Multiheme hydroxylamine oxidoreductases produce NO during ammonia oxidation in methanotrophs.
Aerobic and nitrite-dependent methanotrophs make a living from oxidizing methane via methanol to carbon dioxide. In addition, these microorganisms cometabolize ammonia due to its structural similarities to methane. The first step in both of these processes is catalyzed by methane monooxygenase, which converts methane or ammonia into methanol or hydroxylamine, respectively. Methanotrophs use methanol for energy conservation, whereas toxic hydroxylamine is a potent inhibitor that needs to be rapidly removed. It is suggested that many methanotrophs encode a hydroxylamine oxidoreductase (mHAO) in their genome to remove hydroxylamine, although biochemical evidence for this is lacking. HAOs also play a crucial role in the metabolism of aerobic and anaerobic ammonia oxidizers by converting hydroxylamine to nitric oxide (NO). Here, we purified an HAO from the thermophilic verrucomicrobial methanotroph Methylacidiphilum fumariolicum SolV and characterized its kinetic properties. This mHAO possesses the characteristic P460 chromophore and is active up to at least 80 °C. It catalyzes the rapid oxidation of hydroxylamine to NO. In methanotrophs, mHAO efficiently removes hydroxylamine, which severely inhibits calcium-dependent, and as we show here, lanthanide-dependent methanol dehydrogenases, which are more prevalent in the environment. Our results indicate that mHAO allows methanotrophs to thrive under high ammonia concentrations in natural and engineered ecosystems, such as those observed in rice paddy fields, landfills, or volcanic mud pots, by preventing the accumulation of inhibitory hydroxylamine. Under oxic conditions, methanotrophs mainly oxidize ammonia to nitrite, whereas in hypoxic and anoxic environments reduction of both ammonia-derived nitrite and NO could lead to nitrous oxide (N2O) production.


Family care during the first COVID-19 lockdown in Germany: longitudinal evidence on consequences for the well-being of caregivers.
We examine changes in the well-being of family caregivers during the early phase of the COVID-19 pandemic in Germany, using data from the German Socio-Economic Panel (SOEP) and the SOEP-CoV study. The COVID-19 pandemic posed an extraordinary challenge for family caregivers, as care recipients are a high-risk group requiring special protection, and professional care services were severely cut back. The specific situation of the COVID-19 pandemic allows us to re-examine the caregiver stress process model. Using first difference regression models, we analyse changes in general life satisfaction and depressive symptoms (PHQ-4 score) among family caregivers between 2019 and spring 2020, differentiating by care intensity and duration of the care episode. Caregivers show similar changes in well-being as non-caregivers: a simultaneous increase in depressive symptoms and life satisfaction between 2019 and 2020. However, our results reveal heterogeneity within the group of family caregivers as we find differences according to caregiving dynamics and intensity. Among the group of continuing caregivers, high-intensity caregivers experience a larger increase in life satisfaction, and low-intensity caregivers a smaller increase in life satisfaction, compared to non-caregivers. Our results therefore provide some support for the role enhancement hypothesis for continuing caregivers with high time commitment.


Upregulation of long non-coding RNA HIF 1α-anti-sense 1 induced by transforming growth factor-β-mediated targeting of sirtuin 1 promotes osteoblastic differentiation of human bone marrow stromal cells.
The present study aimed to investigate the regulatory mechanism of long non-coding RNA hypoxia-inducible factor 1α-anti‑sense 1 (lncRNA HIF1α-AS1) in osteoblast differentiation as well as its targeting by sirtuin 1 (SIRT1), which may be inhibited by transforming growth factor (TGF)‑β in bone marrow stromal cells (BMSCs). Real‑time polymerase chain reaction (PCR), western blot analysis, lncRNA PCR arrays and chromatin immunoprecipitation were performed in order to examine the interference of SIRT1 expression by TGF‑β, the effects of SIRT1 overexpression on lncRNA HIF1α‑AS1 and the regulation of the expression of homeobox (HOX)D10, which promotes BMSC differentiation, by lncRNA HIF1α‑AS1. The results showed that TGF‑β interfered with SIRT1 expression. Furthermore, lncRNA HIF1α‑AS1 was significantly downregulated following overexpression of SIRT1. In addition, low expression of HIF1α‑AS1 was sufficient to block the expression of HOXD10. The present study further demonstrated that downregulation of HOXD10 by HIF1α‑AS1 interfered with acetylation, and subsequently resulted in the inhibition of osteoblast differentiation. These results suggested that HIF1α‑AS1 is an essential mediator of osteoblast differentiation, and may thus represent a gene‑therapeutic agent for the treatment of human bone diseases.


Assessment of developmental toxicity potential of chemicals by quantitative structure-toxicity relationship models.
Statistically significant quantitative structure-toxicity relationship (QSTR) models have been developed for assessing developmental toxicity potential (DTP) of chemicals. Three submodels, one each for aliphatic, heteroaromatic and carboaromatic compounds, have been cross-validated to ascertain their robustness. The specificities of the models range from 86% to 97%, and their sensitivities between 86% and 89%. For convenient computer-assisted application, the models are installed in a toxicity assessment software package, TOPKAT, which has been recently enhanced with algorithms to identify whether or not a query structure is inside the optimum prediction space (OPS) of a QSTR model. Different functionalities of the TOPKAT program have been explained by assessing the DTP of a number of compounds not used in the model training sets. The DTP of 18 existing drugs was assessed using these models; the DT assay results were available for 5 of these. Three of these 5 molecules were identified to be inside the OPS and their TOPKAT assessment matched their experimental assignment.


Positioning and the discursive construction of categories.
Psychological phenomena are semiotic, so the best model for understanding them must be 'conversation'. Psychiatric conversations are dominated by complaints. In dealing with them the structure of the consequential conversation must be subjected to 'positioning analysis' to reveal the dynamics of rights and duties among the speakers.


Signal enhancement in solid-state NMR of quadrupolar nuclei.
Recent progress in the development and application of signal enhancement methods for NMR of quadrupolar nuclei in solids is presented. First, various pulse schemes for manipulating the populations of the satellite transitions in order to increase the signal of the central transition (CT) in stationary and rotating solids are evaluated (e.g., double-frequency sweeps, hyperbolic secant pulses). Second, the utility of the quadrupolar Carr-Purcell-Meiboom-Gill (QCPMG) and WURST-QCPMG pulse sequences for the rapid and efficient acquisition of particularly broad CT powder patterns is discussed. Third, less frequently used experiments involving polarization transfer from abundant nuclear spins (cross-polarization) or from unpaired electrons (dynamic nuclear polarization) are assessed in the context of recent examples. Advantages and disadvantages of particular enhancement schemes are highlighted and an outlook on possible future directions for the signal enhancement of quadrupolar nuclei in solids is offered.


Improvement for the production of clavulanic acid by mutant Streptomyces clavuligerus.
To improve the production of clavulanic acid through the development of strains, the selection of a production medium and a pH shift strategy in a bioreactor. Streptomyces clavuligerus mutant 15 was selected by antibacterial activities. As a result of pH control in a 2.5 l bioreactor, the highest productivity (3.37 microg x ml(-1) x h(-1)) was obtained at a controlled pH of 7.0. The highest level of production obtained was an increase of about 36% compared with a non-controlled pH. When the production of clavulanic acid reached the maximum level, the pH was shifted from 7.0 to 6.0 for reduction in decomposition rate. The maximum concentration of clavulanic acid was maintained for 24 h as a result of the pH shift control, and a significant reduction in the decomposition of clavulanic acid was obtained. Clavulanic acid decomposition was considerably reduced as a result of the pH shift control. The results of this study can be applied for the efficient production of beta-lactamase inhibitory antibiotics.


An update on the current epidemiological status of metastatic neoplasms to the thyroid.
Secondary tumours to the thyroid gland are uncommon with an overall prevalence of 5.9% in autopsy studies. In recent clinical series, secondary thyroid cancer is seen in only 1.9% of malignant thyroids. There is no gender predominance both overall (female to male 1.07:1) and when stratified by common histological subtypes (renal cell carcinoma, lung adenocarcinoma and colorectal adenocarcinoma). The median age of patients diagnosed with metastatic thyroid tumours in major studies ranges from 54 to 68 years. Metastases are more frequent in patients with pre-existing or concurrent thyroid pathology. In autopsy studies, the most common primary sites are breast carcinoma and lung carcinoma. Renal cell carcinoma, lung carcinoma and breast carcinoma predominate in clinical series. Upper aerodigestive tract primaries often directly infiltrate the thyroid gland. The underlying frequency of a histological subtype, geographic prevalence and aggressiveness of primary cancer likely contributes to the incidence of metastasis in the thyroid gland. This is seen in case series from Asia where gastric and oesophageal primary cancers predominate. Secondary thyroid cancer can present metachronously (60%), synchronously (34%), or as the first presentation of the underlying cancer (6%). Late metastases and first clinical presentations of disease often originate from renal cell carcinomas while synchronous cases tend to originate from the lungs. Other common primary sites for first presentation of secondary thyroid cancer include the lung and oesophagus. Although rare, secondary thyroid cancer should be considered as a differential particularly in patients with previous malignancy, such as from the kidney, lung, or breast.


Primordial radionuclides in the dust samples from the educational institutions of central Bangladesh: radiological risk assessment.
For the first time, this study presents the radio-activity concentrations of primordial radionuclides in a suite of classroom-dusts collected from 23 schools in central part of Bangladesh. Bulk elemental compositions from instrumental neutron activation analysis (INAA) were transformed into accompanied radio-activity contents (Bq.kg-1). Mean activity contents of 226Ra, 232Th, & 40K in dust samples were 86.0, 43.4, and 448 Bq.kg-1, respectively, which were comparatively elevated relative to the relevant world average value. Higher NORMs abundances were due to the surface soil weathering and aerodynamic fractionations. Estimation of typical radiological-risk indices demonstrates human health risks. Bearing in mind that the greater susceptibility of school-going juveniles & children to the ionizing-radiations & the entering of NORMs-comprising dust-particle into human lungs, calculated radiological indices merely represent the least potential risk. However, in actual cases, α-particles from the 238U and 232Th-decay series can create significant radiation-damage to the respiratory-system.


A comparison of the effects of S-adenosyl-L-homocysteine on sleep in normal and pinealectomized rats.
S-adenosyl-L-homocysteine (SAH) was administered to normal and pinealectomized rats previously implanted with electrodes for polygraphic recording. In normal rats, injected at 17.00 h, 7 mg/kg SAH induced a significant increase of paradoxical sleep (PS) during the night. When injected at 09.00 or 19.00 h, no effect was observed. In pinealectomized rats, SAH had no significant effect on PS amounts but seemed to resynchronize the PS rhythm. Thus, the pineal gland plays an important role in SAH effect. The results are discussed with reference to different mechanisms within the rat pineal gland and a possible implication of beta-adrenergic receptors.


Spontaneous uptake of exogenous DNA by bull spermatozoa.
Sperm-mediated DNA transfer can be used to transfer exogenous DNA into the oocyte for the production of transgenic animals. In spite of controversy in the literature, sperm-mediated DNA transfer is a simple and quick technique that can be used in routine breeding programs (AI, embryo transfer and IVF). The main objective of this study was to determine the factors affecting the spontaneous uptake of exogenous DNA by bull spermatozoa. For this purpose, fresh and frozen spermatozoa (0.25 x 10(6)), from the same ejaculate from each of four bulls were co-incubated with fluorescent-labeled green fluorescent protein (GFP) and chloremphenicol acetyltransferase (CAT) plasmids at 37 degrees C for 30 min. Neither bull nor plasmid significantly affected the uptake of exogenous DNA. However, transfection efficiency was higher in frozen-thawed versus fresh spermatozoa (P<0.001). Regardless of whether transfected spermatozoa were alive or dead, all transfected spermatozoa were immotile. It can be concluded that a population of spermatozoa is present in bull semen which has the ability to uptake exogenous DNA spontaneously. There is tremendous scope to improve transfection efficiency of spermatozoa while maintaining motility; this needs to be achieved in order to more easily use this technique in transgenesis. However, live-transfected bull spermatozoa clearly can incorporate exogenous DNA and should be usable in intracytoplasmic sperm injection protocols.


Immunocytochemical studies of protamine-induced blood-brain barrier opening to endogenous albumin.
The cellular mechanisms of blood-brain barrier (BBB) opening to endogenous albumin in the mouse brain after intracarotid infusion of solutions of protamine free base (PB) or protamine sulfate (PS) were studied using quantitative immunocytochemistry. Ultrathin sections of brain samples embedded at low temperature in Lowicryl K4M were exposed to anti-mouse albumin antiserum followed by protein A-gold. Using morphometry, the density of immunosignals (gold particles per micron2) was recorded over four compartments: vascular lumen, endothelial profiles, subendothelial space (including the basement membrane), and brain parenchyma (neuropil). In addition, the adsorption of endogenous albumin evidenced by the number of gold particles per micron of the endothelial luminal plasmalemma was quantitatively evaluated. In the applied experimental conditions, PB was found to be strongly cytotoxic as indicated by the appearance of rapid degenerative changes and the disruption of the endothelial lining with concomitant clumping of the blood plasma. The action of PS was milder, offering a better opportunity for detailed ultrastructural and morphometric examination of brain samples during consecutive steps of PS action (2, 5, 10 and 30 min). As early as 10 min after infusion of PS solution, the adsorption of blood plasma albumin to the endothelial luminal surface was increased 2.5 times. Simultaneously, the immunolabelling of the endothelial profiles and subendothelial space was significantly increased. These results suggest that BBB disruption occurs through enhanced adsorption of albumin or albumin-protamine complexes to the luminal plasmalemma, followed by transendothelial vesicular transport, rather than through modification of interendothelial junctional complexes.(ABSTRACT TRUNCATED AT 250 WORDS)


[Studies of preparing procedures of Yuhuangliang].
To optimize preparing procedures of Yuhuangliang. The single factor experimets and the L9 (3(4)) orthogonal design were used to optimize the preparing procedures of Yuhuangliang with contents of berberine and total alkaloids as evalustion index. The optimal preparing method was Rhizoma Coptidis adding amount of 10 mL (0.2 g/mL) juice of wuzhuyu mixed thoroughly, baking at 100 degrees C, for 15 min. The preparing procedure is effective, stable and reliable.


Changes of hexose monophosphate pathway and methemoglobin reductase enzyme activity after radiation in guinea pigs.
HMP pathway activity changes occurring after exposure to ionizing radiation (LD50 dose) have been investigated. The study was carried out on 18 experimental guinea pigs subjected to 5 successive exposures of 150 rads 3 or 4 days apart. The control animals were sham radiated but were otherwise treated identically as those of the experimental groups. Blood samples were taken by cardiac puncture before radiation and 30 min after each exposure of 150 rads. The red cells were re-suspended in their own plasma and HMP pathway activity was measured in the suspension. The pathway activity showed a consistent but minor reduction in the experimental group, which became statistically significant after the total dose of 750 rads (P less than 0.020). In a separate study the changes induced by ionizing radiation in the erythrocyte enzyme NADH-methemoglobin reductase were measured using the same experimental protocol. The enzyme activity in the red cells of the experimental group varied between 34.90 +/- 2.17 to 161.95 +/- 5.34 I.U./ml erythrocyte pack. Its activity declined toward the initial value after reaching the peak by the 12th day of ionizing radiation with 600 rads (P less than 0.001).


Triplex Real-Time PCR without DNA Extraction for the Monitoring of Meningococcal Disease.
Detection of Neisseria meningitidis has become less time- and resource-intensive with a monoplex direct real-time PCR (drt-PCR) to amplify genes from clinical specimens without DNA extraction. To further improve efficiency, we evaluated two triplex drt-PCR assays for the detection of meningococcal serogroups AWX and BCY. The sensitivity and specificity of the triplex assays were assessed using 228 cerebrospinal fluid (CSF) specimens from meningitis patients and compared to the monoplex for six serogroups. The lower limit of detection range for six serogroup-specific drt-PCR assays was 178⁻5264 CFU/mL by monoplex and 68⁻2221 CFU/mL by triplex. The triplex and monoplex showed 100% agreement for six serogroups and the triplex assays achieved similar sensitivity and specificity estimates as the monoplex drt-PCR assays. Our triplex method reduces the time and cost of processing CSF specimens by characterizing six serogroups with only two assays, which is particularly important for testing large numbers of specimens for N. meningitidis surveillance.


Explaining and predicting patterns in stochastic population systems.
Lattice effects in ecological time-series are patterns that arise because of the inherent discreteness of animal numbers. In this paper, we suggest a systematic approach for predicting lattice effects. We also show that an explanation of all the patterns in a population time-series may require more than one deterministic model, especially when the dynamics are complex.


Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma.
Although point mutations of the 5' noncoding regions of the BCL-6 proto-oncogene are frequently detected in B-diffuse large cell lymphoma (B-DLCL), a thorough analysis of the clinical correlation of these mutations has not been performed to date. In this study, BCL-6 mutations were examined by DNA direct sequencing in 103 patients with B-DLCL. BCL-6 mutations were found in 53/103 patients, including 38/76 treated with standard chemotherapy and 15/27 treated with autologous stem cell transplantation (ASCT) up front. The presence of BCL-6 mutations was correlated with clinical features at diagnosis and outcome. Mutated patients had a significantly higher LDH level (66% vs 38%, P < 0.05), and bulky disease (51% vs 32%, P = 0.05). In the whole series of patients BCL-6 mutations did not affect CR and OS. Patients with BCL-6 mutations tended to have a prolonged 5-years DFS and FFS compared to those without mutations (DFS 82% vs 63%, FFS 63% vs 49%). Among B-DLCL treated with standard chemotherapy, mutated patients showed a significantly improved 5-year DFS (85% vs 61%, P < 0.05) and, notably, the only four relapses observed among mutated patients occurred in less than 8 months. The multivariate regression analysis (P < 0.01) with DFS as endpoint confirmed the independent prognostic value of BCL-6 mutations. There was a trend for 5-year failure-free survival to be better for patients with BCL-6 mutations (63% vs 43%, P = 0.09). In the 27 patients treated with ASCT, BCL-6 mutations did not correlate with outcome. These results suggest that BCL-6 mutations may predict a higher chance of being free of disease in B-DLCL treated with standard chemotherapy. Larger series of patients need to be analyzed to evaluate the clinical relevance of BCL-6 mutations properly.


The medial frontal cortex and temporal memory: tests using spontaneous exploratory behaviour in the rat.
Evidence from several sources indicates that the frontal cortex is involved in memory involving time, or temporal memory, and in behavioral sequencing. Rats were presented with two familiar objects and the amount of exploration directed at each was recorded. Subjects directed more exploration at the object encountered further ago in the past, even though the two objects differed by only 1 h. After bilateral medial frontal cortex lesion, animals did not differentiate between old and recent objects. Performance on an object recognition test (novel versus familiar objects) that also used exploration time did not change as a result of the medial frontal cortex lesions.


Two-dimensional stress-relaxation behavior of human skin as influenced by non-enzymatic glycation and the inhibitory agent aminoguanidine.
In order to simulate the in vivo stress alterations of diabetic skin in an in vitro model, we examined the viscoelastic properties of long-term glycated human skin samples. Since skin is subjected to biaxial tension, we used two-dimensional multiaxial testing which better reflects the in vivo situation than the uniaxial testing mode. For native skin samples from the abdominal region we found a direction-dependent elastic stress strain behavior. The viscous stress component was separated from the elastic stress component by relaxation tests at consecutive incremental steps of radial strains. We hypothesize that glycation-induced changes in the tissue stiffness are generated in a direction-dependent mode. A marked increase of the direction-dependent stiffness was found upon long-term incubation with glucose-6-phosphate. This increase was statistically significant for the maximum principal elastic stress component which was highly correlated with the degree of non-enzymatic collagen modification. The viscous fractions obtained from two-dimensional relaxation tests at consecutive radial strains were inversely correlated with non-enzymatic modification. Only at 30% radial strain a significant decrease of the viscous fraction engendered by glucose-6-phosphate was observed together with a direction-dependent significant increase of the expectation value of the time constant. The biomechanical and biochemical effects of long-term glycation could be partially reversed by aminoguanidine, a potential therapeutic agent for patients with diabetes mellitus. Our findings suggest that additional cross-links generated by long-term glycation cause two-dimensional biomechanical alterations in human skin, which can be unequivocally detected by multiaxial testing.


Development of high sustained anti-drug antibody titers and corresponding clinical decline in a late-onset Pompe disease patient after 11+ years on enzyme replacement therapy.
A late-onset Pompe disease patient developed high sustained antibody titers (HSAT) of ≥51,200 after 11+ years on alglucosidase alfa and previous tolerance. There was a corresponding worsening of motor function and rise in urinary glucose tetrasaccharide (Glc4). Following immunomodulation therapy, HSAT were eliminated with improved clinical outcomes and biomarker trends. This report highlights the importance of continued surveillance of antibody titers and biomarkers, the negative impact of HSAT, and improved outcomes with immunomodulation therapy.


Errors in the particle flux measurement data relevant to solar energetic particle spectra.
Systematical errors of the spacecraft measured high-energy particle fluxes are analyzed. The errors are shown to be inherent to most of the measurements made to be the monitoring of the high-energy radiation in the space. The level of the systematic errors of the measurements varies with energy, thus resulting in distortions of the solar energetic particle spectra based on the measurement data. The erroneous experimental data have resulted in spurious estimates of space radiation environment and give rise to erroneous physical conclusions.


Impact of 21-Gene Expression Assay on Clinical Outcomes in Node-Negative ≤ T1b Breast Cancer.
Prior to the advent of Oncotype DX 21-gene recurrence score (oDX) assay, the National Comprehensive Cancer Network (NCCN) guideline supported omission of adjuvant chemotherapy in patients with ≤ 1 cm (T1b) hormone receptor-positive (HR +), human epidermal growth factor receptor 2 (HER2-) node tumors. However, around 30% of these patients would have an oDX recurrence score that warrants consideration of adjuvant chemotherapy. To clarify the potential benefit of oDX in these patients, we performed a retrospective analysis comparing clinical outcomes of women with T1a or T1b, N0 HR + HER2- according to performance of oDX. After receiving institutional review board (IRB) approval, an institutional database was queried to identify patients with HR + HER2- ≤ T1bN0 tumors (n = 2307) diagnosed between 2009 and 2018. Patients were further stratified by recurrence score (RS) defined as low (< 18), intermediate (18-30), or high (> 30). Log-rank, Kaplan-Meier, and inverse probability of treatment weighting (IPW) analyses were used to compare disease-free survival (DFS) and overall survival (OS) across groups. Performance of oDX (n = 1149, 49.8%) was associated with larger tumors, younger age, and White race. On univariate analysis, performance of oDX was associated with improved OS (P < 0.01). On multivariate IPW analysis, performance of oDX lengthened DFS by an average of 16.5 months, while OS was similar between groups (P < 0.01 and P = 0.73). The improved DFS was mainly driven by those with tumors ≥ T1b. Overall, outcomes were excellent regardless of oDX testing. Performance of oDX testing was associated with improved DFS in patients with tumors ≥ T1b. Our results support routine use of oDX testing in patients with tumors ≥ T1b.


Influence of Glu/Arg, Asp/Arg, and Glu/Lys Salt Bridges on α-Helical Stability and Folding Kinetics.
Using a combination of ultraviolet circular dichroism, temperature-jump transient-infrared spectroscopy, and molecular dynamics simulations, we investigate the effect of salt bridges between different types of charged amino-acid residue pairs on α-helix folding. We determine the stability and the folding and unfolding rates of 12 alanine-based α-helical peptides, each of which has a nearly identical composition containing three pairs of positively and negatively charged residues (either Glu(-)/Arg(+), Asp(-)/Arg(+), or Glu(-)/Lys(+)). Within each set of peptides, the distance and order of the oppositely charged residues in the peptide sequence differ, such that they have different capabilities of forming salt bridges. Our results indicate that stabilizing salt bridges (in which the interacting residues are spaced and ordered such that they favor helix formation) speed up α-helix formation by up to 50% and slow down the unfolding of the α-helix, whereas salt bridges with an unfavorable geometry have the opposite effect. Comparing the peptides with different types of charge pairs, we observe that salt bridges between side chains of Glu(-) and Arg(+) are most favorable for the speed of folding, probably because of the larger conformational space of the salt-bridging Glu(-)/Arg(+) rotamer pairs compared to Asp(-)/Arg(+) and Glu(-)/Lys(+). We speculate that the observed impact of salt bridges on the folding kinetics might explain why some proteins contain salt bridges that do not stabilize the final, folded conformation.


Enhanced 2,3-butanediol production in fed-batch cultures of free and immobilized Bacillus licheniformis DSM 8785.
2,3-Butanediol (2,3-BD) is a valuable bulk chemical with particular use in industry. 2,3-BD has a potential as solvent and fuel additive, as carrier for pharmaceuticals, or as feedstock for the production of synthetic rubber. Until now, the highest 2,3-BD concentrations were obtained with risk group 2 microorganisms (e.g., Klebsiella oxytoca). In this study, the nonpathogenic bacterium Bacillus licheniformis DSM 8785 was used for 2,3-BD production from glucose. In batch experiments, a maximum 2,3-BD concentration of 72.6 g/L was reached from 180 g/L glucose after 86 h. The yield was 0.42 g/g glucose and the productivity was 0.86 g/(L h). During fed-batch cultivation, 2,3-BD production could be increased up to 144.7 g/L, with a productivity of 1.14 g/(L h). Additionally, repeated batch/fed-batch experiments were conducted using immobilized B. licheniformis in the form of LentiKats®. Results showed a high activity and stability of the immobilizates even after multiple medium replacements, as well as 2,3-BD concentrations, yields, and productivities similar to those obtained with free cells. To our knowledge, these results show the highest 2,3-BD concentration reported so far using a risk group 1 microorganism in general and B. licheniformis in particular. Furthermore, productivity lies in the same range with data reported from risk group 2 strains, which makes B. licheniformis DSM 8785 a suitable candidate for large-scale fermentation processes.


A critical review of exogenous additives for improving the anammox process.
Anammox achieves chemoautotrophic nitrogen removal under anaerobic and anoxic conditions and is a low-carbon wastewater biological nitrogen removal process with broad application potential. However, the physiological limitations of AnAOB often cause problems in engineering applications, such as a long start-up time, unstable operation, easily inhibited reactions, and difficulty in long-term strain preservation. Exogenous additives have been considered an alternative strategy to address these issues by retaining microbes, shortening the doubling time of AnAOB and improving functional enzyme activity. This paper reviews the role of carriers, biochar, intermediates, metal ions, reaction substrates, redox buffers, cryoprotectants and organics in optimizing anammox. The pathways and mechanisms of exogenous additives, which are explored to solve problems, are systematically summarized and analyzed in this article according to operational performance, functional enzyme activity, and microbial abundance to provide helpful information for the engineering application of anammox.


To summarise the approach to and findings of the PPIE undertaken as part of a programme of secondary research with a vulnerable, hard to reach population during the COVID-19 pandemic.
Public and patient involvement and engagement (PPIE) is an important part of research. The inclusion of PPIE in research is becoming more widespread, however, there are some areas where it is still uncommon. For example, undertaking PPIE in secondary analysis projects is uncommon and PPIE with difficult to reach populations and vulnerable groups can be seen as being too difficult to facilitate. The aim was to summarise the approach to and findings of the PPIE undertaken as part of a programme of secondary analysis with a vulnerable, hard to reach population; residents of residential care facilities (RCFs), during the COVID-19 pandemic. As part of a project to develop a publically available database of statutory notifications of adverse events from RCFs in Ireland, residents (n = 9) from RCFs for older people and people with disability were telephone interviewed. Residents were engaged through gatekeepers and posted participant information and consent forms. Themes were identified using content analyses of interview notes. Three parent themes were identified, each with two subthemes: privacy concerns, enthusiasm and dissemination of research findings. Residents highlighted the importance that no personal information be shared in the database. Once data were anonymized, residents thought that the database should be published and shared. Residents reported being happy about research being undertaken using the data and thought that publishing the database would help inform the public about RCFs. Completing a PPIE project with a vulnerable group during the global COVID-19 pandemic required planning and resources. Resources included finances, time and expertise. The involvement of residents informed the data inclusion in the published database and the approach taken in the protection of personal data. Enthusiasm for publication and research using the database by residents encouraged the developers as it was considered something that was wanted by residents. The benefits of PPIE can be achieved with vulnerable groups during unprecedented times with the appropriate planning. It requires dedication of time, finances and expertise. Overcoming the obstacles was achievable and worthwhile. The approach outlined can be used as an example to support PPIE in secondary analysis projects and or with vulnerable groups.


Possible use of a H3R antagonist for the management of nonmotor symptoms in the Q175 mouse model of Huntington's disease.
Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder characterized by motor as well as nonmotor symptoms for which there is currently no cure. The Q175 mouse model of HD recapitulates many of the symptoms identified in HD patients including disruptions of the sleep/wake cycle. In this study, we sought to determine if the daily administration of the histamine-3 receptor (H3R) antagonist/inverse agonist 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) would improve nonmotor symptoms in the Q175 line. This class of drugs acts on autoreceptors found at histaminergic synapses and results in increased levels of histamine (HA). HA is a neuromodulator whose levels vary with a daily rhythm with peak release during the active cycle and relatively lower levels during sleep. H3Rs are widely expressed in brain regions involved in cognitive processes and activation of these receptors promotes wakefulness. We administered GSK189254 nightly to homozygote and heterozygote Q175 mice for 4 weeks and confirmed that the plasma levels of the drug were elevated to a therapeutic range. We demonstrate that daily treatment with GSK189254 improved several behavioral measures in the Q175 mice including strengthening activity rhythms, cognitive performance and mood as measured by the tail suspension test. The treatment also reduced inappropriate activity during the normal sleep time. The drug treatment did not alter motor performance and coordination as measured by the challenging beam test. Our findings suggest that drugs targeting the H3R system may show benefits as cognitive enhancers in the management of HD.


Determining biota succession in a domestic wastewater pond system after treatment with a specific consortium microalgae.
Wastewater stabilization ponds (WSPs) rely on the metabolic activities of the inhabiting microbiota to treat wastewater. A selected consortium of Chlorella vulgaris and Chlorella protothecoides were used to manipulate the natural resident microalgae assemblage to improve the treatment performance of a domestic wastewater pond treatment system in a coastal region. Since information is lacking about the resulting influence on the composition or succession of the phytoplankton or associated microbiota assemblage, the current study aimed to determine how dosing with the microalgae C. vulgaris and C. protothecoides change the efficiency of wastewater effluent treatment, as well as the composition and succession of the natural occurring phytoplankton and microbial assemblage throughout WSP system. After a year of specific microalgae inoculations, the effluent in part complied with the standards set by the Department of Water Affairs and Forestry (DWAF) and the USA, Environmental Protection Agency (EPA). The cyanobacteria Microcystis aeruginosa dominated the sixth (75%) and seventh pond (97%) before the inoculation with C. vulgaris and C. protothecoide commenced. After 12 inoculation events C. vulgaris and C. protothecoides were dominant in ponds three to seven while the dominant microbial groups were Bacteroidetes, Cyanobacteria, Firmicutes, Planctomycetes, Proteobacteria, Spirochaetes, Synergistetes and Verrucomicrobia. After the microalgae treatment, the WSP effluent were more compliant regarding to the set guidelines for effluent than prior to microalgae treatment. Based on the ability of the C. vulgaris and C. protothecoides to improve the effluent water quality, it was evident that the consortium of microalgae can be use improve domestic wastewater effluent in rural nutrient sensitive catchments. The online version contains supplementary material available at 10.1007/s40201-022-00840-z.


Aflatoxins B1 and G 1 solubility in standard solutions and stability during cold storage.
In the present work we study the use of different solvents to store aflatoxins B1 and G1 standard solutions. We have obtained significant differences between aflatoxin B1 and G1 In ethyl acetate, methanol and water, with aflatoxin G1 being less stable. We recommend chloroform as the election solvent to store the aflatoxin solutions. The fact that aflatoxins are highly stable in water may have a potential use in experiments of biological activity.


Occurrence of microplastic pollution in rivers globally: Driving factors of distribution and ecological risk assessment.
Microplastics, as global emerging pollutants, have received significant attention worldwide due to their ubiquitous presence in the rivers. However, there is still a lack of clarity on the occurrence, driving factors, and ecological risks of microplastics in rivers worldwide. In this study, a global microplastic dataset based on 862 water samples and 445 sediment samples obtained from 63 articles was constructed, which revealed the temporal and spatial distribution of abundance and morphological characteristics of microplastics in rivers across the globe. In global rivers, the abundance of MPs in both water and sediment spans across 10 and 4 orders of magnitude, respectively. The MP comprehensive diversity index based on the physical morphological characteristics of MPs indicated a significant positive correlation between the pollution sources of MPs in different environmental media. Based on the data was aligned to the full-scale MPs, a novel framework was provided to evaluate the ecological risk of MPs and the interaction effects between the influencing factors driving the distribution characteristics of MPs in rivers around the world. The results obtained demonstrated a wide variation in the key driving factors affecting the distribution of microplastics in different environmental media (water and sediment) in rivers globally. The diversity indices of the morphological characteristics of MPs in densely populated areas of lower-middle income countries in Asia were significantly higher, implying that the sources of microplastics in these regions are more complex and extensive. More than half of the rivers are exposed to potential ecological risks of MPs; however, microplastics may pose only immediate risks to aquatic species in Burigang River, Bangladesh. This can provide valuable insights for formulating more effective scientific strategies for the management of MP pollution in rivers.


Studies in vitro on mouse-egg radiosensitivity from fertilization up to the first cleavage.
Super-ovulated eggs from the Balb/c strain were incubated, at various times after injection of HCG, in Whitten's medium containing tritiated thymidine. They were fixed on the following day at the 2-cell stage and prepared for autoradiography. On the basis of the results, pregnant mice were irradiated with various doses of X-rays at 15 h post HCG (fertilization), 19 h (pronuclear stage before DNA synthesis), 24 h (maximal DNA synthesis) and 27.5 h (DNA synthesis completed). On the day following irradiation, embryos were collected and classified into uncleaved or 2-cell embryos, and development of the 2-cell embryos was followed in culture. Irradiation was most effective when administered at 19 h after injection of HCG. Such a treatment increased the mortality before the first cleavage and, thereafter, from the 8-cell (100 rad) or morula stage (25, 50 rad). Blastocyst hatching and implantation were also impaired. Irradiation at other times was much less harmful for the embryos, which died mainly from the blastocyst stage. Finally, radiosensitivities of the mouse zygote at the various times studied can be estimated as follows: fertilization, + + +; pronuclear stage before DNA synthesis, + + + + +; maximal DNA synthesis, +; DNA synthesis terminated, + +.


A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis.
Characterizing virus-host interactions during self-limited infectious mononucleosis could explain how Epstein-Barr virus (EBV) replication is normally controlled and provide insight into why certain immunocompromised patients fail to contain it. University students had an average of 7 clinical and virologic evaluations during acute infectious mononucleosis. EBV was quantified in 697 samples of oral wash fluid, whole blood, peripheral blood mononuclear cells (PBMCs), and plasma by a real-time (TaqMan) polymerase chain reaction (qEBV) assay developed in our laboratory. Twenty of 25 subjects had serologically confirmed primary EBV infection. EBV was cleared from whole blood by a first-order process with a median half-life of 3 days, and its quantity was associated with severity of illness (r2=0.82). Oral shedding persisted at a median of >or=1x104 copies/mL for 32 weeks and was unrelated to severity of illness. Subjects with nonprimary EBV infection shed virus intermittently, and median quantities for all samples became undetectable within 4 weeks. Using a novel qEBV assay, we demonstrated that young adults with primary EBV infection rapidly cleared virus from blood but not from the oropharynx. High oral concentrations of EBV in asymptomatic persons who have resumed normal activities support the concept that infectious mononucleosis is most likely acquired by kissing.


Differences among college women for breast cancer prevention acquired information-seeking, desired apps and texts, and daughter-initiated information to mothers.
The purpose of this study was to examine among college women acquired breast cancer prevention information-seeking, desired apps and texts, and information given to mothers. Using a cross-sectional study, a survey was administered to college women at a southwestern university. College women (n = 546) used the Internet (44 %) for active breast cancer prevention information-seeking and used the Internet (74 %), magazines (69 %), and television (59 %) for passive information receipt. Over half of the participants desired breast cancer prevention apps (54 %) and texts (51 %). Logistic regression analyses revealed predictors for interest to receive apps were ethnicity (Hispanic), lower self-efficacy, actively seeking online information, and older age and predictors for interest to receive texts were lower self-efficacy and higher university level. Eighteen percent of college women (n = 99) reported giving information to mothers and reported in an open-ended item the types of information given to mothers. Predictors for giving information to mothers were actively and passively seeking online information, breast self-exam practice, and higher university level. Screenings were the most frequent types of information given to mothers. Breast cancer prevention information using apps, texts, or Internet and daughter-initiated information for mothers should be considered in health promotion targeting college students or young women in communities. Future research is needed to examine the quality of apps, texts, and online information and cultural differences for breast cancer prevention sources.


Effect of organic substrates on available elemental contents in nutrient solution.
In this paper, the changes of available elemental contents in the nutrient solution extracts of organic substrates (peat moss, charred rice husk, chicken manure, sawdust, turfgrass clipping and weathered coal) were studied and compared with that in the water extracts. Results showed that available elemental contents in the nutrient solution extracts are significantly different between organic substrates, whereas ionic concentrations are basically under steady condition after treatment for 36-108 h. Ionic contents in the nutrient solution extracts are not equal to the value of adding ionic concentrations in the supplied nutrient solution to that in the water extract. Thus, a mathematical model was proposed for adjusting the composition of supplied nutrient solution to match plant requirements in the organic soilless culture system.


An Opportunity to Improve Secondary Prevention With Icosapent Ethyl in Patients Who Have Undergone Coronary Artery Bypass Graft Surgery.
Icosapent ethyl reduces cardiovascular events in high-risk patients with hypertriglyceridaemia on statin therapy. However, it is not widely available and the potential application following coronary artery bypass graft (CABG) surgery is not well-established. We aimed to determine the real-world percentage of CABG surgery patients who may be eligible for the therapy. A retrospective analysis was performed between February 2015 and August 2020 in an Australian hospital. Patients were included if a lipid profile was performed at least three weeks following CABG surgery. Data was extracted from electronic medical records. Eligibility for icosapent ethyl was defined according to inclusion criteria from the REDUCE-IT trial. Of 484 patients with follow-up lipid profiles, 21 (4.3%) were not eligible for icosapent ethyl based on age and 39 (8.1%) were not prescribed statin therapy or were prescribed a fibrate. After applying triglyceride and low-density lipoprotein cholesterol level criteria, 124 (25.6%) patients were potentially eligible for icosapent ethyl therapy. Of those eligible, high-intensity statin therapy were prescribed in 108 (87.1%). A substantial percentage of CABG surgery patients may be eligible for icosapent ethyl and could potentially benefit from its cardiovascular protection. Further research should evaluate the additional cardiovascular benefits of icosapent ethyl in this very high-risk group of patients who are already treated with high-intensity statins.


Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.
Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.


Coordination difficulties, IQ and psychopathology in children with high-risk copy number variants.
The prevalence and impact of motor coordination difficulties in children with copy number variants associated with neurodevelopmental disorders (ND-CNVs) remains unknown. This study aims to advance understanding of motor coordination difficulties in children with ND-CNVs and establish relationships between intelligence quotient (IQ) and psychopathology. 169 children with an ND-CNV (67% male, median age = 8.88 years, range 6.02-14.81) and 72 closest-in-age unaffected siblings (controls; 55% male, median age = 10.41 years, s.d. = 3.04, range 5.89-14.75) were assessed with the Developmental Coordination Disorder Questionnaire, alongside psychiatric interviews and standardised assessments of IQ. The children with ND-CNVs had poorer coordination ability (b = 28.98, p < 0.001) and 91% of children with an ND-CNV screened positive for suspected developmental coordination disorder, compared to 19% of controls (OR = 42.53, p < 0.001). There was no difference in coordination ability between ND-CNV genotypes (F = 1.47, p = 0.184). Poorer coordination in children with ND-CNV was associated with more attention deficit hyperactivity disorder (ADHD) (β = -0.18, p = 0.021) and autism spectrum disorder trait (β = -0.46, p < 0.001) symptoms, along with lower full-scale (ß = 0.21, p = 0.011), performance (β = -0.20, p = 0.015) and verbal IQ (β = 0.17, p = 0.036). Mediation analysis indicated that coordination ability was a full mediator of anxiety symptoms (69% mediated, p = 0.012), and a partial mediator of ADHD (51%, p = 0.001) and autism spectrum disorder trait symptoms (66%, p < 0.001) as well as full scale IQ (40%, p = 0.002), performance IQ (40%, p = 0.005) and verbal IQ (38%, p = 0.006) scores. The findings indicate that poor motor coordination is highly prevalent and closely linked to risk of mental health disorder and lower intellectual function in children with ND-CNVs. Future research should explore whether early interventions for poor coordination ability could ameliorate neurodevelopmental risk.


The Clinical Utility of a Brief Psychological Stress Measure (Patient-Reported Outcomes Measurement Information System) in Youth with Chronic Pain.
To preliminarily examine the psychometric properties (i.e., internal consistency reliability, construct validity) and clinical utility of the Patient-Reported Outcomes Measurement Information System (PROMIS) psychological stress experiences scale in a sample of youth with chronic pain. Participant data were gathered from an institutional review board (IRB) approved clinical data registry. One hundred sixty-eight children and adolescents (age: mean = 14.97, SD = 2.78) with chronic pain presenting to a tertiary pain treatment clinic were included in the data set. Internal consistency estimates (i.e., Cronbach's alpha), bivariate correlations, and confirmatory factor analyses were performed to preliminarily examine reliability and validity. Multivariate regression analyses were performed to examine the associations between PROMIS psychological stress and pain-related and psychosocial outcomes. Confirmatory factor analysis and correlational results indicated that the PROMIS psychological stress experiences scale shows promising reliability and validity in the current sample of youth with chronic pain. Additionally, the results indicated that almost 50% of youth with chronic pain report "high" or "very high" stress (T ≥ 60) and significantly higher rates of stress when compared with national validation samples (P < 0.001). The results also indicated that the PROMIS psychological stress experiences scale was significantly associated with both pain-related and psychosocial outcomes (all P <0.01). The PROMIS psychological stress experiences scale shows promising psychometric properties in youth with pediatric pain and may be useful in assessing for psychological impairment. Future research should further examine the use of this brief measure to assess psychological stress in medical clinics as a way to enhance intervention and prevention efforts in these youth.


Current progress of miRNA-derivative nucleotide drugs: modifications, delivery systems, applications.
miRNA-derivative clinical nucleotide drugs (mdCNDs) effectively treat several diseases, with numerous undergoing clinical trials. In early-stage trials in disease therapeutics, such as malignant pleural mesothelioma and hepatic virus C infection, mdCND's therapeutic potency is undeniably good for effectiveness and safety. Fifteen mdCNDs undergoing clinical trials are introduced in this review. MiRNA modifications methods have been summarized, including phosphorothioate, cholesterol, locked nucleic acid, 2'-O-methyl, N,N-diethyl-4-(4-nitronaphthalen1-ylazo)-phenylamine modifications, and many more. Moreover, delivery systems, including self-assembled, inorganic ions nanoparticles, exosomes, and lipid-based nanosystems for mdCNDs targeted delivery, are presented. Among that, EnGeneIC, N-Acetylgalactosamine, liposomal nanoparticles, and cholesterol-conjugated for mdCNDs delivery are currently undergoing clinical trials. The pH, light, temperature, redox-responsive, enzyme, and specific-substance modes to trigger the release of miRNAs to target sites on-demand and the prospects of mdCNDs are discussed in this review. mdNCDs are one type of promising clinical drugs, however, it is still in the infancy. During the development process, it is imperative to advance in modifying miRNAs, especially at the 5'-end, to enhance targetability and stability against nucleases, develop a stimuli-responsive mode to control the release of mdCNDs to tissue cell-type-specific sites.


Pregnancy rate and reproductive hormones in humpback whale blubber: Dominant form of progesterone differs during pregnancy.
To better understand reproductive physiology of humpback whales Megaptera novaeangliae that reside in Hawai'i and Alaska, enzyme immunoassays were validated for both progesterone and testosterone in free-ranging and stranded animals (n = 185 biopsies). Concentrations were analyzed between different depths of large segments of blubber taken from skin to muscle layers of stranded female (n = 2, 1 pregnant, 1 non-pregnant) and male (n = 1) whales. Additionally, progesterone metabolites were identified between pregnant (n = 1) and non-pregnant (n = 3) females using high pressure liquid chromatography (HPLC). Progesterone concentrations were compared between juvenile (i.e., sexually immature), lactating, and pregnant females, and male whales, and pregnancy rates of sexually mature females were calculated. Based on replicate samples from ship struck animals collected at 7 depth locations, blubber containing the highest concentration of progesterone was located 1 cm below the skin for females, and the highest concentration of testosterone was in the skin layer of one male whale. HPLC of blubber samples of pregnant and non-pregnant females contain different immunoreactive progesterone metabolites, with the non-pregnant female eluate comprised of a more polar, and possibly conjugated, form of progesterone than the pregnant female. In females, concentrations of progesterone were highest in the blubber of pregnant (n = 28, 28.6 ± 6.9 ng/g), followed by lactating (n = 16, 0.9 ± 0.1 ng/g), and female juvenile (n = 5, 1.0 ± 0.2 ng/g) whales. Progesterone concentrations in male (n = 24, 0.6 ng/g ± 0.1 ng/g) tissues were the lowest all groups, and not different from lactating or juvenile females. Estimated summer season pregnancy rate among sexually mature females from the Hawai'i stock of humpback whales was 0.562 (95 % confidence interval 0.528-0.605). For lactating females, the year-round pregnancy rate was 0.243 (0.09-0.59), and varies depending on the threshold of progesterone assumed for pregnancy in the range between 3.1 and 28.5 ng/g. Our results demonstrate the synergistic value added when combining immunoreactive assays, HPLC, and long-term sighting histories to further knowledge of humpback whale reproductive physiology.


Serum acute phase reactants in pediatric patients; especially in neonates.
We studied serum acute phase reactant (APR) levels in 45 pediatric surgical patients. Alpha 1-acid glycoprotein (alpha 1-AG) showed a peak value on day 3 postoperatively (P.O.) and alpha 1-antitrypsin (alpha 1-AT) showed a high value on days 3-5 P.O. These glycoproteins returned to normal levels by day 21 P.O., but the level of haptoglobin (Hp) remained high until day 21 P.O. The postoperative changes of alpha 1-AG and alpha 1-AT correlated with the process of recovery from inflammatory conditions, but C-reactive protein (CRP) reached a peak on days 1-2 P.O. and returned to normal limits by day 14 P.O. In patients with infection, CRP returned to the normal level rapidly before recovery from infection. Of the 3 glycoproteins, alpha 1-AG seemed to be a valuable indicator of the pathological conditions. Postoperative changes in APR levels should be useful for early detection of postoperative complications. Persistent ileus led to an increase in APR levels, as a consequence of an inflammatory reaction due to breakdown of the intestinal mucosal barrier.


Effects of chronic hypoxia on the pharmacokinetics of caffeine and cardio-green in micro swine.
The pharmacokinetics of caffeine and cardio-green (ICG) were examined in four micro swine at sea level (SEA) and following 21 d continuous exposure to 4600 m (ALT) in a hypobaric chamber. Caffeine (84.7 mg) and ICG (10 mg) were administered as separate intravenous boluses and sequential blood samples collected. Caffeine clearance significantly (p < 0.05) increased in ALT (96.8 +/- 20.0 ml.min-1) as compared to SEA (53.6 +/- 24.8 ml.min-1), demonstrating that liver function increased in ALT. There was no significant change in the ratio of primary metabolites to caffeine, suggesting that the increase in clearance was not due to a change in the rate of caffeine metabolism. ICG clearance significantly increased in ALT (179.8 +/- 57.4 ml.min-1) as compared to SEA (84.4 +/- 28.9 ml.min-1) indicating that hepatic blood flow (HBF) increased. These results demonstrate that chronic exposure to 4600 m increases the clearance of caffeine and ICG in the micro swine model and suggests that the increase in caffeine clearance is related to HBF.


Modern subcutaneous implantable defibrillator therapy in patients with cardiomyopathies and channelopathies: data from a large multicentre registry.
Patients with cardiomyopathies and channelopathies are usually younger and have a predominantly arrhythmia-related prognosis; they have nearly normal life expectancy thanks to the protection against sudden cardiac death provided by the implantable cardioverter defibrillator (ICD). The subcutaneous ICD (S-ICD) is an effective alternative to the transvenous ICD and has evolved over the years. This study aimed to evaluate the rate of inappropriate shocks (IS), appropriate therapies, and device-related complications in patients with cardiomyopathies and channelopathies who underwent modern S-ICD implantation. We enrolled consecutive patients with cardiomyopathies and channelopathies who had undergone implantation of a modern S-ICD from January 2016 to December 2020 and who were followed up until December 2022. A total of 1338 S-ICD implantations were performed within the observation period. Of these patients, 628 had cardiomyopathies or channelopathies. The rate of IS at 12 months was 4.6% [95% confidence interval (CI): 2.8-6.9] in patients with cardiomyopathies and 1.1% (95% CI: 0.1-3.8) in patients with channelopathies (P = 0.032). No significant differences were noted over a median follow-up of 43 months [hazard ratio (HR): 0.76; 95% CI: 0.45-1.31; P = 0.351]. The rate of appropriate shocks at 12 months was 2.3% (95% CI: 1.1-4.1) in patients with cardiomyopathies and 2.1% (95% CI: 0.6-5.3) in patients with channelopathies (P = 1.0). The rate of device-related complications was 0.9% (95% CI: 0.3-2.3) and 3.2% (95% CI: 1.2-6.8), respectively (P = 0.074). No significant differences were noted over the entire follow-up. The need for pacing was low, occurring in 0.8% of patients. Modern S-ICDs may be a valuable alternative to transvenous ICDs in patients with cardiomyopathies and channelopathies. Our findings suggest that modern S-ICD therapy carries a low rate of IS. URL: http://clinicaltrials.gov/Identifier: NCT02275637.


Author Correction: HYSOGs250m, global gridded hydrologic soil groups for curve-number-based runoff modeling.
The original version of this Data Descriptor incorrectly referenced the "United Nations (UN) Food and Agriculture Organization (FAO) soilGrids250m system". This has been corrected to "SoilGrids predictions" throughout the text in both the HTML and PDF versions.


Selective inhibition of Ras-dependent cell growth by farnesylthiosalisylic acid.
S-trans,trans-Farnesylthiosalicylic acid (FTS) is a novel farnesylated rigid carboxylic acid derivative. In cell-free systems, it acts as a potent competitive inhibitor (Ki = 2.6 microM) of the enzyme prenylated protein methyltransferase (PPMTase), which methylates the carboxyl-terminal S-prenylcysteine in a large number of prenylated proteins including Ras. In such systems, FTS inhibits Ras methylation but not Ras farnesylation. Inhibition of the PPMTase by FTS in homogenates or membranes of a variety of tissues and cell lines is inferred from a block in the methylation of exogenously added substrates such as N-acetyl-S-trans,trans-farnesyl-L-cysteine and of endogenous substrates including small GTP-binding proteins. FTS can also inhibit methylation of these proteins in intact cells (e.g. in Rat-1 fibroblasts, Ras-transformed Rat-1, and B16 melanoma cells). Unlike in cell-free systems, however, relatively high concentrations of FTS (50-100 microM) are required for partial blocking (10-40%) of protein methylation in the intact cells. Thus, FTS is a weak inhibitor of methylation in intact cells. Because methylation is the last step in the processing of Ras and related proteins, FTS is not likely to affect steps that precede it, e.g. protein prenylation. This may explain why the growth and gross morphology of a variety of cultured cell types (including Chinese hamster ovary, NIH3T3, Rat1, B16 melanoma, and PC12) is not affected by up to 25 microM FTS and is consistent with the observed lack of FTS-induced cytotoxicity. Nevertheless, FTS reduces the levels of Ras in cell membranes and can inhibit Ras-dependent cell growth in vitro, independently of methylation. It inhibits the growth of human Ha-ras-transformed cells (EJ cells) and reverses their transformed morphology in a dose-dependent manner (0.1-10 microM). The drug does not interfere with the growth of cells transformed by v-Raf or T-antigen but inhibits the growth of ErbB2-transformed cells and blocks the mitogenic effects of epidermal and basic fibroblast growth factors, thus implying its selectivity toward Ras growth signaling, possibly via modulation of Ras-Raf communication. Taken together, the results raise the possibility that FTS may specifically interfere with the interaction of Ras with a farnesylcysteine recognition domain in the cell membrane.(ABSTRACT TRUNCATED AT 400 WORDS)


Fecal calprotectin as a factor that supports the pathogenicity of Dientamoeba fragilis.
Calprotectin is a protein that is mostly released from neutrophils, monocytes, macrophages and submucosal epithelial cells. Fecal calprotectin (f-CP) is a marker of intestinal inflammation. There are some discussions about the pathogenicity of D. fragilis in the gastrointestinal tract. In this study, we investigated whether f-CP level is a factor supporting the pathogenicity of D. fragilis. The f-CP levels were evaluated in patients with only D. fragilis positive in comparison with healthy controls. Moreover, the levels of f-CP were investigated in fecal samples of D. fragilis negative patients with gastrointestinal complaints. The fecal samples were collected from three groups. Three groups of fecal samples were examined directly microscopy, trichrome staining, cultivation, enzyme immunoassay (EIA) and real-time PCR assay. In the first group (Group 1, n = 34), patient stool samples with gastrointestinal symptoms (without other pathogens) found only with D. fragilis were included. In the second group (Group 2, n = 31), there were patients' stool samples with gastrointestinal symptoms that D. fragilis was negative (but there may be other pathogenic agents). In the control group (Group 3, n = 23), we used fecal samples collected from healthy volunteers without any infection or gastrointestinal complaints. The collected fecal samples were stored at -20 °C until analysis. Levels of f-CP were determined by using human calprotectin ELISA kits. Total of 88 patients were enrolled in three different groups. We obtained f-CP levels as follows: 33.40 ng/mg protein in the group 1, 15.99 ng/mg protein in the group 2 and 1.54 ng/mg protein in the group 3. Statistically significant difference in f-CP levels of the group 1 and the group 2 were obtained when compared with healthy controls (p < 0.0001). However, the f-CP levels of the group 1 were not significantly different from the group 2 (p > 0.99). In conclusion, increased levels of f-CP are shown as a marker of an inflammatory disease of the lower gastrointestinal tract in infected humans. There is continues controversy about the pathogenicity of D. fragilis in symptomatic and asymptomatic patients. The findings of this study contribute to the ongoing debate about the pathogenicity of D. fragilis. In our study, the potential pathogenicity of D. fragilis is associated with increased f-CP concentrations with parasite detection in the fecal samples and therefore we assume that the parasite is not only a harmless commensal. In summary, higher levels of f-CP found in D. fragilis positive patients suggest the importance of researches that support the pathogenicity of indicated parasite.


Free and total lipid myo-inositol concentrations decrease with age in human brain.
An active transport system maintains myo-inositol in the brain at a much higher concentration than in the blood. Free and total lipid inositol has been analysed in samples of normal human anterior temporal cortex of different ages. At age 20 the concentration of inositol was 60 mumols/g protein, and it fell steadily to half that concentration at age 90. There was a similar fall with age in the total inositol lipid concentration.


Value of a cinefluoroscopic assessment of the Lillehei-Kaster prosthetic heart valves.
In order to assess the functioning of the pivoting disc of the Lillehei-Kaster prosthetic valve, a cinefluoroscopic technique using multiple angulations was developed. The disc was detected in 240 (99%) of the 242 valves studied (126 aortic, 107 mitral, and nine tricuspid valves). The maximal-opening angle of the disc was measured in 75% of the aortic but only 20% of the mitral valve prostheses in the 182 valve studies in which this was attempted. Prosthetic dysfunctions were suspected clinically in three aortic and three tricuspid valves and confirmed with the cinefluoroscopic technique. This cinefluoroscopic approach constitutes a rapid, noninvasive, and sensitive evaluation of the function of the Lillehei-Kaster prosthetic valve in the aortic position.


Simultaneous measurement of multiple active kinase states using polychromatic flow cytometry.
Intracellular assays of signaling systems have been limited by an inability to correlate functional subsets of cells in complex populations on the basis of active kinase states. Such correlations could be important in distinguishing changes in signaling status that arise in rare cell subsets during functional activation or in disease manifestation. Here we demonstrate the ability to simultaneously detect activated kinase members of the mitogen-activated protein kinases family (p38 MAPK, p44/42 MAPK, JNK/SAPK), members of cell survival pathways (AKT/PKB), and members of T-cell activation pathways (TYK2), among others, in subpopulations of complex cell populations by multiparameter flow-cytometric analysis. We demonstrate the utility of these probes in identifying distinct signaling cascades for (1) both artificial and physiological stimulatory conditions of peripheral blood mononuclear cells (PBMCs), (2) cytokine stimulation in human memory and naïve lymphocyte subsets as identified by five differentiation markers, and (3) ordering of kinase activation in potential signaling hierarchies. Polychromatic flow-cytometric active kinase measurements demonstrate that multidimensional analysis of signaling pathways can provide functional signaling pathway assessment on a single-cell level and allow for potential correlation with biological and clinical parameters.


Diagnostic value of congenital pulmonary airway malformation volume ratio for fetal hydrops due to congenital lung malformations: a systematic review and meta-analysis.
Meta-analysis was used to evaluate the diagnostic value of a CVR cut-off value of 1.6 for fetal hydrops due to congenital lung malformation (CLM). A systematic search of PubMed, Embase, Web of Science, CNKI, VIP, and Wanfang published before 7/30/2021 for the value of a congenital pulmonary airway malformation volume ratio (CVR) cut-off value of 1.6 for the diagnosis of fetal hydrops. According to the inclusion and exclusion criteria, the literature that met the requirements were obtained. A total of 75 articles were retrieved, and 12 articles were included for further analysis. The quality of these studies was evaluated according to the Quality Assessment for Studies of Diagnostic Accuracy tool (QUADAS-2) criteria. The Q test and heterogeneity I2 were used to evaluate the heterogeneity due to non-threshold effects, and Stata 15.0 was used for statistical analysis to evaluate the diagnostic value of the CVR cutoff value of 1.6 for fetal hydrops due to CLM. A total of 12 studies were included. The QUADAS-2 indicated that the risk of bias was relatively low, and the clinical applicability was relatively high. Statistical analysis was performed on included studies using a random effect model. Meta-analysis showed that the pooled sensitivity, specificity, diagnostic ratio and summary receiver operating characteristic (SROC) for the diagnosis of fetal hydrops by CVR were 0.86 (95% CI, 0.72-0.93; I2 = 59.84), 0.90 (95% CI, 0.88-0.93; I2 = 31.94), 58 (95% CI, 22-149; I2 = 100%), 0.93 (95% CI, 0.91-0.95). The sensitivity and specificity of CVR cut-off value 1.6 for the diagnosis of CLM-induced fetal hydrops were high, no publication bias was observed, and the CVR cut-off value 1.6 is meaningful for the early diagnosis prediction of CLM-induced fetal hydrops.


Allergic-type reactions to oxaliplatin: retrospective analysis of 42 patients.
Oxaliplatin is a platinum salt that is particularly effective in treating gastrointestinal tumours. Its increased use has resulted in emergence of allergic reactions, including anaphylactic shock. Allergic reactions to oxaliplatin documented over the last 5 years have been analysed using predefined criteria. The 42 analysed patients had cancer and received a FOLFOX regimen in first line or beyond. Two types of allergy were observed: a type I immediate allergic reaction in 39 patients in whom the most frequent signs were respiratory (50%) and cutaneous (40%); anaphylactic shock that occurred in three patients; type II allergy (immunological thrombopenia) was observed in three patients. All the toxicities were reversible on symptomatic treatment. No predictive factor was evidenced. Anaphylactic shock, is rare but serious, and must be considered in the event of any severe blood pressure decrease. For the non-life-threatening reactions, prolonging infusion duration, "Stop and Go" regimen seem to be effective means of preventing recurrence.


Veracity and rhetoric in paediatric medicine: a critique of Svoboda and Van Howe's response to the AAP policy on infant male circumcision.
In a recent issue of the Journal of Medical Ethics,Svoboda and Van Howe commented on the 2012 changein the American Academy of Pediatrics (AAP) policy on newborn male circumcision, in which the AAP stated that benefits of the procedure outweigh the risks. Svoboda and Van Howe disagree with the AAP conclusions. We show here that their arguments against male circumcision are based on a poor understanding of epidemiology,erroneous interpretation of the evidence, selective citation of the literature, statistical manipulation of data, and circular reasoning. In reality, the scientific evidence indicates that male circumcision, especially when performed in the newborn period, is an ethically and medically sound low-risk preventive health procedure conferring a lifetime of benefits to health and well-being.Policies in support of parent-approved elective newborn circumcision should be embraced by the medical,scientific and wider communities.


[Relationship between coeliac disease and multifocal tuberculosis: about a case and literature review].
Coeliac disease is an autoimmune enteropathy related to gluten intolerance which occurs in subjects genetically disposed. The diagnosis is based on the combination of clinical biological and histological arguments. It is associated with many complications, including lymphoma. The risk of tuberculosis in patients with coeliac disease is increased. Several hypotheses explaining this association have been discussed. We report a case of coeliac disease associated with multifocal tuberculosis in a 17-year old patient.


Surgical treatment of the severely ischaemic leg: I. Survival rates.
Over a 10-year period, 411 patients with atherosclerotic major artery disease causing severe ischaemia of the legs were treated by surgery. Their survival rate, assessed by the life table method, was 80 per cent at 1 year and 50 per cent at 5 years. Early and late survival rates were significantly worse in elderly patients, and in patients with extensive gangrene. Late survival rates were significantly worse in diabetics, and in patients with clinical myocardial ischaemia. Patients treated by arterial reconstruction showed a better survival rate than those treated by sympathectomy or amputation, though the latter groups contained more poor risk patients. Survival rates were not influenced by the technique of reconstruction.


Synthesis of polyaniline-gold nanocomposites using "grafting from" approach.
Polyaniline-gold nanocomposites containing polyaniline nanostructures attached to well-dispersed uniform-size gold nanoparticles were obtained using a surface initiation approach.


Real-time estimation of the remaining surgery duration for cataract surgery using deep convolutional neural networks and long short-term memory.
Estimating the surgery length has the potential to be utilized as skill assessment, surgical training, or efficient surgical facility utilization especially if it is done in real-time as a remaining surgery duration (RSD). Surgical length reflects a certain level of efficiency and mastery of the surgeon in a well-standardized surgery such as cataract surgery. In this paper, we design and develop a real-time RSD estimation method for cataract surgery that does not require manual labeling and is transferable with minimum fine-tuning. A regression method consisting of convolutional neural networks (CNNs) and long short-term memory (LSTM) is designed for RSD estimation. The model is firstly trained and evaluated for the single main surgeon with a large number of surgeries. Then, the fine-tuning strategy is used to transfer the model to the data of the other two surgeons. Mean Absolute Error (MAE in seconds) was used to evaluate the performance of the RSD estimation. The proposed method is compared with the naïve method which is based on the statistic of the historical data. A transferability experiment is also set to demonstrate the generalizability of the method. The mean surgical time for the sample videos was 318.7 s (s) (standard deviation 83.4 s) for the main surgeon for the initial training. In our experiments, the lowest MAE of 19.4 s (equal to about 6.4% of the mean surgical time) is achieved by our best-trained model for the independent test data of the main target surgeon. It reduces the MAE by 35.5 s (-10.2%) compared to the naïve method. The fine-tuning strategy transfers the model trained for the main target to the data of other surgeons with only a small number of training data (20% of the pre-training). The MAEs for the other two surgeons are 28.3 s and 30.6 s with the fine-tuning model, which decreased by -8.1 s and -7.5 s than the Per-surgeon model (average declining of -7.8 s and 1.3% of video duration). External validation study with Cataract-101 outperformed 3 reported methods of TimeLSTM, RSDNet, and CataNet. An approach to build a pre-trained model for estimating RSD estimation based on a single surgeon and then transfer to other surgeons demonstrated both low prediction error and good transferability with minimum fine-tuning videos.


Discovery of novel conformationally restricted diazocan peptidomimetics as inhibitors of interleukin-1beta synthesis.
A novel diazocan containing dipeptide mimetic was synthesized via reductive N-N bond cleavage of a pyrazolidino-pyrazolidine using Raney-Ni and evaluated as an ICE inhibitor. This versatile 8-membered ring containing scaffold possesses an N-5 ring nitrogen that was used to explore structure-activity relationships in a cell-based assay measuring inhibition of interleukin-1beta.


Predictors of successful chronic total occlusion percutaneous coronary interventions: a systematic review and meta-analysis.
The aim of this study was to identify positive and negative predictors of technical and clinical success for percutaneous coronary intervention (PCI) of chronic total occlusions (CTO). We conducted a systematic review and meta-analysis of studies published between 2000 and 2016 analysing rates of CTO PCI success with respect to demographic and angiographic characteristics. Crude ORs and 95% CIs for each predictor were calculated using a random effects model. Predictors of technical and clinical success were assessed among 28 demographic and 31 angiographic variables. Clinical success was defined as technical success without major adverse cardiac events. A total of 61 studies, totalling 69 886 patients were included in this analysis. The major demographic characteristics associated with a 20% or greater reduction in the odds of technical and clinical success were a history of myocardial infarction, PCI, coronary artery bypass grafting, stroke/transient ischaemic attack and peripheral vascular disease. Angiographic factors were generally stronger predictors of reduced technical and clinical success. Those associated with >20% odds reduction included non-left anterior descending CTOs, multivessel disease, presence of bridging collaterals, moderate-to-severe calcification, >45 degree vessel bending, tortuous vessel, blunt stump and ostial lesions. Of these, novel predictors included prior PCI, prior stroke, peripheral vascular disease, presence of multivessel disease and bridging collaterals. The present study has identified strong negative predictors for clinical success for CTO PCI, which will aid in patient selection for this procedure.


Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea-pig.
1. Antitussive, antinociceptive and respiratory depressant effects of codeine, morphine and H.Tyr.D-Arg.Gly.Phe(4-NO2) Pro.NH2 (compound BW443C) were investigated in unanaesthetized guinea-pigs. Antagonism of the antitussive and antinociceptive effects was investigated by the use of nalorphine and N-methylnalorphine. Naloxone was used to antagonize respiratory depression. 2. Antitussive ED50s (with 95% confidence limits) for inhibition of cough induced by citric acid vapour were for codeine, morphine and BW443C respectively, 9.1(5.8-15), 1.3(0.7-2.4) and 1.2(0.6-2.6) mg kg-1 s.c. and 8.7(4.2-12), 1.6(1.2-1.9) and 0.67(0.002-3.3) mg kg-1, i.v. The antitussive effects of subcutaneous codeine (25 mg kg-1) morphine (8.1 mg kg-1) and BW443C (2.5 mg kg-1) were significantly antagonized by subcutaneous nalorphine (3.0 mg kg-1) and N-methylnalorphine (3.0 mg kg-1). 3. In the multiple toe-pinch test, the antinociceptive ED50s (with 95% confidence limits) of codeine and morphine were 18(16-22) and 2.3(0.4-4.3) mg kg-1, s.c., respectively. Compound BW443C was ineffective in doses of 2.5 and 10 mg kg-1 s.c., a result consistent with its lacking penetration into the CNS. Subcutaneous nalorphine (3.0 mg kg-1) antagonized the antinociceptive action of codeine (25 mg kg-1) and morphine (8.1 mg kg-1). In contrast, N-methylnalorphine (3.0 mg kg-1) had no significant effect on the antinociceptive action of codeine and morphine, suggesting lack of penetration of the CNS by N-methylnalorphine. 4. At doses near to the i.v. ED50 values for the antitussive activity, morphine (1.5mg kg- ', i.v.) and codeine (10mg kg-', i.v.) caused small but significant depressions of ventilation (7.0 +/- 2.3% and 16.5 +/- 8.4% respectively). Higher doses of morphine (10, 30 and 60mg kg- ', i.v.) caused further doserelated depression of ventilation (9.6 +/- 5.3%, 22.4 +/- 6.2% and 36.2 +/- 9.6% respectively) whereas codeine (30 and 60mg kg-' i.v.) caused stimulation of ventilation which was marked (191.3 +/- 43.9%) at 60 mg kg-'. 5. Compound BW443C in doses of 1 or 10mgkg-',i.v. (approximately equal to, and 10 times the EDo for antitussive activity) did not cause significant depression of ventilation. Only at higher doses of 30 and 60mg kg-', i.v. was there a significant decrease in minute volume (13.1 +/- 6.8% and 15.9 +/- 1.89% respectively). The depression of ventilation caused by either BW443C (60mg kg-', i.v.) or morphine (60mg kg-', i.v.) was prevented by pretreatment with naloxone (3mg kg-', i.v.) administered 15 min before morphine or BW443C. 6. These results in the guinea-pig support the hypothesis that the antitussive action of the opiates codeine and morphine and the opioid pentapeptide BW443C do not require penetration of these drugs into the CNS.


Hydrogen-Bonded Organic Framework (HOF)-Based Single-Neural Stem Cell Encapsulation and Transplantation to Remodel Impaired Neural Networks.
Herein we present a new way to encapsulate neural stem cells (NSCs) by using hydrogen-bonded organic frameworks (HOFs) to overcome the common causes of low therapeutic efficacy during NSC transplantation: 1) loss of fundamental stem cell properties, "stemness", before transplantation, 2) cytomembrane damage during transplantation, and 3) apoptosis due to oxidative stress after transplantation. Porous carbon nanospheres (PCNs) are doped into the HOF shell during the process of mineralization to endow the cellular exoskeletons with hierarchical hydrogen bonds, and the ability to resist oxidative stress due to the catalase and superoxide dismutase-like activities of PCN. Under NIR-II irradiation, thermal-responsive hydrogen bonds dissociate to release NSCs. Stereotactic transplanting encapsulated NSC into the brain of an Alzheimer's disease (AD) mouse model further verifies that our design can enhance NSC viability, promote neurogenesis, and ameliorate cognitive impairment. As the first example of using HOFs to encapsulate NSCs, this work may inspire the design of HOF-based exoskeletons to ameliorate neurogenesis and cognitive behavioral symptoms associated with AD.


Surveillance of antimicrobial resistance of Salmonella enterica serotype Typhi in seven Asian countries.
Two hundred and four Salmonella enterica serotype Typhi (S. Typhi) isolates were collected from seven Asian countries during 2002-2004. Multidrug-resistant S. Typhi (resistant to > or = 3 antibiotics) was detected in 84 (41.2%) isolates and 142 (69.6%) showed reduced susceptibility to ciprofloxacin (minimum inhibitory concentration=0.125-1.0 mg/l). This study highlights the worsening situation of antimicrobial resistance of S. Typhi in Asia.


Newborn mass screening for galactosemia.
Methods for mass screening of newborns for galactosemia have been available since 1964. Although galactosemia is rare, many countries have included screening for galactosemia in their national screening programs, yet other countries deny the necessity for screening. Despite the early appearance of clinical symptoms, newborns may be reliably diagnosed in time only through mass screening.


Functional interactions of neuronal heparan sulphate proteoglycans with laminin.
Quantitative biosynthetic studies using cellular extracts and neuron conditioned medium demonstrated that heparan sulphate proteoglycans (HSPGs) comprised 20-25% of the sulphated proteoglycans produced by neurons while the remainder consisted of chondroitin sulphate proteoglycans (CSPGs). When chromatographic fractions containing guanidine extracted and partially purified proteoglycans from culture medium conditioned by neurons (NCM) were used to pretreat a laminin substrate, neurite formation by sensory neurons was enhanced. Enhanced neurite promoting activity was not apparent if, during the pretreatment of the laminin substrate with NCM, heparan sulphate glycosaminoglycans (HS) were present. To determine the molecular basis of cell surface HSPG interactions with immobilized laminin, adhesion and neurite growth by dissociated sensory neurons were quantified at 4 h in vitro--a time at which there was no apparent contribution of released proteoglycans to neurite growth. Whereas adhesion was not influenced, neurite growth was partially inhibited in a dose-dependent manner if the sensory neurons were coincubated with HS, and if the cells were pretreated, prior to seeding, with heparitinase. The inhibitory effect produced by coincubation with saturating concentrations of HS was no longer apparent if the cells had been pretreated with heparitinase. These findings distinguish quantitatively between neurite growth on laminin and on laminin-HSPG complexes, and suggest that some neuronal cell surface and released HSPGs are involved in neurite growth by virtue of non-covalent interactions with glycosaminoglycan binding domains of laminin.


Epidemic Diseases and Chinese Medicine: Example of SARS and COVID-19: Part Two.
Along with the legends about epidemic demons, China has developed over the centuries a medical approach to epidemic diseases based on the teachings of Huang Di Nei Jing ( Huangdi's Internal Classic), Nan Jing ( Classic of Difficult Issues), and Shang Han Lun ( Treatise on Cold Damage). Other doctors and scientists participated in this evolution of knowledge, like Wang Shuhe (), Ge Hong (), Chao Yuanfang (), Sun Simiao (), and Liu Wansu (). However, it was in the 17th century, after the great break of the Song, Jin, and Yuan eras that an innovative spirit, Wu Youke ( 1582-1652) first foresaw the existence of microorganisms as we know them now. His Wen Yi Lun ( Treatise on Pestilence) foreshadows an original approach to epidemic diseases, particularly emerging infectious diseases of the 21st century. After them, traditional Chinese medicine developed a comprehensive method of diagnosing and treating of these diseases (Epidemic Diseases Theory ) within the School of Heat Diseases (). In a third article, we will examine some applications in the treatment of the SARS 2003-2004 epidemic () and the current COVID-19 () pandemic.


Does diversity beget diversity in microbiomes?
Microbes are embedded in complex communities where they engage in a wide array of intra- and inter-specific interactions. The extent to which these interactions drive or impede microbiome diversity is not well understood. Historically, two contrasting hypotheses have been suggested to explain how species interactions could influence diversity. 'Ecological Controls' (EC) predicts a negative relationship, where the evolution or migration of novel types is constrained as niches become filled. In contrast, 'Diversity Begets Diversity' (DBD) predicts a positive relationship, with existing diversity promoting the accumulation of further diversity via niche construction and other interactions. Using high-throughput amplicon sequencing data from the Earth Microbiome Project, we provide evidence that DBD is strongest in low-diversity biomes, but weaker in more diverse biomes, consistent with biotic interactions initially favouring the accumulation of diversity (as predicted by DBD). However, as niches become increasingly filled, diversity hits a plateau (as predicted by EC).


Tracing the route: Using stable isotope analysis to understand microplastic pathways through the pelagic-neritic food web of the Tyrrhenian Sea (Western Mediterranean).
This study provides a pilot investigation of the relationship between microplastic ingestion and the trophic ecology of three pelagic fish species (Engraulis encrasicolus, Scomber scombrus, and Trachurus trachurus) from Anzio coast, Tyrrhenian Sea (Western Mediterranean). Stable isotope analysis has been performed to determine the trophic position and the isotopic niche of the three species. Then, data on the occurrence, abundance, and diversity of ingested microplastics have been analyzed considering the observed foraging patterns. The detected differences in the estimated trophic position (E. encrasicolus = 3.08 ± 0.18; S. scombrus = 3.57 ± 0.21; T. trachurus = 4.07 ± 0.21), together with the absence of overlap in the isotopic niches confirm that the three examined species cover different ecological roles within the coastal-pelagic food web. Results from the analysis of ingested microplastics show that the trophic position has no remarkable effects on the incidence of microplastic ingestion, with no significant differences detected in terms of both frequency of occurrence and number of ingested microplastics per individual. However, differences among species emerge when considering the diversity of ingested microplastic types in terms of shape, size, color, and polymer composition. Species at higher trophic levels have shown to ingest a greater diversity of microplastics, including a significant increase in the size of the ingested particles (median surface area: 0.011 mm2 in E. encrasicolus; 0.021 mm2 in S. scombrus; 0.036 mm2 in T. trachurus). The ingestion of larger microplastics might be due to the larger gape sizes but also to active selection mechanisms, likely stimulated by the similarity of these particles to natural or potential prey of both S. scombrus and T. trachurus. Overall, this study suggests that microplastic ingestion can be affected by the different trophic position of fish species, providing new insights about the impact of microplastic contamination on the pelagic community.


Palonosetron and prednisolone for the prevention of nausea and emesis during fractionated radiotherapy and 5 cycles of concomitant weekly cisplatin-a phase II study.
Recommendations for antiemetic prophylaxis supportive to radiotherapy and concomitant chemotherapy are not evidence-based. The purpose of this study was to evaluate the efficacy of the antiemetic regimen concurrent to fractionated radiotherapy and concomitant weekly cisplatin in two Danish departments of oncology. Patients with gynecological cancer scheduled to receive fractionated radiotherapy and concomitant weekly cisplatin (40 mg/m(2)) were asked to complete a study diary in order to assess episodes of emesis, grade of nausea, and use of rescue antiemetic treatment daily during 5 weeks of treatment. Antiemetic treatment consisted of palonosetron and prednisolone. A patient had completed the study if emesis occurred or if 5 weeks of treatment were accomplished without emesis. The primary endpoint was sustained no emesis during 5 weeks of treatment. A total of 48 patients completed 155 weekly cycles of radiotherapy, concomitant weekly cisplatin, and antiemetic prophylaxis. The probability of completing 5 cycles without emesis (sustained no emesis) was 57 %. During cycle 1, 42 % of the patients were free from nausea. After 5 cycles, only 23 % of patients were continuously free from nausea. One half of the patients used rescue antiemetic treatment at least once during the 5 cycles. The present study demonstrates that an antiemetic prophylaxis consisting of palonosetron and prednisolone is insufficient for the prevention of nausea and vomiting induced by radiotherapy and weekly cisplatin in patients treated for gynecological cancer. The addition of a neurokinin-1 receptor antagonist should be investigated in a randomized, double-blind study in this setting.


Regional radiotherapy versus an axillary lymph node dissection after lumpectomy: a safe alternative for an axillary lymph node dissection in a clinically uninvolved axilla in breast cancer. A case control study with 10 years follow up.
The standard treatment of the axilla in breast cancer used to be an axillary lymph node dissection. An axillary lymph node dissection is known to give substantial risks of morbidity. In recent years the sentinel node biopsy has become common practice. Future randomized study results will determine whether the expected decrease in morbidity can be proven. Before the introduction of the sentinel node biopsy, we conducted a study in which 180 women of 50 years and older with T1/T2 cN0 breast cancer were treated with breast conserving therapy. Instead of an axillary lymph node dissection regional radiotherapy was given in combination with tamoxifen (RT-group). The study group was compared with 341 patients, with the same patient and tumour characteristics, treated with an axillary lymph node dissection (S-group). The treatment groups were comparable, except for age. The RT-group was significantly older than the S-group. The median follow up was 7.2 years. The regional relapse rates were low and equal in both treatment groups, 1.1% in RT-group versus 1.5% in S-group at 5 years. The overall survival was similar; the disease free survival was significant better in the RT-group. Regional recurrence rates after regional radiotherapy are very low and equal to an axillary lymphnode dissection.


(Internet) Gaming Disorder in DSM-5 and ICD-11: A Case of the Glass Half Empty or Half Full: (Internet) Le trouble du jeu dans le DSM-5 et la CIM-11: Un cas de verre à moitié vide et à moitié plein.
Diagnostic and Statistical Manual of Mental Disorders (DSM-5) included in 2013 Internet gaming disorder (IGD) as a condition for further study, and in 2018, the World Health Organization included gaming disorder (GD) as a mental disorder in the International Classification of Disease (ICD-11). We aim to compare disorders of gaming in both diagnostic systems using a sample of young adults in Mexico. Self-administered survey to estimate the prevalence of DSM-5 IGD and ICD-11 GD in 5 Mexican universities; 7,022 first-year students who participated in the University Project for Healthy Students, part of the World Health Organization World Mental Health International College Student Initiative. Cross-tabulation, logistic regression, and item response theory were used to inform on 12- month prevalence of DSM-5 IGD and ICD-11 GD, without and with impairment. The 12-month prevalence of DSM-5 IGD was 5.2% (95% CI, 4.7 to 5.8), almost twice as high as the prevalence using the ICD-11 GD criteria (2.7%; 95% CI, 2.4 to 3.1), and while adding an impairment requirement diminishes both estimates, prevalence remains larger in DSM-5. We found that DSM-5 cases detected and undetected by ICD-11 criteria were similar in demographics, comorbid mental disorders, service use, and impairment variables with the exception that cases detected by ICD-11 had a larger number of symptoms and were more likely to have probable drug dependence than undetected DSM-5 cases. DSM-5 cases detected by ICD-11 are mostly similar to cases undetected by ICD-11. By using ICD-11 instead of DSM-5, we may be leaving (similarly) affected people underserved. It is unlikely that purely epidemiological studies can solve this discrepancy and clinical validity studies maybe needed.