Sodium-dependent glucose transporter reduces peroxynitrite and cell injury caused by cisplatin in renal tubular epithelial cells.
Cisplatin causes nephropathy accompanied by two types of cell death, necrosis and apoptosis, according to its dosage. The mechanisms of necrosis are still unclear. In this study, we examined how high doses of cisplatin induce cell injury and whether a high affinity sodium-dependent glucose transporter (SGLT1) has a cytoprotective function in renal epithelial LLC-PK(1) cells. Cisplatin decreased in transepithelial electrical resistance (TER) and increased in the number of necrotic dead cells in a time dependent manner. Phloridzin, a potent SGLT1 inhibitor, enhanced both TER decrease and increase of necrotic dead cells caused by cisplatin. Cisplatin increased in the intracellular nitric oxide, superoxide anion and peroxynitrite productions. Phloridzin enhanced the peroxynitrite production caused by cisplatin. The intracellular diffusion of ZO-1 and TER decrease caused by cisplatin were inhibited by N-nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor. Protein kinase C was not involved in the cisplatin-induced injury. 5,10,15,20-tetrakis-(4-sulfonatophenyl)-porphyrinato iron (III) and reduced glutathione, peroxynitrite scavengers, inhibited the cisplatin-induced ZO-1 diffusion, TER decrease, and increase of necrotic dead cells. These results suggest that peroxynitrite is a key mediator in the nephrotoxicity caused by high doses of cisplatin. SGLT1 endogenously carries out the cytoprotective function by the reduction of peroxynitrite production.


Quantifying normal lung in pulmonary fibrosis: CT analysis and correlation with %DLCO.
Chest CT scans are routinely obtained to monitor disease progression in pulmonary fibrosis. However, radiologists do not employ a standardized system for quantitative description of the severity of the disease. Development and validation of a grading system offers potential for enhancing the information that radiologists provide clinicians. Our retrospective review analyzed 100 sequential patients with usual interstitial pneumonitis (UIP) on HRCT scans from 2018 and 2019. A radiologic scoring system evaluated the percent of normal lung on the basis of a 0-5 point scale per lobe (findings for the right middle lobe were included in the right upper lobe score), yielding an overall additive numerical score on a scale of 20 (completely normal lung) to 0 (no normal lung). Two radiologists quantified the percentage of normal lung by consensus agreement. Percent DLCO as well as demographic data were obtained from the medical record. Statistical analysis was performed using Spearman correlation to assess correlation between grade and percent DLCO. 96 patients met the inclusion criteria; average age was 71, 68% were male. Score on CT scan ranged from 18 to 4; average 10.9, SD 3.58. The single-breath diffusing capacity (percent DLCO) ranged from 88% to 17%; mean 44.5%, SD 14.3%. Spearman's correlation for CT score and percent DLCO was 0.622, P < 0.001. This scoring system quantifying the amount of normal lung on chest CT of patients with UIP correlated significantly with percent DLCO (P < 0.001) and appears to offer a promising quantitative measure to assess severity of disease.


Magnetic solid-phase extraction based on Fe3O4/graphene nanocomposites for enantioselective determination of representative profens in the environmental water samples and molecular docking study on adsorption mechanism of graphene.
In this work, a nanocomposite, Fe3O4/graphene was prepared and characterized. Five profens (including ibuprofen, flurbiprofen, pranoprofen, indoprofen and loxoprofen sodium) were extracted from three environmental water samples by using the synthetic Fe3O4/graphene, followed by simultaneous determination of the enantiomers on a Chiralcel OJ-RH column coupled with a triple quadrupole mass spectrometry. Factors affecting the extraction efficiency, such as amount of adsorbents, solution pH, ionic strength, type and volume of desorption solvent, as well as elution time were thoroughly investigated. Method validation showed high sensitivity with method quantification limits in the range of 8.49-26.3 ng/L. Satisfactory recovery (73.6-90.2%), good intra-day precision (RSD 3.2-9.7%) and inter-day precision (RSD 5.2-10%) were also obtained. Furthermore, possible interactions between analyte and graphene, such as electrostatic attraction, charge-π interaction, hydrophobic interaction and π-π stacking were discussed by combining the experiment results and molecular docking study, which provided a new insight into the adsorption mechanism of graphene.


Aβ-oligomers: A potential therapeutic target for Alzheimer's disease.
The cascade of amyloid formation relates to multiple complex events at the molecular level. Previous research has established amyloid plaque deposition as the leading cause of Alzheimer's disease (AD) pathogenesis, detected mainly in aged population. The primary components of the plaques are two alloforms of amyloid-beta (Aβ), Aβ1-42 and Aβ1-40 peptides. Recent studies have provided considerable evidence contrary to the previous claim indicating that amyloid-beta oligomers (AβOs) as the main culprit responsible for AD-associated neurotoxicity and pathogenesis. In this review, we have discussed the primary features of AβOs, such as assembly formation, the kinetics of oligomer formation, interactions with various membranes/membrane receptors, the origin of toxicity, and oligomer-specific detection methods. Recently, the discovery of rationally designed antibodies has opened a gateway for using synthesized peptides as a grafting component in the complementarity determining region (CDR) of antibodies. Thus, the Aβ sequence motif or the complementary peptide sequence in the opposite strand of the β-sheet (extracted from the Protein Data Bank: PDB) helps design oligomer-specific inhibitors. The microscopic event responsible for oligomer formation can be targeted, and thus prevention of the overall macroscopic behaviour of the aggregation or the associated toxicity can be achieved. We have carefully reviewed the oligomer formation kinetics and associated parameters. Besides, we have depicted a thorough understanding of how the synthesized peptide inhibitors can impede the early aggregates (oligomers), mature fibrils, monomers, or a mixture of the species. The oligomer-specific inhibitors (peptides or peptide fragments) lack in-depth chemical kinetics and optimization control-based screening. In the present review, we have proposed a hypothesis for effectively screening oligomer-specific inhibitors using the chemical kinetics (determining the kinetic parameters) and optimization control strategy (cost-dependent analysis). Further, it may be possible to implement the structure-kinetic-activity-relationship (SKAR) strategy instead of structure-activity-relationship (SAR) to improve the inhibitor's activity. The controlled optimization of the kinetic parameters and dose usage will be beneficial for narrowing the search window for the inhibitors.


A direct comparison of the properties of natural and designed zinc-finger proteins.
Zinc-finger proteins of the Cys2His2 type constitute an important family of DNA-binding proteins. Each zinc-finger domain has three residues that are thought to be important in determining DNA binding site specificity. Proteins have been designed previously by combining zinc-finger domains with a fixed sequence framework with different DNA-contacting residues. We compared the DNA-binding properties of the DNA-binding domain from the human transcription factor Sp1, which contains three zinc fingers, with designed proteins in which the sequences of the structural framework were greatly modified but the presumed DNA-contacting residues were retained. Frameworks based on a zinc-finger consensus sequence and on a minimalist sequence consisting largely of alanine residues were studied. The preference for binding to the target sequence, 5'-(G,T)GG G(C,A)G GG(G,T)-3', was retained in all cases tested. The consensus framework-based protein was found to be superior to the natural one in terms of overall DNA-binding affinity, the degree of sequence discrimination, and the resistance to inactivation by chelating agents. Our observations provide direct evidence that the residues previously observed to interact with the DNA bases are indeed the most important residues for determining DNA-binding specificity. We have also shown that these domains can tolerate considerable sequence variation while retaining function as well as three-dimensional structure. Finally, they show that framework modification can be used to generate proteins that have normal or enhanced DNA-binding activity but have different metal-binding properties.


Neural substrates of human fear generalization: A 7T-fMRI investigation.
Fear generalization - the tendency to interpret ambiguous stimuli as threatening due to perceptual similarity to a learned threat - is an adaptive process. Overgeneralization, however, is maladaptive and has been implicated in a number of anxiety disorders. Neuroimaging research has indicated several regions sensitive to effects of generalization, including regions involved in fear excitation (e.g., amygdala, insula) and inhibition (e.g., ventromedial prefrontal cortex). Research has suggested several other small brain regions may play an important role in this process (e.g., hippocampal subfields, bed nucleus of the stria terminalis [BNST], habenula), but, to date, these regions have not been examined during fear generalization due to limited spatial resolution of standard human neuroimaging. To this end, we utilized the high spatial resolution of 7T fMRI to characterize the neural circuits involved in threat discrimination and generalization. Additionally, we examined potential modulating effects of trait anxiety and intolerance of uncertainty on neural activation during threat generalization. In a sample of 31 healthy undergraduate students, significant positive generalization effects (i.e., greater activation for stimuli with increasing perceptual similarity to a learned threat cue) were observed in the visual cortex, thalamus, habenula and BNST, while negative generalization effects were observed in the dentate gyrus, CA1, and CA3. Associations with individual differences were underpowered, though preliminary findings suggested greater generalization in the insula and primary somatosensory cortex may be correlated with self-reported anxiety. Overall, findings largely support previous neuroimaging work on fear generalization and provide additional insight into the contributions of several previously unexplored brain regions.


Natriuretic peptides improve the developmental competence of in vitro cultured porcine oocytes.
Natriuretic peptides (NPs), brain and C type NPs (BNP and CNP), were involved in the maintenance of porcine oocyte meiotic arrest. The present study investigated the effects of NPs on developmental competence of immature porcine oocytes with follicles of different sizes. Follicular fluid NP levels were examined by radioimmunoassay. The developmental competence of porcine oocytes was evaluated by cleavage and blastocyst developmental rates after in vitro fertilization (IVF) or parthenogenetic activation (PA) of cumulus oocyte complexes (COCs), which were recovered from follicle with different sizes. NP levels were examined and classified according to the cleavage potential after IVF with COCs released from these follicles. The BNP and CNP concentrations were increased with follicular size in follicular fluid and sustained at the set ranges of 3.0 - 6.0 mm follicles compared to 6.1 - 8.0 mm follicles. The oocytes developed from 3.0 to 6.0 mm follicles demonstrated increased embryo cleavage and blastocyst ratios after IVF, with an increased follicle size (P < 0.05). Moreover, BNP and CNP significantly promoted the blastocyst developmental rates of 3.0 - 6.0 mm follicles, but could not improve the developmental competence of oocytes from 6.1 to 8.0 mm follicles due to low NP levels. The COCs from 3.0 to 4.0 mm follicles were pre-incubated in 100 ng/ml of BNP and CNP media for 20 h before regular in vitro maturation, which demonstrated 2 to 3 folds higher developmental competencies in both PA and IVF groups compared to respective controls (P < 0.01). The effects of BNP and CNP supplementation in the pre-maturation culture media (PMC) on porcine developmental competence from COCs in follicles of different sizes were different and improved the developmental competence of porcine oocytes from small antral follicle in vitro.


A high-stringency proteomics concept aimed for generation of antibodies specific for cDNA-encoded proteins.
A novel dual bacterial expression system, designed for high-throughput generation of antibodies specific for cDNA-encoded proteins, is presented. The concept involves parallel expression of cDNA-encoded proteins, in two vector systems, as fusions with two different tags, both enabling single-step affinity purification under denaturing conditions. One of the fusion tags includes a portion with documented immunopotentiating effect to stimulate antibody production, and the generated fusion proteins are used to elicit antibodies. The second fusion protein is used in an immobilized form as an affinity ligand to enrich, from the generated antisera, antibodies with selective reactivity to the cDNA-encoded part. To evaluate the system, five cDNA clones from a mouse testis cDNA library were expressed, and antibodies to these cDNA-encoded proteins were generated, enriched and used in blotting procedures to determine expression patterns for the native proteins corresponding to the cDNAs. The five antibody preparations showed specific reactivity to the corresponding recombinant cDNA-encoded proteins, and three of the five antibodies gave specific staining in Western-blot screening of various cell types and tissue homogenates. When the same five cDNAs were processed and analysed using a single-vector method, antibodies with a more non-specific staining were generated. We thus conclude that the presented dual-vector method offers a highly stringent strategy for generation of monospecific polyclonal antibodies.


An ordinal radiomic model to predict the differentiation grade of invasive non-mucinous pulmonary adenocarcinoma based on low-dose computed tomography in lung cancer screening.
To construct a radiomic model of low-dose CT (LDCT) to predict the differentiation grade of invasive non-mucinous pulmonary adenocarcinoma (IPA) and compare its diagnostic performance with quantitative-semantic model and radiologists. A total of 682 pulmonary nodules were divided into the primary cohort (181 grade 1; 254 grade 2; 64 grade 3) and validation cohort (69 grade 1; 99 grade 2; 15 grade 3) according to scanners. The radiomic and quantitative-semantic models were built using ordinal logistic regression. The diagnostic performance of the models and radiologists was assessed by the area under the curve (AUC) of the receiver operating characteristic curve and accuracy. The radiomic model demonstrated excellent diagnostic performance in the validation cohort (AUC, 0.900 (95%CI: 0.847-0.939) for Grade 1 vs. Grade 2/Grade 3; AUC, 0.929 (95%CI: 0.882-0.962) for Grade 1/Grade 2 vs. Grade 3; accuracy, 0.803 (95%CI: 0.737-0.857)). No significant difference in diagnostic performance was found between the radiomic model and radiological expert (AUC, 0.840 (95%CI: 0.779-0.890) for Grade 1 vs. Grade 2/Grade 3, p = 0.130; AUC, 0.852 (95%CI: 0.793-0.900) for Grade 1/Grade 2 vs. Grade 3, p = 0.170; accuracy, 0.743 (95%CI: 0.673-0.804), p = 0.079), but the radiomic model outperformed the quantitative-semantic model and inexperienced radiologists (all p < 0.05). The radiomic model of LDCT can be used to predict the differentiation grade of IPA in lung cancer screening, and its diagnostic performance is comparable to that of radiological expert. • Early identifying the novel differentiation grade of invasive non-mucinous pulmonary adenocarcinoma may provide guidance for further surveillance, surgical strategy, or more adjuvant treatment. • The diagnostic performance of the radiomic model is comparable to that of a radiological expert and superior to that of the quantitative-semantic model and inexperienced radiologists. • The radiomic model of low-dose CT can be used to predict the differentiation grade of invasive non-mucinous pulmonary adenocarcinoma in lung cancer screening.


Clinical outcomes and return to sport after single-stage revision anterior cruciate ligament reconstruction by bone-patellar tendon autograft combined with lateral extra-articular tenodesis.
The anterior cruciate ligament reconstruction (ACLR) failure rate continues to increase. Involvement of a young population with a desire to return to sport, explains the increased need for ACLR (revACLR) revision. The aim of this study was to evaluate clinical outcome, complications, failure rate and return to sport of a single-stage revACLR using bone patellar tendon-bone (BTBT) combined with lateral extra-articular tenodesis (LET). A retrospective analysis was performed on 36 patients who underwent revACLR. Knee stability was assessed by Lachman and Pivot shift test. Objective anterior laxity was determined by KT-2000 arthrometer. The IKDC subjective, Lysholm, ACL-RSI Scores, level of sport activity and Forgotten Joint Score-12 were recorded. Of 36 patients, we collected data from 17 who underwent single-stage revACLR with autologous BTBT combined with LET, performed using an extra-articular MacIntosh procedure as modified by Arnold-Coker. The side-to-side difference in Lachman test and Pivot shift test significantly improved postoperatively. The subjective IKDC, Lysholm and ACL-RSI significantly improved from 71.4 ± 9.03 to 92 ± 6.9, from 58.3 ± 19.3 to 66.8 ± 27.7 and from 50.4 ± 12.2 to 68.6 ± 24.5, respectively during the post-operative follow-up. Ten patients (58.8%) returned to their desired level of sport. One patient was considered a failure because of the postoperative laxity. Single-stage revACLR with BPTB combined with LET is a safe procedure that shows good objective and subjective outcomes, and a high rate of return to the same level of sport. Reducing rotational instability and strain on intra-articular reconstructed structures results in a low rate of complications and failure.


Almond and walnut shell-derived biochars affect sorption-desorption, fractionation, and release of phosphorus in two different soils.
Effective soil phosphorus (P) management requires higher level of knowledge concerning its sorption-desorption, fractionation, and release, as well as its interactions with soil amendments including biochar (BC). The purpose of this research was to investigate the influence of two different BCs, derived from almond and walnut shell, on P sorption-desorption and its redistribution among the geochemical fractions in two different soils. The BCs were applied to the soils in four doses (0, 2.5, 5, and 10% w/w) and the mixtures were incubated for one month. Phosphorus sorption increased due to the addition of BCs. Phosphorus sorption data fitted well the Freundlich isotherm and were simulated by the PHREEQC software. Biochar addition increased total P and the added P was mainly distributed in the exchangeable, Fe/Al-P and the residual fractions. Also, BC addition resulted in an increase in the water-soluble-, mobile-, and Olsen-P, making P more available for plant uptake. The kinetics data were well described by the simple Elovich, pseudo-second-order, and intra-particle diffusion equations. Walnut BC-added soils had higher P sorption capacity than those added with the almond BC. The results suggest that BC binds soil P and releases it gradually back into solution, making it thus available to plants; this renders the studied BCs promising materials for protecting P from being lost out of soil. Future research must be conducted over longer-term experiments that would study P dynamics in BC-added soils under real field conditions.


Revealing the effect of the oriented external electronic field on the superatom-polymeric Zr3O3 cluster: Superhalogen modulation and spectroscopic characteristics.
Seeking novel strategies for designing superatoms is of significance for the potential applications in cluster-assembled nanomaterials. Herein, by employing the density functional theory (DFT) calculations, the effect of the oriented external electronic field (OEEF) on the electronic and photoelectron spectroscopic properties of the superatom-polymeric Zr3O3 cluster was explored. We present the evidence that the increment of the OEEF along all directions results in the remarkable enhancement of the electron affinity (EA) of Zr3O3, which turns it into superhalogen with an EA value of 4.02 eV under 0.020 au OEEF along +y direction. Strikingly, this EA value is larger than that of any halogen atoms in the periodic table. The downward shift of the electronic spectrum induced by the OEEF was confirmed to be the origin of the observed EA enhancement. Furthermore, the investigation of the OEEF's effect on the molecular orbitals (MOs) and photoelectron spectra (PES) of the cluster reveals that the OEEF could alter the electron distribution as well as promoting the blue shift of the PES without changing the spacings between different energetic levels. The OEEF highlighted here provides a new strategy in designing superatoms together with tuning their electronic and spectroscopic properties conveniently and precisely. We wish this finding could stimulate more efforts in designing novel superatoms or superatom-assembled materials from both theory and experiments.


Psychosocial Treatments for Bipolar Disorder in Children and Adolescents.
Evidence suggests that adjunctive psychosocial intervention for the treatment of pediatric bipolar spectrum disorders (BPSDs) is effective, feasible, and highly accepted as both an acute and maintenance treatment for youth with BPSD diagnoses as well as a preventive treatment for high-risk youth who are either asymptomatic or exhibit subsyndromal mood symptoms. Here, we provide a comprehensive review of all known evidence-based interventions, including detailed descriptions of treatment targets and core components, results of clinical trials, and updated research on mediators and moderators of treatment efficacy. Treatments are presented systematically according to level of empirical support (i.e., well established, probably efficacious, possibly efficacious, experimental, or questionable); upcoming and ongoing trials are included when possible. In line with a staging approach, preventive interventions are presented separately. Recommendations for best practices based on age, stage, and additional evidence-based child and family factors shown to affect treatment outcomes are provided.


The physicochemical approaches of altering growth and biochemical properties of medicinal plants in saline soils.
Medicinal plants are important sources of biochemical compounds affecting human health. However, because large areas of the world are subjected to different stresses including salinity, it is important to find methods, which may control the growth and biochemical properties of medicinal plants in such conditions. Another aspect of cropping medicinal plants in saline soils is the alteration of their biochemical properties by stress. Due to the significance of planting medicinal plants in saline soils, the objective of the present review article is to investigate and analyze the physicochemical approaches including soil leaching, organic fertilization, mineral nutrition, ozonated water, magnetism, superabsorbent polymers, and zeolite, which may control the effects of salinity stress on the growth and biochemical properties (production of secondary metabolites) of medicinal plants. In our just-published review article, we investigated the biological approaches, which may affect the growth and biochemical properties of medicinal properties in saline soils. Although salinity stress may induce the production of biochemical products in medicinal plants, the use of physicochemical approaches is also recommendable for the improved growth and biochemical properties of medicinal plants in saline soils. More has yet to be indicated on the use of the physicochemical approaches, which may affect the growth and biochemical properties of medicinal plants in salt stress conditions. KEY POINTS: • Growth and physiological alteration of medicinal plants in salt stress conditions. • The physicochemical approaches of such alteration have been reviewed. • More has yet to be indicated on the approaches, which may affect such properties.


Inflammatory pseudotumor of the spleen: report of a case.
A case of an inflammatory pseudotumor arising in the spleen of a 60-year-old Japanese male is described herein. This benign lesion is extremely rare, with only 12 cases, including our own, having been reported in the world literature. We preoperatively diagnosed the splenic tumor as a metastasis, due to the coexistance of advanced stage carcinoma in the sigmoid colon. However, after splenectomy, histopathological examination of the mass revealed an inflammatory process. Inflammatory pseudotumors often pose diagnostic difficulties because the clinical and radiologic findings are suggestive of malignancy. The clinical and pathological features of cases previously reported are reviewed following the presentation of this case.


Comparative aspects of lipid metabolism in two shrews (Suncus etruscus and Crocidura russula).
1. The amounts of tissue lipids were higher in S. etruscus than in C. russula. 2. The level of liver phospholipids was specially low in C. russula, 2650 mg/100 g as opposed to 3725 g in S. etruscus. 3. This is in good agreement with a reduced rate of the labelled acetate incorporation into the lipids of C. russula. 4. The proportion of unsaturated fatty acids was greater in the liver of S. etruscus; however, the percentage of arachidonic acid was higher in C. russula--15% as opposed to 8%.


Development and validation of liquid chromatography method for simultaneous determination of multiclass seven antibiotic residues in chicken tissues.
Antibiotics are routinely used on poultry for therapy and prevention of diseases and to enhance animal growth. The objective of this study was to develop and validate a sensitive and reliable liquid chromatography with UV detection (LC-UV) method for the simultaneous determination of seven multiclass antibiotic residues (amoxicillin, ampicillin, penicillin, sulfamethoxazole, gentamicin, ciprofloxacin, and erythromycin) in chicken tissues. The liquid chromatography method with UV detection was optimized for complete separation of the seven selected antibiotic compounds with reversed phase and isocratic elution using Hypersil BDS-C18 (3 µm, 100 mm × 4 mm) column. The mobile phase consisted a ratio of 0.05 M Na2HPO4, acetonitrile and methanol (70:10:20), at UV absorption wavelength of 230 nm. The column thermostat was set at 40 °C, the mobile phase flow rate was 1 mL min-1, and the injection volume was 20 μL. All the seven standard compounds were eluted within 14 min. The results for: linearity, precision, sensitivity, accuracy, specificity, decision limit (CCα), detection capability (CCβ), suitability and method robustness were validated according to the criteria of Commission Decision 2002/657/EC guidelines. Calibration plot correlation coefficients ranged from 0.9983 to 0.9998 and the percent relative standard deviations for repeated analysis were below 5% indicating acceptable method precision. The limits of detection (LODs) and quantification (LOQs) ranged from 0.098-0.255 μg kg-1 to 0.297-0.574 μg kg-1, respectively. The accuracy study yielded recoveries in the ranges 98.1-107% for the pure compounds and 94.0-102% for the spiked drug free chicken tissue samples. The method was found to be appropriate for simultaneous determination of five different classes of seven antibiotic residues in chicken tissues. Furthermore, this is the first instance for the simultaneous determination of seven multiclass, multi-residues analysis using LC-UV from chicken tissue samples. This is a cost-effective and alternative method with simple instrumentation approach for laboratories that lack highly specialized state-of-the-art instrumentation.


Subjective ordering, short-term memory, and the frontal lobes.
Four tasks relying on short-term retention, i.e. digit span, missing scan, randomization span, and pointing span were presented to patients with frontal-lobe lesions and normal controls. Digit span was considered a measure of passive short-term memory, the other three tasks additionally reflect comparing processes, and two of these, the randomization and pointing spans, also measure active ordering by the subject. The results confirmed Petrides and Milner's (Neuropsychologia 20, 249-262, 1982) hypothesis that frontal-lobe patients are typically deficient in subject-ordered tasks. It is also suggested that they are deficient in a spontaneous generation, rather than comparison component of subjective ordering.


Exosomes contribution in COVID-19 patients' treatment.
Adipose cell-free derivatives have been recently gaining attention as potential therapeutic agents for various human diseases. In this context, mesenchymal stromal/stem cells (MSCs), adipocyte mesenchymal stem cells (Ad-MSCs) and adipose-derived stem cells (ADSC) possessing potent immunomodulatory activities are proposed as a therapeutic option for the treatment of coronavirus disease 2019 (COVID-19). The COVID-19 represents a global concern of public health caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in which there is not actually any specific therapy. MSCs exert an immunomodulation effect due to the secretion of endogenous factors, such as vascular endothelial growth factor (VEGF), insulin growth factor (IGF), and nerve growth factor (NGF), transforming growth factor (TGF)-β and growth differentiation factor (GDF)-11. Recent reports are promising for further studies and clinical applications of ADSCs and Ad-MSCs in COVID-19 patients. Experimental and clinical studies are exploring the therapeutic potential of both MSCs and derived-exosomes in moderating the morbidity and mortality of COVID-19. In this field, more preclinical and clinical studies are warranted to find an effective treatment for the patients suffering from COVID-19 infection.


Sarcomatoid tumours of lymph nodes showing follicular dendritic cell differentiation.
Putative sarcomas of follicular dendritic cells are extremely uncommon and only small case numbers have been clearly documented. A major difficulty in their delineation has been the persistent controversy over the phenotype and ontogeny of normal follicular dendritic cells. Two new cases arising in adult females are presented herein, both of which had initially been mistaken for metastases from a true soft tissue sarcoma. Their morphology, immunophenotype, and ultrastructure (in one case) are described in order to aid their wider recognition. In the light of these findings, the nature and origin of follicular dendritic cells are discussed.


Photochemical linking of primary aromatic amines to carrier proteins to elicit antibody response against the amine haptens.
Two chemical methods, diazocoupling and reaction with isocyanates, are commonly used to conjugate primary aromatic amines with carrier proteins in order to elicit antibody responses against the aromatic amine haptenic group. Limitations of these conjugation techniques include the requirement for specific functional groups on the carrier protein which generally limits the degree of haptenic substitution obtainable, the many possible side reactions yielding hapten-hapten and carrier-carrier conjugates which waste valuable materials and lower desired hapten-carrier conjugate yields, and, in some cases, conjugation conditions which may denature the carrier protein (e.g., alkaline coupling conditions). We report here a photolabeling approach for conjugating primary aromatic amines to carrier proteins which avoids some of the problems of other conjugation methods and which was used to elicit antibodies against the primary aromatic amine hapten. The method described here is of general application for coupling primary aromatic amines to the carrier proteins and circumvents many of the problems inherent in the isocyanate or diazocoupling methods. 3-Azido-N-ethylcarbazole (ANEC), the azido analog of 3-amino-N-ethylcarbazole, was conjugated to bovine serum albumin (BSA), human transferrin (TR), thyroglobulin (TH), poly-(lysine X tyrosine), and poly-(lysine X phenylalanine) using standard photolabeling procedures. After photolysis, the conjugated proteins or polypeptides were separated from the unbound products of ANEC photolysis on a Sephadex G-10 column. The conjugated proteins were extracted with isobutanol which demonstrated that approximately 20% of the ANEC was covalently coupled to the protein carriers and that the larger portion of the aromatic haptens was non-covalently and hydrophobically bound to the carriers. The ANEC-protein conjugates used for immunization demonstrated a total covalently and non-covalently bound ANEC epitope density of 90 per BSA, 107 per TR and 800 per TH molecule. Rabbits were immunized with the three conjugated proteins and the production of antibody specific for the 3-amino-N-ethylcarbazole hapten was demonstrated by enzyme-linked immunosorbent assay and by inhibition studies using hapten-carrier conjugates of free hapten. The results demonstrate that antibodies against aromatic amine haptens may be raised by immunizing animals with hapten-carrier protein conjugates produced by photolabeling. Since the coupling conditions are very mild and the functional group requirements are so general (requiring only the presence of C-H, N-H, C = O, C = S, or S-H bonds) most carrier proteins should be suitable for use in this method.(ABSTRACT TRUNCATED AT 400 WORDS)


Scrotal distension after endoscopic harvesting of the saphenous vein in patients with inguinal hernia.
The great saphenous vein remains the most commonly used conduit for coronary artery bypass grafting. The endoscopic vein harvesting technique is widely used due to reduced postoperative complications. We present the case of 5 patients with a history of inguinal hernia undergoing coronary artery bypass grafting, which resulted in CO2 infiltration through the deep inguinal ring and into the scrotum leading to acute scrotal enlargement. Due to the risk of impediment of vascular blood supply and necrosis, endoscopic vein harvesting was withdrawn, and the vein was harvested by using the bridging technique. Postoperatively, severe contusion, inflammation, and erythematous vesicular eruption resulted in a lengthened hospital stay.


Treatments for Non-Syndromic Inherited Ichthyosis, Including Emergent Pathogenesis-Related Therapy.
The term 'inherited ichthyosis' refers to a heterogeneous group of mendelian disorders of cornification that involve the integument with varying degrees of scaling. The management of ichthyosis poses a challenge for most physicians. Treatment options proposed in the literature include moisturizers, topical keratolytics, topical and systemic vitamin D analogues, and topical and systemic retinoids; however, some of these modalities are less reliable than others. Despite the therapeutic impasse imposed by the options above, the emergence of pathogenesis-based treatments along with novel gene therapies appear promising and hold the potential to halt or even revert disorders that arise from single genetic mutations, although research is still quite lacking in this domain. Hence, this review aims to highlight the various treatment modalities available for the management of the cutaneous manifestations of non-syndromic inherited ichthyosis, with an added emphasis on pathogenesis-targeted therapies.


The hidden burden of social anxiety disorder in U.S. military veterans: Results from the National Health and Resilience in Veterans Study.
Social anxiety disorder (SAD) is a chronic and disabling psychiatric disorder associated with low levels of help-seeking. To date, however, scarce research has examined the epidemiology of SAD in veterans. This study examined the prevalence, comorbidities and incremental burden of SAD in relation to suicidality and functioning in a representative sample of U.S. military veterans. A nationally representative sample of 3,157 U.S. veterans completed a web survey containing measures of SAD symptoms, trauma history, psychiatric history and functioning. Multivariable analyses were conducted to examine associations between SAD and psychiatric comorbidities, suicidality and functioning. A total 9.5% (n = 272) of the sample screened positive for lifetime SAD. Veterans with SAD were more likely than those without SAD to be younger, female, single, racial/ethnic minorities and to have experienced childhood abuse. They also had substantially elevated rates of comorbid psychiatric disorders, particularly lifetime major depression (odds ratio [OR]=5.8) and posttraumatic stress disorder (OR=3.1), as well as current suicidal ideation (OR=3.3). Veterans with SAD scored lower on measures of functioning, particularly social, emotional and mental health functioning (d's=0.21-0.34). Data were collected cross-sectionally using self-report. SAD in U.S. veterans is prevalent and associated with psychiatric comorbidities, functional impairment and a more than 3-fold greater risk for suicidal ideation . Given that SAD is associated with low treatment seeking and engagement, it may be undetected and undertreated relative to other psychiatric morbidities. These results underscore the importance of screening, monitoring and treating SAD in this population along with other prevalent mental disorders.


Construction of Genetic Linkage Map and Mapping QTL Specific to Leaf Anthocyanin Colouration in Mapping Population 'Allahabad Safeda' × 'Purple Guava (Local)' of Guava (Psidium guajava L.).
In the present investigation, F1 hybrids were developed in guava (Psidium guajava L.) by crossing high leaf-anthocyanin reflective-index (ARI1) content cultivars purple guava (local) 'PG', 'CISH G-1' and low leaf-ARI1 content cultivar Seedless 'SL' with Allahabad Safeda 'AS'. On the basis of phenotypic observations, high ARI1 content was observed in the cross 'AS' × 'PG' (0.214). Further, an SSR-markers-based genetic linkage map was developed from a mapping population of 238 F1 individuals derived from cross 'AS' × 'PG'. The linkage map comprised 11 linkage groups (LGs), spanning 1601.7 cM with an average marker interval distance of 29.61 cM between adjacent markers. Five anthocyanin-content related gene-specific markers from apple were tested for parental polymorphism in the genotypes 'AS' and 'PG'. Subsequently, a marker, viz., 'MdMYB10F1', revealed a strong association with leaf anthocyanin content in the guava mapping population. QTL (qARI-6-1) on LG6 explains much of the variation (PVE = 11.51% with LOD = 4.67) in levels of leaf anthocyanin colouration. This is the first report of amplification/utilization of apple anthocyanin-related genes in guava. The genotypic data generated from the genetic map can be further exploited in future for the enrichment of linkage maps and for identification of complex quantitative trait loci (QTLs) governing economically important fruit quality traits in guava.


Tourism experiences and the lower risk of mortality in the Chinese elderly: a national cohort study.
Cohort studies about the effects of tourism experiences on the risk of death among Chinese older adults are still lacking. We aimed to examine the association between tourism experiences and mortality in Chinese aged 65 or above. We included 9520 participants aged 65 years or above from the Chinese Longitudinal Healthy Longevity Survey at baseline in 23 provinces in 2011. They were followed up in 2014 and 2018. Cox proportional hazards models were used to assess the association between tourism experiences and the risk of death. Among 9520 participants, 7.85% had at least one tourism experience outside of their local city/county during the past 2 years. During 35,994.26 person-years of follow-up, in total 4635 deaths were observed. The crude rate of death was greater in participants who had no tourism experience than in older travelers (incidence rate: 13.70 versus 5.24 per 100 person-years). Elderly travelers had a significantly lower risk for all-cause mortality (crude hazard ratio: 0.38, 95% CI: 0.33-0.44) compared with non-travelers. After adjustment for all covariates, the risk of all-cause mortality was 27% lower among those with at least one tourism experience than among non-travelers (adjusted hazard ratio: 0.73, 95% CI: 0.62-0.85). Subgroup analysis showed that the associations between tourism and the decreased risk of mortality were stable. Tourism decreases the risk of mortality in the Chinese elderly. Tourism should be considered as a modifiable lifestyle factor and an effective way to reduce mortality and promote longevity and healthy aging.


No effect of omega-3 polyunsaturated fatty acid supplementation on inflammatory markers in familial hypercholesterolemia: a randomized crossover trial.
Individuals with familial hypercholesterolemia (FH) have increased cardiovascular risk despite lipid-lowering therapy, and additional therapy is warranted. Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplements have demonstrated an effect on cardiovascular endpoints in some clinical trials. Platelet-modifying and anti-inflammatory properties are among the proposed beneficial effects of n-3 PUFA. We investigated the effect of a high-dose n-3 PUFA supplement on platelet function and inflammatory markers in FH subjects. We performed a randomized, double-blind trial with a crossover design. Inclusion criteria were genetically verified heterozygous FH, stable disease, statin treatment >12 months, and age 18-75 years. Trial participants were allocated to two treatment periods in random order. The treatment periods (three months each) were separated by a three-month washout period. N-3 PUFA (1840 mg eicosapentaenoic acid and 1520 mg docosahexaenoic acid) and placebo (olive oil) were administered in four capsules daily. Endpoints were platelet function and inflammatory markers, assessed by platelet function analyzer, soluble markers P-selectin, vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM), 27 cytokines, and hematological parameters. Thirty-four heterozygous FH individuals completed the trial. No treatment effect (p = 0.93) from n-3 PUFA on the platelet function analyzer was found (2 s, 95% CI [-13, 6]). In our FH population, n-3 PUFA did not influence the levels of P-selectin (-2.0, 95% CI [-5.0, 2.0], p = 0.41), VCAM (0, 95% CI [-14.2, 14.2], p > 0.99), ICAM (-27.0, 95% CI [-70.1, 16.5]; p = 0.21), cytokine levels, or hematological parameters. In statin-treated FH individuals, high dose n-3 PUFA supplement did not affect platelet function and inflammatory markers.Trial registration number: EUDRACTNR 2012-000505-68; ClinicalTrials.gov NCT01813006HighlightsTrial studying the effect of omega-3 fatty acids supplements in familial hypercholesterolemia.High-dose omega-3 fatty acids supplements had no impact on platelet function.Cytokine levels were unchanged after three months of omega-3 fatty acid supplementation.No effect of omega-3 fatty acids on C-reactive protein was observed.


Spatio-temporal variation of heavy metals in fresh water after dam construction: a case study of the Manwan Reservoir, Lancang River.
This study investigated temporal heavy metal characteristics over the past 20 years and the spatial variation of heavy metal characteristics at the Manwan Reservoir tail, center, and head in the Lancang River, Yunnan Province, China. The following heavy metals were selected for analysis: Hg, Cd, Pb, Cu, Zn, As, Cr, Fe, and Mn. Multivariate statistical methods, including principal component analysis (PCA) and the Pearson correlation matrix were used to distinguish the main pollution factors and sources before and after dam construction. The results indicate that the average annual values of heavy metals were far lower than the recommended values of the surface water quality standards in China with the exception of Hg. The concentration of metals showed considerable variation by season, where higher levels of metals generally occurred in high flow periods. The results from PCA show that three significant components were extracted, explaining 76.25% of the total variance. The ANOVA results indicate that Pb, Fe, Mn, and Cr had significant spatial variation (P < 0.05) at the reservoir tail, center and head. The enrichment factor (EF) used to compare the accumulation effect of heavy metals indicated that there was no enrichment (EF < 1) of heavy metals with the exception of Mn, which showed minor enrichment (1 < EF < 3) between the reservoir center and head. The spatiotemporal variation and the accumulation effects of water heavy metals were not distinct due to the construction of the Manwan Reservoir.


An unusual delusion of duplication in a patient affected by Dementia with Lewy bodies.
Dementia with Lewy bodies (DLB) is the second most frequent diagnosis of progressive degenerative dementia in older people. Delusions are common features in DLB and, among them, Capgras syndrome represents the most frequent disturbance, characterized by the recurrent and transient belief that a familiar person, often a close family member or caregiver, has been replaced by an identical-looking imposter. However, other delusional conditions near to misidentification syndromes can occur in DLB patients and may represent a major psychiatric disorder, although rarely studied systematically. We reported on a female patient affected by DLB who presented with an unusual delusion of duplication. Referring to the female professional caregiver engaged by her relatives for her care, the patient constantly described the presence of two different female persons, with a disorder framed in the context of a delusion of duplication. A brain 99Tc-hexamethylpropyleneamineoxime SPECT was performed showing moderate hypoperfusion in both occipital lobes, and associated with marked decreased perfusion in parieto-fronto-temporal lobes bilaterally. An occipital hypoperfusion was identified, although in association with a marked global decrease of perfusion in the remaining lobes. The role of posterior lobes is certainly important in all misidentification syndromes where a natural dissociation between recognition and identification is present. Moreover, the concomitant presence of severe attentional and executive deficits evocative for a frontal syndrome and the marked global decrease of perfusion in the remaining lobes at the SPECT scan also suggest a possible dysfunction in an abnormal connectivity between anterior and posterior areas.


Studying the Influence of Copper on the Growth Behavior, Antioxidative Status, and Histology of the Intestine and Liver of Striped Catfish (Pangasianodon hypophthalmus).
Microelements are well recognized as an essential approach in the field of aquaculture nutrition. Thus, this study aimed to evaluate copper (Cu) inclusion (0, 0.5, 1, and 2 mg/kg) on Striped catfish performances. Fish fed the Cu-incorporated diets for 60 days, then their growth behavior, antioxidative capacity, and intestinal and liver histological features were evaluated. The results showed a marked enhancement in Striped catfish's growth behavior fed 1-2 mg/kg of Cu, as shown by the final weight, weight gain, and specific growth rate. The feed and protein efficiency ratios were significantly affected by Cu in a dose-dependent manner. The highest level of Cu was accumulated in the whole body, muscle, liver, and gills of fish fed 2 mg/kg of Cu. The carcass composition of Striped catfish showed higher protein content in groups received 0.5, 1, and 2 mg/kg Cu in a linear and quadratic manner (p=0.001). The ash content was quadratically increased in Striped catfish fed 2 mg/kg Cu (p=0.001). However, no marked effects were observed on the moisture and lipid contents and the somatic indices (p>0.05). The incorporation of Cu showed meaningfully increased superoxide dismutase, catalase, and glutathione peroxidase but decreased malondialdehyde level in Striped catfish. The villous height exhibited visible growth and branching with increased doses of Cu without a significant increase in the goblet cells. No abnormal features were observed in the liver and hepatocytes of fish treated with Cu. It can be concluded that Cu is required at 1-2 mg/kg for better performances of Striped catfish.


Effects of intake of four types of snack with different timings on postprandial glucose levels after dinner.
It has been reported that the consumption of fruit granola (FG), mulberry leaves, and barley cookies as an afternoon snack suppresses the postprandial increase in glucose levels at dinner. However, there have been no reports on the second-meal effect of snacking on popular snacks, such as potato chips (PC), roasted sweet potato (SP), and black beans (BB), or on the interval between snacking and dinner. The present study was an open-label randomized crossover trial of five study groups (PC, SP, BB, FG, and no snack) regarding the second-meal effects with different intervals between snacks and dinner. The subjects consumed prescribed meals for lunch and dinner at 12:00 and 19:00, and a snack fixed at 838 kJ (= 200 kcal) at 15:00 or 17:00. When the participants snacked at 15:00, the postprandial glucose elevation at dinner was suppressed in the FG and SP groups, and the area under the curve (AUC) was also low. When they snacked at 17:00, the postprandial glucose elevation was suppressed in all the groups. The AUCs for PC, FG, and SP were lower than those for no snacking. On the other hand, carbohydrate intake increased with snacking, but the total AUC of snacks and dinner did not differ in any of the groups. The duration of hyperglycemia decreased with snack intake, as did the glucose amplitude. We believe that the intake of carbohydrates and soluble fiber in snacks is an important factor in the second-meal effect at dinner. These results will contribute to the development of snacking and research into the second-meal effect.


Serum markers of collagen metabolism and serum osteocalcin in relation to pubertal development in 57 boys at 14 years of age.
We investigated whether levels of serum collagen markers and serum osteocalcin are related to pubertal growth and development in a cross-sectional study of 57 healthy boys at 14 y of age. The level of the soft tissue marker, serum amino-terminal propeptide of type III procollagen (PIIINP) was higher in boys at Tanner stages G3 versus G2 (p < 0.01). The levels of the markers of bone collagen matrix differed only at a more advanced pubertal stage: the formation markers, carboxy-terminal and amino-terminal propeptides of type I procollagen, and the degradation marker, carboxy-terminal telopeptide of type I collagen were higher only at stage G4 versus G3 (p < 0.01). The marker of bone mineralization, serum osteocalcin was also higher only at stage G4 versus G3 (p < 0.01). Stage G4 was associated with the pubertal growth spurt. The results demonstrate that pubertal development should be taken into account when serum levels of collagen markers and osteocalcin are evaluated, and suggest that an increase in serum PIINP in boys at G3 might predict a normal pubertal growth spurt, but the finding remains to be confirmed in longitudinal studies.


BTG1 underexpression is an independent prognostic marker in esophageal squamous cell carcinoma.
To determine the expression and function of B cell translocation gene 1 (BTG1) in esophageal carcinoma, esophageal samples were taken from cancer lesions (n = 74) and adjacent normal tissue (n = 34) in esophageal cancer patients immediately after endoscopic biopsy. BTG1 expression was determined by immunohistochemistry and Western blotting. The effect of BTG1 overexpression was examined in vitro utilizing a human esophageal cancer cell line ECA-109 stably transfected with a recombinant lentivirus (LeBTG1 cells) and compared to empty vector-transfected controls (LeEmpty). BTG1 overexpression was verified by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot. The expression of proteins involved in cell cycle regulation (cyclin D1) and apoptosis (Bcl-2) and cell migration (MMP-9) in LeBTG1 cells was analyzed by Western blot. The effect of BTG1 overexpression on cell viability and proliferation was assessed by an MTT assay in LeBTG1 and LeEmpty cells. Flow cytometric analyses were used to evaluate the effect of BTG1 expression on cell cycle distribution and apoptosis. The migration and invasion potential of LeBTG1 cells was examined by plating cells in Matrigel-coated chambers. The level of BTG1 protein expression was found to be significantly lower in esophageal cancer tissue than normal tissues (P < 0.05). Decreased expression of BTG1 was significantly correlated with lymph node metastasis, clinical stage, and histological grade of patients with esophageal cancer (P < 0.05). Meanwhile, loss of BTG1 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result of biological function shown that Eca-109 cell-transfected BTG1 had a lower survival fraction, higher percentage of the G0/G1 phases, higher cell apoptosis, significant decrease in migration and invasion, and lower cylin D1, Bcl-2, and MMP-9 protein expression compared with Eca-109 cell-untransfected BTG1 (P < 0.05). Reduced BTG1 expression is associated with increased disease severity, suggesting it is a negative regulator of esophageal cancer and can serve as a prognostic indicator.


What can we learn from kidney organoids?
The ability to generate 3-dimensional models of the developing human kidney via the directed differentiation of pluripotent stem cells-termed kidney organoids-has been hailed as a major advance in experimental nephrology. Although these provide an opportunity to interrogate human development, model-specific kidney diseases facilitate drug screening and even deliver bioengineered tissue; most of these prophetic end points remain to be realized. Indeed, at present we are still finding out what we can learn and what we cannot learn from this approach. In this review, we will summarize the approaches available to generate models of the human kidney from stem cells, the existing successful applications of kidney organoids, their limitations, and remaining challenges.


SUMmOning Daxx-mediated repression.
An intimate relationship exists between the transcriptional coregulator Daxx, SUMO, and PML nuclear bodies. In this issue, Chang et al. (2011) provide structural insights into how phosphorylation of Daxx increases its affinity toward SUMOs and functional insights into how enhanced SUMO binding affects Daxx-PML interactions, PML nuclear body localization, and Daxx-mediated repression of genes encoding for antiapoptotic factors.


Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC.
Since the discovery of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) gene fusion in non-small cell lung carcinoma (NSCLC) in 2007, more than 10 EML4-ALK variants based on the exon breakpoints in EML4 have been identified. Unlike other receptor tyrosine kinase fusion positive NSCLC such as ROS1 or RET fusion, EML4-ALK is the dominant fusion variant in ALK+ NSCLC accounting for approximately 85 % of all fusion variants in ALK+ NSCLC. Currently, eight EML4-ALK variants are generally recognized with a number (1, 2, 3a/b, 4', 5a/b, 5', 7, 8) with EML4-ALK variants 1 and 3 being the two most common variants accounting for 75-80 % of the total EML4-ALK variants. Preclinical, retrospective analyses of institutional databases, and global randomized phase 3 trials have demonstrated differential clinical response (overall response rate, progression-free survival) to ALK tyrosine kinase inhibitors (TKIs) between the "short" (v3 and v5) and "long" (v1, v2, v5', v7, and v8) EML4-ALK variants. We discuss in more details how EML4-ALK variant structure influences protein stability and response to ALK TKIs. Additionally, the most recalcitrant single solvent-front mutation ALK G1202R is more prone to develop among EML4-ALK v3 following sequential use of next-generation ALK TKIs. Furthermore, TP53 mutations being the most common genomic co-alterations in ALK+ NSCLC also contribute to the heterogeneous response to ALK TKIs. Recognizing ALK+ NSCLC is not one homogeneous disease entity but comprised of different ALK fusion variants with different underlying genomic alterations in particular TP53 mutations that modulate treatment response will provide insight into the further optimization of treatment of ALK+ NSCLC patients potentially leading to improvement in survival.


TAp63 plays compensatory roles in p53-deficient cancer cells under genotoxic stress.
p53, p63, and p73 belong to the p53 family of proteins, which mediate development, differentiation, and various other cellular responses. p53 is involved in many anti-cancer mechanisms, such as cell cycle regulation, apoptosis, and the maintenance of genomic integrity. The p63 gene is controlled by two promoters that direct the expression of two isoforms, one with and one without transactivating properties, known as TAp63 and ΔNp63. In this study, p53-deficient cells (Hep3B and PC-3) and p53-expressing cells (A549 and HepG2) were treated with doxorubicin to examine the possible roles of TAp63 in these cells under genotoxic stress; TAp63 expression was induced in p53-deficient cell lines, but not in p53-expressing cell lines. The ectopic expression of p53 in p53-deficient cells (Hep3B) reduced TAp63 promoter activity, and knockdown of TAp63 attenuated doxorubicin-induced cell growth arrest by promoting cell cycle progression, leading to an increase in the percentage of G(2)/M cells. Moreover, knockdown of TAp63 increased cell sensitivity to doxorubicin-induced genomic damage. Our results suggest that TAp63 may play a compensatory role in cell cycle regulation and DNA damage repair in p53-deficient cancer cells.


A Subset of Breg Cells, B10, Contributes to the Development of Radiation-Induced Pulmonary Fibrosis.
Radiation-induced pulmonary fibrosis (RIPF) is a serious side effect of radiation therapy, but the underlying mechanisms are unknown. B10 cells, as negative B regulatory cells, play important roles in regulating inflammation and autoimmunity. However, the role of B10 cells in RIPF progression is unclear. The aim of this study was to determine the role of B10 cells in aggravating RIPF and the underlying mechanism. The role of B10 cells in RIPF was studied by constructing mouse models of RIPF and depleting B10 cells with an anti-CD22 antibody. The mechanism of B10 cells in RIPF was further explored through cocultivation of B10 cells and MLE-12 or NIH3T3 cells and administration of an interleukin (IL)-10 antibody to block IL-10. B10 cell numbers increased significantly during the early stage in the RIPF mouse models compared with the controls. In addition, depleting B10 cells with the anti-CD22 antibody attenuated the development of lung fibrosis in mice. Subsequently, we confirmed that B10 cells induced epithelial-mesenchymal transition and the transformation of myofibroblasts via activation of STAT3 signaling in vitro. After blockade of IL-10, it was verified that IL-10 secreted by B10 cells mediates the epithelial-mesenchymal transition of myofibroblasts, thereby promoting RIPF. Our study uncovers a novel role for IL-10-secreting B10 cells that could be a new target of research for relieving RIPF.


Advanced glycation end products measured by skin autofluorescence are associated with melancholic depressive symptoms - Findings from Helsinki Birth Cohort Study.
Millions of people live with depression and its burden of disease. Depression has an increased comorbidity and mortality that has remained unexplained. Studies have reported connections between advanced glycation end products (AGEs) and various disease processes, including mental health. The present study evaluated associations between AGEs, depressive symptoms, and types of depressive symptoms. From the Helsinki Birth Cohort Study, 815 participants with a mean age of 76 years were recruited for this cross-sectional study. Characteristics regarding self-reported lifestyle and medical history, as well as blood tests were obtained along with responses regarding depressive symptoms according to the Beck Depression Inventory (BDI) and Mental Health Inventory-5. Each participant had their AGE level measured non-invasively with skin autofluorescence (SAF). Statistical analyses looked at relationships between types of depressive symptoms and AGE levels by sex. Of women, 27% scored ≥10 on the BDI and 18% of men, respectively. Men had higher crude AGE levels (mean [standard deviation], arbitrary units) (2.49 [0.51]) compared to women (2.33 [0.46]) (p < 0.001). The highest crude AGE levels were found in those with melancholic depressive symptoms (2.61 [0.57]), followed by those with non-melancholic depressive symptoms (2.45 [0.45]) and those with no depressive symptoms (2.38 [0.49]) (p = 0.013). These findings remained significant in the fully adjusted model. The current study shows an association between depressive symptoms and higher AGE levels. The association is likely part of a multi-factorial effect, and hence no directionality, causality, or effect can be inferred solely based on the results of this study.


Standardized Procedure of Transperineal Minimally Invasive Abdominoperineal Resection for Low Rectal Cancer.
Although transperineal minimally invasive abdominoperineal resection (tp-APR) based on the concept of transanal total mesorectal excision has recently been used for rectal cancer, the operative procedure has not been standardized to date due to its technical difficulty. The tp-APR procedure used by the authors for a male patient with low rectal cancer is presented in this video.


Termination of ongoing spike-wave discharges investigated by cortico-thalamic network analyses.
While decades of research were devoted to study generation mechanisms of spontaneous spike and wave discharges (SWD), little attention has been paid to network mechanisms associated with the spontaneous termination of SWD. In the current study coupling-dynamics at the onset and termination of SWD were studied in an extended part of the cortico-thalamo-cortical system of freely moving, genetic absence epileptic WAG/Rij rats. Local-field potential recordings of 16 male WAG/Rij rats, equipped with multiple electrodes targeting layer 4 to 6 of the somatosensory-cortex (ctx4, ctx5, ctx6), rostral and caudal reticular thalamic nucleus (rRTN & cRTN), ventral postero medial (VPM), anterior- (ATN) and posterior (Po) thalamic nucleus, were obtained. Six seconds lasting pre-SWD->SWD, SWD->post SWD and control periods were analyzed with time-frequency methods, and between-region interactions were quantified with frequency-resolved Granger Causality (GC) analysis. Most channel pairs showed increases in GC lasting from onset to offset of the SWD. While for most thalamo-thalamic pairs a dominant coupling direction was found during the complete SWD, most cortico-thalamic pairs only showed a dominant directional drive (always from cortex to thalamus) during the first 500ms of SWD. Channel pair ctx4-rRTN showed a longer lasting dominant cortical drive, which stopped 1.5sec prior to SWD offset. This early decrease in directional coupling was followed by an increase in directional coupling from cRTN to rRTN 1sec prior to SWD offset. For channel pairs ctx5-Po and ctx6-Po the heightened cortex->thalamus coupling remained until 1.5sec following SWD offset, while the thalamus->cortex coupling for these pairs stopped at SWD offset. The high directional coupling from somatosensory cortex to the thalamus at SWD onset is in good agreement with the idea of a cortical epileptic focus that initiates and entrains other brain structures into seizure activity. The decrease of cortex to rRTN coupling as well as the increased coupling from cRTN to rRTN preceding SWD termination demonstrates that SWD termination is a gradual process that involves both cortico-thalamic as well as intrathalamic processes. The rostral RTN seems to be an important resonator for SWD and relevant for maintenance, while the cRTN might inhibit this oscillation. The somatosensory cortex seems to attempt to reinitiate SWD following its offset via its strong coupling to the posterior thalamus.


Coal fly ash and lime addition enhances the rate and efficiency of decomposition of food waste during composting.
To evaluate the use of coal fly ash (CFA) on the decomposition efficiency of food waste, synthetic food waste was mixed with lime at 1.5% and 3% (equivalent to 0.94% and 1.88% CaCO(3), respectively), CFA at 5%, 10% and 15% with lime so as to achieve CaCO(3) equivalent of 1.88% and composted for 42 days in a thermophilic 20 l composter with two replicates each. Alkaline materials at 1.88% CaCO(3) equivalent successfully buffered the pH during the composting and enhanced the decomposition efficiency. When these buffering was achieved with CFA+lime, the composting period could be shortened to approximately 28 days compared with approximately 42 days in 3% lime. Organic decomposition in terms of CO(2) loss, carbon turnover and nitrogen transformation were significantly higher for treatments with 1.88% CaCO(3) equivalent. Nutrient transformations and compost maturity parameters indicated that addition of CFA (5-10%) with lime at 1.88% CaCO(3) equivalent enhances the decomposition efficiency and shortens the composting period by 35%.


Dietary micro-fibrillated cellulose improves growth, reduces diarrhea, modulates gut microbiota, and increases butyrate production in post-weaning piglets.
Dietary fiber (DF) supplementation is one of the strategies to prevent on-farm infections; it has the capability to improve gut health and piglet performance. Among the beneficial DFs, micro-fibrillated cellulose (MFC) is a new-generation plant-derived innovative feed ingredient; MFC, originating from sugar-beet pulp, has a hyper-branched structure with the ability to form shear-thinning hydrogel and has a high water-binding capacity. We aimed to determine the effects of MFC supplementation on piglets' performance before and after weaning. We included 45 sows and their piglets in this trial and monitored the results until the piglets were 7 weeks old. Piglets supplemented with MFC had higher body weight and average daily growth (ADG) than did control piglets, both pre- and post-weaning. In addition, MFC supplementation in post-weaning piglets improved butyrate content, and reduced diarrhea incidence. These phenomena, perhaps due to the MFC supplementation at different stages until age 7 weeks. In addition, after weaning, MFC supplementation stimulated the growth of butyrate-producing bacteria such as Ruminococcus.2, Ruminococcaceae.UCG.014, Intestinibacter, Roseburia, and Oribacterium genera, as well as reduced the pathogenic bacteria, such as Campylobacter, and Escherichia. Evidently, supplementation of MFC in feed to young piglets can improve growth performance and butyric acid content and reduce post-weaning diarrhea.


Corneal wound healing after excimer laser ablation in rabbits: expanding versus contracting apertures.
Photorefractive keratectomy for myopia can be performed using an expanding or contracting iris diaphragm, either of which allows for greater ablation centrally and less tissue ablation toward the edge of the treatment zone. To compare the effects of these two strategies, eight rabbits underwent bilateral 5.00-diopter myopic ablations, performed with a contracting diaphragm in one eye and an expanding diaphragm in the other. The rate of epithelial healing and degree of anterior stromal haze, monitored by a masked observer, were similar for the two groups, as was the amount of corneal flattening. These results in rabbit corneas do not suggest a particular advantage of either the expanding or contracting apertures for achieving central corneal flattening in photorefractive keratectomy.


The RUNX Genes as Conditional Oncogenes: Insights from Retroviral Targeting and Mouse Models.
The observation that the Runx genes act as targets for transcriptional activation by retroviral insertion identified a new family of dominant oncogenes. However, it is now clear that Runx genes are 'conditional' oncogenes whose over-expression is growth inhibitory unless accompanied by another event such as concomitant over-expression of MYC or loss of p53 function. Remarkably, while the oncogenic activities of either MYC or RUNX over-expression are suppressed while p53 is intact, the combination of both neutralises p53 tumour suppression in vivo by as yet unknown mechanisms. Moreover, there is emerging evidence that endogenous, basal RUNX activity is important to maintain the viability and proliferation of MYC-driven lymphoma cells. There is also growing evidence that the human RUNX genes play a similar conditional oncogenic role and are selected for over-expression in end-stage cancers of multiple types. Paradoxically, reduced RUNX activity can also predispose to cell immortalisation and transformation, particularly by mutant Ras. These apparently conflicting observations may be reconciled in a stage-specific model of RUNX involvement in cancer. A question that has yet to be fully addressed is the extent to which the three Runx genes are functionally redundant in cancer promotion and suppression.


Use of rifampin in persistent coagulase negative staphylococcal bacteremia in neonates.
Coagulase negative staphylococci (CoNS) are the most common cause of neonatal sepsis in the Neonatal Intensive Care Unit (NICU). A minority of neonates does not respond to vancomycin therapy and develops persistent bacteremia, which may be treated with rifampin. We evaluated the use of rifampin in persistent CoNS bacteremia. Retrospective study of 137 neonates with CoNS bacteremia during admission to a tertiary NICU between July 2006 and July 2009. Main outcome measures were total duration of bacteremia and the adequacy of vancomycin and rifampin therapy. 137/1696 (8.0%) neonates developed a CoNS bacteremia. Eighteen were treated with rifampin because of persistent bacteremia (3 positive blood cultures at least 48 hours apart with clinical symptoms) or (a serious suspicion of) an intravascular thrombus. Duration of bacteremia prior to rifampin therapy (8.0 ± 3.6 days) was positively correlated (p < 0.001) to the total duration of bacteremia (10.3 ± 3.7 days). After starting rifampin therapy C-reactive protein (CRP) levels of all neonates declined and blood cultures became sterile after 2.3 ± 1.6 days. Vancomycin levels were not consistently measured in all neonates, resulting in late detection of subtherapeutic trough levels. Rifampin may be effective in the treatment of persistent CoNS infections in neonates. Outcome may be improved by adequate monitoring of vancomycin trough levels.


Erratum: McNulty JP, Hahn K. Compounded oral ketamine for severe depression, anxiety, and pain in a hospice patient with end-stage chronic obstructive pulmonary disease, cardiopulmonary failure, and severe : A case report. IJPC. 2012; 16(5): 364-368.
The erratum pertains to the formula for Ketamine 40-mg/5-mL Flavored Oral Solution that was included within the original article. The yield of this formula should have been shown as 135 mL instead of 100 mL.


Intravenous contrast extravasation during CT: a national data registry and practice quality improvement initiative.
Establish 3 performance benchmarks for intravenous contrast extravasation during CT examinations: extravasation frequency, distribution of extravasation volumes, and severity of injury. Evaluate the effectiveness of implementing practice quality improvement (PQI) methodology in improving performance for these 3 benchmarks. The Society of Abdominal Radiology and ACR developed a registry collecting data for contrast extravasation events. The project includes a PQI initiative allowing for process improvement. As of December 2013, a total of 58 radiology practices have participated in this project, and 32 practices have completed the 2-cycle PQI. There were a total of 454,497 contrast-enhanced CT exams and 1,085 extravasation events. The average extravasation rate is 0.24%. The median extravasation rate is 0.21%. Most extravasations (82.9%) were between 10 mL and 99 mL. The majority of injuries, 94.6%, are mild in severity, with 4.7% having moderate and 0.8% having severe injuries. Data from practices that completed the PQI process showed a change in the average extravasation rate from 0.28% in the first 6 months to 0.23% in the second 6 months, and the median extravasation rate dropped from 0.25% to 0.16%, neither statistically significant. The distribution of extravasation volumes and the severity of injury did not change between the first and second measurement periods. National performance benchmarks for contrast extravasation rate, distribution of volumes of extravasate, and distribution of severity of injury are established through this multi-institutional practice registry. The application of PQI failed to have a statistically significant positive impact on any of the 3 benchmarks.


The patient perspective of clinical training-an empirical study about patient motives to participate.
This study introduces a comprehensive model to explain patients' prosocial behavioral intentions to participate in clinical training. Using the helping decision model, the authors analyze the combined impact of factors that affect participation intentions. The model includes intrapersonal and interpersonal appraisals triggered by an awareness of the societal need for clinical training as a practical part of medical education. The results of our empirical study (N=317) show that personal costs and anxiety as negative appraisals and a warm glow as a positive appraisal affect participation intentions and fully mediate the effect of the patient's awareness of the societal need. The study results indicate that communication strategies should address patient beliefs about negative personal consequences of participation rather than highlighting the societal need for practical medical education related to clinical training. Based on the results, medical associations could develop guidelines and provide training for physicians on how to motivate patients to participate in clinical training, resulting in more patient-centered standardized consent discussions.


Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study.
Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia in elderly individuals. According to the current biomarker framework for "unbiased descriptive classification", biomarkers of neurodegeneration, "N", constitute a critical component in the tri-category "A/T/N" system. Current biomarkers of neurodegeneration suffer from potential drawbacks such as requiring invasive lumbar puncture, involving ionizing radiation, or representing a late, irreversible marker. Recent human studies have suggested that reduced brain oxygen metabolism may be a new functional marker of neurodegeneration in AD, but the heterogeneity and the presence of mixed pathology in human patients did not allow a full understanding of the role of oxygen extraction and metabolism in AD. In this report, global brain oxygen metabolism and related physiological parameters were studied in two AD mouse models with relatively pure pathology, using advanced MRI techniques including T2 -relaxation-under-spin-tagging (TRUST) and phase contrast (PC) MRI. Additionally, regional cerebral blood flow (CBF) was determined with pseudocontinuous arterial spin labeling. Reduced global oxygen extraction fraction (by -18.7%, p = 0.008), unit-mass cerebral metabolic rate of oxygen (CMRO2 ) (by -17.4%, p = 0.04) and total CMRO2 (by -30.8%, p < 0.001) were observed in Tau4RΔK mice-referred to as the tau AD model-which manifested pronounced neurodegeneration, as measured by diminished brain volume (by -15.2%, p < 0.001). Global and regional CBF in these mice were not different from those of wild-type mice (p > 0.05), suggesting normal vascular function. By contrast, in B6;SJL-Tg [APPSWE]2576Kha (APP) mice-referred to as the amyloid AD model-no brain volume reduction, as well as relatively intact brain oxygen extraction and metabolism, were found (p > 0.05). Consistent with the imaging data, behavioral measures of walking distance were impaired in Tau4RΔK mice (p = 0.004), but not in APP mice (p = 0.88). Collectively, these findings support the hypothesis that noninvasive MRI measurement of brain oxygen metabolism may be a promising biomarker of neurodegeneration in AD.


Maternal control of early patterning in sea urchin embryos.
Sea urchin development has been studied extensively for more than a century and considered regulative since the first experimental evidence. Further investigations have repeatedly supported this standpoint by revealing the presence of inductive mechanisms that alter cell fate decisions at early cleavage stages and flexibility of development in response to environmental conditions. Some features indicate that sea urchin development is not completely regulative, but actually includes determinative events. In 16-cell embryos, mesomeres and macromeres represent multipotency, while the cell fate of most vegetal micromeres is restricted. It is known that the mature sea urchin eggs are polarized by the asymmetrical distribution of some maternal mRNAs and proteins. Spatially-distributed maternal factors are necessary for the orientation of the primary animal-vegetal axis, which is established by both maternal and zygotic mechanisms later in development. The secondary dorsal-ventral axis is conditionally specified later in development. Dorsal-ventral polarity is very liable during the early cleavages, though more recent data argue that its direction may be oriented by maternal asymmetry. In this review, we focus on the role of maternal factors in initial embryonic patterning during the first cleavages of sea urchin embryos before activation of the embryonic genome.


Cellular biology of human intimal hyperplastic stenosis.
Restenosis after angioplasty and vascular surgery remains a major unsolved clinical problem. Vascular smooth muscle cell (VSMC) hyperplasia is an invariable response, but in 20-50% of cases proceeds to compromise the vessel lumen. We sought to identify cellular characteristics of human VSMC which are associated with restenosis. Human VSMC were grown from 135 samples of vascular tissue derived from patients undergoing primary cardiovascular surgery and revision surgery for restenosis. Cells derived from normal vein and artery, atherosclerotic plaques and from stenotic lesions were studied for successful proliferation in cell culture. Furthermore, growth rates were measured in response to 15% foetal calf serum +/- inhibition with heparin (100 micrograms/ml). Significantly fewer cells from atherosclerotic plaques progress to the third passage in cell culture than those derived from stenoses and controls (p < 0.001, Chi square) and growth rates after the third passage could not be studied in these cells. Of cells that progress to this stage, growth rates do not differ between stenosis-derived and normal cells under standard conditions. VSMC from mature atherosclerotic plaques may have undergone senescent changes. Stenosis-derived cells do not grow more rapidly than normal cells, but are significantly less sensitive to heparin (p < 0.001, Mann-Witney test), which is a major physiological inhibitor of VSMC growth. Differences in biological characteristics of human VSMC, observed in cell culture, may provide important insights into human vascular disease.


Congenital intrathoracic kidney: a 5-year radionuclide follow-up.
Congenital intrathoracic kidney (CIK) is an exceedingly rare anomaly. IN a study of 15,919 autopsies of children by Campbell [1], only one CIK was noted. Less than 50 cases have been reported so far in English literature [3]. Most of the CIK are asymptomatic normal organs which require no medical or surgical treatment. We have had the opportunity of applying scintiphotographic techniques exclusively to follow up a 9 1/2-month-old infant with CIK for 5 years.


Urologic aspects of pancreatic adenocarcinoma.
Pancreatic adenocarcinoma can present initially as urologic disease. The 15 reported cases in the literature are analyzed and 5 cases, featuring ureteral obstruction, renal artery compression, abdominal bruit, positive urinary cytology, varicocele, renal mass and hematuria as the initial presentation of this disease, are added. The diagnosis and management are reviewed.


Bis(μ-pyridine-2,5-dicarboxyl-ato)-κN,O:O;κO:N,O-bis-[aqua-(2,2'-bipyridine-κN,N')cobalt(II)] dihydrate.
In the centrosymmetric title compound, [Co(2)(C(7)H(3)NO(4))(2)(C(10)H(8)N(2))(2)(H(2)O)(2)]·2H(2)O, the two Co(II) cations are bridged by pairs of pyridine-2,5-dicarboxyl-ate anions across an inversion center. Besides two pyridine-2,5-dicarboxyl-ate anions, one bidentate 2,2'-bipyridine and one water mol-ecule coordinate to the Co cation, completing a distorted octa-hedral coordination geometry. Within the dinuclear mol-ecule, π-π stacking occurs between parallel pyridine rings with centroid-centroid distances of 3.802 (2) Å. The crystal structure contains extensive O-H⋯O and weak C-H⋯O hydrogen bonds and C-H⋯π inter-actions.


Bloodstream infections in neutropenic patients with cancer: differences between patients with haematological malignancies and solid tumours.
We sought to identify the characteristics, aetiology, antibiotic resistance and outcomes of bloodstream infection (BSI) in neutropenic patients with haematological malignancies (HM) and in those with solid tumours (ST) and assess their impact on empirical therapy and outcomes. All episodes of BSI in neutropenic patients with HM and ST were prospectively recorded and compared. Of 579 episodes of BSI, 493 occurred in patients with HM and 86 in patients with ST. An endogenous source and catheter-related infection were more frequent in patients with HM, whereas pneumonia and urinary tract were more common in the ST group. BSI was mainly due to Gram-negative bacilli. Coagulase-negative staphylococci were more frequent in patients with HM, while Pseudomonas aeruginosa was more common in patients with ST and was the leading cause of pneumonia. Multidrug-resistant Gram-negative bacilli (MDRGNB) were more frequently isolated in haematological patients who more often received inadequate empirical therapy than those with ST. Case-fatality rates were higher in patients with ST. We identified significant differences in BSI in neutropenic patients with HM and ST. MDRGNB were more often isolated in patients with HM. Pneumonia due to P. aeruginosa was particularly frequent among patients with ST. Case-fatality rates were higher in patients with ST.


Chelation therapy with 3,4,3-Li(1,2-HOPO) after pulmonary exposure to plutonium in rats.
Internal exposure to plutonium can occur through inhalation for the nuclear worker, but also for the public if the radionuclide was released into the atmosphere in the context of a nuclear accident or terrorist attack. DieThylenetriaminePentaAcetic acid (DTPA) is currently still the only authorized chelator that can be used to decorporate internalized plutonium. The Linear HydrOxyPyridinOne-based ligand named 3,4,3-Li(1,2-HOPO) remains the most promising drug candidate to replace it in the hopes of improving chelating treatment. This study aimed to assess the efficacy of 3,4,3-Li(1,2-HOPO) in removing plutonium from rats exposed to the lungs, depending on the timing and route of treatment, and almost always compared to DTPA at a ten-fold higher dose used as a reference chelator. First, early intravenous injection or inhalation of 3,4,3-Li(1,2-HOPO) demonstrated superior efficacy over DTPA in preventing plutonium accumulation in liver and bone in rats exposed by injection or lung intubation. However, this superiority of 3,4,3-Li(1,2-HOPO) was much less pronounced with delayed treatment. In rats given plutonium in the lungs, the experiments also showed that 3,4,3-Li-HOPO reduced pulmonary retention of plutonium more effectively than DTPA only when the chelators were injected early but not at delayed times, while it was always the better of the two chelators when they were inhaled. Under our experimental conditions, the rapid oral administration of 3,4,3-Li(1,2-HOPO) was successful in preventing systemic accumulation of plutonium, but not in decreasing lung retention. Thus, after exposure to plutonium by inhalation, the best emergency treatment would be the rapid inhalation of a 3,4,3-Li(1,2-HOPO) aerosol to limit pulmonary retention of plutonium and prevent extrapulmonary deposition of plutonium in target systemic tissues.


Supernumerary auricle on the lateral canthus.
A boy was born with an appendage on his right lateral canthus, with associated supernumerary auricles on the right cheek and a right ocular dermoid. We resected the appendage. Its core was composed of elastic cartilage, as is the external auricle. The lateral canthus overlaps facial cleft line No. 8 in Tessier's classification [Plast Reconstr Surg 4 (1976) 69] and forms the upper part of the first branchial arch. It appears that our patient's appendage was a supernumerary auricle, which had developed from the first branchial arch.


Persistent hypomagnesemia following cisplatin chemotherapy in patients with ovarian cancer.
The development of acute hypomagnesemia following cisplatin administration is a well-recognized complication associated with the use of this chemotherapeutic agent. However, there is limited information available in the medical literature concerning how long this abnormality may persist following the discontinuation of cisplatin. Of 13 patients with ovarian cancer who had a baseline serum magnesium determination obtained prior to the initiation of a second-line cisplatin-based chemotherapy regimen, 9 (69%) were found to be hypomagnesemic (serum magnesium less than 1.4 mg/l), including 3 patients with serum magnesium values less than 1.0 mequiv/l. The median cisplatin-free interval for these 9 patients was 19 months (range 6-40 months). We conclude that persistent, and possibly permanent, hypomagnesemia is common following cisplatin chemotherapy.


A pipeline approach to single-particle processing in RELION.
The formal concept of a workflow to single-particle analysis of cryo-electron microscopy (cryo-EM) images in the RELION program is described. In this approach, the structure-determination process is considered as a graph, where intermediate results in the form of images or metadata are the vertices, and different functionalities of the program are the edges. The new implementation automatically logs all user actions, facilitates file management and disk cleaning, and allows convenient browsing of the history of a project. Moreover, new functionality to iteratively execute consecutive jobs allows on-the-fly image processing, which will lead to more efficient data acquisition by providing faster feedback on data quality. The possibility of exchanging data-processing procedures among users will contribute to the development of standardized image-processing procedures, and hence increase accessibility for new users in this rapidly expanding field.


Integrated antimicrobial and antifouling ultrafiltration membrane by surface grafting PEO and N-chloramine functional groups.
Ultrafiltration membranes with integrated antimicrobial and antifouling properties were fabricated using an engineering thermoplastic (carboxylated cardopoly(aryl ether ketone, PEK-COOH). Different molecular weights of PEO (Mw: 120, 350, 550) were grafted to the PEK-COOH membrane surface via EDC/NHS methodology. N-chloramine modified membranes then were prepared by simple exposure to dilute sodium hypochlorite solution. The surface grafting processes were all performed in water (i.e. without organic solvent). With this surface modification, the hydrophilicity of membranes improved significantly and the pure water flux increased compared to the unmodified PEK-COOH membrane. Furthermore, the PEO and N-chloramine modified membranes were resistant not only to both protein adsorption and bacterial adhesion, but also to microbial proliferation. The results of this work suggest that PEO and N-chloramine modified membranes are promising as fouling-resistant membranes.


A guide to sample delivery systems for serial crystallography.
Crystallography has made a notable contribution to our knowledge of structural biology. For traditional crystallography experiments, the growth of crystals with large size and high quality is crucial, and it remains one of the bottlenecks. In recent years, the successful application of serial femtosecond crystallography (SFX) provides a new choice when only numerous microcrystals can be obtained. The intense pulsed radiation of X-ray free-electron lasers (XFELs) enables the data collection of small-sized crystals, making the size of crystals no longer a limiting factor. The ultrafast pulses of XFELs can achieve 'diffraction before destruction', which effectively avoids radiation damage and realizes diffraction near physiological temperatures. More recently, the SFX has been expanded to serial crystallography (SX) that can additionally employ synchrotron radiation as the light source. In addition to the traditional ones, these techniques provide complementary opportunities for structural determination. The development of SX experiments strongly relies on the advancement of hardware including the sample delivery system, the X-ray source, and the X-ray detector. Here, in this review, we categorize the existing sample delivery systems, summarize their progress, and propose their future prospectives.


Patients' perspectives on the role of radiation therapists.
To examine patients' perspectives on the role of radiation therapists and to develop substantive theory about the relationships patients form with their radiation therapists. Semi-structured interviews were conducted with 34 breast cancer patients in Western Australia. Interviews were tape-recorded and transcribed verbatim. Grounded theory and the constant comparative method were used to analyse the data. The major finding from this study was the importance that patients placed on achieving a sense of emotional comfort during their radiation therapy. Two ways in which patients achieved this comfort were by forming relationships with radiation therapists and gaining information related to their treatment and care. Radiation therapists played a central role in enabling patients to achieve a sense of emotional comfort. Although radiation therapists have a technical job they need to remain aware of their role in providing patient care and take appropriate steps to ensure that they can assist patients in feeling comfortable during their radiation therapy. The role of the radiation therapist in assisting patients to achieve a sense of emotional comfort needs to be formalised to ensure that all patients in radiation therapy are aware of the radiation therapist's role and receive a similar level of care during treatment.


Molecular cloning of toxins expressed by the venom gland of Lasiodora sp.
The present work describes the identification of toxins expressed by the venom gland of the spider Lasiodora sp. The toxins LTx1, LTx2 and LTx3 were identified by the screening of a cDNA library. These toxins showed significant similarity at the amino acid level with spider toxins from Lasiodora parahybana, Eurypelma californicum, Brachypelma smithii, Selenocosmia huwena.


The Role of Endoplasmic Reticulum Chaperones in Protein Folding and Quality Control.
Molecular chaperones assist the folding of nascent chains in the cell. Chaperones also aid in quality control decisions as persistent chaperone binding can help to sort terminal misfolded proteins for degradation. There are two major molecular chaperone families in the endoplasmic reticulum (ER) that assist proteins in reaching their native structure and evaluating the fidelity of the maturation process. The ER Hsp70 chaperone, BiP, supports adenine nucleotide-regulated binding to non-native proteins that possess exposed hydrophobic regions. In contrast, the carbohydrate-dependent chaperone system involving the membrane protein calnexin and its soluble paralogue calreticulin recognize a specific glycoform of an exposed hydrophilic protein modification for which the composition is controlled by a series of glycosidases and transferases. Here, we compare and contrast the properties, mechanisms of action and functions of these different chaperones systems that work in parallel, as well as together, to assist a large variety of substrates that traverse the eukaryotic secretory pathway.


Synthesis of new uracil-5-sulfonamide derivatives and immunostimulatory effect of a chemically modified hemolymph of Biomphalaria alexandrina on Schistosoma mansoni infected mice.
Some N-p-substituted phenyl uracil-5-sulphonamide derivatives have been synthesized to be evaluated as molluscicides against Biomphalanaria alexandrina snails, the intermediate host of Schistosoma mansoni. Schistosoma mansoni infected mice were treated with hemolymph obtained from pre-treated Biomphalana alexandrina snails with the products 4a, 10a, 10b and 4b or obtained from non-treated snails. The selection of the concentration based on the predetermined dose which caused mortality of less than 50% of snails/24 h. LC50 of compounds 4a, 10a, 10b and 4b was 50, 100, 200 and 50 ppm respectively. The result showed that immunostimulatory effect of treated hemolymph with compounds 4a, 10a and 4b was related to significant protective effects (44.4, 34.6 and 50.4% reduction in worm burden respectively). In addition, mean total worm burdens were significantly reduced in non treated hemolymph by 33.8%. The effect of hemolymph obtained from treated or non treated snails on S. mansoni adult worms antigens was studied by indirect immunofluorescence technique using chronic mouse sera (CMS). The results indicated that there was a strong reaction with epitopes in gut epithelium, tubercles, teigument and subtegumental musculature of untreated and treated S. mansoni adult worms antigens. Therefore, treatment of hemolymph obtained from pre-treated snails with compounds 4a, 10a, and 4b can stimulate specific immune response and induce protective effects against S. mansoni infection.


Angiography in chronic/recurrent gastrointestinal bleeding: a nine year study.
Undiagnosed chronic/recurrent gastrointestinal bleeding, as defined, is a severe problem to those afflicted, both physically and psychologically as well as socioeconomically. During the past nine years, 60 such patients received aortography and panvisceral arteriography (that is, celiac, superior mesenteric, and inferior mesenteric arteriography) in a search for the lesions that may be responsible for the bleeding. Results of angiography were "positive" in 26 patients for a diagnostic yield of 43 per cent. Fifteen of the 26 patients with positive angiographic findings demonstrated arteriovenous malformations of the gastrointestinal tract. Two separate lesions were identified in three patients. This series is compared with other published series of angiography for chronic gastrointestinal bleeding. One difference from the other series is the demonstration of three patients with arteriovenous malformation of the gastric antrum. The diagnostic angiographic features of this condition are presented, along with the interestng finding of état mammelonné in two of the three patients. Another difference from the other series is the demonstration of four arteriovenous malformations involving the left side of the colon, whereas other series report none in this location. One possible explanation for this descrepancy is our routine use of inferior mesenteric arteriography in all cases of chronic gastrointestinal bleeding. Ten arteriovenous malformations of the colon are reported along with a review of the angiographic diagnostic features in this condition. The precise incidence of false-positive and false-negative diagnoses is unknown since surgery was not performed on all patients. However, each patient studied represented a total failure, by traditional diagnostic studies, to determine the cause of bleeding. The incidence of positive findings with angiography (43 per cent) in patients with undiagnosed chronic/recurrent gastrointestinal bleeding is sufficient to encourage the continued use of panvisceral arteriography in this condition.


IiWRKY34 positively regulates yield, lignan biosynthesis and stress tolerance in Isatis indigotica.
Yield potential, pharmaceutical compounds production and stress tolerance capacity are 3 classes of traits that determine the quality of medicinal plants. The autotetraploid Isatis indigotica has greater yield, higher bioactive lignan accumulation and enhanced stress tolerance compared with its diploid progenitor. Here we show that the transcription factor IiWRKY34, with higher expression levels in tetraploid than in diploid I. indigotica, has large pleiotropic effects on an array of traits, including biomass growth rates, lignan biosynthesis, as well as salt and drought stress tolerance. Integrated analysis of transcriptome and metabolome profiling demonstrated that IiWRKY34 expression had far-reaching consequences on both primary and secondary metabolism, reprograming carbon flux towards phenylpropanoids, such as lignans and flavonoids. Transcript-metabolite correlation analysis was applied to construct the regulatory network of IiWRKY34 for lignan biosynthesis. One candidate target Ii4CL3, a key rate-limiting enzyme of lignan biosynthesis as indicated in our previous study, has been demonstrated to indeed be activated by IiWRKY34. Collectively, the results indicate that the differentially expressed IiWRKY34 has contributed significantly to the polyploidy vigor of I. indigotica, and manipulation of this gene will facilitate comprehensive improvements of I. indigotica herb.