A hypothetical skin sensitisation next generation risk assessment for coumarin in cosmetic products.
Next generation Risk Assessment (NGRA) is an exposure-led, hypothesis-driven approach which integrates new approach methodologies (NAMs) to assure safety without generating animal data. This hypothetical skin allergy risk assessment of two consumer products - face cream containing 0.1% coumarin and deodorant containing 1% coumarin - demonstrates the application of our skin allergy NGRA framework which incorporates our Skin Allergy Risk Assessment (SARA) Model. SARA uses Bayesian statistics to provide a human relevant point of departure and risk metric for a given chemical exposure based upon input data that can include both NAMs and historical in vivo studies. Regardless of whether NAM or in vivo inputs were used, the model predicted that the face cream and deodorant exposures were low and high risk respectively. Using only NAM data resulted in a minor underestimation of risk relative to in vivo. Coumarin is a predicted pro-hapten and consequently, when applying this mechanistic understanding to the selection of NAMs the discordance in relative risk could be minimized. This case study demonstrates how integrating a computational model and generating bespoke NAM data in a weight of evidence framework can build confidence in safety decision making.


New cell sources for CAR-based immunotherapy.
Chimeric antigen receptor (CAR) T cell therapy, in which a patient's own T lymphocytes are engineered to recognize and kill cancer cells, has achieved striking success in some hematological malignancies in preclinical and clinical trials, resulting in six FDA-approved CAR-T products currently available in the market. Despite impressive clinical outcomes, concerns about treatment failure associated with low efficacy or high cytotoxicity of CAR-T cells remain. While the main focus has been on improving CAR-T cells, exploring alternative cellular sources for CAR generation has garnered growing interest. In the current review, we comprehensively evaluated other cell sources rather than conventional T cells for CAR generation.


Host proteins in dental plaques of caries-resistant versus caries-susceptible human groups.
The level of host proteins in 3-day supragingival plaque extracts was compared in caries-resistant (CR) and caries-susceptible (CS) adults with little or no gingival inflammation to minimize the contribution of gingival crevicular fluid ( GCF ). Except for IgA, all the host proteins examined were present at similar levels in both groups of subjects. Although the IgA exhibited fragmentation on sodium dodecylsulphate gradient-polyacrylamide gel electrophoresis (SDS-PAGE) and transfer electrophoresis in both groups, the amount of binding to a standard antisecretory IgA antiserum was higher in CR than in CS subjects. This could be a reflection of the trend towards a higher concentration of IgA in saliva of CR subjects or the result of less proteolytic activity in CR plaque. Even in 3-day plaque in the absence of gingival inflammation, GCF contributes a significant share of the host proteins to plaque extracts. Salivary proteins in plaque do not parallel their relative concentration in saliva.


Aerophagia and rumination: recognition and therapy.
Aerophagia and rumination syndrome are functional upper gastrointestinal disorders that are becoming increasingly recognized in otherwise-healthy children and adults. Aerophagia is primarily characterized by troublesome repetitive belching and abdominal symptoms that result from air sucking and swallowing. Rumination syndrome is primarily characterized by regurgitation occurring shortly after meal intake. Physiologic studies suggest that both disorders are a result of habitual behavior with associated esophageal and gastric physiologic deviations. However, the underlying etiology of these disorders remains unclear. Studies examining optimal treatments are lacking. However, therapeutic approaches utilizing biofeedback may be helpful in alleviating symptoms for patients with these conditions.


Pain, pain anxiety and emotional and behavioural problems in children with cerebral palsy.
Pain is commonly experienced in those with cerebral palsy (CP), and previous research suggests an increase in behavioural and emotional problems in children experiencing pain and pain anxiety. Therefore, it was hypothesised that pain intensity and pain anxiety would predict behavioural and emotional problems in children with CP. Parents or guardians of 61 children (38 boys, 23 girls) with CP, aged 5-15 years completed an online questionnaire on pain intensity, pain anxiety and behavioural and emotional problems. Correlation and a multiple linear regression analyses were conducted to examine whether pain intensity and/or pain anxiety predicts behavioural and emotional problems. A total of 59% of participants reported that their children with CP currently experiences pain. Multiple regression analyses revealed that pain intensity (p = 0.038) and pain anxiety (p < 0.001) both made a significant and independent contributions in predicting anxiety in children, however, pain anxiety was the only predictor that made a significant and independent contribution to the depression (p = 0.001) and the behavioural and emotional problems measure (p = 0.004). Whilst pain intensity appears to be associated with behavioural and emotional problems in children, pain anxiety may be more strongly associated still.


Changes in cellular levels of cyclic AMP in rat mast cells during secretion of histamine induced by immunoglobulin E decapeptide and ACTH(1-24) peptide. Comparison with immunological and ionophore triggers.
The role of cyclic AMP in the secretory mechanism of mast cells has been investigated by comparing the time course of changes in cellular levels of this cyclic nucleotide with the kinetics of secretion induced by basic peptides, antigen, anti-IgE and calcium ionophore. ACTH(1-24) peptide and a synthetic decapeptide representative of the sequence 497-506 within the C epsilon 4 domain of human IgE induced a transient rise in cyclic AMP which reached approx. 150% of the resting levels by 10 s. Peptide-induced secretion of histamine was also rapid, reaching a maximum after 5-10 s. Immunological triggering of mast cells with antigen and anti-IgE raised levels of cyclic AMP to 150% of resting levels within 15 s, accompanying secretion of histamine which reached a maximum after 30 s. A relatively slower release of histamine induced by the calcium ionophore A23187 was paralleled by a significant reduction in cyclic AMP to 50% of the resting levels after 300 s. These data suggest a relationship between the accumulation of cyclic AMP in mast cells and secretion of histamine mediated by the C epsilon 4 decapeptide and the ACTH(1-24) peptide as well as by IgE-dependent mechanisms. However, the simultaneous increase in cyclic AMP and secretion of histamine suggests that the two events may not be causally related.


Cause and treatment of insufficiency in the cerebral circulation.
The term cerebrovascular insufficiency describes reversible attacks of focal cerebral ischaemia affecting patients with extensive extracranial artery disease. The attacks are caused by failure of collateral blood supply and are often related to minor reductions in blood pressure. Characteristic clinical features such as jerking, involuntary movements and loss of vision in response to bright light may allow insufficiency attacks to be distinguished from other varieties of focal cerebral ischaemia. The treatment of patients with cerebral insufficiency aims to increase collateral blood supply by surgical removal of arterial obstruction and by medical therapy to prevent episodes of systemic hypotension.


A simple periodic-forced model for dengue fitted to incidence data in Singapore.
Dengue is the world's major arbovirosis and therefore an important public health concern in endemic areas. The availability of weekly reports of dengue cases in Singapore offers the opportunity to analyze the transmission dynamics and the impact of vector control strategies. Based on a previous model studying the impact of vector control strategies in Singapore during the 2005 outbreak, a simple vector-host model accounting for seasonal fluctuation in vector density was developed to estimate the parameters governing the vector population dynamics using dengue fever incidence data from August 2003 to December 2007. The impact of vector control, which consisted principally of a systematic removal of actual and potential breeding sites during a six-week period in 2005, was also investigated. Although our approach does not account for the complex life cycle of the vector, the good fit between data and model outputs showed that the impact of seasonality on the transmission dynamics is highly important. Moreover, the periodic fluctuations of the vector population were found in phase with temperature variations, suggesting a strong climate effect on the vector density and, in turn, on the transmission dynamics.


The 16S rRNA lung microbiome in mechanically ventilated patients: a methodological study.
Characterization of the respiratory tract bacterial microbiome is in its infancy when compared to the gut microbiota. To limit bias mandates a robust methodology. Specific amplification of the hypervariable (V) region of the 16SrRNA gene is a crucial step. Differences in accuracy exist for one V region to another depending on the sampled environment. We aimed to assess the impact of the primer sequences targeting the V4 region currently used for gut microbiota studies in respiratory samples. Materials and methods: The original 515 F-806R primer pair targets the V4 region of the 16SrRNA gene. We compared two different 515 F-806R primer pairs before Illumina 250 paired-end sequencing for bacterial microbiome analyses of respiratory samples from critically-ill ventilated patients. "S-V4" for "Stringent V4" primer pair is used in two ongoing international projects "the Integrative Human microbiome project (iHMP)" and "the Earth microbiome project (EMP)." "R-V4" for "Relaxed V4" primer pair has been modified to reduce biases against specific environmental taxa. The optimal method was determined by concordance with conventional microbiology. Results: Twenty samples from three patients who developed a ventilator-associated pneumonia (VAP) and four who did not (control ventilated patients) were sequenced. Highly different results were obtained. "S-V4" provided the best agreement with the conventional microbiology for endotracheal aspirate: 89% as compared to 56% for "R-V4." The main difference related to poor Enterobacteriaceae detection with "R-V4" primers. Conclusions: Accuracy of the bacterial lung microbiome composition was highly dependent on the primers used for amplification of the 16 s rRNA hypervariable sequence. This work validates for future lung microbiome studies the use of the 515 F-806R "S-V4" primer pair associated to Illumina® MiSeq paired-end sequencing.


Identification of expression quantitative trait loci of RPTOR for susceptibility to glioma.
Expression quantitative trait loci (eQTLs) have been recognized to be more likely to associate with complex diseases including cancer. As an essential scaffold for MTOR complex 1, RPTOR is necessary for the MTOR-catalyzed phosphorylation. This study examined the associations between the eQTLs of RPTOR and glioma susceptibility. The eQTLs of RPTOR were obtained from GTEx eQTL Browser. Associations were estimated by logistic regression models. On the basis of analysis of 138 cases with glioma and 327 cancer-free population controls, we demonstrated that the eQTL of RPTOR, rs7502563, was significantly associated with a decreased glioma risk [odds ratio (OR) = 0.59, 95 % confidence interval (CI) = 0.38-0.89, P = 0.0123] in a dominant manner. Stratified analyses indicated that the association between rs7502563 and glioma was more pronounced in females (OR = 0.40, 95 % CI = 0.20-0.80, P = 0.0091), older subjects (OR = 0.47, 95 % CI = 0.26-0.86, P = 0.0135), and subjects with high-grade glioma (OR = 0.45, 95 % CI = 0.27-0.77, P = 0.0031). Moreover, an interest gradual decrease in OR with higher grade glioma was observed. Further analysis of the extracted data from GTEx eQTL Browser found that rs7502563 G allele was associated with significantly higher expression of RPTOR in all HapMap populations. Our results demonstrate for the first time that the eQTL of RPTOR, rs7502563, is susceptible to glioma.


Genetic and antigenic variability in bovine viral diarrhea virus (BVDV) isolates from Belgium.
This report describes the genetic and antigenic variability of bovine viral diarrhea virus strains isolated in Belgium. Part of the 5' untranslated region and the 5' end of the gp53 (E2) coding sequence were amplified by PCR and sequenced. Phylogenetic analysis showed that most field isolates segregated into genotypes Ib or II. Only one out of 28 field isolates belonged to genotype Ia. Interestingly, some type I strains were equally divergent from types Ia and Ib strains and clustered into additional subtypes within genotype I. Immune sera from young calves experimentally inoculated with field isolates first identified on the basis of their sequences were used in two-way neutralisation experiments. The results clearly differentiated type I from type II strains although some degree of cross-neutralisation was observed. Within type I, the new clusters could not be antigenically differentiated from the more prevalent type Ib strains or from type Ia strain NADL, suggesting that BVDV genotype I is antigenically homogeneous. The isolation of BVDV types I and II strains from cell lines and from a bovine vaccine suggest that molecular epidemiology surveillance is warranted for BVDV.


Effectiveness of Biocidal Paint Containing Permethrin, Ultramarine and Violet 23 Against Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae) in Laboratories and Poultry Houses.
Reducing Alphitobius diaperinus in poultry production is a difficult task. However, attempts should be made to control the insect pest, as it poses a serious threat to the life and health of the chickens, as well as the workers on a farm. Our research was conducted in two stages to assess the effectiveness of the biocidal paint against A. diaperinus, containing active substances such as permethrin and a mixture of ultramarine and violet 23. In the first stage, under laboratory conditions, after 22 days, 100% mortality of A. diaperinus larvae and adults was achieved. This allowed us to assume that the biocidal paint may also be effective in poultry houses. In the poultry house where biocidal paint was applied, the number of insects decreased continuously alongside the sampling dates. In both research stages, the biocidal paint proved more effective against A. diaperinus than traditional limewash, and also the time to effective interaction of the paint was noted. Additionally, it was observed that the larvae were more susceptible to the active substances than adults. The research was practical, however, further analyses are necessary to fully control A. diaperinus, especially in poultry houses.


Understanding the new trends in pedestrian injury distribution and mechanism through data linkage and modeling.
The objectives of this study were to 1) collect and analyze recent pedestrian crash cases for better understanding of the pedestrian injury distribution and mechanism, 2) use computational simulations to reconstruct pedestrian cases and estimate potential benefit of pedestrian automatic emergency braking (PedAEB) in reducing pedestrian injury risks, and 3) estimate how future pedestrian crash distribution might influence priorities for pedestrian protection. Analyses of national crash-injury dataset showed that the overall number of pedestrians in crashes as well as the serious and fatal pedestrian injuries in the U.S. have been increasing in recent years. Striking vehicle type has changed (i.e., decreased proportion of passenger cars and increase of SUVs and pickup trucks) from 20 years ago mirroring changes in the fleet distribution of vehicle sales. A total of 432 pedestrian injury cases were generated by linking the Michigan trauma data and police-reported crash data from 2013 to 2018. Among the linked cases, pickup trucks and SUVs were involved in crashes with more injuries across body regions. Notably, AIS 3+ chest injuries occur at almost the same rate as lower extremity injuries. A method, combining MADYMO simulations (n = 3,500), response surface model, and data mining, was developed to reconstruct 25 linked pedestrian crash cases to estimate the effectiveness of PedAEB. Based on national field data and MADYMO simulations, PedAEB was estimated to be effective in reducing the risk of head and lower extremity injuries but is relatively less effective in reducing the risk of chest injuries. The increased proportions of SUVs and pickup trucks in the vehicle fleet and the higher penetration of PedAEB may highlight the importance of future research into chest injury risk for pedestrian protection.


3,4-diaminopyridine. A potent new potassium channel blocker.
3,4-diaminopyridine has been found to act very potently in selectively blocking the potassium channels of squid axon membranes. The apparent dissociation constants for this action are estimated to be 5.8 micron and 0.7 micron for external and internal applications, respectively, the potency being about 50 times higher than that of 4-aminopyridine. The block depends upon the membrane potential, time, and stimulus frequency. 3,4-diaminopyridine shows great promise as a useful tool for the study of membrane ionic channels.


Functional and effective connectivity based features of EEG signals for object recognition.
Classifying different object categories is one of the most important aims of brain-computer interface researches. Recently, interactions between brain regions were studied using different methods, such as functional and effective connectivity techniques. Functional and effective connectivity techniques are applied to estimate human brain areas connectivity. The main purpose of this study is to compare classification accuracy of the most advanced functional and effective methods in order to classify 12 basic object categories using Electroencephalography (EEG) signals. In this paper, 19 channels EEG signals were collected from 10 healthy subjects; when they were visiting color images and instructed to select the target images among others. Correlation, magnitude square coherence, wavelet coherence (WC), phase synchronization and mutual information were applied to estimate functional cortical connectivity. On the other hand, directed transfer function, partial directed coherence, generalized partial directed coherence (GPDC) were used to obtain effective cortical connectivity. After feature extraction, the scalar feature selection methods including T-test and one-sided-anova were applied to rank and select the most informative features. The selected features were classified by a one-against-one support vector machine classifier. The results indicated that the use of different techniques led to different classifying accuracy and brain lobes analysis. WC and GPDC are the most accurate methods with performances of 80.15% and 64.43%, respectively.


Preparation of quaternized chitosan/Ag composite nanogels in inverse miniemulsions for durable and antimicrobial cotton fabrics.
It is an urgent task to exploit effective antimicrobial agents due to the rise of drug-resistant pathogens. Herein, antimicrobial quaternized chitosan/Ag composite nanogels (QCS/Ag CNGs) with tunable properties were fabricated through inverse miniemulsion technique with a high encapsulation efficiency of NH2-Ag nanoparticles (NPs). The QCS/Ag CNGs possess superior broad-spectrum antimicrobial activity and low biotoxicity, via synergistic sterilization of Ag NPs and QCS. Furthermore, the NH2-Ag NPs were chemically linked to the QCS matrix through Schiff base reactions, and the QCS/Ag CNGs have reactive groups, making it possible to obtain durable antibacterial cotton fabrics. Thus, QCS/Ag CNGs modified cotton fabrics exhibited laundering durability of antimicrobial effect after 100 washing cycles without sacrificing other inherent properties of cotton fabrics. Our study provides a facile and controllable method to construct polymer/inorganic CNGs to address the urgent need for antibacterial agents/fabrics.


Clinical Assessment of Endovascular Stenting Compared with Compression Therapy Alone in Post-thrombotic Patients with Iliofemoral Obstruction.
The study aimed to evaluate the clinical results of stent placement in post-thrombotic patients with iliofemoral obstruction compared with results in those treated with elastic compression stockings (ECS). A retrospective analysis of post-thrombotic patients with iliofemoral obstruction was conducted in a single institution from January 2007 to December 2012. Duplex ultrasound and selective phlebography were performed in patients with chronic venous disease and previous deep venous thrombosis (DVT). Post-thrombotic syndrome (PTS) with iliofemoral vein obstruction (Villalta score ≥10) was diagnosed in 216 patients. Among these, 122 patients were treated by stent placement, and the remaining 94 patients were treated conservatively with 30-40 mmHg ECS therapy. Technical success, stent patency rates, and complications were recorded after the interventions. Results including Villalta score, pain, edema, ulcer, and popliteal vein reflux were assessed in both groups. Percutaneous iliofemoral venous stenting was successful in 116 of 122 patients (95.1%) without major complications. Follow up periods ranged from 3 to 58 months (median 21 months). Cumulative primary, assisted primary, and secondary stent patency rates at 3 years were 68.9%, 79.0%, and 91.6%, respectively. Among patients with severe PTS, the Villalta score decreased significantly with endotreatment, compared to the score of those treated by ECS therapy (16.12 ± 4.91 vs. 10.98 ± 5.89, p < .01). However, there was no significant score improvement between the two therapies in patients with moderate PTS (6.59 ± 2.37 vs. 5.75 ± 3.03, p = .22). There was a significantly higher 24 month recurrence free ulcer healing rate in the endotreatment groups (86.6% vs. 70.6%, p < .01). Both edema and pain improved significantly in the two groups. The popliteal vein reflux rate showed no significant change after endotreatment. Endovascular treatment is a safe, effective, and feasible method to correct the iliofemoral obstruction of PTS. Only post-thrombotic patients with severe PTS as assessed by the Villalta score appear to benefit from the endovascular treatment.


Nanodrugs with intrinsic radioprotective exertion: Turning the double-edged sword into a single-edged knife.
Ionizing radiation (IR) poses a growing threat to human health, and thus ideal radioprotectors with high efficacy and low toxicity still receive widespread attention in radiation medicine. Despite significant progress made in conventional radioprotectants, high toxicity, and low bioavailability still discourage their application. Fortunately, the rapidly evolving nanomaterial technology furnishes reliable tools to address these bottlenecks, opening up the cutting-edge nano-radioprotective medicine, among which the intrinsic nano-radioprotectants characterized by high efficacy, low toxicity, and prolonged blood retention duration, represent the most extensively studied class in this area. Herein, we made the systematic review on this topic, and discussed more specific types of radioprotective nanomaterials and more general clusters of the extensive nano-radioprotectants. In this review, we mainly focused on the development, design innovations, applications, challenges, and prospects of the intrinsic antiradiation nanomedicines, and presented a comprehensive overview, in-depth analysis as well as an updated understanding of the latest advances in this topic. We hope that this review will promote the interdisciplinarity across radiation medicine and nanotechnology and stimulate further valuable studies in this promising field.


Enhanced delivery of Paclitaxel using electrostatically-conjugated Herceptin-bearing PEI/PLGA nanoparticles against HER-positive breast cancer cells.
We have developed a novel nanoparticle delivery system fabricated from polyethylenimine (PEI) and poly(d,l-lactide-co-glycolide) (PLGA), which were able to deliver the chemotherapeutic agent Paclitaxel, while the biomacromolecule Herceptin acted as a targeting ligand that was conjugated onto the surfaces of the nanoparticles via electrostatic interactions. In this study, these electrostatically-conjugated Herceptin-bearing PEI/PLGA nanoparticles (eHER-PPNs) were optimized and employed as vectors to target HER2-positive breast cancer cells. The eHER-PPNs had an average diameter of ∼ 280 nm and a neutral surface charge (1.00 ± 0.73 mV), which remained stable under physiological conditions. The anticancer effects of eHER-PPNs were investigated in HER2-positive BT474 cells and HER2-negative MCF7 cells. The eHER-PPNs showed enhanced cytotoxicity that was dependent on the receptor expression levels and the incubation time. These conjugated nanoparticles deliver Paclitaxel more efficiently (p<0.001) than unmodified PPNs, Herceptin and the combined effects of these two monotherapies. Furthermore, the chemically-conjugated Herceptin-bearing PEI/PLGA nanoparticles (cHER-PPNs) were fabricated as a comparison. The eHER-PPNs exhibited lower cell viability (46.7%) than that of cHER-PPNs (65.1%). The targeting ability of eHER-PPNs was demonstrated through confocal microscopy images and flow cytometry, which showed that eHER-PPNs displayed higher cellular uptake efficiency (p<0.001) in comparison with cHER-PPNs. Therefore, eHER-PPNs could provide promising platforms for the delivery of therapeutic drugs against HER2-positive breast cancers.


Differential expression patterns of Nqo1, AKR1B8 and Ho-1 in the liver and small intestine of C57BL/6 mice treated with sulforaphane.
This data article contains complementary figures and results related to the research article entitled "butylated hydroxyanisole induces distinct expression patterns of Nrf2 and detoxification enzymes in the liver and small intestine of C57BL/6 mice" (Luo et al., 2015 [1]), which defined the basal and butylated hydroxyanisole (BHA)-induced expression patterns of Phase II enzymes Nqo1, AKR1B8, and Ho-1 in the liver and small intestine of C57BL/6 mice. Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane] (SFN), a naturally occurring isothiocyanate derived from cruciferous vegetables, is a highly potent inducer of phase II cytoprotective enzymes. This dataset reports the histological changes of Nqo1, AKR1B8, and Ho-1 in wild-type (WT) and Nrf2 (-/-) mice induced by SFN. The mice were given a 25 mg/kg single oral dose of SFN for 24 h and 48 h. Immunohistochemistry revealed that, in the liver from WT mice, SFN increased Nqo1 staining in hepatocytes with slight higher staining in the pericentral region. The induction of AKR1B8 appeared mostly in hepatocytes in the periportal region. The basal and inducible Ho-1 was located predominately in Kupffer cells. In the small intestine from WT mice, the inducible expression of Nqo1 and AKR1B8 appeared more obvious in the villus than that in the crypt.


Crunch time. CIOs balance cost and flexibility to plan for storing large volumes of diagnostic imaging data.
Faced with skyrocketing imaging data storage costs, CIOs at three healthcare facilities found alternatives that have enabled them to slash expenditures, monitor their storage requirements, and provide more cost-effective backup solutions.


Fsp27 plays a crucial role in muscle performance.
Fsp27 was previously identified as a lipid droplet-associated protein in adipocytes. Various studies have shown that it plays a role in the regulation of lipid homeostasis in adipose tissue and liver. However, its function in muscle, which also accumulate and metabolize fat, remains completely unknown. Our present study identifies a novel role of Fsp27 in muscle performance. Here, we demonstrate that Fsp27-/- and Fsp27+/- mice, both males and females, had severely impaired muscle endurance and exercise capacity compared with wild-type controls. Liver and muscle glycogen stores were similar among all groups fed or fasted, and before or after exercise. Reduced muscle performance in Fsp27-/- and Fsp27+/- mice was associated with severely decreased fat content in the muscle. Furthermore, results in heterozygous Fsp27+/- mice indicate that Fsp27 haploinsufficiency undermines muscle performance in both males and females. In summary, our physiological findings reveal that Fsp27 plays a critical role in muscular fat storage, muscle endurance, and muscle strength.NEW & NOTEWORTHY This is the first study identifying Fsp27 as a novel protein associated with muscle metabolism. The Fsp27-knockout model shows that Fsp27 plays a role in muscular-fat storage, muscle endurance, and muscle strength, which ultimately impacts limb movement. In addition, our study suggests a potential metabolic paradox in which FSP27-knockout mice presumed to be metabolically healthy based on glucose utilization and oxidative metabolism are unhealthy in terms of exercise capacity and muscular performance.


Qualitative and quantitative changes in the guinea pig organ of Corti after pure tone acoustic overstimulation.
A direct relationship between delivered sound energy and morphological overstimulation has been formulated in the so-called equal energy principle. The validity of this principle was systematically tested by studying the effects of acoustic overstimulation on the guinea pig cochlea by means of scanning electron microscopy (SEM) and light microscopy (LM) techniques. The animals in the present study were exposed to 3.85 kHz pure tones of various durations and intensities and allowed a recovery period of 4 weeks before the morphological changes in the cochlea were assessed. A 4-grade scale was devised in order to achieve a qualitative as well as a quantitative SEM evaluation of the cochlear damage. The results of the examinations by LM and SEM were compared and analysed statistically. No significant difference was observed between groups of animals exposed to a sound energy of 9.4 and 37.5 Pa2.h, irrespective of sound intensity (114 or 120 dB SPL). Groups of animals exposed to a higher energy level (150 Pa2.h) differed significantly from those exposed to higher and also lower sound energy levels. Groups exposed to different intensities (108, 114 and 120 dB SPL) did not differ significantly within this energy level.


Rapidly Growing Superficial Angiomyxoma in Mandibular Gingiva: A Case Report and Literature Review.
Superficial angiomyxoma (SA) is a benign tumor characterized by extensive myxoid stroma, numerous small blood vessels, sparse spindle-shaped fibroblastic cells, and inflammatory cell infiltrate. Oral cavity SA is extremely rare and typically presents as a painless, slow growth. We experienced SA in the mandibular gingiva that is rapidly growing. The patient was a 15-year-old female whose chief complaint was a painless mass in the lingual gingiva of the mandible that increased in size over 1 month. An excisional biopsy was performed under local anesthesia. According to histopathological examination, the mass was diagnosed as SA. The patient experienced recurrence twice because of positive margins. The second recurrent lesion, including periosteum, was resected, and no recurrence has been observed for 1 year. The cause of rapid growth was attributed to edematous changes due to tongue habit or traumatic stimuli. As this case exhibited repeated local recurrence, careful follow-up is required.


Radioimmunoscintigraphy of xenografted human thyroid carcinoma.
We developed monoclonal antibodies against human thyroid cancer-associated antigen by fusing mouse myeloma cells with mouse spleen cells immunized by insoluble fraction of homogenized thyroid papillary carcinoma cells. One monoclonal antibody (KTC-3, IgM) was selected to evaluate basic usefulness for radioimmunoscintigraphy in xenografted human thyroid carcinoma. KTC-3 was labeled with 131I by Iodogen method of 20 to 1 Iodogen to IgM molar ratio. It was also labeled with 111In by cyclic DTPA anhydride method of 20 to 1 DTPA to IgM molar ratio. The labeling efficiency and specific activity for 131I labeling were 16.5% and 0.66 mCi/mg IgM respectively, and those for 111In labeling were 12.7% and 1.6 mCi/mg IgM. Imaging and biodistribution of labeled KTC-3 were evaluated in nude mice bearing thyroid anaplastic carcinoma (THC-5-JCK). The tumors were well visualized 3 and 5 days after injection of 131I KTC-3. Tumor uptake of 131I KTC-3 on day 7 was 0.52 +/- 0.27% ID/g and tumor to blood ratio was 1.98 +/- 0.76 (n = 6). Those of 111In KTC-3 were 0.88 +/- 0.09% ID/g and 5.51 +/- 3.36 (n = 6). In conclusion, KTC-3 is promising for radioimmunoscintigraphy of thyroid cancer.


Myotrophic effects on denervated fast-twitch muscles of mice: correlation of physiologic, biochemical, and morphologic findings.
Certain morphological, biochemical, and physiological parameters were assessed in fast-twitch muscles of 6-week-old mice with unilateral hindlimb denervation for 4 weeks. Some of the mice received daily injections (i.p.) of nerve extract throughout the period of denervation. Values from treated and untreated denervated muscles were compared with each other and with those from contralateral, innervated controls. The cross-sectional areas of denervated types IIA and IIATy muscle fibers were 45% and 28% greater, respectively, in muscles of treated than of untreated mice, which resulted in greater maximal tetanic tension. Injection with nerve extract did not influence the postdenervation reduction of phosphorylation of myosin light chain 2-fast nor the loss of posttetanic twitch potentiation, two parameters thought to be related. Denervation produced a significant decrease in relative content of cytosolic parvalbumin; however, this change was completely prevented by administration of nerve extract. This latter finding correlated with the amelioration of greater than 50% of the postdenervation prolongation of half-relaxation time of the twitch in treated than in untreated muscles. More than half of the prolongation of time-to-peak of the twitch was also prevented in denervated muscles of treated than of untreated mice.


Neonatal resuscitation: in pursuit of evidence gaps in knowledge.
Guidelines for the techniques of resuscitating newly born infants have undergone major revisions over the past 25 years. The International Liaison Committee on Resuscitation (ILCOR) is committed to "periodically developing and publishing a consensus on resuscitation science" every five years with the most recent Consensus on Science and Treatment Recommendations (CoSTR) statement published in 2010. The CoSTR document is used as a basis for developing specific resuscitation guidelines felt to be appropriate for implementation in respective countries. A "gaps in knowledge" summary is created at the conclusion of a cycle. It is a goal that identification of these knowledge gaps will stimulate investigators to pursue more targeted studies to help close the gaps. The current document is based on the "gaps in knowledge" summary for neonatal resuscitation that was created at the conclusion of the 2005-2010 ILCOR cycle.


Comparison of the acute effects of a selective endothelin ETA and a mixed ETA/ETB receptor antagonist in heart failure.
Both the selective endothelin (ET) ETA receptor and mixed ETA/ETB receptor antagonists improve haemodynamics in patients and experimental models with congestive heart failure (CHF) and reduce the mortality in CHF rats. However, it remains unclear which of these antagonists is superior in the treatment of CHF. In addition, there is little information as to whether these ET receptor antagonists contribute to the neuroendocrine regulation and body fluid balance. We therefore investigated the cardiorenal and neurohumoral benefits of selective ETA receptor and mixed ETA/ETB receptor antagonists in CHF. We administered acutely either the selective ETA receptor antagonist FR139317 (FR, n = 6, 1 and 10 mg/kg) or the mixed ETA/ETB receptor antagonist TAK-044 (TAK, n = 6, 1 and 3 mg/kg) to conscious dogs with CHF induced by rapid right ventricular pacing for ten days. Both FR and TAK decreased the cardiac pressures and the plasma atrial natriuretic peptide level and increased the cardiac output and urinary sodium excretion. FR increased the urine flow rate in association with an increased glomerular filtration rate and renal plasma flow, while TAK reduced the plasma aldosterone level. Neither antagonist increased the plasma renin activity or norepinephrine levels. These ETA/ETB antagonist. However, the long-term administration of a mixed ETA/ETB receptor antagonist would improve not only the haemodynamics but also prevent fluid retention by suppressing secretion of aldosterone during the treatment of chronic CHF.


Expression of a cDNA encoding human 5-lipoxygenase under control of the STA1 promoter in Saccharomyces cerevisiae.
A yeast-expression vector utilizing the STA1 promoter was constructed, and shown to be useful for the expression of a heterologous gene. A cDNA, encoding human 5-lipoxygenase (5LO), was inserted into the vector and expressed in Saccharomyces cerevisiae. The enzyme (yh5LO) produced in the transformant was purified to homogeneity from the cellular soluble fraction. The purified enzyme showed both 5LO and leukotriene A4 synthase activities, which were stimulated by Ca2+ and ATP. The N-terminal end of yh5LO contained five extra amino acids not present in 5LO purified from human leukocytes. A human 5LO-secretion vector containing the STA1 signal sequence was also constructed. When this hybrid gene was expressed in S. cerevisiae, its product was glycosylated and accumulated in the fractions related to the secretory pathway.


Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease.
The population-based incidence of early-onset (<34 weeks) and late-onset preeclampsia (≥34 weeks) has not been adequately studied. We examined the gestational age-specific incidence of preeclampsia onset and identified the associated risk factors and birth outcomes. All singleton deliveries in Washington State, 2003-2008 (n = 456,668), were included, and preeclampsia onset was determined from hospital records linked to birth certificates. Cox and logistic regression models were used to obtain adjusted hazard ratios and odds ratios (AORs) for risk factors and birth outcomes, respectively. The overall preeclampsia rate was 3.1% and the incidence increased sharply with gestation; early- and late-onset preeclampsia rates were 0.38% and 2.72%, respectively. Among women with early-onset preeclampsia, 12% delivered at a gestation of 34 weeks or longer. Risk/protective factors common to both diseases included older maternal age, Hispanic and Native-American race, smoking, unmarried status, and male fetus. African-American race, chronic hypertension, and congenital anomalies were more strongly associated with early-onset preeclampsia, whereas younger maternal age, nulliparity, and diabetes mellitus were more strongly associated with late-onset disease. Early- but not late-onset preeclampsia conferred a high risk of fetal death (AOR, 5.8; 95% confidence interval [CI], 4.0-8.3 vs AOR, 1.3; 95% CI, 0.8-2.0, respectively). The AOR for perinatal death/severe neonatal morbidity was 16.4 (95% CI, 14.5-18.6) in early-onset and 2.0 (95% CI, 1.8-2.3) in late-onset preeclampsia. Early- and late-onset preeclampsia shares some etiological features, differ with regard to several risk factors, and lead to different outcomes. The 2 preeclampsia types should be treated as distinct entities from an etiological and prognostic standpoint.


Biosynthesis of glycoproteins in Candida albicans: solubilization and partial characterization of dolichol phosphate mannose synthase and protein mannosyl transferases.
Incubation of a mixed membrane fraction isolated from C. albicans yeast cells with Nonidet P-40 at a detergent/protein ratio as low of 0.025 (0.016-0.019%, w/v) yielded a soluble fraction that catalyzed the transfer of mannose from GDP-[14C] Man into dolichol phosphate mannose and from this intermediate into mannoproteins. Over 95% of the sugar in mannoproteins was O-linked as judged from its release after beta-elimination. Mannose was identified as the sole product after this treatment. Transfer activity did not depend on exogenous lipid acceptor indicating that the latter was solubilized along with the mannosyl transferases. Synthesis of mannolipid and mannoproteins occurred at optima temperatures of 20 degrees C, and 37 degrees C, respectively, and at a pH in the range of 7.5-9.5. Mannosyl transfer into the mannolipid was stimulated by Mg2+ and inhibited by Ca2+ and Mn2+ whereas mannoprotein labeling was stimulated by Mn2+ and to a lower extent by Mg2+. When measured as a function of substrate concentration, the synthesis of the mannolipid was a nearly linear function of GDP-Man concentration in the range of 5 to 32 microM whereas protein mannosylation exhibited hyperbolic kinetics with saturation reached at about 10 microM. The solubilized preparation was able to utilize an exogenous source of mannolipid as sugar donor for protein mannosylation. Dinucleotides and, to a higher extent trinucleotides, inhibited mannosyl transfer into the mannolipid and hence into mannoproteins.


Endoscopic retrograde cholangiopancreatography-related complications for bile duct stones in asymptomatic and symptomatic patients.
Current guidelines recommend the removal of common bile duct (CBD) stones by endoscopic retrograde cholangiopancreatography (ERCP) for both asymptomatic and symptomatic patients. We conducted this study because of the limited research comparing the risks of ERCP-related complications between these two groups. This retrospective study involved 1491 patients with native major duodenal papilla diagnosed with choledocholithiasis at three institutions in Japan. The rates of ERCP-related complications, including post-ERCP pancreatitis (PEP), cholangitis, bleeding, and perforation, were compared using one-to-one propensity score matching between the asymptomatic and symptomatic patients. Complications were observed in 112 (7.5%) of the 1491 patients (asymptomatic group: 31/172 [18.0%] vs symptomatic group: 81/1319 [6.1%], P < 0.001). The rate of severe complications was higher in the asymptomatic group than that in the symptomatic group (asymptomatic group: 5/31 [16.1%] vs symptomatic group: 3/81 [3.7%], P = 0.036). In the propensity-matched asymptomatic and symptomatic patients, the incidences of PEP, cholangitis, bleeding, and perforation were 18/143 (12.6%) vs 4/143 (2.8%) (P = 0.003); 4/107 (3.7%) vs 6/107 (5.6%) (P = 0.75); 1/140 (0.7%) vs 3/140 (2.1%) (P = 0.62); and 2/140 (1.4%) vs 2/140 (1.4%) (P = 1.0). ERCP for asymptomatic patients with CBD stones is associated with a higher risk of overall and severe complications than that for symptomatic patients with CBD stones; the overall rate is influenced by the high incidence of PEP in the asymptomatic group. Endoscopists should explain the risk of ERCP-related complications for asymptomatic patients before performing the procedure.


The human health risk assessment of particulate air pollution (PM2.5 and PM10) in Romania.
Air pollution, especially the concentration of particulate matter (PM2.5, PM10) is a major issue and is the biggest environmental risk for early death. In the present study, we aimed to estimate the human health risk and to describe the spatial and temporal variation of particulate matter in Romania between 2009 and 2018. The average concentration of PM2.5 and PM10 particulate matter in the eight studied regions varied between 17.01 and 22.91 µg m-3 and 23.02-33.29 µg m-3, while the PM2.5/PM10 ratio varied between 0.52 and 0.76, respectively. The relative risk generated by PM10 in all-cause mortality had a significant variation between the regions, a relative risk of 1.017 in case of Bucharest and1.025 for western regions, with an average of 1.020 ( ± 0.002). According to our observations, a positive relative risk was identified in the case of cardiopulmonary and lung cancer morbidity mainly attributed to PM2.5 exposure, hence the resulted risk for the country average values was 1.26 ( ± 0.023) and 1.42 ( ± 0.037), respectively. The results revealed that the excess risk and attributable fraction for cardiopulmonary mortality can be reduced by 26.7% and 21.0%. Analyzing the evolution of particulate matters and the possible health impacts of PM2.5 and PM10 in all region of Romania a strong positive correlation was observed. Since the distributions of PM in different region had significant variation, more investigation is required to understand and decipher the most important regional emission sources for each region. In order to address this issue an in-depth investigation should separately analyze the regional characteristics of air pollution.


Evaluation of the safety and feasibility of rapid rituximab infusion.
To assess safety of rapid infusion by measuring infusion-related side effects and toxicities. Participants received the first rituximab infusion according to the manufacturers' recommendations. If well-tolerated, they then received the second and subsequent infusions at a rate of 20% of the dose over the first 30 min and the remaining 80% over the next hour. Premedication was administered for all the infusions. A total of 243 infusions in 65 consecutive participants were evaluated. Six experienced a grade 1 reaction and one a grade 3 transfusion-related adverse event. Three of these participants were withdrawn from the rapid infusion study. The other four participants (grade 1 only participants) were re-challenged. The same premedication was used as in the first rapid infusion. On experiencing a grade 1 reaction, promethazine 12.5 mg i.v. was administered and infusion recommenced at 50% of the previous rate upon the resolution of symptoms. Three patients developed a grade 1 adverse event and one patient experienced no adverse reaction. The three patients who did not tolerate the second rapid infusion were withdrawn from this study. A rituximab infusion over 90-min was safe and feasible for participants who seek treatment at ambulatory cancer centre. The new regimen has been adopted as a standard practice with better resource utilization.


Assessing motile cilia coverage and beat frequency in mammalian in vitro cell culture tissues.
Cilia density, distribution and beating frequency are important properties of airway epithelial tissues. These parameters are critical in diagnosing primary ciliary dyskinesia and examining in vitro models, including those derived from induced pluripotent stem cells. Video microscopy can be used to characterize these parameters, but most tools available at the moment are limited in the type of information they can provide, usually only describing the ciliary beat frequency of very small areas, while requiring human intervention and training for their use. We propose a novel and open-source method to fully characterize cilia beating frequency and motile cilia coverage in an automated fashion without user intervention. We demonstrate the ability to differentiate between different coverage densities, identifying even small patches of cilia in a larger field of view, and to fully characterize the cilia beating frequency of all moving areas. We also show that the method can be used to combine multiple fields of view to better describe a sample without relying on small pre-selected regions of interest. This is released with a simple graphical user interface for file handling, enabling a full analysis of individual fields of view in a few minutes on a typical personal computer.


INTERNAL DRAINAGE OF SUBRETINAL FLUID DURING CHANDELIER-ASSISTED SCLERAL BUCKLING.
To describe the surgical technique of internal drainage of subretinal fluid as an adjunct to chandelier-assisted scleral buckling for the repair of rhegmatogenous retinal detachment. The technique of internal drainage with a sharp needle or cannula through a trocar is described and shown in a Supplemental Digital Content 1 (see Video, http://links.lww.com/ICB/A87). Three patients (3 eyes) underwent scleral buckling for rhegmatogenous retinal detachment repair. Subretinal fluid was drained using the internal drainage approach in all cases. All three patients had successful reattachment of retina with improvement in visual function. No complications were reported related to vitreous loss, retinal incarceration, or redetachment following primary surgery. Internal drainage of subretinal fluid during chandelier-assisted scleral buckling is a useful technique that can be considered for repairing rhegmatogenous retinal detachment.


Renal angiomyolipoma: a study of 13 cases.
Arteriographic studies are valuable in the differentiation of angiomyolipoma from adenocarcinoma. Herein are described 13 cases of angiomyolipoma, in 10 of which angiographic studies were done. A correct preoperative diagnosis was made in 3 of the 10 cases and partial nephrectomy was done in 2. Since angiomyolipomas are benign tumors therapy differs greatly from that for adenocarcinoma. Early diagnosis of angiomyolipomas can prevent total or extensive nephrectomy and postoperative radiotherapy or cytostatic therapy, which are not necessary and are harmful to the patient.


Comparative pyrolysis studies of lignocellulosic biomasses: Online gas quantification, kinetics triplets, and thermodynamic parameters of the process.
This study focused on the analysis of the pyrolytic behavior of four lignocellulosic biomasses: avocado stone (AS), Agave salmiana bagasse (AB), cocoa shell (CS), and α-cellulose (CEL). According to the triplet kinetics analysis, the order of pyrolytic decomposition was AS < AB < CEL < CS. The AS was dominated by a second-order reaction, while AB followed a 2D diffusion-Valensi model. On the other hand, the pyrolysis of CS starts with an nth-order reaction and ends random nucleation model, and CEL was dominated by one-dimensional diffusion and first-order reaction. Thermodynamic studies reveal that the difference between the activation energy versus enthalpy change was<6.5 kJ/mol for all biomasses, thus showing the ease of pyrolysis reaction of these biomasses. Furthermore, the AS and AB showed that the reactions are close to thermodynamic equilibrium and stability, whereas CS and CEL indicated high reactivity.


Diesel exhaust particles induce apoptosis via p53 and Mdm2 in J774A.1 macrophage cell line.
Diesel exhaust particles (DEP) are known to cause cardiopulmonary diseases due to their proinflammatory and cytotoxic effects. Continuous exposure to DEP potentiates chronic inflammatory processes and acute symptomatic responses in the respiratory tract. Recent studies have emphasized that alveolar cell apoptosis is a crucial step in chronic inflammation and lung injury. The phenomenon of apoptosis is a key event that successfully clears damaged cells, and its failure leads to the development of more serious diseases, such as lung cancer. The mechanism and molecular target of DEP-induced apoptosis in the respiratory tract remain unclear. In this study, J774A.1 macrophage cells were used to investigate the p53-mediated apoptotic pathway induced by DEP exposure. The results showed that murine double minute 2 (Mdm2), a negative regulator of p53, was downregulated at the protein level by DEP exposure. In contrast, the pro-apoptotic protein Bcl-2-associated X protein (Bax), an endogenous target of p53-dependent transcriptional activation, was continuously upregulated at the mRNA and protein levels by DEP exposure. Furthermore, pifithrin-alpha (p53 inhibitor) blocked DEP-induced apoptosis as well as p53 activation. Taken together, the findings of the present study suggest that DEP trigger apoptosis in J774A.1 macrophage cells via the activation of p53, followed by Bax.


Membrane expression of thymidine kinase 1 and potential clinical relevance in lung, breast, and colorectal malignancies.
Lung, breast, and colorectal malignancies are the leading cause of cancer-related deaths in the world causing over 2.8 million cancer-related deaths yearly. Despite efforts to improve prevention methods, early detection, and treatments, survival rates for advanced stage lung, breast, and colon cancer remain low, indicating a critical need to identify cancer-specific biomarkers for early detection and treatment. Thymidine kinase 1 (TK1) is a nucleotide salvage pathway enzyme involved in cellular proliferation and considered an important tumor proliferation biomarker in the serum. In this study, we further characterized TK1's potential as a tumor biomarker and immunotherapeutic target and clinical relevance. We assessed TK1 surface localization by flow cytometry and confocal microscopy in lung (NCI-H460, A549), breast (MDA-MB-231, MCF7), and colorectal (HT-29, SW620) cancer cell lines. We also isolated cell surface proteins from HT-29 cells and performed a western blot confirming the presence of TK1 on cell membrane protein fractions. To evaluate TK1's clinical relevance, we compared TK1 expression levels in normal and malignant tissue through flow cytometry and immunohistochemistry. We also analyzed RNA-Seq data from The Cancer Genome Atlas (TCGA) to assess differential expression of the TK1 gene in lung, breast, and colorectal cancer patients. We found significant expression of TK1 on the surface of NCI-H460, A549, MDA-MB-231, MCF7, and HT-29 cell lines and a strong association between TK1's localization with the membrane through confocal microscopy and Western blot. We found negligible TK1 surface expression in normal healthy tissue and significantly higher TK1 expression in malignant tissues. Patient data from TCGA revealed that the TK1 gene expression is upregulated in cancer patients compared to normal healthy patients. Our results show that TK1 localizes on the surface of lung, breast, and colorectal cell lines and is upregulated in malignant tissues and patients compared to healthy tissues and patients. We conclude that TK1 is a potential clinical biomarker for the treatment of lung, breast, and colorectal cancer.


[The excision of villous tumours of the rectum via a trans-sphincterian anal approach (author's transl)].
Cleavage in the thickness of the internal sphincter and of the circular layer of the rectum is performed. By progressive drawing down, this method makes it possible to obtain complete excision, passing at a distance from the tumour in its different planes.


Phosphorus vertical migration in aquic brown soil and light chernozem under different phosphorous application rate: a soil column leaching experiment.
A soil column leaching experiment was conducted to study the vertical migration of phosphorus in aquic brown soil and light chernozem under different phosphorus fertilization rates. The results showed that total dissolved phosphorus concentration in the leachates from the two soils was nearly the same, but dissolved inorganic phosphorus concentration was obviously different. In all fertilization treatments, aquic brown soil had a higher content of phosphorus in calcium chloride extracts compared with light chernozem. But Olsen phosphorus content was higher at the soil depth beneath 0-20 cm, and increased with increasing phosphorus application rate.


Foreword: Implementing cancer prevention in Europe.
The understanding of risk factors underpinning the aetiology of many common cancers is well established, yet the conversion of this knowledge into prevention lags considerably behind. The title of this Special Issue - Implementing cancer prevention in Europe - captures the central theme within; namely, the translation of cancer epidemiology into public health policy. The Special Issue is supported by focused evidence-based case studies of how these processes might be best taken forward.


Emergence of the primordial pre-60S from the 90S pre-ribosome.
Synthesis of ribosomes begins in the nucleolus with formation of the 90S pre-ribosome, during which the pre-40S and pre-60S pathways diverge by pre-rRNA cleavage. However, it remains unclear how, after this uncoupling, the earliest pre-60S subunit continues to develop. Here, we reveal a large-subunit intermediate at the beginning of its construction when still linked to the 90S, the precursor to the 40S subunit. This primordial pre-60S is characterized by the SPOUT domain methyltransferase Upa1-Upa2, large α-solenoid scaffolds, Mak5, one of several RNA helicases, and two small nucleolar RNA (snoRNAs), C/D box snR190 and H/ACA box snR37. The emerging pre-60S does not efficiently disconnect from the 90S pre-ribosome in a dominant mak5 helicase mutant, allowing a 70-nm 90S-pre-60S bipartite particle to be visualized by electron microscopy. Our study provides insight into the assembly pathway when the still-connected nascent 40S and 60S subunits are beginning to separate.


Association of vaccination, international travel, public health and social measures with lineage dynamics of SARS-CoV-2.
Continually emerging SARS-CoV-2 variants of concern that can evade immune defenses are driving recurrent epidemic waves of COVID-19 globally. However, the impact of measures to contain the virus and their effect on lineage diversity dynamics are poorly understood. Here, we jointly analyzed international travel, public health and social measures (PHSM), COVID-19 vaccine rollout, SARS-CoV-2 lineage diversity, and the case growth rate (GR) from March 2020 to September 2022 across 63 countries. We showed that despite worldwide vaccine rollout, PHSM are effective in mitigating epidemic waves and lineage diversity. An increase of 10,000 monthly travelers in a single country-to-country route between endemic countries corresponds to a 5.5% (95% CI: 2.9 to 8.2%) rise in local lineage diversity. After accounting for PHSM, natural immunity from previous infections, and waning immunity, we discovered a negative association between the GR of cases and adjusted vaccine coverage (AVC). We also observed a complex relationship between lineage diversity and vaccine rollout. Specifically, we found a significant negative association between lineage diversity and AVC at both low and high levels but not significant at the medium level. Our study deepens the understanding of population immunity and lineage dynamics for future pandemic preparedness and responsiveness.


Effects of Dietary Zeolite Supplementation as an Antibiotic Alternative on Growth Performance, Intestinal Integrity, and Cecal Antibiotic Resistance Genes Abundances of Broilers.
The study investigated the effects of dietary zeolite supplementation as an antibiotic alternative on growth performance, intestinal integrity, and cecal antibiotic resistance genes abundances of broilers. One-day-old chicks were assigned into three groups and fed a basal diet or a basal diet supplemented with antibiotics (50 mg/kg) or zeolite (10 g/kg). Antibiotic or zeolite increased (p < 0.05) average daily gain (ADG) from 1 to 42 days and duodenal villus height to crypt depth ratio (VH:CD) at 21 days. Zeolite increased (p < 0.05) ADG and average daily feed intake from 1 to 21 days, jejunal VH:CD at 21 and 42 days, ileal VH and VH:CD at 42 days, zonula occludens-1 mRNA abundance at 21 days, and duodenal occludin mRNA abundance at 42 days, whereas reduced (p < 0.05) jejunal CD and malondialdehyde levels in ileum at 21 days and duodenum at 42 days, serum D-lactic acid and diamine oxidase levels at 42 days, and plasma lipopolysaccharide content at 21 and 42 days. Antibiotics reduced (p < 0.05) duodenal claudin-2 mRNA abundance at 21 days, whereas increased (p < 0.05) cecal tetB abundance at 42 days. These findings suggested that the beneficial effects of zeolite in broilers were more pronounced than that of antibiotics.


Significance of Serum Procalcitonin Levels in Differential Diagnosis of Pediatric Pneumonia.
The objective of this study was to explore the early diagnosis methods of severe pediatric pneumonia. A total of 65 cases hospitalized in pediatric departments and ICU of our hospital because of severe pneumonia were divided into two groups according to pathogen detection. The groups were as follows: 34 cases of bacterial pneumonia, 32 cases of a non-bacterial pneumonia, and 37 cases of healthy children after physical examination in our hospital as the control group. The peripheral blood was sampled from each of the three groups for procalcitonin (PCT). The pediatric PCT level in peripheral blood of the bacterial pneumonia group was significantly higher than that of non-bacterial pneumonia group and the control group. The statistical differences (each at p < 0.01) and the level of pediatric serum PCT in the bacterial pneumonia group before treatment were statistically different from that in the same group after treatment (p < 0.01), while the level of pediatric serum PCT in non-bacterial pneumonia group before treatment was statistical indifferent from that in the same group after treatment (p > 0.01). PCT level in pediatric peripheral blood is an important diagnostic indicator of bacterial infection and a sensitive indicator of distinction between bacterial pneumonia and the non-bacterial pneumonia, thus being of great significance for clinical and differential diagnosis.


[First report of one imported case of schistosomiasis haematobia in Guangxi Zhuang Autonomous Region].
The first case of imported schistosomiasis haematobia in Guangxi Zhuang Autonomous Region is reported in this paper, so as to improve the doctors' understanding of the common tropic diseases abroad.


Tobacco advertising, environmental smoking bans, and smoking in Chinese urban areas.
To evaluate whether cigarette smoking in Chinese urban areas was respectively associated with exposure to tobacco advertising and smoking bans in households, workplaces, and public places. Participants were 4735 urban residents aged 15 years and older, who were identified through multi-stage quota-sampling conducted in six Chinese cities. Data were collected on individual sociodemographics and smoking status, and regional tobacco control measures. The sample was characterized in terms of smoking prevalence, and multilevel logistic models were employed to analyze the association between smoking and tobacco advertising and environmental smoking restrictions, respectively. Smoking prevalence was 30%. Multilevel logistic regression analysis showed that smoking was positively associated with exposure to tobacco advertising, and negatively associated with workplace and household smoking bans. The association of smoking with both tobacco advertising and environmental smoking bans further justifies implementation of comprehensive smoking interventions and tobacco control programs in China.


Trastuzumab Deruxtecan (DS-8201a): The Latest Research and Advances in Breast Cancer.
The development of antibody-drug conjugates composed of a cytotoxic agent and a monoclonal antibody carrier offers an important alternative to classic chemotherapy strategies. Trastuzumab deruxtecan (DS-8201a) is a next-generation antibody-drug conjugate composed of a monoclonal anti-HER2 antibody and a topoisomerase I inhibitor, an exatecan derivative (DX-8951f). DS-8201a resulted in favorable outcomes in HER2-positive heavily pretreated breast cancer patients and also had a promising efficacy in patients with HER2-negative/low-expressing disease, whose options are limited. Interestingly, a recently published phase 2 trial (NCT03248492) reported 60% overall response and 97% disease control in patients with HER2-positive disease previously treated with multiple regimens, including trastuzumab emtansine. On the basis of recent clinical trials, the US Food and Drug Administration granted accelerated approval to DS-8201a in advanced or unresectable HER2-positive breast cancer pretreated with at least two HER2-targeting treatment lines. We review all preclinical and clinical data of DS-8201a regarding breast cancer.


Draft Genome Sequence of Stutzerimonas stutzeri NT-I, Which Reduces Selenium Oxyanions into Elemental Selenium and Volatile Selenium Species.
Stutzerimonas stutzeri strain NT-I effectively reduces selenate and selenite into elemental selenium and volatile selenium species. It is thus a promising biological agent for treatment of selenium-contaminated wastewater. We here report the draft genome sequence of this strain.


In vitro induction and differentiation of umbilical cord mesenchymal stem cells into neuron-like cells by all-trans retinoic acid.
To determine the optimal concentration for inducing the differentiation of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) into neuron-like cells, although it is understood that all-trans retinoic acid (ATRA) regulates cell proliferation in the nervous system by modulating the balance between mitosis and apoptosis. The abilities of ATRA to promote apoptosis as well as neural differentiation were assessed in cultured hUC-MSCs by morphological observation, MTT assay, annexin V-FITC/PI flow cytometry and immunocytochemistry. The data showed that low concentrations of ATRA (0.5 µmol, 0.25 µmol) had no effect on the number of cells. However, treatment with 1.0 µmol or 2.0 µmol ATRA induced a 24.16% and 52.67% reduction in cell number, respectively, compared with vehicle-treated cultures. Further, 4.0 µmol ATRA had a potent effect on cell number, with almost no adherent cells recovered after 24h. We further showed that 0.5 µmol ATRA caused these cells to express characteristic markers of neuronal progenitor cells. Taken together, we conclude that ATRA has a dose-dependent influence on the neural differentiation and apoptosis of hUC-MSCs. These findings have implications on the use of ATRA-differentiated hUC-MSCs for the study of neural degeneration diseases.


The HIV-1 epidemic in Bolivia is dominated by subtype B and CRF12_BF "family" strains.
Molecular epidemiological studies of HIV-1 in South America have revealed the occurrence of subtypes B, F1 and BF1 recombinants. Even so, little information concerning the HIV-1 molecular epidemiology in Bolivia is available. In this study we performed phylogenetic analyses from samples collected in Bolivia at two different points in time over a 10 year span. We analyzed these samples to estimate the trends in the HIV subtype and recombinant forms over time. Fifty one HIV-1 positive samples were collected in Bolivia over two distinct periods (1996 and 2005). These samples were genetically characterized based on partial pol protease/reverse transcriptase (pr/rt) and env regions. Alignment and neighbor-joining (NJ) phylogenetic analyses were established from partial env (n = 37) and all pol sequences using Mega 4. The remaining 14 env sequences from 1996 were previously characterized based on HMA-env (Heteroduplex mobility assay). The Simplot v.3.5.1 program was used to verify intragenic recombination, and SplitsTree 4.0 was employed to confirm the phylogenetic relationship of the BF1 recombinant samples. Phylogenetic analysis of both env and pol regions confirmed the predominance of "pure" subtype B (72.5%) samples circulating in Bolivia and revealed a high prevalence of BF1 genotypes (27.5%). Eleven out of 14 BF1 recombinants displayed a mosaic structure identical or similar to that described for the CRF12_BF variant, one sample was classified as CRF17_BF, and two others were F1pol/Benv. No "pure" HIV-1 subtype F1 or B" variant of subtype B was detected in the present study. Of note, samples characterized as CRF12_BF-related were depicted only in 2005. HIV-1 genetic diversity in Bolivia is mostly driven by subtype B followed by BF1 recombinant strains from the CRF12_BF "family". No significant temporal changes were detected between the mid-1990s and the mid-2000s for subtype B (76.2% vs 70.0%) or BF1 recombinant (23.8% vs 30.0%) samples from Bolivia.


Engineering fructosyl peptide oxidase to improve activity toward the fructosyl hexapeptide standard for HbA1c measurement.
The recently discovered fructosyl peptide oxidase from Phaeosphaeria nodorum (PnFPOX) was demonstrated to react with the glycated hexapeptide measurement standard of hemoglobin A1c, fVHLTPE. The highly reactive Coniochaeta FPOX (FPOX-C) showed no detectable activity with the hexapeptide. Two loop regions were identified as having important effects on the enzymatic properties of FPOX. The first loop has a strong influence on the ability to bind larger glycated peptides, while the second loop has a significant effect on catalytic activity. Loop-substitution mutants showed that the highest activity against fVHLTPE resulted from the combination of the first loop from PnFPOX and the second loop from FPOX-C. The most promising engineered FPOX created, which showed 17-fold greater dehydrogenase activity against fVHLTPE than wild-type PnFPOX, was the FPOX-C mutant with a PnFPOX-derived loop 1 region and an Asn56Ala substitution.


Graft and Mesh Use in Transvaginal Prolapse Repair: A Systematic Review.
To update clinical practice guidelines on graft and mesh use in transvaginal pelvic organ prolapse repair based on systematic review. Eligible studies, published through April 2015, were retrieved through ClinicalTrials.gov, MEDLINE, and Cochrane databases and bibliography searches. We included studies of transvaginal prolapse repair that compared graft or mesh use with either native tissue repair or use of a different graft or mesh with anatomic and symptomatic outcomes with a minimum of 12 months of follow-up. Study data were extracted by one reviewer and confirmed by a second reviewer. Studies were classified by vaginal compartment (anterior, posterior, apical, or multiple), graft type (biologic, synthetic absorbable, synthetic nonabsorbable), and outcome (anatomic, symptomatic, sexual function, mesh complications, and return to the operating room). We found 66 comparative studies reported in 70 articles, including 38 randomized trials; quality of the literature has improved over time, but some outcomes still show heterogeneity and limited power. In the anterior vaginal compartment, synthetic nonabsorbable mesh consistently showed improved anatomic and bulge symptom outcomes compared with native tissue repairs based on meta-analyses. Other subjective outcomes, including urinary incontinence or dyspareunia, generally did not differ. Biologic graft or synthetic absorbable mesh use did not provide an advantage in any compartment. Synthetic mesh use in the posterior or apical compartments did not improve success. Mesh erosion rates ranged from 1.4-19% at the anterior vaginal wall, but 3-36% when mesh was placed in multiple compartments. Operative mesh revision rates ranged from 3-8%. Synthetic mesh augmentation of anterior wall prolapse repair improves anatomic outcomes and bulge symptoms compared with native tissue repair. Biologic grafts do not improve prolapse repair outcomes in any compartment. Mesh erosion occurred in up to 36% of patients, but reoperation rates were low.


Facultative sex ratio shifts by a herbivorous insect in response to variation in host plant quality.
We tested predictions of sex allocation theory with a series of field experiments on sex allocation in an herbivorous, haplodiploid, sawfly, Euura lasiolepis. Our experiments demonstrated the following points. 1) Adult females allocated progeny sex in response to plant growth. 2) Population sex ratios varied in response to plant quality, being male-biased where plant growth was slow and female-biased where plant growth was rapid. 3) Family sex ratios varied in response to plant quality, being male-biased on slow-growing plants and female-biased on rapidly-growing plants. 4) Female fitness increased more rapidly as the result of developing on more rapidly-growing plants than male mass. We conclude from these results that there are unequal returns on investment in male and female progeny. This results in facultatively biased sawfly sex ratios as an adaptive response to variation in plant quality.


The biology of reactive sulfur species (RSS).
Sulfur is an essential and quantitatively important element for living organisms. Plants contain on average approximately 1 g S kg⁻¹ dry weight (for comparison plants contain approximately 15 g N kg⁻¹ dry weight). Sulfur is a constituent of many organic molecules, for example amino acids such as cysteine and methionine and the small tripeptide glutathione, but sulfur is also essential in the form of Fe-S clusters for the activity of many enzymes, particularly those involved in redox reactions. Sulfur chemistry is therefore important. In particular, sulfur in the form of thiol groups is central to manifold aspects of metabolism. Because thiol groups are oxidized and reduced easily and reversibly, the redox control of cellular metabolism has become an increasing focus of research. In the same way that oxygen and nitrogen have reactive species (ROS and RNS), sulfur too can form reactive molecular species (RSS), for example when a -SH group is oxidized. Indeed, several redox reactions occur via RSS intermediates. Several naturally occurring S-containing molecules are themselves RSS and because they are physiologically active they make up part of the intrinsic plant defence repertoire against herbivore and pathogen attack. Furthermore, RSS can also be used as redox-active pharmacological tools to study cell metabolism. The aim of this review is to familiarize the general reader with some of the chemical concepts, terminology and biology of selected RSS.


Review of salivary papers published in the British Journal of Oral & Maxillofacial Surgery during 2009-2010.
The management of salivary gland disease forms an appreciable part of the work undertaken by our specialty. Fast-track and one-stop clinics for head and neck lumps allow for early diagnosis of salivary gland tumours in most units, and for the sharing of cases between our ear, nose and throat (ENT) colleagues. The emphasis on benign salivary gland disease is very much on outcome after operation, and there have been improvements in surgical technique, particularly in relation to minimal dissection of salivary adenomas and sialendoscopy. This article continues a series of reviews, which aim to provide readers with a quick overview and update of recent publications in the British Journal of Oral and Maxillofacial Surgery (BJOMS) within a particular subspecialty.


Prospective randomized comparison of laparoscopic-assisted vaginal hysterectomy (LAVH) with abdominal hysterectomy (AH) for the treatment of the uterus weighing >200 g.
Laparoscopic-assisted vaginal hysterectomy (LAVH) can be used for the vaginal removal of large uteri (200 g), which are conventionally treated with an abdominal approach (AH). Forty-eight women with a sonographically estimated uterine weight of >200 g were prospectively randomized to undergo either LAVH (n = 28) or AH (n = 20). The median uterus weight was 334 g for LAVH vs 428 g for AH (not significant). The median operative time (133 vs 132 min) and duration of recuperation (42 vs 42 days) were similar. LAVH was associated with significantly less intraoperative blood loss (median, 200 vs 600 ml; p < 0.05), a lower pain index at postoperative day 4 (median [who scale], 0 VS 5; P < 0.05), a lower decrease in hemoglobin (median,-0.6 VS -1.55 MG/DL; P < 0.05), and a lower decrease in hematocrit (median, -0.03% VS -0.07%; P < 0.05). There were no significant differences in the frequency of postoperative complications (14.3% for LAVH VS 30% for AH). Although all LAVH patients who answered the questionnaire said they would undergo the same procedure again, only 45% of the AH group were satisfied (P < 0.05). For the treatment of uteri >200 g, LAVH has several advantages over AH: lower postoperative morbidity, quicker short-term recuperation, and better patient acceptance.


L6H9 attenuates LPS-induced acute lung injury in rats through targeting MD2.
Acute lung injury (ALI) is a clinical syndrome characterized by respiratory failure and acute inflammatory response. Myeloid differentiation protein 2 (MD2) has been reported to play a pivotal role in the recognition of LPS and LPS-mediates inflammatory response. There have been no clinically effective therapeutic drugs for ALI. L6H9, an inhibitor of MD2, showed anti-inflammatory effects and cardiac protective activity. However, its effect on ALI has not been elucidated. In this study, intratracheal instillation of LPS was employed to induce ALI in rats. L6H9 pretreatment attenuates LPS-induced pathological variations in lung tissue and pulmonary edema. LPS instillation enhanced lung microvascular permeability, thereby causing inflammatory cells flow into bronchoalveolar lavage fluid (BALF). However, L6H9 inhibited the LPS-induced upregulation of total protein concentration and the number of inflammatory cells in BALF. In the meantime, macrophages infiltration in lung tissue induced by LPS was also mitigated by L6H9 treatment. Furthermore, L6H9 suppressed LPS-induced inflammatory cytokines expression in BALF, serum, and lung tissue. It is noteworthy that LPS-induced MD2/TLR4 complex formation was inhibited by L6H9 in lung tissue. On the whole, these results show that L6H9 can attenuate LPS-induced ALI in vivo by targeting MD2. Our study provide new candidate for the treatment of ALI.


Effect of culture parameters on the heat tolerance and inorganic polyphosphate accumulation by Lacticaseibacillus rhamnosus CRL1505, a multifunctional bacterium.
Lacticaseibacillus rhamnosus CRL1505 can be used in functional products as a probiotic powder (dried live cells) or as a postbiotic intracellular extract containing inorganic polyphosphate as a functional biopolymer. Thus, the aim of this work was to optimize the production of Lr-CRL1505 depending on the target of the functional product (probiotic or postbiotic). For this purpose, the effect of culture parameters (pH, growth phase) on cell viability, heat tolerance and polyphosphate accumulation by Lacticaseibacillus rhamnosus CRL1505 was evaluated. Fermentations at free pH produced less biomass (0.6 log units) than at controlled pH while the growth phase affected both polyphosphate accumulation and cell heat tolerance. Exponential phase cultures showed 4-15 times greater survival rate against heat shock and 49-62% increased polyphosphate level, compared with the stationary phase. Results obtained allowed setting the appropriate culture conditions for the production of this strain according to its potential application, i.e., as live probiotic cells in powder form or postbiotic. In the first case, running fermentations at pH 5.5 and harvesting the cells at the exponential phase are the best conditions for obtaining a high live biomass yield capable of overcoming heat stress. Whereas the postbiotic formulations production requires fermentations at free pH and harvesting the cells in exponential phase to increase the intracellular polyphosphate level as a first step.


Cyanoacrylate glue in socket repair: a comparative study.
This study aimed to compare socket repair with Nylon 5-0 suture and closure using cyanoacrylate biological glue after tooth extraction. Twenty male Wistar rats, each weighing approximately 200 g were submitted to the extraction of the right and left first molar teeth. On the right side, the alveolus was closed with 2 ethyl-cyanoacrylate glue, whereas on the left side closure was with a single interrupted Nylon 5-0 suture (Ethilon). The animals were sacrificed after 3, 7, 15, and 30 postoperative days, and images of histological sections of the alveolus were captured for analysis. Histomorphometry was performed using Image J software to quantify bone neoformation in the alveolus. The results showed that on the seventh postoperative day the side treated with 2-ethyl-cyanoacrylate presented a delay in relation to the sutured side. However, on days 15 and 30, the difference in bone neoformation between gradually decreased until the thirtieth postoperative day, with no significant difference in bone neoformation in the last period of analysis. There was no difference between neoformation in the two sides (p = 0.902) after statistical analysis of the histomorphometric results. In conclusion, socket repair after alveolus closure with 2-ethyl-cyanoacrylate allows complete bone neoformation after tooth extraction, and there is no significant difference when compared with closure with Nylon 5-0.


Identification of novel surfactin derivatives from NRPS modification of Bacillus subtilis and its antifungal activity against Fusarium moniliforme.
Bacillus subtilis strain PB2-L1 produces the lipopeptide surfactin, a highly potent biosurfactant synthesized by a large multimodular nonribosomal peptide synthetase (NRPS). In the present study, the modules SrfA-A-Leu, SrfA-B-Asp, and SrfA-B-Leu from surfactin NRPS in B. subtilis BP2-L1 were successfully knocked-out using a temperature-sensitive plasmid, pKS2-mediated-based, homologous, recombination method. Three novel surfactin products were produced, individually lacking amino acid Leu-3, Asp-5, or Leu-6. These surfactins were detected, isolated, and characterized by HPLC and LC-FTICR-MS/MS. In comparison with native surfactin, [∆Leu(3)]surfactin and [∆Leu(6)]surfactin showed evidence of reduced toxicity, while [∆Asp(5)]surfactin showed stronger inhibition than native surfactin against B. pumilus and Micrococcus luteus. These results showed that the minimum inhibitory concentration of [∆Leu(6)]surfactin for Fusarium moniliforme was 50 μg/mL, such that [∆Leu(6)]surfactin could lead to mycelium projection, cell damage, and leakage of nucleic acids and protein. These factors all contributed to stimulating apoptosis in F. moniliforme. The present results revealed that [∆Leu(6)]surfactin showed a significant antifungal activity against F. moniliforme and might successfully be employed to control fungal food contamination and improve food safety.


Pathologico-optic approach to cataract and lens.
From the weight of the lenses of patients with senile cataract, ultrasonic measurements of the eyes of patients with acute diabetic refractive changes, and calculations on the basis of Legrand's theoretical eye, it appears that the conclusion can be drawn that these refractive changes are due to alterations in the refractive indices of the lens.


Pharmacokinetics of pyrazinamide under fasting conditions, with food, and with antacids.
To determine intrasubject and intersubject variability in, and the effects of food and antacids on, the pharmacokinetics of pyrazinamide (PZA). Randomized, four-period, crossover phase I study. Fourteen healthy men and women volunteers. Subjects ingested single doses of PZA 30 mg/kg under fasting conditions twice, without a high-fat meal and with an aluminum-magnesium antacid. They also received standard dosages of isoniazid, rifampin, and ethambutol. Serum was collected for 48 hours and assayed by gas chromatography with mass selective detector. Data were analyzed by noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: mean PZA Cmax 53.4+/-10.4 microg/ml, Tmax 1.43+/-1.06 hours, and AUC(0-infinity) 673+/-79.7 microg x hr/ml. Fasting results are similar to those in previous reports. In the presence of antacids, subjects had a mean Cmax of 55.6+/-9.0 microg/ml, Tmax of 1.43+/-1.23 hours, and AUC(0-infinity) of 628+/-88.4 microg x hr/ml. In the presence of the high-fat meal, mean Cmax was 45.6+/-9.44 pg/ml, Tmax 3.09+/-1.74 hours, and AUC(0-infinity) 687+/-116 microg x hr/ml. These small changes in Cmax, Tmax, and AUC(0-infinity) can be avoided by giving PZA on an empty stomach whenever possible.


Ultra-low-dose multiphase CT angiography derived from CT perfusion data in patients with middle cerebral artery stenosis.
Computed tomography (CT) perfusion (CTP) source images contain both brain perfusion and cerebrovascular information, and may allow a dynamic assessment of collaterals. The purpose of the study was to compare the image quality and the collaterals identified on multiphase CT angiography (CTA) derived from CTP datasets (hereafter called CTPA) reconstructed with iterative model reconstruction (IMR) algorithm in patients with middle cerebral artery (MCA) steno-occlusion with those of routine CTA. Consecutive patients with a unilateral MCA steno-occlusion underwent non-contrast CT (NCCT), CTP, and CTA. CTPA images were reconstructed from CTP datasets. The vascular attenuation, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) of routine CTA and CTPA were measured and analyzed by Student's t test. Subjective image quality and collaterals were scored and compared using the Wilcoxon signed-rank test. Fifty-eight patients (mean age 61.7 years, 78% males, median National Institutes of Health Stroke Scale score = 12) were included. The effective radiation dose of CTP was 1.28 mSv. The vascular attenuation, SNR, CNR, and the image quality of CTPA were considerably higher than that of CTA (all, p < 0.001). Collaterals were rated higher on CTPA compared with CTA (1.79 ± 0.64 vs. 1.22 ± 0.84, p < 0.001). Fifty-three percent of patients with poor collaterals assessed on single-phase CTA had good collaterals on CTPA. CTPA derived from CTP datasets reconstructed with IMR algorithm offers image quality comparable to routine CTA and provides time-resolved evaluation of collaterals in patients with MCA ischemic disease.


The potent role of Src kinase-regulating glucose metabolism in cancer.
Src kinase is a membrane-related nonreceptor tyrosine kinase that plays an essential role in cell growth, division, migration, and survival signaling pathways. In addition, it regulates glucose metabolism in cancer cells through different mechanisms, such as directly regulating glucose metabolism related enzymes and glucose transporters or indirectly regulating transcription factors and signal transduction pathways. In this review, we clarify the role of Src kinase in regulating glucose metabolism in cancer cells, and partially explain the pathogenesis of malignant tumors. We also discuss that further understanding and study of the role of Src kinase in glucose metabolism will provide a potential therapeutic window for cancer treatment.


Genotypic-specific hormonal reprogramming and crosstalk are crucial for root growth and salt tolerance in bermudagrass (Cynodon dactylon).
Salt stress is one of the major abiotic factors limiting the productivity of bermudagrass (Cynodon dactylon). However, the role of hormonal reprogramming and crosstalk in regulating root growth and salt tolerance in bermudagrass was not reported. Here, we examined the physiological and hormonal responses of two contrasting bermudagrass genotypes; 'C43,' salt-tolerant 'C198' salt-sensitive. Under salt stress, 'C43' had better membrane stability and higher photosynthetic activity than the 'C198.' Salt stress promoted root growth and improved root/shoot ratio and root activity in 'C43,' but the root growth of 'C198' was inhibited by salt stress, leading to diminished root activity. The two bermudagrass genotypes also showed critical differences in hormonal responses, especially in the roots. The root contents of indole-3-acetic acid (IAA), cytokinin derivatives, such as trans-zeatin riboside (tZR) and dihydrozeatin riboside (DHZR) were increased in 'C43,' but decreased in 'C198' when exposed to salt stress. The root growth rate was positively correlated with the root IAA, tZR and DHZR, indicating their crucial role in root growth under salt stress. The expressions of TAA/YUCCA and CYP735A involved in IAA and tZR biosynthesis were induced by salt stress in 'C43,' but inhibited in 'C198,' leading to reduced hormone accumulations. Salt stress decreased the iP, tZ, and DHZ content in the roots of both genotypes, and no significant difference was observed between the two genotypes. Salt stress reduced the content of GA3 in both genotypes by inhibiting GA20ox and GA2ox genes, which could be attributed to the reduced shoot growth in both genotypes. The increased ABA level by salt stress was significantly higher in 'C198' than 'C43.' Furthermore, there were positive and negative correlations between different hormones and root growth, suggesting that root growth could be regulated by complex hormonal reprogramming and crosstalk. This study provides a foundation for understanding the underlying mechanisms of hormonal-mediated root growth and salt tolerance in bermudagrass.


Cell Culture Models and Animal Models for HBV Study.
Highly representative and relevant cell and mouse models are required for HBV study, including uncovering its lifecycle, investigation of the viral-host interaction, and development and evaluation of the novel antiviral therapy. During the past 40 years, both HBV cell culture models and animal models have evolved over several generations, each with significant improvement for specific purposes. In one aspect, HBV cell culture models experienced the original noninfection model including HBV plasmid DNA transfection and HBV genome integrated stable cells such as HepG2.2.15 which constitutively produces HBV virus and HepAD38 cells and its derivatives which drug-regulated HBV production. As for HBV infection models, HepaRG cells once dominated the HBV infection field for over a decade, but its complicated and labor-extensive cell differentiation procedures discouraged primary researchers from stepping in the field. The identification of human NTCP as HBV receptor evoked great enthusiasm of the whole HBV field, and its readily adaptive characteristic makes it popular in many HBV laboratories. Recombinant cccDNA (rc-cccDNA) emerged recently aiming to tackle the very basic question of how to eventually eradicate cccDNA without HBV real virus infection. In the other aspect, HBV transgenic mouse was firstly generated in the 1990s, which was helpful to decipher HBV production in vivo. However, the HBV transgenic mice were naturally immune tolerant to HBV viral products. Subsequently, a series of nonintegrated HBV mouse models were generated through plasmid hydrodynamic tail vein injection and viral vector-mediated delivery approaches, and HBV full life cycle was incomplete as cccDNA was not formed from HBV relaxed circular DNA (rcDNA). Human NTCP transgenic mouse still could not support productive HBV infection, and humanized mouse liver with human hepatocytes which supported whole HBV life cycle still dominates HBV infection in vivo, a value but expensive model until now. Other methods to empower mouse to carry HBV cccDNA were also exploited. In this chapter, we summarized the advantages and disadvantages of each model historically and provided protocols for HBV infection in HepG2-NTCP cells, HBV rc-cccDNA transfection in HepG2 cells, and HBV infection in NRG-Fah-/- liver humanized mouse.


Feasibility and Safety of a Powered Exoskeleton for Assisted Walking for Persons With Multiple Sclerosis: A Single-Group Preliminary Study.
To examine the feasibility, safety, and secondary benefit potential of exoskeleton-assisted walking with one device for persons with multiple sclerosis (MS). Single-group longitudinal preliminary study with 8-week baseline, 8-week intervention, and 4-week follow-up. Outpatient MS clinic, tertiary care hospital. Participants (N=13; age range, 38-62y) were mostly women with Expanded Disability Status Scale scores ranging from 5.5 to 7.0. Exoskeleton-assisted walk training. Primary outcomes were accessibility (enrollment/screen pass), tolerability (completion/dropout), learnability (time to event for standing, walking, and sitting with little or no assistance), acceptability (satisfaction on the device subscale of the Quebec User Evaluation of Satisfaction with Assistive Technology version 2), and safety (event rates standardized to person-time exposure in the powered exoskeleton). Secondary outcomes were walking without the device (timed 25-foot walk test and 6-minute walk test distance), spasticity (Modified Ashworth Scale), and health-related quality of life (Patient-Reported Outcomes Measurement and Information System pain interference and Quality of Life in Neurological Conditions fatigue, sleep disturbance, depression, and positive affect and well-being). The device was accessible to 11 and tolerated by 5 participants. Learnability was moderate, with 5 to 15 sessions required to walk with minimal assistance. Safety was good; the highest adverse event rate was for skin issues at 151 per 1000 hours' exposure. Acceptability ranged from not very satisfied to very satisfied. Participants who walked routinely improved qualitatively on sitting, standing, or walking posture. Two participants improved and 2 worsened on ≥1 quality of life domain. The pattern of spasticity scores may indicate potential benefit. The device appeared feasible and safe for about a third of our sample, for whom routine exoskeleton-assisted walking may offer secondary benefits.


The quantum efficiency of photosynthesis in macroalgae and submerged angiosperms.
Photon absorption and photosynthesis under conditions of light limitation were determined in six temperate marine macroalgae and eight submerged angiosperms. Photon absorption and photosynthetic efficiency based on incident light increased in proportion to chlorophyll density per area and approached saturation at the highest densities (∼300 mg chlorophyll m-2) encountered. Absorption and photosynthetic efficiency were higher in brown and red algae than in green algae and angiosperms for the same chlorophyll density because of absorption by accessory pigments. Among thin macroalgae and submerged angiosperms chlorophyll variations directly influence light absorption and photosynthesis, whereas terrestrial leaves have chlorophyll in excess and thus there is only a minor influence of pigment variability on light-limited photosynthesis. The quantum efficiency of photosynthesis averaged 0.062±0.019 (±SD) mol O2 mol-1 photons absorbed for macroalgae and, significantly less, 0.049±0.016 mol O2 mol-1 photons for submerged angiosperms. Of the measurements 80% were between 0.037 and 0.079 mol O2 mol-1 photons. The results are lower than values given in the literature for unicellular algae and terrestrial C3 species at around 0.1 mol O2 mol-1 photons, but resemble values for other marine macroalgae and terrestrial C4 species. The reason for these differences remains unknown, but may be sought for in differential operation of cyclic photophosphorylation and photorespiration.


[Effect of isometric exercise on the lesser circulation in a group of patients with mitral stenosis].
The hemodynamic changes of the pulmonary vascular system in patients with mitral stenosis, has been evaluated during isometric exercise (handgrip). Heart rate, pulmonary artery sistolic, dyastolic, mean and "wedged" pressure, end-dyastolic pulmonary vascular and trans-mitralic gradient, total pulmonary resistences increase significantly. Cardiac output and pulmonary vascular bed are probably related to the tachycardia induced by the handgrip, and to the conseguent shortening of the dyastolic left ventricular filling time.


A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: Study design of the TANDEM trial.
Nonalcoholic steatohepatitis (NASH) is a multifactorial disease involving different contributing mechanisms, with no approved therapies so far. Tropifexor (TXR), a farnesoid X receptor agonist, and cenicriviroc (CVC), a chemokine receptor types 2/5 antagonist, target the steatotic, inflammatory, and/or fibrotic pathways involved in NASH. TANDEM (CLJC242A2201J; NCT03517540) is a 48-week, phase 2b, randomized, double-blind, multicenter study in 200 adult patients with biopsy-proven NASH and liver fibrosis. Patients will be randomized in a 1:1:1:1 ratio to receive either TXR 140 μg once daily (qd), CVC 150 mg qd, TXR 140 μg + CVC 150 mg qd, or TXR 90 μg + CVC 150 mg qd. The study comprises a 48-week treatment period and 4 weeks of follow-up. The key inclusion criterion is presence of NASH with fibrosis stage F2/F3 as seen on screening liver biopsy or on historical liver biopsy performed within 6 months prior to screening. The primary objective is evaluation of the safety and tolerability of combination therapy compared with the monotherapies over 48 weeks. The secondary objective is to evaluate efficacy as assessed by ≥1-point improvement in liver fibrosis versus baseline or resolution of steatohepatitis after 48 weeks. TANDEM will evaluate the combination of TXR and CVC with respect to safety and efficacy outcomes related to improvement in fibrosis or resolution of steatohepatitis. Given the effects of TXR and CVC in multiple pathophysiological pathways associated with NASH, combination therapy is likely to show additional benefits compared with monotherapy.


Murine mucosal T cells have VIP receptors functionally distinct from those on intestinal epithelial cells.
Reports suggest that vasoactive intestinal peptide (VIP) binds to lymphocytes and modulates immune responses. The intestines are richly innervated with VIP-producing nerves. Thus, VIP from nerves or other sources may participate in mucosal immunoregulation. To explore this hypothesis further, murine intestinal mucosal inflammatory cells were scrutinized for functional VIP receptors. An [125I]VIP competitive binding assay characterized VIP receptors. Unfractionated lamina propria inflammatory cells bound [125I]VIP specifically. This binding was abrogated by T cell depletion. The VIP receptor on lamina propria T cells was of a single class with a Kd of 9.08 x 10(-9) M. It bound PHI and other peptide analogs poorly. The intestinal epithelial cell had a high-affinity VIP receptor (Kd 4.17 x 10(-10) M) that bound one VIP analog with moderate affinity. Both VIP and ConA stimulated mucosal inflammatory cells to release interleukin-5 (IL-5). Mucosal inflammatory cells depleted of T cells did not release IL-5 in response to VIP or ConA. It is concluded that: (1) some murine mucosal T lymphocytes have VIP receptors that may be distinct from those displayed on mucosal epithelial cells; (2) VIP affects mucosal T lymphocyte function.