Prolonged Exposure of Primary Human Muscle Cells to Plasma Fatty Acids Associated with Obese Phenotype Induces Persistent Suppression of Muscle Mitochondrial ATP Synthase β Subunit.
Our previous studies show reduced abundance of the β-subunit of mitochondrial H+-ATP synthase (β-F1-ATPase) in skeletal muscle of obese individuals. The β-F1-ATPase forms the catalytic core of the ATP synthase, and it is critical for ATP production in muscle. The mechanism(s) impairing β-F1-ATPase metabolism in obesity, however, are not completely understood. First, we studied total muscle protein synthesis and the translation efficiency of β-F1-ATPase in obese (BMI, 36±1 kg/m2) and lean (BMI, 22±1 kg/m2) subjects. Both total protein synthesis (0.044±0.006 vs 0.066±0.006%·h-1) and translation efficiency of β-F1-ATPase (0.0031±0.0007 vs 0.0073±0.0004) were lower in muscle from the obese subjects when compared to the lean controls (P<0.05). We then evaluated these same responses in a primary cell culture model, and tested the specific hypothesis that circulating non-esterified fatty acids (NEFA) in obesity play a role in the responses observed in humans. The findings on total protein synthesis and translation efficiency of β-F1-ATPase in primary myotubes cultured from a lean subject, and after exposure to NEFA extracted from serum of an obese subject, were similar to those obtained in humans. Among candidate microRNAs (i.e., non-coding RNAs regulating gene expression), we identified miR-127-5p in preventing the production of β-F1-ATPase. Muscle expression of miR-127-5p negatively correlated with β-F1-ATPase protein translation efficiency in humans (r = - 0.6744; P<0.01), and could be modeled in vitro by prolonged exposure of primary myotubes derived from the lean subject to NEFA extracted from the obese subject. On the other hand, locked nucleic acid inhibitor synthesized to target miR-127-5p significantly increased β-F1-ATPase translation efficiency in myotubes (0.6±0.1 vs 1.3±0.3, in control vs exposure to 50 nM inhibitor; P<0.05). Our experiments implicate circulating NEFA in obesity in suppressing muscle protein metabolism, and establish impaired β-F1-ATPase translation as an important consequence of obesity.


Role of prostaglandin E receptor subtypes EP2 and EP4 in autocrine and paracrine functions of vascular endothelial growth factor in the inner ear.
The physiological effects of prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) are mediated by the prostaglandin E receptor subtypes EP1, EP2, EP3, and EP4, and the respective agonists have been purified. PGE1 and PGE2 can increase the production of vascular endothelial growth factor (VEGF), particularly through EP2 and EP4. The biological effects of VEGF are mediated by the phosphotyrosine kinase receptors fms-related tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1). Here we examined the effects of EP2 and EP4 agonists on the production of VEGF proteins and VEGF messenger RNAs (mRNAs) in the inner ear, using an enzyme-linked immunosorbent assay and the real-time quantitative reverse transcription-polymerase chain reaction, respectively. We also examined the localization of EP2, VEGF, Flt-1, and Flk-1 in the cochlea by immunohistochemistry. The expression of EP2 occurred in the cochlea, and the local application of an EP2 or EP4 agonist increased VEGF protein and VEGF mRNA levels in the inner ear. Furthermore, the intensity of the VEGF immunoreactivity in the spiral ganglion appeared to be increased by the local EP2 or EP4 agonist treatment. Immunoreactivity for Flt-1, and Flk-1 was found in the cochlear sensory epithelium, spiral ganglion, spiral ligament, and stria vascularis. These findings demonstrate that EP2 and EP4 agonists stimulate VEGF production in the inner ear, particularly in the spiral ganglions. Moreover, the Flt-1 and Flk-1 expression observed in the present study suggests that VEGF has autocrine and paracrine actions in the cochlea. Thus, EP2 and EP4 might be involved in the mechanisms underlying the therapeutic effects of PGE1 on acute sensorineural hearing loss via VEGF production.


Characterization of lbpA, the structural gene for a lactoferrin receptor in Neisseria gonorrhoeae.
Neisseria gonorrhoeae acquires iron (Fe) efficiently from lactoferrin (LF). A 103-kDa gonococcal outer membrane LF-binding protein (Lbp) was identified previously. We isolated the structural gene lbpA for Lbp1 by screening a gonococcal library for a clone that could repair an LF- receptor mutant. An mTnCm3 transposon insertion mutant of lbpA was unable to use LF-bound Fe for growth, unable to bind LF to whole cells, and unable to express Lbp1. The DNA sequence of lbpA predicted a protein that shared 94% identity with the meningococcal LF receptor protein, Lbp, and was closely related to Tbp1, one of the transferrin receptor proteins. Clinical isolates of gonococci are frequently unable to acquire Fe from LF, and LF- isolates do not have a functional LF receptor. The wild-type lbpA gene transformed most tested LF- clinical isolates to LF+, indicating that lbpA is defective in many clinical isolates.


Bend-insensitive lasing characteristics of single-mode, large-mode-area ytterbium-doped photonic crystal fiber.
The bend-insensitive lasing characteristics of a newly designed ytterbium-doped photonic crystal fiber (YPCF) are evaluated numerically. The designed YPCF remains single-mode and possesses large-mode-area of 1400 microm(2) at 1064 nm wavelength with the beam quality factor (M(2)) of 1.15, suggesting a diffraction-limited and continuous-wave lasing operation. The doped-region size is optimized for maximum conversion efficiency and it is found through numerical simulations that the doped radius should be more than 21 microm. The "mode expansion", which is the self-expansion of the fundamental mode within the doped region with wavelength increments on bending the fiber, is the basic physical mechanism to give the bend-insensitive lasing performances of YPCF. It leads to an unusual variation of overlap factor when the wavelength is increased. A 41 cm long piece of YPCF demonstrates more than 83% of slope efficiency with 75% of conversion efficiency when pumped with a 975 nm laser source delivering an input power of 1 W.


A spatially specified systems pharmacology therapy for axonal recovery after injury.
There are no known drugs or drug combinations that promote substantial central nervous system axonal regeneration after injury. We used systems pharmacology approaches to model pathways underlying axonal growth and identify a four-drug combination that regulates multiple subcellular processes in the cell body and axons using the optic nerve crush model in rats. We intravitreally injected agonists HU-210 (cannabinoid receptor-1) and IL-6 (interleukin 6 receptor) to stimulate retinal ganglion cells for axonal growth. We applied, in gel foam at the site of nerve injury, Taxol to stabilize growing microtubules, and activated protein C to clear the debris field since computational models predicted that this drug combination regulating two subcellular processes at the growth cone produces synergistic growth. Physiologically, drug treatment restored or preserved pattern electroretinograms and some of the animals had detectable visual evoked potentials in the brain and behavioral optokinetic responses. Morphology experiments show that the four-drug combination protects axons or promotes axonal regrowth to the optic chiasm and beyond. We conclude that spatially targeted drug treatment is therapeutically relevant and can restore limited functional recovery.


Relationship Between External and Internal Loads of Professional Soccer Players During Full Matches in Official Games Using Global Positioning Systems and Heart-Rate Technology.
To analyze the match running profile, distance traveled over successive 15 min of match play, heart rates (HRs), and index of performance efficiency (effindex) of professional soccer players with a global positioning system (GPS) and HR in official competition. Twenty-six professional players were investigated during full matches in competitive club-level matches (N = 223). Time-motion data and HR were collected using GPS and HR technology. The relative total distance was 113 ± 11 m/min, with substantial differences between halves. For all playing positions, a substantial decrease in total distance and distance covered at >13.0 km/h was observed in the second half in comparison with the first. The decrease during the second half in distance covered at >13.0 km/h was substantially higher than in total distance. The average HR recorded was 86.0% maximal HR, and the relationship between external and internal load (effindex) was 1.3, with substantial differences between halves in all playing positions, except strikers for effindex. Wide midfielders reflected substantially the lowest mean HR and highest effindex, whereas center backs showed substantially the lowest effindex of all playing positions. The current study confirmed the decrement in a player's performance toward the end of a match in all playing positions. Wide midfielders displayed the highest and fittest levels of physical and physiological demands, respectively, whereas center backs had the lowest and least-fit levels of physical and physiological demands, respectively. The position-specific relationship between external and internal load confirms that players with more overall running performance during the full match were the best in effindex.


Does Previous Transradial Catheterization Preclude Use of the Radial Artery as a Conduit in Coronary Artery Bypass Surgery?
The radial artery (RA) is a commonly used conduit for coronary artery bypass grafting, and recent studies have demonstrated that it provides superior long-term patency rates to the saphenous vein in most situations. In addition, the RA is also being used with increasing frequency as the access point for coronary angiography and percutaneous coronary interventions. However, there has been concern for many years that these transradial procedures may have a detrimental impact on the function of RA grafts used in coronary artery bypass grafting, and there is now comprehensive evidence that such interventions cause morphologic and functional damage to the artery in situ. Despite this, there remain remarkably few studies investigating the use of previously cannulated RAs as grafts in coronary artery bypass surgery, and there are no clear guidelines on the use of the RA in coronary artery bypass grafting after its catheterization. This article will review concisely the evidence that transradial procedures cause damage to the RA, and discuss the impact this could have on previously cannulated RAs used as coronary artery bypass grafting conduits. On the basis of the evidence assessed, we make a number of recommendations to both surgeons and cardiologists regarding use of the RA in cardiovascular procedures.


Long-term obesity promotes alterations in diastolic function induced by reduction of phospholamban phosphorylation at serine-16 without affecting calcium handling.
Few studies have evaluated the relationship between the duration of obesity, cardiac function, and the proteins involved in myocardial calcium (Ca(2+)) handling. We hypothesized that long-term obesity promotes cardiac dysfunction due to a reduction of expression and/or phosphorylation of myocardial Ca(2+)-handling proteins. Thirty-day-old male Wistar rats were distributed into two groups (n = 10 each): control (C; standard diet) and obese (Ob; high-fat diet) for 30 wk. Morphological and histological analyses were assessed. Left ventricular cardiac function was assessed in vivo by echocardiographic evaluation and in vitro by papillary muscle. Cardiac protein expression of sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a), calsequestrin, L-type Ca(2+) channel, and phospholamban (PLB), as well as PLB serine-16 phosphorylation (pPLB Ser(16)) and PLB threonine-17 phosphorylation (pPLB Thr(17)) were determined by Western blot. The adiposity index was higher (82%) in Ob rats than in C rats. Obesity promoted cardiac hypertrophy without alterations in interstitial collagen levels. Ob rats had increased endocardial and midwall fractional shortening, posterior wall shortening velocity, and A-wave compared with C rats. Cardiac index, early-to-late diastolic mitral inflow ratio, and isovolumetric relaxation time were lower in Ob than in C. The Ob muscles developed similar baseline data and myocardial responsiveness to increased extracellular Ca(2+). Obesity caused a reduction in cardiac pPLB Ser(16) and the pPLB Ser(16)/PLB ratio in Ob rats. Long-term obesity promotes alterations in diastolic function, most likely due to the reduction of pPLB Ser(16), but does not impair the myocardial Ca(2+) entry and recapture to SR.


Sequence analysis of the human virome in febrile and afebrile children.
Unexplained fever (UF) is a common problem in children under 3 years old. Although virus infection is suspected to be the cause of most of these fevers, a comprehensive analysis of viruses in samples from children with fever and healthy controls is important for establishing a relationship between viruses and UF. We used unbiased, deep sequencing to analyze 176 nasopharyngeal swabs (NP) and plasma samples from children with UF and afebrile controls, generating an average of 4.6 million sequences per sample. An analysis pipeline was developed to detect viral sequences, which resulted in the identification of sequences from 25 viral genera. These genera included expected pathogens, such as adenoviruses, enteroviruses, and roseoloviruses, plus viruses with unknown pathogenicity. Viruses that were unexpected in NP and plasma samples, such as the astrovirus MLB-2, were also detected. Sequencing allowed identification of virus subtype for some viruses, including roseoloviruses. Highly sensitive PCR assays detected low levels of viruses that were not detected in approximately 5 million sequences, but greater sequencing depth improved sensitivity. On average NP and plasma samples from febrile children contained 1.5- to 5-fold more viral sequences, respectively, than samples from afebrile children. Samples from febrile children contained a broader range of viral genera and contained multiple viral genera more frequently than samples from children without fever. Differences between febrile and afebrile groups were most striking in the plasma samples, where detection of viral sequence may be associated with a disseminated infection. These data indicate that virus infection is associated with UF. Further studies are important in order to establish the range of viral pathogens associated with fever and to understand of the role of viral infection in fever. Ultimately these studies may improve the medical treatment of children with UF by helping avoid antibiotic therapy for children with viral infections.


Expression of a novel TGIF subclass homeobox gene, Tex1, in the spermatids of mouse testis during spermatogenesis.
The homeobox gene superfamily is highly conserved during evolution. These genes act as transcription factors during several important developmental processes through their 60 amino acid homeodomains that recognize and bind to the regulatory region of their target genes. We isolated a novel homeobox gene designated Tex1 from a mouse testis cDNA library by degenerate oligonucleotide polymerase chain reaction (PCR) screening. Three extra amino acid residues, AYP, are inserted between the first and second helices of the homeodomain, which makes Tex1 a TGIF subclass homeobox gene. Tex1 was expressed specifically in the testis as seen by both Northern blot and RT-PCR analysis. Tex1 expression is initiated at around day 20 of testes. Furthermore, the results of in situ hybridization analysis reveal that the expression of Tex1 in testis is restricted in the germ cells at spermatid stage. Based on these data, it is suggested that Tex1, a novel testis homeobox gene, may play a crucial role during spermatogenesis.


Projected Outcomes of Nurse-Family Partnership Home Visitation During 1996-2013, USA.
Nurse-Family Partnership (NFP) targets intensive prenatal and postnatal home visitation by registered nurses to low-income first-time mothers. Through 2013, 177,517 pregnant women enrolled in NFP programs. This article projects how NFP will affect their lives and the lives of their babies. NFP has been evaluated in six randomized trials and several more limited analyses of operational programs. We systematically reviewed evaluation findings on 21 outcomes and calculated effects on three more. We added outcome data from the NFP national data system and personal communications that filled outcome data gaps on some trials. We assumed effectiveness in replication declined by 21.8 %, proportionally with the decline in mean visits per family from trials to operational programs. By 2031, NFP program enrollments in 1996-2013 will prevent an estimated 500 infant deaths, 10,000 preterm births, 13,000 dangerous closely spaced second births, 4700 abortions, 42,000 child maltreatment incidents, 36,000 intimate partner violence incidents, 90,000 violent crimes by youth, 594,000 property and public order crimes (e.g., vandalism, loitering) by youth, 36,000 youth arrests, and 41,000 person-years of youth substance abuse. They will reduce smoking during pregnancy, pregnancy complications, childhood injuries, and use of subsidized child care; improve language development; increase breast-feeding; and raise compliance with immunization schedules. They will eliminate the need for 4.8 million person-months of child Medicaid spending and reduce estimated spending on Medicaid, TANF, and food stamps by $3.0 billion (present values in 2010 dollars). By comparison, NFP cost roughly $1.6 billion. Thus, NFP appears to be a sound investment. It saves money while enriching the lives of participating low-income mothers and their offspring and benefiting society more broadly by reducing crime and safety net demand.


The Utility of an English Semantics Measure for Identifying Developmental Language Disorder in Spanish-English Bilinguals.
Purpose We examined the English semantic performance of three hundred twenty-seven 7- to 10-year-old Spanish-English bilinguals with (n = 66) and without (n = 261) developmental language disorder (DLD) with varying levels of English experience to classify groups. Method English semantic performance on the Bilingual English-Spanish Assessment-Middle Extension Experimental Test Version (Peña et al., 2008) was evaluated by language experience, language ability, and task type. Items that best identified DLD for children with balanced and high English experience were selected. Separately, items that best identified children with high Spanish experience were selected. Results Typically developing bilingual children performed significantly higher than their peers with DLD across semantic tasks, with differences associated with task type. Classification accuracy was fair when item selection corresponded to balanced or high level of experience in English, but poor for children with high Spanish experience. Selecting items specifically for children with high Spanish experience improved classification accuracy. Conclusions Tailoring semantic items based on children's experience is a promising direction toward organizing items on a continuum of exposure. Here, classification effectively ruled in impairment. Future work to refine semantic items that more accurately represent the continuum of exposure may help rule out language impairment.


Meta-analyses of cognitive and motor function in youth aged 16 years and younger who subsequently develop schizophrenia.
Previous reviews have reported cognitive and motor deficits in childhood and adolescence among individuals who later develop schizophrenia. However, these reviews focused exclusively on studies of individuals with affected relatives or on population/birth cohorts, incorporated studies with estimated measures of pre-morbid intelligence, or included investigations that examined symptomatic at-risk participants or participants 18 years or older. Thus, it remains unclear whether cognitive and motor deficits constitute robust antecedents of schizophrenia. Meta-analyses were conducted on published studies that examined cognitive or motor function in youth aged 16 years or younger who later developed schizophrenia or a schizophrenia spectrum disorder (SSD) and those who did not. Twenty-three studies fulfilled the following inclusion criteria: (1) written in English; (2) prospective investigations of birth or genetic high-risk cohorts, or follow-back investigations of population samples; (3) objective measures of cognitive or motor performance at age 16 or younger; (4) results provided for individuals who did and who did not develop schizophrenia/SSD later in life; and (5) sufficient data to calculate effect sizes. Four domains of function were examined: IQ; Motor Function; General Academic Achievement; and Mathematics Achievement. Meta-analyses showed that, by age 16, individuals who subsequently developed schizophrenia/SSD displayed significant deficits in IQ (d=0.51) and motor function (d=0.56), but not in general academic achievement (d=0.25) or mathematics achievement (d=0.21). Subsidiary analysis indicated that the IQ deficit was present by age 13. These results demonstrate that deficits in IQ and motor performance precede the prodrome and the onset of illness.


Fast perturbation Monte Carlo method for photon migration in heterogeneous turbid media.
We present a two-step Monte Carlo (MC) method that is used to solve the radiative transfer equation in heterogeneous turbid media. The method exploits the one-to-one correspondence between the seed value of a random number generator and the sequence of random numbers. In the first step, a full MC simulation is run for the initial distribution of the optical properties and the "good" seeds (the ones leading to detected photons) are stored in an array. In the second step, we run a new MC simulation with only the good seeds stored in the first step, i.e., we propagate only detected photons. The effect of a change in the optical properties is calculated in a short time by using two scaling relationships. By this method we can increase the speed of a simulation up to a factor of 1300 in typical situations found in near-IR tissue spectroscopy and diffuse optical tomography, with a minimal requirement for hard disk space. Potential applications of this method for imaging of turbid media and the inverse problem are discussed.


Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators.
The E2F proteins form a family of transcription factors that regulate the transition from the G1 to the S phase in the cell cycle. E2F activity is regulated by members of the retinoblastoma protein (pRb) family, ensuring the tight control of E2F-responsive genes. During the G1 phase, phosphorylation of pRb by cyclin-dependent kinases (CDKs), most notably cyclin D-CDK complexes, releases pRb from E2F, facilitating cell-cycle progression by the timely induction of E2F-targeted genes such as cyclin E. However, it is not known whether E2F proteins are directly targeted by CDKs. Here we show that E2F-5 is phosphorylated by the cyclin E-Cdk2 complex, which functions in the late G1 phase, but not by the early-G1-phase-acting cyclin D-CDK complex. A phosphorylation site in the trans-activation domain of E2F-5 stimulates transcription and cell-cycle progression by the recruitment of the p300/CBP family of co-activators, whose binding to E2F-5 is stabilized upon phosphorylation by cyclin E-Cdk2. These results indicate that E2F activity may be directly regulated by cyclin E-Cdk2, and imply an autoregulatory mechanism for cell-cycle-dependent transcription through the CDK-stimulated interaction of E2F with p300/CBP co-activators.


Liraglutide: A New Option for the Treatment of Obesity.
Obesity continues to pose a major public health risk to the United States and across the world, with an estimated one-third of adult Americans being defined as obese. Obesity treatment guidelines recommend the use of pharmacologic therapy in adults who have a body mass index (BMI) of 30 kg/m(2) or higher or in patients with a BMI of 27 kg/m(2) or higher who have at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, insulin resistance, type 2 diabetes mellitus). Liraglutide is a glucagon-like peptide-1 receptor agonist that has been successfully used in the treatment of type 2 diabetes for several years. Weight loss has been well described as an additional benefit with liraglutide therapy, which prompted the manufacturer to evaluate and develop a higher dose formulation specifically for the treatment of obesity. Liraglutide 3 mg/day was approved by the U.S. Food and Drug Administration for this indication in December 2014. We performed a search of the Medline database to identify relevant literature focused on liraglutide's role specifically in treating obesity. Five clinical trials with this primary end point were identified. Data demonstrated that liraglutide can successfully achieve weight-loss benchmarks of 5% or more and 10% or more loss from baseline. The most common adverse effects were gastrointestinal and mild to moderate in intensity. The cost of therapy is high, averaging over $1000/month for out-of-pocket expenses if insurance coverage is not available. Liraglutide is also available for delivery only by subcutaneous injection, which may represent a barrier for patients. Liraglutide 3 mg/day represents another pharmacologic option for the treatment of obesity.


An exploration of plastic deformation dependence of cell viability and adhesion in metallic implant materials.
The relationship between cell viability and adhesion behavior, and micro-deformation mechanisms was investigated on austenitic 316L stainless steel samples, which were subjected to different amounts of plastic strains (5%, 15%, 25%, 35% and 60%) to promote a variety in the slip and twin activities in the microstructure. Confocal laser scanning microscopy (CLSM) and field emission scanning electron microscopy (FESEM) revealed that cells most favored the samples with the largest plastic deformation, such that they spread more and formed significant filopodial extensions. Specifically, brain tumor cells seeded on the 35% deformed samples exhibited the best adhesion performance, where a significant slip activity was prevalent, accompanied by considerable slip-twin interactions. Furthermore, maximum viability was exhibited by the cells seeded on the 60% deformed samples, which were particularly designed in a specific geometry that could endure greater strain values. Overall, the current findings open a new venue for the production of metallic implants with enhanced biocompatibility, such that the adhesion and viability of the cells surrounding an implant can be optimized by tailoring the surface relief of the material, which is dictated by the micro-deformation mechanism activities facilitated by plastic deformation imposed by machining.


The stability of psychopathy across adolescence.
The current diagnostic system suggests that personality disorder categories be applied to children and adolescents in rare circumstances because of expected changes in personality pathology across development. The present study examined the stability in personality pathology, specifically psychopathy, across childhood and adolescence. Using a short form of the CPS and mixed models incorporating fixed and random effects, we examined the reliability, individual stability, mean-level stability, and predictive utility of juvenile psychopathy as a function of age (i.e., from 7 to 17 years old) in over 1,500 boys from the three cohorts of the Pittsburgh Youth Study. If adolescent development contributes to instability in personality pathology, large age-related fluctuations in reliability, stability, and predictive utility should be observed, particularly in the latter part of adolescence when normative changes are hypothesized to influence levels of psychopathy. Such fluctuations were not observed. In general, juvenile psychopathy could be reliably assessed beginning in childhood, was fairly stable across short and long intervals, showed little mean-level fluctuation, and predicted delinquency across adolescence. These results suggest that concerns about large changes in personality pathology across childhood and adolescence may be overstated. Implications and future directions are discussed.


Comparing quality of care in the Medicare program.
To compare the clinical quality of care between Medicare fee-for-service (FFS) and Medicare Advantage (MA) programs. We compared 11 Healthcare Effectiveness Data and Information Set (HEDIS) quality measures nationwide for MA managed care plans and the FFS program in 2006 and 2007. We adjusted FFS measures to match the geographic distribution of MA. Medicare Advantage plans scored substantially better (4-16 percentage points; median, 7.8 percentage points) on 8 measures, slightly better (1.5 percentage points) on 1 measure, and worse than FFS (2-5 percentage points; median, 4.1 percentage points) on 2 measures. The 8 measures on which MA scored substantially better were well established in the HEDIS measure set (introduced in the 1990s), whereas the other 3 were all newer (introduced in 2004-2005 data). Data and program differences complicated the comparison, but it is unlikely that they were large enough to explain the sizable MA-FFS gaps observed. Quality measures showed large, though mixed, differences between MA and FFS. The dichotomy between older and newer measures in MA suggests a learning effect, with plans improving measurement and quality over time as measures become more familiar.


Cassini observes the active south pole of Enceladus.
Cassini has identified a geologically active province at the south pole of Saturn's moon Enceladus. In images acquired by the Imaging Science Subsystem (ISS), this region is circumscribed by a chain of folded ridges and troughs at approximately 55 degrees S latitude. The terrain southward of this boundary is distinguished by its albedo and color contrasts, elevated temperatures, extreme geologic youth, and narrow tectonic rifts that exhibit coarse-grained ice and coincide with the hottest temperatures measured in the region. Jets of fine icy particles that supply Saturn's E ring emanate from this province, carried aloft by water vapor probably venting from subsurface reservoirs of liquid water. The shape of Enceladus suggests a possible intense heating epoch in the past by capture into a 1:4 secondary spin/orbit resonance.


Role of selenium in mercury intoxication in mice.
Studies were conducted to examine the effect of pre and post-treatment of selenium in mercury intoxication (20 micromole/ kg b.w. each given intraperitoneally) in mice in terms of lipid peroxidation (LPO), glutathione (GSH) content, activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and mercury concentration in liver, kidney and brain. No significant alteration was observed in all the organs examined after mercury or selenium treatment in LPO and GSH but administration of selenium (pre and post) resulted in an increase in the level of LPO and GSH. The activity of SOD was depleted in liver and kidney while that of GPx was lowered in liver of mercury exposed animals. Selenium administration resulted in restoration of the depletion of these enzymatic activities. The activity of CAT in liver and brain was enhanced both in mercury and selenium treated animals. Administration of selenium significantly arrested enhanced CAT activity. Kidney showed the highest mercury concentration among the organs examined. Administration of selenium resulted in further enhancement of mercury concentration in the tissues. An increase in selenium level in liver was observed after mercury treatment, which was also restored by mercury selenium co-administration. Our results indicate that the prooxidant effect of selenium was greater by its pretreatment.


Effects of decontamination at varying contamination levels of Campylobacter jejuni on broiler meat.
When assessing effects of decontamination techniques on counts of Campylobacter spp. on broiler meat, it is essential that the results reflect the variations that may exist. Decontamination studies often use high inoculation levels (10(7) to 10(8) cfu) and one or few strains of Campylobacter jejuni, thereby restricting the results to reflect only a limited part of the true situation. This study presents results from physical and chemical decontamination of broiler meat medallions using different strains and different initial concentrations of C. jejuni. For 3 strains of C. jejuni, mean log reductions obtained by freezing at -20°C for 7 d was significantly higher for an initial concentration of 10(7) cfu/sample on the meat compared with an initial concentration of 10(3) cfu/sample. For freezing at -20°C for 24 h or application of 6% tartaric acid and subsequent storage for 24 h, no statistically significant difference in reductions was found for initial concentrations ranging from 10(3) to 10(7) cfu per sample. The mean log reductions obtained by all techniques were strongly dependent on the strain tested. The results reveal that reductions obtained with high inoculation levels of C. jejuni (10(7) cfu/sample) or single or few strains of the species (or both) should not be interpreted as a generic result for the species. If inoculation studies cannot be replaced by investigations of naturally contaminated meat, we advise using a mixture of strains found in the production environment at levels as close as possible to the natural contamination level.


Non-Contact Sensor for Long-Term Continuous Vital Signs Monitoring: A Review on Intelligent Phased-Array Doppler Sensor Design.
It has been the dream of many scientists and engineers to realize a non-contact remote sensing system that can perform continuous, accurate and long-term monitoring of human vital signs as we have seen in many Sci-Fi movies. Having an intelligible sensor system that can measure and record key vital signs (such as heart rates and respiration rates) remotely and continuously without touching the patients, for example, can be an invaluable tool for physicians who need to make rapid life-and-death decisions. Such a sensor system can also effectively help physicians and patients making better informed decisions when patients' long-term vital signs data is available. Therefore, there has been a lot of research activities on developing a non-contact sensor system that can monitor a patient's vital signs and quickly transmit the information to healthcare professionals. Doppler-based radio-frequency (RF) non-contact vital signs (NCVS) monitoring system are particularly attractive for long term vital signs monitoring because there are no wires, electrodes, wearable devices, nor any contact-based sensors involved so the subjects may not be even aware of the ubiquitous monitoring. In this paper, we will provide a brief review on some latest development on NCVS sensors and compare them against a few novel and intelligent phased-array Doppler-based RF NCVS biosensors we have built in our labs. Some of our NCVS sensor tests were performed within a clutter-free anechoic chamber to mitigate the environmental clutters, while most tests were conducted within the typical Herman-Miller type office cubicle setting to mimic a more practical monitoring environment. Additionally, we will show the measurement data to demonstrate the feasibility of long-term NCVS monitoring. The measured data strongly suggests that our latest phased array NCVS system should be able to perform long-term vital signs monitoring intelligently and robustly, especially for situations where the subject is sleeping without hectic movements nearby.


The effect of simulated lens yellowing and opacification on blue-on-yellow acuity and contrast sensitivity.
Short-wavelength-sensitive (SWS) resolution acuity has been reported to be limited by the density of the responding ganglion cells for people without appreciable age-related lenticular change. This study measured the robustness of SWS-cone acuity and contrast sensitivity (CS) to simulated lens yellowing and opacification. Resolution acuity at 8 deg eccentricity proved robust to significant amounts of yellowing and remained lower than detection acuity, indicating that the resolution continued to be limited by ganglion cell density. Both the detection and resolution CS functions were affected by simulated lens yellowing, except for resolution close to the CS cut-off. For simulated opacification, only dense opacity significantly affected performance. SWS resolution acuity and CS close to the resolution limit are resistant to moderate simulated age-related lens changes and continue to be mediated by the density of the responding ganglion cells, indicating important clinical potential to measure SWS neural losses of vision in older subjects.


Predictors of pouchitis after ileal pouch-anal anastomosis: a retrospective review.
The primary end point of this study was to determine the risk factors that predict chronic pouchitis in those patients having ileal pouch-anal anastomosis. A total of 237 patients with ulcerative colitis and undergoing ileal pouch-anal anastomosis by one surgeon at Oregon Health & Science University from 1993 to 2003 were evaluated. Data were gathered via retrospective chart reviews and by a questionnaire administered by telephone in 2004. Patients were excluded if there was less than one-year follow-up documented in the chart or they could not be contacted by telephone (n = 62), postoperative diagnosis of Crohn's disease (n = 3), failed ileoanal procedure (n = 1), and one-stage ileal pouch-anal anastomosis (n = 3), leaving 167 patients for evaluation. Patients were defined as having chronic pouchitis (> 3 episodes of pouchitis) or no pouchitis (< or = 3 episodes of pouchitis). Potential risk factors included number of operations used to perform ileal pouch-anal anastomosis, fulminant ulcerative colitis with two-stage operation, duration of diverting ileostomy after pouch formation, primary sclerosing cholangitis, other extraintestinal manifestations of ulcerative colitis, preoperative liver function tests, duration of ulcerative colitis, and the occurrence of postoperative complications. Initial univariate analysis was performed on all risk factors. Multivariate analysis was performed on all univariate risk factors with P values < 0.2. The prevalence of chronic pouchitis in our population was 46 percent. The following variables were identified during univariate analysis and entered into a multivariate model: preoperative serum albumin (P = 0.07), PSC (P = 0.126), duration of diverting ileostomy (P = 0.111), fulminant ulcerative colitis with two-stage operation, (P = 0.051), the presence of postoperative complications (P = 0.031), and the type of postoperative complications (anastomotic complications, P = 0.013). Patients who did not undergo diverting ileostomy at the time of their ileal pouch-anal anastomosis trended toward a lower likelihood of developing chronic pouchitis (P = 0.06). Multivariate analysis showed that patients with postoperative complications (53 percent, P = 0.042), specifically anastomotic complications, were more likely to develop chronic pouchitis (P = 0.005). Eight percent of patients had primary sclerosing cholangitis and 11 percent of patients had at least one extraintestinal manifestation of ulcerative colitis. Patients with primary sclerosing cholangitis were not more likely to develop chronic pouchitis (P = 0.168). Patients with extraintestinal manifestations also were not more likely to develop chronic pouchitis (P = 0.273). Chronic pouchitis is a frequent complication after ileal pouch-anal anastomosis. In this study patients with primary sclerosing cholangitis or other extraintestinal manifestations of ulcerative colitis were not more likely to develop chronic pouchitis. Patients with postoperative complications, specifically anastomotic complications after ileal pouch-anal anastomosis, were more likely to develop chronic pouchitis and may benefit from early strategies to prevent pouchitis.


Photon lifetime in a cavity containing a slow-light medium.
We investigate experimentally the lifetime of the photons in a cavity containing a medium exhibiting strong positive dispersion. This intracavity positive dispersion is provided by a metastable helium gas at room temperature in the electromagnetically induced transparency regime, in which light propagates at a group velocity of the order of 10⁴ m·s⁻¹. The results definitely prove that the lifetime of the cavity photons is governed by the group velocity of light in the cavity and not its phase velocity.


Health Care Transition Preparation and Experiences in a U.S. National Sample of Young Adults With Type 1 Diabetes.
Young adults with type 1 diabetes transitioning from pediatric to adult care are at risk for adverse outcomes. We developed a survey to evaluate transition experiences in two groups of young adults with type 1 diabetes, before (PEDS) and after (ADULT) transition to adult care. We fielded an electronic survey to young adults (18 to <30 years) at 60 T1D Exchange Clinic Registry centers. Surveys were completed by 602 young adults, 303 in the PEDS group (60% female, age 20 ± 2 years) and 299 in the ADULT group (62% female, age 24 ± 3 years). In the PEDS group, mean anticipated transition age was 22 ± 2 years; 64% remained in pediatric care because of emotional attachment to the provider. The ADULT group transitioned at age 19 ± 2 years, mainly after pediatric provider recommendation. More than 80% of respondents reported receiving counseling on type 1 diabetes self-management and screening tests from pediatric providers, but less than half (43% PEDS and 33% ADULT) reported discussing reproductive health. In the PEDS group, half had discussed transfer with pediatric providers. Of the ADULT participants, 63% received an adult provider referral, and 66% felt mostly/completely prepared to transition. ADULT participants with fewer pretransition pediatric visits or who felt unprepared for transition had increased odds of gaps >6 months between pediatric and adult care. Receipt of transition preparation counseling was not associated with self-reported hemoglobin A1c <7.0% in either group. These results support the need for intensive efforts to integrate transition preparation counseling and care coordination into pediatric type 1 diabetes care.


Prevention of fall incidents in patients with a high risk of falling: design of a randomised controlled trial with an economic evaluation of the effect of multidisciplinary transmural care.
Annually, about 30% of the persons of 65 years and older falls at least once and 15% falls at least twice. Falls often result in serious injuries, such as fractures. Therefore, the prevention of accidental falls is necessary. The aim is to describe the design of a study that evaluates the efficacy and cost-effectiveness of a multidisciplinary assessment and treatment of multiple fall risk factors in independently living older persons with a high risk of falling. The study is designed as a randomised controlled trial (RCT) with an economic evaluation. Independently living persons of 65 years and older who recently experienced a fall are interviewed in their homes and screened for risk of recurrent falling using a validated fall risk profile. Persons at low risk of recurrent falling are excluded from the RCT. Persons who have a high risk of recurrent falling are blindly randomised into an intervention (n = 100) or usual care (n = 100) group. The intervention consists of a multidisciplinary assessment and treatment of multifactorial fall risk factors. The transmural multidisciplinary approach entails close cooperation between geriatrician, primary care physician, physical therapist and occupational therapist and can be extended with other specialists if relevant. A fall calendar is used to record falls during one year of follow-up. Primary outcomes are time to first and second falls. Three, six and twelve months after the home visit, questionnaires for economic evaluation are completed. After one year, during a second home visit, the secondary outcome measures are reassessed and the adherence to the interventions is evaluated. Data will be analysed according to the intention-to-treat principle and also an on-treatment analysis will be performed. Strengths of this study are the selection of persons at high risk of recurrent falling followed by a multidisciplinary intervention, its transmural character and the evaluation of adherence. If proven effective, implementation of our multidisciplinary assessment followed by treatment of fall risk factors will reduce the incidence of falls. Current Controlled Trials ISRCTN11546541.


Screening natural libraries of human milk oligosaccharides against lectins using CaR-ESI-MS.
Human milk oligosaccharides (HMOs) afford many health benefits to breast-fed infants, such as protection against infection and regulation of the immune system, through the formation of non-covalent interactions with protein receptors. However, the molecular details of these interactions are poorly understood. Here, we describe the application of catch-and-release electrospray ionization mass spectrometry (CaR-ESI-MS) for screening natural libraries of HMOs against lectins. The HMOs in the libraries were first identified based on molecular weights (MWs), ion mobility separation arrival times (IMS-ATs) and collision-induced dissociation (CID) fingerprints of their deprotonated anions. The libraries were then screened against lectins and the ligands identified from the MWs, IMS-ATs and CID fingerprints of HMOs released from the lectin in the gas phase. To demonstrate the assay, four fractions, extracted from pooled human milk and containing ≥35 different HMOs, were screened against a C-terminal fragment of human galectin-3 (hGal-3C), for which the HMOs specificities have been previously investigated, and a fragment of the blood group antigen-binding adhesin (BabA) from Helicobacter pylori, for which the HMO specificities have not been previously established. The structures of twenty-one ligands, corresponding to both neutral and acidic HMOs, of hGal-3C were identified; all twenty-one were previously shown to be ligands for this lectin. The presence of HMO ligands at six other MWs was also ascertained. Application of the assay to BabA revealed nineteen specific HMO structures that are recognized by the protein and HMO ligands at two other MWs. Notably, it was found that BabA exhibits broad specificity for HMOs, and recognizes both neutral HMOs, including non-fucosylated ones, and acidic HMOs. The results of competitive binding experiments indicate that HMOs can interact with BabA at previously unknown binding sites. The affinities of eight purified HMOs for BabA were measured by ESI-MS and found to be in the 103 M-1 to 104 M-1 range.


Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells.
The heat and capsaicin receptor, TRPV1, is required for the detection of painful heat by primary afferent pain fibers (nociceptors), but the extent to which functional TRPV1 channels are expressed in the CNS is debated. Because previous evidence is based primarily on indirect physiological responses to capsaicin, here we genetically modified the Trpv1 locus to reveal, with excellent sensitivity and specificity, the distribution of TRPV1 in all neuronal and non-neuronal tissues. In contrast to reports of widespread and robust expression in the CNS, we find that neuronal TRPV1 is primarily restricted to nociceptors in primary sensory ganglia, with minimal expression in a few discrete brain regions, most notably in a contiguous band of cells within and adjacent to the caudal hypothalamus. We confirm hypothalamic expression in the mouse using several complementary approaches, including in situ hybridization, calcium imaging, and electrophysiological recordings. Additional in situ hybridization experiments in rat, monkey, and human brain demonstrate that the restricted expression of TRPV1 in the CNS is conserved across species. Outside of the CNS, we find TRPV1 expression in a subset of arteriolar smooth muscle cells within thermoregulatory tissues. Here, capsaicin increases calcium uptake and induces vasoconstriction, an effect that likely counteracts the vasodilation produced by activation of neuronal TRPV1.


Extracting a biologically relevant latent space from cancer transcriptomes with variational autoencoders.
The Cancer Genome Atlas (TCGA) has profiled over 10,000 tumors across 33 different cancer-types for many genomic features, including gene expression levels. Gene expression measurements capture substantial information about the state of each tumor. Certain classes of deep neural network models are capable of learning a meaningful latent space. Such a latent space could be used to explore and generate hypothetical gene expression profiles under various types of molecular and genetic perturbation. For example, one might wish to use such a model to predict a tumor's response to specific therapies or to characterize complex gene expression activations existing in differential proportions in different tumors. Variational autoencoders (VAEs) are a deep neural network approach capable of generating meaningful latent spaces for image and text data. In this work, we sought to determine the extent to which a VAE can be trained to model cancer gene expression, and whether or not such a VAE would capture biologically-relevant features. In the following report, we introduce a VAE trained on TCGA pan-cancer RNA-seq data, identify specific patterns in the VAE encoded features, and discuss potential merits of the approach. We name our method "Tybalt" after an instigative, cat-like character who sets a cascading chain of events in motion in Shakespeare's "Romeo and Juliet". From a systems biology perspective, Tybalt could one day aid in cancer stratification or predict specific activated expression patterns that would result from genetic changes or treatment effects.


Phorbol myristate acetate stimulates phagosome-lysosome fusion in mouse macrophages.
The effect of the tumor promoter phorbol myristate acetate (PMA) on phagosome-lysosome (P-L) fusion in mouse macrophages has been studied using a previously described (10) fluorescence assay. Treatment with 0.1--1.0 microgram PMA/ml caused a striking increase in the rate and extent of P-L fusion. Exposure of cells to phorbol, free myristate, or the monoesters of PMA did not reproduce this effect. Macrophages required from 2 to 3 h of pretreatment to express maximal P-L fusion, and this was maintained for at least 20 h when cells were returned to PMA-free medium. Catalase, superoxide dismutase, indomethacin, and hydrocortisone, agents that are known to block the effect of PMA on H2O2, O2-, prostaglandins, or plasminogen activator, did not affect the stimulation of P-L fusion by PMA. The protein-synthesis inhibitors puromycin and cycloheximide did block the PMA effect under conditions in which the high fusion rate of 4-d cells was not affected. Labeled PMA was rapidly taken up by macrophages, with a plateau of uptake at approximately 3 h. When cells were returned to PMA-free medium, cel-associated label was rapidly released, returning to background level within 1 h. The released label was found to be a metabolite of PMA by thin-layer chromatography. This product migrated between the monoester phorbol-12-myristate and free phorbol. Rapid metabolism of PMA was also observed by a macrophage cell line, J774, and, to a lesser extent, by primary rat embryo fibroblasts.


Repair of Bronchial Anastomosis Following Lung Transplantation.
Bronchial anastomotic complications are reported in 2 to 18% of patients after lung transplantation. The majority of complications can be managed with bronchoscopic intervention. When extensive dehiscence is present, surgical intervention can be entertained. Between March 1, 2006, and December 31, 2019, our program performed 244 lung transplantations. We conducted a retrospective review of our patient cohort and identified patients who suffered from significant anastomotic complications that required surgical interventions. Twenty-eight and 216 patients underwent single and bilateral lung transplantations, respectively. Eighteen patients developed airway complications (7.4%). The incidence of anastomotic complications was 5.2% (24 complications for a total of 460 bronchial anastomoses). Four patients were managed conservatively. The majority of the bronchial anastomotic complications were managed endoscopically (eight patients). Four patients with associated massive air leak underwent repair of the bronchial anastomosis and two patients were retransplanted because they developed severe distal airway stenosis. Bronchial anastomotic complications are a major cause of morbidity in lung transplantation. The majority of cases can be managed bronchoscopically. In more severe cases associated with massive air leak or imminent massive hemoptysis from bronchopulmonary arterial fistula, surgical intervention is necessary. Aortic homograft interposition along with vascularized pedicle wrapping may be a viable option to re-establish airway continuity when tension-free bronchial anastomotic revision is not possible. In cases with smaller bronchial defects, primary repair with utilization of a vascularized flap can be effective as treatment option.


The effect of stimulants on nocturnal motor activity and sleep quality in adults with ADHD: an open-label case-control study.
Sleep disturbances are common in adults with attention-deficit/hyperactivity disorder (ADHD). In a case-control study, adult ADHD was associated with increased nocturnal motor activity and reduced self-perceived quality of sleep. Eight adults with DSM-IV-diagnosed ADHD (combined type, N = 7; inattentive type, N = 1) were treated with stimulants in open-label form at 8:00 a.m., 12:00 noon, and 4:00 p.m. The mean daily dose was 51 mg of methylphenidate (range, 30-90 mg) in 7 subjects and 30 mg of dextroamphetamine in 1 subject. Actimeters were used to assess nocturnal motor activity during 6 consecutive nights both at baseline and after 3 weeks of treatment. The data were compared with those of 8 matched normal controls. ADHD patients slept worse and showed significantly higher nocturnal motor activity at baseline compared with controls. No baseline differences between patients and controls were found in sleep latency, number of awakenings, and total time in bed. Changes from baseline to week 3 within the ADHD patients indicated improvement of sleep quality (p = .05) and reduction of Activity Level (p = .10) and Movement Index (p = .07) scores. When within-group changes were compared between ADHD subjects and controls, treatment with stimulants tended to be associated with a reduction of Activity Level (p < .01) and Movement Index (p = .04) scores and improved sleep quality (p = .02) in ADHD patients. Sleep latency, number of awakenings, and total time in bed were unaffected in within-group and between-group analyses. The results should be interpreted cautiously given the open-label design and small sample size. Further study is warranted into the influence of stimulants on sleep in larger samples of ADHD patients by using controlled designs, multiple dose levels, and polysomnographic measures.


Longitudinal analysis of the development of filarial infection and antifilarial immunity in a cohort of Haitian children.
Longitudinal studies are being conducted in Leogane, Haiti to investigate the relationship between acquisition of filarial infection and development of antifilarial immunity as well as the impact of maternal infection on this relationship. Children (0-24 months of age) residing in Leogane were enrolled and were examined periodically to monitor parasitologic status and to collect serum for antigen and antifilarial antibody determinations. To examine the development of filarial antigenemia and antifilarial antibody responses in this cohort, serum samples were selected from a cross section of the population at two (n = 82) and four years of age (n = 76). Antigen prevalence increased from 6% among two-year-olds to more than 30% among four-year-olds, but in only one four-year-old child were microfilaria detected in a 20-microl smear. The proportion of antigen-positive children born to antigen-positive mothers was higher than the proportion of antigen-positive children born to antigen-negative mothers (9.8% versus 0% for two-year-olds; P = 0.15; and 39.6% versus 22.7% for four-year-olds; P = 0.18). Antifilarial IgG4 levels were significantly higher among antigen-positive children at both two and four years of age (P < 0.001). In analyses of paired samples, antifilarial IgG4 responses increased significantly more among children who acquired infection by four years of age than among children who remained antigen negative, whereas antifilarial IgG1 and IgG2 responses changed equally for antigen-positive and -negative children. Antifilarial antibody levels were not influenced by maternal infection status, but were significantly influenced by age, antigen status, and the neighborhood within the community. These results provide evidence that children acquire infection early in life and suggest that antifilarial antibody responses may peak in early childhood.


Transient Alpha and Beta Synchrony Underlies Preparatory Recruitment of Directional Motor Networks.
Modulations in motor cortical beta and alpha activity have been implicated in the preparation, execution, and termination of voluntary movements. The functional role of motor cortex beta activity is yet to be defined, though two opposing theories prevail. The idling cortex theory suggests that large-scale motor networks, in the absence of input, revert to an intrinsic oscillatory state. The alternative theory proposes that beta activity promotes postural tone at the expense of voluntary movement. These theories are primarily based on observations of event-related desynchronization associated with movement onset. Here, we explore the changes in alpha and beta oscillatory activity associated with the specific behavioral patterns during an established directional uncertainty paradigm. We demonstrate that, consistent with current proposals, alpha and beta desynchronization reflects a process of disengagement from existing networks to enable the creation of functional assemblies. We demonstrate that, following desynchronization, a novel signature of transient alpha synchrony underlies the recruitment of functional assemblies required for directional control. Although alpha and beta desynchronization are dependent upon the number of cues presented, they are not predictive of movement preparation. However, the transient alpha synchrony occurs only when participants have sufficient information to prepare for movement and shows a direct relationship with behavioral performance measures.


Trait dominance promotes reflexive staring at masked angry body postures.
It has been shown that dominant individuals sustain eye-contact when non-consciously confronted with angry faces, suggesting reflexive mechanisms underlying dominance behaviors. However, dominance and submission can be conveyed and provoked by means of not only facial but also bodily features. So far few studies have investigated the interplay of body postures with personality traits and behavior, despite the biological relevance and ecological validity of these postures. Here we investigate whether non-conscious exposure to bodily expressions of anger evokes reflex-like dominance behavior. In an interactive eye-tracking experiment thirty-two participants completed three social dominance tasks with angry, happy and neutral facial, bodily and face and body compound expressions that were masked from consciousness. We confirmed our predictions of slower gaze-aversion from both non-conscious bodily and compound expressions of anger compared to happiness in high dominant individuals. Results from a follow-up experiment suggest that the dominance behavior triggered by exposure to bodily anger occurs with basic detection of the category, but not recognition of the emotional content. Together these results suggest that dominant staring behavior is reflexively driven by non-conscious perception of the emotional content and triggered by not only facial but also bodily expression of anger.


Epitope map of human immunodeficiency virus type 1 gp41 derived from 47 monoclonal antibodies produced by immunization with oligomeric envelope protein.
The biologically relevant form of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein is oligomeric, with the major points of contact between oligomeric partners located in the ectodomain of gp41. To identify and map conserved epitopes and regions in gp41 where structure is influenced by quaternary interactions, we used a panel of 38 conformation-dependent and 9 conformation-independent anti-gp41 monoclonal antibodies (MAbs) produced by immunization of mice with oligomeric Env protein. By cross-competition experiments using these MAbs and several others previously described, six distinct antigenic determinants were identified and mapped. Three of these determinants are conformational in nature and dependent in part on Env oligomeric structure. MAbs to two of these determinants were broadly cross-reactive with Env proteins derived from primary virus strains. The prevalence of antibodies in HIV-1-positive human sera to the antigenic determinants was determined by the ability of such sera to block binding of MAbs to Env protein. Strong blocking activity that correlated with cross-reactivity was found.


Quality and correlates of medical record documentation in the ambulatory care setting.
Documentation in the medical record facilitates the diagnosis and treatment of patients. Few studies have assessed the quality of outpatient medical record documentation, and to the authors' knowledge, none has conclusively determined the correlates of chart documentation. We therefore undertook the present study to measure the rates of documentation of quality of care measures in an outpatient primary care practice setting that utilizes an electronic medical record. We reviewed electronic medical records from 834 patients receiving care from 167 physicians (117 internists and 50 pediatricians) at 14 sites of a multi-specialty medical group in Massachusetts. We abstracted information for five measures of medical record documentation quality: smoking history, medications, drug allergies, compliance with screening guidelines, and immunizations. From other sources we determined physicians' specialty, gender, year of medical school graduation, and self-reported time spent teaching and in patient care. Among internists, unadjusted rates of documentation were 96.2% for immunizations, 91.6% for medications, 88% for compliance with screening guidelines, 61.6% for drug allergies, 37.8% for smoking history. Among pediatricians, rates were 100% for immunizations, 84.8% for medications, 90.8% for compliance with screening guidelines, 50.4% for drug allergies, and 20.4% for smoking history. While certain physician and patient characteristics correlated with some measures of documentation quality, documentation varied depending on the measure. For example, female internists were more likely than male internists to document smoking history (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.27 - 2.83) but were less likely to document drug allergies (OR, 0.51; 95% CI, 0.35 - 0.75). Medical record documentation varied depending on the measure, with room for improvement in most domains. A variety of characteristics correlated with medical record documentation, but no pattern emerged. Further study could lead to targeted interventions to improve documentation.


Multichannel-Hadamard calibration of high-order adaptive optics systems.
we present a novel technique of calibrating the interaction matrix for high-order adaptive optics systems, called the multichannel-Hadamard method. In this method, the deformable mirror actuators are firstly divided into a series of channels according to their coupling relationship, and then the voltage-oriented Hadamard method is applied to these channels. Taking the 595-element adaptive optics system as an example, the procedure is described in detail. The optimal channel dividing is discussed and tested by numerical simulation. The proposed method is also compared with the voltage-oriented Hadamard only method and the multichannel only method by experiments. Results show that the multichannel-Hadamard method can produce significant improvement on interaction matrix measurement.


Choice making to promote adaptive behavior for students with emotional and behavioral challenges.
Two analyses investigated the effects of choice making on the responding of elementary school students with emotional and behavioral challenges. In the first analysis, 2 participants were given choices from menus of academic tasks, all of which were pertinent to their educational objectives in English and spelling, respectively. Reversal designs showed that the choice-making conditions increased task engagement and reduced disruptive behavior for both students. An additional analysis was performed with a 3rd student in an effort to further distinguish the effects of choice making from preference. In this study, one of the no-choice phases was yoked to a previous choice-making condition. This analysis demonstrated that the choice-making condition was superior to baseline and yoked control phases as determined by levels of task engagement and disruptive behavior. The findings of the two analyses contribute information relevant to students with emotional and behavioral disorders, and to a growing literature on the desirable effects of choice making for students with disabilities and challenging behaviors.


Storing Tooth Segments for Optimal Esthetics.
A fractured whole crown segment can be reattached to its remnant; crowns from extracted teeth may be used as pontics in splinting techniques. We aimed to evaluate the effect of different storage solutions on tooth segment optical properties after different durations. Sixty central incisor crowns were divided into 6 groups (n = 10); Group 1 was kept dry; Groups 2, 3, 4, 5, and 6 were placed in an isotonic solution, water, milk, saliva, and casein-phosphopeptide-amorphous-calcium-phosphate (CPP-ACP), respectively, for 30 min, 12 h, 1 day, 1 week, and 3 weeks. Color values were measured using a colorimeter. Data were analyzed with Kruskal-Wallis tests, Mann-Whitney U-tests, and Friedman Wilcoxon tests with Bonferroni stepwise corrections (p < 0.05). ΔE* values varied from 0.3 to 15.3 over the 3 week period. Group 1 demonstrated the greatest color changes over all durations; Group 6 exhibited the least. L*, a*, b*, and ΔE* values varied between time periods in all groups; the differences were significant (p < 0.01), except for L* and ΔE* values in Group 2 and a* values in Group 6 (p > 0.01). Comparing ΔE* values, Group 6 was significantly different from the other groups for all durations (p < 0.01), except Group 4. A CPP-ACP complex solution seems a good choice for tooth fragment storage. Milk and saliva solutions may cause perceptible color changes if tooth fragments are stored for 3 weeks before use.


Quantifying resilience of multiple ecosystem services and biodiversity in a temperate forest landscape.
Resilience is increasingly being considered as a new paradigm of forest management among scientists, practitioners, and policymakers. However, metrics of resilience to environmental change are lacking. Faced with novel disturbances, forests may be able to sustain existing ecosystem services and biodiversity by exhibiting resilience, or alternatively these attributes may undergo either a linear or nonlinear decline. Here we provide a novel quantitative approach for assessing forest resilience that focuses on three components of resilience, namely resistance, recovery, and net change, using a spatially explicit model of forest dynamics. Under the pulse set scenarios, we explored the resilience of nine ecosystem services and four biodiversity measures following a one-off disturbance applied to an increasing percentage of forest area. Under the pulse + press set scenarios, the six disturbance intensities explored during the pulse set were followed by a continuous disturbance. We detected thresholds in net change under pulse + press scenarios for the majority of the ecosystem services and biodiversity measures, which started to decline sharply when disturbance affected >40% of the landscape. Thresholds in net change were not observed under the pulse scenarios, with the exception of timber volume and ground flora species richness. Thresholds were most pronounced for aboveground biomass, timber volume with respect to the ecosystem services, and ectomycorrhizal fungi and ground flora species richness with respect to the biodiversity measures. Synthesis and applications. The approach presented here illustrates how the multidimensionality of stability research in ecology can be addressed and how forest resilience can be estimated in practice. Managers should adopt specific management actions to support each of the three components of resilience separately, as these may respond differently to disturbance. In addition, management interventions aiming to deliver resilience should incorporate an assessment of both pulse and press disturbances to ensure detection of threshold responses to disturbance, so that appropriate management interventions can be identified.


Patients' and caregivers' experiences of using continuous glucose monitoring to support diabetes self-management: qualitative study.
Continuous glucose monitoring (CGM) enables users to view real-time interstitial glucose readings and provides information on the direction and rate of change of blood glucose levels. Users can also access historical data to inform treatment decisions. While the clinical and psychological benefits of CGM are well established, little is known about how individuals use CGM to inform diabetes self-management. We explored participants' experiences of using CGM in order to provide recommendations for supporting individuals to make optimal use of this technology. In-depth interviews (n = 24) with adults, adolescents and parents who had used CGM for ≥4 weeks; data were analysed thematically. Participants found CGM an empowering tool because they could access blood glucose data effortlessly, and trend arrows enabled them to see whether blood glucose was rising or dropping and at what speed. This predicative information aided short-term lifestyle planning and enabled individuals to take action to prevent hypoglycaemia and hyperglycaemia. Having easy access to blood glucose data on a continuous basis also allowed participants to develop a better understanding of how insulin, activity and food impacted on blood glucose. This understanding was described as motivating individuals to make dietary changes and break cycles of over-treating hypoglycaemia and hyperglycaemia. Participants also described how historical CGM data provided a more nuanced picture of blood glucose control than was possible with blood glucose self-monitoring and, hence, better information to inform changes to background insulin doses and mealtime ratios. However, while participants expressed confidence making immediate adjustments to insulin and lifestyle to address impending hypoglycaemia and hypoglycaemia, most described needing and expecting health professionals to interpret historical CGM data and determine changes to background insulin doses and mealtime ratios. While alarms could reinforce a sense of hypoglycaemic safety, some individuals expressed ambivalent views, especially those who perceived alarms as signalling personal failure to achieve optimal glycaemic control. CGM can be an empowering and motivational tool which enables participants to fine-tune and optimize their blood glucose control. However, individuals may benefit from psycho-social education, training and/or technological support to make optimal use of CGM data and use alarms appropriately.


Ultrasound Localization of Resuscitative Endovascular Balloon Occlusion of the Aorta in a Human Cadaver Model.
Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a method of gaining proximal control of noncompressible torso hemorrhage (NCTH). Catheter placement is traditionally confirmed with fluoroscopy, but few studies have evaluated whether ultrasound (US) can be used. Using a pressurized human cadaver model, a certified REBOA placer was shown one of four randomized cards that instructed them to place the REBOA either correctly or incorrectly in Zone 1 (the distal thoracic aorta extending from the celiac artery to the left subclavian artery) or Zone 3 (in the distal abdominal aorta, from the aortic bifurcation to the lowest renal artery). Once the REBOA was placed, 10 US-trained locators were asked to confirm balloon placement via US. The participants were given 3 minutes to determine whether the catheter had been correctly placed, repeating this 20 times on two cadavers. Overall, US exhibited an average sensitivity of 83%, specificity of 76%, and accuracy of 80%. For Zone 1, US showed a sensitivity of 78% and specificity of 83%, and for Zone 3, a sensitivity of 88% and specificity of 76%. In addition, US exhibited a likelihood positive ratio (LR+) of 3.73 and a likelihood negative ratio (LR-) of 0.22 for either position, with similar numbers for Zone 1 (+4.57, -0.26) and Zone 3 (+3.16, -0.16). Ultrasound could prove to be a useful tool for confirming placement of a REBOA catheter, especially in austere environments.


Amelioration of acetaminophen induced hepatotoxicity by methanolic extract of pomegranate peels in rats.
To observe the ameliorating effect by methanolic extract of pomegranate peel in acetaminophen-induced hepatotoxicity. The randomised controlled study was conducted from July 2013 to June 2014 at the University of Health Sciences, Lahore, Pakistan, and comprised rats that were randomly divided into three equal groups. Control group A was given normal saline (5ml/kg), whereas group B and C were given 750mg/kg acetaminophen intraperitoneally dissolved in normal saline (5ml/kg) on 1st day of experiment. From Day 2 till day 14, group A and B were given distilled water (5ml/kg), while group C was given 50mg/kg methanolic extract of pomegranate peel dissolved in distilled water (5ml/kg) orally. On day 15, blood was collected through cardiac puncture, and livers were removed and processed for histological examination. There were 24 rats weighing 175±25gm each. Each group had 8(33.3%) rats. Mean liver aspartate aminotransferase at the end of the experiment in groups A, B and C were 97.88±19.45, 148.25±16.48 and 96.13±17.95U/L, while alanine transaminase levels were 51.50±15.38, 96.75±10.91 and 49.63±12.08 U/L (p<0.05 each) On histological examination of group B, the normal hepatic architecture was distorted with loss of classically arranged hepatic cords. Vascular congestion was present with centrilobular necrosis, marked by pyknotic nuclei and vacuoles. Acetaminophen is hepatotoxic and methanolic extract of pomegranate peel ameliorated the hepatic picture probably because of its antioxidant properties.


The Pseudomonas fluorescens Siderophore Pyoverdine Weakens Arabidopsis thaliana Defense in Favor of Growth in Iron-Deficient Conditions.
Pyoverdines are siderophores synthesized by fluorescent Pseudomonas spp. Under iron-limiting conditions, these high-affinity ferric iron chelators are excreted by bacteria in the soil to acquire iron. Pyoverdines produced by beneficial Pseudomonas spp. ameliorate plant growth. Here, we investigate the physiological incidence and mode of action of pyoverdine from Pseudomonas fluorescens C7R12 on Arabidopsis (Arabidopsis thaliana) plants grown under iron-sufficient or iron-deficient conditions. Pyoverdine was provided to the medium in its iron-free structure (apo-pyoverdine), thus mimicking a situation in which it is produced by bacteria. Remarkably, apo-pyoverdine abolished the iron-deficiency phenotype and restored the growth of plants maintained in the iron-deprived medium. In contrast to a P. fluorescens C7R12 strain impaired in apo-pyoverdine production, the wild-type C7R12 reduced the accumulation of anthocyanins in plants grown in iron-deficient conditions. Under this condition, apo-pyoverdine modulated the expression of around 2,000 genes. Notably, apo-pyoverdine positively regulated the expression of genes related to development and iron acquisition/redistribution while it repressed the expression of defense-related genes. Accordingly, the growth-promoting effect of apo-pyoverdine in plants grown under iron-deficient conditions was impaired in iron-regulated transporter1 and ferric chelate reductase2 knockout mutants and was prioritized over immunity, as highlighted by an increased susceptibility to Botrytis cinerea This process was accompanied by an overexpression of the transcription factor HBI1, a key node for the cross talk between growth and immunity. This study reveals an unprecedented mode of action of pyoverdine in Arabidopsis and demonstrates that its incidence on physiological traits depends on the plant iron status.


Multiplex Real-time PCR Detection and Differentiation of Colletotrichum Species Infecting Soybean.
Colletotrichum species are fungal plant pathogens of worldwide significance. Colletotrichum species were isolated from soybean with anthracnose symptoms in five states in the United States from 2009 to 2013. Among 240 isolates collected, four Colletotrichum species were initially identified by morphological and sequence analysis, including C. chlorophyti, C. incanum, C. truncatum, and Colletotrichum sp. (henceforth Glomerella glycines, the name of its sexual state). To increase diagnostic efficiency and accuracy, real-time multiplex PCR assays based on a double-stranded DNA-binding dye coupled with dissociation curve analysis were designed, using a region of the cytochrome c oxidase subunit 1 (cox1) gene to discern these four Colletotrichum species. Two sets of duplex, real-time PCR assays were established and species differentiation was based upon amplicon melting point temperatures (Tm) in the dissociation curve analysis. The Set 1 duplex assay distinguished C. chlorophyti and G. glycines, and the Set 2 duplex assay distinguished C. incanum and C. truncatum. Successful detection was achieved with as little as 1 pg DNA. The assays were especially useful for differentiating C. chlorophyti, C. incanum, and C. truncatum, which have similar morphological features. Colletotrichum gloeosporioides, another pathogen associated with soybean anthracnose, was not resolved from G. glycines by the melting curve analysis. The two duplex real-time PCR assays were used to screen more than 200 purified Colletotrichum isolates, showing that they were rapid and effective methods to detect and differentiate Colletotrichum species infecting soybean.


A Novel Approach to Safer Glucocorticoid Receptor-Targeted Anti-lymphoma Therapy via REDD1 (Regulated in Development and DNA Damage 1) Inhibition.
Glucocorticoids are widely used for therapy of hematologic malignancies. Unfortunately, chronic treatment with glucocorticoids commonly leads to adverse effects including skin and muscle atrophy and osteoporosis. We found recently that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. Here, we tested whether REDD1 suppression makes glucocorticoid-based therapy of blood cancer safer. Unexpectedly, approximately 50% of top putative REDD1 inhibitors selected by bioinformatics screening of Library of Integrated Network-Based Cellular Signatures database (LINCS) were PI3K/Akt/mTOR inhibitors. We selected Wortmannin, LY294002, and AZD8055 for our studies and showed that they blocked basal and glucocorticoid-induced REDD1 expression. Moreover, all PI3K/mTOR/Akt inhibitors modified glucocorticoid receptor function shifting it toward therapeutically important transrepression. PI3K/Akt/mTOR inhibitors enhanced anti-lymphoma effects of Dexamethasone in vitro and in vivo, in lymphoma xenograft model. The therapeutic effects of PI3K inhibitor+Dexamethasone combinations ranged from cooperative to synergistic, especially in case of LY294002 and Rapamycin, used as a previously characterized reference REDD1 inhibitor. We found that coadministration of LY294002 or Rapamycin with Dexamethasone protected skin against Dexamethasone-induced atrophy, and normalized RANKL/OPG ratio indicating a reduction of Dexamethasone-induced osteoporosis. Together, our results provide foundation for further development of safer and more effective glucocorticoid-based combination therapy of hematologic malignancies using PI3K/Akt/mTOR inhibitors.


High time to omit oxygen therapy in ST elevation myocardial infarction.
Supplemental oxygen (O2) therapy in patients with chest pain has been a cornerstone in the treatment of suspected myocardial infarction (MI). Recent randomized controlled trials have, however, shown that supplemental O2 therapy has no positive nor negative effects on cardiovascular functions, mortality, morbidity or pain in normoxic patients with suspected MI and foremost patients with ST Elevation Myocardial Infarction (STEMI). O2 therapy in normoxic STEMI patients should therefore be omitted. More studies are needed in discussing hemodynamically unstable STEMI patients, as well as patients with non-STEMI, unstable angina and other emergency conditions.


A case of behavioural diversification in male floral function - the evolution of thigmonastic pollen presentation.
Obvious movements of plant organs have fascinated scientists for a long time. They have been studied extensively, but few behavioural studies to date have dealt with them, and hardly anything is known about their evolution. Here, we present a large experimental dataset on the stamen movement patterns found in the Loasaceae subfam. Loasoideae (Cornales). An evolutionary transition from autonomous-only to a combination of autonomous and thigmonastic stamen movement with increased complexity was experimentally demonstrated. We compare the stamen movement patterns with extensive pollinator observations and discuss it in the context of male mating behavior. Thigmonastic pollen presentation via stamen movements appears to be a crucial component of floral adaptation to pollinator behaviour, evolving in concert with complex adjustments of flower signal, reward and morphology. We hypothesize that rapid adjustments of pollen presentation timing may play a significant role in the diversification of this plant group, representing a striking example for the evolutionary significance of plant behaviour.


Potential Role of Endothelin in Early Vascular Aging.
Early vascular aging is a process associated with gradual alterations in the vessels, regarding their structure and function, taking a more rapid course than normal biological aging in the arteries. In the presence of cardiovascular disease, these age-associated alterations are accelerated, contributing in the appearance or the progression of cardiovascular disease, such as high blood pressure, dyslipidemia, smoking and diabetes. Endothelin-1 (ET-1) is the most abundant and important endothelin produced by vascular cells. ET-1 exerts its biological actions through the activation of two receptors: ETA and ETB. Many important functions are mediated by the activation of these receptors, such as cardiovascular remodeling, vasoconstriction, cell proliferation and differentiation, production of extracellular matrix, and water and sodium secretion control. ETA receptor seems to participate in the pathogenesis and development of diseases, such as diabetes, atherosclerosis, systemic and pulmonary hypertension, and cardiac remodeling after myocardial ischemia, whereas ETB receptor seems to prevent the overstimulation of ETA receptor, acting as a clearance receptor. Increased ET-1 system activity may contribute to vascular dysfunction in aging via multiple pathways, such as direct hemodynamic effects, vascular oxidative stress, inflammatory activity, mitogenic stimulation of the vascular smooth muscle cells and fibrotic processes. Endothelin receptor antagonists were considered to be used for the treatment of some diseases like hypertension, diabetes and chronic kidney disease. However, besides pulmonary hypertension, this class is not in clinical use because of the side effects and the availability of safer drugs for the treatment of these diseases.


Calculations of vibrationally resonant sum- and difference-frequency-generation spectra of chiral molecules in solutions: three-wave-mixing vibrational optical activity.
Determining absolute configuration of chiral molecule can be achieved by using vibrational optical activity (VOA) measurement methods, such as vibrational circular dichroism and Raman optical activity (ROA). Recently, vibrationally resonant sum frequency generation and difference frequency generation utilizing circularly polarized beams were theoretically studied and shown that they can be alternative and complementary VOA measurement techniques [S. Cheon and M. Cho, Phys. Rev. A 71, 013808 (2005); J. Phys. Chem. A 113, 2438 (2009)]. Even for randomly oriented chiral molecules in solutions, the sum- and difference-frequency-generation signals induced by linearly polarized incident beams with mutually perpendicular polarization directions can be nonzero and are determined by the optical activity hyperpolarizability given by a product of antisymmetric Raman tensor and vibrational transition dipole. If one of the beams involved in the three-wave-mixing processes is circularly polarized and if the difference signal is measured, not only the same optical activity hyperpolarizability but also that including electric quadrupole-ROA tensor are required to determine the signals. Here, we carried out quantum chemistry calculations to obtain these quantities for a representative chiral molecule, (S)-methyl lactate, and numerically simulated the corresponding spectra. It is shown that the circular polarization three-wave-mixing signal intensities are quantitatively similar to those of the linear polarization three-wave-mixing signals, respectively, and that they are sensitive to the absolute configuration of chiral molecule. The calculation results thus suggest that these two novel techniques will be of use in studying molecular chirality even in time domain, once polarization-modulated ultrashort pulses are used to carry out circular polarization three-wave-mixing experiments.


Transcriptional profiling of Legionella pneumophila biofilm cells and the influence of iron on biofilm formation.
In aquatic environments, biofilms constitute an ecological niche where Legionella pneumophila persists as sessile cells. However, very little information on the sessile mode of life of L. pneumophila is currently available. We report here the development of a model biofilm of L. pneumophila strain Lens and the first transcriptome analysis of L. pneumophila biofilm cells. Global gene expression analysis of sessile cells as compared to two distinct populations of planktonic cells revealed that a substantial proportion of L. pneumophila genes is differentially expressed, as 2.3 % of the 2932 predicted genes exhibited at least a twofold change in gene expression. Comparison with previous results defining the gene expression profile of replicative- and transmissive-phase Legionella suggests that sessile cells resemble bacteria in the replicative phase. Further analysis of the most strongly regulated genes in sessile cells identified two induced gene clusters. One contains genes that encode alkyl hydroperoxide reductases known to act against oxidative stress. The second encodes proteins similar to PvcA and PvcB that are involved in siderophore biosynthesis in Pseudomonas aeruginosa. Since iron has been reported to modify biofilm formation in other species, we further focused on iron control of gene expression and biofilm formation. Among the genes showing the greatest differences in expression between planktonic cells and biofilm, only pvcA and pvcB were regulated by iron concentration. A DeltapvcA L. pneumophila mutant showed no changes in biofilm formation compared to the wild-type, suggesting that the pvcA product is not mandatory for biofilm formation. However, biofilm formation by L. pneumophila wild-type and a DeltapvcA strain was clearly inhibited in iron-rich conditions.


A cascade model of mentorship for frontline health workers in rural health facilities in Eastern Uganda: processes, achievements and lessons.
There is increasing demand for trainers to shift from traditional didactic training to innovative approaches that are more results-oriented. Mentorship is one such approach that could bridge the clinical knowledge gap among health workers. This paper describes the experiences of an attempt to improve health-worker performance in maternal and newborn health in three rural districts through a mentoring process using the cascade model. The paper further highlights achievements and lessons learnt during implementation of the cascade model. The cascade model started with initial training of health workers from three districts of Pallisa, Kibuku and Kamuli from where potential local mentors were selected for further training and mentorship by central mentors. These local mentors then went on to conduct mentorship visits supported by the external mentors. The mentorship process concentrated on partograph use, newborn resuscitation, prevention and management of Post-Partum Haemorrhage (PPH), including active management of third stage of labour, preeclampsia management and management of the sick newborn. Data for this paper was obtained from key informant interviews with district-level managers and local mentors. Mentorship improved several aspects of health-care delivery, ranging from improved competencies and responsiveness to emergencies and health-worker professionalism. In addition, due to better district leadership for Maternal and Newborn Health (MNH), there were improved supplies/medicine availability, team work and innovative local problem-solving approaches. Health workers were ultimately empowered to perform better. The study demonstrated that it is possible to improve the competencies of frontline health workers through performance enhancement for MNH services using locally built capacity in clinical mentorship for Emergency Obstetric and Newborn Care (EmONC). The cascade mentoring process needed strong external mentorship support at the start to ensure improved capacity among local mentors to provide mentorship among local district staff.


Kinetics, structure, and mechanism of 8-Oxo-7,8-dihydro-2'-deoxyguanosine bypass by human DNA polymerase η.
DNA damage incurred by a multitude of endogenous and exogenous factors constitutes an inevitable challenge for the replication machinery. Cells rely on various mechanisms to either remove lesions or bypass them in a more or less error-prone fashion. The latter pathway involves the Y-family polymerases that catalyze trans-lesion synthesis across sites of damaged DNA. 7,8-Dihydro-8-oxo-2'-deoxyguanosine (8-oxoG) is a major lesion that is a consequence of oxidative stress and is associated with cancer, aging, hepatitis, and infertility. We have used steady-state and transient-state kinetics in conjunction with mass spectrometry to analyze in vitro bypass of 8-oxoG by human DNA polymerase η (hpol η). Unlike the high fidelity polymerases that show preferential insertion of A opposite 8-oxoG, hpol η is capable of bypassing 8-oxoG in a mostly error-free fashion, thus preventing GC→AT transversion mutations. Crystal structures of ternary hpol η-DNA complexes and incoming dCTP, dATP, or dGTP opposite 8-oxoG reveal that an arginine from the finger domain assumes a key role in avoiding formation of the nascent 8-oxoG:A pair. That hpol η discriminates against dATP exclusively at the insertion stage is confirmed by structures of ternary complexes that allow visualization of the extension step. These structures with G:dCTP following either 8-oxoG:C or 8-oxoG:A pairs exhibit virtually identical active site conformations. Our combined data provide a detailed understanding of hpol η bypass of the most common oxidative DNA lesion.


White matter damage along the uncinate fasciculus contributes to cognitive decline in AD and DLB.
This study investigates the patho-physiological implications of the uncinate fasciculus (UF) in the two most common forms of dementia, namely Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Forty-five consecutive patients diagnosed with either probable AD or DLB, and 16 individuals with amnesic mild cognitive impairment (a-MCI) were investigated using diffusion tensor MRI. Thirteen healthy subjects (HS) were also studied as controls. In each subject, the UF was bilaterally reconstructed by probabilistic tractography. From each UF, macroscopic volume and correspondent fractional anisotropy (FA) (an index of microscopic white matter integrity) were derived for the whole tract, and for the frontal and temporal portion of the UF. No significant between-group volumetric differences were found. In contrast, FA values from the UF were reduced bilaterally in patients with dementia (either AD or DLB) compared to HS. In addition, patients with AD showed reduced FA values compared to those with a-MCI. No significant FA difference was found between AD and DLB patients, nor between a-MCI and HS. Finally, in all patients, UF FA values were associated with neuropsychological scores at tests exploring memory and executive functions. This study indicates that the UF is remarkably damaged in patients at the stage of dementia, independently from the diagnostic form. Moreover, this UF damage seems to be driven by temporal involvement in AD, for which a prodromal stage (a-MCI) is defined.


Guillain-Barré syndrome complicating pregnancy and correlation with maternal and fetal outcome in North Eastern India: A retrospective study.
Guillain-Barré syndrome (GBS) is rare in pregnancy with an estimated incidence between 1.2 and 1.9 cases per 100,000 people annually, and it is generally accepted that it carries a high maternal risk. Most reports of GBS with pregnancy are case reports only. Purpose of this retrospective study was to find the correlation between pregnancy and GBS. Records of patients admitted in neurology division were analyzed in a tertiary care teaching hospital in the northeastern Indian pregnant female population with GBS between 15-49 years during the period of 2009-2013. We analyzed the records of 47 patients with pregnancy and GBS, evaluated and treated in our institute from August 2009 to December 2013. This is retrospective observational study done in North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS), India. Predominant form of GBS was acute inflammatory demyelinating polyneuropathy (AIDP). The weakness started from the lower limbs in majority of patients. Ten percent of women had bifacial weakness. Most of patients had good maternal and fetal outcome. Two patients received intravenous immunoglobulin (IVIG). Only two patient required ventilator supports and one patient had intrauterine death (IUD) and died due to respiratory failure. Our results indicate that risk of GBS increases in third trimester and first 2 weeks after delivery. Demyelinating variety of GBS was common in our population. GBS natural course during pregnancy is mild and showed quick recovery. Maternal and perinatal outcome was good.


Antibacterial Efficacy of Different Concentrations of Sodium Hypochlorite Gel and Solution on Enterococcus faecalis Biofilm.
This in vitro study compared the antibacterial efficacy of 2.5% sodium hypochlorite gel and 2.5% and 5.25% sodium hypochlorite solutions on Enterococcus faecalis (E. faecalis) biofilm. The root canals of 60 extracted human single-rooted teeth were contaminated with E. faecalis and incubated for 6 weeks. The samples were randomly assigned to three experimental groups and one control group (n=15). The study protocol in the experimental groups consisted of injection of 5 mL of each irrigant into the root canals. Samples were collected from the root canal walls and 1:10 serial dilutions were prepared and added to Muller Hinton Agar (MHA) plates and incubated at 37°C for 48 h. A classic colony counting technique was used for determining vital E. faecalis bacterial counts in MHA plates. The Kruskal-Wallis test was used for statistical analysis of the data. The level of significance was set at 0.05. The antibacterial effect of the irrigants in all three experimental groups was significantly greater than the control group (P<0.05), with no significant difference between 2.5% and 5.25% NaOCl solutions (P>0.05). The effect of 2.5% and 5.25% NaOCl solutions were significantly superior to 2.5% NaOCl gel (P<0.05). Under the limitations of this study, 2.5% NaOCl gel was effective in reducing E. faecalis counts; however this effect was less than that of NaOCl solutions.