Lactoferricin-inspired peptide AMC-109 augments the effect of ciprofloxacin against Pseudomonas aeruginosa biofilm in chronic murine wounds.
Chronic wounds are characterised by prolonged inflammation, low mitogenic activity, high protease/low inhibitor activity, microbiota changes and biofilm formation, combined with the aetiology of the original insult. One strategy to promote healing is to terminate the parasitism-like relationship between the biofilm-growing pathogen and host response. Antimicrobial peptide AMC-109 is a potential treatment with low resistance potential and broad-spectrum coverage with rapid bactericidal effect. We aimed to investigate whether adjunctive AMC-109 could augment the ciprofloxacin effect in a chronic Pseudomonas aeruginosa wound model. Third-degree burns were inflicted on 33 BALB/c mice. Pseudomonas aeruginosa embedded in seaweed alginate was injected sub-eschar to mimic biofilm. Mice were randomised to receive AMC-109, combined AMC-109 and ciprofloxacin, ciprofloxacin, or placebo for 5 days followed by sample collection. A lower bacterial load was seen in the double-treated group compared with either monotherapy group (AMC-109, p = 0.0076; ciprofloxacin, p = 0.0266). To evaluate the innate host response, cytokines and growth factors were quantified. The pro-inflammatory response was dampened in the double-treated mice compared with the mono-ciprofloxacin-treated group (p = 0.0009). Lower mobilisation of neutrophils from the bone marrow was indicated by reduced G-CSF in all treatment groups compared with placebo. Improved tissue remodelling was indicated by the highest level of tissue inhibitor of metalloproteases and low metalloprotease level in the double-treated group. AMC-109 showed adjunctive antipseudomonal abilities augmenting the antimicrobial effect of ciprofloxacin in this wound model. The study indicates a potential role for AMC-109 in treating chronic wounds with complicating biofilm infections.


Misoprostol for the termination of pregnancy up to 12 completed weeks of pregnancy.
The aim was to review the current knowledge about the use of misoprostol alone for abortion induction during the first 12 weeks of pregnancy. Publications reporting experiences with misoprostol alone for pregnancy termination within the first 12 weeks of pregnancy were included in the analysis. Vaginal administration of 800 microg repeated up to three times at 6, 12 or 24 h intervals has an 85% to 90% effectiveness, defined as complete abortion, in most studies. Oral administration is less effective, but sublingual administration at 3-hour interval has the same effectiveness, with more frequent side effects. The oral and sublingual routes appear to be better accepted than vaginal administration. Most studies are limited to the first 9 weeks of pregnancy. The experience on pregnancy termination between 10 and 12 weeks is not yet sufficient for a recommendation.


Cortical blepharoptosis.
A 59-year-old man with a previous left frontal lobe infarction sustained an infarction of the right frontal lobe. The patient manifested a bilateral symmetrical blepharoptosis that resolved in two months. Eyelid movements seem to be bilaterally represented in the frontal lobes. Bilateral cortical disease can produce supranuclear eyelid abnormalities such as blepharoptosis, difficulty maintaining eyelid position, and difficulty initiating eyelid movement.


Isolation of two new genes encoding heat shock protein 70 in Bemisia tabaci and analysis during thermal stress.
The heat shock protein 70 family (HSP70) is among the most varied HSP family with respect to structure and function. The phloem-feeding insect Bemisia tabaci (Gennadius) is an important pest of cotton, vegetables and ornamentals that transmits several plant viruses and causes enormous agricultural losses. In this study, two new HSP70 genes (Bthsp70-2 and Bthsp70-3) were isolated from the MED cryptic species B. tabaci, an important phloem-feeding pest of vegetables and ornamentals. Bthsp70-2 and Bthsp70-3 encoded proteins comprised of 652 and 676 amino acids, and the deduced proteins were closely related to other HSP70s in Hemiptera. Expression analyses using real-time quantitative PCR indicated that Bthsp70-2 and Bthsp70-3 were induced in B. tabaci pupae and adults during high and low thermal stress. Bthsp70-2 and Bthsp70-3 exhibited similar, but not identical, expression patterns when exposed to different durations of high temperature stress. Oral ingestion of dsBthsp70 reduced the expression level of Bthsp70-2 and Bthsp70-3 in B. tabaci and increased the mortality of B. tabaci during heat shock. In conclusion, Bthsp70-2 and Bthsp70-3 exhibit different expression patterns during thermal stress, thus expanding the roles of HSPs in B. tabaci.


Defining risk thresholds for a 10-year probability of hip fracture model that combines clinical risk factors and quantitative ultrasound: results using the EPISEM cohort.
Using a large prospective cohort of over 12,000 women, we determined 2 thresholds (high risk and low risk of hip fracture) to use in a 10-yr hip fracture probability model that we had previously described, a model combining the heel stiffness index measured by quantitative ultrasound (QUS) and a set of easily determined clinical risk factors (CRFs). The model identified a higher percentage of women with fractures as high risk than a previously reported risk score that combined QUS and CRF. In addition, it categorized women in a way that was quite consistent with the categorization that occurred using dual X-ray absorptiometry (DXA) and the World Health Organization (WHO) classification system; the 2 methods identified similar percentages of women with and without fractures in each of their 3 categories, but the 2 identified only in part the same women. Nevertheless, combining our composite probability model with DXA in a case findings strategy will likely further improve the detection of women at high risk of fragility hip fracture. We conclude that the currently proposed model may be of some use as an alternative to the WHO classification criteria for osteoporosis, at least when access to DXA is limited.


What is the rate-limiting step towards aging? Chemical reaction kinetics might reconcile contradictory observations in experimental aging research.
Modern geroscience is divided as regards the validity of the free radical theory of aging. Thermodynamic arguments and observations from comparative zoology support it, whereas results from experimental manipulations in representative animal species sometimes strongly contradict it. From a comparison of the multi-step aging process with a linear metabolic pathway (glycolysis), we here argue that the identification of the rate-limiting kinetic steps of the aging cascade is essential to understand the overall flux through the cascade, i.e., the rate of aging. Examining free radical reactions as a case in point, these reactions usually occur as chain reactions with three kinetically independent steps: initiation, propagation, and termination, each of which can be rate-limiting. Revisiting the major arguments in favor and against a role of free radicals in aging, we find that the majority of arguments in favor point to radical propagation as relevant and rate-limiting, whereas almost all arguments in disfavor are based on experimental manipulations of radical initiation or radical termination which turned out to be ineffective. We conclude that the overall lack of efficacy of antioxidant supplementation (which fosters termination) and antioxidant enzyme overexpression (which inhibits initiation) in longevity studies is attributable to the fact that initiation and termination are not the rate-limiting steps of the aging cascade. The biological and evolutionary plausibility of this interpretation is discussed. In summary, radical propagation is predicted to be rate-limiting for aging and should be explored in more detail.


Cardiovascular risk prediction model and stratification in patients with type 2 diabetes enrolled in a Medicare Advantage plan.
BACKGROUND: Cardiovascular (CV) risk tools have been developed both nationally and internationally to identify patients at risk for developing CV disease or experiencing a CV event. However, these tools vary widely in the definitions of endpoints, the time at which the endpoints are measured, patient populations, and their validity. The primary limitation of some of the most commonly utilized tools is the lack of specificity for a type 2 diabetes (T2D) population and/or among older patients. OBJECTIVE: To develop a predictive model within an older population of patients with T2D to identify patients at risk for CV events. METHODS: This retrospective cohort study used claims, laboratory, and enrollment data during the 2011-2018 study period. Patients with T2D were identified based on diagnoses and/or medications from 2012-2013. The patient cohort was split into 3 different datasets. The holdout dataset included only those patients residing in the northeastern United States. The rest of the sample was then randomly split: 70% for the training dataset, which were used to fit the predictive model, and 30% for the test dataset to assess internal validity. The primary outcome was the first composite CV event defined as at least 1 of the following: inpatient hospitalization for myocardial infarction, ischemic stroke, unstable angina, or heart failure; or any evidence of revascularization. A survival model for the composite outcome was fitted with baseline demographic and clinical characteristics prognostic for the dependent variable utilizing augmented backwards elimination. For assessing model performance, accuracy, sensitivity, specificity, and the c-statistic were used. Patients were ranked as having a low, moderate, or high probability of a future CV event. RESULTS: A total of 362,791 patients were identified. The holdout dataset included only those patients residing in the northeastern United States (n = 8,303). There were 248,142 patients included in the training dataset and 106,346 patients in the test dataset. The proportion with at least 1 observed composite CV event was 20.9%. The final model included 42 variables. The c-statistic was 0.68, and the accuracy, sensitivity, and specificity were approximately 63%. Results were consistent across the training, test, and holdout samples. The optimal cut points minimizing the difference in sensitivity and specificity for low-, moderate-, and high-risk future CV events were determined to be less than 0.18, 0.18-0.63, and greater than 0.63, respectively, in the training dataset at 5 years. The 5-year observed event risk was 11%, 27%, and 51% for patients classified as low, moderate, and high risk of a future CV event, respectively. CONCLUSIONS: A model predicting CV events among older patients with T2D using administrative claims to identify those at risk may be used for focusing interventions to prevent future events. DISCLOSURES: This study was funded by Boehringer Ingelheim (BI) and conducted as part of the BI-Humana Research Collaboration. Caplan is employed by Humana Healthcare Research, Inc., a wholly owned subsidiary of Humana Inc., which received fees to conduct the study from the sponsor BI. At the time of the study, Hayden and Harvey were employees of Humana Healthcare Research, Inc. Additionally, Prewitt, who owns stock in Humana Inc, and Chiguluri are employees of Humana Inc. Kattan, associated with the Cleveland Clinic in Ohio, served as a consultant to BI, and Pimple and Goss are employees of BI. Luthra was employed by BI for the duration of the study. Portions of this work were accepted as an abstract and presented as a poster at the American Diabetes Association 2020 virtual meeting, June 12-16, 2020.


The action of phenylarsine oxide on the stereospecific uptake of D-glucose in basal and insulin-stimulated rat adipocytes.
Phenylarsine oxide (PAO) has been used to inhibit the stereospecific uptake of D-glucose in basal and insulin-stimulated rat adipocytes. The inhibition is dose dependent and is partially reversed by dithiothreitol. The results are consistent with a direct interaction between the glucose transporter and PAO. By manipulating the sequence of exposure of cells to PAO and insulin it is possible to differentiate between the effects of PAO on transport into cells with receptor-rich and transporter-rich plasma membranes. PAO rapidly inhibits transport in insulin-stimulated adipocytes but at low concentrations inhibition is transient and recovery of stereospecific uptake takes place after approx. 20 min. The results can be interpreted in terms of the recruitment mechanism of insulin stimulation of transport and demonstrate that a relatively large intracellular pool of transporters exists after insulin stimulation. It also follows that sulphydryl groups probably play a critical role in the mechanism of glucose uptake.


SMN protects cells against mutant SOD1 toxicity by increasing chaperone activity.
Deletion or mutation of the survival of motor neuron (SMN1) gene causes Spinal Muscular Atrophy (SMA), a motor neuron degenerative disease. To study the SMN function, we co-transfected mouse NSC34 cells with SMN and mutant superoxide dismutase 1 (SOD1) constructs. We demonstrated that SMN protected NSC34 cells against cell death induced by mutant SOD1 under oxidative stress. Further studies indicated that over-expression of wild-type SMN up-regulated chaperone activity. In contrast, chaperone activity was decreased in cells expressing SMN mutant Y272C or in cells with SMN suppressed by shRNA. In vitro assays using bacteria lysates expressing GST-SMN or purified GST-SMN protein showed that the GST-SMN reduced catalase aggregation, indicating that SMN may possess chaperone activity. We conclude that SMN plays a protective role in motor neurons by its chaperone activity. Our results provide support for the potential development of therapy for SMA and amyotrophic lateral sclerosis (ALS).


Quantifying Perfusion Properties with DCE-MRI Using a Dictionary Matching Approach.
Perfusion properties can be estimated from pharmacokinetic models applied to DCE-MRI data using curve fitting algorithms; however, these suffer from drawbacks including the local minimum problem and substantial computational time. Here, a dictionary matching approach is proposed as an alternative. Curve fitting and dictionary matching were applied to simulated data using the dual-input single-compartment model with known perfusion property values and 5 in vivo DCE-MRI datasets. In simulation at SNR 60 dB, the dictionary estimate had a mean percent error of 0.4-1.0% for arterial fraction, 0.5-1.4% for distribution volume, and 0.0% for mean transit time. The curve fitting estimate had a mean percent error of 1.1-2.1% for arterial fraction, 0.5-1.3% for distribution volume, and 0.2-1.8% for mean transit time. In vivo, dictionary matching and curve fitting showed no statistically significant differences in any of the perfusion property measurements in any of the 10 ROIs between the methods. In vivo, the dictionary method performed over 140-fold faster than curve fitting, obtaining whole volume perfusion maps in just over 10 s. This study establishes the feasibility of using a dictionary matching approach as a new and faster way of estimating perfusion properties from pharmacokinetic models in DCE-MRI.


Creating Age-Friendly Communities: Housing and Technology.
Taking an international perspective of healthy ageing, people are living longer and are generally in better health than previous generations [...].


Changes in search rate but not in the dynamics of exogenous attention in action videogame players.
Many previous studies have shown that the speed of processing in attentionally demanding tasks seems enhanced following habitual action videogame play. However, using one of the diagnostic tasks for efficiency of attentional processing, a visual search task, Castel and collaborators (Castel, Pratt, & Drummond, Acta Psychologica 119:217-230, 2005) reported no difference in visual search rates, instead proposing that action gaming may change response execution time rather than the efficiency of visual selective attention per se. Here we used two hard visual search tasks, one measuring reaction time and the other accuracy, to test whether visual search rate may be changed by action videogame play. We found greater search rates in the gamer group than in the nongamer controls, consistent with increased efficiency in visual selective attention. We then asked how general the change in attentional throughput noted so far in gamers might be by testing whether exogenous attentional cues would lead to a disproportional enhancement in throughput in gamers as compared to nongamers. Interestingly, exogenous cues were found to enhance throughput equivalently between gamers and nongamers, suggesting that not all mechanisms known to enhance throughput are similarly enhanced in action videogamers.


Probing the interactions of the solvated electron with DNA by molecular dynamics simulations: II. bromodeoxyuridine-thymidine mismatched DNA.
The interaction of solvated electrons (e(-)(aq)) with DNA results in various types of DNA lesions. The in vitro and in vivo sensitisation of DNA to (e(-)(aq))-induced damage is achieved by incorporation of the electron-affinity radiosensitiser bromodeoxyuridine (BUdR) in place of thymidine. However, in DNA duplexes containing single-stranded regions (bulged BUdR-DNA), the type of lesion is different and the efficiency of damage is enhanced. In particular, DNA interstrand crosslinks (ICL) form at high efficiency in bulged DNA but are not detectable in completely duplex DNA. Knowledge about the processes and interactions leading to these differences is obscure. Previously, we addressed the problem by applying molecular modelling and molecular dynamics (MD) simulations to a system of normal (BUdR.A)-DNA and a hydrated electron, where the excess electron was modelled as a localised e(-)(H2O6) anionic cluster. The goal of the present study was to apply the same MD simulation to a wobble DNA-e(-)(aq) system, containing a pyrimidine-pyrimidine mismatched base pair, BUdR.T. The results show an overall dynamic pattern similar to that of the e(-)(aq) motion around normal DNA. However, the number of configuration states when e(-)(aq)) was particularly close to DNA is different. Moreover, in the (BUdR.T)-wobble DNA system, the electron frequently approaches the brominated strand, including BUdR, which was not observed with the normal (BUdR.A)-DNA. The structure and exchange of water at the sites of e(-)(aq) immobilisation near DNA were also characterised. The structural dynamics of the wobble DNA is prone to more extensive perturbations, including frequent formation of cross-strand (cs) interatomic contacts. The structural deviations correlated with e(-)(aq) approaching DNA from the major groove side, with sodium ions trapped deep in the minor groove. Altogether, the obtained results confirm and/or throw light on dynamic-structure determinants possibly responsible for the enhanced radiation damage of wobble DNA.


Role of extracellular polymeric substances in biofilm formation by Pseudomonas stutzeri strain XL-2.
Pseudomonas stutzeri strain XL-2 exhibited significant performance on biofilm formation. Extracellular polymeric substances (EPS) secreted by strain XL-2 were characterized by colorimetry and Fourier transform infrared (FT-IR) spectroscopy. The biofilm growth showed a strong positive correlation (rP=0.96, P<0.01) to extracellular protein content, but no correlation to exopolysaccharide content. Hydrolyzing the biofilm with proteinase K caused a significant decrease in biofilm growth (t=3.7, P<0.05), whereas the changes in biofilm growth were not significant when the biofilm was hydrolyzed by α-amylase and β-amylase, implying that proteins rather than polysaccharides played the dominant role in biofilm formation. More specifically, confocal laser scanning microscopy (CLSM) revealed that the extracellular proteins were tightly bound to the cells, resulting in the cells with EPS presenting more biofilm promotion protein secondary structures, such as three-turn helices, β-sheet, and α-helices, than cells without EPS. Both bio-assays and quantitative analysis demonstrated that strain XL-2 produced signal molecules of N-acylhomoserine lactones (AHLs) during biofilm formation process. The concentrations of C6-HLS and C6-oxo-HLS were both significantly positively correlated with protein contents (P<0.05). Dosing exogenous C6-HLS and C6-oxo-HLS also resulted in the increase in protein content. Therefore, it was speculated that C6-HLS and C6-oxo-HLS released by strain XL-2 could up-regulate the secretion of proteins in EPS, and thus promote the formation of biofilm.


Noble gases confirm plume-related mantle degassing beneath Southern Africa.
Southern Africa is characterised by unusually elevated topography and abnormal heat flow. This can be explained by thermal perturbation of the mantle, but the origin of this is unclear. Geophysics has not detected a thermal anomaly in the upper mantle and there is no geochemical evidence of an asthenosphere mantle contribution to the Cenozoic volcanic record of the region. Here we show that natural CO2 seeps along the Ntlakwe-Bongwan fault within KwaZulu-Natal, South Africa, have C-He isotope systematics that support an origin from degassing mantle melts. Neon isotopes indicate that the melts originate from a deep mantle source that is similar to the mantle plume beneath Réunion, rather than the convecting upper mantle or sub-continental lithosphere. This confirms the existence of the Quathlamba mantle plume and importantly provides the first evidence in support of upwelling deep mantle beneath Southern Africa, helping to explain the regions elevation and abnormal heat flow.


Adeno-associated virus (AAV) cell entry: structural insights.
Adeno-associated virus (AAV) is the leading vector in emerging treatments of inherited diseases. Higher transduction efficiencies and cellular specificity are required for broader clinical application, motivating investigations of virus-host molecular interactions during cell entry. High-throughput methods are identifying host proteins more comprehensively, with subsequent molecular studies revealing unanticipated complexity and serotype specificity. Cryogenic electron microscopy (cryo-EM) provides a path towards structural details of these sometimes heterogeneous virus-host complexes, and is poised to illuminate more fully the steps in entry. Here presented, is progress in understanding the distinct steps of glycan attachment, and receptor-mediated entry/trafficking. Comparison with structures of antibody complexes provides new insights on immune neutralization with implications for the design of improved gene therapy vectors.


Experiments of the origins of optical activity.
Two recent reports claim that (1) aqueous L-aspartic acid polymerizes faster than D-Asp in the presence of kaolin at 90 degrees, and (2) L-phenylalanine is adsorbed by kaolin more extensively than D-Phe at pH 4(the reverse being true at pH2). The novelty of these observations and their potential significance for the origin of optical activity has prompted us to duplicate these experiments using more sensitive methods. L- and D, L-Asp in 0.01 M solution were incubated with kaolin at 90 degrees for 8 days. Careful examination of the aqueous residues from such experiments failed to demonstrate any preferential polymerization of L-Asp over D-Asp, or indeed any significant gross polymerization of Asp at all. In other experiments 0.001 M solutions of D, L-Phe at pH 6 and pH 2 were stirred with large excesses of kaolin for 24 hr, and the aqueous extracts from these mixtures were examined for gross adsorption using the amino acid analyzer. No significant gross adsorption was noted. We then looked for asymmetric adsorption in the aqueous residues using optical rotatory dispersion, gas chromatography and thin layer chromatography. By none of these analytical criteria could we find any evidence whatsoever for the preferential adsorption of D- versus L-Phe from either pH 6 or pH 2 solutions. Finally, in experiments bearing on the origin of optical activity by parity violation during beta-decay, we have irradiated solid samples of D-, L- and D,L-leucine in a 61700 Ci Sr-90 source at Oak Ridge National Lab. for 1.34 yr (total dose: 4.2 x 10(8) rad). Gas chromatographic examination of the (appropriately derivitized) recovered samples showed that the L-Leu was 16.7% decomposed, the D-Leu 11.4% and theD,L-Leu 13.8% decomposed. The recovered D,L-Leu sample had a gas-chromatographically determined enantiomeric composition of 50.8% D-leu and 49.2% L-Leu. These data, though very close to experimental error, may indicate a slight preferential radiolysis of L-Leu compared to D-Leu by the Bremsstrahlung from Sr-90 beta-decay. These high intensity irradiation experiments are being continued on a prolonged basis in order to reach more definitive conclusions.


Screening for partner violence in the early postpartum period: are we missing families most at risk of experiencing violence?
In Manitoba, government policy is for public health nurses to screen families with newborns within 1-week post-discharge for risk factors associated with poor child developmental health. The purpose of this study was to compare the characteristics of families who are screened for intimate partner violence (IPV) with families without a documented response to an IPV screen item. This information can be used to help identify and target families in need of support whose needs are not being met within the current system. Manitoban women giving birth to a live singleton in the province from January 1, 2003 to December 31, 2006 were included in the analyses (N = 52,710). Data were part of a larger research study following these families for several years to examine longer-term developmental outcomes. Administrative databases from the Manitoba Centre for Health Policy provided data for the study. Descriptive statistics and logistic regression were used to examine relationships between IPV screen status and socio-demographic covariates and birth outcomes. In the study population, 66.7% of the sample were screened for IPV. Women less than 20 years of age, not in married or common-law unions, and living in lower income areas were less likely to have a documented response to the IPV screen item. A low number of prenatal care visits, prenatal mental health problems, and prenatal substance use, as well as premature and low birthweight delivery, were associated with a decreased likelihood of having a documented response to the IPV screen item. Incorporating violence screening into routine prenatal and postnatal care, rather than only screening women after birth, may help to better identify families with unmet needs and ensure more timely referrals to positive strengths-based supports and services.


Baculoviral p35 inhibits oxidant-induced activation of mitochondrial apoptotic pathway.
In this study we report that the baculovirus p35 anti-apoptotic protein prevents cell death by quenching free radicals at a very upstream step in the apoptotic pathway. Mitochondria of activated rat peritoneal macrophages as well as Spodoptera frugiperda (Sf9) insect cells, following treatment with oxidants, H(2)O(2)/UVB irradiation, release cytochrome c followed by activation of caspase-3. Transfection of macrophages/Sf9 cells with a construct carrying the p35 gene under the CMV/HSP promoters resulted in p35 expression and consequent arrest of oxidative stress-induced apoptosis. p35 expression also inhibited cytochrome c release from the mitochondria of oxidant-exposed cells and blocked caspase-3 activation.


Feasibility of energy-guided short duration protocol of laser balloon based pulmonary vein isolation for atrial fibrillation (EG-Laser Study).
Laser balloon-based pulmonary vein isolation (LB-PVI) is available for atrial fibrillation (AF) ablation. The lesion size depends on laser energy; however, the default protocol is not an energy-based setting. We hypothesized that an energy-guided (EG) short-duration protocol may be an alternative to shorten the procedure time without affecting efficacy and safety. We evaluated the efficacy and safety of the EG short-duration protocol (EG group) (target energy 120 J/site [12W/10s; 10W/12s; 8.5W/14s; 5.5W/22s]) compared with the default protocol (control group) (12W/20s; 10W/20s; 8.5W/20s; 5.5W/30s). A total of 52 consecutive patients (EG: n = 27 [103veins] and control: n = 25 [91veins]) undergoing LB-PVI (64 ± 10 years, 81% male, 77% paroxysmal) were enrolled. The EG group had a shorter total time in the pulmonary vein (PV) (43.0 ± 13.9 min vs. 61.1 ± 16.0 min, p < .0001), a shorter total laser application time (1348 ± 254 sec vs. 2032 ± 424 sec, p < .0001), and lower total laser energy (12455 ± 2284J vs. 18084 ± 3746J, p < .0001). There was no difference in the total number of laser applications (p = 0269) or first-pass isolation (p = .725). Acute reconduction was identified only in one vein in the EG. No significant differences were observed in the incidence of pinhole rupture (7.4% vs. 4%, p = 1.000) or phrenic nerve palsy (3.7% vs. 12%, p = .341). During a mean follow-up of 13.5 ± 6.1 months, Kaplan-Meier analysis revealed no significant difference in atrial tachyarrhythmia recurrence (p = .227). LB-PVI with the EG short-duration protocol may be achieved in a shorter procedure time to avoid deterioration of efficacy and safety. The EG protocol is feasible as a novel point-by-point manual laser-application approach.


Epstein-Barr virus-induced gene 3 (EBI3) polymorphisms and expression are associated with susceptibility to pulmonary tuberculosis.
Tuberculosis (TB) remains a major global health problem and host genetic factors play a critical role in susceptibility and resistance to TB. The aim of this study was to identify novel candidate genes associated with TB susceptibility. We performed a population-based case-control study to genotype 13 tag SNPs spanning Epstein-Barr virus-induced gene 3 (EBI3), colony stimulating factor 2 (CSF2), IL-4, interferon beta 1 (IFNB1), chemokine (C-X-C motif) ligand 14 (CXCL14) and myeloid differentiation primary response gene 88 (Myd88) genes in 435 pulmonary TB patients and 375 health donors from China. We observed that EBI3 gene rs4740 polymorphism was associated with susceptibility to pulmonary tuberculosis (PTB) and the allele G was associated with a protective effect against PTB. Furthermore, EBI3 deficiency led to reduced bacterial burden and histopathological impairment in the lung of mice infected with Mycobacterium bovis BCG. Meanwhile, higher abundance of EBI3 was observed in the granuloma of PTB patients and in the lung tissue of BCG-infected mice. Of note, the expression of EBI3 in macrophages was remarkably induced by mycobacteria infection at both mRNA and protein level. In conclusion, EBI3 gene rs4740 polymorphism is closely associated with susceptibility to PTB and the elevation and enrichment of EBI3 in the lung which at least partially derived from macrophages may contribute to the exacerbation of mycobacterial infection.


Serum Vitamin D Level and Erectile Dysfunction in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.
A few studies involved the relationship between vitamin D and diabetes mellitus (DM) with erectile dysfunction (ED), and no meta-analysis was conducted to pool these data. The main purpose of our study was to examine the changes in serum vitamin D levels in patients with DM combined with ED. An extensive search was performed, including the following words: "erectile dysfunction," "diabetes," and "vitamin D." Databases, including Cochrane Library, PubMed, and Web of Science, were retrieved to identify studies published up to September 30, 2021. Four studies were eligible for our meta-analysis. The weighted mean difference and their corresponding 95% confidence intervals were calculated to the data we selected. The results showed that the level of vitamin D in DM with ED was significantly lower (12.5 nmol/mL) than patients with diabetes alone (p = 0.002). Our novel meta-analysis suggests that vitamin D may be a risk factor for DM with ED, which can provide a new idea for the treatment and prevention of DM with ED.


Expression of glial cell line-derived neurotrophic factor mRNA in the human newborn and adult hippocampal formation.
Glial cell line-derived neurotrophic factor (GDNF) mRNA-containing neurons were found in normal neonate and adult human hippocampus with a localization pattern consistently similar among different ages. They were numerous in proximal CA1 to CA3 pyramidal layer, granular layer and hilus, and sparse in oriens and molecular layers. The present data provide a map of GDNF-producing neurons in the human archicortex and suggest a role for GDNF in neuronal function throughout life.


Dual-Stream Subspace Clustering Network for revealing gene targets in Alzheimer's disease.
The rapid development of scRNA-seq technology in recent years has enabled us to capture high-throughput gene expression profiles at single-cell resolution, reveal the heterogeneity of complex cell populations, and greatly advance our understanding of the underlying mechanisms in human diseases. Traditional methods for gene co-expression clustering are limited to discovering effective gene groups in scRNA-seq data. In this paper, we propose a novel gene clustering method based on convolutional neural networks called Dual-Stream Subspace Clustering Network (DS-SCNet). DS-SCNet can accurately identify important gene clusters from large scales of single-cell RNA-seq data and provide useful information for downstream analysis. Based on the simulated datasets, DS-SCNet successfully clusters genes into different groups and outperforms mainstream gene clustering methods, such as DBSCAN and DESC, across different evaluation metrics. To explore the biological insights of our proposed method, we applied it to real scRNA-seq data of patients with Alzheimer's disease (AD). DS-SCNet analyzed the single-cell RNA-seq data with 10,850 genes, and accurately identified 8 optimal clusters from 6673 cells. Enrichment analysis of these gene clusters revealed functional signaling pathways including the ILS signaling, the Rho GTPase signaling, and hemostasis pathways. Further analysis of gene regulatory networks identified new hub genes such as ELF4 as important regulators of AD, which indicates that DS-SCNet contributes to the discovery and understanding of the pathogenesis in Alzheimer's disease.


[The "two positions" lipoabdominoplasty].
Lipoabdominoplasty is a way to improve morphological outcomes by treating the areas not accessible to resection during classical abdominoplasty, especially hips. However, patients can present a lateral and posterior fat extension, not accessible to an anterior liposuction. This situation is managed by a first step with liposuction in the prone position. The aim of this study was to determine whether lipoabdominoplasty performed in two positions increases morbidity compared with lipoabdominoplasty in supine position only. This was a retrospective study of 137 patients who underwent lipoabdominoplasty between 2009 to 2013. Eighty-five patients underwent a one position lipoabdomynoplasty and 52 a two positions lipoabdomynoplasty. Medical records were reviewed to collect data regarding patient demographics, operative technique, volume of liposuction and complications. The posterior liposuction has significantly increased the length of procedure (mean: 43.3 minutes). The volume of liposuction was significantly higher when the procedure was performed with prone and supine position (2789.6 mL versus 1373.8 mL, P<0.001). There was no significant difference between the two groups regarding complications and blood loss. Lipoabdominoplasty in two positions is an effective technique with the same morbidity as a lipoabdominoplasty in supine position only. The procedure finds its indication, between classic abdominoplasty and bodylift, for patients with lateral and posterior fat extension without posterior skin excess.


The diagnostic utility of EZH2 H-score and Ki-67 index in non-invasive breast apocrine lesions.
In diagnostic breast pathology, there is no reliable applicable immunostain to help discern atypical and in situ apocrine lesions from benign apocrine tissue. At present, the diagnosis of non-invasive apocrine lesions remains challenging with current diagnoses rendered based on discrete morphologic characteristics on conventional hematoxylin and eosin staining. Interobserver variability is significant even among subspecialists partly due to lack of adjuvant diagnostic immunohistochemical stains. Herein, we set to elucidate the potential utility of EZH2 and Ki-67 immunostains as tangible tools in non-invasive apocrine proliferations. A cohort of apocrine breast lesions [Benign apocrine hyperplasia (BAH), n = 10; Atypical apocrine hyperplasia (AAH), n = 16; Apocrine ductal carcinoma in situ (ADCIS), n = 12] were subjected to EZH2 immunostaining and analyzed via H-scoring of nuclear expression. Mean H-scores for EZH2 progressively increased from BAH (23.5), to AAH (47.4) and ADCIS (196.4), and showed a significant difference utilizing the Kruskal-Wallis test (p < 0.0001). Further interrogation of Ki-67 demonstrated incremental expression from BAH to AAH and ADCIS at 1.6 %, 4.7 % and 24.7 %, respectively (p < 0.0001, Kruskal-Wallis test), suggesting an association with increased proliferation. Our results demonstrate that a combination of EZH2 and Ki-67 immunostaining may be employed in differentiating among challenging apocrine breast lesions and suggest a putative diagnostic utility for EZH2 and Ki-67 in non-invasive apocrine breast lesions.


Challenge with mammary tumor cells expressing MHC class II and CD80 prevents the development of spontaneously arising tumors in MMTV-neu transgenic mice.
The HER-2/Neu oncogene has been implicated in human and mouse breast cancer. Indeed, transgenic MMTV-neu mice expressing this oncogene from the mammary tumor virus long terminal repeat develop spontaneous mammary tumors and die within 1 year of life. We have expressed the class II transactivator (CIITA) and/or the costimulatory molecule CD80 (B7.1) in a mammary carcinoma cell line (MCNeuA) derived from these mice. Class II transactivator directs the expression of MHC class II and the machinery for antigen processing and presentation by this pathway. When injected into MMTV-neu mice, tumor cells expressing CD80 or CD80 and CIITA, were rejected completely. In addition, following the rejection of dual expressing cells, 75% of the mice were protected against the development of subsequent spontaneous tumors. Cells expressing only CD80 or CIITA were not as effective as antitumor vaccines in preventing the development of spontaneous tumors. Thus, converting cancer cells into antigen presenting cells could represent an effective immunotherapy for breast cancer.


Assistive Devices for Personal Mobility in Parkinson's Disease: A Systematic Review of the Literature.
Gait abnormalities are a hallmark of Parkinson's disease and contribute to falling risk. As disease symptoms progress, assistive devices are often prescribed. However, there are no guidelines for choosing appropriate ambulatory devices for gait impairment. To review the scientific evidence on assistive devices for gait impairment in Parkinson's disease. We performed a systematic literature review for articles relating to parkinsonian gait impairment and assistive devices. We assessed the studies' methodological quality and risk of bias using the PEDro scale. Seventeen articles were reviewed. Four articles (23.53%) showed that canes and standard and two-wheeled walkers without visual cues decreased gait speed and stride length, with no significant effects on freezing of gait or falls. Instead, improvements were observed with the use of visual [seven articles (41.18%)] and auditory cues [three articles (17.65%)], including decreased number of freezing episodes and increased stride length. Although assistive devices seem to improve confidence, there is still limited information about the efficacy of assistive devices on gait parameters and functional disability in Parkinson's disease. Further, longitudinal, multicenter, randomized, blinded, and controlled studies using assistive devices in a free-living context are required to provide the best scientific evidence.


Assessment of HbA1c as a diagnostic tool in diabetes and prediabetes.
To evaluate HbA1c as a diagnostic tool in prediabetes-impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), and newly detected diabetes (NDD), defined by plasma glucose and OGTT. 2,231 subjects, of mean age 50.3 ± 13.9 years and mean BMI 29.5 ± 6.2 kg/m(2), underwent an OGTT. HbA1c performance was assessed using the area under the receiver operating characteristics curve (AUC-ROC). HbA1c was significantly higher in all groups with altered glucose tolerance-5.72 ± 0.61% in IFG, 5.84 ± 0.63% in IGT, and 7.5 ± 1.69% in NDD when compared to normal glucose tolerance-5.23 ± 0.65% (P < 0.0001). HbA1c of both prediabetic groups was significantly lower in comparison with NDD (P < 0.0001); in IGT being significantly higher than in IFG (P = 0.02). ROC analysis demonstrated good performance of HbA1c for diagnosing diabetes-AUC-ROC 0.958 (95% CI: 0.946-0.970), as well as prediabetes-AUC-ROC 0.729 (95% CI: 0.702-0.755). The optimal cut-off level of HbA1c for diagnosing diabetes was 6.1% (sensitivity 86%, specificity 92%) and for undiagnosed prediabetes-5.5% (sensitivity 71%, specificity 64%). HbA(1c) appears to be a useful, convenient, and reliable tool for identifying subjects with prediabetes and diabetes and should be considered in the development of diagnostic strategies.


Different effects of the selective serotonin reuptake inhibitors fluvoxamine, paroxetine, and sertraline on the pharmacokinetics of fexofenadine in healthy volunteers.
Although the interaction between selective serotonin reuptake inhibitors (SSRIs) and other drugs is important in the treatment of depression, there have been few studies of SSRIs concerning transporter-mediated interactions in humans. The objective of this study was to evaluate the in vivo effects of commonly used SSRIs on the pharmacokinetics of fexofenadine, a P-glycoprotein substrate.Twelve healthy volunteers (3 females and 9 males) were enrolled in this study. Each subject received a 60-mg dose of fexofenadine orally at baseline. Afterward, they were randomly assigned to receive 3 treatments with a 60-mg dose of fexofenadine after a 7-day treatment with fluvoxamine (50 mg/d), paroxetine (20 mg/d), or sertraline (50 mg/d), with 2-week intervals between the agents.Fluvoxamine pretreatment significantly increased the maximum plasma concentration, the area under the concentration time curves, and the 24-hour urinary fexofenadine excretion by 66% (P = 0.004), 78% (P = 0.029), and 78% (P < 0.001), respectively, without prolonging its elimination half-life. Paroxetine extended the elimination half-life of fexofenadine by 45% (P = 0.042), and it increased the 24-hour urinary fexofenadine excretion by 55% (P = 0.002). Sertraline did not alter any of the pharmacokinetic parameters of fexofenadine.This is the first report of the different effects of 3 commonly used SSRIs on fexofenadine pharmacokinetics in humans. Our 7-day, repeated-dose clinical study in healthy volunteers indicates that fluvoxamine and paroxetine, but not sertraline, may impact the patient exposure to fexofenadine, which is likely the result of P-glycoprotein inhibition in the small intestine and/or the liver.


Exposure histories derived from selenium in otoliths of three cold-water fish species captured downstream from coal mining activity.
Establishing exposure to contaminants within a given environment is often difficult for fish species with large home ranges. Chemical analyses of muscle or visceral tissue are useful indicators of recent exposure, but depuration, metabolic transformation, and tissue redistributions can alter temporal resolution. Otoliths are metabolically stable and thus provide complete chemical records within their calcified tissues that, when coupled to the annular structure, can provide temporal resolution for exposure to trace metals. Otoliths from bull trout, cutthroat trout, and mountain whitefish from an area rich in seleniferous soils and with active coal mining activity were analyzed for selenium to determine any history of exposure to elevated levels of selenium. Selenium concentrations in otolith primordia tended to be low, indicating that these fish emerged in low selenium areas. Later life stages showed peaks of high Se concentrations, suggesting that individuals moved into areas of increased selenium later in life. Individuals captured from the same area had a wide variety of selenium exposure profiles, indicating that these fish do not move en masse into and out of high-selenium areas. Year-to-year variability of selenium exposure patterns within an otolith suggests inconsistent utilization of high- and low-selenium areas by the individual. The inconsistent exposure profiles for these fish, in addition to their home range of tens of kilometres, indicate that soft tissue concentrations, while useful indicators of recent exposure, cannot be relied upon to provide a life history recording of exposure.


Concurrent elimination and stepwise recovery of Pb(II) and bisphenol A from water using β-cyclodextrin modified magnetic cellulose: adsorption performance and mechanism investigation.
Coexistence of heavy metals and endocrine disrupting compounds in polluted water with competitive adsorption behavior necessitates design of tailored adsorbents. In this work, β-cyclodextrin modified magnetic rice husk-derived cellulose (β-CD@MRHC) which can provide independent functional sites for effectively binding the above two types of contaminants was synthesized and used for Pb(II) and BPA elimination in both unit and multivariate systems. Characterizations results confirmed successful β-CD grafting and Fe3O4 loading, and the β-CD@MRHC had excellent magnetic property for its effectively recovery from water, which was not affected by the adsorption of pollutants. The β-CD@MRHC possessed superior adsorption performance with maximal Pb(II)/BPA uptake of 266.2 or 412.8 mg/g, severally, and the adsorption equilibrium was fleetly reached in 30 and 7.5 min. Moreover, the β-CD@MRHC could accomplish synergetic Pb(II) and BPA elimination through averting their competitive behaviors owing to diverse capture mechanisms for Pb(II) (ion exchange, complexation and electrostatic attraction) and BPA (hydrogen bonding and host-guest inclusion). Furthermore, after three cycles of step-wise desorption, the binding of Pb(II) as well as BPA byβ-CD@MRHC dropped slightly in dualistic condition. In summary, β-CD@MRHC was a promising tailored adsorbent to practical application for simultaneously removing heavy metals and organic matters from wastewater with high-performance magnetic recovery.


Identification of two theranostic biomarker panels for epithelial ovarian cancer.
Epithelial Ovarian cancer (EOC) is the leading cause of death associated with gynecologic tumors. Because the disease is asymptomatic in early-stage, the majority of patients are not diagnosed until late stages, highlighting the need for the development of novel diagnostic biomarkers. Mediators of tumoral microenvironment may affect EOC progression and resistance to treatment. Analysis of serum proteins to identify a panel of theranostic biomarkers for EOC. Serum levels of 65 analytes were determined in EOC patients, and healthy controls with the ProcartaPlex Human Immune Monitoring 65-Plex Panel. Twenty-one analytes: 7 cytokines (IFN-γ, IL-12p70, IL-13, IL-18 and TSLP), 7 chemokines (Eotaxin, eotaxin-2, IP-10, BLC, I-TAC, SDF-1α, and fractalkine), 2 growth factors (MMP-1, VEGF-α), and 5 soluble receptors (APRIL, CD40L, TWEAK, CD30 and TNFRII; were significantly differentially expressed between the two groups. ROC curves showed that only seven of them (IL-9, TNF-α, Eotaxin, IP-10, BLC, Fractalkine, and Tweak) had AUC values greater than 0.70 and thus had potential clinical utility. Moreover, five cytokines: IFN-γ, IL-1 β, IL-8, MIP-1β, and TNF-α are positively associated with patients who developed resistance to taxol-platinum-based chemotherapy (CT). This study has revealed a first panel of 7 analytes (IL-9, TNF-α, Eotaxin, IP-10, BLC, Fractalkine and Tweak) that can be used for early detection of EOC and a second panel of five cytokines (IFN-γ, IL-1β, IL-8, MIP-1β, TNF-α) that can help clinicians to identify EOC patients who are at higher risk to develop resistance to CT of EOC.


Tracheobronchitis in ulcerative colitis: a case report of therapeutic response with infliximab and review of the literature.
The extra-intestinal manifestation of tracheobronchitis is a rare complication of ulcerative colitis (UC). Here, we present a case of UC-related tracheobronchitis wherein the positive clinical effects of infliximab are demonstrated. We report the case of a 39-year old woman who presented with a chronic productive cough on a distant background of surgically managed ulcerative colitis (UC). Our patient failed to achieve a satisfactory clinical improvement despite treatment with high dose inhaled corticosteroids, oral corticosteroids and azathioprine. Infliximab therapy was commenced and was demonstrated to achieve macroscopic and symptomatic remission of disease. We present the first case report documenting the benefits of infliximab in UC-related tracheobronchitis.


Molinate quantification in environmental water by a glutathione-S-transferase based biosensor.
A glutathione-S-transferase (GST) based biosensor was developed to quantify the thiocarbamate herbicide molinate in environmental water. The biosensor construction was based on GST immobilization onto a glassy carbon electrode via aminosilane-glutaraldehyde covalent attachment. The principle supporting the use of this biosensor consists of the GST inhibition process promoted by molinate. Differential pulse voltammetry was used to obtain a calibration curve for molinate concentration, ranging from 0.19 to 7.9 mg L(-1) and presenting a detection limit of 0.064 mg L(-1). The developed biosensor is stable, and reusable during 15 days. The GST-based biosensor was successfully applied to quantify molinate in rice paddy field floodwater samples. The results achieved with the developed biosensor were in accordance with those obtained by high performance liquid chromatography. The proposed device is suitable for screening environmental water analysis and, since no sample preparation is required, it can be used in situ and in real-time measurements.


Presenteeism and absenteeism before and after single-level lumbar spine surgery.
Health can impact work performance through absenteeism, time spent away from work, and presenteeism, inhibited at-work performance. Low back pain is common and costly, both in terms of direct medical expenditures and indirect reduced work performance. Surgery for lumbar spinal pathology is an important part of treatment for patients who do not respond to nonsurgical management. While the indirect costs of return to work and absenteeism among employed patients undergoing lumbar spine surgery have been studied, little work has been done to quantify presenteeism before and after lumbar spine surgery. Prospective cohort study at a single high-volume urban musculoskeletal specialty hospital. Patients undergoing single-level lumbar spinal fusion and/or decompression surgery. Presenteeism and absenteeism were measured using the World Health Organization's Health and Work Performance Questionnaire before surgery, as well as 6 weeks, 6 months, and 12 months after surgery. Average presenteeism and absenteeism were evaluated at pre-surgical baseline and each follow-up timepoint. Monthly average time lost to presenteeism and absenteeism were calculated before surgery and 12 months after surgery. Study data were collected and managed using REDCap electronic data capture tools with support from Clinical and Translational Science Center grant, UL1TR002384. One author discloses royalties, private investments, consulting fees, speaking/teaching arrangements, travel, board of directorship, and scientific advisory board membership totaling >$300,000. We enrolled 134 employed surgical patients, among whom 115 (86%) responded at 6 weeks, 105 (78%) responded at 6 months, and 115 (86%) responded at 12 months. Preoperatively, mean age was 56.4 years (median 57.5), and 41.0% were women; 68 (50.7%) had only decompressions, while 66 (49.3%) had fusions. Among respondents at each time point, 98%, 92%, and 92% were still employed, among whom 76%, 96%, and 96% had resumed working, respectively (median 29 days). Average at-work performance among working patients (who responded at each pair of timepoints) moved from 75.4 to 78.7 between baseline and 6 weeks, 71.8 to 85.9 between baseline and 6 months, and 73.0 to 88.1 between baseline and 12 months. Gains were concentrated among the 52.0% of patients whose at-work performance was declining (and low) leading up to surgery. Average absenteeism was relatively unmoved between baseline and each follow-up. Before surgery, the monthly average time lost to presenteeism and absenteeism was 19.8% and 18.9%, respectively; 12 months after surgery, these numbers were 9.7% and 16.0%; changes represent a mitigated loss of 13.0 percentage points of average monthly value. Presenteeism and absenteeism contributed roughly evenly to preoperative average monthly lost time. Although average changes in absenteeism and 6-week at-work performance were small, average changes in at-work performance at 6 and 12 months were significant. Cost-benefit analyses of lumbar spine surgery should therefore consider improved presenteeism, which appears to offset some of the direct and indirect costs of surgical treatment.


Activity of metabolic enzymes and muscle-specific gene expression in parr and smolts Atlantic salmon Salmo salar L. of different age groups.
This study was conducted to characterize the energy metabolism level and the features of muscle growth regulation during the development of Atlantic salmon (Salmo salar) inhabiting the Indera River (Kola Peninsula, Russia). The activities of aerobic and anaerobic enzymes (cytochrome c oxidase and lactate dehydrogenase) and carbohydrate metabolism enzymes (glucose-6-phosphate dehydrogenase, glycerol-3-phosphate dehydrogenase, and aldolase) were measured in muscle and liver tissue. Gene expression levels of myosin heavy chain (MyHC), myostatin (MSTN-1a), and myogenic regulatory factors (MRFs-MyoD1a, MyoD1b, MyoD1c, Myf5, myogenin) were measured in the white muscles of salmon parr of ages 0+, 1+, 2+, and 3+ and smolts of ages 2+ and 3+. Multidirectional changes in the activity of enzymes involved in aerobic and anaerobic energy metabolism with age were shown in the white muscles of the parr. The cytochrome c oxidase activity was higher in muscles of underyearlings (0+) and yearlings (1+) and decreased in 2+ and 3+ age groups. The activity of lactate dehydrogenase, in contrast, increased with age. The patterns of changes in expression levels of MyoD1a, MyoD1b, myogenin, MyHC, and MSTN-1a at different ages of the parr were similar. Particularly, the expression of these genes peaked in the yearling parr (1+) and then decreased in elder groups. The differences were revealed in parameters studied between the parr and smolts. The level of aerobic and anaerobic metabolism enzyme activities was higher in the white muscles of smolts than in parr. The activity of carbohydrate metabolism enzymes was decreased in the smolts' livers. The expression levels of MyHC, MyoD1a, MyoD1b, and myogenin were lower in smolts at age 2+ compared to parr. These findings expand our knowledge of age-related and stage-related features of energy metabolism and muscle development regulation in young Atlantic salmon in their natural habitat. The results might be used for monitoring of the salmon population during restoration and rearing.


Direct Imaging of Atomic Permeation Through a Vacancy Defect in the Carbon Lattice.
Porous graphene has shown promise as a new generation of selective membrane for sieving atoms, ions and molecules. However, the atomistic mechanisms of permeation through defects in the graphenic lattice are still unclear and remain unobserved in action, at the atomic level. Here, the direct observation of palladium atoms from a nanoparticle passing through a defect in a single-walled carbon nanotube one-by-one has been achieved with atomic resolution in real time, revealing key stages of the atomic permeation. Bonding between the moving atom and dangling bonds around the orifice, immediately before and after passing through the subnano-pore, plays an important role in the process. Curvature of the graphenic lattice crucially defines the direction of permeation from concave to convex side due to a difference in metal-carbon bonding at the curved surfaces as confirmed by density functional theory calculations, demonstrating the potential of porous carbon nanotubes for atom sieving.


Multiple glycosaminoglycan-binding epitopes of monocyte chemoattractant protein-3/CCL7 enable it to function as a non-oligomerizing chemokine.
The interaction of chemokines with glycosaminoglycans (GAGs) facilitates the formation of localized chemokine gradients that provide directional signals for migrating cells. In this study, we set out to understand the structural basis and impact of the differing oligomerization propensities of the chemokines monocyte chemoattractant protein (MCP)-1/CCL2 and MCP-3/CCL7 on their ability to bind GAGs. These chemokines provide a unique comparison set because CCL2 oligomerizes and oligomerization is required for its full in vivo activity, whereas CCL7 functions as a monomer. To identify the GAG-binding determinants of CCL7, an unbiased hydroxyl radical footprinting approach was employed, followed by a focused mutagenesis study. Compared with the size of the previously defined GAG-binding epitope of CCL2, CCL7 has a larger binding site, consisting of multiple epitopes distributed along its surface. Furthermore, surface plasmon resonance (SPR) studies indicate that CCL7 is able to bind GAGs with an affinity similar to CCL2 but higher than the non-oligomerizing variant, CCL2(P8A), suggesting that, in contrast to CCL2, the large cluster of GAG-binding residues in CCL7 renders oligomerization unnecessary for high affinity binding. However, the affinity of CCL7 is more sensitive than CCL2 to the density of heparan sulfate on the SPR surfaces; this is likely due to the inability of CCL7 to oligomerize because CCL2(P8A) also binds significantly less tightly to low than high density heparan sulfate surfaces compared with CCL2. Together, the data suggest that CCL7 and CCL2 are non-redundant chemokines and that GAG chain density may provide a mechanism for regulating the accumulation of chemokines on cell surfaces.


L-glutamine Schiff base copper complex as a proteasome inhibitor and an apoptosis inducer in human cancer cells.
Interest in the use of metallic compounds for cancer treatment has been increasing since the discovery of cisplatin. Clinical studies suggest the use of proteasome inhibitors as potential novel anticancer agents. L-glutamine is the most abundant free amino acid in the body, and has been shown to play a regulatory role in several cellular processes, including metabolism, degradation, redox potential and cellular integrity. Although glutamine is reported to play a role in the regulation of apoptosis, the effect of glutamine copper complex on tumor cells and the involved molecular mechanism have not been investigated. Here, for the first time, we report that a newly synthesized L-glutamine-containing copper complex has proteasome-inhibitory activity in human breast cancer and leukemia cells. The inhibition of the tumor proteasomal activity results in the accumulation of ubiquitinated proteins and ubiquitinated form of IkappaB-alpha, a natural proteasome substrate, followed by induction of apoptosis. Furthermore, this glutamine Schiff base copper complex selectively inhibits the proteasomal activity and induces cell death in cultured breast cancer cells, but not normal, immortalized breast cells. Our data suggest that glutamine Schiff base copper complexes have a potential use for to be used in cancer treatment and prevention.


Vibrational spectra of tris(dmit) complexes of main group metals: infrared, Raman and ab initio calculations.
Infrared Fourier Transform investigation of several metal tris-complexes of 1,3-dithiole-2-thione-4,5-dithiolate (dmit) ligand have been recorded within a theoretical-experimental investigation of the vibrational molecular spectra of crystalline [NEt4]2[Sn(dmit)3] and [NEt4][Sb(dmit)3] compounds. For the [Sn(dmit)3]-2 anion we recorded as well the Raman Fourier Transform spectra. Ab initio calculations have been carried with several ECPs, basis sets and methodologies (RHF and DFT) in order to assess family and methodological errors precisely. Geometry optimization and subsequent hessian calculation lead to the vibration frequencies reported. These calculated frequencies and intensities assisted the fundamental, overtones and combinations bands assignments. Remarkable agreement has been found between the experimental geometries and frequencies to those here calculated. Besides the bands traditionally studied for the dmit compounds, as CC and CS stretchings, also the region below 500 cm(-1) was evaluated, allowing to characterize several modes involving angular deformation of the dmit as the MS stretching of these octahedral distorted systems.


Differentially expressed gene (DEG) based protein-protein interaction (PPI) network identifies a spectrum of gene interactome, transcriptome and correlated miRNA in nondisjunction Down syndrome.
Down syndrome, a genetic disorder of known attribution reveals several types of brain abnormalities resulting in mental retardation, inadequacy in speech and memory. In this study, we have presented a consolidative network approach to comprehend the intricacy of the associated genes of Down syndrome. In this analysis, the differentially expressed genes (DEG's) were identified and the central networks were constructed as upregulated and downregulated. Subsequently, GNB5, CDC42, SPTAN1, GNG2, GNAZ, PRKACB, SST, CD44, FGF2, PHLPP1, APP, and FYN were identified as the candidate hub genes by using topological parameters. Later, Fpclass a PPI tool identified WASP gene, a co-expression interacting partner with highest network topology. Moreover, an enhanced enrichment pathway namely Opioid signaling was obtained using ClueGo, depicting the roles of the hub genes in signaling and neuronal mechanisms. The transcriptional regulatory factors and the common miRNA connected to them were identified by using MatInspector and miRTarbase. Later, a regulatory network constructed showed that PLAG, T2FB, CREB, NEUR, and GATA were the most commonly connected transcriptional factors and hsa-miR-122-5p was the most prominent miRNA. In a nutshell, these hub genes and the enriched pathway could help understand at a molecular level and eventually used as therapeutic targets for Down syndrome.


Sustainable management of drinking plastic straws is required to reduce plastic pollution: Are we using them more during COVID-19?
Nowadays, single-use plastic pollution attracts the attention of scholars, policymakers, and practitioners. In addition to personal protective equipment (PPEs) waste during the COVID-19 pandemic, other unpreceded plastic wastes such as packaging from online shopping and food delivery, viruses confirmatory testing, and drinking straws also contributed to pollution and worsened around the globe. This perspective aimed to provide insights into drinking plastic straws as an important source of plastic pollution. Literature searches confirmed that drinking plastic straws, unlike PPEs, have not been researched whether it is an important contributor to pollution or not during the COVID-19 pandemic. Thus, research on the pollution level of this plastic waste and its association with COVID-19 is required. Drinking straw producers and users require adequate strategies and management of this plastic pollution and more widespread rules and regulations to prevent environmental implications and health risks. This study can usefully give highlights for environmentalists, solid waste management experts, policymakers, and governments by describing the environmental impact and raising health risks of drinking plastic straw pollution.


Schematic pancreatic configuration: a risk assessment for postoperative pancreatic fistula after pancreaticoduodenectomy.
Postoperative pancreatic fistula (POPF) remains a serious complication after pancreaticoduodenectomy (PD). Preoperative risk assessment of POPF is desirable in careful preparation for operation. The aim of this study was to assess simple and accurate risk factors for clinically relevant POPF based on a schematic understanding of the pancreatic configuration using preoperative multidetector computed tomography. Three hundred and eighteen consecutive patients who underwent PD in the National Cancer Center Hospital East between November 2006 and March 2013 were investigated. Pre-, intra-, and postoperative clinicopathological findings as well as pancreatic configuration data were analyzed for the risk of clinically relevant POPF. POPF was defined according to the International Study Group of Pancreatic Fistula classification. POPF grade A occurred in 52 patients (16.4%), grade B in 84 (26.4%), and grade C in 6 (1.9%). Independent risk factors for POPF grade B/C included main pancreatic duct diameter (MPDd) < 2 mm (P = 0.001), parenchymal thickness ≥ 8 mm (P = 0.018), not performing portal vein/superior mesenteric vein resection (P = 0.004), and amylase level of drainage fluid on postoperative day 3 ≥ 375 IU/L (P < 0.001). Pancreatic configuration data including MPDd and parenchymal thickness were good indicators of clinically relevant POPF.


The fairness of PAYT systems: some guidelines for decision-makers.
Although the whole idea behind the PAYT approach is to develop a fairer system of waste charges than currently used, there still remains a number of issues that need to be considered when designing any given application of the PAYT principle, bearing in mind the variety of possible PAYT systems and the set of factors that influence their implementation. We assume that the perception of the system's fairness affects acceptance and thus participation, in the sense that the higher the perceived fairness the higher will be the acceptance of the system and, therefore, the higher the participation will be. Consequently, when it comes to analysing the acceptance of the implementation of a PAYT system or its effective functioning, waste management decision-makers should be interested in making sure that the system is perceived as fair in order to ensure a high participation rate. In addition, from a social point of view, decision-makers and politicians may be interested in the consequences of the operation of the system for other social values and in its impacts on particular groups of participants. This presentation examines the conditions for fairness and the considerations that should be taken into account so as to design a fair PAYT system in a specific municipality.


Coordinated regulation of TORC2 signaling by MCC/eisosome-associated proteins, Pil1 and tetraspan membrane proteins during the stress response.
MCCs are linear invaginations of the yeast plasma membrane that form stable membrane microdomains. Although over 20 proteins are localized in the MCCs, it is not well understood how these proteins coordinately maintain normal MCC function. Pil1 is a core eisosome protein and is responsible for MCC-invaginated structures. In addition, six-tetraspan membrane proteins (6-Tsp) are localized in the MCCs and classified into two families, the Sur7 family and Nce102 family. To understand the coordinated function of these MCC proteins, single and multiple deletion mutants of Pil1 and 6-Tsp were generated and their MCC structure and growth under various stresses were investigated. Genetic interaction analysis revealed that the Sur7 family and Nce102 function in stress tolerance and normal eisosome assembly, respectively, by cooperating with Pil1. To further understand the role of MCCs/eisosomes in stress tolerance, we screened for suppressor mutants using the SDS-sensitive phenotype of pil1Δ 6-tspΔ cells. This revealed that SDS sensitivity is caused by hyperactivation of Tor kinase complex 2 (TORC2)-Ypk1 signaling. Interestingly, inhibition of sphingolipid metabolism, a well-known downstream pathway of TORC2-Ypk1 signaling, did not rescue the SDS-sensitivity of pil1Δ 6-tspΔ cells. These results suggest that Pil1 and 6-Tsp cooperatively regulate TORC2 signaling during the stress response.


Insights into greenhouse gas emissions from a wastewater treatment plant in vulnerable water areas of China.
Wastewater treatment plants (WWTPs) are a significant anthropogenic source of greenhouse gas (GHG), but the quantitative assessment of GHG emissions from WWTPs in vulnerable water areas under stricter discharge limits remains unclear. Herein, depending on a case WWTP in southern China, we investigated the impacts of discharge standard improvement and key drivers of GHG emissions using daily operating data. We demonstrated that the stricter discharge limits increased the total GHG emission intensity by 18.2 %, with direct emissions increasing more than indirect GHG emissions. The GHG emissions were negatively correlated with water quantity, showing the scale effect, which became more pronounced after the discharge standard improvement. Increasing influent chemical oxygen demand and total nitrogen concentrations significantly drove the variations in GHG emissions, which were accelerated under stricter discharge limits. This study provides insights into the evaluation of GHG emission from WWTPs in vulnerable water areas and carbon-neutral wastewater management policies.


[Infectious disease epidemiology education and training Programs. FETP and EPIET].
The German Field Epidemiology Training Programme (FETP) and the European Programme for Intervention Epidemiology Training (EPIET) were founded to develop a network of epidemiologists for the surveillance and control of communicable diseases. During their 2-year training, FETP or EPIET fellows are based at the Robert Koch-Institut or other European host institutes and have to conduct outbreak investigations, carry out surveillance and research projects and publish the results. Since 1995, all 22 FETP and 94 EPIET fellows have conducted and published numerous outbreak investigations, surveillance and research projects, for example on pathogens inducing salmonellosis, influenza, SARS or avian influenza. Currently, 70% of FETP and EPIET alumni are working in key positions in communicable disease control on a regional, national or international level. The German FETP and the European EPIET programme offer high quality practical training in applied epidemiology. The expert knowledge of the alumni of both training programmes will be incorporated into the new European Centre for Disease Control (ECDC) and determine the future direction of infectious disease epidemiology in Germany and Europe.


High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin.
In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.


Current Management of Adhesive Small Bowel Obstructions in Children.
Adhesive small bowel obstructions are a common cause of morbidity in children who underwent prior abdominal surgery. The concept of partial versus complete bowel obstruction is outdated and lacks precision to be clinically useful. Identifying patients with indications for immediate operative intervention is critical and must be recognized to limit morbidity. Clinical protocols and contrast challenge algorithms have attempted to identify patients that will resolve their bowel obstruction nonoperatively; there has been slow uptake in the pediatric patient population versus adults until recently. Incorporating predictive models and standardized contrast challenge protocols will help reduce interpractitioner variability and improve clinical outcomes.


Correction to "Expression of Dehydroshikimate Dehydratase in Sorghum Improves Biomass Yield, Accumulation of Protocatechuate, and Biorefinery Economics".
[This corrects the article DOI: 10.1021/acssuschemeng.2c01160.].


[Effect of reducing sensory and environmental stimuli during hospitalized premature infant sleep].
To compare the total sleep time of premature infant in the presence or absence of reducing sensory and environmental stimuli in the neonatal unit. Longitudinal study in a Neonatal Intermediate Care Unit of a public hospital in Sao Paulo. The sample consisted of 13 premature infants. We used polysomnograph and unstructured observation for data collection. We analyzed 240 and 1200 minutes corresponding to the periods of the presence and absence of environmental management, respectively. Data were compared in proportion to the total sleep time in the two moments proposed by the study. The total sleep time in periods without environmental management was on average 696.4 (± 112.1) minutes and with management 168.5 (± 27.9) minutes, proportionally premature infant slept an average of 70.2% during periods with no intervention and 58.0% without management (p=0.002). Reducing stimulation and handling of premature infant environment periods was effective to provide greater total sleep time.


Changes in serum miRNA-let-7 level in children with attention deficit hyperactivity disorder treated by repetitive transcranial magnetic stimulation or atomoxetine: An exploratory trial.
We aimed to investigate whether microRNA-let-7d (miRNA-let-7d) and miRNA-107 may serve as diagnostic and therapeutic biomarkers of attention deficit hyperactivity disorder (ADHD). The relative expression level of miRNA-let-7d and miRNA-107 in patients with ADHD and in a healthy control group was detected by real-time polymerase chain reaction. The blood samples were collected at 6 weeks after repetitive transcranial magnetic stimulation (rTMS) or atomoxetine (ATX) in ADHD patients, and the relative expression levels of the two miRNAs before and after treatments were compared. There were significant differences in the expression level of miRNA-let-7d between ADHD patients and healthy children, as well as before and after rTMS or ATX treatment in ADHD patients. However, the expression of miRNA-107 showed no significant difference between ADHD patients and healthy children or before and after rTMS (or ATX treatment). These results suggest that serum miRNA-let-7d may serve as a potential diagnostic and therapeutic biomarker for children with ADHD.


Comparison between idiopathic deep vein thrombosis of the upper and lower extremity regarding risk factors and recurrence.
The pathogenesis and natural course of idiopathic upper extremity deep vein thrombosis (UEDVT) are unclear. To compare patients with UEDVT and with idiopathic lower extremity deep vein thrombosis (LEDVT) regarding risk factors and recurrence. We followed 50 patients with first idiopathic UEDVT and 841 patients with first idiopathic LEDVT for an average of 59 and 46 months, respectively. We excluded patients with natural inhibitor deficiency, lupus anticoagulant, cancer, pregnancy, isolated pulmonary embolism (PE), or long-term antithrombotic treatment. The endpoint was recurrent venous thromboembolism (VTE). In comparison to LEDVT patients, UEDVT patients were younger (38 +/- 13 years vs. 49 +/- 16 years, P < 0.001), slimmer (body mass index: 24 +/- 4 vs. 27 +/- 5, P < 0.001), less frequently had a family history of VTE (18% vs. 31%, P = 0.06) or concomitant PE (8% vs. 31%, P =0.001), were less frequently carriers of factor V Leiden (12% vs. 30%, P = 0.009), and had lower thrombin generation marker levels (D-dimer, 283 +/- 361 ng mL(-1) vs. 456 +/- 446 ng mL(-1), P < 0.001; peak thrombin, 298 +/- 101 nm vs. 363 +/- 111 nm, P = 0.001). Recurrence occurred in two of 50 patients with UEDVT (4%) and in 129 of 841 patients with LEDVT (15%). After 5 years, the likelihood of recurrence was 2% [95% confidence interval (CI) 0-6] among UEDVT patients and 19% (95% CI 16-22; P = 0.02) among LEDVT patients. As compared to LEDVT patients, the adjusted risk of recurrence was 0.26 (95% CI 0.06-1.05; P = 0.059) in UEDVT patients. The pathogenesis and natural course of the disease differ between patients with idiopathic UEDVT and LEDVT.


Structural breakdown and phytotoxic assessments of PE degradation through acid hydrolysis, starch addition and Pseudomonas aeruginosa bioremediation.
Vast amounts of plastic waste are causing serious environmental issues and urge to develop of new remediation methods. The aim of the study is to determine the role of inorganic (nitric acid), organic (starch addition), and biological (Pseudomonas aeruginosa) soil amendments on the degradation of Polyethylene (PE) and phytotoxic assessment for the growth of lettuce plant. The PE-degrading bacteria were isolated from the plastic-contaminated soil. The strain was identified as Pseudomonas aeruginosa (OP007126) and showed the highest degradation percentage for PE. PE was pre-treated with nitric acid as well as starch and incubated in the soil, whereas P. aeruginosa was also inoculated in PE-contaminated soils. Different combinations were also tested. FTIR analysis and weight reduction showed that though nitric acid was efficient in degradation, the combined application of starch and bacteria also showed effective degradation of PE. Phytotoxicity was assessed using morphological, physiological, and biochemical parameters of plant. Untreated PE significantly affected plants' physiology, resulting in a 45% reduction in leaf chlorophyll and a 40% reduction in relative water content. It also had adverse effects on the biochemical parameters of lettuce. Bacterial inoculation and starch treatment mitigated the harmful impact of stress and improved plants' growth as well as physiological and biochemical parameters; however, the nitric treatment proved phytotoxic. The observed results revealed that bacteria and starch could be effectively used for the degradation of pre-treated PE.


Cast versus removable orthosis for the management of stable type B ankle fractures: a systematic review and meta-analysis.
There is currently no consensus on nonoperative management in adult patients after a stable type B ankle fracture. The aim of this review is to compare a removable orthosis versus a cast regarding safety and functional outcome in the NOM of stable type B ankle fractures. A systematic review and meta-analysis were performed using randomized clinical trials and observational studies. The methodological quality of the included studies was assessed with the methodological index for non-randomized studies instrument. Nonoperative management was compared using the number of complications and functional outcome measured using the Olerud and Molander Score (OMAS) or the American Academy of Orthopaedic Surgeons Ankle Score. Five studies were included. Two were randomized clinical trials, and three were observational studies, including a total of 516 patients. A meta-analysis showed statistically significant higher odds of developing complications in the cast group [odds ratio (OR), 4.67 (95% confidence interval (CI) 1.52-14.35)]. Functional outcome in OMAS did not vary significantly at 6 weeks, mean difference (MD) - 6.64 (95% CI - 13.72 to + 0.45), and at 12 weeks, MD - 6.91 (95% CI - 18.73 to + 4.91). The mean difference of functional outcome in OMAS at 26 weeks or longer was significantly better in the removable orthosis group; MD - 2.63 (95% CI - 5.01 to - 0.25). Results of this systematic review and meta-analysis show that a removable orthosis is a safe alternative type of NOM, as complication numbers are significantly lower in the orthosis group. In addition, no statistically significant differences were found in terms of functional outcome between a removable orthosis and a cast at 6 and 12 weeks. The 6-week and the 26-week OMAS results show that in patients with stable type B ankle fractures, a removable orthosis is non-inferior to a cast in terms of functional outcome.


Focus issue: a cell's sense of direction.
The process by which cells orient their movement according to external gradients plays important roles in physiological and pathological processes. This Focus Issue of Science Signaling highlights the interplay between molecules, signaling pathways, and mechanisms that enable directional movement.


Carbohydrate plasma expanders for passive tumor targeting: in vitro and in vivo studies.
The objective of this study was to investigate the suitability of carbohydrate plasma volume expanders as a novel polymer platform for tumor targeting. Many synthetic polymers have already been synthesized for targeted tumor therapy, but potential advantages of these carbohydrates include inexpensive synthesis, constant availability, a good safety profile, biodegradability and the long clinical use as plasma expanders. Three polymers have been tested for cytotoxicity and cytokine activation in cell cultures and conjugated with a near-infrared fluorescent dye: hydroxyethyl starches (HES 200 kDa and HES 450 kDa) and dextran (DEX 500 kDa). Particle size and molecular weight distribution were determined by asymmetric flow field-flow fractionation (AF4). The biodistribution was investigated non-invasively in nude mice using multispectral optical imaging. The most promising polymer conjugate was characterized in human colon carcinoma xenograft bearing nude mice. A tumor specific accumulation of HES 450 was observed, which proves it's potential as carrier for passive tumor targeting.


ABCA3 deficiency presenting as persistent pulmonary hypertension of the newborn.
A newborn with persistent pulmonary hypertension (PH) unresponsive to conventional therapies was found to be homozygous for a mutation in the gene encoding adenosine triphosphate binding cassette protein, member A3 (ABCA3). Most causes of PH respond to lung recruitment, inhaled nitric oxide, and hemodynamic support. When PH is prolonged and does not respond to standard therapies, genetic causes of surfactant abnormalities should be considered in the differential diagnosis.


Clinical and Laboratory Characteristics of Patients infected by Listeria monocytogenes at a Tertiary Hospital in Hefei City, China.
Human listeriosis is a severe foodborne infection caused by Listeria monocytogenes and the data of patients with this infection are largely limited for the Hefei population. This is a retrospective study that evaluated the clinical and laboratory data of patients with listeriosis at a tertiary hospital in Hefei City. A total of 24 listeriosis patients were admitted to the First Affiliated Hospital of Anhui Medical University from January 2003 to July 2021. Data from all patients were collected from the hospital's electronic medical records. The most common symptom of all patients was fever (91.7%), followed by altered consciousness (50.0%), rashes (45.8%), respiratory distress symptoms (37.5%), nuchal rigidity (29.2%), and headaches (20.8%). Laboratory results also indicated elevated C-reactive protein (CRP) (79.1%), hypoproteinemia (75.0%), anemia (62.5%), leukocytosis (45.8%), and neutrophilia (45.8%). The mean value of 5.1 μg/mL (SD, 3.8) for D-dimer (D-D) was significantly higher than the normal value ((0.00-0.50) μg/mL), while both altered consciousness (6 vs 4, P = 0.034) and headaches (4 vs 1, P = 0.036) occurred more frequently in the neurolisteriosis group compared with the bacteremia one. Additionally, the mean maximal body temperature (°C) (40.5 ± 0.7) as well as white blood cell (WBC) (15.3 vs 7.5 ×109/L, P = 0.014) and neutrophil (NEUT#) (13.2 vs 6.1 ×109/L, P = 0.026) counts of neurolisteriosis patients were higher than those of bacteremia (39.4 ± 0.4) (P = 0.001). Of all patients, four (50%) from the maternal-neonatal group remained uncured. Listeriosis is a rare disease with extremely variable clinical characteristics in Hefei City. Our data indicated that unexplained fever, altered consciousness, hypoproteinemia, anemia, elevated CRP and DD should be considered to assist diagnosis of listeriosis for early treatment interventions.


Background concentrations of Argon-39 in shallow soil gas.
While radioisotopes of noble gases are known to be indicators of underground nuclear explosions (UNE), McIntyre et al. (2017) was the first to report the presence of 39Ar in shallow soil gas in association with a decades old UNE. While this finding hinted at the potential application of 39Ar to be used as an indicator of a UNE, doing so would also require an understanding of the natural concentrations of 39Ar present in soil gas. Without knowing the expected range and variability of naturally occurring concentrations of 39Ar, it is difficult to determine what measured concentrations would be indicative of an elevated concentration. This paper presents results from 16 soil gas samples and three atmospheric air samples collected from various locations across the western United States. Shallow soil gas samples were collected into self-contained underwater breathing apparatus (SCUBA) tanks using a custom-built soil gas sampling system and then processed and analyzed for 39Ar. The measured concentrations of 39Ar varied from atmospheric air concentrations to about 3.5 times atmospheric air concentrations (58 mBq/m3). The results presented here represent the first measurements of natural background 39Ar concentrations in shallow soil gas. This data will be necessary if 39Ar is to be used as an indicator of UNE.


Binding of fibronectin, fibrinogen and type II collagen to streptococci isolated from bovine mastitis.
Binding of 125I-labelled fibronectin, fibrinogen and type II collagen to group B (S. agalactiae), group C (S. dysgalactiae and S zooepidemicus), group E (S. uberis) and nontypable streptococci isolated from bovine mastitis was studied. S. agalactiae and S. uberis were found to bind low levels of all three proteins, while S. zooepidemicus bound high levels. Binding of the proteins to S. dysgalactiae varied, i.e. fibronectin was high, fibrinogen moderate and collagen low. Nontypable strains showed moderate or low binding of all proteins. Both hydrophobic and hydrophilic strains were found to bind fibronectin. For S. dysgalactiae the specific fibronectin binding ranged from 70% to 10% and for S. zooepidemicus it was more than 80% and this binding was sensitive to papain treatment. The binding of 29K-fibronectin fragment to one S. dysgalactiae strain showed an affinity of KD = 2.6 x 10(-8) M and the number of binding sites per colony forming unit (CFU) was calculated at 11,000.


Toothpick obstruction of the ureter.
We report an unusual case of ureteral obstruction from a toothpick that migrated from the cecum to the right ureter.


Laying performance, egg quality, fertility, nutrient digestibility, digestive enzymes activity, gut microbiota, intestinal morphology, antioxidant capacity, mucosal immunity, and cytokine levels in meat-type Japanese quail breeders fed different phytogenic levels.
A total of 180 female Japanese quail breeders were allocated to 5 treatments with 6 replicates of 6 birds and fed a diet supplemented with 0, 125, 250, 500, or 1000 mg/kg of a phytogenic feed additive (PFA) in a 9-wk experiment. Egg weight, feed efficiency, shell breaking strength and calcium content, specific gravity, Haugh unit, and percentages of fertile eggs increased with increasing PFA levels (P < 0.05). Increasing of PFA levels increased nutrient digestibility, dietary AMEn, and activities of digestive enzymes in the pancreas and intestinal digesta (P < 0.05). Supplementation of PFA reduced Escherichia coli (P < 0.05), Clostridium spp. (P < 0.05) and Salmonella spp. counts (P < 0.05), while increased Lactobacillus and Bifidobacterium spp. counts in the ileal and cecal contents (P < 0.05). Dietary PFA increased jejunal villus height and decreased ileal crypt depth (P < 0.05). Serum diamine oxidase activity and D-lactate level were decreased with increase in PFA level (P < 0.05). Increasing PFA levels increased glutathione peroxidase activity in the pancreas, small intestine, and cecal tonsil, but decreased malondialdehyde contents (P < 0.05). Birds fed PFA exhibited increased levels of secretory IgA in the intestinal mucosa (P < 0.05), and increased the percentage of CD3+ T cells, ratio of CD4+/CD8+ T cells, and cytokine concentrations in the cecal tonsils (P < 0.05). In conclusion, PFA could improve gut health and nutrient utilization and, therefore, benefit productivity, egg quality, and fertility in quails.


Sirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression.
Expanding the exercise capacity of skeletal muscle is an emerging strategy to combat obesity-related metabolic diseases and this can be achieved by shifting skeletal muscle fibers toward slow-twitch oxidative type. Here, we report that Sirt6, an anti-aging histone deacetylase, is critical in regulating myofiber configuration toward oxidative type and that Sirt6 activator can be an exercise mimetic. Genetic inactivation of Sirt6 in skeletal muscle reduced while its transgenic overexpression increased mitochondrial oxidative capacity and exercise performance in mice. Mechanistically, we show that Sirt6 downregulated Sox6, a key repressor of slow fiber specific gene, by increasing the transcription of CREB. Sirt6 expression is elevated in chronically exercised humans, and mice treated with an activator of Sirt6 showed an increase in exercise endurance as compared to exercise-trained controls. Thus, the current study identifies Sirt6 as a molecular target for reprogramming myofiber composition toward the oxidative type and for improving muscle performance.


Age-related decrements in the analgesic and hyperphagic responses to 2-deoxy-D-glucose.
Among the compromised physiological responses affected by aging is an impaired response to glucose. Since administration of 2-deoxy-D-glucose (2DG) produces both analgesic and hyperphagic responses in young adult rats, the present study examined whether systematic variations in these responses occurred as a function of age. Separate cohorts of 4, 9, 14, 19 and 24 month old female rats received ascending doses of 2DG (0, 50, 250, 450, 650 mg/kg) with tail-flick latencies and jump thresholds assessed 30, 60 and 120 min later. Then the same rats received 2DG injections (0, 650, 1200 mg/kg) and food intake was assessed 5 hr later. Significant decreases in 2DG analgesia were observed on the tail-flick test as a function of age with the maximal decrease observed at the highest 2DG dose. Significant decreases in 2DG analgesia were generally observed on the jump test as a function of age, although this effect was not as robust as that observed on the tail-flick test. Finally, significant and systematic decreases in 2DG hyperphagia were observed as a function of age following both the 650 mg/kg and the 1200 mg/kg doses. The observed decrements in the analgesic and hyperphagic responses to 2DG as a function of age appear to represent an orderly alteration in responses to glucoprivation through adulthood.


Systems for the cell-free synthesis of proteins.
We describe a system for the cell-free expression of proteins based on extracts from Escherichia coli. Two reaction configurations, batch and continuous exchange, are discussed and analytical scale as well as preparative scale setups are documented. Guidelines for the systematic development and optimization of cell-free expression protocols are given in detail. We further provide specific protocols and parameters for the cell-free production of membrane proteins. High-throughput screening applications of CF expression systems are exemplified as new tools for genomics and proteomics studies.


Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain.
Chronic pain is a devastating problem affecting one in five individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics have contributed to cataloguing diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses. To identifying new types of pain-relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross-sex and cross-species, and imputed commonalities, as well as differences in cellular pathways and gene regulation. We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signalling nodes. We investigated the interactome with the Drug-Gene database to predict FDA-approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non-receptor spleen associated tyrosine kinase (Syk), which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406 and another Syk inhibitor P505-15, significantly reversed pain hypersensitivity in both sexes. Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties.


Knowledge of obstructive sleep apnoea in final year medical students and junior doctors-a multi-centre cross-sectional study.
Sleep medicine is an under-recognised medical specialty in Pakistan and obstructive sleep apnoea (OSA) often goes unnoticed. Final year medical students and junior doctors are the primary medical contact to elicit patient history and physical examination. We aimed to measure the current knowledge of OSA amongst the final year medical students and junior doctors at four university teaching hospitals across three large Pakistani cities. Cross-sectional survey of final year medical students and junior doctors rotating through medical wards of four university teaching hospitals were conducted during August-October 2019. The knowledge section of the OSA knowledge and attitude (OSAKA) questionnaire was used. Descriptive statistics were used to present the data with Chi-Square test and independent samples student t-test to compare the differences between individual items and mean scores of the participants, respectively. A total 282 final year medical students and 204 junior doctors completed the survey yielding a response rate of 53% for medical students and 97% for junior doctors. The knowledge of sleep apnoea was poor in both groups of participants with a mean score of 7.6 (42%) on the knowledge scale of OSAKA questionnaire. Medical students scored higher on the item related to snoring as the most prevalent symptom in OSA patients when compared to the junior doctors (χ2 = 8.92, P = 0.003). More junior doctors responded correctly about the role of uvulopalatopharyngoplasty in the management of OSA when compared to the medical students (χ2 = 5.14, P = 0.02). Differences in scores of both groups of participants on other items were small and did not reach statistical significance. Final year medical students and junior doctors from a sample of four university teaching hospitals in three large cities of Pakistan have limited knowledge about the diagnosis and management of OSA. The observed limited knowledge of OSA may contribute towards under-diagnosis of this increasingly prevalent medical condition.