Thymic dependency of the humoral regulation of CFU-s proliferation in mice bearing a CSF-producing tumor.
A better understanding of the mechanisms involved in the proliferation of splenic colony-forming units (CFU-s) during tumor growth is important for the prevention of bone marrow aplasia during chemotherapy. The in vivo growth of EMT6 cells, a colony-stimulating factor-secreting mammary tumor, in BALB/c and nude mice resulted in splenomegaly and an increase in the number of splenic granulocyte/macrophage colony-forming cells (GM-CFC). Proliferation of CFU-s, observed in BALB/c mice but not in nude mice, most likely resulted from combined direct and indirect actions of factors secreted by tumor and host cells (in particular helper T cells). These factors were detectable in the serum immediately following tumor cell injection. Thus, the GM-CFC response to factors secreted by the EMT6 tumors is thymus-independent while the CFU-s response is dependent upon the presence of T cells. Finally, we show that EMT6 tumor growth had no effect on the determination of CFU-s differentiation toward the various myeloid cell lineages.


Suppression of ethanol-reinforced lever pressing by delaying food availability.
When food was initially available to rats under a fixed-interval 26-second schedule and each liquid-reinforced lever press delayed food availability 8 seconds, suppression of liquid-reinforced lever pressing and liquid consumption occurred when the liquid presented was 4, 8, 16, 32, and 0% ethanol. Suppression did not occur in yoked-control animals, which received food coincidentally with experimental animals but were not directly exposed to the delay dependency. After exposure to the food schedule, each ethanol solution served as a reinforcer in the absence of food presentation. Delaying food availability for increasingly long periods (8 to 2048 seconds) suppressed ethanol-reinforced lever pressing and consumption relative to baseline levels, with the maximum decrease being below the level maintained in the absence of food. However, degree of suppression did not increase monotonically with delay length. Liquid-reinforced performance of yoked-control animals indicated that suppression did not result from changes in the sequencing of food presentation alone.


Spirituality in terminal illness. An alternative view of theory.
I use data and insights gained from 10 years of research and practice on psychosocial and spiritual aspects of living with HIV to outline a critique of extant knowledge on spirituality and to propose an alternative. Nurses are in an excellent position to experience the human spirit. We can use the resultant understandings to be present with others and to become more self-aware and self-loving. I present here my philosophy and personal rules for understanding the spirit that were taught to me by patients and knowledgeable research participants as they helped me to see how my professional objectivity and application of professional knowledge were anathema to their self-discovery. I present a critique of some of the confining aspects of nursing theory, particularly that which is built on developmental frameworks to show how our vision is skewed negatively by these frameworks, and how it may cause us to look down at patients rather than at them as equals.


Experimental and Theoretical Studies on the Adsorption Mechanisms of Uranium (VI) Ions on Chitosan.
An experiment on the adsorption of uranium (VI) by chitosan was conducted to investigate the efficiency of chitosan as an adsorbent for U(VI). The adsorption potential of U(VI) by chitosan was investigated with ICP-MS by varying the experimental conditions such as the pH in order to obtain the optimum conditions. Adsorption dependence on the pH was confirmed, and the highest uptake of U(VI) was observed at pH 5. In addition, to scrutinize the experimental results, quantum chemistry calculations were performed. The results, taking into account the experimental conditions, show that the adsorption efficiency increases as the total charge of the adsorbent and adsorbate species decreases if both of them are positively charged. It was also found that a slight change in the adsorption geometric configuration controls the adsorption efficiency.


OsCYP21-4, a novel Golgi-resident cyclophilin, increases oxidative stress tolerance in rice.
OsCYP21-4 is a rice cyclophilin protein that binds to cyclosporine A, an immunosuppressant drug. CYP21-4s in Arabidopsis and rice were previously shown to function as mitochondrial cyclophilins, as determined by TargetP analysis. In the current study, we found that OsCYP21-4-GFP localized to the Golgi, rather than mitochondria, in Nicotiana benthamiana leaves, which was confirmed based on its co-localization with cis Golgi α-ManI-mCherry protein. OsCYP21-4 transcript levels increased in response to treatments with various abiotic stresses and the phytohormone abscisic acid, revealing its stress-responsiveness. CYP21-4 homologs do not possess key peptidyl prolyl cis/trans isomerase (PPIase) activity/cyclosporine A (CsA) binding residues, and recombinant OsCYP21-4 protein did not convert the synthetic substrate Suc-AAPF-pNA via cis- trans- isomerization in vitro. In addition, transgenic plants overexpressing OsCYP21-4 exhibited increased tolerance to salinity and hydrogen peroxide treatment, along with increased peroxidase activity. These results demonstrate that OsCYP21-4 is a novel Golgi-localized cyclophilin that plays a role in oxidative stress tolerance, possibly by regulating peroxidase activity.


MiRNA-7 Replacement Effect on Proliferation and Tarceva-Sensitivity in U373-MG Cell Line.
Deregulation of the EGFR signaling pathway activity has been shown to can be effective in resistance to EGFR-TKIs, such as Tarceva (erlotinib), in glioblastoma cells. In addition, reports have shown that the reduction of miRNA-7 expression levels is associated with an increase in the expression of EGFR. Here, we evaluated the effect of miRNA-7 on EGFR expression and sensitivity of the U373-MG glioblastoma to erlotinib. The effect of miRNA-7 on EGFR expression was examined using RT-qPCR and western blotting. Trypan blue and MTT assays were performed to explore the effect of treatments on cell growth and survival, respectively. The combination index analysis was used to evaluate the interaction between drugs. Apoptosis was measured by ELISA cell death assay. We showed that miRNA-7 markedly inhibited the expression of EGFR and decreased the growth of glioblastoma cells, relative to blank control and negative control miRNA (p < 0.05). Introduction of miRNA-7 synergistically increased the sensitivity of the U373-MG cells to erlotinib. Results of apoptosis assay demonstrated that miRNA-7 can trigger apoptosis and enhance the erlotinib-mediated apoptosis. Our results show that miRNA-7 plays a critical role in the growth, survival and sensitivity of the U373-MG cells to erlotinib by targeting EGFR. Thus, miRNA-7 replacement therapy can become an effective therapeutic procedure in glioblastoma.


Subjective socioeconomic status and cigarette smoking interact to delay discounting.
People generally discount future outcomes, and accordingly accept immediate but smaller gain. This research examined whether this tendency (i.e., delay discounting) is associated with socioeconomic status (SES) and smoking status, and hypothesized that the influence of SES on delay discounting would be moderated by smoking status. Using an Internet survey, 206 participants made choices between receiving hypothetical monetary rewards immediately or with a delay of 1 year. As predicted, the rates of delay discounting were higher as subjective socioeconomic status indicating one's relative position and standing in a society was lower. Moreover, the tendency was clearer in smokers than in non-smokers, suggesting that cigarette smoking has a moderating effect. In contrast, there was no effect of objective socioeconomic status representing how individuals are able to access valued goods and services.


Small cell lung cancer with paraneoplastic nephrotic syndrome.
We present a case of nephrotic syndrome, associated with small cell lung carcinoma. Renal biopsy revealed membranous glomerulonephritis, probably due to immune complex deposition with tumour antigen. Complete remission of the small cell lung carcinoma after chemotherapy was followed by regression of the nephrotic syndrome. This regression persisted even when brain metastases developed, without simultaneous relapse of tumour outside the central nervous system.


Biochar decreased microbial metabolic quotient and shifted community composition four years after a single incorporation in a slightly acid rice paddy from southwest China.
While numerous studies both in laboratory and field have showed short term impacts of biochar on soil microbial community, there have been comparatively few reports addressing its long term impacts particular in field condition. This study investigated the changes of microbial community activity and composition in a rice paddy four years after a single incorporation of biochar at 20 and 40t/ha. The results indicated that biochar amendment after four years increased soil pH, soil organic C (SOC), total N and C/N ratio and decreased bulk density, particularly for the 40t/ha treatment compared to the control (0t/ha). Though no significant difference was observed in soil basal respiration, biochar amendment increased soil microbial biomass C and resulted in a significantly lower metabolic quotient. Besides, dehydrogenase and β-glucosidase activities were significantly decreased under biochar amendment relative to the control. The results of Illumina Miseq sequencing showed that biochar increased α-diversity of bacteria but decreased that of fungi and changed both bacterial and fungal community structures significantly. Biochar did not change the relative abundances of majority of bacteria at phylum level with the exception of a significant reduction of Actinobacteria, but significantly changed most of bacterial groups at genus level, particularly at 40t/ha. In contrast, biochar significantly decreased the relative abundances of Ascomycota and Basidiomycota by 11% and 66% and increased the relative abundances of Zygomycota by 147% at 40t/ha compared to the non-amended soil. Redundancy analysis (RDA) indicated that biochar induced changes in soil chemical properties, such as pH, SOC and C/N, were important factors driving community composition shifts. This study suggested that biochar amendment may increase microbial C use efficiency and reduce some microorganisms that are capable of decomposing more recalcitrant soil C, which may help stabilization of soil organic matter in paddy soil in long term.


Adjuvant therapy in node-positive vulvar cancer.
Due to an increasing incidence with concurrently decreasing age at onset, vulvar cancer represents a current challenge for gynecologic oncologists. Positive lymph nodes of the groins have been proven to be the most important prognostic factor for affected patients, significantly impairing overall survival. Distinct criteria for indication of adjuvant therapy following primary tumor resection and groin surgery are still under debate. At present, only patients with two or more positive lymph nodes are treated with adjuvant radiotherapy despite growing evidence that patients with only one nodal macrometastasis already have a significantly worse outcome and might benefit from adjuvant treatment. This review discusses existing evidence focusing on different therapeutic approaches and their potential indication in vulvar cancer. Based on the available data the need for future trials is being elaborated.


Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms as risk factors for hepatocellular carcinoma in a Korean population.
Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer death in South Korea, but genetic susceptibility factors of HCC have not been examined extensively. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) play an essential role in both DNA synthesis and methylation and polymorphisms in the MTHFR gene, 677C>T, 1298A>C and the MTRR gene, 66A>G, are associated with several types of malignancy. In this study, the allelic frequencies and genotype distribution of three polymorphisms in the MTHFR and MTRR genes from 96 hepatocellular carcinoma (HCC) patients and 201 controls were examined to assess the association between these polymorphisms and the development of HCC in this Korean population. The 66AG+GG (G allele-bearing) genotype of the MTRR gene was significantly associated with an increased risk of HCC (odds ratio, OR, 1.687; 95% confidence interval, CI=1.022-2.787). Moreover, the combination of MTHFR 1298AA/MTRR 66AG+GG (OR=1.854, 95% CI=1.005-3.420) and MTHFR 1298AC+CC/MTRR 66AG+GG (OR=2.733, 95% CI=1.195-6.249) showed a significant association with HCC risk. In the data classified by age and etiology, MTRR 66A>G over the age of 65 years, MTHFR 1298A>C under the age of 65 years and the MTRR 66AG+GG genotype in the hepatitis B virus (HBV) patients were increased risk factors for the disease. The MTHFR 1298A>C and the MTRR 66A>G genotypes were associated with an increased risk of HCC in this Korean population. Further studies involving larger and varied populations could provide a potential tool for cancer risk assessment in patients who are at risk of developing HCC.


[Clinical significance of echocardiographic techniques of right heart examination].
Study of the role and function of the right heart and the peculiarities of their remodeling in a range of diseases (heart valvular diseases, pulmonary thromboembolism and its complications, cardiomyopathy, combined cardiorespiratory pathology, heart failure, essential hypertension etc.) is of great scientific and practical interest. An optimal right ventricular (RV) examination should be precise, reflect its function objectively, be feasible in everyday clinical practice, and provide accurate prognosis. The last decade has been marked by search for possibilities to evaluate the systolic and diastolic R Vfunction, especially after clinical introduction of Doppler EchoCG. However, publications dedicated to the protocol of EchoCG study of the RV, the normal values of its structure and function, and their clinical interpretation are still rare. The authors of the present work analyze studies on the investigation of the R V and offer a protocol with a method of calculation of EchoCG parameters and their reference values concerning the right heart.


Effects of angiotensin peptides on colonic motility in rats.
Renin-angiotensin system (RAS) is involved in the pathophysiology of colonic inflammation. The aim of this study was to investigate whether small angiotensins (Angs) peptides play a role in the regulation of colonic motility and their roles are modulated in colitis. Experimental colitis was induced by an intake of 5% dextran sulfate sodium (DSS) dissolved in tap water for 7 days in Sprague-Dawley rats. After sacrifice, plasma hormone concentrations and messenger RNAs (mRNAs) for RAS were measured. Functional analysis of colonic motility in response to Angs peptides was performed using Taenia coli. DSS-treated colon showed an increased necrosis with massive infiltration of inflammatory cells. The mRNA level of colonic angiotensin II receptor type 2 (AT2R) in DSS-treated rats was higher than that in control rats whereas the mRNA levels of angiotensin II converting enzyme (ACE), ACE2, AT1R, AT4R, and Mars receptor were not different from those in control rats. Ang III, Ang IV, and Ang-(1-9) (1, 3 μM) increased the frequency of basal colonic motility. Ang-(1-7) did not cause any significant changes in frequency and amplitude of basal motility. The order of potency for an increased frequency of basal motility seems to be Ang II>>Ang IV>Ang III=Ang-(1-9). The increased frequency of basal motility by Ang-(1-9) but not Ang IV was significantly enhanced in DSS-treated rat colon. In conclusion, these data suggest that small Angs peptides are partly involved in the pathophysiological regulation of colonic motility in experimental colitis.


On the collective network of ionic liquid/water mixtures. II. Decomposition and interpretation of dielectric spectra.
This study deals with the dielectric spectra of mixtures of the ionic liquid 1-butyl-3-methyl-imidazolium (BMIM(+)) tetrafluoroborate with water at three selected mole fractions 0.767<or=x(H(2)O)<or=0.967. The focus lies on the comparison of experimental and computational data. On the one hand, a computational analysis permits a complete decomposition of spectra, both with respect to dynamical behavior (translation and rotation) as well as to composition of the mixture (cation, anion, and water). Thereby, not only the peak assignment in experimental spectra is enabled but one can also learn more about solvation properties. Of particular importance is the interplay of the dielectric constant and the conductivity representing a measure of collective rotational and translational motion. On the other hand, the comparison with experimental spectra is essential for the validation of the force fields used in simulation. The satisfying agreement between corresponding peaks in the dielectric spectra confirms not only computed dielectric relaxation times but also other collective dynamical properties such as the viscosity. Nevertheless, the detailed fine structure of the conductivity regime reveals specific ion-pair effects not covered by the simulation. A possible confinement of dynamical heterogeneity as a consequence of a system size effect is also indicated.


Redox, spectroscopic, and photophysical properties of Ru-Pt mixed-metal complexes incorporating 4,7-diphenyl-1,10-phenanthroline as efficient DNA binding and photocleaving agents.
The redox, spectroscopic, and photophysical properties as well as DNA interactions of the new bimetallic complexes [(Ph2phen)2Ru(BL)PtCl2](2+) (Ph2phen = 4,7-diphenyl-1,10-phenanthroline, and BL (bridging ligand) = dpp = 2,3-bis(2-pyridyl)pyrazine, or dpq = 2,3-bis(2-pyridyl)quinoxaline) were investigated. These Ru-polyazine chromophores with Ph2phen TLs (terminal ligands) and polyazine BLs are efficient light absorbers. The [(Ph2phen)2Ru(BL)PtCl2](2+) complexes display reversible Ru(II/III) oxidations at 1.57 (dpp) and 1.58 (dpq) V vs SCE (saturated calomel electrode) with an irreversible Pt(II/IV) oxidation occurring prior at 1.47 V vs SCE. Four, reversible ligand reductions occur at -0.50 dpp(0/-), -1.06 dpp(-/2-), -1.37 Ph2phen(0/-), and -1.56 V vs SCE Ph2phen(0/-). For the [(Ph2phen)2Ru(dpq)PtCl2](2+) complex, the first two reductions shift to more positive potentials at -0.23 and -0.96 V vs SCE. The electronic absorption spectroscopy is dominated in the UV region by π → π* ligand transitions and in the visible region by metal-to-ligand charge transfer (MLCT) transitions at 517 nm for [(Ph2phen)2Ru(dpp)PtCl2](2+) and 600 nm for [(Ph2phen)2Ru(dpq)PtCl2](2+). Emission spectroscopy shows that upon attaching Pt to the Ru monometallic precursor the λmax(em) shifts from 664 nm for [(Ph2phen)2Ru(dpp)](2+) to 740 nm for [(Ph2phen)2Ru(dpp)PtCl2](2+). The cis-Pt(II)Cl2 bioactive site offers the potential of targeting DNA by covalently binding the mixed-metal complex to DNA bases. The multifunctional interactions with DNA were assayed using both linear and circular plasmid pUC18 DNA gel shift assays. Both title complexes can bind to and photocleave DNA with dramatically enhanced efficiency relative to previously reported systems. The impact of the Ph2phen TL on photophysics and bioreactivity is somewhat surprising given the Ru → BL charge transfer (CT) nature of the photoreactive state in the complexes.


Kinetic and Thermodynamic Insights into Agonist Interactions with the Parathyroid Hormone Receptor-1 from a New NanoBRET Assay.
Polypeptides that activate the parathyroid hormone receptor-1 (PTHR1) are important in human physiology and medicine. Most previous studies of peptide binding to this receptor have involved the displacement of a radiolabeled ligand. We report a new assay format based on bioluminescence resonance energy transfer (BRET). Fusion of a NanoLuc luciferase (nLuc) unit to the N-terminus of the PTHR1 allows the direct detection of binding by an agonist peptide bearing a tetramethylrhodamine (TMR) unit. Affinity measurements from the BRET assay align well with results previously obtained via radioligand displacement. The BRET assay offers substantial operational benefits relative to affinity measurements involving radioactive compounds. The convenience of the new assay allowed us to explore several questions raised by earlier reports. For example, we show that although the first two residues of PTH(1-34) (the drug teriparatide) are critical for PTHR1 activation, these two residues contribute little or nothing to affinity. Comparisons among the well-studied agonists PTH(1-34), PTHrP(1-34), and "long-acting PTH" (LA-PTH) reveal that the high affinity of LA-PTH arises largely from a diminished rate constant for dissociation relative to the other two. A D-peptide recently reported to be comparable to PTH(1-34) as an agonist of the PTHR1 was found not to bind detectably to the receptor and to be a very weak agonist.


Educator's Learning Alignment Instrument (ELAI).
To report the development and initial testing of a questionnaire designed to assess the concept of learning alignment within chiropractic college courses. A 36-item questionnaire, Educator's Learning Alignment Instrument (ELAI), was created to evaluate how learning goals, course activities, and assessments align within a college course. Questionnaire development was informed by learning theories and tested using a 2-phased electronic survey mechanism among a chiropractic college faculty. Phase 1 included completing the ELAI for a currently implemented course. Phase 2 included questions about confidential reports generated from ELAI data. Thirty-one of 46 (67%) respondents completed an ELAI. Twelve (38%) participated in phase 2. Twenty-one (68%) courses demonstrated consistent learning focus across goals, activities, and assessments. Aggregate data from early, middle, and late chiropractic program courses revealed progressive shifts toward higher-level learning. Eighty-seven percent of courses contained 1 or more individual learning areas with potentially misaligned goals, activities, or assessment. Ninety-seven percent of respondents completed ELAI questions within 20 minutes. Most (87%) phase 2 respondents noted the report accurately reflected the course. Sixty-seven percent of phase 2 respondents agreed that confidential reports provided useful information to inform course design. The ELAI is a nonburdensome instrument that can facilitate faculty reflection on how aligned learning concepts are applied in a course and provide novel data to assess general learning focus within college courses and within programs. Results indicate ELAI questions can be revised to improve clarity. Additional research comparing ELAI responses from experts, peer educators, and students is recommended.


Clinical analysis of osteosarcoma patients treated with high-dose methotrexate-free neoadjuvant chemotherapy.
High-dose methotrexate (hdmtx) is a common therapeutic agent in the treatment of osteosarcoma. However, hdmtx is highly toxic and requires complex pharmacokinetic monitoring and leucovorin rescue. Thus, alternative therapeutic strategies are necessary. Here, we analyzed the clinical efficacy of a dia regimen (cisplatin-ifosfamide-doxorubicin) to evaluate its potential as an alternative to hdmtx-based therapy. Patients received 12 cycles of chemotherapy administered over 2 years (2 preoperative cycles and 10 postoperative cycles). Cumulative dose was the same in all cycles: cisplatin 120 mg/m(2) on day 1 of week 1, followed by ifosfamide 2.0 g/m(2) days 1-5 of week 2, and doxorubicin 20 mg/m(2) days 1-3 of week 2. Between January 2004 and October 2008, 39 eligible patients (median age: 16 years) were enrolled, with 36 being evaluable for the study. Of those 36 patients, 20 (55.6%) had a good histologic response to preoperative chemotherapy (>90% tumour necrosis). The estimated 5-year rates of event-free survival (efs) and overall survival were 54.8% and 61.5% respectively. The results of our study suggest that, in osteosarcoma patients, the dia regimen produces an efs rate and survival outcomes comparable to those attained with hdmtx-containing regimens, with fewer adverse reactions. The dia regimen is well tolerated, and we observed a high level of patient compliance. Our results demonstrate that hdmtx-free osteosarcoma treatment regimens can be effective, warranting further investigation.


Fluid management for dengue in children.
Dengue is a serious public health problem worldwide. Dengue shock syndrome (DSS), the severe form of dengue fever, can cause death within 12-24 hours if appropriate treatment is not promptly administered. For patients with DSS and the 30% of non-shocked dengue patients who require intravenous fluid therapy, a range of solutions is available for plasma volume support. Crystalloid solutions, such as normal 0·9% saline or Ringer's lactate, are the ones most commonly used. In severe cases, colloid solutions may be administered for their greater osmotic effect, although they carry a greater risk of adverse events. This paper summarises the key clinical data, comparing fluid regimens in children with severe dengue, and concludes that the majority of patients with DSS can be treated successfully with isotonic crystalloid solutions. If a colloid is thought necessary, a medium-molecular-weight preparation that combines good initial plasma volume support with good intravascular persistence and an acceptable side-effect profile is optimal. Further research should aim to determine whether there are benefits to early treatment with colloids, and which colloid solution is most effective for resuscitation of DSS patients.


Preparing psychologists to prescribe.
In this report, an investigation of the training received by professionals currently authorized to prescribe medications is considered as a step toward understanding what might be involved in preparing psychologists appropriately if prescription privileges for psychology were to be obtained. Information about admission and curriculum requirements was collected from medical schools, dental schools, physician assistant programs, nurse practitioner programs, and schools of optometry. Results suggest a high level of pharmacologically relevant coursework is required for admission to, and the completion of, programs that currently prepare their professionals to prescribe. It is argued that preparing psychologists to prescribe would likely entail similar training requirements in addition to, or instead of, those already in place, leaving clinical psychology dramatically and permanently altered.


Evidence for a phase transition in the early development of prehension.
A longitudinal study was conducted to examine the hypothesis that the development of prehension during the first 5 months of life is characterized by the presence of a discontinuous phase transition. Ten infants were observed weekly from 8 to 24 weeks of age. Video recordings were made of movements toward an attractive object which were classified according to two behavioral categories: reaching without grasping and reaching with grasping. The time evolution of the relative incidence of these behavioral categories was analyzed statistically. Evidence was found for a sudden jump from a (developmental) state in which reaching without grasping is predominant to a state in which reaching with grasping is predominant. Evidence was also found for bimodality, inaccessibility, and anomalous variance. In combination, these findings support the hypothesis that the investigated behavioral change constitutes a discontinuous phase transition. The behavioral change in question occurred at the moment in developmental time at which the attractor strength of reaching for objects as such relative to that of other behavioral activities appeared to be increased.


[Characteristics of sleep disturbances related to substance use disorders].
Sleep disturbances are frequently observed in patients with substance use disorders during active use as well as in withdrawal period and in remission. However, there is limited information about the association between sleep disturbances and substance use disorders. This review summarizes results of the studies on specific characteristics of sleep disturbances related to alcohol, opioids and psychostimulants (cocaine) use. Data on objective and subjective measurements of sleep characteristics at different stages of the course of an addiction disorder (active use, withdrawal, remission) are presented.


[Post-traumatic knee joint arthroscopy in children and adolescents].
In a retrospective study we analyzed the arthroscopic findings of 166 knee-arthroscopies performed in children and young people up to the age of 16 years. A sports related trauma was present in 54%, a traffic injury in 15% and in 11% an other casualty. In 4% the precise injury was not sure and 16% did not refer any injury. Among the sports injuries (n = 90) ski injuries were the most frequent with 30% of all, followed by gymnastic injuries in 28%, soccer in 25% and other indoor sport injuries in 12%. 57% of all arthroscopies presented a hemarthrosis. The main finding of all arthroscopies was an cartilage lesion. The anterior cruciate ligament was torn in 30% and a dislocated patella was established in 22% of the arthroscopy while a meniscus injury was found in 17%. The injury of the collateral ligaments or of the retinaculum was found in 22%. In all cases of hemarthrosis origin of bleeding was found and only in 6% (n = 10) of all arthroscopy no pathological finding was established.


Development of epidermal growth factor receptor tyrosine kinase inhibitors against EGFR T790M. Mutation in non small-cell lung carcinoma.
Individualized therapies targeting epidermal growth factor receptor (EGFR) mutations show promises for the treatment of non small-cell lung carcinoma (NSCLC). However, disease progression almost invariably occurs 1 year after tyrosine kinase inhibitor (TKI) treatment. The most prominent mechanism of acquired resistance involves the secondary EGFR mutation, namely EGFR T790M, which accounts for 50%-60% of resistant tumors. A large amount of studies have focused on the development of effective strategies to treat TKI-resistant EGFR T790M mutation in lung tumors. Novel generations of EGFR inhibitors are producing encouraging results in patients with acquired resistance against EGFR T790M mutation. This review will summarize the novel inhibitors, which might overcome resistance against EGFR T790M mutation.


Current state of kidney utilization in multiorgan transplants.
In the United States, the leading indication for kidney transplant is primary kidney dysfunction arising from chronic hypertension and diabetes. However, an increasing indication for kidney transplantation is secondary kidney dysfunction in the setting of another severe organ dysfunction, including pancreas, liver, heart, and lung disease. In these settings, multiorgan transplantation is now commonly performed. With the increasing number of multiorgan kidney transplants, an assessment of guidelines and trends for in multiorgan kidney is necessary. Although the utilization of kidney transplants in combined liver-kidney transplant was sharply rising, following the introduction of the 'safety net' policy, combined liver-kidney transplant numbers now remain stable. There is an increasing trend in the utilization of kidney transplantation in heart and lung transplantation. However, as these surgeries were historically uncommon, guidelines for patients who require simultaneous heart or lung transplants are limited and are often institution specific. Strict guidelines need to be established to assess candidacy for kidney transplantation in multiorgan failure patients, particularly for combined heart-kidney and lung-kidney patients.


Hemophagocytic Lymphohistiocytosis Associated with Anaplasmosis.
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by unregulated macrophage and T-lymphocyte activation resulting in cytokine overproduction and subsequent histiocytic phagocytosis. Variant infections, particularly viruses have been postulated as the inciting factor for this potentially fatal disease. Herein, we will report a case of HLH associated with anaplasmosis.


Can diffuse extrasynaptic signaling form a guiding template?
Brain functions such as information processing, learning and memory are commonly associated with changes in synaptic strength, the synaptic plasticity. Extrasynaptic diffusion of transmitters thought to mediate only a modulatory effect. Here I suggest a hypothesis that concentration profile of signaling molecules in the extracellular space can form a "diffuse guiding template" for signal propagation through neuronal network. Such template can be potentially involved in information processing and storage. This hypothesis requires further experimental investigation and, thus, provides a framework for future studies in the field of non-synaptic transmission in the brain.


Pyruvate increases threshold for preconditioning in globally ischemic rat hearts.
Isolated rat hearts can be protected by preconditioning, although this has not been found when they are perfused with pyruvate. We addressed the question of whether pyruvate could increase the threshold for preconditioning in isolated rat hearts and whether this could be overcome with increased durations of ischemia. A protocol of four periods of 5 min of ischemic preconditioning (4 x 5 min) protected hearts (improved recovery of function, reduced lactate dehydrogenase release) not perfused with pyruvate from a subsequent 30-min period of global ischemia, but did not protect pyruvate-perfused hearts. Pilot studies indicated that hearts perfused in the presence of pyruvate must be ischemic for approximately 40% longer to produce equivalent ischemic damage in nonpyruvate-treated hearts. Thus the preconditioning period of 5 min was increased by approximately 40% to 7 min to produce equivalent degrees of preconditioning. Hearts preconditioned with the 4 x 7 min protocol with pyruvate were significantly protected against a subsequent severe global ischemia (enhanced recovery of function, reduced lactate dehydrogenase release). High-energy phosphates were measured at the end of the preconditioning protocol (before final global ischemia) to determine whether there was a correlation between cardioprotection and high-energy phosphate levels. There was no correlation between ATP, ADP, or AMP levels and the efficacy of preconditioning. However, an increase in creatine phosphate was associated with cardioprotection, although the importance of this in mediating preconditioning is doubtful. Thus the ability to precondition rat hearts is somewhat dependent on their energy source, but this appears to be due to changes in the severity of the ischemic preconditioning event.


Photophysical properties of closely-coupled, binuclear ruthenium(II) bis(2,2':6',2''-terpyridine) complexes.
The photophysical properties of closely-coupled, binuclear complexes formed by connecting two ruthenium(II) bis(2,2':6',2''-terpyridine) complexes via an alkynylene group are compared to those of the parent complex. The dimers exhibit red-shifted emission maxima and prolonged triplet lifetimes in deoxygenated solution. Triplet quantum yields are much less than unity and the dimers generate singlet molecular oxygen with low quantum efficiency. Temperature dependence emission studies indicate coupling to higher-energy triplet states while cyclic voltammetry shows that the metal centres are only very weakly coupled but that extensive electron delocalization occurs upon one-electron reduction. The radiative rate constants derived for these dimers are relatively low, because the lowest-energy metal-to-ligand, charge-transfer states possess increased triplet character. In contrast, the rate constants for nonradiative decay of the lowest-energy triplet states are kept low by extended electron delocalization over the polytopic ligand. The poor triplet yields are a consequence of partitioning at the second triplet level.


Hypoxia and Inflammation in Cancer, Focus on HIF and NF-κB.
Cancer is often characterised by the presence of hypoxia and inflammation. Paramount to the mechanisms controlling cellular responses under such stress stimuli, are the transcription factor families of Hypoxia Inducible Factor (HIF) and Nuclear Factor of κ-light-chain-enhancer of activated B cells (NF-κB). Although, a detailed understating of how these transcription factors respond to their cognate stimulus is well established, it is now appreciated that HIF and NF-κB undergo extensive crosstalk, in particular in pathological situations such as cancer. Here, we focus on the current knowledge on how HIF is activated by inflammation and how NF-κB is modulated by hypoxia. We summarise the evidence for the possible mechanism behind this activation and how HIF and NF-κB function impacts cancer, focusing on colorectal, breast and lung cancer. We discuss possible new points of therapeutic intervention aiming to harness the current understanding of the HIF-NF-κB crosstalk.


Promising candidate cerebrospinal fluid biomarkers of seizure disorder, infection, inflammation, tumor, and traumatic brain injury in pediatric patients.
Cerebrospinal fluid (CSF) is a dynamic metabolically active body fluid that has many important roles and is commonly analyzed in pediatric patients, mainly to diagnose central nervous system infection and inflammation disorders. CSF components have been extensively evaluated as biomarkers of neurological disorders in adult patients. Circulating microRNAs in CSF are a promising class of biomarkers for various neurological diseases. Due to the complexity of pediatric neurological disorders and difficulty in acquiring CSF samples from pediatric patients, there are challenges in developing CSF biomarkers of pediatric neurological disorders. This review aimed to provide an overview of novel CSF biomarkers of seizure disorders, infection, inflammation, tumor, traumatic brain injuries, intraventricular hemorrhage, and congenital hydrocephalus exclusively observed in pediatric patients.


Visual agnosia.
The visual agnosias are an intriguing class of clinical phenomena that have important implications for current theories of high-level vision. Visual agnosia is defined as impaired object recognition that cannot be attributed to visual loss, language impairment, or a general mental decline. At least in some instances, agnostic patients generate an adequate internal representation of the stimulus but fail to recognize it. In this review, we begin by describing the classic works related to the visual agnosias, followed by a description of the major clinical variants and their occurrence in degenerative disorders. In keeping with the theme of this issue, we then discuss recent contributions to this domain. Finally, we present evidence from functional imaging studies to support the clinical distinction between the various types of visual agnosias.


Transplantation of organs: a European perspective.
The development of transplantation technology increasingly places before society a multitude of diverse, complex ethical and legal problems. The subject is the more complex because of the various divergent interests involved. There are the interests of the donor of organs, who has a right to protection of his legal position, and those of the patient in need of an often lifesaving organ. There are also the interests of the donor's relatives, after his death, and those of the transplantation surgeons. The international dimension of transplantation technology makes the picture even more complicated. Though this article is devoted to the European situation, the problems are similar all over the world.... These matters are solved primarily within the national context: answers are given in accordance with the national socio-cultural background. The overall European (legislative) picture is one of diversity.... This paper will, however, not present a comparative review of legislation in European countries. Instead, it concentrates on the European dimension of the various problems surrounding transplantation technology. First, some specific problems common to the majority of European countries will be presented. Following that, the European dimension will be reflected upon from the perspective of enlarging the potential donor pool.


Curcumin treatment recovery the decrease of protein phosphatase 2A subunit B induced by focal cerebral ischemia in Sprague-Dawley rats.
Curcumin provides various biological effects through its anti-inflammatory and antioxidant properties. Moreover, curcumin exerts a neuroprotective effect against ischemic condition-induced brain damage. Protein phosphatase 2A (PP2A) is a ubiquitous serine and threonine phosphatase with various cell functions and broad substrate specificity. Especially PP2A subunit B plays an important role in nervous system. This study investigated whether curcumin regulates PP2A subunit B expression in focal cerebral ischemia. Cerebral ischemia was induced surgically by middle cerebral artery occlusion (MCAO). Adult male rats were injected with either vehicle or curcumin (50 mg/kg) 1 h after MCAO and cerebral cortex tissues were isolated 24 h after MCAO. A proteomics study, reverse transverse-PCR and Western blot analyses were performed to examine PP2A subunit B expression levels. We identified a reduction in PP2A subunit B expression in MCAO-operated animals using a proteomic approach. However, curcumin treatment prevented injury-induced reductions in PP2A subunit B levels. Reverse transverse-PCR and Western blot analyses confirmed that curcumin treatment attenuated the injury-induced reduction in PP2A subunit B levels. These findings can suggest that the possibility that curcumin maintains levels of PP2A subunit B in response to cerebral ischemia, which likely contributes to the neuroprotective function of curcumin in cerebral ischemic injury.


Oligonucleotide Bioconjugation with Bifunctional Palladium Reagents.
Organometallic reagents enable practical strategies for bioconjugation. Innovations in the design of water-soluble ligands and the enhancement of reaction rates have allowed for chemoselective cross-coupling reactions of peptides and proteins to be carried out in water. There are currently no organometallic-based methods for oligonucleotide bioconjugation to other biomolecules. Here we report bifunctional palladium(II)-oxidative addition complexes (OACs) as reagents for high-yielding oligonucleotide bioconjugation reactions. These bifunctional OACs react chemoselectively with amine-modified oligonucleotides to generate the first isolable, bench stable oligonucleotide-palladium(II) OACs. These complexes undergo site-selective C-S arylation with a broad range of native thiol-containing biomolecules at low micromolar concentrations in under one hour. This approach provided oligonucleotide-peptide, oligonucleotide-protein, oligonucleotide-small molecule, and oligonucleotide-oligonucleotide conjugates in >80 % yield and afforded conjugation of multiple copies of oligonucleotides onto a monoclonal antibody.


Enhanced Stability of the Magnetic Skyrmion Lattice Phase under a Tilted Magnetic Field in a Two-Dimensional Chiral Magnet.
The magnetic skyrmion is a topologically stable vortex-like spin texture that offers great promise as information carriers for future spintronic devices. In a two-dimensional chiral magnet, it was generally considered that a tilted magnetic field is harmful to its formation and stability. Here we investigated the angular-dependent stability of magnetic skyrmions in FeGe nanosheets by using high-resolution Lorentz transmission electron microscopy (Lorentz TEM). Besides the theoretically predicted destruction of skyrmion lattice state by an oblique magnetic field as the temperature closes to its magnetic Curie temperature Tc ∼ 278 K, we also observed an unexpected reentry-like phenomenon at the moderate temperatures near the border between conical and skyrmion phase, Tt ∼ 240 K. This behavior is completely beyond the theoretical prediction in a conventional two-dimensional (2D) system. Instead, a three-dimensional (3D) model involving the competition between conical phase and skyrmions is likely to play a crucial role.


Effectiveness of weight-loss prevention with continual nutrition counseling in postoperative outpatients with stage IA and IB gastric cancer.
Outpatient nutritional counseling by a registered dietitian is often performed to prevent weight loss, but evidence supporting this practice is insufficient. In this study, we aimed to clarify the effectiveness of four-time outpatient nutritional counseling in weight-loss prevention compared with conventional intervention limited to one-time nutritional counseling. This study was designed as a retrospective cohort study. The target population was postoperative patients with stage IA and IB gastric cancer. Groups that received one-time and four-time nutritional counseling included patients who underwent gastrectomy from May 2014 to April 2017 and May 2017 to December 2019, respectively. The one-time group received counseling at discharge; the four-time group received counseling at discharge, at the first outpatient visit, and at 3 and 6 months postoperatively. There were 58 patients in the one-time group and 27 patients in the four-time group, with a significant difference in length of hospital stay (p = 0.042). Thirty-six patients (62.1%) in the one-time nutritional counseling group and 12 (44.4%) in the four-time group had a weight loss of 5% or more from hospital discharge to 6 months postoperatively. The adjusted risk ratio for the effectiveness of four counseling sessions compared with one session was 0.69 (95% confidence interval 0.35-1.34). In subgroup analysis, the effect of nutritional guidance was greater for patients with body mass index ≥23 kg/m2, but this depended on the outcome and number of cases, and there was no essential difference between the groups. In postoperative patients with stage IA and stage IB gastric cancer, four sessions of outpatient nutrition counseling may be not superior to one counseling session in preventing weight loss.


Regeneration of Jaw Joint Cartilage in Adult Zebrafish.
The poor intrinsic repair capacity of mammalian joint cartilage likely contributes to the high incidence of arthritis worldwide. Adult zebrafish can regenerate many structures that show limited or no healing capacity in mammals, including the jawbone. To test whether zebrafish can also regenerate damaged joints, we developed a surgical injury model in which the zebrafish jaw joint is destabilized via transection of the major jaw joint ligament, the interopercular-mandibular (IOM). Unilateral transection of the IOM ligament in 1-year-old fish resulted in an initial reduction of jaw joint cartilage by 14 days, with full regeneration of joint cartilage by 28 days. Joint cartilage regeneration involves the re-entry of articular chondrocytes into the cell cycle and the upregulated expression of sox10, a marker of developing chondrocytes in the embryo that becomes restricted to a subset of joint chondrocytes in adults. Genetic ablation of these sox10-expressing chondrocytes shows that they are essential for joint cartilage regeneration. To uncover the potential source of new chondrocytes during joint regeneration, we performed single-cell RNA sequencing of the uninjured adult jaw joint and identified multiple skeletal, connective tissue, and fibroblast subtypes. In particular, we uncovered a joint-specific periosteal population expressing coch and grem1a, with the jaw joint chondrocytes marked by grem1a expression during regeneration. Our findings demonstrate the capacity of zebrafish to regenerate adult joint cartilage and identify candidate cell types that can be tested for their roles in regenerative response.


Kinetically Accelerated Lithium Storage in High-Entropy (LiMgCoNiCuZn)O Enabled By Oxygen Vacancies.
High-entropy oxides (HEOs) are gradually becoming a new focus for lithium-ion battery (LIB) anodes due to their vast element space/adjustable electrochemical properties and unique single-phase retention ability. However, the sluggish kinetics upon long cycling limits their further generalization. Here, oxygen vacancies with targeted functionality are introduced into rock salt-type (MgCoNiCuZn)O through a wet-chemical molten salt strategy to accelerate the ion/electron transmission. Both experimental results and theoretical calculations reveal the potential improvement of lithium storage, charge transfer, and diffusion kinetics from HEO surface defects, which ultimately leads to enhanced electrochemical properties. The currently raised strategy offers a modular approach and enlightening insights for defect-induced HEO-based anodes.


[Excessive body weight and coexisting with it changes in levels of hormones of adrenal and gonadal origin are associated with coronary artery disease in men].
The aim of study was to estimate relation between excessive body weight (EBW) and coronary artery disease (CAD) in men and to assess changes in concentrations of hormones due to EBW which may predispose to atherogenesis. Study group (CADM) - 33 men in the age 52 +/- 6 years, with body mass index (BMI) above 25 kg/m2 and angiographically documented CAD. Comparative group (CM) - 13 men in the same age without CAD. Apart from evaluation of occurence of risk factors in men of both groups concentrations of hormones in blood were assessed: insulin, insulin-like growth factor I, estradiol (E2), testosterone (T), dehydroepiandrosterone sulfate (DHEAS), follicle-stimulating hormone, luteinizing hormone, progesterone (Prog), cortisol (Cort) and leptin (Lept). In CADM, comparing to CM, greater values of parameters related to EBW, BMI (30,0 +/- 2,6 vs. 26,8 +/- 2,6 kg/m2, p<0,0007) and waist-hip ratio (WHR 1,07 +/- 0,04 vs. 0,92 +/- 0,03, p<0,000001), higher concentrations of Prog (3,0 +/- 1,3 vs. 1,4 +/- 0,9 nmol/l, p<0,0003), Kort (350 +/- 108 vs. 246 +/- 97nmol/l, p<0,006) and Lept (18,2 +/- 10,5 vs. 8,0 +/- 3,6 lU/l, p<0,0003) and lower of T (9,9 +/- 4,0 vs. 12,3 +/- 3,2 nmol/l, p<0,046) were found. In regression analysis coexistence of EBW and eleveted level of Prog revealed the best fit with presence of CAD. Positive correlation between EBW and concentration of Lept and E2 and negative correlation between EBW and concentrations of T, Cort and DHEAS in CADM were found. EBW is a highly aggravating risk factor of CAD in men and is linked to proatherogenic changes in levels of steroid hormones of adrenal and gonadal origin.


CD8+ T cell exhaustion during persistent viral infection is regulated independently of the virus-specific T cell receptor.
During chronic viral infections, responses by virus-specific CD8(+) T cells become marginalized by the acquisition of functional defects and reduced cell numbers in a process defined as T cell exhaustion. Similarly, T cell tolerance to self-antigen is also characterized by impaired effector function and eventual deletion of self-reactive T cells. Induction of both tolerance and exhaustion involve many shared inhibitory mechanisms, thus similar therapeutic approaches have proven effective in these distinct environments. We previously demonstrated that tolerant self-reactive CD8(+) T cells expressing dual-T cell receptors (i.e., dual-TCR) could be rescued by immunization through a second TCR specific for a foreign antigen. These data revealed that T cell tolerance was regulated at the level of the self-reactive TCR. Here, dual-TCR CD8(+) T cells were used to examine if exhaustion during persistent viral infection could be rescued by an analogous strategy of immunization through a second TCR not involved in recognition of virus. In direct contrast to the rescue achievable in tolerant CD8(+) T cells, exhausted T cells were equally impaired through both TCR. These findings suggest that exhaustion is maintained by defects downstream of the virus-specific TCR, and establish that exhaustion and tolerance are distinctly regulated states of T cell dysfunction.


Coronary vasodilation produced by tachycardia under various basal flow conditions.
Some properties of coronary vasodilation produced by heart rate elevation under various basal coronary flow levels was studied. Coronary sinus blood flow, myocardial oxygen consumption and left ventricular contractile force were measured in anaesthetized, open-chest dogs. Heart rate was progressively increased by electrical stimulation at rates ranging from 60/min to 210/min. This was repeated during control, noradrenaline infusion (0.2 microgram kg-1 min-1), in the presence of propranolol (0.25 mg/kg), and during hypopneic positive pressure respiration. It was found that under all experimental conditions, coronary perfusion increased linearly with heart rate. At each rate, coronary flow was greater during noradrenaline infusion and hypopneic respiration than that observed during control or following beta-blockade. Myocardial oxygen consumption behaved similarly to flow, and MVO2 was lowest in the presence of propranolol, and highest during hypopneic ventilation and catecholamine infusion. Contractile force per min (heart rate x tension) also increased with increasing heart rate, but was greatest during noradrenaline infusion, lowest during beta-blockade, and similar during both control and hypopneic respiration. These results indicate that the oxygen cost of contraction was different under the various conditions, and was particularly wasteful during hypopneic respiration. It is concluded that autoregulation caused by heart rate elevation is not dependent on the initial state of coronary blood flow, and that endogenous catecholamine release cannot account for this phenomenon.


Field Trials With Blends of Pheromones of Native and Invasive Cerambycid Beetle Species.
A number of recent studies have demonstrated the potential for using blends of pheromones of cerambycid beetles to attract several species simultaneously. Here, we tested the effects of adding the pheromones of two invasive species, Trichoferus campestris (Faldermann) and Aromia bungii (Faldermann), on the attraction of native species to a generic blend of synthesized pheromones, in season-long field trials at 12 sites in Pennsylvania. Of the four species attracted in significant numbers, Megacyllene caryae (Gahan), Phymatodes amoenus (Say), and P. testaceus (L.) (all subfamily Cerambycinae) were not significantly affected by the addition of the T. campestris pheromone trichoferone and the A. bungii pheromone (E)-2-cis-6,7-epoxynonenal to the generic blend. In contrast, trap catches of Sternidius alpha (Say) (subfamily Lamiinae) were completely shut down by addition of the pheromones of the two exotic species. In addition, there was no indication that any native species were attracted to trichoferone or (E)-2-cis-6,7-epoxynonenal, suggesting that these pheromones are probably not used by species native to eastern North America.


Modulating in vitro gastric digestion of emulsions using composite whey protein-cellulose nanocrystal interfaces.
In this study, we designed emulsions with an oil-water interface consisting of a composite layer of whey protein isolate (WPI, 1wt%) and cellulose nanocrystals (CNCs) (1-3wt%). The hypothesis was that a secondary layer of CNCs at the WPI-stabilized oil-water interface could protect the interfacial protein layer against in vitro gastric digestion by pepsin at 37°C. A combination of transmission electron microscopy, ζ-potential measurements, interfacial shear viscosity measurements and theoretical surface coverage considerations suggested the presence of CNCs and WPI together at the O/W interface, owing to the electrostatic attraction between complementarily charged WPI and CNCs at pH 3. Microstructural analysis and droplet sizing revealed that the presence of CNCs increased the resistance of the interfacial protein film to rupture by pepsin, thus inhibiting droplet coalescence in the gastric phase, which occurs rapidly in an emulsion stabilized by WPI alone. It appeared that there was an optimum concentration of CNCs at the interface for such barrier effects. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) results further confirmed that the presence of 3wt% of CNCs reduced the rate and extent of proteolysis of protein at the interface. Besides, evidence of adsorption of CNCs to the protein-coated droplets to form more rigid layers, there is also the possibility that network formation by the CNCs in the bulk (continuous) phase reduced the kinetics of proteolysis. Nevertheless, structuring emulsions with mixed protein-particle layers could be an effective strategy to tune and control interfacial barrier properties during gastric passage of emulsions.


Neuronal activity and outcomes from thalamic surgery for spinocerebellar ataxia.
We investigated the effects of deep brain stimulation (DBS) or lesions of the ventral intermediate nucleus (Vim) of the thalamus for spinocerebellar ataxia (SCA) and examined the pathophysiological role of neuronal activity of the Vim underlying ataxia. Five patients with SCA with cortical atrophy (ages 60-69 years; 2 sporadic and three familial SCA) and five patients with essential tremor (ET) (ages 57-71 years) were treated with Vim surgery. Intraoperatively, we recorded neuronal activity from single neurons in the Vim thalamus while patients were at rest and compared the physiological properties of those neurons between patients with SCA and those with ET. Postsurgery mean scores for the Fahn-Tolosa-Marin Tremor Scale were improved from 78 to 44 in SCA patients and from 54 to 21 in ET patients. Stronger stimulation was necessary to optimize outcomes in SCA as compared to ET patients. We analyzed 68 Vim neurons in SCA and 60 Vim neurons in ET. Mean discharge rates, burst characteristics, and oscillatory activity were similar for both patient groups, however, we observed that the ratio of cells responding to passive manipulation was significantly smaller (P = 0.0001) in SCA (22%) than in ET (71%). Thalamic surgery led to a significant improvement in tremor in SCA patients. One potential mechanism underlying ataxia in SCA may be disruption of cerebellar sensory feedback, which modulates motor commands in the cerebello-thalamo-cortical network.


Various reduced-order surrogate models for fluid flow and mass transfer in human bronchial tree.
The bronchial tree plays a main role in the human respiratory system because the air distribution throughout the lungs and gas exchange with blood occur in the airways whose dimensions vary from several centimeters to micrometers. Organization of about 60,000 conducting airways and 33 million respiratory airways in a limited space results in a complex structure. Due to this inherent complexity and a high number of airways, using target-oriented dimensional reduction is inevitable. In addition, there is no general reduced-order model for various types of problems. This necessitates coming up with an appropriate model from a variety of different reduced-order models to solve the desired problem. Lumped formulation, trumpet, or typical path model of whole or parts of bronchial tree are frequently used reduced-order models. On the other hand, using any of these models results in underestimation of flow heterogeneity leading to inaccurate prediction of the systems whose mechanisms depend on the fluid heterogeneity. In this study, a simple robust model combining mechanistic and non-mechanistic modeling approaches of the bronchial tree is proposed which overcomes the limitations of the previous reduced-order models and gives the same results of a detailed mechanistic model for the first time. This model starts from an accurate multi-branching model of conducting and respiratory airways (i.e., the base model) and suggests a proxy model of conducting airway and reduced-order model of respiratory airways based on the base model to significantly reduce computational cost while retaining the accuracy. The combination of these models suggests various reduced-order surrogate models of the human bronchial tree for different problems. The applications and limitations of each reduced-order model are also discussed. The accuracy of the proposed model in the prediction of fluid heterogeneity has been examined by the simulation of multi-breath inert gas washout because the alveolar slope is the reflection of fluid heterogeneity where the computational time decreases from 121 h (using the base model) to 4.8 s (using the reduced-order model). A parallel strategy for solving the equations is also proposed which decreases run time by 0.18 s making the model suitable for real-time applications. Furthermore, the ability of the model has been evaluated in the modeling of asthmatic lung as an instance of abnormal lungs, and in the modeling of O2-CO2 exchange as an instance of nonlinear reacting systems. The results indicate that the proposed model outperforms previous models based on accuracy, robustness, and run time.


N-(4-Hydroxyphenyl)-3,4,5-trimethoxybenzamide derivatives as potential memory enhancers: synthesis, biological evaluation and molecular simulation studies.
The present paper describes the synthesis, biological evaluation and molecular simulation studies of a series of N-(4-hydroxyphenyl)-3,4,5-trimethoxybenzamide derivatives with N,N-dialkylaminoethoxy/propoxy moiety as potential memory enhancers with acetylcholinesterase-inhibiting activity having IC50 in low micromolar range (4.0-16.5 μM). All the compounds showed a good degree of agreement between in vivo and in vitro results as most of these derivatives showed dose-dependent increase in percent retention. Compound 10a showed significant % retention of 84.73 ± 4.51 as compared to piracetam (46.88 ± 5.42) at 3 mg kg-1 and also exhibited a maximal percent inhibition of 97% at 50 μM. Molecular docking, MM-GBSA and molecular simulation studies were performed establishing a correlation between the experimental biology and in silico results. In silico results indicate that all the compounds have better docking scores and predicted binding free energies as compared to cocrystallized ligand with the best potent ligand retaining conserved hydrophobic interactions with residues of catalytic triad (HIS447), catalytic anionic site (CAS) (TRP86, TYR337, PHE338) and peripheral anionic site (PAS) (TYR72, TYR124, TRP286 and TYR341). Root mean square deviation (RMSD = 2.4 Å) and root mean square fluctuations of 10a-AChE complex during simulation proved its stable nature in binding toward acetylcholinesterase. The docked conformation of 10a and other analogs at the binding site have also been simulated with polar and nonpolar interactions interlining the gorge residues from PAS to catalytic triad.


Age-related alterations in the modulation of intracortical inhibition during stopping of actions.
We investigated the effect of age on the ability to modulate GABAA-ergic and GABAB-ergic inhibitory activity during stopping of action (reactive inhibition) and preparation to stop (proactive inhibition). Twenty-five young and twenty-nine older adults performed an anticipated response version of the stop-signal task with varying levels of stop-signal probability. Paired-pulse transcranial magnetic stimulation was applied to left primary motor cortex to assess the modulation of GABAA-mediated short-interval intracortical inhibition (SICI) during stopping and GABAB-mediated long-interval intracortical inhibition (LICI) during the anticipation of a stop-signal. At the behavioral level, reactive inhibition was affected by aging as indicated by longer stop-signal reaction times in older compared to young adults. In contrast, proactive inhibition was preserved at older age as both groups slowed down their go response to a similar degree with increasing stop-signal probability. At the neural level, the amount of SICI was higher in successful stop relative to go trials in young but not in older adults. LICI at the start of the trial was modulated as a function of stop-signal probability in both young and older adults. Our results suggest that specifically the recruitment of GABAA-mediated intracortical inhibition during stopping of action is affected by aging.


Early decompression fasciotomy in the treatment of high-voltage electrical burns of the extremities.
Based on a knowledge of electropathophysiology, a recommended treatment has been proposed for the management of extensive high-voltage electrical burns. Early, aggressive, surgical intervention consisting of adequate decompression fasciotomy and wound debridement has been emphasized as the first line of treatment. Frequent redebridements under general anesthesia are important to the preservation of viable tissue. Early coverage procedures or attempts at primary closure following decompression are contraindicated in high-voltage injuries. This method of treatment in eight cases of high-voltage, electrical injury has preserved viable tissue, decreased the incidence of fatal sepsis and renal shutdown, decreased patient morbidity, and generally facilitated patient rehabilitation.


Holistic face processing can inhibit recognition of forensic facial composites.
Facial composite systems help eyewitnesses to show the appearance of criminals. However, likenesses created by unfamiliar witnesses will not be completely accurate, and people familiar with the target can find them difficult to identify. Faces are processed holistically; we explore whether this impairs identification of inaccurate composite images and whether recognition can be improved. In Experiment 1 (n = 64) an imaging technique was used to make composites of celebrity faces more accurate and identification was contrasted with the original composite images. Corrected composites were better recognized, confirming that errors in production of the likenesses impair identification. The influence of holistic face processing was explored by misaligning the top and bottom parts of the composites (cf. Young, Hellawell, & Hay, 1987). Misalignment impaired recognition of corrected composites but identification of the original, inaccurate composites significantly improved. This effect was replicated with facial composites of noncelebrities in Experiment 2 (n = 57). We conclude that, like real faces, facial composites are processed holistically: recognition is impaired because unlike real faces, composites contain inaccuracies and holistic face processing makes it difficult to perceive identifiable features. This effect was consistent across composites of celebrities and composites of people who are personally familiar. Our findings suggest that identification of forensic facial composites can be enhanced by presenting composites in a misaligned format.


Tubulysin Synthesis Featuring Stereoselective Catalysis and Highly Convergent Multicomponent Assembly.
A concise and modular total synthesis of the highly potent N14-desacetoxytubulysin H (1) has been accomplished in 18 steps in an overall yield of up to 30%. Our work highlights the complexity-augmenting and route-shortening power of diastereoselective multicomponent reaction (MCR) as well as the role of bulky ligands to perfectly control both the regioselective and diastereoselective synthesis of tubuphenylalanine in just two steps. The total synthesis not only provides an operationally simple and step economy but will also stimulate major advances in the development of new tubulysin analogues.


Clinical characteristics of disseminated cryptococcosis in previously healthy children in China.
Disseminated cryptococcosis is a rare and fatal disease, and limited data exist regarding it in children. This study aimed to investigate the clinical characteristics of disseminated cryptococcosis in previously healthy children in China. Hospitalized patients with disseminated cryptococcosis were enrolled during January 1996 to December 2015 in Beijing Children's Hospital, Capital Medical University, China. Data on clinical manifestations, laboratory tests, treatment, and prognosis were evaluated. A total of 52 pediatric patients with no underlying disease were enrolled, including 38 boys and 14 girls. Only 10 cases had a history of exposure to pigeon droppings. Fever, cough, and hepatomegaly were 3 main manifestations of disseminated cryptococcosis. However, headache was more common in patients with central nervous system (CNS) invasion than in patients with non-CNS invasion (P < 0.05). Lung (96.2%, 50/52) was the most commonly invaded organ, but only 9.6% (5/52) of patients had respiratory signs. The most common findings on chest imaging were hilar or mediastinal lymphadenopathy (46.8%, 22/47), and nodules (44.7%, 21/47), including small nodules in a scattered distribution (57.1%, 12/21) or miliary distribution (42.9%, 9/25), especially localized in subpleural area. Subsequent invasion occurred in the CNS, abdomen lymph nodes, liver, spleen, peripheral lymph nodes, and skin. In all patients, 42.3% (22/52) and 51.9% (27/52) had elevated eosinophils or IgE, respectively. The positive rate of serum cryptococcal antigen was higher, especially in patients with CNS invasion (approximately 83.3%), than with other primary methods used for pathogen detection, including cerebrospinal fluid (CSF) cryptococcal antigen, cultures of blood, bone marrow, or CSF, and CSF ink staining. The overall mortality rate of pediatric patients in our study was 11.5% (6/52). Some cases had long-term sequela, including hydrocephalus, cirrhosis, or blindness. Disseminated cryptococcosis can occur in previously healthy or immunocompetent children in China. Lung and CNS were most commonly invaded by this disease. Furthermore, most cases usually showed no obvious or specific symptoms or signs, and therefore pediatricians should pay more careful attention to identify this disease.


Immunisation in the first year of life.
Over 10 percent of a group of 1180 Christchurch infants received either no immunisation, incomplete immunisation or late immunisation during the first year of life. Failure to provide the child with the recommended course of immunisation was most common amongst families of non-European ethnic origin, single parent families and families with depressed living standards.


Registered dietitians' coding practices and patterns of code use.
Coding, coverage, and reimbursement are vital to the clinical segment of our profession. The objective of this study was to assess understanding and use of the medical nutrition therapy (MNT) procedure codes. Its design was a targeted, cross-sectional, Internet survey. Participants were registered dietitians (RDs) preselected based on Medicare Part B provider status, randomly selected RDs from the American Dietetic Association database based on clinical practice designation, and self-selected RDs. Parameters assessed were knowledge and use of existing MNT and/or alternative procedure codes, barriers to code use/compensation, need for additional codes for existing/emerging services, and practice demographics. Results suggest that MNT is being reimbursed for a variety of diseases and conditions. Many RDs working in clinic settings are undereducated about code use of any kind, reporting that code selection frequently is determined not by the RD providing the service, but by "someone else." Self-employed RDs are less likely to rely on others to administrate paperwork required for reimbursement, including selection of procedure codes for billable nutrition services. Self-employed RDs are more likely to be reimbursed by private or commercial payers and RDs working in clinic settings are more likely to be reimbursed by Medicare; however, the proportion of Medicare providers in both groups is high. RDs must be knowledgeable and accountable for both the business and clinical side of their nutrition practices; using correct codes and following payers' claims processing policies and procedures. This survey and analysis is a first step in understanding the complex web of relationships between clinical practice, MNT code use, and reimbursement.


A multinomial model to assess central characteristics of mental operators.
Knowledge about potential operators, about the preconditions of their applicability, and about their effects is essential to interact effectively with the physical world. Four classes of representational units of this knowledge can be distinguished: I) rules, II) structures, III) instances, and IV) episodes. Two important characteristics of these units are the abstractness of content and the directionality of access. A multinomial model is presented that enables the measurement of these characteristics. Three experiments were conducted to validate the parameters of the model. The multinomial model could be fitted very well to the empirical data of each experiment. Moreover, the parameter estimates showed the expected effects. The model allows the investigation of the influence of important variables (for example, knowledge domain, type of instruction, or amount of practice) on characteristics of mental operators without a strong commitment to any specific process theory. Debates regarding the contribution of different kinds of knowledge can be converted into statistical tests of the corresponding model parameters.


The Interaction of Adrenomedullin and Macrophages Induces Ovarian Cancer Cell Migration via Activation of RhoA Signaling Pathway.
Tumor-associated macrophages (TAMs) are correlated with poor prognosis in many human cancers; however, the mechanism by which TAMs facilitate ovarian cancer cell migration and invasion remains unknown. This study was aimed to examine the function of adrenomedullin (ADM) in macrophage polarization and their further effects on the migration of ovarian cancer cells. Exogenous ADM antagonist and small interfering RNA (siRNA) specific for ADM expression were treated to macrophages and EOC cell line HO8910, respectively. Then macrophages were cocultured with HO8910 cells without direct contact. Flow cytometry, Western blot and real-time PCR were used to detect macrophage phenotype and cytokine production. The migration ability and cytoskeleton rearrangement of ovarian cancer cells were determined by Transwell migration assay and phalloidin staining. Western blot was performed to evaluate the activity status of signaling molecules in the process of ovarian cancer cell migration. The results showed that ADM induced macrophage phenotype and cytokine production similar to TAMs. Macrophages polarized by ADM promoted the migration and cytoskeleton rearrangement of HO8910 cells. The expression of RhoA and its downstream effector, cofilin, were upregulated in macrophage-induced migration of HO8910 cells. In conclusion, ADM could polarize macrophages similar to TAMs, and then polarized macrophages promote the migration of ovarian cancer cells via activation of RhoA signaling pathway in vitro.


Prevalence and Risk Factors of Human Papillomavirus in Male Patients: A Systematic Review and Meta-Analysis.
Human papillomavirus (HPV) is one of the most prevalent sexually transmitted infections. Although the research focus has been on women, men are also affected. Thus, the aim was to estimate the prevalence of HPV in men and to analyse its risk factors. A systematic review with meta-analysis was performed. The main health science databases were consulted. The search terms were was: "papilloma virus AND (prevalence OR risk factors) AND men". The final sample of studies was n = 16 and the men sample for the meta-analysis was n = 18,106. The meta-analysis revealed a prevalence of 49% (95% Confidence Interval (CI): 35⁻64%) of any type of human papillomavirus in men and 35% (95% CI: 26⁻45%) of high-risk human papillomavirus in men. The included studies showed that stable sexual habits, circumcision and condom use are protective factors against HPV. In addition, there is a certain positive association with tobacco use and the early initiation of sexual intercourse. In conclusion, the prevalence of HPV in men is high. The risk factors for HPV infection are sexual promiscuity, early sexual debut, absence of circumcision, lack of condom use and smoking. Further study in this field about the effectiveness of the vaccine and health education should be conducted.


Iodine-catalysed transfer hydrogenation of a carbon-carbon σ-bond with water.
Iodine catalysed the transfer hydrogenation of a benzylic C-C σ-bond in [2.2]paracyclophane with water to yield 4,4'-dimethylbibenzyl. The C-C σ-bond was first cleaved by homolytic substitution with iodine radicals to produce a 4,4'-diiodomethylbibenzyl intermediate. The benzylic C-I bonds in this intermediate were subsequently reduced by HI, generated in situ from the disproportionation of I2 with H2O, to achieve transfer hydrogenation and regenerate I2.


Quality of clinical practice guidelines for inadequate response to first-line treatment for depression according to AGREE II checklist and comparison of recommendations: a systematic review.
To assess similarities and differences in the recommended sequence of strategies among the most relevant clinical practice guidelines (CPGs) for the treatment of depression in adults with inadequate response to first-line treatment. We performed a systematic review of the literature spanning January 2011 to August 2020 in Medline, Embase, Cochrane Library and 12 databases recognised as CPGs repositories. CPGs quality was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II). The eligibility criteria were CPGs that described pharmacological recommendations for treating depression for individuals aged 18 years or older in outpatient care setting. We included CPGs considered of high-quality (≥80% in domain 3 of AGREE II) or recognised as clinically relevant. Two independent researchers extracted recommendations for patients who did not respond to first-line pharmacological treatment from the selected CPGs. We included 46 CPGs and selected 8, of which 5 were considered high quality (≥80% in domain 3 of AGREE II) and 3 were recognised as clinically relevant. Three CPGs did not define inadequate response to treatment and 3 did not establish a clear sequence of strategies. The duration of treatment needed to determine that a patient had not responded was not explicit in 3 CPGs and was discordant in 5 CPGs. Most CPGs agree in reassessing the diagnosis, assessing the presence of comorbidities, adherence to treatment, and increase dosage as first steps. All CPGs recommend psychotherapy, switching antidepressants, and considering augmentation/combining antidepressants. Relevant CPGs present shortcomings in recommendations for non-responders to first-line antidepressant treatment including absence and divergencies in definition of inadequate response and sequence of recommended strategies. Overall, most relevant CPGs recommend reassessing the diagnosis, evaluate comorbidities, adherence to treatment, increase dosage of antidepressants, and psychotherapy as first steps. CRD42016043364.


Excision of head and neck basal cell carcinoma with a rapid, cross-sectional, frozen-section technique.
To compare a rapid, cross-sectional frozen-section technique with Mohs micrographic surgery, using recurrence rate and cost of treatment for excision of basal cell carcinoma as indicators to validate our indications for Mohs surgery. Retrospective study of 557 head and neck basal cell carcinomas excised over 10 years. Recurrence rates; tumor comparisons by size, location, and subtype; a life table, and a patient satisfaction survey. Recurrence rate for the cross-sectional technique was 2.1% at 5 years. Recurrent tumors had an average diameter of 1.56 cm (vs 1.04 cm for nonrecurrent tumors). Recurrences were in the cheek (30%), nose (20%), temple (20%), forehead/brow (10%), conchal bowl (10%), and postauricular crease (10%). Recurrences were nodular cystic (40%), micronodular (20%), multifocal (10%), and infiltrating (30%). A total of 86.6% of patients surveyed rated the aesthetic outcome of their surgery favorably. The cost compared with the cost of Mohs excision varied depending on the Current Procedural Terminology coding technique. Cross-sectional frozen-section recurrence rates can compare favorably with Mohs micrographic surgery. The cross-sectional frozen-section technique generated a cost savings over Mohs surgery that may not hold true for all practice settings. Margin size did not adversely affect aesthetic results. Loupe magnification x2.5 is important in our technique. We also offer a useful definition for recurrence.


The Kata Kolok pointing system: morphemization and syntactic integration.
Signed utterances are densely packed with pointing signs, reaching a frequency of one in six signs in spontaneous conversations (de Vos, 2012; Johnston, 2013a; Morford & MacFarlane, 2003). These pointing signs attain a wide range of functions and are formally highly diversified. Based on corpus analysis of spontaneous pointing signs in Kata Kolok, a rural signing variety of Bali, this paper argues that the full meaning potentials of pointing signs come about through the integration of a varied set of linguistic and extralinguistic cues. Taking this hybrid nature of pointing phenomena into account, it is argued that pointing signs may become an intrinsic aspect of sign language grammars through two mechanisms: morphemization and syntactic integration. Although not entailed in this research, this approach could implicate that some highly systematized pointing systems of speaking communities may to a degree be grammatical as well.


Distinct fatty acid composition of some edible by-products from bovines fed high or low silage diets.
In the present study, it was hypothesized that the incorporation of fatty acids is distinct among ruminant tissues and that it could be modulated by diet composition. To test this hypothesis, fatty acid composition, including conjugated linoleic acid isomers, of the most relevant beef by-products (brain, heart, kidney, liver, pancreas and tongue) from young bulls those fed distinct silage levels was assessed. Data indicated a large variation in fatty acid profile and conjugated linoleic acid composition among edible by-products. The most abundant fatty acids were C16:0 (kidney), C18:0 (heart and liver) and C18:1 c9 (brain, pancreas and tongue) followed by C20:4 n-6, except in brain (C22:6 n-3 predominates). Brain, as shown by principal component analysis, presents a distinct fatty acid composition compared to the other beef by-products analysed. In addition, high silage diet relative to low silage diet promoted an increase of n-3 polyunsaturated fatty acid, t11, t13 and t11, c13 conjugated linoleic acid in heart, kidney, liver and pancreas. Overall, the data suggested that beef by-products had, in general, high contents of cholesterol, saturated fatty acid and trans fatty acid, as well as high levels of conjugated linoleic acid. Therefore, from a nutritional point of view they are recommended only in small amounts as part of a balanced diet.


Effects of suspended sulfates on human health.
Recent evidence from epidemiologic studies conducted in several areas of the United States shows an association of excess risk of asthmatic attacks with elevated levels of suspended sulfates within specific temperature ranges. These findings are disscussed in the context of experimental animal studies which tend to support these observations.


A colon cancer-derived mutant of Krüppel-like factor 5 (KLF5) is resistant to degradation by glycogen synthase kinase 3β (GSK3β) and the E3 ubiquitin ligase F-box and WD repeat domain-containing 7α (FBW7α).
Krüppel-like factor 5 (KLF5) is a zinc finger transcription factor that is highly expressed in the crypt epithelial cells of the intestine and plays a critical role in regulating proliferation of both normal intestinal epithelial cells and colorectal cancer cells. Stability of the KLF5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3β (GSK3β) and recognition by F-box and WD repeat domain-containing 7 (FBW7) of a phosphodegron sequence surrounding serine 303 in KLF5. A genomic analysis of colorectal cancer tissues identified a somatic mutation (P301S) in KLF5 within the phosphodegron sequence. We hypothesized that due to its close proximity to the phosphodegron sequence, the P301S mutation may affect signaling that is involved in proper KLF5 degradation. We demonstrated that the P301S KLF5 mutant has a longer half-life than wild type (WT) KLF5. Furthermore, P301S KLF5 has a higher transcriptional activity than WT KLF5 as demonstrated by luciferase assays using cyclin D1 and CDC2 promoter constructs. In contrast to WT KLF5, P301S KLF5 does not physically interact with FBW7α. Concomitantly, the P301S KLF5 mutant displays reduced levels of phosphorylation at serine 303 in comparison with WT KLF5. These results of our study indicate that amino acid residue 301 of KLF5 is critical for proper recognition of the phosphodegron sequence by FBW7α and that the P301S mutation inhibits this recognition, leading to a degradation-resistant protein with elevated levels and enhanced transcriptional activity. These findings raise a potentially oncogenic role for the P301S KLF5 mutant in colorectal cancer.


Multiphotoconductance Levels of the Organic Semiconductor of Polyimide-Based Memristor Induced by Interface Charges.
A memristor with Au/polyimide (PI)/Au structure is prepared by magnetron sputtering to investigate the multiphotoconductance resistive switching (RS) memory behavior. The PI-based memristor presents stable bipolar RS memory and is sensitive to visible light. Four discrete conductance states in both high-resistance state (HRS) and low-resistance state (LRS) are obtained when illuminating by 365, 550, 590, and 780 nm light. Electron trapping and detrapping from the defects distributed at interfaces and the PI switching layer are responsible for the observed RS memory behavior. The enhanced trapping and detrapping process by light illumination is responsible for the multiconductance states. This work provides the possibility for further development of neuromorphic vision sensors using an organic semiconductor-based memristor.


The medium and long-term effect of electrophysiologic monitoring on the facial nerve function in minimally invasive surgery treating acoustic neuroma.
The medium and long-term effects of electrophysiologic monitoring on the facial nerve function in minimally invasive surgery treating acoustic neuroma were studied. Sixty-two patients with acoustic neuroma taking minimally invasive surgeries in Dezhou Hospital from August 2014 to September 2015 were selected and randomly divided into 29 cases of the control group and 33 cases of the observation group. Intraoperative electrophysiologic monitoring was applied to the observation group, but not to the control group. The effects of the surgeries were compared. Comparisons on the surgical resection rate and the surgery length between two groups showed no statistical differences (P>0.05); the anatomical and functional preservation rate of facial nerves, as well as the score of survival quality in the observation group prominently proceeded that in the control group, and the differences were statistically significant (P>0.05). In conclusion, the application of the electrophysiologic monitoring on facial nerve function in minimally invasive surgery treating acoustic neuroma can effectively increase the anatomical and functional preservation rate of facial nerves, providing certain clinical significance to the improvement of living quality.


Gibberellic acid by solid state fermentation: Consistent and improved yields.
Five strains each of Gibberella fujikuroi and Fusarium monoliforme were screened to select G. fujikuroi P-3, a strain capable of giving consistent production of gibberellic acid (GA(3)) by solid state fermentation (SSF). The comparative production of GA(3) by SSF and submerged fermentation (SmF) indicated better productivity with the former technique. The accumulation of GA(3) was 1.626 times higher in the case of SSF. On the basis of available carbohydrates in the media, the percent conversions were 0.096 and 0.156 in SmF and SSF, respectively. The use of coarse wheat bran of the particle size of 0.3-0.4 cm resulted in an increase of 2.5 times in the yield of GA(3). The enrichment of commercial wheat bran with soluble starch gave enhanced accumulation to an extent of 3.5 times. The relation between GA(3) production and cell growth in SSF was similar to that encountered in SmF. The consistent and improved yields to a tune of 1.22 g GA(3) per kilogram dry moldy bran (DMB) establish the potential and feasibility of SSF for the production of GA(3) by G. fujikuroi P-3. On preliminary cost analysis, a net savings of about 60% and 50% on fermentation medium cost and the expenditure on down-stream processing, respectively, as compared to the presently employed SmF technique was evident.


Azobenzene C-Nucleosides for Photocontrolled Hybridization of DNA at Room Temperature.
Herein, we report the reversible light-regulated destabilization of DNA duplexes by using azobenzene C-nucleoside photoswitches. The incorporation of two different azobenzene residues into DNA and their photoswitching properties are described. These new residues demonstrate a photoinduced destabilization effect comparable to the widely applied D-threoninol-linked azobenzene switch, which is currently the benchmark. The photoswitches presented herein show excellent photoswitching efficiencies in DNA duplexes - even at room temperature - which are superior to commonly used azobenzene-based nucleic acid photoswitches. In addition, these photoswitching residues exhibit high thermal stability and excellent fatigue resistance, thus rendering them one of the most efficient candidates for the regulation of duplex stability with light.


Effectiveness of mRNA COVID-19 Vaccines in Japan during the Nationwide Pandemic of the Delta Variant.
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remained a major global health concern in 2021. To suppress the spread of infection, mass vaccinations have been performed across countries worldwide. In Japan, vaccinations of the first and second doses for most of the nation were performed during the nationwide outbreak of the B.1.617.2 (Delta) variant with the L452R spike protein mutation, and the effectiveness of the vaccinations to suppress the spread of COVID-19 among the people in Japan remains uncertain. In this study, adults aged ≥18 years, who were in contact with patients with COVID-19 and underwent nasopharyngeal swab reverse transcription-polymerase chain reaction (RT-PCR) tests during August and September 2021 at a mass screening test center in Japan, were enrolled. In this period, more than 95% of the COVID-19 infections were reportedly caused by the Delta variant. As a result, a total of 784 adults with recent contact history, including 231 (29.5%) RT-PCR test-positive cases, were enrolled. The test positivity rate was lower in individuals who had been vaccinated twice than in unvaccinated individuals (12.5% vs. 39.0%, p < 0.0001), with the risk ratio of 0.32 (95% confidence interval 0.23-0.46). The vaccine effectiveness was the highest between 7-90 days after the second vaccine dose. In conclusion, two doses of mRNA COVID-19 vaccines effectively suppressed transmission in Japan during the nationwide pandemic of the Delta variant, estimated to have prevented 50-80% of the infection.


Connexin Hemichannels Contribute to the Activation of cAMP Signaling Pathway and Renin Production.
Connexin hemichannels play an important role in the control of cellular signaling and behaviors. Given that lowering extracellular Ca2+, a condition that activates hemichannels, is a well-characterized stimulator of renin in juxtaglomerular cells, we, therefore, tested a potential implication of hemichannels in the regulation of renin in As4.1 renin-secreting cells. Lowering extracellular Ca2+ induced hemichannel opening, which was associated with cAMP signaling pathway activation and increased renin production. Blockade of hemichannels with inhibitors or downregulation of Cxs with siRNAs abrogated the activation of cAMP pathway and the elevation of renin. Further analysis revealed that cAMP pathway activation was blocked by adenylyl cyclase inhibitor SQ 22536, suggesting an implication of adenyl cyclase. Furthermore, the participation of hemichannels in the activation of the cAMP signaling pathway was also observed in a renal tubular epithelial cell line NRK. Collectively, our results characterized the hemichannel opening as a presently unrecognized molecular event involved in low Ca2+-elicited activation of cAMP pathway and renin production. Our findings thus provide novel mechanistic insights into the low Ca2+-initiated cell responses. Given the importance of cAMP signaling pathway in the control of multiple cellular functions, our findings also highlight the importance of Cx-forming channels in various pathophysiological situations.


Commentary: deconstructing gender difference.
In Japan, as in the United States, a growing proportion of physicians are women. Hence, the different social roles that men and women occupy and the gendered norms for behavior are increasingly relevant in ensuring that male and female physicians have equal opportunity to participate and advance in all aspects of medicine. Elsewhere in this issue, Nomura and colleagues report on a large survey of primary care residents in Japan. They found that on average women's self-rated confidence on many clinical tasks was lower than men's. This is not surprising given similar gender differences in self-assessed competence in other research and the socialization of women in virtually all cultures to be modest. The actual differences in average scores were small suggesting considerable overlap in the distributions of responses from male and female residents. In addition, research from other countries finds no association between physicians' self-reported confidence in clinical tasks and objective measures of competence on which female physicians rate at or above the level of their male counterparts. Congruent with different social roles for men and women, Nomura and colleagues also found gender differences in the average responses about work-family priorities and aspirations toward leadership, but some women indicated a desire for research careers and some men were "life-oriented." The author of this commentary argues that to draw conclusions about all male or all female physicians from average differences of a large group of residents may reinforce gender stereotypes that continue to impede each individual female physician's career advancement and each individual male physician's struggle for work-life balance.


Treatment Patterns and Characteristics of Individuals Initiating High-Dose Insulin for Type 2 Diabetes Mellitus.
Few studies have examined patient characteristics and treatment patterns of high-dose insulin therapy (> 200 units/day) among patients with type 2 diabetes mellitus (T2DM). To understand patient characteristics, dosing, adherence, and persistence related to high-dose insulin therapy. This was a retrospective observational study that used administrative claims from a large national health plan. Patients were identified who had been diagnosed with T2DM and who were aged 18-89 years, enrolled in a commercial or Medicare Advantage Prescription Drug plan, newly initiated on a total daily dose (TDD) > 200 units of insulin between January 2011 and August 2015. Patients were required to be enrolled 6 months before and 12 months after the index date. Patients were categorized to Regimen-100 if treated with U-100 insulin only or Regimen-500 if treated with U-500R with or without U-100. Baseline demographic and clinical characteristics were evaluated. An adjustment factor for the days supply was calculated as the ratio of median time between insulin claims, and median pharmacy reported days supply for each insulin prescription. Adjusted days supply, quantity, and concentration were used to calculate TDD for each quarter after the index date. Adherence was measured as the proportion of days covered (PDC) for each regimen. Persistence was measured in 2 ways: the percentage of patients remaining on index medications in each quarter and the proportion of patients who maintained TDD > 200 units during all 4 quarters of the 12-month post-index period. We identified 2,339 patients newly titrated up to TDD > 200 units on either Regimen-100 (2,062, 88.2%) or Regimen-500 (277, 11.8%). Patients on Regimen-500 were slightly younger with higher prevalence of comorbidities. The mean TDD (SD) for Regimen-100 decreased from 228.6 (36.0) units during the first quarter to 194.2 (181.4) units during the last quarter. The mean TDD (SD) for Regimen-500 increased from 294.2 (102.2) units in the first quarter to 304.8 (281.6) units in last quarter. The average adherence to the high-dose insulin regimen was 68.2% (30.7; median 72.6%) for the Regimen-100 cohort and 75.5% (27.0; median 85.2%) for the Regimen-500 cohort. In the Regimen-100 and Regimen-500 cohorts, 45.3% and 55.2% had a PDC ≥ 80%, respectively. Only 23.0% and 51.6% of patients maintained TDD > 200 units for the Regimen-100 and Regimen-500 cohorts, respectively, throughout the 4 quarters after the index date. We observed that many patients did not maintain high-dose insulin use over time, especially those on standard U-100 insulin only. This dosing pattern appears to reflect the differences in patient characteristics, insulin needs, and adherence/persistence behavior between those on Regimen-100 and those on Regimen-500. This study was supported by funding from Eli Lilly and Company to Humana as a collaborative research project involving employees of both companies. Chen, Brown, Fan, Taylor, and He are employees of Eli Lilly and Company. Nair and Meah are employees of Humana, which received funding to complete this research. Siadaty was an employee of Humana at the time of this study.