Psoralen plus ultraviolet A +/- interferon-alpha treatment resistance in mycosis fungoides: the role of tumour microenvironment, nuclear transcription factor-kappaB and T-cell receptor pathways.
Interferon (IFN)-alpha is widely used in the treatment of mycosis fungoides (MF) and when used in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA) both improved response and duration of complete remission have been reported. However, in spite of encouraging results of the initial studies, currently there is no information available on specific prognostic factors enabling prediction of patients' resistance to PUVA +/- IFN-alpha treatment. To identify factors responsible for resistance to PUVA +/- IFN-alpha treatment in MF patients. The gene expression profiling of pretreatment samples from 29 patients diagnosed as IA, IB or IIA stage of MF enrolled in a randomized PUVA vs. PUVA + IFN-alpha clinical trial was analysed using cDNA microarrays. A Cox model (SAM) and gene set enrichment analysis (GSEA) were used for identification of genes and biologically significant pathways related to resistance to treatment. Genes involved in NF-kappaB signalling, T-cell receptor (TCR) signalling, cytokine signalling and proliferation were differentially expressed between responders and nonresponders. Interestingly, expression of markers representative of those pathways was found not only in the tumoral cells, but also in specific subpopulations of macrophages, dendritic cells and other non-neoplastic cell types constituting the tumour microenvironment, likely involved in the promotion of survival and proliferation of cutaneous T-cell lymphoma. Gene expression changes in both the tumour and the tumour microenvironment are an important determinant of treatment outcome in early-stage MF patients. Some proinflammatory factors such as NF-kappaB, inflammatory cytokines and their receptors in addition to TCR-associated molecules could be promising targets for MF treatment.


Cytotoxic and antibacterial labdane-type diterpenes from the aerial parts of Cistus incanus subsp. creticus.
Seven labdane-type diterpenoids were isolated from the leaves of Cistus incanus subsp. creticus; their structures were established by spectroscopic means. All compounds were tested in vitro for their cytotoxicity against three cell line systems: KB, P-388; and NSCLC-N6. Their antibacterial and antifungal activities were tested against Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosae, Enterobacter cloacae, Escherichia coli, Klebsiella pneumonia, Torulopsis glabrata, Saccharomyces cerevisiae, and Candida albicans as well.


A multi-institutional pilot clinical trial of spectroscopic MRI-guided radiation dose escalation for newly diagnosed glioblastoma.
Glioblastomas (GBMs) are aggressive brain tumors despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Spectroscopic magnetic resonance imaging (sMRI), which measures levels of specific brain metabolites, can delineate regions at high risk for GBM recurrence not visualized on contrast-enhanced (CE) MRI. We conducted a clinical trial to assess the feasibility, safety, and efficacy of sMRI-guided RT dose escalation to 75 Gy for newly diagnosed GBMs. Our pilot trial (NCT03137888) enrolled patients at 3 institutions (Emory University, University of Miami, Johns Hopkins University) from September 2017 to June 2019. For RT, standard tumor volumes based on T2-FLAIR and T1w-CE MRIs with margins were treated in 30 fractions to 50.1 and 60 Gy, respectively. An additional high-risk volume based on residual CE tumor and Cho/NAA (on sMRI) ≥2× normal was treated to 75 Gy. Survival curves were generated by the Kaplan-Meier method. Toxicities were assessed according to CTCAE v4.0. Thirty patients were treated in the study. The median age was 59 years. 30% were MGMT promoter hypermethylated; 7% harbored IDH1 mutation. With a median follow-up of 21.4 months for censored patients, median overall survival (OS) and progression-free survival were 23.0 and 16.6 months, respectively. This regimen appeared well-tolerated with 70% of grade 3 or greater toxicity ascribed to TMZ and 23% occurring at least 1 year after RT. Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for patients with newly diagnosed GBMs. OS outcome is promising and warrants additional testing. Based on these results, a randomized phase II trial is in development.


Hepatocyte-specific deletion of XBP1 sensitizes mice to liver injury through hyperactivation of IRE1α.
X-box binding protein-1 (XBP1) is a transcription factor that plays a central role in controlling cellular responses to endoplasmic reticulum (ER) stress. Under stress conditions, the transcriptionally active form of XBP1 is generated via splicing of Xbp1 mRNA by the ER-resident protein inositol-requiring enzyme-1 (IRE1α). Genetic deletion of XBP1 has multiple consequences: some resulting from the loss of the transcription factor per se, and others related to compensatory activation of IRE1α. The objective of the current study was to investigate the effects of XBP1 deletion in adult mouse liver and determine to what extent they are direct or indirect. XBP1 was deleted from hepatocytes in adult Xbp1fl/fl mice using AAV8-Transthyretin-Cre (Xbp1Δhep). Xbp1Δhep mice exhibited no liver disease at baseline, but developed acute biochemical and histologic liver injury in response to a dietary challenge with fructose for 4 weeks. Fructose-mediated liver injury in Xbp1Δhep mice coincided with heightened IRE1α activity, as demonstrated by Xbp1 mRNA splicing, JNK activation, and regulated IRE1α-dependent RNA decay (RIDD). Activation of eIF2α was also evident, with associated up-regulation of the pro-apoptotic molecules CHOP, BIM, and PUMA. To determine whether the adverse consequences of liver-specific XBP1 deletion were due to XBP1 loss or heightened IRE1α activity, we repeated a fructose challenge in mice with liver-specific deletion of both XBP1 and IRE1α (Xbp1Δhep;Ire1aΔhep). Xbp1Δhep;Ire1aΔhep mice were protected from fructose-mediated liver injury and failed to exhibit any of the signs of ER stress seen in mice lacking XBP1 alone. The protective effect of IRE1α deletion persisted even with long-term exposure to fructose. Xbp1Δhep mice developed liver fibrosis at 16 weeks, but Xbp1Δhep;Ire1aΔhep mice did not. Overall, the results indicate that the deleterious effects of hepatocyte-specific XBP1 deletion are due primarily to hyperactivation of IRE1α. They support further exploration of IRE1α as a contributor to acute and chronic liver diseases.


What Is New in Medical Student and Resident Education?: Best Articles From the Past Year.
This month we focus on current research in medical student and resident education. Dr. Fox discusses four recent publications, which are concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in Box 1 on this page, along with direct links to the abstracts.


[UPLC/Q-TOF MS-Based Metabolomics Analysis of Chemical uiterences in Different Polygala tenuifolia Varieties].
The chemical differences of Polygala tenuifolia varieties-JinYuan 1 (JY1), FenYuan 2 (FY2) and traditional FenYang (FY) were studied, in order to provide reference for the breeding of Polygala tenuifolia. The samples of JY1, FY2 and FY were subjected to ultra-high performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis. The obtained data were analyzed using Principal Component Analysis (PCA) and other statistical analysis methods, and differential metabolites were further figured out. Compared with FY,sucrose esters (such as sibiricoses A5 and tenuifoliside B) and oligosaccharides (such as tenuifoliose K) in JY1 and FY2 contributed more to the separation of Polygala tenuifolia varieties in the PCA score plot. Compared with JYl, The sugar esters (such as tenuifoliside B and tenuifoliside A) and oligosaccharides( such as tenuifoliose A) in the FY2 also contributed more to the separation of Polygala tenuifolia varieties in the PCA score plot. In addition, the relative contents of sibiricaxanthone A,3,6'-disinapoly sucrose and senegin III showed significant differences among FY, JY1 and FY2. As new Polygala tenuifolia varieties, JY1 and FY2 had certain differences and respective advantages on the chemical composition compared with FY,which could provide data support for the directional breeding of Polygala tenuifolia based on the contents of some active compounds.


Comparison of Familial Clustering of Anogenital and Skin Cancers Between In Situ and Invasive Types.
Literature on familial risk of carcinomas in situ (CISs) is limited because many cancer registries do not collect information on CIS. In Sweden CISs are collected, and we used these data to analyze familial relative risks (RRs) for concordant (CIS-CIS) types of anogenital (cervical, other female and male genital and anal) and skin squamous cell CIS; additionally RRs were assessed between CIS types and between CIS and invasive forms. RRs were calculated for the offspring generations when family members were diagnosed CIS. Case numbers for CIS ranged from 330 in anal to 177,285 in cervical CIS. Significant concordant CIS-CIS RRs were 2.74 for female genital, 1.77 for cervical and 2.29 for SCC skin CISs. The CIS forms associated also with each other, except for cervical and skin CIS types. RRs for concordant CIS-invasive cancer associations were lower than CIS-CIS associations. Cervical CIS associated with non-Hodgkin CIS which may suggest immune dysfunction as a contributing factors. The results for anogenital CIS types suggest that life style related human papilloma virus infections contributed to the observed familial associations. Lower risks for CIS-invasive cancer than CIS-CIS suggest that CIS and invasive cancers share only partially risk factors that underlie familial clustering.


Schizophrenia and Psychosis: Diagnosis, Current Research Trends, and Model Treatment Approaches with Implications for Transitional Age Youth.
This article reviews the current state of diagnosis and treatment of schizophrenia, describing the recent proliferation of research in high-risk psychosis spectrum conditions, which are different from childhood-onset and early onset schizophrenia, and findings of psychotic-like experiences in the normal population. Taken from adult and childhood literature, clinical quandaries in accurate diagnosis, and treatment gaps in co-occurring, or sometimes confounding, conditions are discussed. Thoughts on the impact of schizophrenia on an emerging adulthood trajectory are offered. Recent best practices in the treatment of schizophrenia are consistent with a recovery-oriented model of mental health services for transitional age youth.


Gamified learning in dermatology and dermoscopy education: a paradigm shift.
Teaching methods in medical education have been changing. More recent teaching modalities have gone beyond the traditional delivery of knowledge, promoting learning motivation, and improving teaching and learning outcomes. 'Gamification' and 'serious games' are methodologies that use the principles of games to facilitate learning processes and the acquisition of skills and knowledge, thereby improving attitudes towards learning when compared with traditional teaching methods. As dermatology is a visual field, images are a key component of different teaching strategies. Likewise, dermoscopy, a noninvasive diagnostic technique that allows the visualization of structures within the epidermis and upper dermis, also uses images and pattern recognition strategies. A series of Apps using game-based strategy have been created to teach and facilitate dermoscopy learning; however, studies are required to demonstrate their effectiveness. This review summarizes the current evidence of game-based learning strategies in medical education, including dermatology and dermoscopy.


Physical mapping of loci in the distal half of the short arm of the human X chromosome: implications for the spreading of X-chromosome inactivation.
The relative order of 11 loci in the distal half of the short arm of the human X chromosome was examined using a panel of somatic cell hybrids containing structurally rearranged X chromosomes. The results show that the gene for phosphoribosylpyrophosphate synthetase 2 (PRPS2) is located between ZFX (zinc finger protein, X-linked) and STS (steroid sulfatase). The results also confirm the localization of ZFX distal to POLA (alpha-DNA polymerase). Previous studies have shown that STS and ZFX escape X-inactivation whereas POLA undergoes inactivation. Evaluation of PRPS2 expression in somatic cell hybrids containing inactive human X chromosomes showed that PRPS2 undergoes X-inactivation. These results provide further evidence for interspersion of loci that do and do not undergo X-inactivation on the human X chromosome.


Naked-eye Detection of Hg2+ in Practical Applications Using a Highly Selective and Sensitive Fluorescent Probe.
A highly selective and sensitive probe, DAC-Hg, has been designed and synthesized for the naked-eye detection of Hg2+ in practical applications. DAC-Hg showed applicative "turn-off" sensing for Hg2+ over other ions. The detection limit was determined to be 5.0 nM, the same as the strictest standard of Hg2+ measurements. A naked-eye evaluation with test strips demonstrated the potential of DAC-Hg for conveniently handled in-situ detection. The application of this established method for analyzing environmental and seafood samples supplied satisfactory results. Therefore, DAC-Hg offered a promising approach for Hg2+ detection as well as hints for sensing other heavy and transition metal ions.


Biopsy-coagulation forceps to simplify biopsy of the bladder.
Until now the forceps used for biopsy of the bladder has required a second procedure to coagulate the bleeding resulting from tissue removal. A new biopsy forceps is described, which makes it possible to perform the biopsy and coagulation simultaneously, thus, eliminating the inconvenience of having to change instruments during the operation. The shaft of the forceps through which the high frequency current flows is insulated completely so that the current exits only via the tips of the prongs. This design eliminates the danger of the specimen being subjected to thermal damage. The advantages offered by the new forceps are vision remains good, orientation is facilitated, loss of blood is minimal, operation time is reduced and the necessity of changing instruments is eliminated.


Antinociceptive action of intrathecal neurotensin in mice.
Neurotensin has been demonstrated to be analgesic in rodents. This study used intrathecal injection of neurotensin in unanesthetized mice to evaluate the effect of the peptide at the spinal level on unconditioned behavior. Intrathecal administration of neurotensin produced dose-related inhibition of locomotor activity and of the response elicited by subcutaneous hypertonic saline. The effects of the peptide in the tail flick assay were variable and it produced no inhibition of the behavioral response to intrathecal substance P. The results indicate that neurotensin antinociception at the spinal level does not result from locomotor impairment, may be somewhat selective for chemically induced pain, and may be mediated by a presynaptic action on primary afferent fibers.


Diagnostic utility of magnetic resonance imaging texture analysis in suppurative osteomyelitis of the mandible.
This study aimed to determine the diagnostic utility of magnetic resonance imaging (MRI) texture analysis for evaluating mandibular suppurative osteomyelitis (OM). In this retrospective cohort study, we analyzed the records of 50 patients with and without OM who underwent MRI between April 2019 and March 2021. The presence or absence of OM served as a predictor variable. The outcome variables were the texture features of the region of interest, which were analyzed. Quantitative parameters based on histogram features (90th percentile) and gray-level co-occurrence matrix (GLCM) features (Sum Averg) were calculated using short-tau inversion-recovery data with a region of interest. These six features out of 279 parameters were selected using Fisher, probability of error, and average correlation coefficient methods in MaZda. For the analysis of trivariate statistics, the post-Mann-Whitney test of the Kruskal-Wallis test with Bonferroni adjustment was used, and the p value was set to 0.05. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic effect of texture function to distinguish between acute and chronic diseases. One histogram feature and five GLCM features showed differences among the non-OM patients, acute OM patients, and chronic OM patients (p < 0.05). The ROC analysis revealed a high area under the curve ranging from 0.91 to 0.96 for six texture features. The six texture features of the mandibular bone marrow demonstrated differences among patients without and with acute and chronic OM. MRI texture analysis may facilitate accurate assessment of the mandibular OM stage.


Succinic Ester-Based Shape Memory Gelatin Sponge for Noncompressible Hemorrhage without Hindering Tissue Regeneration.
Shape memory sponges are very promising in stopping the bleeding from noncompressible and narrow entrance wounds. However, few shape memory sponges have fast degradable properties in order to not hinder tissue healing. In this work, based on cryopolymerization, a succinic ester-based sponge (Ssponge) is fabricated using gelatin and bi-polyethylene glycol-succinimidyl succinate (Bi-PEG-SS). Compared with the commercially available gelatin sponge (Csponge), Ssponge possesses better water/blood absorption ability and higher mechanical pressure over the surrounding tissues. Moreover, in the models of massive liver hemorrhage after transection and noncompressive liver wounds by penetration, Ssponge exhibits a better hemostasis performance than Csponge. Furthermore, in a liver regeneration model, Ssponge-treated livers shows higher regeneration speed compared with Csponge, including a lower injury score, more cavity-like tissues, less fibrosis and enhanced tissue regeneration. Overall, it is shown that Ssponge, with a fast degradation behavior, is not only highly efficient in stopping bleeding but also not detrimental for tissue healing, possessing promising clinical translational potential.


CP2 skyrmions and skyrmion crystals in realistic quantum magnets.
Magnetic skyrmions are nanoscale topological textures that have been recently observed in different families of quantum magnets. These objects are called CP1 skyrmions because they are built from dipoles-the target manifold is the 1D complex projective space, CP1 ≅ S2. Here we report the emergence of magnetic CP2 skyrmions in a realistic spin-1 model, which includes both dipole and quadrupole moments. Unlike CP1 skyrmions, CP2 skyrmions can also arise as metastable textures of quantum paramagnets, opening a new road to discover emergent topological solitons in non-magnetic materials. The quantum phase diagram of the spin-1 model also includes magnetic field-induced CP2 skyrmion crystals that can be detected with regular momentum- (diffraction) and real-space (Lorentz transmission electron microscopy) experimental techniques.


Effects of early postnatal sibling deprivation on anxiety and vulnerability to cocaine in offspring rats.
Early-life experience has long-term consequences on affective behavior and drug abuse in adults. While many manipulations used to study these consequences alter mother-infant interactions, the effects of sibling interactions are less well characterized. To examine the long-term effects of early postnatal sibling deprivation (EPSD) on anxiety-like behavior, sucrose preference and behavioral responses to cocaine in adult rats. After EPSD manipulation, in which litters were culled to one pup on postnatal day 1 (PN1) or 7 (PN7), the dams' maternal behavior was observed. After the pups reached adulthood, we tested their behavioral responses in the elevated plus maze and sucrose consumption, and to cocaine conditioned place preference and cocaine sensitization. The pups with EPSD on PN1 received more maternal licking/grooming during the first postnatal week. EPSD on PN1 but not PN7 enhanced locomotor activity in the open field test and exploration of open arms in the elevated plus maze in both female and male offspring. While EPSD had no effect on sucrose intake in adult rats, it decreased vulnerability to cocaine sensitization and cocaine conditioned place preference in male but not female rats. Our findings that early postnatal sibling deprivation influences maternal licking/grooming behavior, as well as anxiety-like behavior and vulnerability to drugs in pups that have grown to adulthood, suggests that both sibling interaction and maternal behavior, play critical roles in individual development.


Author Correction: Impact of ionizing radiation on superconducting qubit coherence.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


CDKN2A (p16) mRNA decreased expression is a marker of poor prognosis in malignant high-grade glioma.
Human high-grade glioma is heterogeneous in nature based on pathological and genetic profiling. Various tumour suppressor gene alterations are considered as prognostic markers in high-grade glioma. Gene expression of CDKN2A (p16) is used in various cancers as a prognostic biomarker along with methylation and deletion status of this gene. Expression levels of p16 mRNA were not studied as a biomarker in gliomas before. In this study, we have performed mRNA quantification analysis on 48 high-grade glioma tissues and checked for a possible prognostic role. The decreased expression of p16 mRNA in majority of the tumour tissues (57.1 %) was observed when compared to control tissues (P = 0.02). mRNA expression level was correlated with clinical variables also. p16 deletion status and BMI1 mRNA expression were also considered for comparison. p16 mRNA was negatively correlated with the BMI1 mRNA (P = <0.0001) but not with p16 deletion. p16 mRNA expression, midline shift in MRI and tumour type were able to predict patient survival in overall survival (OS) and progression-free survival (PFS). p16 mRNA could independently predict prognosis of OS (P = 0.0146) and PFS (P = 0.0305) in multivariate analysis. We have shown that p16 mRNA expression can act as an independent prognostic biomarker in high-grade glioma.


Total and free ketoprofen in serum and synovial fluid after intramuscular injection.
Free and total ketoprofen levels in serum and synovial fluid were determined in 37 patients after a single intramuscular injection of ketoprofen, 100 mg. Free drug was separated by equilibrium dialysis. Ketoprofen was assayed by HPLC. Ketoprofen penetrated into the joints rapidly and significant concentrations were found at 15 minutes. The equilibrium time was about 3 1/2 hours. The AUC for total ketoprofen was greater in serum than in synovial fluid. On the other hand, the free fraction AUC in the serum and synovial fluid were quite similar. The mean residence time in the joint was about three times that in the systemic circulation. Ketoprofen was strongly bound to proteins and the percentage of free ketoprofen was not significantly different between serum and synovial fluid. These results provide a possible explanation for duration of the therapeutic effect of ketoprofen despite the short elimination half-life from the serum.


Expression and clinical significance of hepatoma-derived growth factor as a prognostic factor in human hilar cholangiocarcinoma.
Overexpressions of hepatoma-derived growth factor (HDGF) and vascular endothelial growth factor (VEGF) play important roles in the development and progression of cancers. This study investigates the expression of HDGF combined with VEGF, their correlation with clinicopathologic features, and their prognosis in human hilar cholangiocarcinoma. The expressions of HDGF and VEGF were analyzed by immunohistochemistry using the streptavidin peroxidase complex method for 58 patients with hilar cholangiocarcinoma receiving surgery. Their correlation with clinicopathologic features was then investigated. The relationships between them and the survival time of patients were retrospectively analyzed. HDGF and VEGF were positively expressed in 27 (46.6%) and 42 (72.4%) patients, respectively. HDGF and VEGF had a positive correlation (r = 0.370, P = 0.004) in the Spearman rank correlation analysis. HDGF expression was associated with gender and histological type. Patients with positive HDGF expression had a significantly poorer overall survival rate than those with negative HDGF expression (35.7 vs. 73.3%, P = 0.003). Multivariate analysis showed that HDGF expression is an independent prognostic factor. HDGF expression significantly correlates with VEGF expression and is a valuable prognostic factor for human hilar cholangiocarcinoma.


Tin disulphide/nitrogen-doped reduced graphene oxide/polyaniline ternary nanocomposites with ultra-high capacitance properties for high rate performance supercapacitor.
In this work, tin disulfide/nitrogen-doped reduced graphene oxide/polyaniline ternary composites are synthesized via in situ polymerization of aniline monomers on the surface of tin disulfide/nitrogen-doped reduced graphene oxide nanosheets binary composites with different loading of the conducting polymers. The tin disulfide/nitrogen-doped reduced graphene oxide/polyaniline ternary composites electrode shows much higher specific capacitance, specific energy and specific power values than those of pure polyaniline and tin disulfide/nitrogen-doped reduced graphene oxide binary composites. The highest specific capacitance, specific energy and specific power values of 1021.67 F g-1, 69.53 W h kg-1 and 575.46 W kg-1 are observed for 60% polyaniline deposited onto tin disulfide/nitrogen-doped reduced graphene oxide composites at a current density of 1 A g-1. The above composites also show superior cyclic stability and 78% of the specific capacitance can be maintained after 5000 galvanostatic charge-discharge cycles. The good charge-storage properties of tin disulfide/nitrogen-doped reduced graphene oxide/polyaniline ternary composites is ascribed to the organic-inorganic synergistic effect. This study paves the way to consider tin disulfide/nitrogen-doped reduced graphene oxide/polyaniline ternary composites as excellent electrode materials for energy storage applications.


The complications of intravenous Corynebacterium parvum infusion.
100 intravenous infusions of Corynebacterium parvum were given to thirty-six patients at a dose of 5 mg/m2. Fever and rigors occurred in all patients but these acute side effects were acceptable to all but two patients. Seventeen patients suffered a delayed fall in blood pressure, which was marked in eight of them but was generally well tolerated. One patient died 18 hr after infusion from extensive myocardial infarction. Herpes labialis complicated the first infusion in nine instances, which may reflect transient immunosuppression following immunotherapy.


Stress distribution analysis in anterior teeth caused by several retraction mechanics.
Orthodontic retraction of the anterior teeth is indicated when the patient has a malocclusion with protrusion of the incisors. Several mechanics are indicated to perform this retraction. The objective of this study was to compare the strains generated by four different types of retraction mechanics along the roots of the anterior teeth. A photoelastic model simulating an arch with first premolars extraction was made. Sixty retraction archwires were prepared, including fifteen for each type of mechanics evaluated: sliding, teardrop loop spring, T-loop spring and double key loop archwire. The strains were observed in two perspectives: occlusal and oblique. In the occlusal perspective, strains were compared among the six anterior teeth. From the oblique perspective, strains were compared among the thirds of the left canine root. In the occlusal perspective, the teardrop loop spring mechanics presented greater strains, followed by T-loop spring, double key loop archwire and sliding mechanics. In all mechanics, strains were more concentrated in the canines than in the incisors. From the oblique perspective, the teardrop loop mechanics generated greater strains in the cervical regions of the canine, and in the apical regions, no differences were found in strains among the four types of mechanics. In the same mechanics, greater strains were present in the cervical zones. The teardrop loop spring retraction mechanic presented the greatest mean strain, and the sliding retraction mechanic presented the lowest mean strain on the root of anteroinferior teeth in the occlusal and oblique perspectives.


Reversal of Experimental Autoimmune Diabetes With an sCD39/Anti-CD3 Treatment.
Extracellular (e)ATP, a potent proinflammatory molecule, is released by dying/damaged cells at the site of inflammation and is degraded by the membrane ectonucleotidases CD39 and CD73. In this study, we sought to unveil the role of eATP degradation in autoimmune diabetes. We then assessed the effect of soluble CD39 (sCD39) administration in prevention and reversal studies in NOD mice as well as in mechanistic studies. Our data showed that eATP levels were increased in hyperglycemic NOD mice compared with prediabetic NOD mice. CD39 and CD73 were found expressed by both α- and β-cells and by different subsets of T cells. Importantly, prediabetic NOD mice displayed increased frequencies of CD3+CD73+CD39+ cells within their pancreata, pancreatic lymph nodes, and spleens. The administration of sCD39 into prediabetic NOD mice reduced their eATP levels, abrogated the proliferation of CD4+- and CD8+-autoreactive T cells, and increased the frequency of regulatory T cells, while delaying the onset of T1D. Notably, concomitant administration of sCD39 and anti-CD3 showed a strong synergism in restoring normoglycemia in newly hyperglycemic NOD mice compared with monotherapy with anti-CD3 or with sCD39. The eATP/CD39 pathway plays an important role in the onset of T1D, and its targeting might represent a potential therapeutic strategy in T1D.


Cerebellar actions on cochlear microphonics and on auditory nerve action potential.
The influence exerted by cerebellar stimulation upon cochlear microphonics (CM) and auditory nerve action potential (AP) has been analyzed in curarized guinea pigs. Round window recordings demonstrated that conditioning electrical stimulus trains delivered to the cerebellar cortex diminished the CM and AP amplitude at the same time and in a parallel fashion. On the other hand, cooling of the cerebellar cortex showed the opposite results of increased amplitudes. All pre-receptorial mechanisms were avoided. A PDP-12 computer performed parametric and non-parametric statistical analysis showing the differences to be significant for the shifts. Evidence of simultaneous inhibitory cerebellar action on both potentials has been demonstrated and a cerebello-olivo-cochlear pathway is proposed for such action upon the receptor cells and/or incoming fibers.


Modeling Antibody-Antigen Complexes by Information-Driven Docking.
Antibodies are Y-shaped proteins essential for immune response. Their capability to recognize antigens with high specificity makes them excellent therapeutic targets. Understanding the structural basis of antibody-antigen interactions is therefore crucial for improving our ability to design efficient biological drugs. Computational approaches such as molecular docking are providing a valuable and fast alternative to experimental structural characterization for these complexes. We investigate here how information about complementarity-determining regions and binding epitopes can be used to drive the modeling process, and present a comparative study of four different docking software suites (ClusPro, LightDock, ZDOCK, and HADDOCK) providing specific options for antibody-antigen modeling. Their performance on a dataset of 16 complexes is reported. HADDOCK, which includes information to drive the docking, is shown to perform best in terms of both success rate and quality of the generated models in both the presence and absence of information about the epitope on the antigen.


Pharmacological and biomedical properties of sea anemones Paracondactylis indicus, Paracondactylis sinensis, Heteractis magnifica and Stichodactyla haddoni from East coast of India.
To explore the biomedical and pharmacological activity of Paracondactylis indicus (P. indicus), Paracondactylis sinensis (P. sinensis), Heteractis magnifica (H. magnifica) and Stichodactyla haddoni (S. haddoni). The live sea anemones were kept inside the glass bowl along with some amount of distilled water in an ice container for 15 min. During stress condition, nematocysts released from the tentacles were collected and centrifuged at 5,000 rpm for 15 min. The supernatant were collected in separate cleaned beakers for lyophilisation. The protein content of crude extracts was 15.2, 28.7, 18.2 and 35.4 μg/mL. In hemolytic assay, the P. indicus was sensitive (16.842 HT/mg) on chicken blood but P. sinensis was less sensitive (1.114 HT/mg) on chicken and goat blood. Whereas H. magnifica and S. haddoni showed hemolysis (0.879, 0.903 HT/mg and 56.263, 0.451 HT/mg) in chicken and goat blood. In antimicrobial assay, the methanol extract of P. indicus showed maximum inhibition zone of 9.7 mm against S. typhii and P. sinensis showed 9.8 mm against K. pneumonia in methanol and ethanol extracts. Whereas the H. magnifica and S. haddoni showed maximum of 10 mm against S. typhii, K. pneumonia in methanol and ethanol extracts. The high toxic sea anemones may also contain some biologically active agents which has haemolytic, analgesic and anti-infilamatory activity.


The correlation between muscles insertions and topography of break lines in pertrochanteric fractures: a comprehensive anatomical approach of complex proximal femur injuries.
The purpose of our work was to verify the hypothesis that muscle insertions and ligament attachments have an impact on the course of typical break lines in the area of the trochanteric massif, i.e., to provide a more detailed description of the origins and insertions of the musculo-ligamentous apparatus on the surface of the proximal femur, and to find a potential morphological correlate between muscle insertions and ligament attachments to the proximal femur and the course of the break line in a typical pertrochanteric fracture. A detailed dissection of areas of trochanter major et minor, linea et crista intertrochanterica was performed in 50 anatomical preparations of the proximal femur, and the insertions of the muscular-ligamentous structures were described. The set of 600 radiographs were used to obtain projections of typical break lines on the proximal femur, and corresponding areas of exposed bone surface were identified in the anatomical preparations based on the projections and on 15 real specimens of patients after the pertrochanteric fracture osteosynthesis. Bone covered only with the periosteum, with no reinforcing elements of the origin or insertions of muscles or attachments of ligaments, represents the locus minoris resistentiae for beginning of fractures. Variability in the sizes and shapes of pertrochanteric fracture fragments also depends on variability of the locations and sizes of soft tissue attachment areas at specified sites on the proximal femur.


The role of ncRNA in the co-regulation of autophagy and exosome pathways during cancer progression.
Since its discovery a few decades ago, autophagy has been recognized as a crucial signaling pathway, linked to the recycling of cellular components in nutrient stress. Autophagy is a two-way sword, playing a dual role in tumorigenesis. In this catabolic process, dysfunctional organelles, biomolecules, and misfolded proteins are sequestered in the autophagosome and sent to the lysosome for degradation. Alongside, there are cellular messengers called exosomes, which are released from cells and are known to communicate and regulate metabolism in recipient cells. Multivesicular bodies (MVB) act as the intricate link between autophagy and exosome pathways. The continuous crosstalk between the two pathways is coordinated and regulated by multiple players among which ncRNA is the emerging candidates. The exosomes carry varied cargo of which non-coding RNA exerts an immediate regulatory effect on recipient cells. ncRNA is known to exhibit dual behavior in both promoting and inhibiting tumor growth. There is increasing evidence for the involvement of ncRNAs' in the regulation of different hallmarks of cancer. Different ncRNAs are involved in the co-regulation of autophagy and exosome pathways and therefore represent a superior therapeutic approach to target cancer chemoresistance. Here, we will discuss the ncRNA involved in regulating autophagy, and exosomes pathways and its relevance in cancer therapeutics.


Inhibition of the hypothalamic paraventricular nucleus in spontaneously hypertensive rats dramatically reduces sympathetic vasomotor tone.
Experimental evidence indicates that the hypothalamic paraventricular nucleus modulates sympathetic vasomotor tone and blood pressure and that this modulation is altered in some cardiovascular diseases. This study tested the hypothesis that this nucleus exerts a more significant tonic excitatory modulation of basal sympathetic vasomotor activity in spontaneously hypertensive rats. In anesthetized, artificially-ventilated rats, bilateral microinjections of the GABA(A) receptor agonist, muscimol (1 to 1.5 nmoles per side), into the paraventricular nucleus produced a depressor and sympathoinhibitory response that did not recover. When compared with normotensive rats, this response was more marked in spontaneously hypertensive rats, where lumbar sympathetic nerve discharge was reduced by 75 +/- 3% and mean arterial pressure fell from 119 +/- 7 mm Hg to 58 +/- 3 mm Hg. Blockade of excitatory and inhibitory amino acid receptors in the rostral ventrolateral medulla significantly attenuated this response. Microinjections of small volumes (<20 nL) of GABA were used to localize precisely the responsive region of the paraventricular nucleus. Unilateral injections of GABA into the dorsomedial cap of the paraventricular nucleus induced a brisk depressor (decrease of 42 +/- 4 mm Hg), sympathoinhibitory (decrease by 72 +/- 2%), and bradycardic (decrease of 77 +/- 16 bpm) response. The mechanisms underlying the sympathoinhibition after inactivation of the paraventricular nucleus are not elucidated, but evidence discussed suggests the involvement of a supracollicular sympathoinhibitory pathway. The results presented demonstrate that the paraventricular nucleus exerts a powerful, tonic effect on the control of sympathetic vasomotor tone under basal conditions in anesthetized rats and that this is enhanced in spontaneously hypertensive rats.


Revascularization Versus Medical Therapy in Takayasu's Arteritis Patients with Coronary Artery Involvement.
Treatment strategies to improve clinical outcomes in Takayasu's arteritis (TA) with coronary lesions have ranged from pharmacological therapy to invasive procedures, such as coronary angioplasty, stenting, and surgery. However, the therapeutic strategy for this kind of patient is still unclear. This study aimed to investigate the clinical characteristics and influence of revascularization versus medical therapy in TA patients with coronary artery involvement. We analyzed the medical records of 806 TA patients between January 2008 and December 2019. Clinical features and treatment were analyzed, and patients were categorized into medical treatment and revascularization. Additionally, patients were sorted as percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) based on the strategy of revascularization. Ninety cases with coronary lesions induced by TA were enrolled. Among 90 cases, 39 patients adopted conservative treatment, and 51 patients received revascularization (28 subjects with PCI, 23 participants with CABG). The median follow-up time was 63 (45-91) months. There is no significant difference in cardiovascular death between medical treatment and revascularization (2/39, 5.1% vs. 5/51, 9.8%, P = 0.971). The analysis of subgroup indicated that the mortality caused by cardiovascular disease was also similar in the CABG and PCI (2/28, 7.1% vs. 3/23, 13.0%, P = 0.772). However, the proportion of restenosis is much higher in the PCI compared with that of CABG (39.3%, 8.7%, P = 0.022, respectively). Heart failure is an independent predictor of death in these patients. There is no significant difference in cardiovascular death between medical treatment and revascularization. The analysis of the subgroup indicated that the mortality caused by cardiovascular disease was also similar in the CABG and PCI, but the restenosis is much higher in the PCI compared with that of CABG. Heart failure is an independent predictor of death in these patients.


Parallels and Mutual Lessons in Tuberculosis and COVID-19 Transmission, Prevention, and Control.
The coronavirus disease (COVID-19) pandemic has had unprecedented negative effects on global health and economies, drawing attention and resources from many other public health services. To minimize negative effects, the parallels, lessons, and resources from existing public health programs need to be identified and used. Often underappreciated synergies relating to COVID-19 are with tuberculosis (TB). COVID-19 and TB share commonalities in transmission and public health response: case finding, contact identification, and evaluation. Data supporting interventions for either disease are, understandably, vastly different, given the diseases' different histories. However, many of the evolving issues affecting these diseases are increasingly similar. As previously done for TB, all aspects of congregate investigations and preventive and therapeutic measures for COVID-19 must be prospectively studied for optimal evidence-based interventions. New attention garnered by the pandemic can ensure that knowledge and investment can benefit both COVID-19 response and traditional public health programs such as TB programs.


Expression of oligodendrocyte-associated genes in dorsolateral prefrontal cortex of patients with schizophrenia.
Prior studies have found decreased mRNA expression of oligodendrocyte-associated genes in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia. However, it is unclear which specific genes are affected and whether the changes occur in the cortical white or grey matter. We assessed the mRNA expression levels of four oligodendrocyte-related genes: myelin-associated basic protein (MOBP), myelin-associated glycoprotein (MAG), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and oligodendrocyte-lineage transcription factor 2 (OLIG2) in DLPFC white and grey matter using quantitative-PCR (approximately 70 controls and approximately 30 patients with schizophrenia). We also examined the effects of high-risk polymorphisms in CNP and OLIG2 on mRNA levels of these genes. We found that genetic polymorphisms in CNP (rs2070106) and OLIG2 (rs1059004 and rs9653711), previously associated with schizophrenia, predicted low expression of these genes. Expression of MAG, CNP and OLIG2 did not differ between patients with schizophrenia and controls in the grey or white matter but MOBP mRNA levels were increased in the DLPFC white matter in patients with a history of substance abuse. MOBP and CNP protein in the white matter was not altered. Although previously reported reductions in the expression of myelin-related genes in the DLPFC were not detected, we show that individuals carrying risk-associated alleles in oligodendrocyte-related genes had relatively lower transcript levels. These data illustrate the importance of genetic background in gene expression studies in schizophrenia.


Tumour infiltrating B cells discriminate checkpoint blockade-induced responses.
Immune cell-driven anti-cancer activity is paramount for effective responses to checkpoint inhibitors (ICB). However, the contribution of the different immune cell subsets in the circulation and within the tumour is poorly understood. To elucidate the role of the different cell subsets in anti-tumour responses elicited by ICB, we performed single-cell analysis of the transcriptome and surface proteome of paired pre- and early on-treatment metastatic melanoma tumour biopsies and matched peripheral blood mononuclear cell samples. We next compared the survival of metastatic melanoma patients treated with ICB according to the abundance of pre-treatment tumour-infiltrating B cell clonotypes. We identified cell clusters associated with disease control or progression, defined differential expression of biological pathways likely involved in the immune awakening against the tumour and examined how cell-cell communication patterns between the tumour cell subsets change during treatment. Furthermore, we discovered that B cells (immunoglobulin expression and abundance of B cell clonotypes) discriminate the clinical response after ICB and propose that B cells likely contribute to anti-tumour immunity by antigen presentation through major histocompatibility complex molecules. Finally, we demonstrated that the abundance of tumour-infiltrating B cell clonotypes at baseline identifies two distinct risk groups, a finding that we confirmed in an independent cohort. Our exploratory translational study provides new insights on the mechanistic role of B cells in anti-melanoma immunity during treatment with ICB. Additionally, we support pre-treatment B cell tumour infiltration as a promising prognostic biomarker to be further validated as a tool for clinical risk stratification.


The pharmacokinetics and pharmacodynamics of fludarabine in rheumatoid arthritis.
To describe the pharmacokinetics and pharmacodynamics of fludarabine in patients with rheumatoid arthritis (RA). Open-label, staggered trial conducted in conjunction with a phase I-II clinical trial. Government research hospital. Twenty-six patients with refractory RA. Fludarabine 20 or 30 mg/m2/day was administered as a 0.5-hour infusion for 3 consecutive days (1 cycle) for 6 months (1 cycle/mo). Serial plasma samples were collected for pharmacokinetic analysis on day 2 of the first cycle of therapy. Relationships between pharmacokinetic parameters and hematologic and efficacy parameters were examined. The disposition of fludarabine was characterized by a two-compartment model. There were no differences in pharmacokinetics between the low- and high-dose groups. The mean+/-SD total clearance, volume of distribution at steady state, and beta-half-life were 13.68+/-5.1 L/hour, 170.08+/-86.5 L, and 10.9+/-3.1 hours, respectively. The volume of the peripheral compartment was approximately twice as large as the volume of the central compartment, indicating a significant amount of tissue distribution. No significant pharmacodynamic relationships were observed between pharmacokinetic parameters and hematologic and efficacy parameters. Fludarabine pharmacokinetics in patients with RA are characterized by an intermediate-length distribution phase (approximately 40 min), terminal half-life of 10.9 hours, and significant amount of tissue distribution.


Quality of prescribing in care homes and the community in England and Wales.
Care home residents are vulnerable to the adverse effects of prescribing but there is limited monitoring in the UK. To compare prescribing quality in care homes in England and Wales with the community and with US nursing homes. Cross-sectional analysis of a UK primary care database and comparison with the US National Nursing Home Survey including 326 general practices in 2008-2009 in England and Wales, with 10 387 care home and 403 259 community residents aged 65 to 104 years. Comparison of age- and sex-standardised use of 'concern' and common drug groups in the last 90 days and potentially inappropriate prescribing based on a consensus list of medications best avoided in older people (Beers criteria). Compared to the community, care home residents were more likely to receive 'concern' drugs, including benzodiazepines (relative risk (RR) = 2.05, 95% confidence interval (CI) = 1.90 to 2.22), anticholinergic antihistamines (RR = 2.78, 95% CI = 2.38 to 3.23), loop diuretics (RR = 1.47, 95% CI = 1.41 to 1.53), and antipsychotics (RR = 22.7, 95% CI = 20.6 to 24.9). Use of several common drug groups, including laxatives, antidepressants, and antibiotics, was higher, but use of cardiovascular medication was lower. Thirty-three per cent (95% CI = 31.7% to 34.3%) of care home residents in England and Wales received potentially inappropriate medication, compared to 21.4% (95% CI = 20.9% to 21.8%) in the community. The potentially inappropriate prescribing rate in US nursing homes was similar to England and Wales. Care home prescribing has the potential for improvement. High use of anticholinergic and psychotropic medication may contribute to functional and cognitive decline. The targeting and effectiveness of medication reviews in care homes needs to be improved.


The role of the 47-kDa membrane lipoprotein of Treponema pallidum in promoting maturation of peripheral blood monocyte-derived dendritic cells without enhancing C-C chemokine receptor type 7-mediated dendritic cell migration.
The 47-kDa membrane lipoprotein (Tp47) is the most representative membrane protein of Treponema pallidum (T. pallidum). Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) that connect innate and acquired immunity. The regulatory role of Tp47 on DCs remains unclear. To evaluate the effects of Tp47 on DC maturation and migration, and research the changes of the main chemokine C-C chemokine receptor type 7 (CCR7) involved in DC migration. A transwell assay was applied to assess the migration of DCs. Cytokines (interleukin (IL)-6, IL-10, IL-12, and tumor necrosis factor alpha (TNF-α)) in the supernatants were measured using enzyme-linked immunosorbent assay (ELISA), and the expression of cell surface markers (CD80, CD86, CD40, and human leukocyte antigen (HLA)-DR) and CCR7 was assessed using flow cytometry. The expression of CCR7 in DCs was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). The Tp47 promoted DC phenotypic maturation, such as increased CD40, CD80, CD86, and HLA-DR expression, as well as DC functional maturation, thus stimulating DCs to secrete inflammatory cytokines, including IL-6, IL-10, IL-12, and TNF-α. At the same time, Tp47 did not enhance DC migration and did not increase the expression of CCR7. The Tp47 promoted the maturation of DCs while not enhancing CCR7-mediated DC migration ability. This may be one of the mechanisms by which T. pallidum escapes host immune clearance.


Cutaneous myelofibrosis with JAK2 V617F mutation: metastasis, not merely extramedullary hematopoiesis!
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm. There are 31 reported cases of cutaneous involvement by PMF, most of which have been described as "extramedullary hematopoiesis." We report a new case of cutaneous involvement by PMF and demonstrate mutation of the Janus kinase 2 gene in the cutaneous lesions. Extramedullary myelofibrosis is best considered a metastatic phenomenon. Reporting such cases as extramedullary hematopoiesis may cause confusion with reactive forms of extramedullary hematopoiesis.


Reduction of orthophosphates loss in agricultural soil by nano calcium sulfate.
Nutrient loss from soil, especially phosphorous (P) from farmlands to natural water bodies via surface runoff or infiltration, have caused significant eutrophication problems. This is because dissolved orthophosphates are usually the limiting nutrient for algal blooms. Currently, available techniques to control eutrophication are surprisingly scarce. Calcium sulfate or gypsum is a common soil amendment and has a strong complexation to orthophosphates. The results showed that calcium sulfate reduced the amount of water extractable P (WEP) through soil incubation tests, suggesting less P loss from farmlands. A greater decrease in WEP occurred with a greater dosage of calcium sulfate. Compared to conventional coarse calcium sulfate, nano calcium sulfate further reduced WEP by providing a much greater specific surface area, higher solubility, better contact with the fertilizer and the soil particles, and superior dispersibility. The enhancement of the nano calcium sulfate for WEP reduction is more apparent for a pellet- than a powdered- fertilizer. At the dosage of Ca/P weight ratio of 2.8, the WEP decreased by 31±5% with the nano calcium sulfate compared to 20±5% decrease with the coarse calcium sulfate when the pellet fertilizer was used. Computation of the chemical equilibrium speciation shows that calcium hydroxyapatite has the lowest solubility. However, other mineral phases such as hydroxydicalcium phosphate, dicalcium phosphate dihydrate, octacalcium phosphate, and tricalcium phosphate might form preceding to calcium hydroxyapatite. Since calcium sulfate is the major product of the flue gas desulfurization (FGD) process, this study demonstrates a potential beneficial reuse and reduction of the solid FGD waste.


[Experimental treatment of malignant melanoma and its rationale].
To treat malignant melanoma successfully currently means to recognize the tumor at an early stage and to remove it immediately. Aside from individual cases, available treatment modalities are not able to increase survival, especially in the palliative situation. Thus innovative experimental approaches are urgently needed to strongly improve the palliative and adjuvant treatment of melanoma. Anti-tumor effects are expected from targeted therapies, which are directed against defined molecules decisive for tumor pathogenesis. Crucial points of attack are signaling pathways, angiogenesis and apoptosis resistance. New diagnostic and therapeutic developments have enhanced the efficacy of chemotherapies. Increasing insights into tumor immunology provide new treatment approaches of vaccination, cell transfer and especially of blocking immune tolerance mechanisms. It will be challenging for the future to identify and characterize more precisely those patients who might most benefit from a certain treatment approach.


Well-differentiated giant scrotal liposarcoma: case presentation and management.
Scrotal liposarcoma is an uncommon disease, usually found after the fifth decade. We describe the case of a well-differentiated scrotal liposarcoma associated with a considerable inflammatory reaction, treated with surgical ablation.


Dermoscopy of fully regressive cutaneous melanoma.
Metastatic melanoma of unknown origin is a difficult challenge diagnostically and therapeutically. Diagnosis of the putative primary lesion is difficult. This difficulty increases when the primary lesion has undergone complete regression. To define the dermoscopic features of fully regressed melanoma. A single-institution, register-based study of an unselected consecutive series of seven cases of metastatic melanoma in the lymph nodes with no known or visible primary lesion was carried out. Skin examination included dermoscopy; when a suspicious area was found, observed dermoscopic features were recorded and a biopsy was performed. Diagnosis of completely regressive cutaneous melanoma was based on clinical-pathological correlation according to widely accepted criteria. Seven dermoscopic features were associated with completely regressive melanoma: scar-like depigmentation (100%); pink coloration of the background (100%); linear-irregular vessels (86%); globular pattern of the vessels (43%); remnants of pigmentation (86%), either macular (43%) or with a peppering aspect (43%); and white lighter transverse bands (43%). The last feature was only observed with polarized light dermoscopy devices. Dermoscopy more accurately distinguishes the vascular, pigmentary and scarring changes of fully regressive melanoma. We believe that dermoscopy should be included in the search for a regressive primary lesion in case of metastatic melanoma of unknown origin.


Biobleaching application of cellulase poor and alkali stable xylanase from Bacillus pumilus SV-85S.
The potential of extracellular alkali stable and thermo tolerant xylanase produced by Bacilluspumilus SV-85S through solid state fermentation was investigated in pulp bleaching in association with conventional bleaching using chlorine and chlorine dioxide. The biobleaching of kraft pulp with xylanase was the most effective at an enzyme dose of 10 IU/g oven dried pulp, pH 9.0 and 120 min incubation at 55 °C. Under the optimized conditions, xylanase pretreatment reduced Kappa number by 1.6 points and increased brightness by 1.9 points. Subsequently, chlorine dioxide and alkaline bleaching sequences (CDE1D1D2) finally resulted in brightness gain of 2.7 points as compared with the control. The pretreatment of pulp with xylanase resulted in 29.16 % reduction in chlorine consumption by maintaining the same brightness as in control. An improvement in pulp strength properties was also observed after bleaching of xylanase pretreated pulp. Scanning electron microscopy revealed loosening and swelling of pulp fibers after enzyme treatment. These results clearly demonstrated that the B. pumilus SV-85S xylanase was effective as a pulp biobleaching agent. The decrease in chlorine consumption by pretreatment of pulp with xylanase apparently made the biobleaching process not only economical but also eco-friendly.


Genome-Wide Identification of SSR and SNP Markers Based on Whole-Genome Re-Sequencing of a Thailand Wild Sacred Lotus (Nelumbo nucifera).
Genomic resources such as single nucleotide polymorphism (SNPs), insertions and deletions (InDels) and SSRs (simple sequence repeats) are essential for crop improvement and better utilization in genetic breeding. However, the resources for the sacred lotus (Nelumbo nucifera Gaertn.) are still limited. In the present study, to dissect large-scale genomic molecular marker resources for sacred lotus, we re-sequenced a Thailand sacred lotus cultivar 'Chiang Mai wild lotus' and compared with the reported lotus genome 'Middle lake wild lotus'. A total of 3,180,059 SNPs, 328, 251 InDels and 14,191 SVs were found between the two genomes. The functional impact analyses of these SNPs indicated that they may be involved in metabolic processes, binding, catalytic activity, etc. Mining the genome sequences for SSRs showed that 191,657 SSRs were identified with a frequency of one SSR per 4.23 kb and 103,656 SSR primer pairs were designed. Furthermore, 14, 502 EST-SSRs were also indentified using the available RNA-seq data in the NCBI. A subset of 150 SSRs (genomic and EST-SSRs) was randomly selected for validation and genetic diversity analysis. The genotypes could be easily distinguished using these SSR markers and the 'Chiang Mai wild lotus' was obviously differentiated from the other Chinese accessions. This study provides considerable amounts of genomic resources and markers for the quantitative trait locus (QTL) identification and molecular selection of the species, which could have a potential role in various applications in sacred lotus breeding.


Normal trunk muscle strength and endurance in women and the effect of exercises and electrical stimulation. Part 1: Normal endurance and trunk muscle strength in 101 women.
The lack of trunk muscle strength and endurance has frequently been cited as a suspected factor in the etiology of low-back pain. Several investigators have suggested that asymptomatic patients have stronger trunk muscles than patients with low-back pain. People who are physically fit appear to have a decreased incidence of low-back pain. Increased trunk muscle endurance also have been observed to decrease the incidence of low-back pain. The objective evaluation of the strength and endurance of trunk musculature may, therefore, be significant. Part 1 of this study was designed to develop a reproducible strength-endurance screening procedure and to establish normal isometric-isokinetic trunk muscle strength and endurance parameters for women. This study showed that isometric trunk flexion varied from 19-109 Nm and trunk extension from 38-168 Nm. Peak values for isokinetic trunk flexion at two speeds (30 degrees per second and 60 degrees per second) varied from 17-191 Nm and isokinetic trunk extension from 14-208 Nm. The average endurance time for trunk extensors tested with the Sorensen test was 196 seconds.


Exploring the effects of phylogenetic uncertainty and consensus trees on stratigraphic consistency scores: a new program and a standardized method.
The stratigraphic record of first appearances provides an independent source of data for evaluating and comparing phylogenetic hypotheses that include taxa with fossil histories. However, no standardized method exists for calculating these metrics for polytomous phylogenies, restricting their applicability. Previously proposed methods insufficiently deal with this problem because they skew or restrict the resulting scores. To resolve this issue, we propose a standardized method for treating polytomies when calculating these metrics: the Comprehensive Polytomy approach (ComPoly). This approach accurately describes how phylogenetic uncertainty, indicated by polytomies, affects stratigraphic consistency scores. We also present a new program suite (Assistance with Stratigraphic Consistency Calculations) that incorporates the ComPoly approach and simplifies the calculation of absolute temporal stratigraphic consistency metrics. This study also demonstrates that stratigraphic consistency scores calculated from strict consensus trees can be overly inclusive and those calculated from less-than-strict consensus trees inaccurately describe the phylogenetic signal present in the source most-parsimonious trees (MPTs). Therefore, stratigraphic consistency scores should be calculated directly from the source MPTs whenever possible to ensure their accuracy. Finally, we offer recommendations for standardizing comparisons between molecular divergence dates and the stratigraphic record of first appearances, a promising new application of these methods. © The Willi Hennig Society 2010.


(Mouse cursor)-Tracking food decisions in binge eating disorder reveals preference for high-energy foods and a role of BMI.
Binge Eating Disorder (BED) has been associated with deficits in cognitive control and decision-making. Yet, no study has yet investigated the characteristics of food choice and the involved choice conflict in this disorder. In the present study individuals with BED (N = 22) and without BED (N = 61), with a body mass index (BMI) between 21 and 44 completed 153 binary food decisions among foods varying in palatability and energy density. To assess conflict during choice we recorded computer mouse paths and reaction times. Subsequently, participants rated all foods on liking and energy content. Finally, participants completed a bogus taste test with the same foods to measure actual consumption. Predictors were modelled continuously using Bayesian mixed-effects modelling. Individuals with BED liked foods with higher energy content more and chose them more often in the choice task. Yet, actual consumption in the taste test did not differ between groups, neither regarding total consumption, nor of foods with higher energy. Mouse cursor-tracking revealed that control participants with higher BMIs showed more choice conflict than those with lower BMIs. This pattern was reversed in those with BED. The high-energy preference in ratings and food choice represent the first evidence in a controlled laboratory context for disorder-congruent food choice in BED. The fact that this was not reflected in actual consumption might have methodological implications for measuring laboratory eating behaviour. Mouse cursor-tracking gave further insights into choice processes and showed a less conflicted food choice in those with BED with higher BMI compared to those with lower BMI.


Sensitivity of adipocyte basal and insulin-stimulated hexose transport to the membrane lipid structure.
A series of anesthetic alcohols inhibited basal and insulin-stimulated 2-deoxy-D-[1-14C]glucose transport in adipocytes over total alcohol concentration ranges that cause local anesthesia of rat sciatic nerve. The relative potencies of the inhibition caused by the alcohols increased in the following order: methanol less than ethanol less than propanol less than butanol less than benzyl alcohol less than hexanol less than octanol. The inhibition was reversible and correlated well with the known partitioning of the alcohols into lipids of biological membranes. Adipocyte membranes were labeled with the 5-nitroxide stearate spin probe to investigate the effects of the alcohols on the dynamic structure of membrane lipids of the adipocyte. The alcohols increased the membrane "fluidity", and the relative concentration dependence of the effects closely paralleled that noted from methanol to octanol in transport studies. Alcohols from methanol to hexanol caused inhibition of hexose transport at molar potencies comparable to that observed for membrane disordering. This suggests that hydrophobic regions of the transporter and its lipid environment are perturbed by a comparable mechanism for each alcohol. The cholesterol-complexing polyene antibiotic filipin inhibited hexose transport and influenced the mobility of lipid domains sampled with the nitroxide cholestane, cholesterol-like spin probe. The data are consistent with the concept that the membrane structural/functional effects are mediated by formation of 1:1 cholesterol:filipin complexes. Alcohols and filipin inhibited inherent transporter activity and perturbed the membrane lipid structure without dramatically diminishing transport stimulation by insulin above basal. The specific organization of membrane lipids (particularly cholesterol) may provide an essential environment for optimal transport system activity.


Real-time monitoring of cyclic nucleotide signaling in neurons using genetically encoded FRET probes.
Signaling cascades involving cyclic nucleotides play key roles in signal transduction in virtually all cell types. Elucidation of the spatiotemporal regulation of cyclic nucleotide signaling requires methods for tracking the dynamics of cyclic nucleotides and the activities of their regulators and effectors in the native biological context. Here we review a series of genetically encoded FRET-based probes for real-time monitoring of cyclic nucleotide signaling with a particular focus on their implementation in neurons. Current data indicate that neurons have a very active metabolism in cyclic nucleotide signaling, which is tightly regulated through a variety of homeostatic regulations.


Biological responses of osteocytic connexin 43 hemichannels to simulated microgravity.
Connexin 43 (Cx43) hemichannels and gap junctions in osteocytes are responsive to mechanical loading, which is important for bone formation and remodeling. However, the mechanism of these Cx43-forming channels in the process of mechanical unloading is still not very clear. In this study, unloading caused by weightlessness was simulated by using a random position machine (RPM). Osteocytic MLO-Y4 cells were subjected to 2 h of RPM treatment, and levels of Cx43 mRNA and total and cell surface expressed protein were determined by quantitative real-time PCR, western blotting, and biotinylation analysis. Although mRNA was elevated by RPM, total protein level of Cx43 was not altered; however, surface biotinylated Cx43 was significantly reduced. Interestingly, RPM promoted the retention of Cx43 in the Golgi apparatus detected by co-immunofluorescence with antibodies against Cx43 and 58 K Golgi marker protein. Dye uptake assay showed that hemichannels were induced open after RPM for 2 h. Consistently, prostaglandin E2 release was increased and this increase was completely attenuated with the treatment of a Cx43 hemichannel blocking antibody. Together, this study demonstrates increased activity of Cx43 hemichannels to RPM, and active Cx43 hemichannels with prostaglandin E2 release are likely to module biological function under simulated weightless conditions. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1195-1202, 2017.


Mitotic clustering of pulverized chromosomes from micronuclei.
Complex genome rearrangements can be generated by the catastrophic pulverization of missegregated chromosomes trapped within micronuclei through a process known as chromothripsis1-5. As each chromosome contains a single centromere, it remains unclear how acentric fragments derived from shattered chromosomes are inherited between daughter cells during mitosis6. Here we tracked micronucleated chromosomes with live-cell imaging and show that acentric fragments cluster in close spatial proximity throughout mitosis for asymmetric inheritance by a single daughter cell. Mechanistically, the CIP2A-TOPBP1 complex prematurely associates with DNA lesions within ruptured micronuclei during interphase, which poises pulverized chromosomes for clustering upon mitotic entry. Inactivation of CIP2A-TOPBP1 caused acentric fragments to disperse throughout the mitotic cytoplasm, stochastically partition into the nucleus of both daughter cells and aberrantly misaccumulate as cytoplasmic DNA. Mitotic clustering facilitates the reassembly of acentric fragments into rearranged chromosomes lacking the extensive DNA copy-number losses that are characteristic of canonical chromothripsis. Comprehensive analysis of pan-cancer genomes revealed clusters of DNA copy-number-neutral rearrangements-termed balanced chromothripsis-across diverse tumour types resulting in the acquisition of known cancer driver events. Thus, distinct patterns of chromothripsis can be explained by the spatial clustering of pulverized chromosomes from micronuclei.


Aging and temporal integration in the visual perception of object shape.
It has been known for more than 160 years that highly occluded objects that would normally be visually unrecognizable can be successfully identified when they move. This anorthoscopic perception relies on the visual system's ability to integrate information over time to complete the perception of an entire object's shape. In this experiment, 16 younger and older adults (mean ages were 20.5 and 74.6 years, respectively) were familiarized with the (unoccluded) shapes of five naturally-shaped objects (bell peppers, Capsicum annuum) until they could be easily identified (i.e., with accuracies of at least 90 percent correct). All observers then viewed the stimulus objects anorthoscopically as they moved behind narrow slits; only small object fragments could be seen at any given time, because the objects were almost totally occluded from view. Even though the object identification performance for all observers was equivalent when whole object shapes were visible, a large age-related deficit in object identification emerged during anorthoscopic viewing such that the younger adults' identification performance was 45.4 percent higher than that of the older adults. This first ever study of aging and anorthoscopic perception demonstrates that there is an age-related deficit in performing the temporal integration needed for successful object recognition.


Biphasic inhibitory and stimulatory effects of thyrotropin on the mitotic activity of thyroid explants cultured in vitro.
An influence of thyrotropin (TSH), dibutyryl cyclic AMP (dbcAMP), triiodothyronine (T3) and thyroxine (T4) on the mitotic incidence in the organ-cultured rat thyroid was studied. The study has revealed biphasic inhibitory and stimulatory effects of TSH on the thyroid mitotic activity. The inhibitory effect occurred 14 h after an exposure of the thyroid explants to TSH and was enhanced by T3. A similar inhibitory effect was observed after an exposure of the explants to dbcAMP. 24 h after the exposure of the thyroid explants to TSH a stimulatory effect on the mitotic incidence was observed. The latter effect was not reproduced by dbcAMP.


Lenalidomide: a review of its continuous use in patients with newly diagnosed multiple myeloma not eligible for stem-cell transplantation.
Lenalidomide (Revlimid(®)) is a second-generation immunomodulatory drug structurally related to thalidomide, with improved efficacy and tolerability, for which the label in the EU was recently expanded to include continuous therapy in patients with previously untreated multiple myeloma not eligible for stem-cell transplantation. In randomized, controlled clinical trials, continuous lenalidomide therapy, either in combination with dexamethasone (FIRST trial) or as maintenance monotherapy following induction with melphalan/prednisone/lenalidomide (MM-015 trial), significantly improved progression-free survival (PFS) compared with induction therapy alone (with non-lenalidomide- or lenalidomide-containing regimens) in patients with newly diagnosed multiple myeloma not eligible for stem-cell transplantation. The improvements in PFS with continuous lenalidomide were reflected in improved health-related quality-of-life measures. An overall survival benefit was observed in the FIRST trial, but not in the MM-015 trial. Continuous lenalidomide and continuous thalidomide regimens displayed similar efficacy, but lenalidomide was associated with significantly less toxicity than thalidomide. Continuous use of lenalidomide did not appear to negatively impact on the drug's tolerability and did not increase the incidence of neutropenia or second primary malignancy compared with shorter-term use. The incidence of most adverse events began to reduce after about 18 months of therapy. In conclusion, continuous lenalidomide regimens provide an effective longer-term treatment option in patients with newly diagnosed multiple myeloma ineligible for stem-cell transplantation.


Temporal trends and sources of PCDD/Fs, pentachlorophenol and chlornitrofen in paddy field soils along the Yoneshiro River basin, Japan.
In order to understand the long-term behaviors of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), pentachlorophenol (PCP), and 2,4,6-trichlorophenyl-4'-nitrophenyl ether (chlornitrofen, CNP) in paddy soil, we measured their concentrations in paddy soil samples collected in 1982 and 1984 (1980s) and in 2000 and 2002 (2000s) from the Yoneshiro River basin, Japan. The concentrations of PCP and CNP decreased from the 1980s to the 2000s, whereas the concentrations of PCDD/Fs and their toxic equivalency (WHO2006-TEQ) remained. The major sources of PCDD/Fs in the paddy soil samples were attributed to impurities in PCP and CNP as a result of comparisons of homologue and congener profiles and principal component analysis. Based on the results of comparison of total input and remaining amount, it is estimated that more than 99% of PCP and CNP applied to the paddy fields had disappeared, whereas most of the applied PCDD/Fs and TEQ remained.


The role of local food availability in explaining obesity risk among young school-aged children.
In recent years, research and public policy attention has increasingly focused on understanding whether modifiable aspects of the local food environment - the types and composition of food outlets families have proximate access to - are drivers of and potential solutions to the problem of childhood obesity in the United States. Given that much of the earlier published research has documented greater concentrations of fast-food outlets alongside limited access to large grocery stores in neighborhoods with higher shares of racial/ethnic minority groups and residents living in poverty, differences in retail food contexts may indeed exacerbate notable child obesity disparities along socioeconomic and racial/ethnic lines. This paper examines whether the lack of access to more healthy food retailers and/or the greater availability of "unhealthy" food purveyors in residential neighborhoods explains children's risk of excessive weight gain, and whether differential food availability explains obesity disparities. I do so by analyzing a national survey of U.S. children followed over elementary school (Early Childhood Longitudinal Study - Kindergarten Cohort) who are linked to detailed, longitudinal food availability measures from a comprehensive business establishment database (the National Establishment Time Series). I find that children who live in residentially poor and minority neighborhoods are indeed more likely to have greater access to fast-food outlets and convenience stores. However, these neighborhoods also have greater access to other food establishments that have not been linked to increased obesity risk, including large-scale grocery stores. When examined in a multi-level modeling framework, differential exposure to food outlets does not independently explain weight gain over time in this sample of elementary school-aged children. Variation in residential food outlet availability also does not explain socioeconomic and racial/ethnic differences. It may thus be important to reconsider whether food access is, in all settings, a salient factor in understanding obesity risk among young children.


Unlikely intersections on the p-adic formal ball.
We investigate generalizations along the lines of the Mordell-Lang conjecture of the author's p-adic formal Manin-Mumford results for n-dimensional p-divisible formal groups F . In particular, given a finitely generated subgroup Γ of F ( Q ¯ p ) and a closed subscheme X ↪ F , we show under suitable assumptions that for any points P ∈ X ( C p ) satisfying n P ∈ Γ for some n ∈ N , the minimal such orders n are uniformly bounded whenever X does not contain a formal subgroup translate of positive dimension. In contrast, we then provide counter-examples to a full p-adic formal Mordell-Lang result. Finally, we outline some consequences for the study of the Zariski-density of sets of automorphic objects in p-adic deformations. Specifically, we do so in the context of the nearly ordinary p-adic families of cuspidal cohomological automorphic forms for the general linear group constructed by Hida.


The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.
Phosphatidylinositol 3-kinases (PI3Ks) evolved from a single enzyme that regulates vesicle trafficking in unicellular eukaryotes into a family of enzymes that regulate cellular metabolism and growth in multicellular organisms. In this review, we examine how the PI3K pathway has evolved to control these fundamental processes, and how this pathway is in turn regulated by intricate feedback and crosstalk mechanisms. In light of the recent advances in our understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, we discuss the exciting therapeutic opportunities for targeting this pathway to treat these diseases.


An updated and comprehensive review on the ethnomedicinal uses, phytochemistry, pharmacological activity and toxicological profile of Tinospora crispa (L.) Hook. f. & Thomson.
Tinospora crispa (L.) Hook. f. & Thomson (Menispermaceae) is a plant indigenous to Africa and South-East Asia. It is widely used in ethnomedicine to alleviate various diseases including hypertension, diabetes, rheumatism, jaundice, inflammation, fever, fractures, scabies, and urinary disorders. A total of 167 phytoconstituents, belonging to 12 different chemical categories, including alkaloids, flavonoids, terpenoids, and phenolic compounds have thus far been isolated from various parts of T. crispa. Numerous in vitro and in vivo investigations have already established the antidiabetic, anticancer, antiparasitic, antimicrobial, immunomodulatory, hepatoprotective, analgesic, antipyretic, antihyperuricemic, and pesticidal activity of this plant, as well as its effects on the cardiac and the central nervous system. Most pharmacological investigations to date have been carried out on plant extracts and fractions. The exact identity of the phytoconstituents responsible for the observed biological effects and their mode of action at the molecular level are yet to be ascertained. Toxicological studies have demonstrated that T. crispa is relatively safe, although dose-dependent hepatotoxicity is a concern at high doses. This review presents a comprehensive update and analysis on studies related to the ethnomedicinal uses, phytochemistry, pharmacological activity and toxicological profile of T. crispa. It provides some critical insights into the current scientific knowledge on this plant and its future potential in pharmaceutical research.


Motional dynamics of single Patched1 molecules in cilia are controlled by Hedgehog and cholesterol.
The Hedgehog-signaling pathway is an important target in cancer research and regenerative medicine; yet, on the cellular level, many steps are still poorly understood. Extensive studies of the bulk behavior of the key proteins in the pathway established that during signal transduction they dynamically localize in primary cilia, antenna-like solitary organelles present on most cells. The secreted Hedgehog ligand Sonic Hedgehog (SHH) binds to its receptor Patched1 (PTCH1) in primary cilia, causing its inactivation and delocalization from cilia. At the same time, the transmembrane protein Smoothened (SMO) is released of its inhibition by PTCH1 and accumulates in cilia. We used advanced, single molecule-based microscopy to investigate these processes in live cells. As previously observed for SMO, PTCH1 molecules in cilia predominantly move by diffusion and less frequently by directional transport, and spend a fraction of time confined. After treatment with SHH we observed two major changes in the motional dynamics of PTCH1 in cilia. First, PTCH1 molecules spend more time as confined, and less time freely diffusing. This result could be mimicked by a depletion of cholesterol from cells. Second, after treatment with SHH, but not after cholesterol depletion, the molecules that remain in the diffusive state showed a significant increase in the diffusion coefficient. Therefore, PTCH1 inactivation by SHH changes the diffusive motion of PTCH1, possibly by modifying the membrane microenvironment in which PTCH1 resides.


Pre-operative assessment of fitness score.
Death within 30 days or survival after a major operation depends on three things: the severity of the disease and the operation, the technical proficiency of the surgeon and the ability of the patient to withstand both disease and operation. The first of these can be estimated by reference to published figures, the second can only be guessed at and the third has in the past been a matter of subjective judgement. With the aim of producing an objective assessment of the likelihood of survival, we have constructed a score system comprising 26 items including age, chronic disease and acute presenting disease. These items are each given a weight of 1 to 4 and the total fitness score for any patient ranges from 0 (fit) to 10 (unlikely to survive). We have validated this score prospectively in 1517 consecutive patients undergoing emergency or elective major abdominal operations (excluding appendicectomies and hernia repairs). In 492 operations in which the patient scored 0 or 1, one patient died (0.2 per cent); in 290 with scores of 2 or 3, one died (0.3 per cent); in 313 with scores of 4 or 5, five died (1.6 per cent). It was when the score rose to 6 or over that the chances of survival progressively declined: 16 died of the 105 patients who scored 6 (15.2 per cent) as did 74 of the 191 who scored 7 or 8 (38.7 per cent) and 70 of the 126 who scored 9 or 10 (55.6 per cent). We now use the score as part of our audit and enquire particularly closely into the death of any patient with a pre-operative score of less than 6.


A specific enzyme-linked immunosorbent assay (ELISA) for the determination of human C5a antigen.
An enzyme-linked immunosorbent assay has been developed to detect human C5a antigen. This ELISA methodology has been shown to be a highly sensitive technique capable of detecting C5a antigen concentrations below 10 ng/ml. The microELISA technique used in this study is specific for human C5a and C5a des arg (C5a antigen) but not for human C5. Conditions to establish sensitivity and specificity are outlined in ths report.


Design, synthesis and Structure-activity relationship studies of new thiazole-based free fatty acid receptor 1 agonists for the treatment of type 2 diabetes.
The free fatty acid receptor 1 (FFA1/GPR40) has attracted interest as a novel target for the treatment of type 2 diabetes. Several series of FFA1 agonists including TAK-875, the most advanced compound terminated in phase III studies due to concerns about liver toxicity, have been hampered by relatively high molecular weight and lipophilicity. Aiming to develop potent FFA1 agonists with low risk of liver toxicity by decreasing the lipophilicity, the middle phenyl of TAK-875 was replaced by 11 polar five-membered heteroaromatics. Subsequently, systematic exploration of SAR and application of molecular modeling, leads to the identification of compound 44, which was an excellent FFA1 agonist with robustly hypoglycemic effect both in normal and type 2 diabetic mice, low risks of hypoglycemia and liver toxicity even at the twice molar dose of TAK-875. Meanwhile, two important findings were noted. First, the methyl group in our thiazole series occupied a small hydrophobic subpocket which had no interactions with TAK-875. Furthermore, the agonistic activity revealed a good correlation with the dihedral angle between thiazole core and the terminal benzene ring. These results promote the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.


Effects of urban living environments on mental health in adults.
Urban-living individuals are exposed to many environmental factors that may combine and interact to influence mental health. While individual factors of an urban environment have been investigated in isolation, no attempt has been made to model how complex, real-life exposure to living in the city relates to brain and mental health, and how this is moderated by genetic factors. Using the data of 156,075 participants from the UK Biobank, we carried out sparse canonical correlation analyses to investigate the relationships between urban environments and psychiatric symptoms. We found an environmental profile of social deprivation, air pollution, street network and urban land-use density that was positively correlated with an affective symptom group (r = 0.22, Pperm < 0.001), mediated by brain volume differences consistent with reward processing, and moderated by genes enriched for stress response, including CRHR1, explaining 2.01% of the variance in brain volume differences. Protective factors such as greenness and generous destination accessibility were negatively correlated with an anxiety symptom group (r = 0.10, Pperm < 0.001), mediated by brain regions necessary for emotion regulation and moderated by EXD3, explaining 1.65% of the variance. The third urban environmental profile was correlated with an emotional instability symptom group (r = 0.03, Pperm < 0.001). Our findings suggest that different environmental profiles of urban living may influence specific psychiatric symptom groups through distinct neurobiological pathways.


Atmospheric turbulence strength distribution along a propagation path probed by longitudinally structured optical beams.
Atmospheric turbulence can cause critical problems in many applications. To effectively avoid or mitigate turbulence, knowledge of turbulence strength at various distances could be of immense value. Due to light-matter interaction, optical beams can probe longitudinal turbulence changes. Unfortunately, previous approaches tended to be limited to relatively short distances or large transceivers. Here, we explore turbulence probing utilizing multiple sequentially transmitted longitudinally structured beams. Each beam is composed of Bessel-Gaussian ([Formula: see text]) modes with different [Formula: see text] values such that a distance-varying beam width is produced, which results in a distance- and turbulence-dependent modal coupling to [Formula: see text] orders. Our simulation shows that this approach has relatively uniform and low errors (<0.3 dB) over a 10-km path with up to 30-dB turbulence-structure-constant variation. We experimentally demonstrate this approach for two emulated turbulence regions (~15-dB variation) with <0.8-dB errors. Compared to previous techniques, our approach can potentially probe longer distances or require smaller transceivers.


Validation of deep learning natural language processing algorithm for keyword extraction from pathology reports in electronic health records.
Pathology reports contain the essential data for both clinical and research purposes. However, the extraction of meaningful, qualitative data from the original document is difficult due to the narrative and complex nature of such reports. Keyword extraction for pathology reports is necessary to summarize the informative text and reduce intensive time consumption. In this study, we employed a deep learning model for the natural language process to extract keywords from pathology reports and presented the supervised keyword extraction algorithm. We considered three types of pathological keywords, namely specimen, procedure, and pathology types. We compared the performance of the present algorithm with the conventional keyword extraction methods on the 3115 pathology reports that were manually labeled by professional pathologists. Additionally, we applied the present algorithm to 36,014 unlabeled pathology reports and analysed the extracted keywords with biomedical vocabulary sets. The results demonstrated the suitability of our model for practical application in extracting important data from pathology reports.


Nuclear reprogramming of somatic nucleus hybridized with embryonic stem cells by electrofusion.
Cell fusion is a powerful tool for understanding the molecular mechanisms of epigenetic reprogramming. In hybrid cells of somatic cells and pluripotential stem cells, including embryonic stem (ES) and embryonic germ cells, somatic nuclei acquire pluripotential competence. ES and embryonic germ cells retain intrinsic trans activity to induce epigenetic reprogramming. For generating hybrid cells, we have used the technique of electrofusion. Electrofusion is a highly effective, reproducible, and biomedically safe in vitro system. For successful cell fusion, two sequential steps of electric pulse stimulation are required for the alignment (pearl chain formation) of two different types of cells between electrodes in response to alternating current stimulation and for the fusion of cytoplasmic membranes by direct current stimulation. Optimal conditions for electrofusion with a pulse generator are introduced for ES and somatic cell fusion. Topics in the field of stem cell research include the successful production of cloned animals via the epigenetic reprogramming of somatic cells and contribution of spontaneous cell fusion to generating intrinsic plasticity of tissue stem cells. Cell fusion technology may make important contributions to the fields of epigenetic reprogramming and regenerative medicine.


Investigation on the key factors associated with flavor quality in northern strong aroma type of Baijiu by flavor matrix.
The strong aroma type of Baijiu is popular with its balanced flavor. However, the flavor characteristics of strong aroma type of Baijiu in different regions have significant diversities. Among them, the key aroma compounds in northern strong aroma type of Baijiu and the factors affecting the aroma profile and flavor quality are still unclear. In this study, a total of 78 aroma compounds were identified by gas chromatography-olfactometry-mass spectrometry (GC-O-MS). The quantitative analysis was completed and ethyl hexanoate (1003.24-4506.04 mg/L) was the highest. Aroma profile was successfully simulated by reconstitution, and omission test was applied to investigate the effects of the important aroma compounds on the aroma profile. Additionally, the relationship between expression of aroma compounds and sensory characteristics of samples was illustrated by flavor matrix. The overall aroma profile of northern strong aroma type of Baijiu was formed by the key aroma compounds with different aroma expression.


Stroke: Hospital Nursing Management Within the First 24 Hours.
Within the United States, someone will have a stroke approximately every 40 seconds. Eighty-five percent of strokes are ischemic, with 15% classified as either intracranial or subarachnoid hemorrhage. Stroke care is complex, and nurses play a critical role in identification, assessment, management, and coordination throughout the stroke continuum of care. This article will explore the nursing care of the patient with ischemic and hemorrhagic stroke during the first 24 hours.


Phytohaemagglutinin activation of T cells through the sheep red blood cell receptor.
Expression of receptors for sheep red blood cells and the ability to proliferate in response to phytohaemagglutinin (PHA) are the traditional properties of human T cells, but the function of the sheep red cell receptor (the T11 antigen) is controversial and the mechanism of PHA-induced mitogenesis unclear. Mitogenesis involves a complex series of cell-mediated and factor-dependent interactions, but a rise in intracellular free calcium concentration, [Ca2+]i, seems to be an important primary event in T-cell activation. We have now investigated the effects of three monoclonal antibodies, previously shown to inhibit mitogen-induced proliferation, on T-cell [Ca2+]i. We find that anti-LFA-2 and OKT11, which react with the sheep red cell receptor, have no effect on [Ca2+]i, nor do they inhibit the rise in [Ca2+]i induced by concanavalin A (Con A) or the mitogenic anti-T3 monoclonal antibody UCHT1 (ref. 11). They do, however, block PHA-induced Ca2+ mobilization. Anti-LFA-1, which reacts with the lymphocyte function-associated antigen, has no effect on intracellular Ca2+. These studies suggest that the sheep red blood cell receptor is an activation pathway for T cells and that the effects of PHA are mediated through this pathway.


Bistachybotrysin K, one new phenylspirodrimane dimer from Stachybotrys chartarum with potent cytotoxic activity.
Bistachybotrysin K (1), one new phenylspirodrimane dimer with a central 6/7 oxygen heterocycle core, was isolated from the fungus Stachybotrys chartarum CGMCC 3.5365. Its structure was elucidated by extensive spectroscopic data and single-crystal X-ray diffraction. Compound 1 showed significant cytotoxicity against human tumor cell lines HCT116, NCI-H460, BGC823, Daoy, and HepG2 with IC50 values in the range of 1.1-4.7 µM.


Sleep modulates word-pair learning but not motor sequence learning in healthy older adults.
Sleep benefits memory across a range of tasks for young adults. However, remarkably little is known of the role of sleep on memory for healthy older adults. We used 2 tasks, 1 assaying motor skill learning and the other assaying nonmotor/declarative learning, to examine off-line changes in performance in young (20-34 years), middle-aged (35-50 years), and older (51-70 years) adults without disordered sleep. During an initial session, conducted either in the morning or evening, participants learned a motor sequence and a list of word pairs. Memory tests were given twice, 12 and 24 hours after training, allowing us to analyze off-line consolidation after a break that included sleep or normal wake. Sleep-dependent performance changes were reduced in older adults on the motor sequence learning task. In contrast, sleep-dependent performance changes were similar for all 3 age groups on the word pair learning task. Age-related changes in sleep or networks activated during encoding or during sleep may contribute to age-related declines in motor sequence consolidation. Interestingly, these changes do not affect declarative memory.


The localization of a platelet GpIIb-IIIa-related protein in endothelial cell adhesion structures.
Previous studies have shown that human endothelial cells (ECs) adhere to fibrinogen (fg) and fibronectin (fn) and organize their cytoskeleton on these substrata. However, the mechanism governing this chain of events is poorly known. In ECs glycoproteins immunologically and biochemically similar to the platelet membrane GpIIb-IIIa complex have been described. The functional role of this complex in ECs remains to be established. In this study we show that the antigens recognized by polyclonal antibodies raised against human platelet GpIIb-IIIa and crossreacting with the EC form have a discrete and well-organized distribution at cell adhesion structures. Indeed these antigens are located at vinculin-rich focal contacts found at the membrane insertion of microfilament bundles of the stress fiber type. They are also found at cell-to-cell contacts and, with a diffuse pattern, at the dorsal surface of ECs. GpIIb-IIIa antibodies, added to EC suspensions prior to plating, inhibit EC spreading on fg and vitronectin (vn) substrata in a concentration-dependent way. In contrast, the antibodies are very poorly active when the cells are seeded on fn-coated glass. The same antibodies, added to adherent cells, disrupt cell-to-cell contacts and cause their rounding and detachment. Overall these results indicate that EC GpIIb-IIIa complex is involved in controlling the adhesion mechanism of these cells to extracellular matrix proteins.


The cavovarus/supinated foot deformity and external tibial torsion: the role of the posterior tibial tendon.
This article describes one surgeon's experience in pediatric orthopedic surgery. His experiences treating cavovarus/supinated foot deformities and external tibial torsion are described.