CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.
Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort. We retrospectively investigated the CNVs' contribution to AR conditions in cases subjected to chromosomal microarray analysis (CMA, N = ~70,000) and/or clinical exome sequencing (ES, N = ~12,000) at Baylor Genetics; most had pediatric onset neurodevelopmental disorders. CNVs contributed to biallelic variations in 87 cases, including 81 singletons and three affected sibling pairs. Seventy cases had CNVs affecting both alleles, and 17 had a CNV and a single-nucleotide variant (SNV)/indel in trans. In total, 94.3% of AR-CNVs affected one gene; among these 41.4% were single-exon and 35.0% were multiexon partial-gene events. Sixty-nine percent of homozygous AR-CNVs were embedded in homozygous genomic intervals. Five cases had large deletions unmasking an SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses. AR-CNVs are often smaller in size, transmitted through generations, and underrecognized due to limitations in clinical CNV detection methods. Our findings from a large clinical cohort emphasized integrated CNV and SNV/indel analyses for precise clinical and molecular diagnosis especially in the context of genomic disorders.


Biodegradation of marine crude oil pollution using a salt-tolerant bacterial consortium isolated from Bohai Bay, China.
This study aims at constructing an efficient bacterial consortium to biodegrade crude oil spilled in China's Bohai Sea. In this study, TCOB-1 (Ochrobactrum), TCOB-2 (Brevundimonas), TCOB-3 (Brevundimonas), TCOB-4 (Bacillus) and TCOB-5 (Castellaniella) were isolated from Bohai Bay. Through the analysis of hydrocarbon biodegradation, TCOB-4 was found to biodegrade more middle-chain n-alkanes (from C17 to C23) and long-chain n-alkanes (C31-C36). TCOB-5 capable to degrade more n-alkanes including C24-C30 and aromatics. On the basis of complementary advantages, TCOB-4 and TCOB-5 were chosen to construct a consortium which was capable of degrading about 51.87% of crude oil (2% w/v) after 1week of incubation in saline MSM (3% NaCl). It is more efficient compared with single strain. In order to biodegrade crude oil, the construction of bacterial consortia is essential and the principle of complementary advantages could reduce competition between microbes.


[Further data on the dependence of the agglutination titre of T4 streptococci on the haptoglobin type (Hp 2-2 and Hp 2-1)].
Anti-streptococcal T4 titres in human sera tend to be higher in normal sera of the Hp type hp 2-2 than in normal sera of hp 2-1 subjects. If the sera are heated above a temperature of 50 degrees C the difference disappeared and the titres are reduced. When heating sera to 63 degrees for 10 min no agglutination activity for T4 streptococci can be observed.


Effect of Liuzijue on pulmonary rehabilitation in patients with chronic obstructive pulmonary disease: study protocol for a multicenter, non-randomized, prospective study.
Traditional Chinese exercise as a new pulmonary rehabilitation technique has been increasingly used and achieved good results in pulmonary rehabilitation of chronic obstructive pulmonary disease (COPD). The aim of this study is to investigate the protective effects of Liuzijue on exercise tolerance, lung function, and quality of life in patients with COPD. This study is a multicenter, non-randomized, prospective study. Patients will be divided into a control group (CG) and a Liuzijue group (LG) based on their willingness to learn Liuzijue. None of the outcome assessors will know the grouping of patients. Participants in this study will be collected from stable COPD patients who are outpatients or inpatients in 3 centers in China since September 2021. Patients will meet the diagnostic criteria for GOLD stage I-II COPD (FEV1% ≥ 0.5 and FEV1/FVC < 0.7) and be aged 40 years or older. Patients voluntarily will take part in the clinical study and sign an informed consent form. All participants will follow their existing medication. For LG patients, Liuzijue training has been added. Patients will practice Liuzijue for more than 30 minutes a day, more than 5 days a week, and adhere to the training for 3 months. Outcome indicators are 6-minute walk test (6MWT), lung function (FEV1%, FEV1/FVC, MMEF, PEF), modified British Medical Research Council (mMRC) score, COPD assessment test score (CAT), acute exacerbations and changes in drug treatment. This study quantified the effect of Liuzijue on the pulmonary rehabilitation of COPD patients in the stable phase of the disease, and provided a basis for the use of Liuzijue in COPD patients. Chinese clinical trial registry, ChiCTR2100048945. Date: 2021-07-19. http://www.chictr.org.cn/showproj.aspx?proj=129094.


A MoS2QDs/chitin nanofiber composite for improved antibacterial and food packaging.
Chitin nanofiber has potential application as antibacterial nanocomposite material because of its inherent biocompatibility, biological activity, amino containing macromolecular structure and nano-size effect. Molybdenum disulfide quantum dots (MoS2QDs) were uniformly bonded on partially deacetylated chitin nanofibers (DEChNs) by hydrothermal reactions. The antibacterial properties of MoS2QDs/DEChN against Escherichia coli were detected under different conditions. When the antibacterial agent was fixed at 200 μg/mL, the survival rates of bacteria were 2.77% (pH = 4), 5.58% (pH = 5) and 7.83% (pH = 6), which were lower than those in the DEChN groups. Unlike DEChN, which only had excellent antibacterial activity under acidic conditions (pH < 5), the combination of DEChN and MoS2QDs had antibacterial activity close to neutral conditions, with a bacteriostatic rate > 90%. When TEMPO-oxidized cellulose nanofibers (TOCN) were applied for the preparation of MoS2QDs/TOCN, they did not show obvious antibacterial ability, which proved the positive role of DEChN and its amino groups. The MoS2QDs/DEChN assembled film could be applied to preserve meat by delaying spoilage. The current study might inspire new ideas for designing food packaging based on the prepared MoS2QDs/DEChN films.


Adjunctive Aesthetic Procedures in Orthognathic Surgery.
An important aesthetic goal in orthognathic planning is to improve facial balance, harmony, volume, and symmetry. It is therefore logical that adjunctive aesthetic procedures become a part of the overall orthognathic treatment plan and that their possibilities are discussed with orthognathic candidates. Such procedures help to improve the final outcome of the orthognathic treatment and enhance patient satisfaction. Training and experience are of utmost importance when offering and performing aesthetic facial surgery. This article discusses various facial aesthetic procedures that can be combined with orthognathic surgery, to the patient's benefit, to help them become the most beautiful version of themselves.


Refinement of the selection of physicochemical properties for grouping and read-across of nanoforms.
Before placing a new nanoform (NF) on the market, its potential adverse effects must be evaluated. This may e.g. be done via hazard and risk assessment. Grouping and read-across of NFs is a possible strategy to reduce resource consumption, maximising the use of existing data for assessment of NFs. The GRACIOUS project provides a framework in which possible grouping and read-across for NFs is mainly based on an evaluation of their similarity. The impact of NFs on human health and the environment depends strongly on the concentration of the NF and its physicochemical properties, such as chemical composition, size distribution, shape, etc. Hence, knowledge of the most relevant physicochemical properties is essential information for comparing similarity. The presented work aims to refine existing proposals for sets of descriptors (descriptor array) that are needed to describe distinct NFs of a material to identify the most relevant ones for grouping and read-across. The selection criteria for refining this descriptor array are explained and demonstrated. Relevant protocols and methods are proposed for each physicochemical property. The required and achievable measurement accuracies of the refined descriptor array are reviewed, as this information is necessary for similarity assessment of NFs based on individual physicochemical properties.


Hierarchical Bayesian Modelling of Variability and Uncertainty in Synthetic Action Potential Traces.
There are many sources of uncertainty in the recording and modelling of membrane action potentials (APs) from cardiomyocytes. For example, there are measurement, parameter, and model uncertainties. There is also extrinsic variability between cells, and intrinsic beat-to-beat variability within a single cell. These combined uncertainties and variability make it very difficult to extrapolate predictions from these models, since current AP models have single parameter values and thus produce a single AP trace. We aim to re-parameterise existing AP models to fit experimental data, and to quantify uncertainty associated with ion current densities when measuring and modelling these APs. We then wish to propagate this uncertainty into model predictions, such as ion channel block effected by a pharmaceutical compound. We perform an in silico study using synthetic data generated from different sets of parameters. We then 'forget' these parameter values and re-infer their distributions using hierarchical Markov chain Monte Carlo methods. We find that we can successfully infer the 'correct' distributions for most ion current densities for each AP trace, along with an approximation to the higher-level distribution from which these parameter values were sampled. There is, however, some level of unidentifiability amongst some of the current densities.


Selection for loss of RpoS in Cronobacter sakazakii by growth in the presence of acetate as a carbon source.
We demonstrate that growth of Cronobacter sakazakii in the presence of acetate as a carbon source promotes loss of RpoS, with a consequent reduction in stress tolerance. This suggests that C. sakazakii is capable of regulating cell fitness through mutation of the rpoS gene.


Riboflavin depletion impairs cell proliferation in adult human duodenum: identification of potential effectors.
Riboflavin (vitamin B2) is an essential dietary component with a known function in oxidative metabolism. Our previous data using a rat model of riboflavin deficiency suggested that riboflavin also functions as a luminal signaling molecule regulating crypt development and cell turnover. Riboflavin deficiency is prevalent in both high- and low-income countries across the globe. This study aims to establish whether riboflavin deficiency has consequences for gastrointestinal (GI) morphology in adults and what the effects and effectors of any such alteration may be. Duodenal biopsies and blood samples were collected from a cross-section of gastroscopy patients. Crypt morphology and cell division were studied by immunohistochemistry, and biochemical riboflavin status was determined. Additionally a cell culture model of riboflavin deficiency was developed and analyzed using a combination of flow cytometry, and microarray and clonogenic assays. Duodenal crypts from subjects in the lowest quartile of riboflavin status were significantly shorter (P=0.023), less cellular (P=0.007), and had fewer cell divisions (P=0.034) than the crypts of subjects in the top quartile of riboflavin status. Following riboflavin depletion of colon cells in culture, cell cycle slowed. Microscopy revealed impaired mitosis and accumulation of aneuploid cells. Alterations in gene expression profiles reflected this alteration, with several mitosis-related genes altered, including AspM, cyclin B1, and Birc5 downregulated and Kif23 upregulated. Riboflavin depletion in vitro caused irreversible loss of proliferative potential of cells. Riboflavin depletion in adult humans impairs proliferation and proliferative potential of intestinal cells, which may have implications for gastrointestinal function.


Image-guided treatment of Budd-Chiari syndrome: a giant leap from the past, a small step towards the future.
Budd-Chiari syndrome (BCS) is a relatively rare vascular disease characterized by hepatic outflow tract obstruction, and image-guided endovascular treatment, namely percutaneous angioplasty, stenting, and transjugular intrahepatic portosystemic shunt (TIPS), has proven to be effective treatment modalities to alleviate symptoms and markedly improve the prognosis of the disease. Specifically, a step-wise approach is recommended, i.e., angioplasty and stenting are the prioritized choice for patients with membranous obstruction and short-length stenosis, whereas TIPS is the option for patients who fail this treatment. Currently, 5-year survival with the step-wise approach is about 75%, and the most promising way to further improve this value is to identify candidates who are at high risk of failing angioplasty, and perform pre-emptive TIPS in these patients.


An evaluation of the clinical tests and outcome measures used to assess patellar instability.
A literature review was undertaken to determine which clinical tests and outcome measures have been described to diagnose and evaluate patellar instability, and to assess the literature examining the sensitivity and specificity of these diagnostic tests, or the reliability, validity and responsiveness of the outcome measures identified. An electronic search was undertaken using standard databases as well as a hand search of specialist journals, reference lists and local medical libraries. All English language publications describing and/or evaluating diagnostic tests and outcome measures for patellar instability patients were included. On review, 104 papers and 64 textbooks were included. Eighteen diagnostic tests and 10 outcome measures were identified. Of these only five diagnostic tests (Bassett's sign; apprehension test; gravity subluxation test; clinical assessment of the tibial tubercle to trochlear groove value; Q-angle) and seven outcome measures (modified International Knee Documentation Committee knee ligament standard evaluation form; Kujala anterior knee pain scale; Fulkerson knee instability scale; Lysholm knee scoring scale; Tegner activity level scale; Short Form-36; Musculoskeletal Function Assessment injury and arthritis survey) had been assessed for accuracy in five studies. The sensitivity, specificity, reliability or validity, of these tests remains unclear for this patient population. Further work is needed to assess the appropriateness of the identified tests and outcomes for patellar instability cohorts.


Further evidence of the involvement of the Wnt signaling pathway in Dupuytren's disease.
Genetic background plays an important role in the development of Dupuytren's disease. A genome-wide association study (GWAS) showed that nine loci are associated with the disease, six of which contain genes that are involved in Wnt signaling (WNT2, WNT4, WNT7B, RSPO2, SFRP4, SULF1). To obtain insight in the role of these genes, we performed expression studies on affected and unaffected patient's tissues. Surgically obtained nodules and cords from eight Dupuytren's patients were compared to patient-matched control tissue (unaffected transverse palmar fascia). The Wnt-related genes found in the GWAS, the classical Wnt-downstream protein β-catenin, as well as (myo)fibroblast markers were analyzed using real-time qPCR and immunohistochemical stainings for mRNA levels and protein levels, respectively. The collagen-coding genes COL1A1 and COL3A1 were highly upregulated on mRNA level, both in cords and nodules. Three Wnt-related genes were found to be differently regulated compared to control tissue: WNT2 was downregulated in nodules, WNT7B was upregulated in nodules, and SFRP4 was upregulated in nodules and cords. Immunohistochemistry revealed significantly less staining of Wnt2 in cords, but significantly more staining for Wnt7b in nodules. There was significantly more staining of α-SMA in nodules and cord and β-catenin in nodules than in control tissue. We found differences in expression, both at mRNA and protein level, in several Wnt-related genes found earlier to be associated with Dupuytren's disease. Of these, Wnt7b was upregulated and found in close association with both α-SMA and β-catenin expressing cells, making it a candidate pro-fibrotic mediator in Dupuytren's disease.


Energetic, economic and environmental assessment for the anaerobic digestion of pretreated and codigested press mud.
This study investigates the feasibility of anaerobic digestion (AD) of press mud previously pretreated, using two methods: Liquid Hot Water (LHW) and Thermo-Alkaline (TA), from an economic, energetic and environmental point of view. Two scenarios, a sugar mill with and without distillery were studied, considering monodigestion and vinasse codigestion. The results have shown that the LHW and TA pretreatments are self-sufficient in terms of thermal requirements since they can recover heat from the biogas engine, but the maximum electric and thermal net energy (64 MWh d-1 and 95 MWh d-1, respectively) was obtained during co-digestion with vinasse. The results of the environmental Life Cycle Analysis (LCA) show that the alternatives improve the environmental profiles, in both scenarios. The endpoint impact category "Human health" had the highest contribution because of both: the burning of fossil fuel at refinery to supply the required electricity; and the production of Ca(OH)2 when vinasse was fed. The AD of pretreated press mud by LHW in CSTR reactors was the most viable for the scenario of a sugar mill without distillery, while the alternative co-digestion with the vinasse of the press mud without pretreatment was the most viable for the scenario of a sugar mill with distillery. This research shows that both the environmental and energetic profiles and the profitability of methane production can improve when the pretreatment and co-digestion of these wastes from the sugar - alcohol production process are considered.


Enhanced stability of beta-galactosidase in parenchymal and nonparenchymal liver cells by conjugation with dextran.
In order to enhance the stability of beta-galactosidase, we conjugated the enzyme with dextran T-10 (Mr approx. 10 000). The conjugate contained 9-10 mol dextran/mol protein (beta-galactosidase, Mr 68 000), and the specific activity retained after conjugation was 90 +/- 4% (n = 3) of the initial activity. Uptake and degradation of native and conjugated beta-galactosidase in isolated hepatocytes and nonparenchymal liver cells was studied. There was a marked increase in stability against degradation in both cell types when beta-galactosidase was conjugated with Dextran. The degradation of dextran-conjugated enzyme was reduced by 35% in hepatocytes and by 43% in nonparenchymal cells, after 80 and 40 min, respectively, as compared with the free enzyme. However, there was insignificant difference between the uptake of native and conjugated enzyme into the liver cells. Upon intravenous infusion into rats, native and conjugated enzyme were cleared from plasma with only a slight difference in the clearance rate. The observed stability of dextran-conjugated beta-galactosidase towards cellular degradation was in accordance with the in vitro experiments. The conjugate showed marked thermal stability at 50 degrees C and enhanced resistance towards proteolysis by the broad specific protease subtilopeptidase A. This demonstrates that dextran conjugation may be used as a means of stabilizing lysosomal enzymes for therapeutic purposes.


A ratiometric fluorescent probe based on quinoline for monitoring and imaging of Leucine aminopeptidase in liver tumor cells.
Leucine aminopeptidase (LAP) is known as an important potential biomarker for liver malignancy and it is urgent to develop an intuitive and effective method to monitor the activity of LAP in liver cancer. Although, numerous LAP fluorescent probes had been developed, it is still a challenge to detect LAP activity in liver cancer. Herein, combained with the DFT, we reported a novel galactose-appended hepatoma-specific ratiometric fluorescent probe (Gal-QL-Leu) based on quinoline group for imaging and tracing LAP in liver tumor cells. Probe Gal-QL-Leu demonstrated a obvious ratiometric characteristics, better selectivity, good biocompatibility and high sensitivity. Moreover, the selective imaging of LAP in HepG2, HCT116, A549 and HeLa cells had been achieved with probe Gal-QL-Leu, demonstrating good application prospect in the detection of LAP activity in liver tumor cells.


Correction to: Afatinib is active in osteosarcoma cell lines.
The title of the article is incorrectly published in the original article. The correct article title is "Afatinib is active in osteosarcoma cell lines".


Ruptured aneurysms of the intradural artery of adamkiewicz: Angiographic features and treatment options.
We present an unusual case of a 59year old male patient who presented with acute, bilateral lower extremity weakness and was found to have non-traumatic spinal subarachnoid hemorrhage. Diagnostic workup including MRI and angiography revealed an aneurysm of the artery of Ademkiewicz. This was managed conservatively and the patient has had marked clinical improvement. We present the details of this unusual case as well as a literature review related to aneurysms of the artery of Ademkiewicz.


Metformin enhances anti-tumor effect of L-type amino acid transporter 1 (LAT1) inhibitor.
In many cancer cells, L-type amino acid transporter 1 (LAT1) transports neutral amino acids with bulky side chain, which activate mammalian target of rapamycin (mTOR) to cause cell proliferation. An anti-diabetic drug, metformin, has been shown to activate AMP-activated protein kinase (AMPK), which leads to inhibition of mTOR. LAT1 inhibition in combination with metformin could result in more prominent suppression of mTOR activity. Anti-proliferative effect of a newly developed LAT1 specific inhibitor JPH203 in combination with metformin is evaluated in 2 head and neck cancer cell lines, Ca9-22 and HEp-2 cells and in nude mice inoculated with Ca9-22 cells. By MTT assay, 0.5 mM metformin inhibited proliferation of Ca9-22 cells to 70% of control. In the presence of 100 μM JPH203, proliferation of Ca9-22 cells was inhibited to 60% of control. By combining these 2 drugs, proliferation of Ca9-22 was significantly inhibited to 40% of control. However, this regimen was not very effective against HEp-2 cells. This combination also suppressed in vivo growth of Ca9-22 cells in a xenotransplant model. A combination of anti-LAT1 drug with metformin may be an effective anti-proliferative therapy for certain subsets of cancers.


Ultrasound nanotheranostics: Toward precision medicine.
Ultrasound (US) is a mechanical wave that can penetrate biological tissues and trigger complex bioeffects. The mechanisms of US in different diagnosis and treatment are different, and the functional application of commercial US is also expanding. In particular, recent developments in nanotechnology have led to a wider use of US in precision medicine. In this review, we focus on US in combination with versatile micro and nanoparticles (NPs)/nanovesicles for tumor theranostics. We first introduce US-assisted drug delivery as a stimulus-responsive approach that spatiotemporally regulates the deposit of nanomedicines in target tissues. Multiple functionalized NPs and their US-regulated drug-release curves are analyzed in detail. Moreover, as a typical representative of US therapy, sonodynamic antitumor strategy is attracting researchers' attention. The collaborative efficiency and mechanisms of US and various nano-sensitizers such as nano-porphyrins and organic/inorganic nanosized sensitizers are outlined in this paper. A series of physicochemical processes during ultrasonic cavitation and NPs activation are also discussed. Finally, the new applications of US and diagnostic NPs in tumor-monitoring and image-guided combined therapy are summarized. Diagnostic NPs contain substances with imaging properties that enhance US contrast and photoacoustic imaging. The development of such high-resolution, low-background US-based imaging methods has contributed to modern precision medicine. It is expected that the integration of non-invasive US and nanotechnology will lead to significant breakthroughs in future clinical applications.


Pre-exposure to morphine and the attenuation of conditioned taste aversion in rats.
Three experiments were done using male Wistar rats to determine whether the mechanisms underlying the attenuation of a conditioned taste aversion to morphine by pre-exposure to the drug were similar to those involved in the development of tolerance to the analgesic response to morphine. This was tested by determining whether the effect of pre-exposure on conditioned taste aversion was situation-specific. In Experiment 1 it was found that having different environments for the pre-exposure injections and for the conditioning injections of morphine had no effect on the attenuation of the taste aversion. This finding was replicated in Experiment 2 in which it was also found that the attenuation of the analgesic effect, tested for in the same animals, was specific to the environment in which repeated injections were given. It was concluded that the attenuation of conditioned taste aversion involved processes different from those responsible for the attenuation of the analgesic effect of morphine. Experiment 3 showed that pairing the pre-exposure injections of morphine with one distinctive taste stimulus prevented the attenuation of the conditioned taste aversion to a second taste stimulus. These results suggest that different associative processes are responsible for the two types of attenuation.


Development of a defined approach for eye irritation or serious eye damage for liquids, neat and in dilution, based on cosmetics Europe analysis of in vitro STE and BCOP test methods.
The focus of Cosmetics Europe's programme on serious eye damage/eye irritation is on development of testing strategies and defined approaches for identification of ocular effects of chemicals in the context of OECD's Guidance Document on an Integrated Approach on Testing and Assessment (IATA) for Serious Eye Damage and Eye Irritation. Cosmetics Europe created a comprehensive database of chemicals for which in vitro data are available with corresponding historical in vivo Draize eye data. This database allowed further exploration of the initially proposed strategies from the CON4EI project and to identify opportunities for refinement. The current analysis focused on the development of a defined approach, applicable to liquid non-surfactant chemicals, neat and in dilution, that can distinguish between the three UN GHS categories (Cat. 1, Cat. 2, and No Cat.). Combining the modified-protocol Short Time Exposure (STE) test method (OECD TG 491 with extension to highly volatile substances) with the Bovine Corneal Opacity and Permeability Laser Light-Based Opacitometer (BCOP LLBO) test method in a Bottom-Up approach identified 81.2% Cat. 1, 56.3% Cat. 2, and 85.3% No. Cat correctly, with an NPV of 96.7% and a PPV of 68.6%. Therefore, the performance of the defined approach was better than the standalone test methods.


A new frameshift mutation encoding a truncated amelogenin leads to X-linked amelogenesis imperfecta.
The amelogenin proteins are the most abundant organic components of developing dental enamel. Their importance for the proper mineralization of enamel is evident from the association between previously identified mutations in the X-chromosomal gene that encodes them and the enamel defect amelogenesis imperfecta. In this investigation, an adult male presenting with a severe hypoplastic enamel phenotype was found to have a single base deletion at the codon for amino acid 110 of the X-chromosomal 175-amino acid amelogenin protein. The proband's mother, who also has affected enamel, carries the identical deletion on one of her X-chromosomes, while the father has both normal enamel and DNA sequence. This frameshift mutation deletes part of the coding region for the repetitive portion of amelogenin as well as the hydrophilic tail, replacing them with a 47-amino acid segment containing nine cysteine residues. While greater than 60% of the protein is predicted to be intact, the severity of this phenotype illustrates the importance of the C-terminal region of the amelogenin protein for the formation of enamel with normal thickness.


Early experiences of vasodilators and hypotensive anesthesia in children.
The physiological application of OHMS LAW explains the basis of hypotensive anesthesia. V = IR translates into: Pressure = Flow × Resistance or Blood pressure = Cardiac Output × Peripheral Resistance. If peripheral resistance is reduced by a vasodilator such as sodium nitroprusside (a short acting, vascular smooth muscle relaxant) or phenoxybenzamine (a long acting α adrenoreceptor antagonist), blood pressure will fall and vasoconstriction and bleeding will be reduced. A less desirable alternative to lowering blood pressure could be to reduce cardiac output by suppressing myocardial contractility using a ß(1) adrenoceptor antagonist or an inhalational agent such as isoflurane.


Assessment of implicit sexual associations in non-incarcerated pedophiles.
Offences committed by pedophiles are crimes that evoke serious public concern and outrage. Although recent research using implicit measures has shown promise in detecting deviant sexual associations, the discriminatory and predictive quality of implicit tasks has not yet surpassed traditional assessment methods such as questionnaires and phallometry. The current research extended previous findings by examining whether a combination of two implicit tasks, the Implicit Association Task (IAT) and the Picture Association Task (PAT), was capable of differentiating pedophiles from non-pedophiles, and whether the PAT, which allows separate analysis for male, female, boy and girl stimulus categories, was more sensitive to specific sexual associations in pedophiles than the IAT. A total of 20 male self-reported pedophiles (10 offender and 10 non-offenders) and 20 male self-reported heterosexual controls completed the two implicit measures. Results indicated that the combination of both tasks produced the strongest results to date in detecting implicit pedophilic preferences (AUC = .97). Additionally, the PAT showed promise in decomposing the sexual associations in pedophiles. Interestingly, as there was an equal distribution of offenders and non-offenders in the pedophile group, it was possible to test for implicit association differences between these groups. This comparison showed no clear link between having these implicit sexual associations and actual offending.


Association of ECG characteristics with clinical and echocardiographic outcome to CRT in a non-LBBB patient population.
Effectiveness of cardiac resynchronization therapy (CRT) in patients without left bundle branch block (non-LBBB) QRS morphology is limited. Additional selection criteria are needed to identify these patients. Seven hundred ninety consecutive patients with non-LBBB morphology, who received a CRT-device in 3 university centers in the Netherlands, were selected. Pre-implantation 12-lead ECGs were evaluated on morphology, duration, and area of the QRS complex, as well as on PR interval, left ventricular activation time (LVAT), and the presence of fragmented QRS (fQRS). Association of these ECG features with the primary endpoint: a combination of left ventricular assist device (LVAD) implantation, cardiac transplantation and all-cause mortality, and secondary endpoint-echocardiographic reduction of left ventricular end-systolic volume (LVESV)-were evaluated. The primary endpoint occurred more often in non-LBBB patients with with PR interval ≥ 230ms, QRS area < 109μVs, and with fQRS. Multivariable regression analysis showed independent associations of QRS area (HR 2.33 [1.44, 3.77], p = 0.001) and PR interval (HR 2.03 [1.51, 2.74], p < 0.001) only. Mean LVESV reduction was significantly lower in patients with baseline RBBB, QRS duration < 150 ms, PR interval ≥ 230 ms, and in QRS area < 109 μVs. Multivariable regression analyses only showed significant associations between QRS area ≥ 109 μVs (OR 2.00 [1.09, 3.66] p = 0.025) and probability of echocardiographic response to CRT. In the heterogeneous non-LBBB patient population, QRS area and PR prolongation rather than traditional QRS duration and morphology are associated to both clinical and echocardiographic outcomes of CRT.


Comparison of two extended depth of focus intraocular lenses with a monofocal lens: a multi-centre randomised trial.
The AT LARA 829MP is a next-generation extended depth of focus (EDOF) intraocular lens (IOL) providing continuous vision over a range of distances. The aim of this prospective multi-centre randomised trial was to compare two EDOF IOLs and one monofocal IOL. Cataract patients between 50 and 80 years were randomised for bilateral implantation with either the AT LARA 829MP (EDOF), the TECNIS Symfony (EDOF) or the CT ASPHINA 409MP (monofocal). Follow-up was at 1 to 2 weeks, 1 month and 4 to 6 months. A total of 211 patients were randomised and included in the final analysis. Monocular depth of focus was significantly better for AT LARA 829MP eyes compared with that for TECNIS Symfony at all thresholds (p = 0.024, 0.001 and 0.006, for 0.1, 0.2 and 0.3 logMAR respectively) with no significant difference for binocular depth of focus. LARA eyes had significantly better monocular depth of focus at all levels compared with ASPHINA eyes (all p < 0.0001), while there was no significant difference between Symfony and ASPHINA eyes at 0.1 logMAR and 0.2 logMAR. Both EDOF IOLs were significantly better than the monofocal ASPHINA at all levels for binocular depth of focus (LARA: all p < 0.0001; Symfony: all p = 0.002). Distance visual acuity was similar for all IOLs at 6 months; intermediate and near visual acuity were significantly better for the EDOF IOLs than for the monofocal (p < 0.0001). Refraction improved in all groups relative to baseline. Contrast sensitivity was higher with the CT ASPHINA 409MP but both EDOF lenses had a better spectacle independence rate. At 6 months, all IOLs were well centred with no cases of tilt. No general safety issues were raised for any of the groups. The two EDOF intraocular lenses investigated provided good visual outcomes with comparable visual acuity at all distances. The AT LARA 829MP provided the widest monocular depth of focus at 0.1 and 0.2 logMAR, with a clear superiority compared with the monofocal IOL. TECNIS Symfony was superior to the monofocal control at 0.3 logMAR. Spectacle independence and patient satisfaction were comparable. Trial registered on https://clinicaltrials.gov/ under the identification NCT03172351 (date of registration 1 June May 2017).


Ethical challenges of the linear non-threshold (LNT) cancer risk assessment revolution: History, insights, and lessons to be learned.
This paper provides historical review and evaluation of the development, adoption, and advocacy of the linear non-threshold (LNT) dose response model for cancer risk assessment as applied in practices and policies worldwide. It extends previous historical assessments and provides novel insights regarding: 1) how LNT bias became institutionalized in US governmental agencies, 2) how improper editorial practices at the journal Science promoted the adoption of LNT, 3) how a Nobel Prize winning scientist unjustifiably espoused and influenced support for replacing the threshold dose response model with the LNT model, 4) how the cover-up of striking and substantial experimental cancer data by US government scientists reduced support for the threshold dose response model at a critical period of cancer risk assessment policy adoption, and 5) how these events have negatively influenced cancer risk assessment practices and environmental and public health decisions for decades. These findings are presented to illustrate how profound and recognized mistakes, biases and unethical activities, inclusive of frank scientific misconduct, converged, and should motivate regulatory agencies worldwide to critically evaluate any existing policies that apply the LNT model as well as to serve as object lessons for current and future ethical conduct of research, and the provision of ethico-legal education in and across scientific curricula and institutions.


Identification of the Pseudomonas aeruginosa acid phosphatase as a phosphorylcholine phosphatase activity.
Choline, betaine and N,N-dimethylglycine as the sole carbon and nitrogen source induced a periplasmic acid phosphatase activity in Pseudomonas aeruginosa. This enzyme produced the highest rates of hydrolysis in phosphorylcholine and phosphorylethanolamine among the various phosphoric esters tested. At saturating concentrations of Mg2+, the Km values were 0.2 and 0.7 mM for phosphorylcholine and phosphorylethanolamine respectively. At high concentrations both compounds were inhibitors of the enzyme activity. The Ksi values for phosphorylcholine and phosphorylethanolamine were 1.0 and 3.0 mM respectively. The higher catalytic efficiency was that of phosphorylcholine. Considering these results it is possible to suggest that the Pseudomonas aeruginosa acid phosphatase is a phosphorylcholine phosphatase. The existence of this activity which is induced jointly with phospholipase C by different choline metabolites, in a high phosphate medium, suggests that the attack of Pseudomonas aeruginosa on the cell host may also be produced under conditions of high phosphate concentrations, when the alkaline phosphatase is absent.


18 F-FDG PET/CT of Alveolar Rhabdomyosarcoma of Prostate in a 17-Year-Old Boy.
Rhabdomyosarcoma of the prostate is a rare malignancy that usually presents in childhood and adolescence with symptoms of bladder outlet obstruction. Serum prostate-specific antigen is usually normal, and 18 F-FDG PET/CT has a crucial role to rule out distant metastases. We present a case of alveolar rhabdomyosarcoma of the prostate in a 17-year-old boy.


Delayed parenthood and its influence on offspring health: what have we learned from the mouse model†.
Delayed parenthood is constantly increasing worldwide due to various socio-economic factors. In the last decade, a growing number of epidemiological studies have suggested a link between advanced parental age and an increased risk of diseases in the offspring. Also, poor reproductive outcome has been described in pregnancies conceived by aged parents. Similarly, animal studies showed that aging negatively affects gametes, early embryonic development, pregnancy progression, and the postnatal phenotype of resulting offspring. However, how and to what extent parental age is a risk factor for the health of future generations is still a subject of debate. Notwithstanding the limitation of an animal model, the mouse model represents a useful tool to understand not only the influence of parental age on offspring phenotype but also the biological mechanisms underlying the poor reproductive outcome and the occurrence of diseases in the descendants. The present review aims at i) providing an overview of the current knowledge from mouse model about the risks associated with conception at advanced age (e.g. neurodevelopmental and metabolic disorders), ii) highlighting the candidate biological mechanisms underlying this phenomenon, and iii) discussing on how murine-derived data can be relevant to humans.


How does nudging the COVID-19 vaccine play out in people who are in doubt about vaccination?
In spite of the growing availability of COVID-19 vaccines, a substantial number of people is reluctant or uncertain about getting the vaccine. Nudges may improve vaccine uptake but it is unclear how this plays out with the experience of autonomous choice, decision competence, decision satisfaction, and being pressured to make a choice. In an online experiment among a representative sample (N = 884), we examined whether a social norm nudge or a default nudge (either or not transparent) was effective in steering the desired choice of making a hypothetical early vaccination appointment as compared to making a later appointment or no appointment. We also examined how both nudges affected autonomy and related downstream consequences. None of the nudges proved effective in making the desired choice of early vaccination and neither did they impact on downstream consequences. Rather, our results indicate that participants who were certain about their choice (i.e., opted for the earliest available vaccination opportunity or not getting vaccinated at all) reported higher levels of autonomy, competence and satisfaction than participants who did not know yet about vaccination or who postponed the moment of getting their vaccination. We conclude that the experience of autonomy and related downstream consequences is determined by having made up one's mind about vaccination, and is not affected by attempts to nudge the individual.


Binuclear centre structure of terminal protonmotive oxidases.
The recent proliferation of data obtained from mutant forms of cytochrome oxidase and analogous enzymes has necessitated a re-examination of existing structural models. A new model is proposed, consistent with these data, which brings several protonatable residues (Y244, D298, D300, T309, T316, K319, T326) into the vicinity of the binuclear centre, suggestive of a proton-transferring function. In addition, we also consider those residues which may participate in electron transport between CuA and haem a. We suggest several potential lines of investigation.


Long-term sclerotherapy of bleeding esophageal varices in patients with liver cirrhosis. An evaluation of mortality and rebleeding risk factors.
Ninety-six liver cirrhosis patients with bleeding esophageal varices receiving long-term sclerotherapy with the flexible endoscope were studied prospectively to analyze mortality and rebleeding risk factors. The difference in the 1-year survival rates of Child's groups A (100%) and B (82%) versus Child's C patients (38%) was highly significant (p less than 0.001). Multivariate analysis revealed that, as single factors, serum bilirubin, grade of ascites, and prothrombin time and, as a combination, the four variables bilirubin, ascites, aspartate aminotransferase, and age distinguished best between survivors and non-survivors during the first 6 months after inclusion in the study. For the separation of rebleeders and non-rebleeders during the first 2 months, prothrombin time and grade of ascites gave the best distinction. Thus, cirrhotics with variceal hemorrhage, ascites, jaundice, and a prolonged prothrombin time remain a high-risk group also with long-term sclerotherapy.


Inhibition of herpes simplex virus 1 gene expression and replication by RNase P-associated external guide sequences.
An external guide sequence (EGS) is a RNA sequence which can interact with a target mRNA to form a tertiary structure like a pre-tRNA and recruit intracellular ribonuclease P (RNase P), a tRNA processing enzyme, to degrade target mRNA. Previously, an in vitro selection procedure has been used by us to engineer new EGSs that are more robust in inducing human RNase P to cleave their targeted mRNAs. In this study, we constructed EGSs from a variant to target the mRNA encoding herpes simplex virus 1 (HSV-1) major transcription regulator ICP4, which is essential for the expression of viral early and late genes and viral growth. The EGS variant induced human RNase P cleavage of ICP4 mRNA sequence 60 times better than the EGS generated from a natural pre-tRNA. A decrease of about 97% and 75% in the level of ICP4 gene expression and an inhibition of about 7,000- and 500-fold in viral growth were observed in HSV infected cells expressing the variant and the pre-tRNA-derived EGS, respectively. This study shows that engineered EGSs can inhibit HSV-1 gene expression and viral growth. Furthermore, these results demonstrate the potential for engineered EGS RNAs to be developed and used as anti-HSV therapeutics.


A transcriptome multi-tissue analysis identifies biological pathways and genes associated with variations in feed efficiency of growing pigs.
Animal's efficiency in converting feed into lean gain is a critical issue for the profitability of meat industries. This study aimed to describe shared and specific molecular responses in different tissues of pigs divergently selected over eight generations for residual feed intake (RFI). Pigs from the low RFI line had an improved gain-to-feed ratio during the test period and displayed higher leanness but similar adiposity when compared with pigs from the high RFI line at 132 days of age. Transcriptomics data were generated from longissimus muscle, liver and two adipose tissues using a porcine microarray and analyzed for the line effect (n = 24 pigs per line). The most apparent effect of the line was seen in muscle, whereas subcutaneous adipose tissue was the less affected tissue. Molecular data were analyzed by bioinformatics and subjected to multidimensional statistics to identify common biological processes across tissues and key genes participating to differences in the genetics of feed efficiency. Immune response, response to oxidative stress and protein metabolism were the main biological pathways shared by the four tissues that distinguished pigs from the low or high RFI lines. Many immune genes were under-expressed in the four tissues of the most efficient pigs. The main genes contributing to difference between pigs from the low vs high RFI lines were CD40, CTSC and NTN1. Different genes associated with energy use were modulated in a tissue-specific manner between the two lines. The gene expression program related to glycogen utilization was specifically up-regulated in muscle of pigs from the low RFI line (more efficient). Genes involved in fatty acid oxidation were down-regulated in muscle but were promoted in adipose tissues of the same pigs when compared with pigs from the high RFI line (less efficient). This underlined opposite line-associated strategies for energy use in skeletal muscle and adipose tissue. Genes related to cholesterol synthesis and efflux in liver and perirenal fat were also differentially regulated in pigs from the low vs high RFI lines. Non-productive functions such as immunity, defense against pathogens and oxidative stress contribute likely to inter-individual variations in feed efficiency.


Can different primary care databases produce comparable estimates of burden of disease: results of a study exploring venous leg ulceration.
Primary care databases from the UK have been widely used to produce evidence on the epidemiology and health service usage of a wide range of conditions. To date there have been few evaluations of the comparability of estimates between different sources of these data. To estimate the comparability of two widely used primary care databases, the Health Improvement Network Database (THIN) and the General Practice Research Database (GPRD) using venous leg ulceration as an exemplar condition. Cross prospective cohort comparison. GPRD and the THIN databases using data from 1998 to 2006. A data set was extracted from both databases containing all cases of persons aged 20 years or greater with a database diagnosis of venous leg ulceration recorded in the databases for the period 1998-2006. Annual rates of incidence and prevalence of venous leg ulceration were calculated within each database and standardized to the European standard population and compared using standardized rate ratios. Comparable estimates of venous leg ulcer incidence from the GPRD and THIN databases could be obtained using data from 2000 to 2006 and of prevalence using data from 2001 to 2006. Recent data collected by these two databases are more likely to produce comparable results of the burden venous leg ulceration. These results require confirmation in other disease areas to enable researchers to have confidence in the comparability of findings from these two widely used primary care research resources.


Transient reduction in the tRNA 4-thiouridine content induced by ultraviolet A during post-irradiation growth in Enterobacter cloacae.
The influence of previous exposure to ultraviolet-A radiation (UVA) was studied on the susceptibility of Enterobacter cloacae to undergo the growth delay effect. Comparison of growth curves corresponding to irradiated and control cells showed that a previous treatment with UVA almost abolished the growth delay effect. UV absorption spectra of tRNA, and reverse phase HPLC analysis of hydrolysed tRNA, demonstrated a low content of 4-thiouridine in E. cloacae cells grown after UVA exposure at low doses. Since 4-thiouridine is the UVA target responsible for initiation of growth delay, this observation explained the influence of previous exposure to UVA on the susceptibility of this organism to undergo growth delay. A similar but weaker alteration was found when Escherichia coli was assayed. The results suggest that, in addition to cross-linking with cytidine residues, the content of 4-thiouridine in tRNA may be modified by UVA by an unknown mechanism.


The role of a common TNNT2 polymorphism in cardiac hypertrophy.
We found a five-basepair insertion/deletion polymorphism in intron 3 of TNNT2, one of the genes responsible for hypertrophic cardiomyopathy. These five bases may be part of an intronic polypyrimidine tract sequence that may affect splicing. The purpose of the study was to examine the association of the polymorphism with cardiac hypertrophy. The study population consisted of 151 subjects with prominent concentric left ventricular hypertrophy, and 987 healthy subjects recruited from medical checkups (control population). The deletion/deletion genotype tended to be associated with a larger left ventricular mass/height ratio in the HCM population ( p<0.0001). Multiple regression analyses indicated that the left ventricular mass/height ratio was determined ( p<0.0001, R=0.738) by the TNNT2 genotype. Moreover, the frequency of the deletion allele was significantly higher in the hypertrophy population than in the control population ( p<0.0001). In vitro expression study revealed the deletion allele significantly affected the mRNA expression pattern by skipping exon 4 during splicing. In conclusion, TNNT2 deletion allele could be associated with a predisposition to prominent left ventricular hypertrophy.


Mean cell volume of human blood leucocytes and resident and activated murine macrophages.
The mean cell volume (MCV) of human blood leucocytes and resident and activated murine macrophages was measured with a Coulter counter connected to a 256 channelyzer. The values found for human blood monocytes, granulocytes, and lymphocytes were 421 +/- 24 femtolitre (fl), 334 +/- 32 fl, and 204 +/- 19 fl, respectively. Resident murine peritoneal macrophages were significantly smaller than rIFN-gamma-activated and BCG/PPD-activated peritoneal macrophages and resident alveolar macrophages.


Genotoxicity of low dose N-nitroso propoxur to human gastric cells.
Propoxur is among the most popular insect control agents in subtropical countries such as Taiwan. As a member of the N-methylcarbamate insecticide group, propoxur is notorious for its potential for conversion into highly genotoxic N-nitroso derivatives. Due to the fact that the stomach has been identified as the major target for N-nitroso N-methylcarbamates, this investigation used a human gastric cell line, SC-M1, in order to obtain results pertinent to the authentic adverse effects of this compound on human health. This report reveals that at dose levels inhibiting < or = 10% cell growth, a 2-h pulsed treatment of N-nitroso propoxur induced significant amounts of DNA damage. Most of the damaged DNA was repaired within 24 h after treatment removal, such that an outcome with a significant induction of chromosomal aberrations was not observed. Gene mutations and anchorage independence, on the other hand, were significantly induced by this same treatment. In conclusion, exposure to low doses of N-nitroso propoxur is not cytotoxic nor clastogenic, nevertheless, has the potential to increase genetic instability and, possibly as a result, to enhance the malignant potential of treated cells. We suggest that although the damaged DNA was repaired during the transient G2/M arrest period, it was probably not done in an appropriate way which would preserve the original genetic stability.


Cloning, over-expression and characterization of an alkali-tolerant endo-β-1,4-mannanase from Penicillium freii F63.
A glycosyl hydrolase family 5 endo-β-mannanase gene (man5F63) was cloned from Penicillium freii F63 and overexpressed in Pichia pastoris. man5F63 contained an open reading frame of 1260 bp that encoded a polypeptide of 419 amino acids including a putative 18-residue signal peptide. The recombinant enzyme (rMan5F63) was secreted into the culture supernatant to near electrophoretic homogeneity with a high yield (1.1 gl(-1) in flask). Its apparent molecular weight was approximately 72.0 kDa, 29.0 kDa higher than the theoretical molecular mass. rMan5F63 was optimal at pH 4.5 and 60 °C and exhibited good stability over a broad pH range from acidic to alkaline (>85.0% activity at pH 4.0-9.0, >70.0% activity at pH 10.0 and 43.7% even at pH 12.0). The activity of rMan5F63 was significantly enhanced in the presence of Co(2+), Cu(2+), Mn(2+) and β-mercaptoethanol and was strongly inhibited by Hg(2+) and SDS. The specific activity, K(m) and V(max) values were 47.5 U mg(-1), 7.8 mg ml(-1) and 70.4 μmol min(-1)mg(-1), respectively, for locust bean gum, and 40.3 U mg(-1), 2.3 mg ml(-1) and 61.7 μmol min(-1)mg(-1), respectively, for konjac flour. All these favorable enzymatic properties make it cost-effective to commercialization and valuable in various industries.


Robotic versus laparoscopic ureteroplasty with a lingual mucosa graft for complex ureteral stricture.
Ureteroplasty with a lingual mucosa graft (LMG) for complex ureteral stricture was reported promising. We aimed to compare outcomes of robotic versus laparoscopic ureteroplasty using a LMG (RU-LMG vs. LU-LMG, respectively). From October 2018 to January 2021, 32 ureteroplasties using LMGs were performed by one experienced surgeon, including 16 robotic and laparoscopic procedures each. Patient demographics and peri-operative, post-operative, and follow-up data were prospectively collected and compared. The robotic group had a higher rate of previous reconstruction than the laparoscopic group (62.50% vs. 18.75%; p = 0.012). The stricture length was significantly longer in the robotic group (4.8 ± 1.2 cm) than the laparoscopic group (3.7 ± 1.2 cm; p = 0.013). All procedures were completed successfully without open conversion. The operative time was shorter in the robotic group (192 ± 54 min) than the laparoscopic group (254 ± 46 min; p = 0.001). The robotic group had a shorter length of post-operative stay (6.1 ± 2.4 d vs. 8.9 ± 4.3 d; p = 0.033) but a higher hospital cost (76,801 ± 17,974 vs. 42,214 ± 15,757 RMB; p < 0.001) than the laparoscopic group. The mean follow-up time was 21 ± 7 months for the robotic group and 29 ± 9 months for the laparoscopic group respectively (p = 0.014). No difference was detected in the success rate (93.75% and 100%, respectively; p = 0.309) and complication rate (18.75% and 31.25%, respectively; p = 0.414) between the robotic and laparoscopic groups. Both RU-LMG and LU-LMG are feasible, effective, and safe for repair of complex ureteral strictures. RU-LMG had a shorter operative time and a shorter length of post-operative stay but a higher hospital cost.


Anaphylaxis following single component measles and rubella immunisation.
Anaphylaxis as an adverse event following immunisation (AEFI) is a rare occurrence. We report four cases of anaphylaxis following administration of single component measles or rubella vaccine between January 2003 and June 2007. We estimate that the incidence of anaphylaxis to measles and rubella single component vaccines is 18.9 and 22.4 cases/100,000 doses, respectively. These figures are likely to be an underestimate but are higher than expected. Our calculations were hampered by lack of immunisation reporting data from the private sector. We recommend that NHS standards of vaccine data reporting are also applied to private clinics.


Visual assessment of the mandibular cortex on panoramic radiographs to identify postmenopausal women with low bone mineral densities.
The purpose of this study was to determine whether simple visual estimation of the mandibular inferior cortex width on panoramic radiographs is useful for identifying postmenopausal women with low skeletal bone mineral density (BMD). Panoramic radiographs were made on 100 women aged 50-84 years who also had BMD assessment of the lumbar spine and femoral neck by dual-energy x-ray absorptiometry. The panoramic images were examined twice by 4 observers to evaluate the thickness of the mandibular inferior cortex. Intraobserver agreement varied from moderate to almost perfect. Interobserver agreements varied from fair to almost perfect. Overall mean sensitivity, specificity and positive predictive value in identifying women with low BMD were 54.7%, 82.0%, and 72.5% in the lumbar spine and 51.8%, 82.2%, and 75.7% in the femoral neck, respectively. Our results suggest that simple visual estimation of the mandibular inferior cortex on panoramic radiographs may be useful for identifying postmenopausal women with low BMD.


Do you see what I see?: An exploration of inter-ethnic ideal body size comparisons among college women.
The present study explored African American (n=16) and European American (n=19) college women's ideal body size perceptions for their own and the other ethnic group along with reasons behind their selections. Respondents completed an ethnically-neutral figure rating scale and then participated in ethnically-homogenous focus groups. European Americans mostly preferred a curvy-thin or athletic ideal body while most African American students resisted notions of a singular ideal body. European Americans suggested that African Americans' larger ideal body sizes were based on greater body acceptance and the preferences of African American men. African Americans used extreme terms when discussing their perceptions of European Americans' thin idealization, celebrity role models, and weight management behaviors. African Americans' perceptions of European Americans' body dissatisfaction were also attributed to the frequent fat talk they engaged in. Implications for promoting the psychosocial well-being of ethnically-diverse emerging adult females attending college are discussed.


Oridonin promotes endoplasmic reticulum stress via TP53-repressed TCF4 transactivation in colorectal cancer.
The incidence of colorectal cancer and cancer death rate are increasing every year, and the affected population is becoming younger. Traditional Chinese medicine therapy has a unique effect in prolonging survival time and improving the prognosis of patients with colorectal cancer. Oridonin has been reported to have anti-cancer effects in a variety of tumors, but the exact mechanism remains to be investigated. Cell Counting Kit-8 assay (CCK8) and 5-Ethynyl-2'-deoxyuridine (EdU) staining assay, Tranwell, and Wound healing assays were performed to measure cell proliferation, invasion, and migration capacities, respectively. The protein and mRNA expression levels of various molecules were reflected by Western blot and Reverse Transcription quantitative Polymerase Chain Reaction (qRT-PCR). Transcription Factor 4 (TCF4) and its target genes were analyzed by Position Weight Matrices (PWMs) software and the Gene Expression Omnibus (GEO) database. Immunofluorescence (IF) was performed to visualize the expression and position of Endoplasmic Reticulum (ER) stress biomarkers. The morphology of the ER was demonstrated by the ER tracker-red. Reactive Oxygen Species (ROS) levels were measured using a flow cytometer (FCM) or fluorescent staining. Calcium ion (Ca2+) concentration was quantified by Fluo-3 AM staining. Athymic nude mice were modeled with subcutaneous xenografts. Oridonin inhibited the proliferation, invasion, and migration of colorectal cancer, and this effect was weakened in a concentration-dependent manner by ER stress inhibitors. In addition, oridonin-induced colorectal tumor cells showed increased expression of ER stress biomarkers, loose morphology of ER, increased vesicles, and irregular shape. TCF4 was identified as a regulator of ER stress by PWMs software and GEO survival analysis. In vitro and in vivo experiments confirmed that TCF4 inhibited ER stress, reduced ROS production, and maintained Ca2+ homeostasis. In addition, oridonin also activated TP53 and inhibited TCF4 transactivation, further exacerbating the elevated ROS levels and calcium ion release in tumor cells and inhibiting tumorigenesis in colorectal cancer cells in vivo. Oridonin upregulated TP53, inhibited TCF4 transactivation, and induced ER stress dysregulation in tumor cells, promoting colorectal cancer cell death. Therefore, TCF4 may be one of the important nodes for tumor cells to regulate ER stress and maintain protein synthesis homeostasis. And the inhibition of the TP53/TCF4 axis plays a key role in the anti-cancer effects of oridonin.


Development of a nomogram for the early prediction of PACU VAS in patients undergoing laparoscopic radical resection of colorectal cancer with fentanyl.
To make early predictions of PACU VAS before surgery, we created a novel nomogram for the early prediction of PACU VAS in patients having laparoscopic radical excision of colorectal cancer with fentanyl. From July 2018 to December 2020, a total of 101 patients in Zhongshan Hospital Affiliated to Fudan University who underwent laparoscopic radical resection of colorectal cancer were enrolled in this study. For feature selection, a stepwise regression model was utilized. Multivariable logistic regression analysis was used to establish a prediction model. We incorporated age, gender, weight, height, fentanyl dosage during operation, operation time, and OPRM1 genotype, and this was presented with a nomogram. The nomogram's performance was evaluated in terms of discrimination and clinical utility. The signature, which comprised of seven carefully chosen characteristics, was linked to the PACU VAS for the development dataset. Predictors contained in the individualized prediction nomogram included age, gender, weight, height, fentanyl dosage during operation, operation time, and OPRM1 genotype. With an area under the ROC curve of 0.877 (95% CI, 0.6874-1.0000), the model showed good discrimination. The nomogram still had good discrimination. Decision curve analysis demonstrated that the nomogram was clinically useful. The nomogram presented in this study incorporates age, gender, weight, height, fentanyl dosage during operation, operation time, and OPRM1 genotype and can be conveniently used to facilitate the individualized prediction of PACU VAS in patients undergoing laparoscopic radical resection of colorectal cancer with fentanyl.


Particle properties and drug metastable solubility of simvastatin containing PVP matrix particles prepared by electrospraying technique.
In this work the preparation of drug loaded polymeric nanoparticles using electrospraying method and their subsequent characterization is presented. Our purpose was to incorporate the drug with extremely low solubility and low oxidative stability into polyvinylpyrolidone nanoparticles in order to improve its solubility and preserve its chemical stability and hence evaluate the ability of the technology to stabilize such systems in nanoparticulate form. Through the initial screening and optimization of process parameters and polymer solution properties, we detected different morphologies of electrosprayed product particles, where the use of lower molecular weight polymer resulted in a higher process instability as well as in a broader particle size distribution. On the other hand, the solution containing polyvinylpyrolidone with higher molecular weight showed sensitivity to different flow rates and electric field changes, which again resulted in differing the particle size and morphology. The electrosprayed products, prepared by sufficient process stability and having adequately narrow size distribution span, showed lower initial simvastatin contents than theoretically expected, which indicated an oxidative drug degradation already during the electrospraying process. The addition of antioxidants improved simvastatin chemical stability in the particles, during the process itself as well as after accelerated stability study. With an addition of butylated hydroxyanisole antioxidant mixture into initial polymer solution more than 95% of the drug content was preserved after one month at accelerated conditions, whereas in formulations without antioxidants simvastatin content was less than 6%. Antioxidants addition however did not influence only simvastatin stability but also simvastatin solubility. Surprisingly, antioxidants addition did decrease drug solubility in buffers (pH=4 and pH=6.8) for more than a half without any solid state changes of simvastatin. Potential hydrophobic interaction between simvastatin and antioxidants are hindering the drug solubility in the respective buffer, despite drug being in amorphous state.


First-degree relatives of patients with early-onset gastric carcinoma show even at young ages a high prevalence of advanced OLGA/OLGIM stages and dysplasia.
First-degree relatives (FDRs) of early-onset gastric carcinoma (EOGC) patients are at increased risk of cancer development. OLGA/OLGIM (Operative Link on Gastritis/Intestinal Metaplasia Assessment) classifications have been proposed for the identification of individuals at high risk of gastric cancer development. To estimate the prevalence and severity of premalignant conditions and lesions in FDRs of EOGC patients. A case-control study was conducted encompassing 103 FDRs of EOGC patients (cases) and 101 age- and gender-matched controls, all submitted to upper GI endoscopy and OLGA and OLGIM used for staging as well as modified versions with exclusion of the biopsies from incisura angularis in the analysis. Helicobacter pylori infection was present in 82% of cases (P = 0.001). Atrophy was present in 70% of cases (OLGA stages I-IV). High-risk stages (III-IV) were identified only in cases (19%) (P < 0.001). Dysplasia was diagnosed only in cases (n = 7, P = 0.007). The application of OLGIM, modified OLGA and modified OLGIM classifications led to downgrade of stages in comparison with the original OLGA classification (27%, 15% and 30% respectively). In all classification systems, dysplastic lesions clustered (86%) in high-risk stages. FDRs of EOGC patients have, even at young ages, a high prevalence of H. pylori infection, high-risk OLGA and OLGIM stages and dysplasia. These patients should undergo accurate endoscopic observation with at least four biopsies in antrum and corpus to allow adequate staging and follow-up of premalignant conditions and lesions scored in high-risk stages, in accordance with international guidelines recently proposed.


Microinvasive germ cell neoplasia of the testis.
The term microinvasive germ cell neoplasia denotes the presence of neoplastic germ cells in the tubuli and interstitium of the testis, unaccompanied by clinically detectable tumor. Testicular biopsy specimens from three patients (age range, 26-38 years) without clinical evidence of tumor showed microinvasive germ cell neoplasia. The indications for biopsy were gynecomastia and testicular atrophy in Patient 1, infertility in Patient 2, and nonseminomatous cancer in the contralateral testicle in Patient 3. In all three cases, orchiectomy specimens disclosed multifocal intratubular and extratubular growth of neoplastic germ cells, occasionally confluent in seminoma-like infiltrates. In Cases 1 and 2, no malignant cells were found at biopsy of the contralateral testis. In contrast to intratubular (in situ) germ cell neoplasia, microinvasion constitutes a definitive malignancy and the starting point of differentiation into seminoma or nonseminomatous tumor. Inguinal orchiectomy is recommended as primary therapy. The necessity of complementary therapy is an issue that must be investigated.


Theoretical studies of phosphorene as a drug delivery nanocarrier for fluorouracil.
The interactions between phosphorene nanosheets (PNSs) and 5-fluorouracil (FLU) were explored using the density functional theory (DFT) method and molecular dynamics (MD) simulations. DFT calculations were performed utilizing M06-2X functional and the 6-31G(d,p) basis set in both gas and solvent phases. Results showed that the FLU molecule is adsorbed horizontally on the PNS surface with an adsorption energy (Eads) of -18.64 kcal mol-1. The energy gap (Eg) between the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO, respectively) of PNS remains constant after the adsorption process. The adsorption behavior of PNS is not affected by carbon and nitrogen doping. The dynamical behavior of PNS-FLU was studied at T = 298, 310, and 326 K reminiscent of room temperature, body temperature, and temperature of the tumor after exposure to 808 nm laser radiation, respectively. The D value decreases significantly after the equilibration of all systems so that the equilibrated value of D is about 1.1 × 10-6, 4.0 × 10-8, and 5.0 × 10-9 cm2 s-1 at T = 298, 310, and 326 K, respectively. About 60 FLU molecules can be adsorbed on both sides of each PNS, indicating its high loading capacity. PMF calculations demonstrated that the release of FLU from PNS is not spontaneous, which is favorable from a sustained drug delivery point of view.


The secondary olfactory connections in two chondrichthians, the shark Scyliorhinus canicula and the ray Raja clavata.
The secondary olfactory connections in the shark Scyliorhinus canicula and the ray Raja clavata have been studied with reduced silver techniques. After transections through the pedunculus olfactorius in Scyliorhinus degenerating fibers could be traced to the telencephalic hemisphere. On entering the hemisphere these fibers subdivide into a small medial and a larger lateral olfactory tract. The medial tract distributes fibers to the lateral part of the ipsilateral pallium dorsale, pars superficialis and area periventricularis pallialis, but the majority of its fibers terminate in the submeningeal zone of the pallium. The medial olfactory tract also projects contralaterally to the submeningeal pallial zone via the commissura olfactoria inferior and to the stratum granulare bulbi olfactorii by way of the commissura olfactoria superior. The lateral olfactory tract distributes mainly to the pallium laterale and to the region superficial to the lateral part of the area superficialis basalis, though the striatum also receives some fibers. In Raja the secondary olfactory tract could not be subdivided into medial and lateral components and its projections seem to be restricted to the ipsilateral pallium laterale. A striking difference between Scyliorhinus and Raja is that in the latter no contralateral projections could be recognized nor a projection to the area superficialis basalis. When these results are compared with those reported in the literature for other cartilaginous fishes, it appears that the secondary olfactory connections of Scyliorhinus are more extensive than in other chondrichthians studied experimentally. In some cases of peduncle transection in Scyliorhinus the lateral part of the striatum was also involved in the lesion. In addition to the pattern of degeneration seen after olfactory peduncle lesions, degenerating fibers could be distinguished both in the stria medullaris and basal forebrain bundle. The former projects to habenular nucleus, whereas the latter distributes to the hypothalamus, ventral thalamus, and brainstem tegmentum.


Plasma lipid and lipoprotein response to carbohydrate feeding in cirrhotic patients.
Serum lipids and lipoproteins, and glucose and insulin, were measured after an overnight fast, and during 3 days of a eucaloric diet rich in carbohydrate, in 15 patients with cirrhosis and seven normal subjects. Following the high-carbohydrate diet triglyceride rose in all groups but the increase in cirrhotics was lower than in normals. In normals and in cirrhotics with good liver function most of the triglyceride increment was carried in VLDL; in cirrhotics with poor liver function only 31% of the increment was found in VLDL, and 56% in triglyceride-rich LDL. In an earlier study on fat feeding, our cirrhotic patients with poor liver function had an impaired chylomicron and VLDL response; they also carried most of the triglyceride increment in triglyceride-rich LDL. The markedly impaired response of triglyceride-rich lipoproteins to both carbohydrate and fat feeding suggests that sick cirrhotics may have a problem with storage of dietary energy and that this contributes to loss of their adipose tissue.


Efficacy of a technology-based client-centred training system in neurological rehabilitation: a randomised controlled trial.
A client-centred task-oriented approach has advantages towards motivation and adherence to therapy in neurorehabilitation, but it is costly to integrate in practice. An intelligent Activity-based Client-centred Training (i-ACT), a low-cost Kinect-based system, was developed which integrates a client-centred and task-oriented approach. The objectives were (1) to investigate the effect of additional i-ACT training on functioning. And (2) to assess whether training with i-ACT resulted in more goal oriented training. A single-blind randomised controlled trial was performed in 4 Belgian rehabilitation centres with persons with central nervous system deficits. Participants were randomly allocated through an independent website-based code generator using blocked randomisation (n = 4) to an intervention or control group. The intervention group received conventional care and additional training with i-ACT for 3 × 45 min/week during 6 weeks. The control group received solely conventional care. Functional ability and performance, quality of life (QoL), fatigue, trunk movement, and shoulder active range of motion (AROM) were assessed at baseline, after 3 weeks and 6 weeks of training, and 6 weeks after cessation of training. Data were analysed using non-parametric within and between group analysis. 47 persons were randomised and 45 analysed. Both intervention (n = 25) and control (n = 22) group improved over time on functional ability and performance as measured by the Wolf Motor Function Test, Manual Ability Measure-36, and Canadian Occupational Performance Measure, but no major differences were found between the groups on these primary outcome measures. Regarding QoL, fatigue, trunk movement, and shoulder AROM, no significant between group differences were found. High adherence for i-ACT training was found (i.e. 97.92%) and no adverse events, linked to i-ACT, were reported. In the intervention group the amount of trained personal goals (88%) was much higher than in the control group (46%). Although additional use of i-ACT did not have a statistically significant added value regarding functional outcome over conventional therapy, additional i-ACT training provides more individualised client-centred therapy, and adherence towards i-ACT training is high. A higher intensity of i-ACT training may increase therapy effects, and should be investigated in future research. ClinicalTrials.gov Identifier NCT02982811. Registered 29 November 2016.


The tau H1 haplotype is associated with Parkinson's disease in the Norwegian population.
We investigated the association of Parkinson's disease (PD) with tau gene H1 haplotypes in the Norwegian population. In a sample of 96 unrelated PD cases and 68 control subjects, we observed an increased risk of PD for persons with the tau H1 haplotype (odds ratio=5.52; 95% confidence interval: 2.64-11.10; P=2.17x10(-6)). Findings provide evidence that tau participates in the PD pathogenic process and demonstrate the value of isolated populations in mapping complex traits.


Chiral spirosiladiphosphines: ligand development and applications in Rh-catalyzed asymmetric hydrosilylation/cyclization of 1,6-enynes with enhanced reactivity.
Spirodiphosphines have been successfully applied in various asymmetric catalytic transformations. However, controlling the coordinating conformations by the direct displacement of the spiro atom remains elusive. Herein, we report the application of Si-centered spirodiphosphine (Si-SDP) ligands in the enantioselective hydrosilylation/cyclization of 1,6-enynes. The Si-SDPs showed superior reactivity to existing C2-symmetric diphosphines, allowing the generation of a range of chiral pyrrolidines with high yields and enantioselectivity (up to 96% yield and 92% ee) at room temperature with low catalyst loading. The mechanistic observations were consistent with the modified Chalk-Harrod mechanism, and the high reactivity of Si-SDPs was further leveraged for the room-temperature Rh-catalyzed hydrosilylation of alkynes.


Consumption of aspartame and other artificial sweeteners and risk of cancer in the Spanish multicase-control study (MCC-Spain).
Use of artificial sweeteners (AS) such as aspartame, cyclamate, saccharin and sucralose is widespread. We evaluated the association of use of aspartame and other AS with cancer. In total 1881 colorectal, 1510 breast, 972 prostate and 351 stomach cancer and 109 chronic lymphocytic leukaemia (CLL) cases and 3629 population controls from the Spanish Multicase-Control (MCC-Spain) study were recruited (2008-2013). The consumption of AS, from table-top sweeteners and artificially sweetened beverages, was assessed through a self-administered and validated food frequency questionnaire (FFQ). Sex-specific quartiles among controls were determined to compare moderate consumers (<third quartile) and high consumers (≥ third quartile) vs non consumers (reference category), distinguishing aspartame-containing products and other AS. Unconditional logistic regression models were used to estimate adjusted OR and 95%CI, and results were stratified by diabetes status. Overall, we found no associations between the consumption of aspartame or other AS and cancer. Among participants with diabetes, high consumption of other AS was associated with colorectal cancer (OR = 1.58, 95% CI 1.05-2.41, P trend = .03) and stomach cancer (OR = 2.27 [0.99-5.44], P trend = .06). High consumption of aspartame, was associated with stomach cancer (OR = 2.04 [0.7-5.4], P trend = .05), while a lower risk was observed for breast cancer (OR = 0.28 [0.08-0.83], P trend = .03). In some cancers, the number of cases in participants with diabetes were small and results should be interpreted cautiously. We did not find associations between use of AS and cancer, but found associations between high consumption of aspartame and other AS and different cancer types among participants with diabetes.


Effects of the levonorgestrel-releasing intrauterine system versus the copper intrauterine device on uterine artery Doppler indices.
The aims of the study were to evaluate the effects of two types of intrauterine contraceptive device (IUCD) on uterine artery Doppler indices. A multicentre randomised clinical trial was conducted between November 2019 and August 2020. Sixty-six multiparous women aged 18-45 years seeking intrauterine contraception were randomly assigned to receive either the levonorgestrel-releasing intrauterine system (LNG-IUS) or the copper intrauterine device (Cu-IUD). Each group comprised 33 participants. Primary outcome measures were menstrual changes and changes in uterine artery Doppler indices 3 and 6 months after IUCD insertion. Secondary outcomes measures were the relation between Doppler indices and menstrual changes, adverse effects of the assigned contraceptive method and user acceptability of the method. Uterine artery pulsatility index (PI) and resistance index (RI) were significantly higher among women in the LNG-IUS group (p < .001 at 6 months). Whereas the number of women reporting heavy menstrual bleeding decreased at 3 and 6 months in the LNG-IUS group it significantly increased in the Cu-IUD group (p < .001 at 6 months). Multiple logistic regression analysis of participant characteristics and occurrence of heavy menstrual bleeding revealed a significant association with uterine artery RI (p < .01) and the type of IUCD (p < .001). IUCDs are associated with Doppler changes that may be associated with their reported side effects.


Soluble salt removal from MSWI fly ash and its stabilization for safer disposal and recovery as road basement material.
Fly ash from municipal solid waste incinerators (MSWI) is classified as hazardous in the European Waste Catalogue. Proper stabilization processes should be required before any management option is put into practice. Due to the inorganic nature of MSWI fly ash, cementitious stabilization processes are worthy of consideration. However, the effectiveness of such processes can be severely compromised by the high content of soluble chlorides and sulphates. In this paper, a preliminary washing treatment has been optimized to remove as much as possible soluble salts by employing as little as possible water. Two different operating conditions (single-step and two-step) have been developed to this scope. Furthermore, it has been demonstrated that stabilized systems containing 20% of binder are suitable for safer disposal as well as for material recovery in the field of road basement (cement bound granular material layer). Three commercially available cements (pozzolanic, limestone and slag) have been employed as binders.


HPLC based method for the measurement of the reduction of aflatoxin B1 by bacterial cultures isolated from different African foods.
The consumption of fermented foods contaminated with aflatoxin B1 is linked to aflatoxicosis. Aflatoxicosis is a serious problem in developing countries with environmental conditions appropriate for the biosynthesis of AFB1 byAspergillus flavus andAspergillus parasiticus. In Africa, especially in Ghana and Nigeria, there is a very high risk of liver cancer which is caused by the consumption of AFB1-intoxicated, traditionally fermented maize and sorghum products. It is suggested that one way to diminish this health risk might be the reduction of the AFB1 concentration in foods by bacteria. Especially bacteria used for food fermentation processes are of great importance, with a special emphasis on lactic acid bacteria which are involved in traditionally fermented African foods based on maize and sorghum.Most publications dealing with aflatoxin degradation by microorganisms describe a phosphate buffer test system for the performance of degradation experiments. In contrast to that, a test system based on physiological active bacterial and yeast cells has been developed, to assess food fermentation organisms for their ability to reduce the AFB1 concentration in vitro. The aflatoxin B1 concentration in test samples was quatitatively determined by HPLC.The assessment of lactic acid bacteria originating from different German and other European culture collections only showed a very slight reduction of the AFB1 concentration from 3% to 12%. Screening experiments in which other bacterial genera and lactic acid bacteria, isolated from different African foods have been assessed, in most cases showed the same results. However, some bacterial strains, e.g. strains of the genusBacillus derived from European culture collections and strains of the genusLactobacillus isolated from African foods, caused a release of AFB1 which was chemically bound before to components of the test medium and which therefore could not be extracted with chloroform.A process quite similar to that may happen during food fermentations. Different experiments showed that e.g. cellulose can bind AFB1 very effectively. Cellulose and different other food components are well known to absorb AFB1. During fermentation the cellulose and other AFB1-absorbing components may be degraded and the AFB1 will be released again.The only bacterial strain known as yet which is able to reduce the AFB1 concentration in vitro and in different food comodities isNocardia corynebacteroides (formerFlavobacterium aurantiacum). Nevertheless the mechanism of this AFB1 reduction is actually not well understood, it still has to be investigated. In the meantime several other bacterial strains, presumably from the taxonomic group of theActinomycetes could be proved to be effective reducers of the AFB1 concentration in our in vitro test system. Because as yet no food relevant microorganism could be found, which is able to degrade AFB1, these new strains in general offer the possibility for a genetic modification of food relevant microorganisms. This seems to be the way to come to starter cultures which are able to degrade AFB1 during food fermentations.


[Isolation and characterization of a new placenta specific protein (PP10) (author's transl)].
PP10 was isolated from aqueous extracts of human term placentae by fractionating the proteins with rivanol and ammonium sulfate, by gelfiltration on Sephadex G-150 and by use of immunoadsorbents. PP10 apparently is a protein specific for the placenta; it could not be detected in extracts from other human tissues. From one human term placenta an average amount of 20 mg PP10 can be extracted. In sera from pregnant women PP10 is usually present only in trace amounts (less than 0.1 mg/100 ml). PP10 has the electrophoretic mobility of an alpha1-globulin and an isoelectric point of 5.1. The purified protein sediments with 3.8 S. PP10 was found to have a molecular weight of 48,000 as determined by ultracentrifugation and a molecular weight of 65,000 as determined by SDS-PAA gel electrophoresis. PP10 is a glycoprotein containing 6.65% carbohydrates (hexoses 4.8%, hexosamines 1.2%, fucose 0.05%, sialic acid 0.6%). The amino acid composition of PP10 has been determined, too; the most abundant amino acids in this protein are glutamic acid, aspartic acid, leucine and alanine.


Ecdysteroids in the pycnogonid Pycnogonum litorale (STROM) (Arthropoda, Pantopoda).
Two ecdysteroids were isolated from juveniles and adults as well as from eggs of the pycnogonid Pycnogonum litorale Ström and characterized by bioassay, thin layer chromatography, gas liquid chromatography, and high performance liquid chromatography. One of the hormones could be identified as 20-hydroxyecdysone whereas the other behaves in HPLC in a way that is similar to but not identical with ecdysone. This unidentified ecdysone-like hormone exceeded 20-hydroxyecdysone in all developmental stages (1.67:1 to 3:1). Determination of moulting hormone titers by a radioimmunoassay showed highest amounts of hormones in juvenile females (150 ng/mg tissue dry wt). The results are compared with those obtained from other arthropods and are discussed in view of the evolution of hormonal systems.


Neurocognitive effects of Moyamoya disease and concomitant epilepsy.
Moyamoya disease (MMD) is a rare degenerative cerebrovascular disorder that leads to recurrent strokes and cerebral hypoperfusion. Seizures are not uncommon in MMD especially following surgical treatment for the disease. Cognitive changes that are largely executive in nature have been documented following MMD and surgical treatment, although research is limited in adults. The present case report details the comprehensive neurocognitive evaluation of a patient with MMD and concomitant epilepsy. Neurocognitive findings revealed a prominent dysexecutive pattern and atypically poor performance in areas such as visual and verbal memory. The patient reported significant affective symptoms and functional decline. This case offers insight into unique neurocognitive results that may present in adult MMD cases and underscores the importance of interpreting results in the context of neurological comorbidities in this rare disease.


The central role of heat shock factor 1 in synaptic fidelity and memory consolidation.
Networks of neuronal synapses are the fundamental basis for making and retaining memory. Reduced synapse number and quality correlates with loss of memory in dementia. Heat shock factor 1 (HSF1), the major transcription factor regulating expression of heat shock genes, plays a central role in proteostasis, in establishing and sustaining synaptic fidelity and function, and in memory consolidation. Support for this thesis is based on these observations: (1) heat shock induces improvements in synapse integrity and memory consolidation; (2) synaptic depolarization activates HSF1; (3) activation of HSF1 alone (independent of the canonical heat shock response) augments formation of essential synaptic elements-neuroligands, vesicle transport, synaptic scaffolding proteins, lipid rafts, synaptic spines, and axodendritic synapses; (4) HSF1 coalesces and activates memory receptors in the post-synaptic dendritic spine; (5) huntingtin or α-synuclein accumulation lowers HSF1 while HSF1 lowers huntingtin and α-synuclein aggregation-a potential vicious cycle; and (6) HSF1 agonists (including physical activity) can improve cognitive function in dementia models. Thus, via direct gene expression of synaptic elements, production of HSPs that assure high protein fidelity, and activation of other neuroprotective signaling pathways, HSF1 agonists could provide breakthrough therapy for dementia-associated disease.


The wearing-off phenomenon of ocrelizumab in patients with multiple sclerosis.
Patients with multiple sclerosis (MS) who are treated with monoclonal antibodies frequently report an increase of MS-related symptoms prior to the next dose known as the wearing-off phenomenon. The objective of this study was to assess the prevalence and predicting factors of the wearing-off phenomenon in patients with MS using ocrelizumab. This was a prospective cohort study in patients with MS receiving ocrelizumab ≥1 year. Most participants received B-cell guided personalized extended interval dosing to limit ocrelizumab exposure and hospital visits during the COVID-19 pandemic (cut-off ≥ 10 cells/µL). Participants completed questionnaires during ocrelizumab infusion and 2 weeks thereafter. Demographics, clinical and radiological characteristics, CD19 B-cell counts, and serum neurofilament light (sNfL) levels were collected. Data were analyzed using logistic regression analyses. Seventy-one (61%) out of 117 participants reported the wearing-off phenomenon during ocrelizumab treatment. The most frequently reported symptoms were fatigue, cognitive disability and sensory symptoms. Wearing-off symptoms started < 1 week (11%), 1-4 weeks (49%) or more than 4 weeks (37%) before ocrelizumab infusion. Fifty participants (43%) reported a current wearing-off phenomenon at the first questionnaire. Higher body mass index (threshold BMI ≥ 25) increased the odds of reporting a current wearing-off phenomenon (OR 2.70, 95% CI 1.26 to 5.80, p = .011). Infusion interval, EDSS score, MRI disease activity, clinical relapses, CD19 B-cell counts, and sNfL levels were no predictors. Disappearance of the wearing-off phenomenon occurred in the first week after ocrelizumab infusion in most participants. Participants with a current wearing-off phenomenon significantly improved in self-reported physical and psychological functioning after ocrelizumab infusion. Reporting the wearing-off phenomenon did not influence treatment satisfaction. Forty of 109 participants (37%) reported post-infusion symptoms, such as fatigue, flu-like symptoms or walking difficulties. These post-infusion symptoms started directly or in the first week after ocrelizumab infusion and disappeared within 2 weeks. The wearing-off phenomenon is reported by more than half of patients with MS using ocrelizumab. Only BMI was identified as a predicting factor. The wearing-off phenomenon was not elicited by extending infusion intervals or higher B-cell counts. The wearing-off phenomenon of ocrelizumab therefore does not seem to reflect suboptimal control of MS disease activity.


Mutational analysis of the effects of N-glycosylation sites on the activity and thermal stability of rutinosidase from Aspergillus oryzae.
Purified recombinant rutinosidase from Aspergillus oryzae expressed in Pichia pastoris (rAoRutM) exhibits increase in thermal stability after treatment with endo-β-N-acetylglucosaminidase H (endo-H). In this study, the role of N-glycosylation in the activity and thermal stability of rAoRutM was analyzed via site-directed mutagenesis. Based on the crystal structure of AoRutM, five N-glycosylation sites (N32, N128, N176, N288, and N359) were identified in the AoRut protein. Among five single variants constructed for these sites, the N128D, N176D, and N359D variants exhibited similar mobility bands compared to that of the wild-type enzyme based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, whereas the N32D and N288D variants exhibited slightly and considerably increasing mobility bands, respectively. The N128D and N288D variants showed increasing and decreasing rutinosidase activity, respectively, compared to the case for the wild-type, without and with endo-H treatments. While the N128D and N176D variants had lower Km values, the N288D and N359D variants had higher Km values, compared to the wild-type, without and with endo-H treatments. Surprisingly, the N32D and N176D variants exhibited considerably greater thermal stability than the wild-type, without or with the endo-H treatments, whereas the N128D and N359D variants exhibited drastically decreased thermal stability. Circular dichroism (CD) spectra of the N128D and N359D variants showed a similar CD profile to that of the wild-type treated with endo-H; however, the molar ellipticity values of the peaks at 208 nm and 212 nm in the above variants varied from those of the intact wild-type and other variants.


Stereoselective Base-Catalyzed 1,1-Silaboration of Terminal Alkynes.
A base-catalyzed reaction that enables stereoselective 1,1-silaboration of terminal alkynes is described. This method not only offers a new strategy to functionalize simple and readily accessible alkynes beyond 1,2-difunctionalization, but also provides an unconventional atom- and step-economical approach to rapidly and reliably access versatile geminal silylboranes in the absence of transition metals and with exquisite stereoselectivity.


Selection and characterization of naturally occurring single-domain (IgNAR) antibody fragments from immunized sharks by phage display.
The novel immunoglobulin isotype novel antigen receptor (IgNAR) is found in cartilaginous fish and is composed of a heavy-chain homodimer that does not associate with light chains. The variable regions of IgNAR function as independent domains similar to those found in the heavy-chain immunoglobulins of Camelids. Here, we describe the successful cloning and generation of a phage-displayed, single-domain library based upon the variable domain of IgNAR. Selection of such a library generated from nurse sharks (Ginglymostoma cirratum) immunized with the model antigen hen egg-white lysozyme (HEL) enabled the successful isolation of intact antigen-specific binders matured in vivo. The selected variable domains were shown to be functionally expressed in Escherichia coli, extremely stable, and bind to antigen specifically with an affinity in the nanomolar range. This approach can therefore be considered as an alternative route for the isolation of minimal antigen-binding fragments with favorable characteristics.


X-ray- and chemically induced germ-line mutation causing phenotypical anomalies in mice.
A large and significant increase of phenotypical anomalies was observed in the progeny of ICR parent mice treated before mating with X-rays, urethane, 7,12-dimethylbenz[a]anthracene, ethylnitrosourea (ENU), and 4-nitroquinoline 1-oxide, but the increase was not significant with furylfuramide. Major types of induced anomalies were cleft palate, dwarf, open eyelid, tail anomalies, and exencephalus. Dwarf, open eyelid and tail anomalies were predominant types of viable anomalies and were inherited as if they were dominant mutations with varying expressivity or penetrance. Incidence of prenatal anomalies increased with treated doses of X-rays, urethan, or ENU for both spermatozoa and spermatogonia. Spermatogonia were less sensitive to X-rays and urethane than spermatozoa, while ENU induced a very high incidence of prenatal anomalies by the spermatogonial treatment. In contrast to the previous works with X-rays, there was a clear, almost linear increase of anomalies in the dose range from 0 to 216 rad after spermatogonial exposure. For treatment of oocytes, there was also a clear increase with doses of X-rays and urethane. Doubling doses of X-rays for prenatal anomalies were 12 rad for spermatozoa, 27 rad for spermatogonia, and 19 rad for mature oocytes. These values are similar to those for ordinary mouse mutations. However, the mean rate of prenatal anomalies per rad (1.2 X 10(-4), 6.6 X 10(-5) and 9.1 X 10(-5) for spermatozoa, spermatogonia and mature oocytes, respectively) and that for 1 micrograms/g of ENU (3.4 X 10(-4) for spermatogonia) were 4-40 times higher than that of ordinary mutation in mice, because overall phenotypical abnormalities were scored in this study. Information obtained from the work on phenotypical anomalies is valuable to assess genetic risk of radiation and chemicals, because a majority of human genetic diseases show this kind of irregular and uncertain inheritance and most of the induced anomalies are similar to those found in humans.