approach to planning, training and conduct, it is feasible to elicit expert beliefs and form a probability distribution in a timely manner. We argue that by further increasing the published accounts of elicitation of expert beliefs in drug development, there will be increased confidence in the feasibility of conducting elicitation sessions. Furthermore, this will lead to wider dissemination of the pertinent issues on how to quantify uncertainty to both practicing statisticians and others involved with designing trials in a Bayesian manner.


Effects of isosorbide dinitrates intravenously in high doses over a short period in anterior acute myocardial infarction.
The effects of intravenous isosorbide dinitrate administered in high doses over a short period of time in 17 patients (14 men, 3 women, mean age 67 years) with anterior wall acute myocardial infarction were evaluated. Patients were classified into 2 groups based on the electrocardiographic pattern of acute ischemia. Patients presented with anterior acute myocardial infarction; an electrocardiographic pattern of third-degree ischemia demonstrated a more favorable electrocardiographic and radionuclear angiographic evolution than similar patients who presented with an electrocardiographic pattern of second-degree ischemia.


Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4.
Egypt has the highest prevalence of chronic hepatitis C virus (HCV) infection in the world, and more than 90% of patients are infected with genotype 4 virus. We evaluated the efficacy and safety of the HCV polymerase inhibitor sofosbuvir in combination with ribavirin in HCV genotype 4 patients in Egypt. Treatment-naïve or treatment-experienced patients with genotype 4 HCV infection (n=103) were randomly assigned to receive either 12 or 24 weeks of sofosbuvir 400 mg and ribavirin 1000-1200 mg daily. Randomization was stratified by prior treatment experience and by presence or absence of cirrhosis. The primary endpoint was the percentage of patients with HCV RNA <25 IU/ml 12 weeks after therapy (SVR12). Among all patients, 52% had received prior HCV treatment and 17% had cirrhosis at baseline. SVR12 rates were 90% (46/51) with 24 weeks and 77% (40/52) with 12 weeks of sofosbuvir and ribavirin therapy. Patients with cirrhosis at baseline had lower rates of SVR12 (63% 12 weeks, 78% 24 weeks) than those without cirrhosis (80% 12 weeks, 93% 24 weeks). The most common adverse events were fatigue, headache, insomnia, and anemia. Two patients experienced serious adverse events (cerebral ischemia, dyspnea). No adverse events resulted in treatment discontinuation. Sofosbuvir plus ribavirin for 12 or 24 weeks is effective in treating both treatment-naïve and treatment-experienced Egyptian patients with genotype 4 HCV.


Simultaneous in situ derivatization and ultrasound-assisted dispersive magnetic solid phase extraction for thiamine determination by spectrofluorimetry.
A simple and rapid method for the simultaneous in situ derivatizaion, preconcentration and extraction of thiamine (vitamin B1) as a model analyte was developed by a novel quantitative method, namely ultrasound-assisted dispersive magnetic solid phase extraction spectrofluorimetry (USA-DMSPE-FL) from different real samples. This method consists of sample preparation, in situ derivatization, exhaustive extraction and clean up by a single process. High extraction efficiency and in situ derivatization in a short period of time is the main advantages of this procedure. For this purpose, the reusable magnetic multi-wall carbon nanotube (MMWCNT) nanocomposite was used as an adsorbent for preconcentration and determination of thiamine. Thiamine was, simultaneously, in situ derivatized as thiochrome by potassium hexacyanoferrate (III) and adsorbed on MMWCNT in an ultrasonic water bath. The MMWCNTs were then collected using an external magnetic field. Subsequently, the extracted thiochrome was washed from the surface of the adsorbent and determined by spectrofluorimetry. The developed method, which has been analytically characterized under its optimal operating conditions, allows the detection of the analyte in the samples with method detection limits of 0.37 µg L(-1). The repeatability of the method, expressed as the relative standard deviation (RSD, n=6), varies between 2.0% and 4.8% in different real samples, while the enhancement factor is 197. The proposed procedure has been applied for the determination of thiamine in biological (serum and urine), pharmaceutical (multivitamin tablet and B complex syrup) and foodstuff samples (cereal, wheat flour, banana and honey) with the good recoveries in the range from 90% to 105%.


Differential susceptibility of immature rat testes to doxorubicin at critical stages of maturation. Biochemical and functional assessment.
The toxic effects of doxorubicin on the reproductive system of the male rat were studied at different susceptible stages of postnatal development. A multidisciplinary approach including the assessment of histopathological, functional and biochemical parameters was chosen. Groups of male rats were treated once with the compound (3 mg/kg) on postnatal day 6, 16, 24 or 45. Both the onset of reproductive capacity and fertility were determined by serially mating ten animals per group for 12 weeks beginning at the age of 45 days. Reproductive organ weights, sperm counts and epididymal androgen binding protein (ABP) were measured at intermediate (80-day-old rats) or terminal sacrifice (129-day-old rats). Age dependent differential doxorubicin toxicity was evident. Treatment of 6-day-old animals with doxorubicin severely impaired development of reproductive functions. Treatment of 16-day-old animals reduced fertility throughout the mating study, as well as body and reproductive organ weights and sperm counts. Initial toxicity was observed in the group treated at 24 days of age; particularly, low reproductive organ weights and low sperm counts were found. These findings proved reversible towards the end of the study. Neither biochemical nor functional impairment of the reproductive system could be observed in the group treated at 45 days of age.


Lactobacillus oris improves non-alcoholic fatty liver in mice and inhibits endogenous cholesterol biosynthesis.
We previously confirmed that a strain of Lactobacillus oris isolated from the fecal samples of healthy Hainan centenarian having potent lipid-lowering ability in HepG2 cells; and this study was to investigate the effect of the stain on non-alcoholic fatty liver in mice in vivio. The Lactobacillus oris strain isolated from Hainan centenarian fecal samples were frozen stored in our laboratory. Thirty ob/ob mice (10 in each group) were orally gavaged with Lactobacillus oris (Lactobacillus, 5 × 109 cfu), mixed probiotics (Mixed, 5 × 109 cfu, a mixture with known lipid-lowering ability), or culture medium (Control) respectively. Lactobacillus oris isolated from fecal samples of Hainan centenarians showed significantly in vivo lipid lowering ability compared with the controls, and the ability was comparable with mixed probiotics strains in mice The possible mechanisms of lipid-lowering of probiotics and Lactobacillus oris may be associated with HMGR inhibition to suppress the synthesis of endogenous cholesterol; bile acids reabsorption, and intestinal FXR-FGF15 signaling pathways promoting the cholesterol conversion into bile acids secretion.


Angiotensin-II type 1 receptor gene polymorphism and long-term survival in patients with idiopathic congestive heart failure.
It has been suggested that a genetic polymorphism in the angiotensin II type 1 receptor gene (ATRG) and the ACE gene DD genotype might have a synergistic influence on the risk of developing cardiovascular disease. To study the possible interaction between polymorphisms in the ACE gene and the ATRG, regarding survival and left ventricular function. Polymorphism of the two genes was studied in a population-based cohort of 194 patients with idiopathic heart failure, recruited from the western part of Sweden 1985-1988. The patients were investigated by echocardiography. The survival status was checked during the 7-year follow-up period. Although there was no statistically significant additive risk of the ATRG polymorphism, patients carrying the ACE gene DD genotype in combination with a C allele of the ATRG tended to have a poorer prognosis. DD +AA, OR 1.24 (95% CI 0.67-2.32, P = 0.49); DD +AC, OR 1.64 (95% CI 0.95-2.83, P = 0.08); DD + CC, OR 3.54 95% CI 0.78-16.1, P = 0.10); DD +AC/CC, OR 1.84 (95% CI 1.10-3.08, P = 0.02). Patients with the DD +AC/CC genotypes tended to have lower ejection fraction and increased left ventricular mass. There was a trend toward a worse prognosis in patients with the combination of a C-allele in the ATRG and the ACE gene DD genotype, suggesting an interaction of these two genetic polymorphisms on disease severity.


The effect of posture, exercise, and atrial pacing on atrioventricular conduction in systolic heart failure.
Optimization of atrioventricular (AV) intervals for cardiac resynchronization therapy (CRT) programming is typically performed in supine patients at rest, which may not reflect AV timing in other conditions. To evaluate the effects of posture, exercise, and atrial pacing on intrinsic AV intervals in patients with CRT devices. Rate-dependent A-V delay by exercise was a multicenter, prospective trial of patients in sinus rhythm following CRT implantation. Intracardiac electrograms were recorded to analyze atrial to right ventricular (ARV), atrial to left ventricular (ALV), and RV to LV (VV) time intervals. Heart rate was increased with incremental atrial pacing in different postures, followed by an exercise treadmill test. This study included 36 patients. At rest, AV intervals changed minimally with posture. With atrial pacing, AV interval immediately increased compared with sinus rhythm, with ARV slopes being 8.1 ± 7.7, 8.8 ± 13.4, and 6.8 ± 6.5 milliseconds per beat per minute (ms/bpm) and ALV slopes being 8.2 ± 7.7, 9.1 ± 12.8, and 7.0 ± 6.5 ms/bpm for supine, standing and sitting positions, respectively. As the paced heart rate increased, ARV and ALV intervals increased more gradually with similar trends. Interventricular conduction times changed less than 0.2 ms/bpm with atrial pacing. During exercise, the direction of change of intrinsic ARV intervals, as heart rate increased, was variable between patients with relatively small overall group changes (0.1 ± 1.4 and 0.2 ± 1.2 ms/bpm for ARV and ALV, respectively). Posture and exercise have a smaller effect on AV timing compared with atrial pacing. However, individualized optimization and dynamic rate related changes may be needed to maintain optimal fusion with left ventricular (LV) stimulation.


CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates.
To assess the role of CCL2/MCP-1 in opiate drug abuse and HIV-1 comorbidity, the effects of systemic morphine and intrastriatal HIV-1 Tat on macrophage/microglial and astroglial activation were assessed in wild type and CCR2 null mice. Tat and/or morphine additively increased the proportion of CCL2 immunoreactive astroglia. The effects of morphine were prevented by naltrexone. Glial activation was significantly reduced in CCR2-/- versus wild-type mice following Tat or morphine plus Tat exposure. Thus, CCR2 contributes to local glial activation caused by Tat alone or in the presence of opiates, implicating CCR2 signaling in HIV-1 neuropathogenesis in drug abusers and non-abusers.


Vigorous convection in porous media.
The problem of convection in a fluid-saturated porous medium is reviewed with a focus on 'vigorous' convective flow, when the driving buoyancy forces are large relative to any dissipative forces in the system. This limit of strong convection is applicable in numerous settings in geophysics and beyond, including geothermal circulation, thermohaline mixing in the subsurface and heat transport through the lithosphere. Its manifestations range from 'black smoker' chimneys at mid-ocean ridges to salt-desert patterns to astrological plumes, and it has received a great deal of recent attention because of its important role in the long-term stability of geologically sequestered CO2. In this review, the basic mathematical framework for convection in porous media governed by Darcy's Law is outlined, and its validity and limitations discussed. The main focus of the review is split between 'two-sided' and 'one-sided' systems: the former mimics the classical Rayleigh-Bénard set-up of a cell heated from below and cooled from above, allowing for detailed examination of convective dynamics and fluxes; the latter involves convection from one boundary only, which evolves in time through a series of regimes. Both set-ups are reviewed, accounting for theoretical, numerical and experimental studies in each case, and studies that incorporate additional physical effects are discussed. Future research in this area and various associated modelling challenges are also discussed.


Molecular characterization of Glaesserella parasuis strains circulating in North American swine production systems.
Glaesserella parasuis is the causative agent of Glässer's disease in pigs. Serotyping is the most common method used to type G. parasuis isolates. However, the high number of non-typables (NT) and low discriminatory power make serotyping problematic. In this study, 218 field clinical isolates and 15 G. parasuis reference strains were whole-genome sequenced (WGS). Multilocus sequence types (MLST), serotypes, core-genome phylogeny, antimicrobial resistance (AMR) genes, and putative virulence gene information was extracted. In silico WGS serotyping identified 11 of 15 serotypes. The most frequently detected serotypes were 7, 13, 4, and 2. MLST identified 72 sequence types (STs), of which 66 were novel. The most predominant ST was ST454. Core-genome phylogeny depicted 3 primary lineages (LI, LII, and LIII), with LIIIA sublineage isolates lacking all vtaA genes, based on the structure of the phylogenetic tree and the number of virulence genes. At least one group 1 vtaA virulence genes were observed in most isolates (97.2%), except for serotype 8 (ST299 and ST406), 15 (ST408 and ST552) and NT (ST448). A few group 1 vtaA genes were significantly associated with certain serotypes or STs. The putative virulence gene lsgB, was detected in 8.3% of the isolates which were predominantly of serotype 5/12. While most isolates carried the bcr, ksgA, and bacA genes, the following antimicrobial resistant genes were detected in lower frequency; blaZ (6.9%), tetM (3.7%), spc (3.7%), tetB (2.8%), bla-ROB-1 (1.8%), ermA (1.8%), strA (1.4%), qnrB (0.5%), and aph3''Ia (0.5%). CONCLUSION: This study showed the use of WGS to type G. parasuis isolates and can be considered an alternative to the more labor-intensive and traditional serotyping and standard MLST. Core-genome phylogeny provided the best strain discrimination. These findings will lead to a better understanding of the molecular epidemiology and virulence in G. parasuis that can be applied to the future development of diagnostic tools, autogenous vaccines, evaluation of antibiotic use, prevention, and disease control.


Efficient use of the Internet.
This section explains how to make most of your time on-line by providing tips on how to reduce the cost of using the internet. Suggestions are given on how to get the best from your existing hardware and software. There are also recommendations for some additional hardware and software.


Uterine compression sutures with additional hemostatic procedures for the management of postpartum hemorrhage.
The aim of the study was to evaluate the efficacies and possible short-term complications in women receiving uterine compression sutures only and those with additional hemostatic procedures for the management of postpartum hemorrhage. It was a retrospective study carried out from year 2009 to 2019 at a tertiary obstetric hospital and included 79 women who underwent uterine compression sutures (B-Lynch sutures, Hayman's sutures and Cho's sutures) for primary postpartum hemorrhage. Thirty-six of these women had additional hemostatic procedures (uterine artery ligation or embolization) performed for bleeding control. Of the 43 women who were primarily treated with uterine compression sutures only, the success rate to preserve the uterus was 97.7% (42/43). In women with uterine compression sutures and additional hemostatic procedures performed, the success rate was 75% (27/36). Among these two groups of women without peripartum hysterectomy, there were no significant differences in the incidence of secondary postpartum hemorrhage (14.8% vs. 11.9%; P = 0.729), postoperative endometritis (14.8% vs. 14.3%; P > 0.99) and retained products of conception (3.7% vs. 9.5%; P = 0.641) during their 6-week postpartum checkup. Three women were diagnosed to have hematometra. No pyometra or uterine necrosis was noted. Uterine compression sutures with additional hemostatic procedures are effective to control postpartum hemorrhage and prevent hysterectomy. The short-term complication rate is low. Long-term monitoring is needed to identify rare but potentially dangerous complications.


An autosomal dominant midline cleft syndrome resembling familial holoprosencephaly.
We have detected a previously unrecognized autosomal dominant syndrome characterized by: mental retardation, microcephaly; craniofacial anomalies including cleft lip and anterior cleft palate, hypotelorism and antimongoloid slant; skeletal anomalies, notably of the foot and spine; and chronic constipation. Despite similarities to familial holoprosencephaly, this disorder appears to be a distinct entity. Incomplete penetrance and variable expressivity accompany transmission of the abnormal allele through four generations of a large kindred. Three of the four affected males survived past 20 years of age; the fourth is an infant. All three affected females died very early in infancy.


Effects of acupressure on the childbirth satisfaction and experience of birth: A randomized controlled trial.
Complementary and alternative medicines have been used to increase comfort and relaxation in mothers during labor. Comforting and preparing the mother in labor can create a positive birth experience. The aim of this study was to evaluate the effect of acupressure on childbirth satisfaction and the experience of giving birth in women with full-term pregnancy, before the onset of labor. In 2016, a randomized clinical trial study was conducted in Shahid Akbar Abadi Hospital, Tehran, Iran, enrolling 120 pregnant women at 39-40 gestational weeks with no signs of the onset of labor. They were divided randomly into acupressure, sham acupressure, and control groups. Acupressure points including SP6, BL 60, and BL 32 were pressured bilaterally. Interventions were performed by the researcher, the mother and her relative (husband). Childbirth satisfaction was measured 24 h after delivery. The collected data were analyzed by SPSS software and comparing tests were Chi-squared, Kruskal-Wallis, ANOVA tests (P ≤ 0.05). The total childbirth satisfaction did not differ significantly among the three groups (P = 0.460), but the acupressure group had a higher level of satisfaction than the other two groups. Moreover, statistical tests regarding the expectations of the childbirth experience showed a significant difference among the groups (P = 0.033). The actual birth was closest to the expectations of subjects in the acupressure group. This study demonstrated that acupressure may be used as a method in order to attempt to provide a good birth experience and satisfaction of childbirth.


[Validity of prediction after standard implant and the implant calculated according to the SRK formula].
The purpose of this study is to appreciate post-operative ametropia in pseudophakic patients (EEC and posterior chamber IOL). Two groups were implanted either with a standard 21 D IOL (group 1) or after calculation of implant power according to the SRK formula (group 2). Results show residual refractive errors over 2 D in 7% of case in group 2 and 22.3% of case in group 1.


Systematic review with meta-analysis of diagnostic test accuracy for COVID-19 by mass spectrometry.
The global COVID-19 pandemic has led to extensive development in many fields, including the diagnosis of COVID-19 infection by mass spectrometry. The aim of this systematic review and meta-analysis was to assess the accuracy of mass spectrometry diagnostic tests developed so far, across a wide range of biological matrices, and additionally to assess risks of bias and applicability in studies published to date. 23 retrospective observational cohort studies were included in the systematic review using the PRISMA-DTA framework, with a total of 2858 COVID-19 positive participants and 2544 controls. Risks of bias and applicability were assessed via a QUADAS-2 questionnaire. A meta-analysis was also performed focusing on sensitivity, specificity, diagnostic accuracy and Youden's Index, in addition to assessing heterogeneity. Sensitivity averaged 0.87 in the studies reviewed herein (interquartile range 0.81-0.96) and specificity 0.88 (interquartile range 0.82-0.98), with an area under the receiver operating characteristic summary curve of 0.93. By subgroup, the best diagnostic results were achieved by viral proteomic analyses of nasopharyngeal swabs and metabolomic analyses of plasma and serum. The performance of other sampling matrices (breath, sebum, saliva) was less good, indicating that these protocols are currently insufficiently mature for clinical application. This systematic review and meta-analysis demonstrates the potential for mass spectrometry and 'omics in achieving accurate test results for COVID-19 diagnosis, but also highlights the need for further work to optimize and harmonize practice across laboratories before these methods can be translated to clinical applications.


Nucleotide and phylogenetic analysis of human papillomavirus type 11 isolated from juvenile-onset recurrent respiratory papillomatosis in China.
To assess the association between sequence variants of human papillomavirus (HPV) 11 and recurrent respiratory papillomatosis and the taxonomy and evolutionary history of HPV 11. Complete HPV 11 nucleotide sequences were sequenced by Illumina HiSeq2000 Analyzers and compared with the HPV 11 prototype isolate (GenBank accession number: M14119) using Blast 2.0 server software. Eighteen full-length HPV 11 genomic sequences were amplified and sequenced. A total of 49 nucleotide mutations were identified, 12 of which resulted in amino acid changes. HPV 11 variants were highly conserved; the maximum pairwise difference was approximately 0.49%. The maximum pairwise difference of the 18 variants in our research was 0.39%. HPV 11 is less polymorphic than the majority of studied HPV genotypes.


Motor protein KIF1A is essential for hippocampal synaptogenesis and learning enhancement in an enriched environment.
Environmental enrichment causes a variety of effects on brain structure and function. Brain-derived neurotrophic factor (BDNF) plays an important role in enrichment-induced neuronal changes; however, the precise mechanism underlying these effects remains uncertain. In this study, a specific upregulation of kinesin superfamily motor protein 1A (KIF1A) was observed in the hippocampi of mice kept in an enriched environment and, in hippocampal neurons in vitro, BDNF increased the levels of KIF1A and of KIF1A-mediated cargo transport. Analysis of Bdnf(+/-) and Kif1a(+/-) mice revealed that a lack of KIF1A upregulation resulted in a loss of enrichment-induced hippocampal synaptogenesis and learning enhancement. Meanwhile, KIF1A overexpression promoted synaptogenesis via the formation of presynaptic boutons. These findings demonstrate that KIF1A is indispensable for BDNF-mediated hippocampal synaptogenesis and learning enhancement induced by enrichment. This is a new molecular motor-mediated presynaptic mechanism underlying experience-dependent neuroplasticity.


Identification of the Escherichia coli cysM gene encoding O-acetylserine sulphydrylase B by cloning with mini-Mu-lac containing a plasmid replicon.
A region located at around 52' on the Escherichia coli chromosome was cloned by use of mini-Mu-lac containing a plasmid replicon and recloned into pBR322. Enzyme assays on transformants carrying the cloned fragments indicated the presence in the latter of the cysA and cysM genes coding for sulphate permease and O-acetylserine sulphydrylase B, respectively.


Fracture strength of Class I versus Class II restored premolars tested at the marginal ridge. 2. Cavosurface bonding and cavosurface plus internal enamel bonding.
The purpose of this study was to test the difference between the strength of the marginal ridge of extracted teeth with a Class I composite resin restoration and the strength of the marginal ridge of teeth with a Class II amalgam restoration with retention grooves. A statistically significant difference in fracture strengths was found among groups. No statistically significant difference was found among restored preparations, beveling technique, and restorative material. Statistically significant differences in fracture strength were found between the whole tooth group and treatment groups; between the whole tooth group and Class II amalgam restoration group; and between the unrestored tooth preparation group and all other tooth groups.


When 1+1>2: Nanostructured composites for hard tissue engineering applications.
Multicomponent, synergistic and multifunctional nanostructures have taken over the spotlight in the realm of biomedical nanotechnologies. The most prospective materials for bone regeneration today are almost exclusively composites comprising two or more components that compensate for the shortcomings of each one of them alone. This is quite natural in view of the fact that all hard tissues in the human body, except perhaps the tooth enamel, are composite nanostructures. This review article highlights some of the most prospective breakthroughs made in this research direction, with the hard tissues in main focus being those comprising bone, tooth cementum, dentin and enamel. The major obstacles to creating collagen/apatite composites modeled after the structure of bone are mentioned, including the immunogenicity of xenogeneic collagen and continuously failing attempts to replicate the biomineralization process in vitro. Composites comprising a polymeric component and calcium phosphate are discussed in light of their ability to emulate the soft/hard composite structure of bone. Hard tissue engineering composites created using hard material components other than calcium phosphates, including silica, metals and several types of nanotubes, are also discoursed on, alongside additional components deliverable using these materials, such as cells, growth factors, peptides, antibiotics, antiresorptive and anabolic agents, pharmacokinetic conjugates and various cell-specific targeting moieties. It is concluded that a variety of hard tissue structures in the body necessitates a similar variety of biomaterials for their regeneration. The ongoing development of nanocomposites for bone restoration will result in smart, theranostic materials, capable of acting therapeutically in direct feedback with the outcome of in situ disease monitoring at the cellular and subcellular scales. Progress in this research direction is expected to take us to the next generation of biomaterials, designed with the purpose of fulfilling Daedalus' dream - not restoring the tissues, but rather augmenting them.


Drug-induced thrombocytopenia: a systematic review of published case reports.
To determine the strength of clinical evidence for individual drugs as a cause of thrombocytopenia. All English-language reports on drug-induced thrombocytopenia. Articles describing thrombocytopenia caused by heparin were excluded from review. Of the 581 articles reviewed, 20 were excluded because they contained no patient case reports. The remaining 561 articles reported on 774 patients. Two of the authors used a priori criteria to independently review each patient case report. Two hundred fifty-nine patient case reports were excluded from further review because of lack of evaluable data, platelet count of 100000 cells/microL or more, use of cytotoxic or nontherapeutic agents, occurrence of drug-induced systemic disease, or occurrence of disease in children. For the remaining 515 patient case reports, a level of evidence for the drug as the cause of thrombocytopenia was assigned. Data on bleeding complications and clinical course were recorded. The evidence supported a definite or probable causal role for the drug in 247 patient case reports (48%). Among the 98 drugs described in these reports, quinidine was mentioned in 38 case reports, gold in 11, and trimethoprim-sulfamethoxazole in 10. Of the 247 patients described in the case reports, 23 (9%) had major bleeding and 2 (0.8%) died of bleeding. Many reports of drug-induced thrombocytopenia do not provide evidence supporting a definite or probable causal relation between the disease and the drug. Future patient case reports should incorporate standard criteria to clearly establish the etiologic role of the drug.


Application of a model to predict cyanobacterial growth patterns in response to climatic change at Farmoor reservoir, Oxfordshire, UK.
The cyanobacterial growth for the next 90 years at Farmoor Reservoir, Oxfordshire is predicted using the cyanobacterial growth model, CLAMM, with data obtained from HADCM2 climate change model. It is predicted that solar radiation at the water-body surface will decrease slightly due to increased cloud cover. Predictions of cyanobacterial growth indicate little change in total production although the main summer growing season may be extended. It is also suggested that increased wind velocities may affect the frequency of 'blooming incidents'.


Total and conjugated urinary paranitrophenol after an acute parathion ingestion.
In a fatal case of acute parathion ingestion, paranitrophenyl sulphate, the paranitrophenyl glucuronide and free paranitrophenol excretion on day 3 were quantitated using a HPLC reverse method with a C18 column following sample preparation using a C18 mini-column and methanol elution. Paranitrophenyl sulphate amounted to about 81% of the total conjugates excreted. The results were confirmed by collecting the fractions identified by high-performance liquid chromatography, hydrolysing them with concentrated hydrochloric acid and quantitating paranitrophenol by gas chromatography. Total paranitrophenol excretion was also determined. The excreted paranitrophenol was equivalent to 76 mg parathion (lethal dose in humans between 20 and 100 mg). No changes in the concentrations of paranitrophenol or its conjugates were seen in the urine on storage, frozen over a one year period.


Teleost swim bladder, an ancient air-filled organ that elicits mucosal immune responses.
The air-filled organs (AOs) of vertebrates (lungs and swim bladders) have evolved unique functions (air-breathing or buoyancy control in water) to adapt to different environments. Thus far, immune responses to microbes in AOs have been described exclusively in the lungs of tetrapods. Similar to lungs, swim bladders (SBs) represent a mucosal surface, a feature that leads us to hypothesize a role for SB in immunity. In this study, we demonstrate that secretory IgT (sIgT) is the key SB immunoglobulin (Ig) responding to the viral challenge, and the only Ig involved in viral neutralization in that organ. In support of these findings, we found that the viral load of the SB from fish devoid of sIgT was much higher than that of control fish. Interestingly, similar to the lungs in mammals, the SB represents the mucosal surface in fish with the lowest content of microbiota. Moreover, sIgT is the main Ig class found coating their surface, suggesting a key role of this Ig in the homeostasis of the SB microbiota. In addition to the well-established role of SB in buoyancy control, our findings reveal a previously unrecognized function of teleost SB in adaptive mucosal immune responses upon pathogenic challenge, as well as a previously unidentified role of sIgT in antiviral defense. Overall, our findings indicate that despite the phylogenetic distance and physiological roles of teleost SB and mammalian lungs, they both have evolved analogous mucosal immune responses against microbes which likely originated independently through a process of convergent evolution.