Delivery of DNAzyme targeting aurora kinase A to inhibit the proliferation and migration of human prostate cancer.
Herein, a polyethylenimine derivative N-acetyl-L-leucine-polyethylenimine (N-Ac-L-Leu-PEI) was employed as a carrier to achieve the delivery of DNAzyme targeting aurora kinase A using PC-3 cell as a model. Flow cytometry and confocal laser scanning microscopy demonstrated that the derivative could realize the cellular uptake of nanoparticles in an energy-dependent and clathrin-mediated pathway and obtain a high DNAzyme concentration in the cytoplasm through further endosomal escape. After DNAzyme transfection, expression level of aurora kinase A would be downregulated at the protein level. Meanwhile, the inhibition of cell proliferation was observed through 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and cell colony formation assay, attributing to the activation of apoptosis and cell cycle arrest. Through flow cytometric analysis, an early apoptotic ratio of 25.93% and G2 phase of 22.58% has been detected after N-Ac-L-Leu-PEI-mediated DNAzyme transfection. Finally, wound healing and Transwell migration assay showed that DNAzyme transfection could efficiently inhibit the cell migration. These results demonstrated that N-Ac-L-Leu-PEI could successfully mediate the DNAzyme delivery and downregulate the expression level of aurora kinase A, triggering a significant inhibitory effect of excessive proliferation and migration of tumor cells.


Accelerated Biologic Aging, Chronic Stress, and Risk for Sepsis and Organ Failure Following Trauma.
Chronic stress and accelerated aging have been shown to impact the inflammatory response and related outcomes like sepsis and organ failure, but data are lacking in the trauma literature. The purpose of this study was to investigate potential relationships between pretrauma stress and posttrauma outcomes. The hypothesis was that pretrauma chronic stress accelerates aging, which increases susceptibility to posttrauma sepsis and organ failure. In this prospective, correlational study, chronic stress and accelerated biologic aging were compared to the occurrence of systemic inflammatory response syndrome, sepsis, and organ failure in trauma patients aged 18-44 years. Results supported the hypothesis with significant overall associations between susceptibility to sepsis and accelerated biologic aging (n = 142). There were also significant negative associations between mean cytokine levels and chronic stress. The strongest association was found between mean interleukin-1β (IL-1β) and human telomerase reverse transcriptase (hTERT), r(101) = -0.28), p = .004. Significant negative associations were found between mean cytokine levels, IL-12p70, r(108) = -0.20, p = .034; and tumor necrosis factor-α (TNF-α), r(108) = -0.20, p = .033, and positive life events via the behavioral measure of chronic stress. Results may help identify individuals at increased risk for poor outcomes of trauma and inform interventions that may reduce the risk for sepsis and organ failure.


How Did the Village Community Perceive and Draw Strategies Against the COVID-19 Pandemic? A Qualitative Exploration.
Objectives There is a lack of evidence about the difficulties faced by the villagers and the mechanisms they adopt to cope with the ongoing coronavirus disease 19 (COVID-19) pandemic. In this study, we tried to explore the various stressors experienced by the villagers and the coping mechanisms. We also tried to document the future strategies that could be adopted to address the current pandemic situation. Methods An exploratory, descriptive qualitative study was conducted in five purposively selected villages in the Kolar district of South India. We conducted face-to-face in-depth interviews among nine key informants, including personnel across various health, education, and administrative domains. Two investigators carried out a manual descriptive content analysis to identify the codes and categories under three broad themes. A hybrid approach was used for coding the respondents' views in the most appropriate words/phrases. Results A total of 146 codes were identified and grouped into 19 different categories under three broad domains viz. 'stressors', 'coping strategies' and 'suggestions for future actions' for the existing COVID-19 pandemic. The stressors mainly were due to household level problems like finance management and familial disruptions. Coping mechanisms adopted include social capital, government support, judicial resource management, child marriages and apathetic attitude. The suggestions for future actions included an emphasis on the involvement of gram panchayats, adoption of the 'stay in village' concept, better communication framework and financial pooling for future exigencies. Conclusion The stressors due to COVID among villagers were mostly related to household level issues. The mechanisms adopted to cope up with the stressors included both positive and negative mechanisms. The suggestions for future actions mainly emphasized the involvement of gram panchayats.


Exoproteome Analysis of the Seaweed Pathogen Nautella italica R11 Reveals Temperature-Dependent Regulation of RTX-Like Proteins.
Climate fluctuations have been linked to an increased prevalence of disease in seaweeds, including the red alga Delisea pulchra, which is susceptible to a bleaching disease caused by the bacterium Nautella italica R11 under elevated seawater temperatures. To further investigate the role of temperature in the induction of disease by N. italica R11, we assessed the effect of temperature on the expression of the extracellular proteome (exoproteome) in this bacterium. Label-free quantitative mass spectrometry was used to identify 207 proteins secreted into supernatant fraction, which is equivalent to 5% of the protein coding genes in the N. italica R11 genome. Comparative analysis demonstrated that expression of over 30% of the N. italica R11 exoproteome is affected by temperature. The temperature-dependent proteins include traits that could facilitate the ATP-dependent transport of amino acid and carbohydrate, as well as several uncharacterized proteins. Further, potential virulence determinants, including two RTX-like proteins, exhibited significantly higher expression in the exoproteome at the disease inducing temperature of 24°C relative to non-inducing temperature (16°C). This is the first study to demonstrate that temperature has an influence exoproteome expression in a macroalgal pathogen. The results have revealed several temperature regulated candidate virulence factors that may have a role in macroalgal colonization and invasion at elevated sea-surface temperatures, including novel RTX-like proteins.


Cardiovascular fitness strengthening using portable device.
The paper describes a reliable and valid Portable Exercise Monitoring system developed using TI eZ430-Chronos watch, which can control the exercise intensity through audio stimulation in order to increase the Cardiovascular fitness strengthening.


Anaerobic bacteria in upper respiratory tract and other head and neck infections.
Anaerobic bacteria are common in chronic upper respiratory tract and head and neck infections. Anaerobes are the most predominant components of the normal human oropharyngeal bacterial flora, and are therefore a common cause of bacterial infections of the upper respiratory tract that are of endogenous origin. Because of their fastidious nature, anaerobes are difficult to isolate from infectious sites and are often overlooked. Anaerobic bacteria can be recovered in chronic otitis media and sinusitis, and play a role in tonsillitis. They are also important in complications of these infections. Anaerobes predominate in deep oral and neck infections and abscesses. In addition to their direct pathogenicity in these infections, they possess an indirect role through their ability to produce the enzyme beta-lactamase. In this fashion, they are capable of "shielding" non-beta-lactamase-producing bacteria from penicillins. The lack of directing adequate therapy against these organisms may lead to clinical failures. Their isolation requires appropriate methods of collection, transportation, and cultivation of specimens. Treatment of anaerobic infections is complicated by the slow growth of these organisms, by their polymicrobial nature, and by the growing resistance of anaerobic bacteria to antimicrobials. Antimicrobial therapy is often the only form of therapy required, whereas in other cases, it is an important adjunct to a surgical approach. Because anaerobic bacteria generally are recovered mixed with aerobic organisms, the choice of appropriate antimicrobial agents should provide for adequate coverage of both types of pathogens.


An unknown mechanism promotes somatic incompatibility in Ceratobasidium bicorne.
Strains of Ceratobasidium bicorne (anamorph uninucleate Rhizoctonia), causing root dieback in nursery-grown conifer seedlings, were fruited in the laboratory and the pairing interactions among sibling, single-basidiospore progeny were investigated. No mating reactions were observed. Instead, a high frequency of somatic incompatibility was observed in progeny pairings, indicated by a killing reaction in hyphal anastomosis and by formation of a demarcation line. The F1 progeny also could be fruited, and the level of somatic incompatibility within the F2 progeny remained high, even if lower than in the F1 progeny. The interaction types in pairings within a family of progeny were similar in all respects to those between field isolates, indicating that the species is homothallic. The uninucleate condition of vegetative cells and the basidial characteristics would indicate homokaryotic fruiting, but the possibility of pseudohomothallism remains. We currently are not able to provide an explanation for the mechanism promoting somatic incompatibility in this species, but it seems likely that the classic heterogenic model of somatic incompatibility recognized in basidiomycetes is not applicable here. Alternative mechanisms are discussed.


Nanobodies Are Potential Therapeutic Agents for the Ebola Virus Infection.
Ebola fever is an acute, highly contagious viral disease with a mortality rate that can reach 90%. There are currently no licensed therapeutic agents specific to Ebola in the world. Monoclonal antibodies (MAbs) with viral-neutralizing activity and high specificity to the Ebola virus glycoprotein (EBOV GP) are considered as highly effective potential antiviral drugs. Over the past decade, nanobodies (single-domain antibodies, non-canonical camelid antibodies) have found wide use in the diagnosis and treatment of various infectious and non-infectious diseases. In this study, a panel of nanobodies specifically binding to EBOV GP was obtained using recombinant human adenovirus 5, expressing GP (Ad5-GP) for alpaca (Vicugna pacos) immunization, for the first time. Based on specific activity assay results, affinity constants, and the virus-neutralizing activity against the recombinant vesicular stomatitis virus pseudotyped with EBOV GP (rVSV-GP), the most promising clone (aEv6) was selected. The aEv6 clone was then modified with the human IgG1 Fc fragment to improve its pharmacokinetic and immunologic properties. To assess the protective activity of the chimeric molecule aEv6-Fc, a lethal model of murine rVSV-GP infection was developed by using immunosuppression. The results obtained in lethal model mice have demonstrated the protective effect of aEv6-Fc. Thus, the nanobody and its modified derivative obtained in this study have shown potential protective value against Ebola virus.


Biophotons from stressed and dying organisms: toxicological aspects.
Cells and organisms exposed to detrimental and toxic substances show different responses in photon emission dependent on amount, kind and exposure time of toxin as well as on the organism investigated. Radical reaction-generating substances and dehydrating, lipid dissolving and protein denaturating toxins which do not induce direct chemiluminescence resulting from reactive oxygen species were applied. Lethal doses of toxins and stress factors such as osmotics and temperature evoke increase in the intensity of photon emission resulting from a rapid and irreversible perturbation of homeostasis. Bacterial and fungal toxins that elicit hypersensitive death of plant cells or defense response correlated with photon emission are also briefly discussed. Collective molecular interactions contribute to the photon-generating degradative processes in stressed and dying organisms. The measurements of biophoton signals and analysis of their parameters are used to elucidate the possible mechanisms of the toxin-organism interaction and the resistance of organisms. Toxicological perspectives of the use of these sensitive and rapid measurements as a part of direct toxicity assessment are discussed.


Recombinant human IL-16 inhibits HIV-1 replication and protects against activation-induced cell death (AICD).
The chemoattractant cytokine IL- 16 has been reported to suppress lymphocyte activation and to inhibit HIV-1 replication in acutely infected T cells. We have cloned and expressed human IL-16 in Escherichia coli and investigated whether the recombinant protein could regulate the level of lymphocyte apoptosis from HIV-1-infected subjects. After purification and refolding, only 2-10% of the recombinant cytokine was present in a biologically active homotetrameric form. This could explain the need for high concentrations of the bacterially derived IL- 16 to induce significant inhibition of HIV-1 replication. Addition of IL-16 to unstimulated peripheral blood mononuclear cell (PBMC) cultures from HIV-1-infected subjects did not modify the observed level of spontaneous lymphocyte apoptosis. In contrast, IL-16 added to PBMC cultures stimulated with anti-CD3, anti-CD95 or dexamethasone reduced significantly the percentage of lymphocytes undergoing AICD. This effect was found to correlate with the ability of the cytokine to decrease CD95 expression on activated CD4+ T cells. Comparative studies on PBMC from healthy individuals indicated that the regulation of apoptosis levels by IL-16 is a complex phenomenon and could depend on the nature of the activator used and/or the immune status of lymphocytes tested. The outcome of CD4 cross-linking on T cells by various ligands is discussed in the context of the observed beneficial activities of IL- 16 and its potential role in the treatment of HIV disease.


Evaluation of pulmonary systemic blood flow using ECG gated acquisition.
We propose a functional parametric analysis method using ECG-gated 99mTc-labeled red blood cell (RBC) imaging for detection and characterization of periodic variations in local blood activity in the lungs during cardiac cycle. We validated in animal experiments that such count variations correlate with cyclical pulmonary blood flow and may be used for evaluation of systemic-to-pulmonary shunts. Clinical studies were performed in 48 patients. After labeling the RBC pool with 99mTc, ECG-gated gamma camera images of both lung fields were acquired and processed to obtain Fourier transforms of time/activity functions in selected regions. The first harmonic parametric images of amplitude and phase were derived. There was an excellent correlation (r = 0.92) between activity variations and pulsatile flow measured by our method with that obtained by the thermodilution method in dog experiments (n = 10) after implantation of a systemic-to-pulmonary shunt. Patient studies showed the technique to be sensitive in detecting and quantifying abnormal systemic-to-pulmonary blood flow. Lung pulsatile flow can thus be noninvasively measured from functional parametric phase and amplitude images; the technique may be useful for detecting and quantifying abnormal systemic-to-pulmonary blood flow in man.


Thoracic Aorta: Anatomy and Pathology.
The aorta is the largest elastic artery in the human body and is classically divided into two anatomical segments, the thoracic and the abdominal aorta, separated by the diaphragm. The thoracic aorta includes the aortic root, the ascending aorta, the arch, and the descending aorta. The aorta's elastic properties depend on its wall structure, composed of three distinct histologic layers: intima, media, and adventitia. The different aortic segments show different embryological and anatomical features, which account for their different physiological properties and impact the occurrence and natural history of congenital and acquired diseases that develop herein. Diseases of the thoracic aorta may present either as a chronic, often asymptomatic disorder or as acute life-threatening conditions, i.e., acute aortic syndromes, and are usually associated with states that increase wall stress and alter the structure of the aortic wall. This review aims to provide an update on the disease of the thoracic aorta, focusing on the morphological substrates and clinicopathological correlations. Information on anatomy and embryology will also be provided.


Chest pain in pediatric patients presenting to a cardiac clinic.
Records of 67 pediatric patients with a primary complaint of chest pain were reviewed to determine the frequency of associated cardiac disease. Only four of 67 (6%) had chest pain associated with cardiac diseases that usually cause chest pain. Fifty-seven (85%) patients had chest pain in which no clear cause could be determined. Of these 57, 20 patients also had isolated congenital cardiac anomalies, i.e., atrial septal defect. A causal relationship of these lesions to the chest pain could not be established. Thirty-four of the 37 patients with chest pain and no cardiac abnormalities were evaluated by telephone at a mean of 13 months after their clinic assessment. Twenty-nine of the 34 were either asymptomatic or had reduced symptoms. There was no correlation between duration of symptoms prior to their clinical study and the persistence of chest pain at follow-up. From this study, we conclude that chest pain in pediatric patients is infrequently due to cardiac disease even when associated with previously unsuspected, isolated congenital cardiac lesions. Idiopathic chest pain tends to be self-limited.


Medical information concerning an infant's congenital anomaly: Successful communication to support parental adjustment and transition.
When a diagnosis of congenital anomaly (CA) is made, parents are confronted with new and complex medical information, which may impact their parental adjustment. However, few studies have explored the role of information concerning the CA in parental adjustment, during the transition to parenthood. This study aimed to characterize both parents' perceptions of information concerning the CA and to investigate their role in maternal and paternal adjustment, one month after the disclosure and six months post-birth. Thirty six couples whose infants were prenatally- or postnatally diagnosed with a CA participated in this prospective longitudinal study. During both assessment times (Time 1: one-month after the disclosure; Time 2: six-month post-birth), they answered the Brief Symptom Inventory-18, the EUROHIS-QOL-8, and other specific questions to assess parents' information perceptions. Mothers were more satisfied than fathers (p < .01) with the amount of information that was received at the disclosure, although mothers and fathers reported similar levels of comprehension of information. Six-month post-birth, both parents were similarly satisfied with the information that was received, although mothers sought significantly more (p < .01) additional information. Both maternal and paternal adjustment were significantly associated with maternal perceptions of information concerning CA. Health professionals should recognize the important role of information concerning CA in parental adjustment and tailor their communication practices in order to promote parents' satisfaction and comprehension of the medical information. Despite the prominent influence of maternal perceptions on parental adjustment, both parents should be included in the communication process.


Achieving Ultralow Fouling under Ambient Conditions via Surface-Initiated ARGET ATRP of Carboxybetaine.
We achieved ultralow fouling on target surfaces by controlled polymerization of carboxybetaine under ambient conditions. The polymerization process for grafting polymer films onto the surfaces was carried out in air and did not require any deoxygenation step or specialized equipment. This method allows one to conveniently introduce a nonfouling polymer network onto large substrates.


Apocytochrome c induces pH-dependent vesicle fusion.
The ability of apocytochrome c and the heme containing respiratory chain component, cytochrome c, to induce fusion of phosphatidylcholine (PC) small unilamellar vesicles containing 0-50 mol % negatively charged lipids was examined. Both molecules mediated fusion of phosphatidylserine (PS):PC 1:1 vesicles as measured by energy transfer changes between fluorescent lipid probes in a concentration- and pH-dependent manner, although cytochrome c was less potent and interacted over a more limited pH range than the apocytochrome c. Maximal fusion occurred at pH 3, far below the pKa of the 19 lysine groups contained in the protein (pI = 10.5). A similar pH dependence was observed for vesicles containing 50 mol % cardiolipin (CL), phosphatidylglycerol (PG), and phosphatidylinositol (PI) in PC but the apparent pKa values varied somewhat. In the absence of vesicles, the secondary structure of apocytochrome c was unchanged over this pH range, but in the presence of negatively charged vesicles, the polypeptide underwent a marked conformational change from random coil to alpha-helix. By comparing the pH dependencies of fusion induced by poly-L-lysine and apocytochrome c, we concluded that the pH dependence derived from changes in the net charge on both the vesicles and apocytochrome c. Aggregation could occur under conditions where fusion was imperceptible. Fusion increased with increasing mole ratio of PS. Apocytochrome c did induce some fusion of vesicles composed only of PC with a maximum effect at pH 4. Biosynthesis of cytochrome c involves translocation of apocytochrome c from the cytosol across the outer mitochondrial membrane to the outer mitochondrial space where the heme group is attached. The ability of apocytochrome c to induce fusion of both PS-containing and PC-only vesicles may reflect characteristics of protein/membrane interaction that pertain to its biological translocation.


The assembly of the major outer membrane protein OmpF of Escherichia coli depends on lipid synthesis.
Cerulenin, a drug which specifically blocks lipid synthesis, prevented both the trimerization of OmpF monomers and their assembly into the outer membrane of Escherichia coli B cells. A monoclonal antibody directed against a surface-exposed epitope of the trimer was used to probe the assembly of OmpF in the presence or absence of the drug. An inhibition level of 80% was reached 16 min after the addition of cerulenin. The accumulated monomeric form could not be assembled even after lipid synthesis was restored. Instead, it was slowly degraded. It was further shown that the inhibition of assembly resulted in a rapid inhibition of OmpF synthesis. These data demonstrate that there is a direct relationship between the synthesis of lipid (most likely lipopolysaccharide) and the correct export of OmpF. This coupling is required to promote the trimerization of the porin monomer and its assembly into the outer membrane.


Strategies to identify genes for complex diseases.
Genes underlie numerous human diseases and traits. Although we have witnessed a great deal of success in identifying disease-susceptible genes, the task remains challenging for most of the complex diseases. This paper reviews evidence for the role of genetic factors in complex diseases including breast cancer, diabetes and multiple sclerosis. We then describe strategies that can potentially optimize our chance of success in identifying genes involved in complex diseases. Advances in molecular biology, particularly mapping of the human genome, statistical methods that provide more accurate models of complex patterns of inheritance, and basic medical science, which have increased our understanding of disease pathophysiology, will ultimately strengthen the ability of the current generation of genetic epidemiological studies to identify the genetic basis of complex human disorders.


Type 2 diabetes and its correlates among adults in Bangladesh: a population based study.
Type 2 diabetes is one of the most prevalent non-communicable diseases in Bangladesh. However, the correlates of type 2 diabetes among adults in Bangladesh remain unknown. We aimed to investigate the correlates of type 2 diabetes among the adults in Bangladesh. We conducted a cross-sectional study using data from the nationally representative 2011 Bangladesh Demographic and Health Survey. A random sample of 7,543 (3,823 women and 3,720 men) adults of age 35 years and older from both urban and rural areas, who participated in the survey was included. Diabetes was defined as having a fasting plasma blood glucose level of ≥ 7 mm/L or taking diabetes medication during the survey. Hypothesized factors, e.g., age, sex, education, place of residence, social status, body mass index, and hypertension were considered in the analyses. Multivariable logistic regression models were used to identify the important correlates of type 2 diabetes. Among the respondents, the overall prevalence of diabetes was 11 %, and the prevalence was slightly higher in women (11.2 %) than men (10.6 %). Respondents with the age group of 55-59 years had higher odds of having diabetes (odds ratios (OR) = 2.37, 95 % confidence interval (CI): 1.76-3.21) than the age group of 35-39 years. Moreover, respondents who had higher educational attainment (OR = 1.67, 95 % CI: 1.18-2.36) and higher social status (OR = 2.01, 95 % CI: 1.50-2.70) had higher odds of having diabetes than the respondents with no education and lower social status, respectively. We also found socioeconomic status, place of residence (rural or urban), regions of residence (different divisions), overweight and obesity, and hypertension as significant correlates of type 2 diabetes in Bangladesh. Our study shows that older age, higher socioeconomic status, higher educational attainment, hypertension, and obesity were found to be significant correlates of type 2 diabetes. Need-based policy program strategies including early diagnosis, awareness via mass media, and health education programs for changing lifestyles should be initiated for older age, wealthy, and/or higher educated individuals in Bangladesh. Moreover, area-specific longitudinal research is necessary to find out the underlying causes of regional variations.


Kalirin Interacts with TRAPP and Regulates Rab11 and Endosomal Recycling.
Coordinated actions of Rab and Rho are necessary for numerous essential cellular processes ranging from vesicle budding to whole cell movement. How Rab and Rho are choreographed is poorly understood. Here, we report a protein complex comprised of kalirin, a Rho guanine nucleotide exchange factor (GEF) activating Rac1, and RabGEF transport protein particle (TRAPP). Kalirin was identified in a mass spectrometry analysis of proteins precipitated by trappc4 and detected on membranous organelles containing trappc4. Acute knockdown of kalirin did not affect trappc4, but significantly reduced overall and membrane-bound levels of trappc9, which specifies TRAPP toward activating Rab11. Trappc9 deficiency led to elevated expression of kalirin in neurons. Co-localization of kalirin and Rab11 occurred at a low frequency in NRK cells under steady state and was enhanced upon expressing an inactive Rab11 mutant to prohibit the dissociation of Rab11 from the kalirin-TRAPP complex. The small RNA-mediated depletion of kalirin diminished activities in cellular membranes for activating Rab11 and resulted in a shift in size of Rab11 positive structures from small to larger ones and tubulation of recycling endosomes. Our study suggests that kalirin and TRAPP form a dual GEF complex to choreograph actions of Rab11 and Rac1 at recycling endosomes.


Rhodium-catalyzed intramolecular formation of N-sulfamoyl 2,3-aziridino-γ-lactones and their use for the enantiospecific synthesis of α,β-diamino acid derivatives.
4-Hydroxymethylbutenolide 4 was transformed into its sulfamoyl derivative 5, which upon treatment with iodosobenzene diacetate and magnesium oxide in the presence of a rhodium catalyst afforded the product of intramolecular aziridination 6. Reaction of 6 with primary or secondary amines in DMA led to regioselective opening of the aziridine ring at C2 to give the corresponding bicyclic derivatives 7a-7g in good to excellent yields. Methanolysis of the lactone ring of the N-benzyl-N-methyl derivative 7c followed by protection of the resulting secondary hydroxy group and treatment of the product with Boc anhydride provided the activated cyclic sulfamates 13 and 14. The latter then reacted with a second nucleophile (azide or thiophenol) to give the corresponding difunctionalized α,β-diamino methyl esters 15-18, 20.


The influence of mechanical stimulation on osteocyte apoptosis and bone viability in human trabecular bone.
It has been shown previously using in vivo and ex vivo animal models, that cyclical mechanical stimulation is capable of maintaining osteocyte viability through the control of apoptotic cell death. Here we have studied the effect of mechanical stimulation on osteocyte viability in human trabecular bone maintained in a 3-D bioreactor system. Bone samples, maintained in the bioreactor system for periods of 3, 7 and 27 days, were subjected to either cyclical mechanical stimulation which engendered a maximum of 3,000 microstrain in a waveform corresponding to physiological jumping exercise for 5 minutes daily or control unloading. Unloading resulted in a decrease in osteocyte viability within 3 days that was accompanied by increased levels of cellular apoptosis. Mechanical stimulation significantly reduced apoptosis (p< or =0.032) and improved the maintenance of osteocyte viability in bone from all patient samples. The percentage Alkaline Phosphatase (ALP) labelled bone surface was significantly increased (p< or =0.05) in response to mechanical stimulation in all samples as was the Bone Formation Rate (BFR/BS) (p=0.005) as determined by calcein label incorporation in the 27-day experiment. These data indicate that in this model system, mechanical stimulation is capable of maintaining osteocyte viability in human bone.


Inclusion body myositis - pathomechanism and lessons from genetics.
Inclusion body myositis is a rare, late-onset myopathy. Both inflammatory and myodegenerative features play an important role in their pathogenesis. Overlapping clinicopathological entities are the familial inclusion body myopathies with or without dementia. These myopathies share several clinical and pathological features with the sporadic inflammatory disease. Therefore, better understanding of the genetic basis and pathomechanism of these rare familial cases may advance our knowledge and enable more effective treatment options in sporadic IBM, which is currently considered a relentlessly progressive incurable disease.


Additive or non-additive effect of mixing oak in pine stands on soil properties depends on the tree species in Mediterranean forests.
This study investigated how oak abundance in pine stands (using relative Oak Basal Area %, OBA%) may modulate soil microbial functioning. Forests were composed of sclerophyllous species i.e. Quercus ilex mixed with Pinus halepensis Miller or of Q. pubescens mixed with P. sylvestris. We used a series of plots with OBA% ranging from 0 to 100% in the two types of stand (n=60) and both OLF and A-horizon compartments were analysed. Relations between OBA% and either soil chemical (C and N contents, quality of organic matter via solid-state NMR, pH, CaCO3) or microbial (enzyme activities, basal respiration, biomass and catabolic diversity via BIOLOG) characteristics were described. OBA% increase led to a decrease in the recalcitrant fraction of organic matter (OM) in OLF and promoted microbial growth. Catabolic profiles of microbial communities from A-horizon were significantly modulated in Q. ilex and P. halepensis stand by OBA% and alkyl C to carboxyl C ratio (characteristic of cutin from Q. ilex tissues) and in Q. pubescens and P. sylvestris stands, by OBA% and pH. In A-horizon under Q. ilex and P. halepensis stands, linear regressions were found between catabolic diversity, microbial biomass and OBA% suggesting an additive effect. Conversely, in A-horizon Q. pubescens and P. sylvestris stands, the relationship between OBA% and either cellulase activities, polysaccharides or ammonium contents, suggested a non-additive effect of Q. pubescens and P. sylvestris, enhancing mineralization of the OM labile fraction for plots characterized by an OBA% ranging from 40% to 60%. Mixing oak with pine thus favored microbial dynamics in both type of stands though OBA% print varied with tree species and consequently sustainable soil functioning depend strongly on the composition of mixed stands. Our study indeed revealed that, when evaluating the benefits of forest mixed stand on soil microbial functioning and OM turnover, the identity of tree species has to be considered.


Fast visible imaging of turbulent plasma in TORPEX.
Fast framing cameras constitute an important recent diagnostic development aimed at monitoring light emission from magnetically confined plasmas, and are now commonly used to study turbulence in plasmas. In the TORPEX toroidal device [A. Fasoli et al., Phys. Plasmas 13, 055902 (2006)], low frequency electrostatic fluctuations associated with drift-interchange waves are routinely measured by means of extensive sets of Langmuir probes. A Photron Ultima APX-RS fast framing camera has recently been acquired to complement Langmuir probe measurements, which allows comparing statistical and spectral properties of visible light and electrostatic fluctuations. A direct imaging system has been developed, which allows viewing the light, emitted from microwave-produced plasmas tangentially and perpendicularly to the toroidal direction. The comparison of the probability density function, power spectral density, and autoconditional average of the camera data to those obtained using a multiple head electrostatic probe covering the plasma cross section shows reasonable agreement in the case of perpendicular view and in the plasma region where interchange modes dominate.


Four Isoforms of Arabidopsis 4-Coumarate:CoA Ligase Have Overlapping yet Distinct Roles in Phenylpropanoid Metabolism.
The biosynthesis of lignin, flavonoids, and hydroxycinnamoyl esters share the first three enzymatic steps of the phenylpropanoid pathway. The last shared step is catalyzed by 4-coumarate:CoA ligase (4CL), which generates p-coumaroyl CoA and caffeoyl CoA from their respective acids. Four isoforms of 4CL have been identified in Arabidopsis (Arabidopsis thaliana). Phylogenetic analysis reveals that 4CL1, 4CL2, and 4CL4 are more closely related to each other than to 4CL3, suggesting that the two groups may serve different biological functions. Promoter-GUS analysis shows that 4CL1 and 4CL2 are expressed in lignifying cells. In contrast, 4CL3 is expressed in a broad range of cell types, and 4CL3 has acquired a distinct role in flavonoid metabolism. Sinapoylmalate, the major hydroxycinnamoyl ester found in Arabidopsis, is greatly reduced in the 4cl1 4cl3 mutant, showing that 4CL1 and 4CL3 function redundantly in its biosynthesis. 4CL1 accounts for the majority of the total 4CL activity, and loss of 4CL1 leads to reduction in lignin content but no growth defect. The 4cl1 4cl2 and 4cl1 4cl2 4cl3 mutants are both dwarf but do not have further reduced lignin than the 4cl1 mutant, indicating that either 4CL1 or 4CL2 is required for normal plant growth. Although 4CL4 has a limited expression profile, it does make a modest contribution to lignin biosynthesis. Together, these data show that the four isoforms of 4CL in Arabidopsis have overlapping yet distinct roles in phenylpropanoid metabolism.


Isolation of monodisperse nanodisc-reconstituted membrane proteins using free flow electrophoresis.
Free flow electrophoresis is used for rapid and high-recovery isolation of homogeneous preparations of functionally active membrane proteins inserted into nanodiscs. The approach enables isolation of integral and membrane anchored proteins and is also applicable following introduction of, e.g., fluorescent tags. Preparative separation of membrane protein loaded nanodiscs from empty nanodiscs and protein aggregates results in monodisperse nanodisc preparations ideal for structural and functional characterization using biophysical methods.


Use of blood donation history of people with HIV infection to identify recipients at risk.
To determine whether previous blood donations from HIV-positive patients posed a threat to recipients. Interviewer-administered questionnaire survey. Regional HIV outpatient referral clinic for southern Alberta. All 478 patients attending the clinic from May 1, 1993, to Mar. 31, 1994; 366 were excluded: 335 had not donated blood, and 31 could not provide reliable information regarding possible donations. Patients were asked at a routine clinic visit regarding the dates, frequency and location of previous blood donations. The Canadian Red Cross was informed, with patient consent, if the previous donations posed a potential risk of HIV transmission. Number of HIV-positive patients whose donations posed a possible or definite risk to recipients. A total of 545 units of blood had been donated by the 112 patients in the study; 57 units (donated by 29 patients) posed a possible risk, and 12 (given by 11 patients) posed a definite risk of HIV transmission to the recipients. Thirty-two of these donors had been unknown to the Red Cross through its "look-back" and "trace-back" protocols. Only 1 of the 13 patients found to be HIV positive by the Red Cross openly admitted donating blood to undergo HIV antibody testing; the remainder were either ill-informed or did not perceive themselves to be at risk. The patients were highly mobile, 36.7% donating blood at some time in a province other than the one where they had received their positive HIV test result. Asking HIV-positive patients about their blood donation history, although subject to recall bias, is a simple and inexpensive method for identifying high-risk blood donations. The Red Cross should routinely be notified, with patient consent, of all donations posing a risk in order to enhance the prospect for identifying HIV-positive blood recipients.


SPARE: Sparse-view reconstruction challenge for 4D cone-beam CT from a 1-min scan.
Currently, four-dimensional (4D) cone-beam computed tomography (CBCT) requires a 3-4 min full-fan scan to ensure usable image quality. Recent advancements in sparse-view 4D-CBCT reconstruction have opened the possibility to reduce scan time and dose. The aim of this study is to provide a common framework for systematically evaluating algorithms for 4D-CBCT reconstruction from a 1-min scan. Using this framework, the AAPM-sponsored SPARE Challenge was conducted in 2018 to identify and compare state-of-the-art algorithms. A clinically realistic CBCT dataset was simulated using patient CT volumes from the 4D-Lung database. The selected patients had multiple 4D-CT sessions, where the first 4D-CT was used as the prior CT, and the rest were used as the ground truth volumes for simulating CBCT projections. A GPU-based Monte Carlo tool was used to simulate the primary, scatter, and quantum noise signals. A total of 32 CBCT scans of nine patients were generated. Additional qualitative analysis was performed on a clinical Varian and clinical Elekta dataset to validate the simulation study. Participants were blinded from the ground truth, and were given 3 months to apply their reconstruction algorithms to the projection data. The submitted reconstructions were analyzed in terms of root-mean-squared-error (RMSE) and structural similarity index (SSIM) with the ground truth within four different region-of-interests (ROI) - patient body, lungs, planning target volume (PTV), and bony anatomy. Geometric accuracy was quantified as the alignment error of the PTV. Twenty teams participated in the challenge, with five teams completing the challenge. Techniques involved in the five methods included iterative optimization, motion-compensation, and deformation of the prior 4D-CT. All five methods rendered significant reduction in noise and streaking artifacts when compared to the conventional Feldkamp-Davis-Kress (FDK) algorithm. The RMS of the three-dimensional (3D) target registration error of the five methods ranged from 1.79 to 3.00 mm. Qualitative observations from the Varian and Elekta datasets mostly concur with those from the simulation dataset. Each of the methods was found to have its own strengths and weaknesses. Overall, the MA-ROOSTER method, which utilizes a 4D-CT motion model for temporal regularization, had the best and most consistent image quality and accuracy. The SPARE Challenge represents the first framework for systematically evaluating state-of-the-art algorithms for 4D-CBCT reconstruction from a 1-min scan. Results suggest the potential for reducing scan time and dose for 4D-CBCT. The challenge dataset and analysis framework are publicly available for benchmarking future reconstruction algorithms.


Anthocyanins: Multi-Target Agents for Prevention and Therapy of Chronic Diseases.
Anthocyanins, a flavonoid class of polyphenols, are water soluble dark colored natural pigments found in fruits and vegetables. Owing to their wide distribution in plant materials, dietary consumption of anthocyanins is high compared to other flavonoids. Anthocyanins, due to their multifaceted medicinal properties are the active components in many herbal folk medicines. As in vitro and in vivo results, animal models, and clinical trials in various cell lines suggest, anthocyanins possess antioxidant, antidiabetic, antihyperlipidemic, anti-inflammatory, anticarcinogenic, antiulcer, and preventive activities against cardiovascular diseases. Additionally, anthocyanins exhibit chemotherapeutic, cardioprotective, hepatoprotective, and neuroprotective activities. In the diet, anthocyanins are absorbed in the stomach and intestinal cells and rapidly detected in the plasma. These promising properties of anthocyanins may well provide health benefits against chronic diseases.


Parental bonding in males with adjustment disorder and hyperventilation syndrome.
The purpose of the study was to identify the style of parental bonding and the personality characteristics that might increase the risk of hyperventilation and adjustment disorder. A total of 917 males were recruited, 156 with adjustment disorder and hyperventilation syndrome (AD + HY), 273 with adjustment disorder without hyperventilation syndrome (AD-HY), and 488 healthy controls. All participants completed the Parental Bonding Instrument, Eysenck Personality Questionnaire, and Chinese Health Questionnaire. Analysis using structural equation models identified a pathway relationship in which parental bonding affected personality characteristics, personality characteristics affected mental health condition, and mental health condition affected the development of hyperventilation or adjustment disorder. Males with AD-HY perceived less paternal care, and those with AD + HY perceived more maternal protection than those with adjustment disorder and those in the control group. Participants with AD-HY were more neurotic and less extroverted than those with AD + HY. Both groups showed poorer mental health than the controls. Although some patients with hyperventilation syndrome demonstrated symptoms of adjustment disorder, there were different predisposing factors between the two groups in terms of parental bonding and personality characteristics. This finding is important for the early intervention and prevention of hyperventilation and adjustment disorder.


siRNA Targeting of MDR1 Reverses Multidrug Resistance in a Nude Mouse Model of Doxorubicin-resistant Human Hepatocellular Carcinoma.
To investigate the effects of vector-based small interfering RNA (siRNA) targeting MDR1 on the reversal of multidrug resistance in a mouse model of doxorubicin (DOX)-resistant human hepatocellular carcinoma. Three siRNAs plasmid vectors (MDR1 siRNA1, MDR1 siRNA2 and MDR1 siRNA3) targeting MDR1 were constructed and transfected into DOX-resistant human hepatocellular carcinoma Bel-7402/ADM cells. The expression of MDR1 mRNA and P-glycoprotein (P-gp) was detected with RT-PCR and western blotting, respectively. A nude mouse model of DOX-resistance was established with untransfected Bel-7402/ADM or Bel-7402/ADM transfected with MDR1 siRNA (Bel-7402/ADMsi). The nude mice with tumors from untransfected Bel-7402/ADM cells were treated with either saline (Group 1); intravenous DOX (Group 2); or the combination of intra-tumoral MDR1 siRNA and intravenous DOX (Group 3). The nude mice with tumors from Bel-7402/ADMsi cells were treated with intravenous DOX (Group 4). DOX and MDR1 siRNA were administered twice a week at 20 mg/kg/dose and 9.8 mg/kg/dose, respectively. Tumor growth was measured to assess reversal of multidrug resistance by MDR1 siRNA. MDRl mRNA and P-gp expression of Bel-7402/ADM cells was reduced by transfection of three siRNAs with different silencing efficiency (p<0.05). DOX treatment (Group 4) resulted in significant reduction in tumor size in the Bel-7402/ADMsi tumor model (p<0.05), indicating reversal of multidrug resistance in tumor by MDR1 siRNA. However, the combination treatment of intratumoral MDR1 siRNA and DOX (Group 3) showed no significant anti-tumor efficacy in the untransfected Bel-7402/ADM (p>0.05) tumor model, suggesting poor in vivo transfection efficiency of MDR1 siRNA. Analysis of the tumor samples showed the reduced expression level of MDR1 mRNA and P-gp was due to efficacy of MDR1 siRNA. In vitro transfection of siRNAs' vectors targeting the MDR1 gene can effectively silence MDR1 mRNA and P-gp expression in DOX-resistant human hepatocellular carcinoma Bel-7402/ADM cells that resulted in reversal of multidrug resistance to DOX in the xenograft tumor model.


Kinetics of proton transfer from cationic carbon acids in water and aqueous DMSO. Effect of activating groups and solvent on intrinsic rate constants.
[reaction: see text] Acidity constants and rates of reversible deprotonation of acetonyltriphenylphosphonium ion (1H+), phenacyltriphenylphosphonium ion (2H+), N-methyl-4-phenacylpyridinium ion (3H+), and N-methyl-4-(phenylsulfonylmethyl)pyridinium ion (4H+) by amines in water, 50% DMSO-50% water (v/v), and 90% DMSO-10% water (v/v) have been determined. From the respective Brønsted plots, log k(o) values for the intrinsic rate constants of the various proton transfers were obtained. Solvent transfer activity coefficients of the carbon acids and their respective conjugate bases were also determined which helped in understanding how the pKa values and intrinsic rate constants depend on the solvent. Some of the main conclusions are as follows: (1) The pK(a) values of 1H+, 2H+, and 3H+ are significantly higher than that of 4H+ because of a stronger resonance stabilization of the corresponding conjugate bases 1, 2 and 3, respectively. (2) The electronic effects of the PPh3+ and the N-methyl-4-pyridylium group are similar but the mix between inductive and resonance effect is different. (3) All four acids become more acidic upon addition of DMSO to the solvent. In all cases, the main factor is the stronger solvation of H3O+ in DMSO; for 1H+, 2H+, and 3H+ but not 4H+ this factor is significantly attenuated by stronger solvation of the carbon acid in DMSO. (4) The intrinsic rate constants for proton transfer are relatively high for all four carbon acids and show little solvent dependence; this contrasts with nitroalkanes which have much lower intrinsic rate constants and show a strong solvent dependence. These results can be understood by a detailed analysis of the interplay between inductive, resonance, and solvation effects.


National Trends in American Heart Association Revised Life's Simple 7 Metrics Associated With Risk of Mortality Among US Adults.
The American Heart Association (AHA) introduced the Life's Simple 7 (LS7) metrics to assess and promote cardiovascular health. However, several shortcomings of these metrics have been identified. Therefore, a revised set of LS7 metrics was developed. To evaluate national trends in the metrics addressed by the revised LS7 and the individual and combined associations of the revised LS7 metrics with all-cause and cause-specific mortality and to compare these measures with the AHA recommended LS7 metrics. This national cross-sectional study used data from the National Health and Nutrition Examination Survey from 1988 to 2016. The revised LS7 metrics included a combination of the body mass index and waist to hip ratio, Healthy Eating Index-2010, and a lower blood pressure threshold of greater than or equal to 130/80 mm Hg in addition to physical activity, smoking, total cholesterol, and fasting blood glucose. Data for this study were analyzed from June 1, 2017, to December 31, 2017. The primary outcome was all-cause mortality. The secondary outcome was cancer and cardiovascular disease (CVD) mortality. Data were available for 13 606 adults in 1988 to 1994 (7329 [53%] female; mean [SD] age, 47 [17.7] years), 6360 in 1999 to 2004 (3442 [54%] female; mean [SD] age, 47 [18.6] years), 10 618 in 2005 to 2010 (5428 [51%] female; mean [SD] age, 47 [17.5] years), and 10 773 in 2011 to 2016 (5474 [50%] female; mean [SD] age, 48 [17.4] years). Compared with a revised LS7 score of 0 to 1, the adjusted hazard ratios for a revised LS7 score of 5 to 7 were 0.46 (95% CI, 0.35-0.61) for all-cause mortality, 0.42 (95% CI, 0.25-0.68) for cancer mortality, and 0.37 (95% CI, 0.24-0.55) for CVD mortality, respectively. The adjusted hazard ratios for participants who met 6 or more AHA recommended ideal LS7 metrics were 0.49 (95% CI, 0.33-0.74) for all-cause mortality, 0.60 (95% CI, 0.29-1.25) for cancer mortality, and 0.24 (95% CI, 0.13-0.47) for CVD mortality. Participants with a body mass index of 29.9 or less but without central obesity were independently associated with lower risk of all-cause and CVD mortality. Blood pressure was associated with 36.7% or more of the observed population-attributable fraction of mortality. The individual revised LS7 metrics with modified criteria regarding weight, blood pressure, and diet provide more information about factors associated with cancer mortality than the original AHA LS7 metrics.


Identification of drought tolerant mechanisms in a drought-tolerant maize mutant based on physiological, biochemical and transcriptomic analyses.
Frequently occurring drought stress negatively affects the production of maize worldwide. Numerous efforts have been made to develop drought-tolerant maize lines and to explore drought tolerant mechanisms in maize. However, there is a lack of comparative studies on transcriptomic changes between drought-tolerant and control maize lines. In the present study, we have developed a drought-tolerant maize mutant (C7-2t) by irradiating the seeds of maize inbred line ChangC7-2 (C7-2) with 60Co-γ. Compared to its wild type C7-2, C7-2t exhibited a significantly delayed wilting and higher drought tolerance under both the controlled and field conditions, indicating its high water-holding ability. Transcriptomic profiling was performed to identify differentially expressed genes (DEGs) between C7-2 and C7-2t during drought. As a result, a total of 4552 DEGs were implied in drought tolerance of C7-2 and C7-2t. In particular, the expression of photosynthesis-related genes in C7-2 was inhibited, whereas these genes in C7-2t were almost unaffected under drought. Moreover, a specific set of the DEGs were involved in phenylpropanoid biosynthesis and taurine (hypotaurine) metabolism in C7-2t; these DEGs were enriched in cell components associated with membrane systems and cell wall biosynthesis. The drought tolerance of C7-2t was largely due to its high water-holding ability, stable photosynthesis (for supporting osmoregulation) and strengthened biosynthesis of cell walls under drought conditions.


White Matter Microstructural Alterations over the Year after Acute Ischemic Stroke in Patients with Baseline Impaired Cognitive Functions.
The disruption of white matter (WM) integrity is related to poststroke cognitive impairment (PSCI). The exploration of WM integrity alterations in the chronic stage of acute ischemic stroke (AIS) may help to improve the long-term outcomes of PSCI. Sixty patients showing impaired cognitive functions within 3 days after AIS (baseline) and 25 healthy controls underwent diffusion kurtosis imaging scan and cognitive assessment at baseline and 1 year. Based on the tract-based spatial statistics (TBSS), kurtosis fractional anisotropy (KFA) and mean kurtosis (MK) were compared in WM tracts between the groups. One year after AIS, 25 patients were diagnosed with PSCI and 35 patients with non-cognitive impairment (NCI). Compared with baseline, cognitive performance improved in 54 patients and remained unchanged in 6 patients at 1 year. TBSS analysis showed that there were no significant differences in WM tract integrity between the AIS and control groups at baseline (P > 0.05). Compared with the control group, the KFA and MK in multiple WM tracts in the AIS group decreased significantly at 1 year (P < 0.05). Longitudinal analysis showed that the KFA and MK of multiple WM tracts recorded at 1 year were significantly lower than those recorded at baseline in the AIS, PSCI, and NCI groups (P < 0.05), and PSCI group had a faster degeneration than NCI group (P < 0.05). The finding suggests that the patients with baseline impaired cognitive functions still have WM microstructural damages at 1 year poststroke, even if their cognitive function has improved or returned to normal. Cautions should be taken against the possible negative impact of these changes on long-term cognition.


Violence and mental illness: a new analytic approach.
Empirical studies of violence and mental illness have used many different methods. Current state-of-the-art methods gather information from both subject and collateral interviews as well as official records. Typically these sources are treated as additive. Any report of a violent incident from any source is treated as true and all reported incidents are added to generate estimates of frequency. This paper presents a new statistical technique that uses the level of agreement between the sources of data to adjust those estimates. The evidence suggests that, although the additive technique for using multiple sources correctly estimates how many people are involved, it substantially underestimates the number of incidents. The new technique substantially reduces both false negatives and false positives.


[Preventive antibiotic administration for prevention of nosocomial septicemia in very small premature infants (VLBW infants)--preventive vancomycin administration against infections with coagulase negative streptococci--prevention of translocation with oral cefixime therapy in intestinal colonization with pathogenic gram-negative pathogens].
VLBW-infants below 1500 g of birth weight have a quite high risk to acquire a nosocomial sepsis. 20-40% of all infants exhibit signs of nosocomial infection once during neonatal intensive care. The rate of infection is related to technique and amount of used invasive devices as to gestational age. Coagulase-negative staphylococci (CONS) and gram-negative organisms contribute most to these cases of sepsis. In a three phase study we tried to demonstrate the efficacy of different mechanisms to change the rate of nosocomial sepsis. During the first phase a strict hygienical protocol was enforced as isolation, care with sterile gloves and aseptic techniques in introducing and maintaining i.v. lines. In a second phase we started a randomized controlled study of prophylactic vancomycin (10 mg/kg/day in two doses). In a third phase we added an oral antibiotic regime with cefixime for all patients with positive cultures for gramnegative organisms under the hypothesis of translocation from the gut as the way of infection. During the first phase 23.7% of 76 patients enrolled acquired CONS-sepsis, 0.52% gramnegative sepsis. During the second phase (41 patients) 6 patients in the control group acquired CONS-sepsis, none in the vancomycin-group. The rate of gramnegative infections was not different (4 and 3 cases). During the third phase (vancomycin plus cefixime eventually in cases of positive stool cultures) no case of nosocomial sepsis occurred (35 patients, 11 positive cultures). The management used in phase 3 reduced the rate of nosocomial infections in VLBW-infants drastically.


[The autocrine-paracrine modulation of natural killer activity in man by peptides of the corticostatin-defensin family].
Corticostatins (CS)-defensins are a family of peptides recently isolated from neutrophils and cells of myeloid lineage. They have been termed CS in that members of the family inhibit ACTH-induced steroidogenesis, and defensins in that they are highly effective as enhancers of intracellular killing of pathogens. Natural killer (NK) cells are an immunocyte subset whose cytotoxic activity is modulated by lymphokines and hormones. Recent evidence suggests a myeloid origin for these cells. We evaluated whether two human CS-defensins, HP-1 and HP-4, are able to modulate in vitro spontaneous NK cell activity of human peripheral blood mononuclear (PBM) cells and in vitro susceptibility to the stimulatory effect by immune interferon (IFN-gamma) or interleukin 2 (IL-2) and to the inhibitory effect of cortisol. PBM cells were incubated for 20 h with HP-1 or HP-4 and IFN-gamma or IL-2 or cortisol. NK cell activity was measured in a 4-h direct cytotoxicity assay (K562 cells as a target). We also searched for CS-defensins in NK-enriched cell preparations by means of HPLC separation of the supernatant obtained from sonicated cells. HP-1 and HP-4 significantly inhibited both spontaneous and lymphokine-inducible NK cell activity, and potentiated cortisol-dependent inhibition. Radioimmunoassay on HPLC purified fractions demonstrated the presence of HP-1 in NK-enriched cell preparations. Our data indicate that HP-1 and HP-4 are negative modulators of NK cell cytotoxicity and that autocrine/paracrine mechanisms are conceivably involved. HP-1 production by NK cells may be viewed as additional support for the thesis of the myeloid origin of these immune effectors.


Fusion of mass spectrometry-based metabolomics data.
A general method is presented for combining mass spectrometry-based metabolomics data. Such data are becoming more and more abundant, and proper tools for fusing these types of data sets are needed. Fusion of metabolomics data leads to a comprehensive view on the metabolome of an organism or biological system. The ideas presented draw upon established techniques in data analysis. Hence, they are also widely applicable to other types of X-omics data provided there is a proper pretreatment of the data. These issues are discussed using a real-life metabolomics data set from a microbial fermentation process.


Nonmelanoma Skin Cancers After Kidney Transplant: Our 15 Years of Experience With Mammalian Target of Rapamycin Inhibitors.
We evaluated patients with nonmelanoma skin cancer after kidney transplant and the effects of immunosuppression reduction and switching to a mammalian target of rapamycin inhibitor drugs. Kidney transplant recipients were evaluated retrospectively from patient medical records (between January 2000 and December 2014). A 30% increase in serum creatinine was accepted as indicating renal failure progression. Of 18 patients included (mean follow-up 98 ± 66 mo), 7 (38.8%) had squamous cell carcinoma, 7 (38.8%) had Kaposi sarcoma, and 4 (22.2%) had basal cell carcinoma. At cancer diagnosis, average serum creatinine was 1.6 ± 0.7 mg/dL and proteinuria was 410 ± 766 mg/d. Immunosuppression regimen was changed in 15 patients (83.3%), with new regimen being a single-drug (only prednisolone) in 4 patients, double-drug in 6 patients, and triple-drug protocol in 8 patients. Eight patients were switched to a mammalian target of rapamycin inhibitor-based double (4 patients) or triple (4 patients) regimen. During follow-up after starting new treatment (average 46 ± 50 mo), 6 patients (33.3%) had progressive kidney failure (0 were receiving triple regimen). Those that progressed were using mammalian target of rapamycin inhibitor-based drugs relatively less (33% vs 50%), although often receiving a single-drug immunosuppression treatment (50% vs 8.3%). Three patients (33.3%) had acute rejection (2 receiving double and 1 receiving single immunosuppression treatment). Five patients (27.7%) had local recurrence of the primary tumor. Mammalian target of rapamycin inhibitor use was relatively less common in patients with tumor relapse (20% vs 46%). One patient died (heart failure), and 1 with chronic rejection returned to dialysis. Mammalian target of rapamycin inhibitorbased drugs could reduce local recurrence rate in kidney transplant recipients with nonmelanoma skin cancers. Aggressive reduction and/or cessation of immunosuppressive drugs after skin cancer can lead to graft rejection.


Outcomes of Goniotomy With or Without Secondary Intraocular Lens Implantation in Pediatric Glaucoma Following Cataract Surgery: A Prospective Pilot Study.
To report the outcomes of a 120-degree goniotomy (GT) with or without secondary intraocular lens (IOL) implantation in glaucoma following cataract surgery (GFCS). Prospective, observational study. Pediatric patients with GFCS who underwent standalone 120-degree GT or 120-degree GT combined with secondary IOL implantation (GT+IOL) from March 2022 to August 2022 at the Zhongshan Ophthalmic Center were recruited. Primary outcomes were intraocular pressure (IOP) and the number of ocular hypotensive medications. A secondary outcome was the surgical success rate. Success was defined as a postoperative IOP within the range of 5-21 mm Hg. Complete and qualified successes were defined, as the above, without and with ocular hypotensive medications, respectively. Thirty-two eyes of 22 patients were included. The mean age at the time of GT was 68.5 ± 29.3 months. The mean follow-up duration was 12.2 ± 2.3 months (9-15 mo). Mean IOP decreased from 30.9 ± 4.8 mm Hg on 2 (interquartile range = 1) medications at baseline to 15.8 ± 3.6 mm Hg on 0 (interquartile range = 1.5) medication at the latest visit in all eyes. The overall complete and qualified success rates were 68.8% and 90.6%, respectively. There were no significant differences in IOP, number of medications, and complete and qualified success rates between the standalone GT and GT+IOL groups at the latest follow-up at 9 months postoperatively. To reduce the need for additional surgery, 120-degree GT was a safe and effective surgical treatment for GFCS in children, which could be combined with secondary IOL implantation in aphakic eyes with GFCS.


A Cone Beam CT Bronchoscopy Study of the Ultrathin Cryoprobe for Biopsy of Peripheral Lung Lesions.
Compared with the standard cryoprobe, the novel ultrathin 1.1 mm cryoprobe (UTCP) has improved ergonomics, shape memory, and flexibility. The performance of UTCP has demonstrated promising results in several small trials. In this single-center, retrospective review, we examine 200 (N=200) consecutive patients referred for cone beam CT bronchoscopic biopsy of peripheral lung lesions. We utilized an extended multimodality approach, including transbronchial needle aspirate, brush, traditional forces biopsies, UTCP biopsies, and BAL. We analyzed tool in lesion, tool touch lesion, center strike rates, and diagnostic yield. We assessed for molecular adequacy and analyzed safety. A total of 222 lesions were biopsied. We achieved a tool in lesion or tool touch lesion confirmation for all biopsy attempts (100%) and a center strike rate of 68%. AQuIRE diagnostic yield was 90%, with 60% malignant, 30% benign lung nodules, and 10% nondiagnostic. UTCP was diagnostic in 3.6 % of peripheral lung lesions biopsies when all other modalities were nondiagnostic; thus, raising our overall diagnostic yield from 86.4% to 90.1%. Our analysis demonstrates superior adequacy for molecular analysis for histologic samples (TBBX or UTCP) versus cytologic samples (FNA) (P<0.001). Three patients (1.5%) had a pneumothorax, and 1 patient (0.5%) had moderate bleeding. UTCP was diagnostic in 3.6% of peripheral lung lesions when all other modalities were nondiagnostic. In the setting of CBCT guidance, UTCP has a similar safety profile to standard biopsy tools. Future trials are warranted to assess UTCP and its impact on peripheral lung lesion biopsies.


Simplified artificial endometrial preparation, using oral estradiol and novel vaginal progesterone tablets: a prospective randomized study.
There are various successful protocols for artificial endometrial preparation, comprising induction of endometrial proliferation with estrogens and secretory transformation with progestins. The aim of this prospective randomized study was to evaluate a simplified approach for endometrial preparation, comparing two constant doses of oral estradiol combined with a novel low-dose vaginal natural progesterone preparation (100 mg Endometrin tablets). Twenty-nine patients were enrolled in the study and divided randomly into two groups. Both groups received oral estradiol tablets from the beginning of menstruation, group A (15 patients) receiving 4 mg/day divided into two doses of 2 mg each, and group B (14 patients) receiving 6 mg/day divided into three doses. Serum estradiol and progesterone and sonographic thickness of the endometrium were measured on the 1st day of menstruation and on the 6th, 11th, 16th and 21st days of the artificial cycle. Following the first 12 days of estradiol priming, with an endometrial thickness of > or = 8 mm, Endometrin vaginal tablets 100 mg were added twice a day for 10 days. On the 21st cycle day, an endometrial biopsy was taken from all patients using Pipelle. In all 29 patients, appropriate changes in estradiol, progesterone and endometrial thickness were observed. Estradiol levels were significantly higher in the 6 mg/day group on days 6 and 11, but no significant difference was noted in serum progesterone level and endometrial thickess between groups. Histological evaluation of endometrial biopsies, on the 21st day, revealed adequate late-secretory endometrium in 14/15 (93.3%) patients of group A and in 13/14 (92.9%) patients of group B. In conclusion, our results demonstrate that an appropriate endometrial secretory transformation may be induced using an economical regimen of fixed low-dose oral estradiol (4 mg/day) and low-dose vaginal progesterone tablets (Endometrin 100 mg twice daily).


A systems biology approach to transcription factor binding site prediction.
The elucidation of mammalian transcriptional regulatory networks holds great promise for both basic and translational research and remains one the greatest challenges to systems biology. Recent reverse engineering methods deduce regulatory interactions from large-scale mRNA expression profiles and cross-species conserved regulatory regions in DNA. Technical challenges faced by these methods include distinguishing between direct and indirect interactions, associating transcription regulators with predicted transcription factor binding sites (TFBSs), identifying non-linearly conserved binding sites across species, and providing realistic accuracy estimates. We address these challenges by closely integrating proven methods for regulatory network reverse engineering from mRNA expression data, linearly and non-linearly conserved regulatory region discovery, and TFBS evaluation and discovery. Using an extensive test set of high-likelihood interactions, which we collected in order to provide realistic prediction-accuracy estimates, we show that a careful integration of these methods leads to significant improvements in prediction accuracy. To verify our methods, we biochemically validated TFBS predictions made for both transcription factors (TFs) and co-factors; we validated binding site predictions made using a known E2F1 DNA-binding motif on E2F1 predicted promoter targets, known E2F1 and JUND motifs on JUND predicted promoter targets, and a de novo discovered motif for BCL6 on BCL6 predicted promoter targets. Finally, to demonstrate accuracy of prediction using an external dataset, we showed that sites matching predicted motifs for ZNF263 are significantly enriched in recent ZNF263 ChIP-seq data. Using an integrative framework, we were able to address technical challenges faced by state of the art network reverse engineering methods, leading to significant improvement in direct-interaction detection and TFBS-discovery accuracy. We estimated the accuracy of our framework on a human B-cell specific test set, which may help guide future methodological development.


Heterosexual risk behaviors in at-risk young men from early adolescence to young adulthood: prevalence, prediction, and association with STD contraction.
Health-compromising lifestyles involve stable patterns of behavior and are associated with high-risk social environments and accelerated developmental trajectories. Developmentally, antisocial behavior is associated with such lifestyles. Mediational models predicting a measure of lifetime average sexual risk behavior assessed over a 10-year period (from ages 13-14 to 22-23 years) were examined for a sample of at-risk young men. The measure included years of abstinence from intercourse as well as levels of 3 key heterosexual indicators of risk: frequency of intercourse, number of intercourse partners, and condom use. Predictors included lifetime average measures of contextual, family, and peer process variables and individual behaviors. In addition, similar models for prediction of STD contraction were assessed. A younger age of onset of intercourse was associated with higher numbers of intercourse partners after onset. As hypothesized, findings indicated mediational associations of socioeconomic status, parental monitoring, deviant-peer association, antisocial behavior, and substance use in the prediction of sexual risk behavior. Lower condom use also predicted STD contraction.


Detecting the differences in responses of stomatal conductance to moisture stresses between deciduous shrubs and Artemisia subshrubs.
Shrubs and subshrubs can tolerate wider ranges of moisture stresses in both soil and air than other plant life forms, and thus represent greater nonlinearity and uncertainty in ecosystem physiology. The objectives of this paper are to model shrub/subshrub stomatal conductance by synthesizing the field leaf gas exchanges data of 24 species in China, in order to detect the differences between deciduous shrubs and Artemisia subshrubs in their responses of stomatal conductance to changes in the moisture stresses. We revised a model of stomatal conductance by incorporating the tradeoff between xylem hydraulic efficiency and cavitation loss risk. We then fit the model at the three hierarchical levels: global (pooling all data as a single group), three functional groups (deciduous non-legume shrubs, deciduous legume shrubs, and subshrubs in Artemisia genus), and individual observations (species × sites). Bayesian inference with Markov Chain Monte Carlo method was applied to obtain the model parameters at the three levels. We found that the model at the level of functional groups is a significant improvement over that at the global level, indicating the significant differences in the stomatal behavior among the three functional groups. The differences in tolerance and sensitivities to changes in moisture stresses are the most evident between the shrubs and the subshrubs: The two shrub groups can tolerate much higher soil water stress than the subshrubs. The analysis at the observation level is also a significant improvement over that at the functional group level, indicating great variations within each group. Our analysis offered a clue for the equivocal issue of shrub encroachment into grasslands: While the invasion by the shrubs may be irreversible, the dominance of subshrubs, due to their lower resistance and tolerance to moisture stresses, may be put down by appropriate grassland management.


Transient and dynamic DNA supercoiling potently stimulates the leu-500 promoter in Escherichia coli.
The inactive prokaryotic leu-500 promoter (Pleu-500) contains a single A-to-G point mutation in the -10 region of the leucine operon promoter, which causes leucine auxotrophy. This promoter can be activated by (-) DNA supercoiling in Escherichia coli topA strains. However, whether this activation arises from global, permanent, or transient, dynamic supercoiling is still not fully understood. In this article, using a newly established in vivo system carrying a pair of divergently coupled promoters, i.e. an IPTG-inducible promoter and Pleu-500 that control the expression of lacZ and luc (the firefly luciferase gene), respectively, we demonstrate that transient, dynamic (-) DNA supercoiling provided by divergent transcription in both wild-type and topA strains can potently activate Pleu-500 We found that this activation depended on the promoter strength and the length of RNA transcripts, which are functional characteristics of transcription-coupled DNA supercoiling (TCDS) precisely predicted by the twin-supercoiled domain model of transcription in which a (+) supercoiled domain is produced ahead of the RNA polymerase and a (-) supercoiled domain behind it. We also demonstrate that TCDS can be generated on topologically open DNA molecules, i.e. linear DNA molecules, in Escherichia coli, suggesting that topological boundaries or barriers are not required for the production of TCDS in vivo This work demonstrates that transient, dynamic TCDS by RNA polymerases is a major chromosome remodeling force in E. coli and greatly influences the nearby, coupled promoters/transcription.


Nucleophilic substitution reactions of aryl dithioacetates with pyridines in acetonitrile.
Kinetic studies of the pyridinolysis (XC(5)H(4)N) of aryl dithioacetates (CH(3)C(=S)SC(6)H(4)Z) are carried out in acetonitrile at 60.0 degrees C. A biphasic Brönsted plot is obtained with a change in slope from a large value (beta(X) congruent with 0.9) to a small value (beta(X) congruent with 0.4) at pK(a) degrees = 5.2, which is attributed to a change in the rate-limiting step from breakdown to formation of a zwitterionic tetrahedral intermediate, T(+/-), in the reaction path as the basicity of the pyridine nucleophile increases. A clear-cut change in the cross-interaction constants rho(XZ) from a large positive value (rho(XZ) = +1.34) to a small negative value (rho(XZ) = -0.15) supports the mechanistic change proposed.


Salicylate induces reactive oxygen species and reduces ultraviolet C susceptibility in Staphylococcus aureus.
This study demonstrates that growth of Staphylococcus aureus in the presence of salicylate reduces ultraviolet C (UVC)-induced cell death and increases the generation of reactive oxygen species (ROS). In addition, compounds that scavenge ROS (N-acetylcysteine, glutathione, catalase and superoxide dismutase) reverse the increased UVC survival induced by growth in the presence of salicylate, while ROS donors (tert-butylhydroperoxide, H2O2 and NaClO) enhance survival of salicylate challenged cultures. Collectively, these findings suggest that ROS production induced by growth in the presence of salicylate protects S. aureus from UVC-induced cell death.


Graphene-Metal Composite Sensors with Near-Zero Temperature Coefficient of Resistance.
This article describes the design of piezoresistive thin-film sensors based on single-layer graphene decorated with metallic nanoislands. The defining characteristic of these composite thin films is that they can be engineered to exhibit a temperature coefficient of resistance (TCR) that is close to zero. A mechanical sensor with this property is stable against temperature fluctuations of the type encountered during operations in the real world, for example, in a wearable sensor. The metallic nanoislands are grown on graphene through thermal deposition of metals (gold or palladium) at a low nominal thickness. Metallic films exhibit an increase in resistance with temperature (positive TCR), whereas graphene exhibits a decrease in resistance with temperature (negative TCR). By varying the amount of deposition, the morphology of the nanoislands can be tuned such that the TCRs of a metal and graphene cancel out. The quantitative analysis of scanning electron microscope images reveals the importance of the surface coverage of the metal (as opposed to the total mass of the metal deposited). The stability of the sensor to temperature fluctuations that might be encountered in the outdoors is demonstrated by subjecting a wearable pulse sensor to simulated solar irradiation.


[NORMATIVE AND LEGAL ASPECTS OF THE FORMATION OF THE BASIC PREREQUISITES OF PUBLIC HEALTH (PUBLICATIONS REVIEW)].
Preservation of public health is the main goal of social progress and development of the society. The search for potential opportunities to improve individual and public health indicators is a positive predictor of increasing the socio-economic efficiency of the society and increasing the healthy life expectancy of citizens. The scientific review provides arguments in favor of the need for professional collaboration of specialists from various industries in order to universally realize the most important right of citizens to protect their own and public health. Regulatory legal documents defining national and international policy in the field of health protection and forming the general vector of development of health care activities were used as the sources of information for the formation of the basis of the study. As a result of a logical generalization of global and national priorities and trends in the development of the healthcare sector, the main prerequisites (determinants) of health saving of citizens, adopted by the world community and reflected in domestic documents, are formulated. The main prerequisites (determinants) of health are defined as: promotion of activities that advantage health protection; creation of a single preventive space; specification of the concept of "responsible attitude to health"; coverage of the entire life cycle of a person and all spheres of his activity in the formation of a responsible attitude to health and motivation for its preservation; development of information technologies in the field of health protection; expansion of intersectoral and interdisciplinary cooperation in order to maintain and strengthen health; improvement of public health literacy; transformation of health services from the standpoint of health protection; development of human resources to ensure health-saving activities. The identified determinants of the preservation of individual and public health can act as a theoretical basis for the development of a scientific and practical methodology aimed at solving problems of improving health through the potential of interdisciplinary interaction of specialists in various fields of activity.


[Research advances in the use of dynamic navigation technology for implantation in the edentulous jaw].
The use of dynamic navigation technology in edentulous jaw implant restoration can solve many problems associated with traditional edentulous jaw implant restoration. The benefits of dynamic navigation include fine positioning guidance, restoration-guided surgery, good aesthetic results, and the possibility of simultaneous conceptual design and real-time implant guidance, as well as the transition from "blind" to "direct" vision during the implantation. It can guide clinicians and adjust the plan in real time, improve the efficiency of communication between the clinician, technician, and patient throughout the process and so on. The workflow, current clinical application and challenges, accuracy analysis, and limitations of the dynamic navigation technology in the edentulous jaw are discussed in this paper, as well as an outlook on its future development, with the goal of contributing to the clinical development of dynamic navigation-guided implantology in the edentulous jaw.


A comparison of rarefaction and bayesian methods for predicting the allelic richness of future samples on the basis of currently available samples.
Rarefaction methods have been introduced into population genetics (from ecology) for predicting and comparing the allelic richness of future samples (or sometimes populations) on the basis of currently available samples, possibly of different sizes. Here, we focus our attention on one such problem: Predicting which population is most likely to yield the future sample having the highest allelic richness. (This problem can arise when we want to construct a core collection from a larger germplasm collection.) We use extensive simulations to compare the performance of the Monte Carlo rarefaction (repeated random subsampling) method with a simple Bayesian approach we have developed-which is based on the Ewens sampling distribution. We found that neither this Bayesian method nor the (Monte Carlo) rarefaction method performed uniformly better than the other. We also examine briefly some of the other motivations offered for these methods and try to make sense of them from a Bayesian point of view.


Pharmacokinetic analysis of paclitaxel and carboplatin in a patient with advanced ovarian cancer during hemodialysis--case report.
We examined pharmacokinetics of paclitaxel and carboplatin in a FIGO Stage IIIb ovarian cancer patient with hemodialysis-dependent chronic renal failure. The patient suffered from recurrence of the disease after treatment with optimal debulking surgery and postoperative chemotherapy consisting of cisplatin, epirubicin and cyclophosphamide, and she was treated with combined paclitaxel and carboplatin as second-line chemotherapy. The carboplatin dose was chosen to produce a target area under the concentration/time curve (AUC) of 5.0 microg-min/ml according to a published formula. Four-hour hemodialysis was started 24 hours and 16 hours after the end of carboplatin administration in the first and second courses of the chemotherapy, respectively. Pharmacokinetic studies showed that the AUCs of free platinum were 8.03 and 5.69 microg-min/ml in the first and second courses of the chemotherapy, respectively, suggesting that the AUC of carboplatin is affected by hemodialysis. However, an attenuation pattern of paclitaxel was almost similar between the first and the second courses, indicating that the change in blood concentration of paclitaxel was similar to that of patients with normal renal function. Hematological and nonhematological adverse effects were at an acceptable degree. The evidence suggests that even patients with chronic renal failure can undergo combination chemotherapy of paclitaxel and carboplatin without suffering any severe adverse effects by determining the time to start hemodialysis.


Inhibition of GGPPS1 attenuated LPS-induced acute lung injury and was associated with NLRP3 inflammasome suppression.
Inhibition of the mevalonate pathway using statins has been shown to be beneficial in the treatment of acute lung injury (ALI). Here, we investigated whether partial inhibition of this pathway by targeting geranylgeranyl pyrophosphate synthase large subunit 1 (GGPPS1), a catalase downstream of the mevalonate pathway, was effective at treating lung inflammation in ALI. Lipopolysaccharide (LPS) was intratracheally instilled to induce ALI in lung-specific GGPPS1-knockout and wild-type mice. Expression of GGPPS1 in lung tissues and alveolar epithelial cells was examined. The severity of lung injury and inflammation was determined in lung-specific GGPPS1 knockout and wild-type mice by measuring alveolar exudate, neutrophil infiltration, lung injury, and cell death. Change in global gene expression in response to GGPPS1 depletion was measured using mRNA microarray and verified in vivo and in vitro. We found that GGPPS1 levels increased significantly in lung tissues and alveolar epithelial cells in LPS-induced ALI mice. Compared with wild-type and simvastatin treated mice, the specific deletion of pulmonary GGPPS1 attenuated the severity of lung injury by inhibiting apoptosis of AECs. Furthermore, deletion of GGPPS1 inhibited LPS-induced inflammasome activation, in terms of IL-1β release and pyroptosis, by downregulating NLRP3 expression. Finally, downregulation of GGPPS1 reduced the membrane expression of Ras-related protein Rab10 and Toll-like receptor 4 (TLR4) and inhibited the phosphonation of IκB. This effect might be attributed to the downregulation of GGPP levels. Our results suggested that inhibition of pulmonary GGPPS1 attenuated LPS-induced ALI predominantly by suppressing the NLRP3 inflammasome through Rab10-mediated TLR4 replenishment.


Role of monoaminergic neurotransmitter systems in MDP-induced adjuvant effect.
The changes in delayed hypersensitivity in guinea pigs stimulated by muramyl dipeptide (MDP) after administration of agonists or antagonists of neurotransmitter systems were studied. Muramyl dipeptide was given in Freund's incomplete adjuvant three weeks before administration of drugs and antigen. Pretreatment with methiotepine, haloperidol and clonidine increased, while lisuride, apomorphine and yohimbine decreased the reaction of delayed hypersensitivity. These results suggest that serotonergic, dopaminergic as well as presynaptic alpha-receptors might have an inhibitory effect on cell-mediated immunity.


On the complexities of measuring naming.
The aims of this study were to investigate the adequacy of electronic voice keys for the purpose of measuring naming latency and to test the assumption that voice key error can be controlled by matching conditions on initial phoneme. Three types of naming latency measurements (hand-coding and 2 types of voice keys) were used to investigate effects of onset complexity (e.g., sat vs. spat) on reading aloud (J. R. Frederiksen & J. F. Kroll, 1976; A. H. Kawamoto & C. T. Kello, 1999). The 3 measurement techniques produced the 3 logically possible results: a significant complexity advantage, a significant complexity disadvantage, and a null effect. Analyses of the performance of each voice key are carried out, and implications for studies of naming latency are discussed.


The Effects of Electronegativity of X and Hybridization of C on the X-C⋅⋅⋅O Interactions: A Statistical Analysis on Tetrel Bonding.
Cone and distance-cone corrected statistical analyses have been performed on X-C⋅⋅⋅O (X=H, B, C, N, O and F; the C atom is sp2 and sp3 hybridized) tetrel bonds. The sp3 -C and sp2 -C prefer to form the interactions through σ-hole (∠XCO≈180°) and π-hole (∠XCO≈90°), respectively. With the increase in electronegativity of X, the preference for the particular angles of the respective geometries increases and the C⋅⋅⋅O distance becomes shorter. The angular preference is found to be more prominent in the cases of π-hole interactions than that in the σ-hole interactions. A similar distance-cone corrected statistical analysis on O=C⋅⋅⋅O interaction also suggests that the preferred ∠OCO angle is ∼90° and the preferred C⋅⋅⋅O distance is around the sum of van der Waals radii (3.22 Å) of the C and O atoms. However, a cone-corrected statistical analysis on X-Si⋅⋅⋅O interactions suggests that the preference for linearity in this case is much higher than that for the X-C⋅⋅⋅O σ-hole interactions.


Preferential immobilization of size-controlled anatase nanoparticles in mesopores.
Precise structural design of a host-guest complex was carried out from the aspects of the size and the location of the guest (anatase particles), and the remaining open space of the host (mesoporous silica). The size of the anatase particles was successfully controlled (3, 5 and 8 nm) during the preparation, and the size-controlled nanoparticles were preferentially encapsulated into the mesopores with a diameter of 8 nm. Due to the precise control of the anatase particles, size dependent photoluminescence of the anatase quantum dots was observed for the first time. The change in the porosity of the mesoporous silica by the immobilization of the anatase in the pore was followed to find a systematic variation of the porosity corresponding to the loaded anatase amount. This correlation can be useful to estimate the location of the guest in/on the host for the host-guest hybrids.


The correlation between the incidence of adverse events and progression-free survival in patients treated with cabozantinib for metastatic renal cell carcinoma (mRCC).
Clinical practice shows significant differences in treatment outcomes across patients treated with cabozantinib for metastatic renal cell carcinoma (mRCC). It is not known whether cabozantinib-induced adverse events are predictive factors of survival as in case of drugs such as sunitinib or axitinib. The study participants were 30 adult patients with mRCC treated with cabozantinib as a second- or further line setting. All adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Progression-free survival (PFS) values were calculated by taking the beginning of cabozantinib treatment as the start date and either disease progression or death as the end date. PFS were estimated using the Kaplan-Meier method, and compared using the log-rank test. We identified independent PFS predictors using multiple Cox proportional hazards models and reported hazard ratios (HR) with 95% confidence intervals. The median observation time cabozantinib treatment was 7.5 months, with a range of 2-15 months. During that time, 11 (37%) of the patients had mRCC progression. Median PFS on cabozantinib was not reached, and lower quartile was 6 months. All patients developed at least one adverse event in the course of cabozantinib therapy. Hypertension, hypothyroidism and HFS were observed most frequently, in about two-thirds of the patients. The co-incidence of multiple adverse events was common. Hypertension, hypothyroidism, diarrhea and liver toxicity were significantly associated with longer PFS values. Patients with three or more side effects had significantly longer PFS than those with two or fewer. Even though this study was conducted in a small patient sample and the observation time was relatively short our results confirm the predictive value of the incidence of adverse events during cabozantinib treatment in mRCC patients. To the best of our knowledge, this is the first study of this kind conducted in this group of patients.


Glowing graphene quantum dots and carbon dots: properties, syntheses, and biological applications.
The emerging graphene quantum dots (GQDs) and carbon dots (C-dots) have gained tremendous attention for their enormous potentials for biomedical applications, owing to their unique and tunable photoluminescence properties, exceptional physicochemical properties, high photostability, biocompatibility, and small size. This article aims to update the latest results in this rapidly evolving field and to provide critical insights to inspire more exciting developments. We comparatively review the properties and synthesis methods of these carbon nanodots and place emphasis on their biological (both fundamental and theranostic) applications.


Effects of Alpha-Tocopherol and Analogs on Cyclic-Amp Systems.
Alpha-tocopherol analogs which lack the terpenoid side chain are non-competitive inhibitors of beef liver phosphodiesterases that act upon cyclic-AMP and cyclic-GMP. Cyclic-AMP phosphodiesterase is elevated in livers from tocopherol-deficient rats, which additionally have decreased glycogen and increased serine dehydratase.


A Core Gene Set Describes the Molecular Basis of Mutualism and Antagonism in Epichloë spp.
Beneficial plant-fungal interactions play an important role in the ability of plants to survive changing environmental conditions. In contrast, phytopathogenic fungi fall at the opposite end of the symbiotic spectrum, causing reduced host growth or even death. In order to exploit beneficial interactions and prevent pathogenic ones, it is essential to understand the molecular differences underlying these alternative states. The association between the endophyte Epichloë festucae and Lolium perenne (perennial ryegrass) is an excellent system for studying these molecular patterns due to the existence of several fungal mutants that have an antagonistic rather than a mutualistic interaction with the host plant. By comparing gene expression in a wild-type beneficial association with three mutant antagonistic associations disrupted in key signaling genes, we identified a core set of 182 genes that show common differential expression patterns between these two states. These gene expression changes are indicative of a nutrient-starvation response, as supported by the upregulation of genes encoding degradative enzymes, transporters, and primary metabolism, and downregulation of genes encoding putative small-secreted proteins and secondary metabolism. These results suggest that disruption of a mutualistic symbiotic interaction may lead to an elevated uptake and degradation of host-derived nutrients and cell-wall components, reminiscent of phytopathogenic interactions.


Serum-Derived Exosomes from Patients with Coronary Artery Disease Induce Endothelial Injury and Inflammation in Human Umbilical Vein Endothelial Cells.
Endothelial injury and inflammation have been found to be essential in the pathogenesis of coronary artery disease (CAD). Circulating exosomes are of great value as novel biomarkers for CAD. However, the role of circulating exosomes in the pathogenesis of CAD remains unclear. Thus, in this study, we aimed to examine whether circulating exosomes from CAD are involved in the endothelial injury and inflammation. The serum-derived exosomes were isolated from CAD and controls using an ExoQuick reagent, and these were then quantified by measuring the protein levels using BCA methods. The uptake of exosomes by human umbilical vein endothelial cells (HUVECs) was observed by laser scanning microscope and analyzed via flow cytometry. Then, HUVECs were treated with vehicle, exosomes from CAD (CAD-exo), and controls (ctrl-exo) in the absence and presence of vascular endothelial growth factor (VEGF). Cell viability, migration, and angiogenesis were evaluated using CCK-8 assay, scratch assay, and tube formation assay. Inflammatory factors including IL-1β, IL-6, TNF-α, ICAM-1, and VCAM-1 levels were detected via qPCR. As per our findings, no significant differences were noted in uptake of ctrl-exo and CAD-exo by HUVECs. CAD-exo suppressed cell viability in a dose-dependent manner. Compared with ctrl-exo, CAD-exo-treated HUVECs significantly suppressed migration and angiogenesis. However, CAD-exo had a stronger inhibitory effect on VEGF-induced migration and angiogenesis compared with ctrl-exo. Moreover, IL-1β, TNF-α, and ICAM-1 were determined to be significantly upregulated in HUVECs treated with CAD-exo, but IL-6 and VCAM-1 expressions were not affected. Overall, our results suggest that CAD-exo are involved in endothelial injury and inflammation, which may, in turn, cause endothelial dysfunction and potentially promote the development of CAD.


Transcranial low-level laser therapy enhances learning, memory, and neuroprogenitor cells after traumatic brain injury in mice.
The use of transcranial low-level laser (light) therapy (tLLLT) to treat stroke and traumatic brain injury (TBI) is attracting increasing attention. We previously showed that LLLT using an 810-nm laser 4 h after controlled cortical impact (CCI)-TBI in mice could significantly improve the neurological severity score, decrease lesion volume, and reduce Fluoro-Jade staining for degenerating neurons. We obtained some evidence for neurogenesis in the region of the lesion. We now tested the hypothesis that tLLLT can improve performance on the Morris water maze (MWM, learning, and memory) and increase neurogenesis in the hippocampus and subventricular zone (SVZ) after CCI-TBI in mice. One and (to a greater extent) three daily laser treatments commencing 4-h post-TBI improved neurological performance as measured by wire grip and motion test especially at 3 and 4 weeks post-TBI. Improvements in visible and hidden platform latency and probe tests in MWM were seen at 4 weeks. Caspase-3 expression was lower in the lesion region at 4 days post-TBI. Double-stained BrdU-NeuN (neuroprogenitor cells) was increased in the dentate gyrus and SVZ. Increases in double-cortin (DCX) and TUJ-1 were also seen. Our study results suggest that tLLLT may improve TBI both by reducing cell death in the lesion and by stimulating neurogenesis.


Transient transmural reduction of myocardial blood flow demonstrated by thallium-201 scintigraphy, as a cause of variant angina.
In previous studies we demonstrated that variant angina could not be attributed to increased myocardial demands. In order to investigate whether a reduction of regional myocardial blood supply could be responsible for these ischemic episodes, we studied regional myocardial perfusion in six patients admitted to our coronary care unit. Myocardial scintigrams, obtained 5-7 min following i.v. injection of 1 mCi of thallium-201, performed during an episode of ST-segment elevation, showed transmural deficits of tracer uptake in the heart wall corresponding to the leads showing ST-segment elevation. These regional deficits ahd disappeared by 2 hours because of late uptake in previously ischemic myocardium. One week later, following injections performed in the absence of acute ischemia, no deficit was apparent. Tracer uptake in ischemic areas was 60% to 85% of that observed a week later. After adjusting for thallium-201 kinetics and counting geometry promblems., these scintigrams actually represent large underestimations of actual flow reduction. Thus variant angina appears to be caused by massive transmural reduction of myocardial blood supply.