Nanoscale transport of charge-transfer states in organic donor-acceptor blends.
Charge-transfer (CT) states, bound combinations of an electron and a hole on separate molecules, play a crucial role in organic optoelectronic devices. We report direct nanoscale imaging of the transport of long-lived CT states in molecular organic donor-acceptor blends, which demonstrates that the bound electron-hole pairs that form the CT states move geminately over distances of 5-10 nm, driven by energetic disorder and diffusion to lower energy sites. Magnetic field dependence reveals a fluctuating exchange splitting, indicative of a variation in electron-hole spacing during diffusion. The results suggest that the electron-hole pair of the CT state undergoes a stretching transport mechanism analogous to an 'inchworm' motion, in contrast to conventional transport of Frenkel excitons. Given the short exciton lifetimes characteristic of bulk heterojunction organic solar cells, this work confirms the potential importance of CT state transport, suggesting that CT states are likely to diffuse farther than Frenkel excitons in many donor-acceptor blends.


Precision of working memory for speech sounds.
Memory for speech sounds is a key component of models of verbal working memory (WM). But how good is verbal WM? Most investigations assess this using binary report measures to derive a fixed number of items that can be stored. However, recent findings in visual WM have challenged such "quantized" views by employing measures of recall precision with an analogue response scale. WM for speech sounds might rely on both continuous and categorical storage mechanisms. Using a novel speech matching paradigm, we measured WM recall precision for phonemes. Vowel qualities were sampled from a formant space continuum. A probe vowel had to be adjusted to match the vowel quality of a target on a continuous, analogue response scale. Crucially, this provided an index of the variability of a memory representation around its true value and thus allowed us to estimate how memories were distorted from the original sounds. Memory load affected the quality of speech sound recall in two ways. First, there was a gradual decline in recall precision with increasing number of items, consistent with the view that WM representations of speech sounds become noisier with an increase in the number of items held in memory, just as for vision. Based on multidimensional scaling (MDS), the level of noise appeared to be reflected in distortions of the formant space. Second, as memory load increased, there was evidence of greater clustering of participants' responses around particular vowels. A mixture model captured both continuous and categorical responses, demonstrating a shift from continuous to categorical memory with increasing WM load. This suggests that direct acoustic storage can be used for single items, but when more items must be stored, categorical representations must be used.


Factors influencing dentists' willingness to treat Medicaid-enrolled adolescents.
To identify factors influencing dentists' willingness to treat Medicaid-enrolled adolescents with intellectual and developmental disabilities in Washington state. Primary data were collected by a survey instrument administered in 2017 to general and pediatric dentists who were Medicaid providers (N = 512). We administered a 40-item survey, which included 20 hypothetical scenarios involving a 12-year-old Medicaid-enrolled adolescent. Based on the characteristics of the potential patient, dentists were asked to rate their willingness to treat (1 = very likely; 5 = very unlikely). We used conjoint analytic techniques to examine the relative importance of six adolescent- and family-level factors (e.g., severity of intellectual and/or developmental disability [IDD], sugar intake, toothbrushing, caregiver beliefs about fluoride, restorative needs, appointment keeping) and state Medicaid reimbursement level (35 percent, 55 percent, 85 percent of usual, customary, and reasonable amount). Analyses focused on data from 178 dentists with complete and varied responses to the scenarios. The mean age of participants was 53.8 ± 10.5 years and 10.7 percent were pediatric dentists. The holdouts correlation statistics indicated excellent fit for the conjoint model (Pearson's R = 0.99, P < 0.0001; Kendall's tau = 0.89, P < 0.0001). Reimbursement level and appointment keeping were the most important factors in dentists' willingness to treat Medicaid-enrolled adolescents (importance scores of 26.7 and 25.7, respectively). Restorative needs, caregiver beliefs about fluoride, and IDD severity were the next most important (importance scores of 15.4, 10.6, and 8.1, respectively). Sugar intake and toothbrushing behaviors were the least important. Reimbursement and appointment keeping were the most important determinants of dentists' willingness to treat Medicaid-enrolled adolescents with IDD.


Vanishing Twins Conceived Through Fresh In Vitro Fertilization: Obstetric Outcomes and Placental Pathology.
To characterize the obstetric outcomes and placental pathology in live births arising from vanishing twin pregnancies compared with nonreduced in vitro fertilization (IVF) pregnancies. This is a retrospective cohort study of live births resulting from fresh embryo transfers after IVF cycles with autologous oocytes from 2004 through 2017 at a large academic fertility center. Clinical information and pathology reports were reviewed. Placental diagnoses were coded using established nosology by expert placental pathologists. Analysis of variance, Kruskal-Wallis, Pearson's χ, and Fisher exact tests were used, as appropriate, to compare pathology categories between pregnancy outcomes. Mixed effects logistic regression models were generated to reveal the association between pregnancy outcome and placenta pathology, controlling for pregnancies arising in the same woman and various suspected confounders. Of 905 fresh autologous IVF cycles with placental pathology available for review, we identified 73 vanishing twin pregnancies (8.1%), 556 singleton pregnancies (61.4%), and 276 twin pregnancies (30.5%). Vanishing twin syndrome was not associated with preterm delivery, route of delivery, growth restriction or other obstetric outcomes as compared with IVF singleton pregnancies. However, vanishing twin syndrome pregnancies showed distinctive placental pathologies including an increased rate of small placentas (less than the 10th percentile by weight), with more anatomical abnormalities than IVF singleton pregnancies (odds ratio 1.73, 95% CI 0.94-3.19; adjusted odds ratio 2.15, 95% CI 1.08-4.28). The frequency of placental vascular and inflammatory pathologies associated with IVF vanishing twin syndrome pregnancies were similar to that of IVF singleton pregnancies. Loss of a twin after 8 weeks of gestation was not associated with greater risks of placental pathologies. In vitro fertilization pregnancies affected by vanishing twin syndrome did not have significant differences in obstetric or perinatal outcomes as compared with twin or singleton gestations. However, early twin loss was potentially associated with differences in placental development associated with a higher rate of small placentas and other anatomic pathologies.


Transgenic expression of the Ly49A natural killer cell receptor confers class I major histocompatibility complex (MHC)-specific inhibition and prevents bone marrow allograft rejection.
Natural killer (NK) cells and some T cells are endowed with receptors specific for class I major histocompatibility complex (MHC) molecules that can inhibit cellular effector functions. The function of the Ly49 receptor family has been studied in vitro, but no gene transfer experiments have directly established the role of these receptors in NK cell functions. We show here that transgenic expression of the H-2Dd-specific Ly49A receptor in all NK cells and T cells conferred class I-specific inhibition of NK cell-mediated target cell lysis as well as of T cell proliferation. Furthermore, transgene expression prevented NK cell-mediated rejection of allogeneic H-2d bone marrow grafts by irradiated mice. These results demonstrate the function and specificity of Ly49 receptors in vivo, and establish that their subset-specific expression is necessary for the discrimination of MHC-different cells by NK cells in unmanipulated mice.


Screening of Neu5Acα(2-6)gal isomer preferences of siglecs with a sialic acid microarray.
Sialic acids (Sias) are important terminal sugars on cell surfaces involved in a wide range of protein-carbohydrate interactions. Hence, agents modulating sias-mediated protein interactions are promising inhibitors or vaccine candidates. Here, we report the synthesis of Neu5Acα(2-6)Gal structural analogs and their binding to a series of siglecs. The results showed distinct binding patterns with conserved siglecs (hCD22 and mCD22) compared to rapid evolving siglecs (Siglecs -3 & -10).


Nutritional composition of commonly consumed composite dishes from rural villages in Empangeni, KwaZulu-Natal, South Africa.
Accurate nutrient composition data for composite dishes unique to a population is essential for the development of a nutrient database and the calculation of dietary intake. The present study aimed to provide the nutritional composition of composite dishes frequently consumed in rural KwaZulu-Natal, South Africa. Commonly consumed composite dishes were identified using 24-h recalls collected from 79 randomly selected community members. Multiple recipes were collected for each reported dish. The mean nutritional composition of each dish was calculated per 100 g using the nutribase clinical nutrition manager (Cybersoft Inc., Phoenix, AZ, USA). A total of 79 recipes were collected for 16 commonly consumed dishes (seven meat-based, five starch-based and four legume/vegetable-based). 'Fried chicken' contained the most energy [1469 kJ (351 kcal)], protein (29.7 g), fat (23.7 g), cholesterol (123 mg) and niacin (8.4 mg). 'Fried beef' contained the most potassium (495 mg) and zinc (6.4 mg), whereas 'fish stew' had the most vitamin D (4.2 μg) and calcium (215 mg). 'Fried cabbage' and 'fried spinach' contained the largest percent energies from fat, at 79% and 76%, respectively. A traditional sweet bread, 'jeqe', made with fortified flour contributed significantly to iron (4.6 mg), niacin (4.5 μg) and folate (129 μg). The sodium content of dishes ranged from 88 to 679 mg per 100 g. The nutritional composition data for commonly consumed dishes in rural KwaZulu-Natal is presented. Although the dishes are good sources of protein, vitamins and minerals, they also contain substantial amounts of fat. This culturally appropriate information will enable the calculation of dietary intake and can be used to encourage the consumption of recipes rich in key nutrients.


Two mitotic kinesins cooperate to drive sister chromatid separation during anaphase.
During anaphase identical sister chromatids separate and move towards opposite poles of the mitotic spindle. In the spindle, kinetochore microtubules have their plus ends embedded in the kinetochore and their minus ends at the spindle pole. Two models have been proposed to account for the movement of chromatids during anaphase. In the 'Pac-Man' model, kinetochores induce the depolymerization of kinetochore microtubules at their plus ends, which allows chromatids to move towards the pole by 'chewing up' microtubule tracks. In the 'poleward flux' model, kinetochores anchor kinetochore microtubules and chromatids are pulled towards the poles through the depolymerization of kinetochore microtubules at the minus ends. Here, we show that two functionally distinct microtubule-destabilizing KinI kinesin enzymes (so named because they possess a kinesin-like ATPase domain positioned internally within the polypeptide) are responsible for normal chromatid-to-pole motion in Drosophila. One of them, KLP59C, is required to depolymerize kinetochore microtubules at their kinetochore-associated plus ends, thereby contributing to chromatid motility through a Pac-Man-based mechanism. The other, KLP10A, is required to depolymerize microtubules at their pole-associated minus ends, thereby moving chromatids by means of poleward flux.


Chromosome segregation at meiosis I in female T(2;4)1Gö/+ mice: no evidence for a decreased crossover frequency with maternal age.
The influence of age and hormones on chromosome segregation at meiosis I was studied in female mice heterozygous for the T(2;4)1Gö translocation. Females of two age groups (18-22 and 40-56 weeks old) were stimulated for ovulation with different doses of gonadotropins (1.5 IU PMS/1.0 IU HCG or 10 IU PMS/10 IU HCG). Analysis of metaphase II oocytes revealed the highest level of hyperhaploidy (1.8%) and presegregation (4.4%) in the young females receiving the low dose. Presegregation preferentially affected the small 4(2) marker chromosome. There was no significant interference of the tetravalent with disjunction of the nontranslocated normal bivalents. Moreover, no remarkable difference in the mode of segregation (adjacent I, II or alternate) was observed. Recombination within the interstitial pairing segments of the chromosomes involved in the translocation allowed us to calculate cross-over frequencies in ovulated oocytes. For both the large 2(4) and the small 4(2) marker chromosomes, this frequency was higher in old than in young T(2;4)1Gö/+ females. Our data do not support the production line hypothesis of Henderson and Edwards (1968) which claims that chiasma frequency in oocytes decreases with maternal age.


The effect of COVID-19 on essential surgical admissions in South Africa: A retrospective observational analysis of admissions before and during lockdown at a tertiary healthcare complex.
With COVID-19 having spread across the globe, it has become standard to implement infection control strategies (colloquially known as lockdown) with the intention of reducing the magnitude and delaying the peak of the epidemiological curve. Personal infection mitigation strategies coupled with lockdown have caused a change in healthcare-seeking behaviour, with individuals not attending to their ill health as they previously did. To determine whether admissions for urgent and emergency surgical pathologies have declined during the COVID-19 lockdown period, and the magnitude of the decline. A retrospective analysis was conducted, comparing pre-lockdown (3 February - 26 March 2020) and lockdown (27 March - 30 April 2020) admission incidences for surgical pathologies at a tertiary healthcare complex in North West Province, South Africa. Poisson regression models were created to determine admission incidence rate ratios (IRRs). Of 769 surgical admissions included in the analysis, 49.7% were male and 67.2% were unemployed. There was a 44% reduction in the incidence of non-trauma admissions during lockdown (IRR 0.56; 95% confidence interval (CI) 0.47 - 0.68; p<0.001) and a 53% reduction in the incidence of trauma-related admissions (IRR 0.47; 95% CI 0.34 - 0.66; p<0.001). Even when the prevalence of SARS-CoV-2 infection was minimal, COVID-19 lockdown in North West was associated with a significant reduction in surgical admissions. In order to ensure an overall benefit to public health, a balance between maintaining the integrity of COVID-19 control mechanisms and access to healthcare services is essential.


Biocompatible dialysis fluids for peritoneal dialysis.
The longevity of peritoneal dialysis (PD) is limited by high rates of technique failure, some of which stem from peritoneal membrane injury. 'Biocompatible' PD solutions have been developed to reduce damage to the peritoneal membrane. This review aimed to look at the benefits and harms of biocompatible PD solutions in comparison to standard PD solutions in patients receiving PD. We searched the Cochrane Renal Group's Specialised Register (28 February 2013), through contact with the Trials Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE, and handsearching conference proceedings. All randomised controlled trials (RCTs) and quasi-RCTs in adults and children comparing the effects of biocompatible PD solutions (neutral pH, lactate-buffered, low glucose degradation product (GDP); neutral pH, bicarbonate (± lactate)-buffered, low GDP; glucose polymer (icodextrin)) in PD were included. Studies of amino acid-based PD solutions were excluded. Two authors extracted data on study quality and outcomes (including adverse effects). The authors contacted investigators to obtain missing information. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for categorical variables, and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous variables. Thirty-six eligible studies (2719 patients) were identified: Neutral pH, lactate-buffered/bicarbonate (± lactate)-buffered, low GDP PD solution (24); icodextrin (12). Allocation methods and concealment were generally incompletely reported, and adequate in only ten studies (27.8%). Patients lost to follow-up ranged from 0% to 83.4%. Neutral pH, low GDP versus conventional glucose PD solutionBased on generally sub-optimal quality evidence, the use of neutral pH, low GDP PD solutions was associated with larger urine volumes at the end of the studies, up to three years of therapy duration (7 studies, 520 patients: MD 126.39 mL/d, 95% CI 26.73 to 226.05). Improved preservation of residual renal function was evident in studies with greater than 12 month follow-up (6 studies, 360 patients: SMD 0.31, 95% CI 0.10 to 0.52). There was no significant effect on peritonitis, technique failure or adverse events with the use of neutral pH, low GDP PD solutions. Glucose polymer (icodextrin) versus conventional glucose PD solutionThere was a significant reduction in episodes of uncontrolled fluid overload (2 studies, 100 patients: RR 0.30, 95% CI 0.15 to 0.59) and improvement in peritoneal ultrafiltration (4 studies, 102 patients, MD 448.54 mL/d, 95% CI 289.28 to 607.80) without compromising residual renal function (4 studies, 114 patients: SMD 0.12, 95% CI -0.26 to 0.49) or urine output (3 studies, 69 patients: MD -88.88 mL/d, 95% CI -356.88 to 179.12) with icodextrin use. A comparable incidence of adverse events with the icodextrin (four studies) was reported. Based on generally sub-optimal quality studies, use of neutral pH, low GDP PD solution led to greater urine output and higher residual renal function after use exceeded 12 months. Icodextrin prescription improved peritoneal ultrafiltration and mitigated uncontrolled fluid overload. There were no significant effects on peritonitis, technique survival, patient survival or harms identified with their use. Based on the best available evidence, the use of these 'biocompatible' PD solutions resulted in clinically relevant benefits without added risks of harm.


Surgery for malignant pleural mesothelioma after radiotherapy (SMART): final results from a single-centre, phase 2 trial.
A novel approach for managing malignant pleural mesothelioma, surgery for mesothelioma after radiotherapy (SMART), consisting of a short accelerated course of high-dose, hemithoracic, intensity modulated radiotherapy (IMRT) followed by extrapleural pneumonectomy was developed. The aim of this study was to evaluate the clinical feasibility of the SMART protocol. In this single-centre, phase 2 trial, patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, with histologically proven, resectable, cT1-3N0M0 disease who had previously untreated malignant pleural mesothelioma were eligible for inclusion. Patients received 25 Gy in five daily fractions over 1 week to the entire ipsilateral hemithorax with a concomitant 5 Gy boost to high risk areas followed by extrapleural pneumonectomy within 1 week. Adjuvant chemotherapy was offered to patients with ypN+ disease on final pathology. The primary endpoint was feasibility, which was defined as the number of patients with 30-day perioperative treatment-related death (grade 5 events) or morbidity (grade 3 or 4 events). A key secondary endpoint was cumulative incidence of distant recurrence. The final analysis was done on an intention-to-treat basis (including all eligible patients). This trial is registered with ClinicalTrials.gov, NCT00797719. Between Nov 1, 2008, and Oct 31, 2019, 102 patients were enrolled onto the trial and 96 eligible patients were treated with SMART on protocol and included in the analysis. Extrapleural pneumonectomy was done at a median of 5 days (range 2-12) after completing IMRT. 47 (49%) patients had 30-day perioperative grade 3-4 events and one (1%) patient died within 30 days perioperatively (grade 5 event; pneumonia). After a median follow-up of 46·8 months (IQR 13·4-61·2), the 5-year cumulative incidence of distant recurrence was 62 (63·3% [95% CI 52·3-74·4]). The most common first sites of recurrence were the contralateral chest (33 [46%] of 72 patients) and the peritoneal cavity (32 [44%]). Results from this study suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. However, minimising grade 4 events on the protocol is technically demanding and might affect survival beyond the post-operative period. Princess Margaret Hospital Foundation Mesothelioma Research Fund.


Are certain life histories particularly prone to local extinction?
Using stochastic simulations and elasticity analysis, we show that there are inherent differences in the risk of extinction between life histories with different demographies. Which life history is the most vulnerable depends on which vital rate varies. When juvenile survival varies semelparous organisms with delayed reproduction are the most vulnerable ones, while a varying developmental rate puts a greater threat to semelparous organisms with rapid development. Iteroparous organisms are the most vulnerable ones when adult survival varies. Generally, we do not expect to observe organisms in nature having variation in vital rates that produce a high risk of extinction. Given the results here we therefore predict that iteroparous organisms should show low variation in adult survival. Moreover, we predict that semelparous organisms should show low variation in juvenile survival and low variation in developmental rate. The effect of temporal correlation on extinction risk is most pronounced in organisms with semelparous life histories.


Exploring the Determinants of the Severity of Pedestrian Injuries by Pedestrian Age: A Case Study of Daegu Metropolitan City, South Korea.
Pedestrian-vehicle crashes can result in serious injury to pedestrians, who are exposed to danger when in close proximity to moving vehicles. Furthermore, these injuries can be considerably serious and even lead to death in a manner that varies depending on the pedestrian's age. This is because the pedestrian's physical characteristics and behaviors, particularly in relation to roads with moving vehicles, differ depending on the pedestrian's age. This study examines the determinants of pedestrian injury severity by pedestrian age using binary logistic regression. Factors in the built environment, such as road characteristics and land use of the places where pedestrian crashes occurred, were considered, as were the accident characteristics of the pedestrians and drivers. The analysis determined that the accident characteristics of drivers and pedestrians are more influential in pedestrian-vehicle crashes than the factors of the built environmental characteristics. However, there are substantial differences in injury severity relative to the pedestrian's age. Young pedestrians (aged under 20 years old) are more likely to suffer serious injury in school zones; however, no association between silver zones and injury severity is found for elderly pedestrians. For people in the age range of 20-39 years old, the severity of pedestrian injuries is lower in areas with more crosswalks and speed cameras. People in the age range of 40-64 years old are more likely to be injured in areas with more neighborhood streets and industrial land use. Elderly pedestrians are likely to suffer fatal injuries in areas with more traffic signals. This study finds that there are differences in the factors of pedestrian injury severity according to the age of pedestrians. Therefore, it is suggested that concrete and efficient policies related to pedestrian age are required to improve pedestrian safety and reduce pedestrian-vehicle crashes.


A highly fluorescent DNA toolkit: synthesis and properties of oligonucleotides containing new Cy3, Cy5 and Cy3B monomers.
Cy3B is an extremely bright and stable fluorescent dye, which is only available for coupling to nucleic acids post-synthetically. This severely limits its use in the fields of genomics, biology and nanotechnology. We have optimized the synthesis of Cy3B, and for the first time produced a diverse range of Cy3B monomers for use in solid-phase oligonucleotide synthesis. This molecular toolkit includes phosphoramidite monomers with Cy3B linked to deoxyribose, to the 5-position of thymine, and to a hexynyl linker, in addition to an oligonucleotide synthesis resin in which Cy3B is linked to deoxyribose. These monomers have been used to incorporate single and multiple Cy3B units into oligonucleotides internally and at both termini. Cy3B Taqman probes, Scorpions and HyBeacons have been synthesized and used successfully in mutation detection, and a dual Cy3B Molecular Beacon was synthesized and found to be superior to the corresponding Cy3B/DABCYL Beacon. Attachment of Cy3, Cy3B and Cy5 to the 5-position of thymidine by an ethynyl linker enabled the synthesis of an oligonucleotide FRET system. The rigid linker between the dye and nucleobase minimizes dye-dye and dye-DNA interactions and reduces fluorescence quenching. These reagents open up new future applications of Cy3B, including more sensitive single-molecule and cell-imaging studies.


Gender-related differences in the antinociceptive properties of morphine.
As part of an effort to examine gender-related differences in the abuse liability of morphine, the present parametric study was undertaken to systematically establish whether there are gender-related differences in the antinociceptive activity of morphine in rats. Our results showed that male rats were uniformly more sensitive to the antinociceptive properties of morphine than were females in three different assays, i.e., the hot-plate, tail-flick and abdominal-constriction tests. This enhanced sensitivity to morphine was reflected in the peak antinociceptive effect, the magnitude of antinociception (i.e., area under the time-action curve), the duration of the antinociceptive response and the 50% effective dose. These differences appear to reflect markedly enhanced central nervous system sensitivity to morphine in males, compared with females, because we observed no gender-linked differences in serum levels of morphine after its injection, at the time when peak antinociceptive effects were observed. Furthermore, these gender-related differences appear to be reflected in antinociception thought to be mediated by both spinal and supraspinal mechanisms. Finally, our results suggest that the acute effects of steroids play little role in the gender-related differences observed, because short-term castration did not alter the gender-related differences we observed. Rather, it appears more probable that the organizational effects of steroids during critical periods in development, which determine gender-related distinctions, may be significant in the male-female differences we have observed. In view of a great deal of largely anecdotal data for humans that suggest that there may be gender-related differences in the abuse liability of psychoactive substances, the model described in this paper may provide a means to examine this important issue.


Dietary inflammatory index and cancer risk in the elderly: A pooled-analysis of Italian case-control studies.
The aim of this study was to evaluate whether the association between the inflammatory potential of one's diet and cancer risk varies across age groups in a population characterized by widespread use of the Mediterranean diet. We analyzed data from a network of case-control studies conducted in Italy between 1991 and 2014. The studies included cancers of the oral cavity (n = 509), pharynx (n = 436), nasopharynx (n = 198), larynx (n = 459), esophagus (n = 304), stomach (n = 230), colon (n = 1225), rectum (n = 728), liver (n = 184), pancreas (n = 326), breast (n = 2569), endometrium (n = 454), ovary (n = 1031), prostate (n = 1294), kidney (n = 767), and bladder (n = 690). Controls were 13 563 patients hospitalized for acute, non-neoplastic conditions. Dietary inflammatory index (DII) scores were computed based on 31 food parameters assessed using a reproducible and validated food frequency questionnaire. Odds ratios were estimated through logistic regression models adjusting for recognized confounding factors. The DII increased with age, with lower scores among men than women, in individuals located in northern rather than in central or southern Italy, and in controls more than in cancer cases. After adjustment for cancer-specific potential confounders, an increasing DII score was directly associated with cancer risk for all considered cancer sites, except for liver and endometrium. Although the DII level varied across age groups, no heterogeneity in cancer risk emerged for any of the considered cancer sites. In the Italian population, DII scores were higher in elderly than in middle-aged individuals. Although not directly affecting cancer risk, this finding may have important implications for the older population because elevated DII scores, indicating a proinflammatory diet, also have been associated with frailty.


Holoprosencephaly--topologic variations in a liveborn series: a general model based upon MRI analysis.
We present an MRI-based anatomic analysis of a series of 9 human brains, representing lobar, semilobar and alobar forms of holoprosencephaly. The analysis of these variable forms of the malformation is based upon a topologic systematics established in a prior analysis of a homogeneous set of semilobar malformations. This systematics has the dual advantage that it serves both as a uniform reference for qualitative description and as a quantitative descriptive base for mathematical correlations between parameters of topology and of growth and development. Within this systematics, the prosencephalic midline is divided from caudal to rostral into diencephalic (DD-right and left, subthalamus through suprachiasmatic junction with telencephalon), telencephalic (TT-right and left, suprachiasmatic border of telencephalon midline to hippocampal commissure) and diencephalic-telencephalic (DT-right and left-hippocampal commissure through temporal limb of choroid fissure) segments. The topologic abnormality of the initial semilobar series was expressed in an orderly rostral to caudal gradient along the TT segment. In each malformation, normal midline topology began with a small posterior corpus callosum. Although the topologic anomaly in the present series invariably also involved the TT segment, this involvement was not continuous and was variably associated with anomalies of the DD in 6 and unilaterally of the DT in 1 brain. In the present as well as with the earlier series of HPE malformations but not in "normative brains," total telencephalic growth is strongly correlated with the length of the midline telencephalic segment. We propose that this system of analysis will be sensitive to the developmental stage and locus of expression of genetic and non-genetic determinants of the formal origin of HPE. For all of the present series, karyotype anlyses were normal. Mutations in the Shh and Zic2 genes were excluded in 2 cases.


Assembly principles of the human R2TP chaperone complex reveal the presence of R2T and R2P complexes.
R2TP is a highly conserved chaperone complex formed by two AAA+ ATPases, RUVBL1 and RUVBL2, that associate with PIH1D1 and RPAP3 proteins. R2TP acts in promoting macromolecular complex formation. Here, we establish the principles of R2TP assembly. Three distinct RUVBL1/2-based complexes are identified: R2TP, RUVBL1/2-RPAP3 (R2T), and RUVBL1/2-PIH1D1 (R2P). Interestingly, we find that PIH1D1 does not bind to RUVBL1/RUVBL2 in R2TP and does not function as a nucleotide exchange factor; instead, RPAP3 is found to be the central subunit coordinating R2TP architecture and linking PIH1D1 and RUVBL1/2. We also report that RPAP3 contains an intrinsically disordered N-terminal domain mediating interactions with substrates whose sequences are primarily enriched for Armadillo repeat domains and other helical-type domains. Our work provides a clear and consistent model of R2TP complex structure and gives important insights into how a chaperone machine concerned with assembly of folded proteins into multisubunit complexes might work.


The binding of human lactoferrin to mouse peritoneal cells.
Human iron-saturated Lf (FeLf), which was labeled with 125I or 50Fe, was found to combine with the membrane of mouse peritoneal cells (MPC) which consisted of 70% macrophages. The following experimental data suggested the involvement of a specific receptor. (a) The binding of FeLf to MPC reached a saturation point. (b) The binding of radioactive FeLf was inhibited by preincubating the cells with cold FeLf but not with human Tf, human aggregated and nonaggregated IgG, or beef heart cytochrome c (c) Succinylation and carbamylation of FeLf resulted in a loss of its inhibiting activity on the binding of radioactive FeLf. Removal of neuraminic acid from FeLf increased its inhibitory activity. (d) The ability of apoLf to inhibit the binding of FeLf to MPC was significantly lower than that of FeLf. The existence of a Lf receptor capable of concentrating Lf released from neutrophils on the membrane of macrophages could explain the apparent blockade of the release of iron from the reticuloendothelial system, which accounts for the hyposideremia of inflammation. A receptor for FeLf was also found on mouse peritoneal lymphocytes. The affinity constant of FeLf for both lymphocytes and macrophages was 0.9 X 12(6) liter/mol. Howerver, macrophages bound three times more FeLf molecules (20 X 10(6)) per cell than did lymphocytes (7 X 10(6)).


Germline TGF-beta receptor mutations and skeletal fragility: a report on two patients with Loeys-Dietz syndrome.
Loeys-Dietz syndrome (LDS, OMIM # 609192) caused by heterozygous mutations in TGFBR1 and TGFBR2 has recently been described as an important cause of familial aortic aneurysms. These patients have craniofacial and skeletal features that overlap with the Marfan syndrome (MFS), and more importantly, have significant vascular fragility as is seen in MFS and Ehlers-Danlos syndrome Type IV (EDS-IV). The skeletal phenotype with respect to low bone mineral density and skeletal fragility is not clear. We present two patients with LDS with significant skeletal fragility. The first is a 17-year-old male who had talipes equinovarus, diaphragmatic and inguinal and herniae, aortic root dilatation necessitating surgical repair, craniofacial and skeletal dysmorphism consistent with LDS, and a history of numerous fragility fractures leading to significant skeletal deformity. He was found to be heterozygous for a c.923T > C transition in exon 4 of TGFBR2. The second is a 26-year-old male with submucous cleft palate, talipes equinovarus, pectus excavatum requiring surgery, inguinal hernia, and aneurysms in the ascending aorta, abdominal aorta, carotid, subclavian, vertebral and brachial arteries requiring surgical repairs. He also had craniofacial and skeletal dysmorphism consistent with LDS, multiple fractures in childhood, low bone mineral density, and was found to be heterozygous for a c.1561 T > C transition in exon 7 of TGFBR2. These case studies highlight the importance of paying close attention to fractures and bone density in patients with LDS. Osteopenia or osteoporosis may become increasingly important issues as earlier detection and treatment of the vascular complications of LDS improves life expectancy in these patients.


Stem cell-derived polarized hepatocytes.
Human stem cell-derived hepatocyte-like cells (HLCs) offer an attractive platform to study liver biology. Despite their numerous advantages, HLCs lack critical in vivo characteristics, including cell polarity. Here, we report a stem cell differentiation protocol that uses transwell filters to generate columnar polarized HLCs with clearly defined basolateral and apical membranes separated by tight junctions. We show that polarized HLCs secrete cargo directionally: Albumin, urea, and lipoproteins are secreted basolaterally, whereas bile acids are secreted apically. Further, we show that enterically transmitted hepatitis E virus (HEV) progeny particles are secreted basolaterally as quasi-enveloped particles and apically as naked virions, recapitulating essential steps of the natural infectious cycle in vivo. We also provide proof-of-concept that polarized HLCs can be used for pharmacokinetic and drug-drug interaction studies. This novel system provides a powerful tool to study hepatocyte biology, disease mechanisms, genetic variation, and drug metabolism in a more physiologically relevant setting.


Reputation-based collaborative network biology.
A pilot reputation-based collaborative network biology platform, Bionet, was developed for use in the sbv IMPROVER Network Verification Challenge to verify and enhance previously developed networks describing key aspects of lung biology. Bionet was successful in capturing a more comprehensive view of the biology associated with each network using the collective intelligence and knowledge of the crowd. One key learning point from the pilot was that using a standardized biological knowledge representation language such as BEL is critical to the success of a collaborative network biology platform. Overall, Bionet demonstrated that this approach to collaborative network biology is highly viable. Improving this platform for de novo creation of biological networks and network curation with the suggested enhancements for scalability will serve both academic and industry systems biology communities.


Comparison of full-night and ambulatory polysomnography with ApneaGraph in the subjects with obstructive sleep apnea syndrome.
The localization of the obstruction is crucial in determining the appropriate surgical treatment for obstructive sleep apnea syndrome (OSAS); ApneaGraph has been introduced for diagnosis of OSAS and localization of airway obstruction level. This study aims to evaluate the diagnostic value of ApneaGraph for both clinical staging and site of obstruction. Thirty male OSAS patients were prospectively enrolled in this clinical trial. The following parameter were included to the study: Body mass indexes and neck circumferences of the subjects, Epworth sleepiness scale, site of obstruction detected by flexible endoscopy and ApneaGraph, apnea hypopnea index (AHI), apnea index, hypopnea index, maximal oxygen desaturation and average oxygen saturation which were detected by both polysomnography (PSG) and ApneaGraph devices. Our data presented that, although AHI measured by ApneaGraph and PSG were significantly correlated; severity stages of the subjects were different in 44 % of the subjects when based on AHI of ApneaGraph, compared to PSG. Majority of the changes were from severe OSAS to mild or moderate levels. Similar dominant collapse levels were detected in 64 % of the subjects by both devices. It was seen that transpalatal obstruction was better correlated between ApneaGraph and flexible endoscopy. As a conclusion, we might assume that ApneaGraph can be used as a screener for OSAS and it appears to be a more reliable device to confirm dominancy of palatal level obstruction.


Modulation of antimicrobial host defense peptide gene expression by free fatty acids.
Routine use of antibiotics at subtherapeutic levels in animal feed drives the emergence of antimicrobial resistance. Development of antibiotic-alternative approaches to disease control and prevention for food animals is imperatively needed. Previously, we showed that butyrate, a major species of short-chain fatty acids (SCFAs) fermented from undigested fiber by intestinal microflora, is a potent inducer of endogenous antimicrobial host defense peptide (HDP) genes in the chicken (PLoS One 2011, 6: e27225). In the present study, we further revealed that, in chicken HD11 macrophages and primary monocytes, induction of HDPs is largely in an inverse correlation with the aliphatic hydrocarbon chain length of free fatty acids, with SCFAs being the most potent, medium-chain fatty acids moderate and long-chain fatty acids marginal. Additionally, three SCFAs, namely acetate, propionate, and butyrate, exerted a strong synergy in augmenting HDP gene expression in chicken cells. Consistently, supplementation of chickens with a combination of three SCFAs in water resulted in a further reduction of Salmonella enteritidis in the cecum as compared to feeding of individual SCFAs. More importantly, free fatty acids enhanced HDP gene expression without triggering proinflammatory interleukin-1β production. Taken together, oral supplementation of SCFAs is capable of boosting host immunity and disease resistance, with potential for infectious disease control and prevention in animal agriculture without relying on antibiotics.


Highly efficient methyl ketone synthesis with photoactivated acetone and olefins assisted by Mg(II)-exchanged zeolite Y.
We previously found that photoirradiation of an acetone/water mixture containing olefins affords the corresponding methyl ketones highly efficiently and selectively via a water-assisted C-C coupling between the acetonyl radical and olefins (Org. Lett. 2008, 10, 3117-3120). The reaction proceeds at room temperature without any additives and has a potential to be a powerful method for methyl ketone synthesis. Here we report that an addition of Mg(2+)-exchanged zeolite Y (MgY) to the above photoreaction system accelerates the methyl ketone formation, while maintaining high selectivity. Ab initio molecular orbital calculation reveals that the accelerated methyl ketone formation is due to the electrostatic interaction between Mg(2+) and excited-state acetone. This leads to a charge polarization of the carbonyl moiety of excited-state acetone and accelerates the hydrogen abstraction from ground-state acetone (acetonyl radical formation). This promotes efficient addition of the acetonyl radical to olefins, resulting in methyl ketone formation enhancement. Adsorption experiments reveal that accumulation of olefins inside the zeolite pore also affects efficient radical addition to olefins. The present process successfully produces various methyl ketones with very high yield, and the MgY recovered can be reused for further reaction without loss of activity.


Energy gaps in "metallic" single-walled carbon nanotubes.
Metallic single-walled carbon nanotubes have been proposed to be good one-dimensional conductors. However, the finite curvature of the graphene sheet that forms the nanotubes and the broken symmetry due to the local environment may modify their electronic properties. We used low-temperature atomically resolved scanning tunneling microscopy to investigate zigzag and armchair nanotubes, both thought to be metallic. "Metallic" zigzag nanotubes were found to have energy gaps with magnitudes that depend inversely on the square of the tube radius, whereas isolated armchair tubes do not have energy gaps. Additionally, armchair nanotubes packed in bundles have pseudogaps, which exhibit an inverse dependence on tube radius. These observed energy gaps suggest that most "metallic" single-walled nanotubes are not true metals, and they have implications for our understanding of the electronic properties and potential applications of carbon nanotubes.


Dietary habits of Palestinian adolescents and associated sociodemographic characteristics in Ramallah, Nablus and Hebron governorates.
To describe food habits and associated sociodemographic factors. Cross-sectional survey in 2005. Ninety-six school classes in Ramallah, Nablus and Hebron governorates, Occupied Palestinian Territory. Grade 8 and 9 students aged 13-15 years (n 2952). Self-administered student and parent questionnaires. High standard of living (STL) index and residence in Ramallah were positively associated with intake of animal foods, Western-style foods, dairy products, fruits and vegetables, sweets and salty snacks. Only 26.1 % of the students ate three main meals daily; 26.2 % of the boys and 51.0 % of the girls had breakfast one to two times per week or less often (P < 0.001). Only one-quarter of students drank milk daily (32.9 % of boys and 18.3 % of girls, P < 0.001). The majority of students, boys and girls in similar proportions, consumed vegetables daily (72.8 % v. 73.8 %, respectively). Daily fruit consumption was also equally common among boys and girls (58.9 % v. 55.2 %, respectively), but with clear differences by STL, region and parents' education. Daily intake of sweets and salty snacks was common among girls, and daily intake of soft drinks was common among boys. Irregular meal patterns were common among Palestinian adolescents. High STL and residence in Ramallah were associated with frequent intake of foods high in sugar and fat, but also with frequent intake of fruits and vegetables. Effective interventions are needed to establish healthy dietary habits.


DNA Damage in Chronic Kidney Disease: Evaluation of Clinical Biomarkers.
Patients with chronic kidney disease (CKD) exhibit an increased cancer risk compared to a healthy control population. To be able to estimate the cancer risk of the patients and to assess the impact of interventional therapies thereon, it is of particular interest to measure the patients' burden of genomic damage. Chromosomal abnormalities, reduced DNA repair, and DNA lesions were found indeed in cells of patients with CKD. Biomarkers for DNA damage measurable in easily accessible cells like peripheral blood lymphocytes are chromosomal aberrations, structural DNA lesions, and oxidatively modified DNA bases. In this review the most common methods quantifying the three parameters mentioned above, the cytokinesis-block micronucleus assay, the comet assay, and the quantification of 8-oxo-7,8-dihydro-2'-deoxyguanosine, are evaluated concerning the feasibility of the analysis and regarding the marker's potential to predict clinical outcomes.


Synchrotron infrared nanospectroscopy on a graphene chip.
A recurring goal in biology and biomedicine research is to access the biochemistry of biological processes in liquids that represent the environmental conditions of living organisms. These demands are becoming even more specific as microscopy techniques are fast evolving in the era of single cell analysis. In the modality of chemical probes, synchrotron infrared spectroscopy (μ-FTIR) is a technique that is extremely sensitive to vibrational responses of materials; however, the classical optical limits prevent the technique to access the biochemistry of specimens at the subcellular level. In addition, due to the intricate environmental requirements and strong infrared absorption of water, μ-FTIR of bioprocesses in liquids remains highly challenging. In phase with these challenges, on-chip liquid cells emerge as a versatile alternative to control the water thickness while providing a biocompatible chemical environment for analytical analyses. In this work we report the development of a liquid platform specially designed for nanoscale infrared analysis of biomaterials in wet environments. A key advantage of our designed platform is the use of graphene as an optical window that interfaces wet and dry environments in the liquid cell. By combining near-field optical microscopy and synchrotron infrared radiation, we measure the nanoscale fingerprint IR absorbance of a variety of liquids often used in biological studies. Further, we demonstrate the feasibility of the platform for the chemical analysis of protein clusters immersed in water with a clear view of the proteins' secondary structure signatures. The simplicity of the proposed platform combined with the high quality of our data makes our findings a template for future microfluidic devices targeting dynamic nanoscale-resolved chemical analysis.


Layer-selective half-metallicity in bilayer graphene nanoribbons.
Half-metallicity recently predicted in the zigzag-edge graphene nanoribbons (ZGNRs) and the hydrogenated carbon nanotubes (CNTs) enables fully spin-polarized electric currents, providing a basis for carbon-based spintronics. In both carbon systems, the half-metallicity arises from the edge-localized electron states under an electric field, lowering the critical electric field Dc for the half-metallicity being an issue in recent works on ZGNRs. A properly chosen direction of the electric field alone has been predicted to significantly reduce Dc in the hydrogenated CNTs, which in this work turned out to be the case in narrow bilayer ZGNRs (biZGNRs). Here, our simple model based on the electrostatic potential difference between the edges predicts that for wide biZGNRs of width greater than ~2.0 nm (10 zigzag carbon chains), only one layer of the biZGNRs becomes half-metallic leaving the other layer insulating as confirmed by our density functional theory (DFT) calculations. The electric field-induced switching of the spin-polarized current path is believed to open a new route to graphene-based spintronics applications.


Masseter muscle myofibrillar protein synthesis and degradation in an experimental critical illness myopathy model.
Critical illness myopathy (CIM) is a debilitating common consequence of modern intensive care, characterized by severe muscle wasting, weakness and a decreased myosin/actin (M/A) ratio. Limb/trunk muscles are primarily affected by this myopathy while cranial nerve innervated muscles are spared or less affected, but the mechanisms underlying these muscle-specific differences remain unknown. In this time-resolved study, the cranial nerve innervated masseter muscle was studied in a unique experimental rat intensive care unit (ICU) model, where animals were exposed to sedation, neuromuscular blockade (NMB), mechanical ventilation, and immobilization for durations varying between 6 h and 14d. Gel electrophoresis, immunoblotting, RT-PCR and morphological staining techniques were used to analyze M/A ratios, myofiber size, synthesis and degradation of myofibrillar proteins, and levels of heat shock proteins (HSPs). Results obtained in the masseter muscle were compared with previous observations in experimental and clinical studies of limb muscles. Significant muscle-specific differences were observed, i.e., in the masseter, the decline in M/A ratio and muscle fiber size was small and delayed. Furthermore, transcriptional regulation of myosin and actin synthesis was maintained, and Akt phosphorylation was only briefly reduced. In studied degradation pathways, only mRNA, but not protein levels of MuRF1, atrogin-1 and the autophagy marker LC3b were activated by the ICU condition. The matrix metalloproteinase MMP-2 was inhibited and protective HSPs were up-regulated early. These results confirm that the cranial nerve innervated masticatory muscles is less affected by the ICU-stress response than limb muscles, in accordance with clinical observation in ICU patients with CIM, supporting the model' credibility as a valid CIM model.


Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia.
Friedreich's ataxia (FRDA) is an autosomal recessive disorder, caused by reduced levels of the protein frataxin. This protein is located in the mitochondria, where it functions in the biogenesis of iron-sulphur clusters (ISCs), which are important for the function of the mitochondrial respiratory chain complexes. Moreover, disruption in iron biogenesis may lead to oxidative stress. Oxidative stress can be the cause and/or the consequence of mitochondrial energy imbalance, leading to cell death. Fibroblasts from two FRDA mouse models, YG8R and KIKO, were used to analyse two different categories of protective compounds: deuterised poly-unsaturated fatty acids (dPUFAs) and Nrf2-inducers. The former have been shown to protect the cell from damage induced by lipid peroxidation and the latter trigger the well-known Nrf2 antioxidant pathway. Our results show that the sensitivity to oxidative stress of YG8R and KIKO mouse fibroblasts, resulting in cell death and lipid peroxidation, can be prevented by d4-PUFA and Nrf2-inducers (SFN and TBE-31). The mitochondrial membrane potential (ΔΨm) of YG8R and KIKO fibroblasts revealed a difference in their mitochondrial pathophysiology, which may be due to the different genetic basis of the two models. This suggests that variable levels of reduced frataxin may act differently on mitochondrial pathophysiology and that these two cell models could be useful in recapitulating the observed differences in the FRDA phenotype. This may reflect a different modulatory effect towards cell death that will need to be investigated further.


Skeletal Muscle Mass and Fat Mass Relationships With Physical Fitness Test Performance in Law Enforcement Recruits Before Academy.
Lockie, RG, Carlock, BN, Ruvalcaba, TJ, Dulla, JM, Orr, RM, Dawes, JJ, and McGuire, MB. Skeletal muscle mass and fat mass relationships with physical fitness test performance in law enforcement recruits before academy. J Strength Cond Res 35(5): 1287-1295, 2021-The purpose of this study was to analyze relationships between skeletal muscle mass percentage (SMM%) and fat mass percentage (FM%) relative to fitness test performance in law enforcement recruits. Retrospective analysis was conducted on 338 recruits (271 men and 67 women) from 4 academy classes. Skeletal muscle mass percentage and FM% were measured using cost-effective and practical bioelectrical impedance analysis (BIA) equipment that used hand and foot placement. The fitness tests included grip strength; vertical jump; 75-yard pursuit run; 2-kg medicine ball throw (MBT); push-ups and sit-ups completed in 60 seconds; and the 20-m multistage fitness test. Partial correlations controlling for sex-derived relationships between SMM%, FM%, and the tests. Recruits were split into quartile groups for SMM% and FM% (group 1 had the lowest SMM% or highest FM% and group 4 the highest SMM% or lowest FM%). A 1-way multivariate analysis of variance (MANOVA), with sex as a covariate and Bonferroni post-hoc, compared between-group results. Skeletal muscle mass percentage correlated with all fitness tests expect for MBT; FM% with all but grip strength and MBT (r = ±0.107-0.293). Greater SMM% or lesser FM% tended to relate to better fitness test performance. The MANOVA data indicated groups 3 and 4 (better SMM% or FM% profiles) exhibited superior fitness than group 1 (poorest SMM% or FM% profile) (p ≤ 0.048). Recruits should ideally increase SMM% and decrease FM% before academy to optimize fitness training and testing performance, although specific guidelines should be agency specific. Staff could use BIA to monitor body composition during academy to indicate how recruits are tolerating training.


C2v symmetrical two-photon polymerization initiators with anthracene core: synthesis, optical and initiating properties.
A series of C(2v) symmetrical two-photon absorption compounds with anthracene core, 2,7-bis[2-(4-substituted phenyl)-vinyl]-9,10-dipentyloxyanthracenes designated as I, II and III (the substituted groups at the 4-position of phenyl of I, II and III were dimethylamino, methyl and cyano, respectively) were designed and synthesized as initiators in two-photon induced polymerization (TPIP). The anthracene ring was modified by linking vinylphenyl groups to the 2,7-position to extend conjugation system length and two pentyloxy groups to the 9,10-position to serve as electronic donors. Two-photon absorption cross section of I was around 300 GM, which was much larger than the 10 GM of II and 29 GM of III at 800 nm. I of 0.18% molar ratio in resin composed of methacrylic acid and dipentaerythritol hexaacrylate exhibited a dramatically low threshold of 0.64 mW compared with commercial photoinitiator benzil at a scanning speed 10 μm s(-1). Moreover, the threshold of photoinitiator I was only increased to 2.53 mW at a scanning speed of 1000 μm s(-1). The dependency of threshold on the concentration and exposure time was in accordance with theoretical calculation. Finally, a reasonable mechanism of the two-photon initiating process was proposed. This study provides good prospects for developing low threshold photoinitiator in TPIP.


Toxicity and survival outcomes in older adults receiving concurrent or sequential chemoradiation for stage III non-small cell lung cancer in Alliance trials (Alliance A151812).
Optimal treatment for older adults with stage III non-small cell lung cancer (NSCLC) remains unclear. Here we hypothesized that sequential chemoradiation therapy (sCRT) is better tolerated than concurrent (cCRT) but confers acceptable efficacy. We evaluated these strategies in older adults utilizing Alliance for Clinical Trials in Oncology data. Pooled analyses from 6 first-line stage III NSCLC CRT trials (Cancer and Leukemia Group B 8433, 8831, 9130, 30106, 30407, 39801) were used to compare toxicity and survival outcomes with cCRT versus sCRT in patients age ≥ 65 years. Grade 3-5 adverse events (AEs), progression-free and overall survival (PFS; OS) are reported with adjustment for covariates. Four hundred older adults, of whom 106 (26.5%) had received sCRT and 294 (73.5%) had received cCRT, comprised the cohorts. Virtually all had an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 (99%). More grade 3-5 AEs were observed at any time-point with cCRT than sCRT (94.2% versus 86.8%; 95% confidence interval for difference in proportions, 1.3%, 15.5%) and this finding remained after adjusting for length of study treatment (P = 0.018). Comparable PFS and OS were observed with sCRT versus cCRT (median: 8.0 versus 9.2 months; median: 11.9 versus 13.4 months, respectively) even after adjustment for age, sex, ECOG PS, body mass index, pretreatment weight loss, stage, and cisplatin-based therapy (P = 0.604 and P = 0.906, respectively). These data show that sCRT was associated with less toxicity than cCRT with no associated statistically significant decrease in efficacy outcomes and that sCRT merits further study in this population.


Carry on: spontaneous object carrying in 13-month-old crawling and walking infants.
Carrying objects requires coordination of manual action and locomotion. This study investigated spontaneous carrying in 24 walkers who were 13 months old and 26 crawlers who were 13 months old during 1-hr, naturalistic observations in the infants' homes. Carrying was more common in walkers, but crawlers also carried objects. Typically, walkers carried objects in their hands, whereas crawlers multitasked by using their hands simultaneously for holding objects and supporting their bodies. Locomotor experience predicted frequency of carrying in both groups, suggesting that experienced crawlers and walkers perceive their increased abilities to handle objects while in motion. Despite additional biomechanical constraints imposed by holding an object, carrying may actually improve upright balance: Crawlers rarely fell while carrying an object, and walkers were more likely to fall without an object in hand than while carrying. Thus, without incurring an additional risk of falling, spontaneous carrying may provide infants with new avenues for combining locomotor and manual skills and for interacting with their environments.


The feasibility of an early hospital discharge following chemotherapy for the acute myeloid leukemia.
The hospitalization of the patient during the critical myelosuppressive period after chemotherapy is often complicated by infections caused by nosocomial pathogens, what is associated with a high antibiotics consumption and with prolongation of the period of hospitalization. These findings have led many centres to change their policy from "in-hospital" to "out-hospital care". In this retrospective study we tried, on the basis of our experiences, to identify the feasibility and safety of this approach. We studied 56 patients with the acute myeloid leukemia treated in our clinic with the consolidation chemotherapy. We compared two groups of patients. In the first group, the patients were discharged upon completion of chemotherapy, consequently followed up as outpatients. Patients in the second group were observed in hospital during the entire nadir. Following 41 courses, patients were discharged and instructed to return immediately if fever or any other change of their clinical status occurred. In 24 cases after chemotherapy, the patients returned to the hospital after a discharge (in 23 cases because of fever), in 17 cases of nadir periods the hospitalisation was not necessary at all. Seven patients were readmitted in septic shock, but rapidly recovered. Two other patients died, one due to an irreversible shock within 12 hours of readmission and one due to bacterial meningitis within 48 hours after readmission. In 10 cases of rehospitalization, patients responded to the first line of antibiotics. In the second group of the patients, only 2 courses of consolidation from a total of 15 were not complicated. In contrast to the first group, we detected only poor effectiveness of broad-spectrum antibiotics in the group of inpatients. For AML patients in a good clinical status without any complicating medical conditions, the early discharge is feasible, safe and cost saving option (Tab. 2, Fig. 2, Ref. 7).


Long-term effects of mammography screening: updated overview of the Swedish randomised trials.
There has been much debate about the value of screening mammography. Here we update the overview of the Swedish randomised controlled trials on mammography screening up to and including 1996. The Kopparberg part of the Two-County trial was not available for the overview, but the continuation of the Malmö trial (MMST II) has been added. The article also contains basic data from the trials that have not been presented before. Methods The trials (n=247010, invited group 129750, control group 117260) have been followed up by record linkage to the Swedish Cancer and Cause of Death Registers. The relative risks (RR) for breast cancer death and mortality were calculated for the invited and the control groups. The trial-specific as well as the age-specific effects were analysed. RRs were calculated by the density method, with total person-time experience of the cohort by time interval of follow-up as a basis for estimating mortality rates. We calculated weighted RRs and 95% CI with the Mantel-Haenszel procedure. The median trial time-the time from randomisation until the first round was completed for the control group or if the control group was not invited, until end of follow-up-was 6.5 years (range 3.0-18.1). The median follow-up time, the time from randomisation, to the end of follow-up, was 15.8 years (5.8-20.2). There were 511 breast cancer deaths in 1864770 women-years in the invited groups and 584 breast cancer deaths in 1688440 women-years in the control groups, a significant 21% reduction in breast cancer mortality (RR=0.79, 95% CI 0.70-0.89). The reduction was greatest in the age group 60-69 years at entry (33%). Looking at 5-year age groups, there were statistically significant effects in the age groups 55-59, 60-64, and 65-69 years (RR=0.76, 0.68, and 0.69, respectively). There was a small effect in women 50-54 years at randomisation (RR=0.95). The benefit in terms of cumulative breast cancer mortality started to emerge at about 4 years after randomisation and continued to increase to about 10 years. Thereafter the benefit in absolute terms was maintained throughout the period of observation. The age-adjusted relative risk for the total mortality was 0.98 (0.96-1.00). The advantageous effect of breast screening on breast cancer mortality persists after long-term follow-up. The recent criticism against the Swedish randomised controlled trials is misleading and scientifically unfounded.


Cerebrospinal fluid biomarkers of neurofibrillary tangles and synaptic dysfunction are associated with longitudinal decline in white matter connectivity: A multi-resolution graph analysis.
In addition to the development of beta amyloid plaques and neurofibrillary tangles, Alzheimer's disease (AD) involves the loss of connecting structures including degeneration of myelinated axons and synaptic connections. However, the extent to which white matter tracts change longitudinally, particularly in the asymptomatic, preclinical stage of AD, remains poorly characterized. In this study we used a novel graph wavelet algorithm to determine the extent to which microstructural brain changes evolve in concert with the development of AD neuropathology as observed using CSF biomarkers. A total of 118 participants with at least two diffusion tensor imaging (DTI) scans and one lumbar puncture for CSF were selected from two observational and longitudinally followed cohorts. CSF was assayed for pathology specific to AD (Aβ42 and phosphorylated-tau), neurodegeneration (total-tau), axonal degeneration (neurofilament light chain protein; NFL), and synaptic degeneration (neurogranin). Tractography was performed on DTI scans to obtain structural connectivity networks with 160 nodes where the nodes correspond to specific brain regions of interest (ROIs) and their connections were defined by DTI metrics (i.e., fractional anisotropy (FA) and mean diffusivity (MD)). For the analysis, we adopted a multi-resolution graph wavelet technique called Wavelet Connectivity Signature (WaCS) which derives higher order representations from DTI metrics at each brain connection. Our statistical analysis showed interactions between the CSF measures and the MRI time interval, such that elevated CSF biomarkers and longer time were associated with greater longitudinal changes in white matter microstructure (decreasing FA and increasing MD). Specifically, we detected a total of 17 fiber tracts whose WaCS representations showed an association between longitudinal decline in white matter microstructure and both CSF p-tau and neurogranin. While development of neurofibrillary tangles and synaptic degeneration are cortical phenomena, the results show that they are also associated with degeneration of underlying white matter tracts, a process which may eventually play a role in the development of cognitive decline and dementia.


Machine learning techniques for the optimization of joint replacements: Application to a short-stem hip implant.
Today, different implant designs exist in the market; however, there is not a clear understanding of which are the best implant design parameters to achieve mechanical optimal conditions. Therefore, the aim of this project was to investigate if the geometry of a commercial short stem hip prosthesis can be further optimized to reduce stress shielding effects and achieve better short-stemmed implant performance. To reach this aim, the potential of machine learning techniques combined with parametric Finite Element analysis was used. The selected implant geometrical parameters were: total stem length (L), thickness in the lateral (R1) and medial (R2) and the distance between the implant neck and the central stem surface (D). The results show that the total stem length was not the only parameter playing a role in stress shielding. An optimized implant should aim for a decreased stem length and a reduced length of the surface in contact with the bone. The two radiuses that characterize the stem width at the distal cross-section in contact with the bone were less influential in the reduction of stress shielding compared with the other two parameters; but they also play a role where thinner stems present better results.


Disseminated cryptococcosis in an AIDS patient caused by a canavanine-resistant strain of Cryptococcus neoformans var. grubii.
A case of disseminated cryptococcosis caused by Cryptococcus neoformans var. grubii is presented in a male diabetic who had AIDS. The diagnosis was based upon the isolation and identification of the aetiological agent from a lymph-node biopsy, cerebrospinal fluid and sputum. The isolate formed spherical, encapsulated yeast cells, produced cherry-brown colonies on niger-seed agar, grew on canavanine-glycine-bromothymol blue (CGB) medium, changing its colour from greenish yellow to blue, and hydrolysed urea weakly in the presence of 100 microM EDTA. The strain was unable to assimilate D-proline and, serologically, it was untypable. The identity of the isolate as C. neoformans var. grubii, serotype A, possessing a mating-type allele A alpha, was confirmed by crossing with standard laboratory test strains and by performing PCR with the mating-type alpha allele-specific primer of the STE12 gene and with serotype (A and D)- and mating type (a and alpha)-specific primers of the STE20 gene. To the best of our knowledge, this is the first report of disseminated cryptococcosis in an AIDS patient caused by a canavanine-resistant strain of C. neoformans var. grubii, serotype A, possessing mating type allele A alpha; the strain is probably a hybrid. The report suggests that, in the absence of a clear-cut serotyping result, a positive CGB reaction alone is not sufficient for intervarietal discrimination and additional confirmatory evidence is required.


Maternal health in resource-poor urban settings: how does women's autonomy influence the utilization of obstetric care services?
Despite various international efforts initiated to improve maternal health, more than half a million women worldwide die each year as a result of complications arising from pregnancy and childbirth. This research was guided by the following questions: 1) How does women's autonomy influence the choice of place of delivery in resource-poor urban settings? 2) Does its effect vary by household wealth? and 3) To what extent does women's autonomy mediate the relationship between women's education and use of health facility for delivery? The data used is from a maternal health study carried out in the slums of Nairobi, Kenya. A total of 1,927 women (out of 2,482) who had a pregnancy outcome in 2004-2005 were selected and interviewed. Seventeen variable items on autonomy were used to construct women's decision-making, freedom of movement, and overall autonomy. Further, all health facilities serving the study population were assessed with regard to the number, training and competency of obstetric staff; services offered; physical infrastructure; and availability, adequacy and functional status of supplies and other essential equipment for safe delivery, among others. A total of 25 facilities were surveyed. While household wealth, education and demographic and health covariates had strong relationships with place of delivery, the effects of women's overall autonomy, decision-making and freedom of movement were rather weak. Among middle to least poor households, all three measures of women's autonomy were associated with place of delivery, and in the expected direction; whereas among the poorest women, they were strong and counter-intuitive. Finally, the study showed that autonomy may not be a major mediator of the link between education and use of health services for delivery. The paper argues in favor of broad actions to increase women's autonomy both as an end and as a means to facilitate improved reproductive health outcomes. It also supports the call for more appropriate data that could further support this line of action. It highlights the need for efforts to improve households' livelihoods and increase girls' schooling to alter perceptions of the value of skilled maternal health care.


Forensic analysis of the microbiome of phones and shoes.
Microbial interaction between human-associated objects and the environments we inhabit may have forensic implications, and the extent to which microbes are shared between individuals inhabiting the same space may be relevant to human health and disease transmission. In this study, two participants sampled the front and back of their cell phones, four different locations on the soles of their shoes, and the floor beneath them every waking hour over a 2-day period. A further 89 participants took individual samples of their shoes and phones at three different scientific conferences. Samples taken from different surface types maintained significantly different microbial community structures. The impact of the floor microbial community on that of the shoe environments was strong and immediate, as evidenced by Procrustes analysis of shoe replicates and significant correlation between shoe and floor samples taken at the same time point. Supervised learning was highly effective at determining which participant had taken a given shoe or phone sample, and a Bayesian method was able to determine which participant had taken each shoe sample based entirely on its similarity to the floor samples. Both shoe and phone samples taken by conference participants clustered into distinct groups based on location, though much more so when an unweighted distance metric was used, suggesting sharing of low-abundance microbial taxa between individuals inhabiting the same space. Correlations between microbial community sources and sinks allow for inference of the interactions between humans and their environment.


Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality.
Immunosuppression after measles is known to predispose people to opportunistic infections for a period of several weeks to months. Using population-level data, we show that measles has a more prolonged effect on host resistance, extending over 2 to 3 years. We find that nonmeasles infectious disease mortality in high-income countries is tightly coupled to measles incidence at this lag, in both the pre- and post-vaccine eras. We conclude that long-term immunologic sequelae of measles drive interannual fluctuations in nonmeasles deaths. This is consistent with recent experimental work that attributes the immunosuppressive effects of measles to depletion of B and T lymphocytes. Our data provide an explanation for the long-term benefits of measles vaccination in preventing all-cause infectious disease. By preventing measles-associated immune memory loss, vaccination protects polymicrobial herd immunity.


Basis of the trade-off between parasitoid resistance and larval competitive ability in Drosophila melanogaster.
Drosophila melanogaster can be artificially selected for increased resistance against parasitoid wasps that attack the larvae. Lines selected for greater resistance are poorer larval competitors under conditions of resource scarcity. Here we investigated the mechanistic basis of this apparent trade-off. We found that resistant lines have approximately twice the density of haemocytes (blood cells) than that of controls. Haemocytes are involved in encapsulation, the chief cellular immune defence against parasitoids. We have previously shown that resistant lines feed more slowly than controls and hypothesize that limiting resources are being switched from trophic to defensive functions.


Conjoined twins: report of a case and review of the literature.
Conjoined twins, known to the layperson as Siamese twins, are a rare and catastrophic obstetric event. With the approximate incidence being 1 in 50,000 births, few physicians practicing obstetrics will have the unfortunate occasion to manage this biologic anomaly. Should this event occur, early diagnosis, close prenatal management, and the proper route of delivery will assure the best possible outcome for mother and both babies. The author describes the anatomic types of conjoined twins, the prenatal diagnosis and management, the route of delivery, and the overall statistical expectation. Under the best of circumstances, a good outcome is rarely achieved, but the obstetric goal should be a healthy mother and two salvageable babies.


Randomizing genome-scale metabolic networks.
Networks coming from protein-protein interactions, transcriptional regulation, signaling, or metabolism may appear to have "unusual" properties. To quantify this, it is appropriate to randomize the network and test the hypothesis that the network is not statistically different from expected in a motivated ensemble. However, when dealing with metabolic networks, the randomization of the network using edge exchange generates fictitious reactions that are biochemically meaningless. Here we provide several natural ensembles of randomized metabolic networks. A first constraint is to use valid biochemical reactions. Further constraints correspond to imposing appropriate functional constraints. We explain how to perform these randomizations with the help of Markov Chain Monte Carlo (MCMC) and show that they allow one to approach the properties of biological metabolic networks. The implication of the present work is that the observed global structural properties of real metabolic networks are likely to be the consequence of simple biochemical and functional constraints.


[Recurrent upper respiratory tract obstruction in children].
The systematic approach of the pediatric patient with recurrent upper airway obstruction (RUAO) must be based on a through clinical history, physical examination, and the adequate use of the laboratory and diagnostic procedures, which must complement the correct identification of the causes of UAO and its interrelation with comorbid conditions as allergic rhinitis, rhinosinusitis and adenoiditis, with or without significant hypertrophy. this work, is to propose the study protocol of the patient with recurrent upper airway obstruction used in our own Instituto Privado de Alergia, Inmunología y Vías Respiratorias. We studied in a prospective fashion, a cohort of 117 pediatric patients, 12 years old and under, with clinical complaints of RUAO. 2/3 of these patients had a suggestive cytology pattern of nasal allergy and infection at the same time, following the method proposed by Dr. Alfredo Jalowayski from UC San Diego. The use of conventional radiology (lateral neck x ray) in the diagnosis of hypertrophy/hyperplasia of adenoidal tissue is useful and give us an orientation regarding the adenoidal size in 75% of the patients; nevertheless, it should not be considered as the most sensible diagnostic procedure to decide the best therapeutic option. If this study shows a decrease in diameter of the airway between the hard palate and the adenoidal shadow of 20% or more, we should proceeded with a flexible rhinopharyngoscopy to evaluate not only the real size of the adenoidal tissue, its mucosal appearance and its relation within the posterior pharynx with the Eustaquian tube (oto-pharyngeal tube-OPT). The endoscopic procedure is easy to perform, even in small children and showed us that almost half of the patients with abnormal lateral X-ray, have at least some degree of OFT obstruction. Aside from these results, the nasopharyngoscope give us useful information about comorbid and or existing conditions such as allergic rhintis, nasal polyposis, status of the osteomeatal complex, presence of bullae, anatomic variations, septal deviations and status of the olfactory epithelium. The use and feasibility to perform the nasal cytology test using the rhinoprobe technique, allow us to know the predominant cellular pattern of the nasal mucous, differentiate the allergic or non allergic rhintis, eosinophilic, basophilic, infectious or non infectious process.


Pancreatic hormones and amino acid levels following liver transplantation.
Glucose intolerance, hyperinsulinemia, peripheral insulin resistance and hyperglucagonemia are common in patients with advanced liver disease. These abnormalities in the plasma levels of the pancreatic hormones, insulin and glucagon have been thought to be responsible, at least in part, for the abnormal plasma ratio of branched-chain amino acids to aromatic amino acids. To evaluate this issue, plasma levels of glucose, insulin, glucagon, C-peptide and the branched-chain and aromatic amino acids were measured before and serially after orthotopic liver transplantation in 9 humans and 5 dogs. The abnormal plasma amino acid levels rapidly improved and achieved normal levels following orthotopic liver transplantation. Insulin levels also became normal following orthotopic liver transplantation, despite enhanced insulin secretion documented by an even further increased level of C-peptide. In contrast, the baseline abnormal plasma glucagon levels which are commonly seen in cirrhotics became even more abnormal following orthotopic liver transplantation. Despite this progressive increase in the abnormally elevated plasma glucagon levels, plasma amino acid levels, both branched-chain and aromatic, became normal. These data demonstrate that before and after orthotopic liver transplantation, there is: (i) no relationship between the changes in the plasma levels of glucagon and changes observed in the plasma level of amino acids; and (ii) plasma insulin and amino acid levels change in the same direction. In addition, these changes in plasma insulin and amino acid levels following orthotopic liver transplantation occur despite enhanced secretion of insulin evidenced by the progressive increase in plasma levels of C-peptide.


Health Care Costs and Utilization of Dabigatran Compared With Warfarin for Secondary Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation: A Retrospective Population Study.
It remains unclear whether the use of new oral anticoagulants, compared with warfarin, is economically beneficial in Asian countries. The objective of this study is to compare the health care costs and utilization between dabigatran and warfarin in a real-world nonvalvular atrial fibrillation (NVAF) population. Data were obtained from the Taiwan National Health Insurance Database, and patients with an NVAF diagnosis between June 1, 2012, and May 31, 2014, were identified using the International Classification of Diseases, Ninth Revision code of 427.31. The patients in the dabigatran cohort were matched 1:2 to those in the warfarin cohort by sex, age, residential region, and a propensity score that incorporated a major bleeding history, CHADS2 score, and Charlson Comorbidity Index. The all-cause health care utilization and associated costs of the 2 treatment groups were compared at 3 and 12 months. A total of 1149 patients taking dabigatran were identified and matched with 2298 warfarin users. During the 3-month observation period, the likelihood of having at least 1 hospitalization among dabigatran users was significantly lower than that of warfarin users (odds ratio=0.78; P=0.001). Patients in the dabigatran group incurred lower mean emergency department costs ($2383.1 vs. $3033.6), mean ischemic stroke-related hospitalization costs ($8869.5 vs. $13,990.5), and mean all-cause hospitalization costs ($32,402.2 vs. $50,669.9) at 3 months. However, both the mean and median outpatient costs of warfarin users were consistently lower than those of dabigatran users ($17,161.2 vs. $24,931.4 and $10,509.0 vs. $20,671.5, respectively). Similar trends were observed at 12 months, except that the 2 groups had comparable total health care costs. The use of dabigatran is associated with lower emergency department and all-cause hospitalization costs but greater outpatient costs in a real-world, NVAF patient population compared with warfarin.


Insight Into Interactions of Thermoacidophilic Archaea With Elemental Sulfur: Biofilm Dynamics and EPS Analysis.
Biooxidation of reduced inorganic sulfur compounds (RISCs) by thermoacidophiles is of particular interest for the biomining industry and for environmental issues, e.g., formation of acid mine drainage (AMD). Up to now, interfacial interactions of acidophiles with elemental sulfur as well as the mechanisms of sulfur oxidation by acidophiles, especially thermoacidophiles, are not yet fully clear. This work focused on how a crenarchaeal isolate Acidianus sp. DSM 29099 interacts with elemental sulfur. Analysis by Confocal laser scanning microscopy (CLSM) and Atomic force microscopy (AFM) in combination with Epifluorescence microscopy (EFM) shows that biofilms on elemental sulfur are characterized by single colonies and a monolayer in first stage and later on 3-D structures with a diameter of up to 100 μm. The analysis of extracellular polymeric substances (EPS) by a non-destructive lectin approach (fluorescence lectin-barcoding analysis) using several fluorochromes shows that intial attachment was featured by footprints rich in biofilm cells that were embedded in an EPS matrix consisting of various glycoconjugates. Wet chemistry data indicate that carbohydrates, proteins, lipids and uronic acids are the main components. Attenuated reflectance (ATR)-Fourier transformation infrared spectroscopy (FTIR) and high-performance anion exchange chromatography with pulsed amperometric detection (HPAE-PAD) indicate glucose and mannose as the main monosaccharides in EPS polysaccharides. EPS composition as well as sugar types in EPS vary according to substrate (sulfur or tetrathionate) and lifestyle (biofilms and planktonic cells). This study provides information on the building blocks/make up as well as dynamics of biofilms of thermoacidophilic archaea in extremely acidic environments.


Extent and ecological consequences of hunting in Central African rainforests in the twenty-first century.
Humans have hunted wildlife in Central Africa for millennia. Today, however, many species are being rapidly extirpated and sanctuaries for wildlife are dwindling. Almost all Central Africa's forests are now accessible to hunters. Drastic declines of large mammals have been caused in the past 20 years by the commercial trade for meat or ivory. We review a growing body of empirical data which shows that trophic webs are significantly disrupted in the region, with knock-on effects for other ecological functions, including seed dispersal and forest regeneration. Plausible scenarios for land-use change indicate that increasing extraction pressure on Central African forests is likely to usher in new worker populations and to intensify the hunting impacts and trophic cascade disruption already in progress, unless serious efforts are made for hunting regulation. The profound ecological changes initiated by hunting will not mitigate and may even exacerbate the predicted effects of climate change for the region. We hypothesize that, in the near future, the trophic changes brought about by hunting will have a larger and more rapid impact on Central African rainforest structure and function than the direct impacts of climate change on the vegetation. Immediate hunting regulation is vital for the survival of the Central African rainforest ecosystem.


Molecular Framework Analysis of the Generated Database GDB-13s.
The generated databases (GDBs) list billions of possible molecules from systematic enumeration following simple rules of chemical stability and synthetic feasibility. To assess the originality of GDB molecules, we compared their Bemis and Murcko molecular frameworks (MFs) with those in public databases. MFs result from molecules by converting all atoms to carbons, all bonds to single bonds, and removing terminal atoms iteratively until none remain. We compared GDB-13s (99,394,177 molecules up to 13 atoms containing simplified functional groups, 22,130 MFs) with ZINC (885,905,524 screening compounds, 1,016,597 MFs), PubChem50 (100,852,694 molecules up to 50 atoms, 1,530,189 MFs), and COCONUT (401,624 natural products, 42,734 MFs). While MFs in public databases mostly contained linker bonds and six-membered rings, GDB-13s MFs had diverse ring sizes and ring systems without linker bonds. Most GDB-13s MFs were exclusive to this database, and many were relatively simple, representing attractive targets for synthetic chemistry aiming at innovative molecules.


Structure of the human clamp loader reveals an autoinhibited conformation of a substrate-bound AAA+ switch.
DNA replication requires the sliding clamp, a ring-shaped protein complex that encircles DNA, where it acts as an essential cofactor for DNA polymerases and other proteins. The sliding clamp needs to be opened and installed onto DNA by a clamp loader ATPase of the AAA+ family. The human clamp loader replication factor C (RFC) and sliding clamp proliferating cell nuclear antigen (PCNA) are both essential and play critical roles in several diseases. Despite decades of study, no structure of human RFC has been resolved. Here, we report the structure of human RFC bound to PCNA by cryogenic electron microscopy to an overall resolution of ∼3.4 Å. The active sites of RFC are fully bound to adenosine 5'-triphosphate (ATP) analogs, which is expected to induce opening of the sliding clamp. However, we observe the complex in a conformation before PCNA opening, with the clamp loader ATPase modules forming an overtwisted spiral that is incapable of binding DNA or hydrolyzing ATP. The autoinhibited conformation observed here has many similarities to a previous yeast RFC:PCNA crystal structure, suggesting that eukaryotic clamp loaders adopt a similar autoinhibited state early on in clamp loading. Our results point to a "limited change/induced fit" mechanism in which the clamp first opens, followed by DNA binding, inducing opening of the loader to release autoinhibition. The proposed change from an overtwisted to an active conformation reveals an additional regulatory mechanism for AAA+ ATPases. Finally, our structural analysis of disease mutations leads to a mechanistic explanation for the role of RFC in human health.


Effects of a dexmedetomidine constant rate infusion and atropine on changes in global perfusion variables induced by hemorrhage followed by volume replacement in isoflurane-anesthetized dogs.
To evaluate the effects of a dexmedetomidine constant rate infusion (CRI) and atropine on changes in global perfusion variables induced by hemorrhage and volume replacement (VR) in isoflurane-anesthetized dogs. 8 adult dogs. Each dog was anesthetized twice, with a 2-week interval between anesthetic sessions. Anesthesia was maintained with 1.3 times the minimum alveolar concentration of isoflurane with and without dexmedetomidine (1.6 μg/kg, IV bolus, followed by 2 μg/kg/h, CRI). Dogs were mechanically ventilated and received an atracurium neuromuscular blockade during both sessions. During anesthesia with isoflurane and dexmedetomidine, atropine was administered 30 minutes before baseline measurements were obtained. After baseline data were recorded, 30% of the total blood volume was progressively withdrawn and VR was achieved with an equal proportion of autologous blood. Following hemorrhage, cardiac index, oxygen delivery index, and mixed-venous oxygen saturation were significantly decreased and the oxygen extraction ratio was significantly increased from baseline. The anaerobic threshold was not achieved during either anesthetic session. When dogs were anesthetized with isoflurane and dexmedetomidine, they had a significantly lower heart rate, cardiac index, and mixed-venous oxygen saturation during VR than they did when anesthetized with isoflurane alone. Plasma lactate concentration, mixed venous-to-arterial carbon dioxide difference, base excess, and anion gap were unaltered by hemorrhage and VR and did not differ between anesthetic sessions. Results indicated that the use of a dexmedetomidine CRI combined with atropine in isoflurane-anesthetized dogs that underwent volume-controlled hemorrhage followed by VR did not compromise global perfusion sufficiently to result in anaerobic metabolism.


Strengthening the diagnostic capacity to detect Bio Safety Level 3 organisms in unusual respiratory viral outbreaks.
Experience with a highly pathogenic avian influenza outbreak in the Netherlands (2003) illustrated that the diagnostic demand for respiratory viruses at different biosafety levels (including BSL3), can increase unexpectedly and dramatically. We describe the measures taken since, aimed at strengthening national laboratory surge capacity and improving preparedness for dealing with diagnostic demand during outbreaks of (emerging) respiratory virus infections, including pandemic influenza virus. Academic and peripheral medical-microbiological laboratories collaborated to determine minimal laboratory requirements for the identification of viruses in the early stages of a pandemic or a large outbreak of avian influenza virus. Next, an enhanced collaborative national network of outbreak assistance laboratories (OAL) was set up. An inventory was made of the maximum diagnostic throughput that this network can deliver in a period of intensified demand. For an estimate of the potential magnitude of this surge demand, historical counts were calculated from hospital- and physician-based registries of patients presenting with respiratory symptoms. Number of respiratory physician-visits ranged from 140,000 to 615,000 per month and hospitalizations ranged from 3000 to 11,500 per month. The established OAL-network provides rapid diagnostic response with agreed quality requirements and a maximum throughput capacity of 1275 samples/day (38,000 per month), assuming other routine diagnostic work needs to be maintained. Thus surge demand for diagnostics for hospitalized cases (if not distinguishable from other respiratory illness) could be handled by the OAL network. Assessing etiology of community acquired acute respiratory infection however, may rapidly exceed the capacity of the network. Therefore algorithms are needed for triaging for laboratory diagnostics; currently this is not addressed in pandemic preparedness plans.


Scale-dependent analysis of an otter-crustacean system in Argentinean Patagonia.
The Southern river otter or 'huillin', Lontra provocax, is an endangered species endemic of the Andean Patagonian region of Argentina and Chile. It feeds almost exclusively on the genera of macro-crustacea: Aegla and Sammastacus. The aim of this study was to analyse the role of food availability on the huillin's distribution using a scale-dependent analysis of crustacean and otter distributions. We compared the distributions of otters and macro-crustaceans along a north-south regional gradient, between river basins of northern Patagonia, in an altitudinal gradient within a river basin, and between habitat types within a lake. We investigated the distribution of otters by sign surveys along lake shores, river banks and marine coasts, and of crustaceans using surveys in the water, undigested remains in mink (Mustela vison) scats, presence of external skeletons at the waterside and through interviews with local people. Our results show that there were heterogeneities in the distributions of macro-crustaceans at four scales and these were generally reflected in the distributions of freshwater otters. We conclude that the main factor limiting the distributions of L. provocax in freshwater environments is the availability of macro-crustaceans. This paper shows how scale-dependent type analyses of population distribution serves as a method for identifying key environmental factors for species for which the use of long-term demographies is unfeasible.


Identifying the educational needs and concerns of newly diagnosed patients with breast cancer after surgery.
Many factors may interfere with the ability of women newly diagnosed with breast cancer to cope with treatment. Nurses should be aware of patients' needs during this critical time. The purpose of this study was to identify the educational needs and concerns of newly diagnosed patients with breast cancer after surgery. A phone interview with patients was conducted approximately one week after breast cancer surgery. A convenience sample of 200 patients was recruited from four hospitals within a large midwestern healthcare system. The subjects were interviewed by breast health specialists and navigators involved in their education and support and were asked to participate in a short interview during a surgical follow-up phone call. Study results indicate that fear of recurrence and anxiety regarding postoperative treatments accounted for more than 65% of the responses to the question "What concerns you most about your new diagnosis?" Emotional, social, and physical limitations were identified as most important in dealing with a breast cancer diagnosis. As breast health specialists and navigators, nurses can improve the quality of care for women with breast cancer and their families by providing additional support services and post-treatment information during the initial education and follow-up call.


Chicken Interferon-induced Protein with Tetratricopeptide Repeats 5 Antagonizes Replication of RNA Viruses.
The intracellular actions of interferon (IFN)-regulated proteins, including IFN-induced proteins with tetratricopeptide repeats (IFITs), attribute a major component of the protective antiviral host defense. Here we applied genomics approaches to annotate the chicken IFIT locus and currently identified a single IFIT (chIFIT5) gene. The profound transcriptional level of this effector of innate immunity was mapped within its unique cis-acting elements. This highly virus- and IFN-responsive chIFIT5 protein interacted with negative sense viral RNA structures that carried a triphosphate group on its 5' terminus (ppp-RNA). This interaction reduced the replication of RNA viruses in lentivirus-mediated IFIT5-stable chicken fibroblasts whereas CRISPR/Cas9-edited chIFIT5 gene knockout fibroblasts supported the replication of RNA viruses. Finally, we generated mosaic transgenic chicken embryos stably expressing chIFIT5 protein or knocked-down for endogenous chIFIT5 gene. Replication kinetics of RNA viruses in these transgenic chicken embryos demonstrated the antiviral potential of chIFIT5 in ovo. Taken together, these findings propose that IFIT5 specifically antagonize RNA viruses by sequestering viral nucleic acids in chickens, which are unique in innate immune sensing and responses to viruses of both poultry and human health significance.