Oral contraceptive use and protective behavior after missed pills.
A three-month prospective study of 103 women initiating oral contraceptive use examined how consistently the women took their pills and whether those who missed pills employed other means to avoid pregnancy. The results showed that 52% took each active pill or never missed more than one pill at a time after the first week of the initial cycle, according to electronic devices that recorded the date and time each pill was removed from the blister pack. Another 21% were protected by behaviors that reduce the risk of pregnancy when two or more consecutive pills have been missed: avoiding coitus for the next seven days (18%) or using backup contraception during that period (3%). The remaining 27% were at increased risk of pregnancy. Predictors of increased risk were receiving low partner support for effective pill use, being unmarried and not considering it especially important to avoid pregnancy. Increased risk was most likely during the first seven days and during the third cycle of pill use.


Intraperitoneal hydrocortisone for pain relief after laparoscopic cholecystectomy.
Laparoscopic cholecystectomy is associated with shorter hospital stay and less pain in comparison to open surgery. The aim of this study was to evaluate the effect of intraperitoneal hydrocortisone on pain relief following laparoscopic cholecystectomy. Sixty two patients were enrolled in a double-blind, randomized clinical trial. Patients randomly received intraperitoneal instillation of either 250 ml normal saline (n=31) or 100 mg hydrocortisone in 250 ml normal saline (n=31) before insufflation of CO2 into the peritoneum. Abdominal and shoulder pain were evaluated using VAS after surgery and at 6, 12, and 24 hours postoperatively. The patients were also followed for postoperative analgesic requirements, nausea and vomiting, and return of bowel function. Sixty patients completed the study. Patients in the hydrocortisone group had significantly lower abdominal and shoulder pain scores (10.95 vs 12.95; P<0.01). The patients were similar regarding analgesic requirements in the recovery room. However, those in the hydrocortisone group required less meperidine than the saline group (151.66 (±49.9) mg vs 61.66 (±38.69) mg; P=0.00). The patients were similar with respect to return of bowel function, nausea and vomiting. No adverse reaction was observed in either group. Intraperitoneal administration of hydrocortisone can significantly decrease pain and analgesic requirements after laparoscopic cholecystectomy with no adverse effects.


Contextual values of observables in quantum measurements.
We introduce contextual values as a generalization of the eigenvalues of an observable that takes into account both the system observable and a general measurement procedure. This technique leads to a natural definition of a general conditioned average that converges uniquely to the quantum weak value in the minimal disturbance limit. As such, we address the controversy in the literature regarding the theoretical consistency of the quantum weak value by providing a more general theoretical framework and giving several examples of how that framework relates to existing experimental and theoretical results.


Test-retest reliability of static postural control in people with multiple sclerosis.
[Purpose] The purpose of this study was to analyse the intraday test-retest reliability of stabilometric measurements on the Centre of Pressure (CoP) in persons with Multiple Sclerosis. [Subjects and Methods] The measurements were taken with the subject standing on the force platform with both feet together, in four different conditions: eyes open and closed whilst standing on both a rigid surface and then on foam. The measurements were taken on three occasions with intervals of 20 minutes between them. 18 persons with confirmed Multiple Sclerosis (MS), (aged 44.4 ± 13.3 years and 3.5 ± 1.5 EDSS) participated in the study. Relative reliability was measured using the intraclass correlation coefficient (ICC) and the 95% confidence interval (95% CI); and the absolute reliability using the coefficient of variation (CV) and standard error of measurement (SEM). [Results] The measurements of the CoP in all of the variables in each of the four conditions, showed a reliability of good to excellent (ICC=0.69-0.92) in the intraday test-retest. The variables which showed greatest consistency with repetition were X Speed, Y Speed and Side Length. [Conclusion] Given the results it would seem that the best variables for monitoring postural control in persons with MS are Speed on X and Y along with Side Length.


The current strategies and parameters for the enhanced microbial production of 2,3-butanediol.
2,3-Butanediol (2,3-BD) is a propitious compound with many industrial uses ranging from rubber, fuels, and cosmetics to food additives. Its microbial production has especially attracted as an alternative way to the petroleum-based production. However, 2,3-BD production has always been hampered by low yields and high production costs. The enhanced production of 2,3-butanediol requires screening of the best strains and a systematic optimization of fermentation conditions. Moreover, the metabolic pathway engineering is essential to achieve the best results and minimize the production costs by rendering the strains to use efficiently low cost substrates. This review is to provide up-to-date information on the current strategies and parameters for the enhanced microbial production of 2,3-BD.


Methicillin-resistant Staphylococcus aureus colonization or infection in Canada: National Surveillance and Changing Epidemiology, 1995-2007.
To determine the incidence and describe the changing epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) colonization or infection in Canadian hospitals from 1995-2007. Forty-eight hospitals participating in the Canadian Nosocomial Infection Surveillance Program. Prospective, laboratory-based surveillance for incident cases of MRSA colonization or infection among hospitalized patients. Clinical and epidemiologic data were obtained by review of hospital records. Standard criteria were used to determine whether MRSA colonization or infection was present and whether the MRSA strain was healthcare associated or community associated. A representative subset of isolates was characterized by use of pulsed-field gel electrophoresis and staphylococcal cassette chromosome (SCC) mec typing. From 1995 to 2007, a total of 37,169 hospitalized patients were newly identified as either infected or colonized with MRSA, and the overall incidence of both MRSA colonization and MRSA infection increased from 0.65 to 11.04 cases per 10,000 patient-days (P < .001). Of these 37,169 patients, 11,828 (32%) had an MRSA infection, and infection rate increased from 0.36 to 3.43 cases per 10,000 patient-days. The proportion of community-associated MRSA strains increased from 6% to 23% (P < .001). The most common genotype (47% of isolates) was CMRSA-2 (USA100/800); in 2007, CMRSA-10 (USA300) was the second most common strain (27% of isolates), associated with SCCmec type IV. Patients with CMRSA-10 were predominantly from western Canada and were more likely to be children (odds ratio [OR], 10.0 [95% confidence interval {CI}, 7.4-13.4]) and to have infection (OR, 2.3 [95% CI, 1.9-2.7]), especially skin and/or soft tissue infection (OR, 5.9 [95% CI, 5.0-6.9]). The overall incidence of both MRSA colonization and MRSA infection increased 17-fold in Canadian hospitals from 1995 to 2007. There has also been a dramatic increase in cases of community-associated MRSA infection due to the CMRSA-10 (USA300) clone. Continued surveillance is needed to monitor the ongoing evolution of MRSA colonization or infection in Canada and globally.


MEDIATOR25 acts as an integrative hub for the regulation of jasmonate-responsive gene expression in Arabidopsis.
The PHYTOCHROME AND FLOWERING TIME1 gene encoding the MEDIATOR25 (MED25) subunit of the eukaryotic Mediator complex is a positive regulator of jasmonate (JA)-responsive gene expression in Arabidopsis (Arabidopsis thaliana). Based on the function of the Mediator complex as a bridge between DNA-bound transcriptional activators and the RNA polymerase II complex, MED25 has been hypothesized to function in association with transcriptional regulators of the JA pathway. However, it is currently not known mechanistically how MED25 functions to regulate JA-responsive gene expression. In this study, we show that MED25 physically interacts with several key transcriptional regulators of the JA signaling pathway, including the APETALA2 (AP2)/ETHYLENE RESPONSE FACTOR (ERF) transcription factors OCTADECANOID-RESPONSIVE ARABIDOPSIS AP2/ERF59 and ERF1 as well as the master regulator MYC2. Physical interaction detected between MED25 and four group IX AP2/ERF transcription factors was shown to require the activator interaction domain of MED25 as well as the recently discovered Conserved Motif IX-1/EDLL transcription activation motif of MED25-interacting AP2/ERFs. Using transcriptional activation experiments, we also show that OCTADECANOID-RESPONSIVE ARABIDOPSIS AP2/ERF59- and ERF1-dependent activation of PLANT DEFENSIN1.2 as well as MYC2-dependent activation of VEGETATIVE STORAGE PROTEIN1 requires a functional MED25. In addition, MED25 is required for MYC2-dependent repression of pathogen defense genes. These results suggest an important role for MED25 as an integrative hub within the Mediator complex during the regulation of JA-associated gene expression.


Early versus delayed laparoscopic cholecystectomy for acute cholecystitis: a prospective, randomized study.
We aimed to compare the clinical outcome and cost of early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Sixty patients with acute cholecystitis were randomized into early (within 24 hours of admission) or delayed (after 6-8 weeks of conservative treatment) laparoscopic cholecystectomy groups. There was no significant difference between study groups in terms of operation time and rates for conversion to open cholecystectomy. On the other hand, total hospital stay was longer (5.2 ± 1.40 versus 7.8 ± 1.65 days; P = 0.04) and total costs were higher (2500.97 ± 755.265 versus 3713.47 ± 517.331 Turkish Lira; P = 0.03) in the delayed laparoscopic cholecystectomy group. Intraoperative and postoperative complications were recorded in 8 patients in the early laparoscopic cholecystectomy group, whereas no complications occurred in the delayed laparoscopic cholecystectomy group (P = 0.002). Despite intraoperative and postoperative complications being associated more with early laparoscopic cholecystectomy compared with delayed intervention, early laparoscopic cholecystectomy should be preferred for treatment of acute cholecystitis because of its advantages of shorter hospital stay and lower cost.


Elder abuse prevalence in community settings: a systematic review and meta-analysis.
Elder abuse is recognised worldwide as a serious problem, yet quantitative syntheses of prevalence studies are rare. We aimed to quantify and understand prevalence variation at the global and regional levels. For this systematic review and meta-analysis, we searched 14 databases, including PubMed, PsycINFO, CINAHL, EMBASE, and MEDLINE, using a comprehensive search strategy to identify elder abuse prevalence studies in the community published from inception to June 26, 2015. Studies reporting estimates of past-year abuse prevalence in adults aged 60 years or older were included in the analyses. Subgroup analysis and meta-regression were used to explore heterogeneity, with study quality assessed with the risk of bias tool. The study protocol has been registered with PROSPERO, number CRD42015029197. Of the 38 544 studies initially identified, 52 were eligible for inclusion. These studies were geographically diverse (28 countries). The pooled prevalence rate for overall elder abuse was 15·7% (95% CI 12·8-19·3). The pooled prevalence estimate was 11·6% (8·1-16·3) for psychological abuse, 6·8% (5·0-9·2) for financial abuse, 4·2% (2·1-8·1) for neglect, 2·6% (1·6-4·4) for physical abuse, and 0·9% (0·6-1·4) for sexual abuse. Meta-analysis of studies that included overall abuse revealed heterogeneity. Significant associations were found between overall prevalence estimates and sample size, income classification, and method of data collection, but not with gender. Although robust prevalence studies are sparse in low-income and middle-income countries, elder abuse seems to affect one in six older adults worldwide, which is roughly 141 million people. Nonetheless, elder abuse is a neglected global public health priority, especially compared with other types of violence. Social Sciences and Humanities Research Council of Canada and the WHO Department of Ageing and Life Course.


Integrative Analysis of Disease Signatures Shows Inflammation Disrupts Juvenile Experience-Dependent Cortical Plasticity.
Throughout childhood and adolescence, periods of heightened neuroplasticity are critical for the development of healthy brain function and behavior. Given the high prevalence of neurodevelopmental disorders, such as autism, identifying disruptors of developmental plasticity represents an essential step for developing strategies for prevention and intervention. Applying a novel computational approach that systematically assessed connections between 436 transcriptional signatures of disease and multiple signatures of neuroplasticity, we identified inflammation as a common pathological process central to a diverse set of diseases predicted to dysregulate plasticity signatures. We tested the hypothesis that inflammation disrupts developmental cortical plasticity in vivo using the mouse ocular dominance model of experience-dependent plasticity in primary visual cortex. We found that the administration of systemic lipopolysaccharide suppressed plasticity during juvenile critical period with accompanying transcriptional changes in a particular set of molecular regulators within primary visual cortex. These findings suggest that inflammation may have unrecognized adverse consequences on the postnatal developmental trajectory and indicate that treating inflammation may reduce the burden of neurodevelopmental disorders.


Extinction and dawn of the modern world in the Carnian (Late Triassic).
The Carnian Pluvial Episode (Late Triassic) was a time of global environmental changes and possibly substantial coeval volcanism. The extent of the biological turnover in marine and terrestrial ecosystems is not well understood. Here, we present a meta-analysis of fossil data that suggests a substantial reduction in generic and species richness and the disappearance of 33% of marine genera. This crisis triggered major radiations. In the sea, the rise of the first scleractinian reefs and rock-forming calcareous nannofossils points to substantial changes in ocean chemistry. On land, there were major diversifications and originations of conifers, insects, dinosaurs, crocodiles, lizards, turtles, and mammals. Although there is uncertainty on the precise age of some of the recorded biological changes, these observations indicate that the Carnian Pluvial Episode was linked to a major extinction event and might have been the trigger of the spectacular radiation of many key groups that dominate modern ecosystems.


Severe acute respiratory syndrome (SARS): knowledge, attitudes, practices and sources of information among physicians answering a SARS fever hotline service.
In June 2003, Taiwan introduced a severe acute respiratory syndrome (SARS) telephone hotline service to provide concerned callers with rapid access to information, advice and appropriate referral where necessary. This paper reports an evaluation of the knowledge, attitude, practices and sources of information relating to SARS among physicians who staffed the SARS fever hotline service. A retrospective survey was conducted using a self-administered postal questionnaire. Participants were physicians who staffed a SARS hotline during the SARS epidemic in Taipei, Taiwan from June 1 to 10, 2003. A response rate of 83% was obtained. All respondents knew the causative agent of SARS, and knowledge regarding SARS features and preventive practices was good. However, only 54% of respondents knew the incubation period of SARS. Hospital guidelines and news media were the major information sources. In responding to two case scenarios most physicians were likely to triage callers at high risk of SARS appropriately, but not callers at low risk. Less than half of all respondents answered both scenarios correctly. The results obtained suggest that knowledge of SARS was generally good although obtained from both medical and non-medical sources. Specific knowledge was however lacking in certain areas and this affected the ability to appropriately triage callers. Standardized education and assessment of prior knowledge of SARS could improve the ability of physicians to triage callers in future outbreaks.


Treatment of Citrobacter koseri infection with ciprofloxacin and cefotaxime in a preterm infant.
To report a case of successful treatment of Citrobacter koseri infection in a preterm infant as a means of challenging the current treatment recommendations on the basis of pharmacodynamic and pharmacokinetic considerations. A premature infant was diagnosed with C. koseri sepsis after 3 weeks in intensive care. Concern for meningitis was based on the propensity for central nervous system (CNS) involvement with Citrobacter infection along with new findings of ventriculomegaly and hydrocephalus shown on cranial ultrasound (CUS). The infant was treated with ciprofloxacin 10-20 mg/day and cefotaxime 100 mg/day for 21 days. After treatment, lumbar puncture was normal, follow-up CUS returned to baseline, and the infant passed a hearing screen after discharge. A favorable outcome was achieved in this case. Approximately 76% of neonatal patients infected with C. koseri develop brain abscesses. The mortality rate for meningitis due to Citrobacter spp. is approximately 30%, and of the infants who survive, more than 80% have some degree of mental retardation. Third-generation cephalosporins and aminoglycosides are traditional therapies against this infection. The current antibiotic strategies have failed to prevent the high rates of morbidity and mortality associated with Citrobacter infections. A possible basis for these poor outcomes is failure to apply appropriate pharmacokinetic and pharmacodynamic principles in selecting antibiotics that will achieve adequate concentrations to kill the bacteria in granulocytes within the CNS. Based on favorable sensitivity data, penetration into neutrophils and the CNS, and favorable toxicity profiles, ciprofloxacin and meropenem would appear to be the most appropriate antibiotic treatment options for systemic infection or meningitis caused by C. koseri. Ciprofloxacin and meropenem should be considered antibiotic treatment options for systemic infection or meningitis caused by C. koseri.


Bridging gaps in handoffs: a continuity of care based approach.
Handoff among healthcare providers has been recognized as a major source of medical errors. Most prior research has often focused on the communication aspects of handoff, with limited emphasis on the overall handoff process, especially from a clinician workflow perspective. Such a workflow perspective that is based on the continuity of care model provides a framework required to identify and support an interconnected trajectory of care events affecting handoff communication. To this end, we propose a new methodology, referred to as the clinician-centered approach that allows us to investigate and represent the entire clinician workflow prior to, during and, after handoff communication. This representation of clinician activities supports a comprehensive analysis of the interdependencies in the handoff process across the care continuum, as opposed to a single discrete, information sharing activity. The clinician-centered approach is supported by multifaceted methods for data collection such as observations, shadowing of clinicians, audio recording of handoff communication, semi-structured interviews and artifact identification and collection. The analysis followed a two-stage mixed inductive-deductive method. The iterative development of clinician-centered approach was realized using a multi-faceted study conducted in the Medical Intensive Care Unit (MICU) of an academic hospital. Using the clinician-centered approach, we (a) identify the nature, inherent characteristics and the interdependencies between three phases of the handoff process and (b) develop a descriptive framework of handoff communication in critical care that captures the non-linear, recursive and interactive nature of collaboration and decision-making. The results reported in this paper serve as a "proof of concept" of our approach, emphasizing the importance of capturing a coordinated and uninterrupted succession of clinician information management and transfer activities in relation to patient care events.


Behavioral consequences of delta-opioid receptor activation in the periaqueductal gray of morphine tolerant rats.
Chronic morphine administration shifts delta-opioid receptors (DORs) from the cytoplasm to the plasma membrane. Given that microinjection of morphine into the PAG produces antinociception, it is hypothesized that the movement of DORs to the membrane will allow antinociception to the DOR agonist deltorphin II as a way to compensate for morphine tolerance. Tolerance was induced by twice daily injections of morphine (5, 10, or 20 mg/kg, subcutaneous) for 3.5 days. Microinjection of deltorphin into the vPAG 6 hours after the last morphine injection produced a mild antinociception that did not vary in a consistent manner across morphine pretreatment doses or nociceptive tests. In contrast, deltorphin caused a decrease in activity in morphine tolerant rats that was associated with lying in the cage. The decrease in activity and change in behavior indicate that chronic morphine administration alters DORs in the vPAG. However, activation of these receptors does not appear to compensate for the decrease in antinociception caused by morphine tolerance.


Incidence and clinical implications of intraoperative bilateral internal thoracic artery graft conversion: Insights from the Arterial Revascularization Trial.
The Arterial Revascularization Trial has been designed to answer the question whether the use of bilateral internal thoracic arteries can improve 10-year outcomes when compared with single internal thoracic arteries. In the Arterial Revascularization Trial, a significant proportion of patients initially allocated to bilateral internal thoracic arteries received other conduit strategies. We sought to investigate the incidence and clinical implication of bilateral internal thoracic artery graft conversion in the Arterial Revascularization Trial. Among patients enrolled in the Arterial Revascularization Trial (n = 3102), we excluded those allocated to single internal thoracic arteries (n = 1554), those who did not undergo surgery (n = 16), and those who underwent operation but withdrew after randomization (n = 7). Propensity score matching was used to compare converted versus nonconverted bilateral internal thoracic artery groups. A total of 1525 patients were operated with the intention to receive bilateral internal thoracic artery grafting. Of those, 233 (15.3%) were converted to other conduit selection strategies. Incidence of conversion largely varied across 131 participating surgeons (from 0% to 100%). The most common reason for bilateral internal thoracic artery graft conversion was the evidence of at least 1 internal thoracic artery that was not suitable, which was reported in 77 cases. Patients with intraoperative bilateral internal thoracic artery graft conversion received a lower number of grafts (2.95 ± 0.84 vs 3.21 ± 0.74; P < .001). However, the hospital mortality rate was comparable to that of those who did not require bilateral internal thoracic artery graft conversion (0% vs 1.6%; P = .1), as well as the incidence of major complications. At 5 years, we found a nonsignificant excess of deaths (11.9% vs 8.4%; P = .1) and major adverse events (17.1% 13.2%; P = .1) mainly driven by an excess of revascularization in patients requiring conversion. The incidence of intraoperative bilateral internal thoracic artery graft conversion is not infrequent. Bilateral internal thoracic artery graft conversion is not associated with increased operative morbidity, but its effect on late outcomes remains uncertain.


Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus.
We assessed whether dietary supplementation with coenzyme Q(10) improves endothelial function of the brachial artery in patients with Type II (non-insulin-dependent) diabetes mellitus and dyslipidaemia. A total of 40 patients with Type II diabetes and dyslipidaemia were randomized to receive 200 mg of coenzyme Q(10) or placebo orally for 12 weeks. Endothelium-dependent and independent function of the brachial artery was measured as flow-mediated dilatation and glyceryl-trinitrate-mediated dilatation, respectively. A computerized system was used to quantitate vessel diameter changes before and after intervention. Arterial function was compared with 18 non-diabetic subjects. Oxidative stress was assessed by measuring plasma F(2)-isoprostane concentrations, and plasma antioxidant status by oxygen radical absorbance capacity. The diabetic patients had impaired flow-mediated dilation [3.8 % (SEM 0.5) vs 6.4 % (SEM 1.0), p = 0.016], but preserved glyceryl-trinitrate-mediated dilation, of the brachial artery compared with non-diabetic subjects. Flow-mediated dilation of the brachial artery increased by 1.6 % (SEM 0.3) with coenzyme Q(10) and decreased by -0.4 % (SEM 0.5) with placebo (p = 0.005); there were no group differences in the changes in pre-stimulatory arterial diameter, post-ischaemic hyperaemia or glyceryl-trinitrate-mediated dilation response. Coenzyme Q(10) treatment resulted in a threefold increase in plasma coenzyme Q(10) (p < 0.001) but did not alter plasma F(2)-isoprostanes, oxygen radical absorbance capacity, lipid concentrations, glycaemic control or blood pressure. Coenzyme Q(10) supplementation improves endothelial function of conduit arteries of the peripheral circulation in dyslipidaemic patients with Type II diabetes. The mechanism could involve increased endothelial release and/or activity of nitric oxide due to improvement in vascular oxidative stress, an effect that might not be reflected by changes in plasma F(2)-isoprostane concentrations.


Identifying multiquark hadrons from heavy ion collisions.
Identifying hadronic molecular states and/or hadrons with multiquark components either with or without exotic quantum numbers is a long-standing challenge in hadronic physics. We suggest that studying the production of these hadrons in relativistic heavy ion collisions offers a promising resolution to this problem as yields of exotic hadrons are expected to be strongly affected by their structures. Using the coalescence model for hadron production, we find that, compared to the case of a nonexotic hadron with normal quark numbers, the yield of an exotic hadron is typically an order of magnitude smaller when it is a compact multiquark state and a factor of 2 or more larger when it is a loosely bound hadronic molecule. We further find that some of the newly proposed heavy exotic states could be produced and realistically measured in these experiments.


Rapid Prototyping Technologies and their Applications in Prosthodontics, a Review of Literature.
The early computer-aided design/computer-aided manufacturing (CAD/CAM) systems were relied exclusively on subtractive methods. In recent years, additive methods by employing rapid prototyping (RP) have progressed rapidly in various fields of dentistry as they have the potential to overcome known drawbacks of subtractive techniques such as fit problems. RP techniques have been exploited to build complex 3D models in medicine since the 1990s. RP has recently proposed successful applications in various dental fields, such as fabrication of implant surgical guides, frameworks for fixed and removable partial dentures, wax patterns for the dental prosthesis, zirconia prosthesis and molds for metal castings, and maxillofacial prosthesis and finally, complete dentures. This paper aimed to offer a comprehensive literature review of various RP methods, particularly in dentistry, that are expected to bring many improvements to the field. A search was made through MEDLINE database and Google scholar search engine. The keywords; 'rapid prototyping' and 'dentistry' were searched in title/abstract of publications; limited to 2003 to 2013, concerning past decade. The inclusion criterion was the technical researches that predominately included laboratory procedures. The exclusion criterion was meticulous clinical and excessive technical procedures. A total of 106 articles were retrieved, recited by authors and only 50 met the specified inclusion criteria for this review. Selected articles had used rapid prototyping techniques in various fields in dentistry through different techniques. This review depicted the different laboratory procedures employed in this method and confirmed that RP technique have been substantially feasible in dentistry. With advancement in various RP systems, it is possible to benefit from this technique in different dental practices, particularly in implementing dental prostheses for different applications.


Ultimate limit of resolution of subwavelength imaging devices formed by metallic rods.
It is demonstrated that the ultimate physical limit of resolution of novel imaging devices based on arrays of metallic rods is determined by the skin depth of the metal. Our theoretical and numerical results show that wire medium lenses may provide a unique solution for subwavelength imaging at frequencies up to the terahertz range and may enable image formation at a significant distance from the source plane.


Clinical issues in occlusion - Part II.
Occlusal diagnosis plays an important role in the planning and subsequent delivery of predictable functional and aesthetic restorations and prostheses. Once an occlusal problem is identified there are a number of techniques and materials that can be utilised to record occlusal relationships, subsequently analyse them and incorporate information obtained into the delivery of tooth restoration or replacement. This paper discusses the clinical and technical aspects of occlusal examination and analysis outlining contemporary and traditional techniques in their utilisation. Aspects of occlusal examination will be revisited; the identification and recording of centric occlusion as well as subsequent articulation will be discussed. The requirement for occlusal splint provision will also be discussed and illustrated.


Comparative genomic analysis of Methanimicrococcus blatticola provides insights into host adaptation in archaea and the evolution of methanogenesis.
Other than the Methanobacteriales and Methanomassiliicoccales, the characteristics of archaea that inhabit the animal microbiome are largely unknown. Methanimicrococcus blatticola, a member of the Methanosarcinales, currently reunites two unique features within this order: it is a colonizer of the animal digestive tract and can only reduce methyl compounds with H2 for methanogenesis, a increasingly recognized metabolism in the archaea and whose origin remains debated. To understand the origin of these characteristics, we have carried out a large-scale comparative genomic analysis. We infer the loss of more than a thousand genes in M. blatticola, by far the largest genome reduction across all Methanosarcinales. These include numerous elements for sensing the environment and adapting to more stable gut conditions, as well as a significant remodeling of the cell surface components likely involved in host and gut microbiota interactions. Several of these modifications parallel those previously observed in phylogenetically distant archaea and bacteria from the animal microbiome, suggesting large-scale convergent mechanisms of adaptation to the gut. Strikingly, M. blatticola has lost almost all genes coding for the H4MPT methyl branch of the Wood-Ljungdahl pathway (to the exception of mer), a phenomenon never reported before in any member of Class I or Class II methanogens. The loss of this pathway illustrates one of the evolutionary processes that may have led to the emergence of methyl-reducing hydrogenotrophic methanogens, possibly linked to the colonization of organic-rich environments (including the animal gut) where both methyl compounds and hydrogen are abundant.


Endocytotic potential governs magnetic particle loading in dividing neural cells: studying modes of particle inheritance.
To achieve high and sustained magnetic particle loading in a proliferative and endocytotically active neural transplant population (astrocytes) through tailored magnetite content in polymeric iron oxide particles. MPs of varying magnetite content were applied to primary-derived rat cortical astrocytes ± static/oscillating magnetic fields to assess labeling efficiency and safety. Higher magnetite content particles display high but safe accumulation in astrocytes, with longer-term label retention versus lower/no magnetite content particles. Magnetic fields enhanced loading extent. Dynamic live cell imaging of dividing labeled astrocytes demonstrated that particle distribution into daughter cells is predominantly 'asymmetric'. These findings could inform protocols to achieve efficient MP loading into neural transplant cells, with significant implications for post-transplantation tracking/localization.


Associations between sexually transmitted disease diagnosis and subsequent sexual risk and sexually transmitted disease incidence among adolescents.
Empiric evidence is lacking in regard to the subsequent sexually transmitted disease (STD)-associated risk behaviors of adolescents diagnosed and treated for an STD. The goal of this study was to prospectively identify associations between STD diagnosis and subsequent sexual risk and STD incidence among a sample of U.S. adolescents. A cohort of 455 adolescents (age 15-21 years) was followed for 3 months. Adolescents were recruited from primary care clinics and through outreach activities. A total of 10.8% were initially diagnosed with at least one STD. After adjusting for observed covariates, these adolescents (compared with those testing negative) were 2.8 times (P = 0.0001) more likely to be abstinent from sex and 2.2 times more likely to report always using condoms (P = 0.04). However, during the ensuing 3 months, they were approximately 2.4 times more likely to report having sex with multiple partners (P = 0.01), 8.9 times more likely to test positive for trichomonas (P = 0.009), and 3.0 times more likely to test positive for chlamydia (P = 0.04). Compared with those testing negative, adolescents diagnosed with an STD may subsequently adopt safer sex behaviors, including abstinence. However, perhaps in part as a result of having sex with multiple partners, they might fail to practice safer sex behaviors stringently enough to avoid subsequent STD acquisition.


Genome sequence of the PCE-dechlorinating bacterium Dehalococcoides ethenogenes.
Dehalococcoides ethenogenes is the only bacterium known to reductively dechlorinate the groundwater pollutants, tetrachloroethene (PCE) and trichloroethene, to ethene. Its 1,469,720-base pair chromosome contains large dynamic duplicated regions and integrated elements. Genes encoding 17 putative reductive dehalogenases, nearly all of which were adjacent to genes for transcription regulators, and five hydrogenase complexes were identified. These findings, plus a limited repertoire of other metabolic modes, indicate that D. ethenogenes is highly evolved to utilize halogenated organic compounds and H2. Diversification of reductive dehalogenase functions appears to have been mediated by recent genetic exchange and amplification. Genome analysis provides insights into the organism's complex nutrient requirements and suggests that an ancestor was a nitrogen-fixing autotroph.


Post-concussion Symptom Factors and Neuropsychological Outcomes in Collegiate Athletes.
Research indicates that symptoms following a concussion are related to cognitive dysfunction; however, less is known about how different types of symptoms may be related to cognitive outcomes or how specific domains of cognition are affected. The present study explored the relationship between specific types of symptoms and these various cognitive outcomes following a concussion. One-hundred twenty-two student-athletes with sports-related concussion were tested with a battery that included a symptom report measure and various cognitive tests. Symptoms factors were: Physical, Sleep, Cognitive, Affective and Headache. Participants were grouped into "symptom" and "no symptom" groups for each factor. Cognitive outcomes included both overall performance as well as impairment scores in which individuals were grouped into impaired and not impaired based on a cutoff of 2 or more tests at the impaired level (<80 in standard scores). These cognitive outcomes were examined for all the tests combined and then specifically for the memory tests and attention/processing speed tests. A Bonferroni correction was used, and the results were considered significant at a level of p<.008. Headache symptoms were significantly (p<.008) associated with overall cognitive impairment as well as memory and attention/processing speed impairment. Sleep symptoms were related to memory impairments. The symptom specific relationships to cognitive outcomes demonstrated by our study can help guide treatment and accommodations for athletes following concussion. (JINS, 2018, 24, 684-692).


Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany.
Chimeric antigen receptor (CAR)-T cell therapies are on the verge of becoming powerful immunotherapeutic tools for combating hematological diseases confronted with pressing medical needs. Lately, CAR-NK cell therapies have also come into focus as novel therapeutic options to address hurdles related to CAR-T cell therapies, such as therapy-induced side effects. Currently, more than 500 CAR-T and 17 CAR-NK cell trials are being conducted worldwide including the four CAR-T cell products Kymriah, Yescarta, Tecartus and Breyanzi, which are already available on the market. Most CAR-T cell-based gene therapy products that are under clinical evaluation consist of autologous enriched T cells, whereas CAR-NK cell-based approaches can be generated from allogeneic donors. Besides modification based on a second-generation CAR, more advanced CAR-immune cell therapeutics are being tested, which utilize precise insertion of genes to circumvent graft-versus-host disease (GvHD) or employ a dual targeting approach and adapter CARs in order to avoid therapy resistance caused by antigen loss. In this review, we are going to take a closer look at the commercial CAR-T cell therapies, as well as on CAR-T and CAR-NK cell products, which are currently under evaluation in clinical trials, that are being conducted in Germany.


Frequency of acute coronary syndrome in patients with normal electrocardiogram performed during presence or absence of chest pain.
The authors hypothesized that patients with active chest pain at the time of a normal electrocardiogram (ECG) have a lower frequency of acute coronary syndrome (ACS) than patients being evaluated for chest pain but with no active chest pain at the time of a normal ECG. The study objective was to describe the association between chest pain in patients with a normal ECG and the diagnosis of ACS. This was a prospective observational study of emergency department (ED) patients with a chief complaint of chest pain and an initial normal ECG admitted to the hospital for chest pain evaluation over a 1-year period. Two groups were identified: patients with chest pain during the ECG and patients without chest pain during the ECG. Normal ECG criteria were as follow: 1) normal sinus rhythm with heart rate of 55-105 beats/min, 2) normal QRS interval and ST segment, and 3) normal T-wave morphology or T-wave flattening. "Normal" excludes pathologic Q waves, left ventricular hypertrophy, nonspecific ST-T wave abnormalities, any ST depression, and discrepancies in the axis between the T wave and the QRS. Patients' initial ED ECGs were interpreted as normal or abnormal by two emergency physicians (EPs); differences in interpretation were resolved by a cardiologist. ACS was defined as follows: 1) elevation and characteristic evolution of troponin I level, 2) coronary angiography demonstrating >70% stenosis in a major coronary artery, or 3) positive noninvasive cardiac stress test. Chi-square analysis was performed and odds ratios (ORs) are presented. A total of 1,741 patients were admitted with cardiopulmonary symptoms; 387 met study criteria. The study group comprised 199 males (51%) and 188 females (49%), mean age was 56 years (range, 25-90 years), and 106 (27%) had known coronary artery disease (CAD). A total of 261 (67%) patients experienced chest pain during ECG; 126 (33%) patients experienced no chest pain during ECG. There was no difference between the two groups in age, sex, cardiac risk factors, or known CAD. The frequency of ACS for the total study group was 17% (67/387). There was no difference in prevalence of ACS based on the presence or absence of chest pain (16% or 42/261 vs. 20% or 25/126; OR = 0.77, 95% confidence interval = 0.45 to 1.33, p = 0.4). Contrary to our hypothesis concerning patients who presented to the ED with a chief complaint of chest pain, our study demonstrated no difference in the frequency of acute coronary syndrome between patients with chest pain at the time of acquisition of a normal electrocardiogram and those without chest pain during acquisition of a normal electrocardiogram.


Is zinc concentration in pancreatic fluid a marker for pancreatic diseases?
An imbalance of free radicals and scavenging processes has been implicated in the pathogenesis of pancreatic tissue injury. Gradual decreases in antioxidant enzyme expression in pancreatic cells from normal pancreas to chronic pancreatitis to pancreatic cancer have been reported. Zinc is one of the components of antioxidant enzymes and may play a role in the pathogenesis of pancreatic diseases. A recent report showed a significant decrease in pancreatic zinc output in patients with chronic pancreatitis and proposed that zinc output can be used as an alternative to enzyme output for the diagnosis. We aimed to determine the zinc concentration in pancreatic fluid of patients with chronic pancreatitis and pancreatic cancer compared to normal pancreas. Seventy-five consecutive patients were prospectively evaluated. Chronic pancreatitis was diagnosed in 20 patients by ERCP (n=16) and histology (n=4). Pancreatic cancer was diagnosed in 17 patients by cytology from EUS-FNA (n=12) or surgical pathology (n=5). Thirty-eight patients were confirmed to have normal pancreas. Patients underwent esophagogastroduodenoscopy following intravenous secretin injection (0.2 microg/kg). Pancreatic fluid collected for 10 minutes was immediately frozen at -80 degrees C and stored until the assay was performed. Zinc concentrations were determined by inductively coupled plasma optical emission spectroscopy. Among the three groups, patients with pancreatic cancer were significant older (P<0.001) with a higher prevalence of diabetes mellitus (P=0.002). Gender distribution (P=0.098), body mass index (P=0.925), and history of alcohol use (P=0.997) were similar among groups. Zinc concentrations in pancreatic fluid were not significantly different among groups (P=0.129). Zinc concentration in pancreatic fluid was comparable in patients with chronic pancreatitis and pancreatic cancer compared to normal pancreas. Zinc concentration in pancreatic fluid collected by our 10-minute endoscopic method cannot reliably be used for the diagnosis of chronic pancreatitis and/or pancreatic cancer.


Enhancing porphyrin photostability when locked in metal-organic frameworks.
Porphyrins have been widely used in many optical devices given their unique photochemical properties. Their poor photostability has, however, limited their wide applications in bioimaging and biosensing schemes. Herein, we report the remarkable photostability enhancement of the porphyrin, carboxyphenyl porphyrin (TCPP-H2) when locked in a zirconium based metal-organic framework (MOF-525). Steady-state ensemble fluorescence spectroscopy experiments showed minimal changes (2%) in the recorded signal when MOF-525 was continuously illuminated as compared to a 16% decrease for free porphyrins. Single particle fluorescence imaging revealed bright microparticles with exceptional photostability and no-blinking within the experiment window. This study highlights the use of metal-organic frameworks for preparing photostable microstructures by leveraging on their unique self-assembly properties.


Use of the Human Vaccine, Mycobacterium bovis Bacillus Calmette Guérin in Deer.
The only vaccine ever approved for human tuberculosis was developed a century ago from an isolate of Mycobacterium bovis derived from a tuberculous cow. Initial safety and efficacy studies of an attenuated version of this isolate were conducted in cattle and other animals. In 1921 the first human, an infant, was orally dosed with this attenuated strain that came to be known as M. bovis bacillus Calmette-Guérin (BCG); named for Albert Calmette and Camille Guérin, the two French scientists that developed the strain. Since 1921, billions of people have been vaccinated with BCG making it the oldest, most widely used, and safest vaccine in use today. It is also the tuberculosis vaccine most studied for use in wildlife, including deer. While BCG vaccination of deer may not reliably prevent infection, it consistently decreases lesion severity, minimizing large, necrotic lesions, which often contain large numbers of bacilli. It is believed that decreased lesion severity correlates with decreased disease transmission; however, this hypothesis remains to be proven. Safety studies in white-tailed deer show BCG may persist in lymphoid tissues for up to 12 months; a factor to be considered in deer used for food. Beyond efficacy and safety, methods of vaccine delivery to free-ranging deer are also under investigation, both in the laboratory and in the field. The ideal delivery method is effective, efficient and safe for non-target species, including livestock. Ingestion of BCG by cattle is of special concern as such cattle may present as "false positives" using currently approved diagnostic methods, thus interfering with efforts by animal health agencies to monitor cattle for tuberculosis. An effective BCG vaccine for deer would be of value in regions where free-ranging deer represent a potential source of M. bovis for livestock. Such a vaccine would also be beneficial to farmed deer where M. bovis represents a serious threat to trade and productivity.


Circulating Plasma Cells in Monoclonal Gammopathies.
Monoclonal gammopathies are characterized by presence of clonal plasma cells in the bone marrow, although peripheral blood circulating plasma cells can be found in a significant proportion of patients. The number of circulating plasma cells is an independent prognostic marker associated with shorter survival, but it can also help to predict early relapse. The reason and mechanism of plasma cell expansion from the bone marrow to enter peripheral blood is still not entirely clear, but possible changes in the expression of adhesion molecules are probably involved. Multiparametric flow cytometry allows simple and exact enumeration of circulating plasma cells in different types of cell suspensions, even in their low quantity. The phenotype profile and confirmation of clonality regarding to their bone marrow clonal counterparts should be verified as well. There is no uniform method used in clinical laboratories for circulating plasma cells analyses at this moment. Review is focused on use of multiparametric flow cytometry for circulating plasma cells analysis in peripheral blood. It is comparing possibilities of their detection by different methods and on clinical relevance of that assessment. The standardization of analyses is the main goal. Multiparametric flow cytometry is a very sensitive method for detection of circulating plasma cells, so using a standardized approach can lead to determination and implementation of the flow cytometry diagnostic threshold in plasma cell leukemia suspicious cases as well as in prognostication of monoclonal gammopathies patients. Moreover, analysis of plasma cells phenotypic profile could probably clarify their future behaviour.Key words: monoclonal gammopathies - circulating plasma cells - plasma cell leukemia - flow cytometry.


Moral character in the workplace.
Using two 3-month diary studies and a large cross-sectional survey, we identified distinguishing features of adults with low versus high levels of moral character. Adults with high levels of moral character tend to: consider the needs and interests of others and how their actions affect other people (e.g., they have high levels of Honesty-Humility, empathic concern, guilt proneness); regulate their behavior effectively, specifically with reference to behaviors that have positive short-term consequences but negative long-term consequences (e.g., they have high levels of Conscientiousness, self-control, consideration of future consequences); and value being moral (e.g., they have high levels of moral identity-internalization). Cognitive moral development, Emotionality, and social value orientation were found to be relatively undiagnostic of moral character. Studies 1 and 2 revealed that employees with low moral character committed harmful work behaviors more frequently and helpful work behaviors less frequently than did employees with high moral character, according to their own admissions and coworkers' observations. Study 3 revealed that adults with low moral character committed more delinquent behavior and had more lenient attitudes toward unethical negotiation tactics than did adults with high moral character. By showing that individual differences have consistent, meaningful effects on employees' behaviors, after controlling for demographic variables (e.g., gender, age, income) and basic attributes of the work setting (e.g., enforcement of an ethics code), our results contest situationist perspectives that deemphasize the importance of personality. Moral people can be identified by self-reports in surveys, and these self-reports predict consequential behaviors months after the initial assessment.


Effects of ammonium perchlorate on the reproductive performance and thyroid follicle histology of zebrafish.
Adult zebrafish were reared up to eight weeks in control water or in water containing ammonium perchlorate (AP) at measured perchlorate concentrations of 18 (environmentally relevant, high) and 677 ppm. Groups of eight females were paired with four males on a weekly basis to assess AP effects on spawned egg volume, an index of reproductive performance. All treatments were applied to four to five spawning replicates. At 677 ppm, spawn volume was reduced within one week and became negligible after four weeks. At 18 ppm, spawn volume was unaffected even after eight weeks. Also, perchlorate at 18 ppm did not affect percentage egg fertilization. Fish were collected at the end of the exposures (677 ppm, four weeks; control and 18 ppm, eight weeks) for whole-body perchlorate content and thyroid histopathological analysis. Fish perchlorate levels were about one-hundredth of those of treatment water levels, indicating that waterborne perchlorate does not accumulate in whole fish. At 677 ppm for four weeks, perchlorate caused thyroid follicle cell (nuclear) hypertrophy and angiogenesis, whereas at 18 ppm for eight weeks, its effects were more pronounced and included hypertrophy, angiogenesis, hyperplasia, and colloid depletion. In conclusion, an eight-week exposure of adult zebrafish to 18 ppm perchlorate (high environmentally relevant concentrations) affected the histological condition of their thyroid follicles but not their reproductive performance. The effect of 677 ppm perchlorate on reproduction may be due to extrathyroidal toxicity. Further research is needed to determine if AP at lower environmentally relevant concentrations also affects the thyroid follicles of zebrafish.


The oncomir face of microRNA-206: A permanent miR-206 transfection study.
MiR-206 is a remarkable miRNA because it functions as a suppressor miRNA in rhabdomyosarcoma while at the same time, as previously showed, it can act as an oncomiRNA in SMARCB1 immunonegative soft tissue sarcomas. The aim of this study was to investigate the effect of miR-206 on its several target genes in various human tumorous and normal cell lines. In the current work, we created miR-206-overexpressing cell lines (HT-1080, Caco2, iASC, and SS-iASC) using permanent transfection. mRNA expression of the target genes of miR-206 (SMARCB1, ACTL6A, CCND1, POLA1, NOTCH3, MET, and G6PD) and SMARCB1 protein expression were examined with quantitative real-time polymerase chain reaction, immunoblotting, immunocytochemistry, and flow cytometry. MiRNA inhibition was used to validate our results. We found a diverse silencing effect of miR-206 on its target genes. While an overall tendency of downregulation was noted, expression profiles of individual cell lines showed large variability. Only CCND1 and MET were consistently downregulated. MiR-206 had an antiproliferative effect on a normal human fibroblast cell line. A strong silencing effect of SMARCB1 in miR-206 transfected SS-iASC was most likely caused by the synergic influence of the SS18-SSX1 fusion protein and miR-206. In the same cell line, a moderate decrease of SMARCB1 protein expression could be observed with immunocytochemistry and flow cytometry. In the most comprehensive analysis of miR-206 effects so far, a modest but significant downregulation of miR-206 targets on the mRNA level was confirmed across all cell lines. However, the variability of the effect shows that the action of this miRNA is largely cell context-dependent. Our results also support the conception that the oncomiR effect of miR-206 on SMARCB1 plays an important but not exclusive role in SMARCB1 immunonegative soft tissue sarcomas so it can be considered important in planning the targeted therapy of these tumors in the future. Impact statement Mir-206 is a very unique microRNA because it can act as a suppressor miRNA or as an oncomiRNA depending on the tumor tissue. In SMARCB1 negative soft tissue sarcomas miR-206 is overexpressed, so thus in epithelioid and synovial sarcomas it functions as an oncomiRNA. MiR-206 has diverse silencing effects on its target genes. We found that the action of miR-206 is largely cell context dependent. The oncomiR role of miR-206 is crucial but not exclusive in SMARCB1 negative soft tissue sarcomas and miR-206 has an antiproliferative effect on a normal human fibroblast cell line. Expressions of miR-206 targets observed in tumors can only be reproduced in the corresponding tumorous cell lines. This is the first study which examined the permanent effect of miR-206 on its target genes in normal, tumor, and genetically engineered cell lines.


Kinetic Analysis of Protein Stability Reveals Age-Dependent Degradation.
Do young and old protein molecules have the same probability to be degraded? We addressed this question using metabolic pulse-chase labeling and quantitative mass spectrometry to obtain degradation profiles for thousands of proteins. We find that >10% of proteins are degraded non-exponentially. Specifically, proteins are less stable in the first few hours of their life and stabilize with age. Degradation profiles are conserved and similar in two cell types. Many non-exponentially degraded (NED) proteins are subunits of complexes that are produced in super-stoichiometric amounts relative to their exponentially degraded (ED) counterparts. Within complexes, NED proteins have larger interaction interfaces and assemble earlier than ED subunits. Amplifying genes encoding NED proteins increases their initial degradation. Consistently, decay profiles can predict protein level attenuation in aneuploid cells. Together, our data show that non-exponential degradation is common, conserved, and has important consequences for complex formation and regulation of protein abundance.


Dynamic ROS Control by TIGAR Regulates the Initiation and Progression of Pancreatic Cancer.
The TIGAR protein has antioxidant activity that supports intestinal tissue repair and adenoma development. Using a pancreatic ductal adenocarcinoma (PDAC) model, we show that reactive oxygen species (ROS) regulation by TIGAR supports premalignant tumor initiation while restricting metastasis. Increased ROS in PDAC cells drives a phenotypic switch that increases migration, invasion, and metastatic capacity. This switch is dependent on increased activation of MAPK signaling and can be reverted by antioxidant treatment. In mouse and human, TIGAR expression is modulated during PDAC development, with higher TIGAR levels in premalignant lesions and lower TIGAR levels in metastasizing tumors. Our study indicates that temporal, dynamic control of ROS underpins full malignant progression and helps to rationalize conflicting reports of pro- and anti-tumor effects of antioxidant treatment.


Shortening of a laser pulse with a self-modulated phase at the focus of a lens.
We found that, at the focus of a chromatic lens, a laser pulse with a self-modulated phase can be shortened due to the radial dependence of the group delay imposed by the lens. Normally, this group delay stretches a short pulse into a long pulse by spreading the arrival time of the pulse at the focus. However, for a pulse with a self-modulated phase, it causes the fields with different phases to overlap, thus resulting in destructive interference that shortens the pulse.


A study of abnormal muscular patterns in diverticular disease of the colon using the polysiloxane foam enema.
Three-dimensional, functional studies of the left colon using a polysiloxane foam enema have shown that three types of impressions due to muscular contractions are commonly found in the region of the rectum and sigmoid, and that at least two of these are closely associated with the presence of diverticular disease. Each type of abnormality has been defined and its extent and frequency assessed. A tentative mechanism for the development of the main muscular abnormality through muscle thickening and simple sigmoid curves is put forward, and it is suggested that the third type of abnormality may be associated with sphincteric action at the recto-sigmoid junction. The reproducibility of findings on repeated examinations must mean that there is a local anatomical basis for the muscular impressions seen and that such contractions do not represent evanescent peristaltic type activity. Sigmoid resection and myotomy as practised for diverticular disease should eliminate the first type of abnormality in the majority of cases, but it is necessary to carry the operation well distally to ensure this. Neither operation is likely to correct the type III abnormality, and further work is necessary to determine whether this is responsible for some of the symptoms persisting after surgery.


Partial promoter substitutions generating transcriptional sentinels of diverse signaling pathways in embryonic stem cells and mice.
Extracellular signals in development, physiology, homeostasis and disease often act by regulating transcription. Herein we describe a general method and specific resources for determining where and when such signaling occurs in live animals and for systematically comparing the timing and extent of different signals in different cellular contexts. We used recombinase-mediated cassette exchange (RMCE) to test the effect of successively deleting conserved genomic regions of the ubiquitously active Rosa26 promoter and substituting the deleted regions for regulatory sequences that respond to diverse extracellular signals. We thereby created an allelic series of embryonic stem cells and mice, each containing a signal-responsive sentinel with different fluorescent reporters that respond with sensitivity and specificity to retinoic acids, bone morphogenic proteins, activin A, Wnts or Notch, and that can be adapted to any pathway that acts via DNA elements.


Attribute-based intervention development for increasing resilience of urban drainage systems.
Resilience building commonly focuses on attributes such as redundancy. Whilst this may be effective in some cases, provision of specific attributes does not guarantee resilient performance and research is required to determine the suitability of such approaches. This study uses 250 combined sewer system virtual case studies to explore the effects of two attribute-based interventions (increasing distributed storage and reducing imperviousness) on performance-based resilience measures. These are found to provide improvement in performance under system failure in the majority of case studies, but it is also shown that attribute-based intervention development can result in reduced resilience.


Activation of excitatory amino acid receptors may mediate the folate-induced stimulation of locomotor activity after bilateral injection into the rat nucleus accumbens.
Folic acid (FA) and 5-formyltetrahydrofolic acid (FTHF) have been shown previously to produce a marked stimulation of locomotor activity after bilateral injection into the rat nucleus accumbens. This study was designed to determine whether the hypermotility response produced by the folates is mediated through the activation of excitatory amino acid receptors in the nucleus accumbens. Although FA stimulated locomotor activity, pteroic acid, a congener of FA that lacks the glutamate moiety, was ineffective, suggesting that the glutamate portion of the molecule is essential for the hypermotility response. The N-methyl-D-aspartic acid (NMDA) receptor antagonists, D-alpha-aminoadipic acid, DL-alpha-epsilon-diaminopimelic acid and MgCl2, at doses that attenuated NMDA-induced hypermotility, were ineffective in decreasing the folate-induced hypermotility response. This behavioral observation is consistent with the biochemical observation that the folates, at a 1 mM concentration, were unable to stimulate the release of [3H]acetylcholine from striatal slices, a model system that is sensitive to the activation of NMDA receptors. In contrast to the ineffectiveness of the NMDA antagonists in inhibiting the response to the folates, the antagonist, glutamic acid diethylester, which inhibited the response to quisqualic acid, but not NMDA, also inhibited the response to both FA and FTHF. Two recently characterized dipeptides, gamma-D-glutamylaminomethylsulfonic acid and gamma-D-glutamyltaurine, antagonized the stimulation of locomotor activity produced by quisqualic acid, FA and FTHF. However, these dipeptides also inhibited the response to NMDA, suggesting that these compounds are not able to distinguish between quisqualate and NMDA receptors in the nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)


Activated microglia are less vulnerable to hemin toxicity due to nitric oxide-dependent inhibition of JNK and p38 MAPK activation.
In intracerebral hemorrhage, microglia become rapidly activated and remove the deposited blood and cellular debris. To survive in a harmful hemorrhagic or posthemorrhagic condition, activated microglia must be equipped with appropriate self-defensive mechanism(s) to resist the toxicity of hemin, a component released from damaged RBCs. In the current study, we found that activation of microglia by pretreatment with LPS markedly reduced their vulnerability to hemin toxicity in vitro. Similarly, intracorpus callosum microinjection of LPS prior to hemin treatment reduced the brain tissue damage caused by hemin and increased microglial density in the penumbra in rats. LPS induced the expressions of inducible NO synthase (iNOS) and heme oxygenase (HO)-1, the rate-limiting enzyme in heme degradation in microglia. The preventive effect by LPS was significantly diminished by an iNOS inhibitor, L-N(6)-(1-iminoethyl)lysine, whereas it was mimicked by a NO donor, diethylamine-NONOate, both suggesting the crucial role of NO in the modulation of hemin-induced toxicity in activated microglia. We further found that NO reduced hemin toxicity via inhibition of hemin-induced activation of JNK and p38 MAPK pathways in microglia. Whereas HO-1 expression in LPS-stimulated microglia was markedly blocked by L-N(6)-(1-iminoethyl)lysine, the HO-1 inhibitor, tin protoporphyrin, increased iNOS expression and decreased the susceptibility of LPS-activated microglia to hemin toxicity. The data indicate that the mutual interaction between NO and HO-1 plays a critical role in modulating the adaptive response of activated microglia to hemin toxicity. Better understanding of the survival mechanism of activated microglia may provide a therapeutic strategy to attenuate the devastating intracerebral hemorrhagic injury.


Consciousness CLEARS the mind.
A full understanding of consciousness requires that we identify the brain processes from which conscious experiences emerge. What are these processes, and what is their utility in supporting successful adaptive behaviors? Adaptive Resonance Theory (ART) predicted a functional link between processes of Consciousness, Learning, Expectation, Attention, Resonance and Synchrony (CLEARS), including the prediction that "all conscious states are resonant states". This connection clarifies how brain dynamics enable a behaving individual to autonomously adapt in real time to a rapidly changing world. The present article reviews theoretical considerations that predicted these functional links, how they work, and some of the rapidly growing body of behavioral and brain data that have provided support for these predictions. The article also summarizes ART models that predict functional roles for identified cells in laminar thalamocortical circuits, including the six layered neocortical circuits and their interactions with specific primary and higher-order specific thalamic nuclei and nonspecific nuclei. These predictions include explanations of how slow perceptual learning can occur without conscious awareness, and why oscillation frequencies in the lower layers of neocortex are sometimes slower beta oscillations, rather than the higher-frequency gamma oscillations that occur more frequently in superficial cortical layers. ART traces these properties to the existence of intracortical feedback loops, and to reset mechanisms whereby thalamocortical mismatches use circuits such as the one from specific thalamic nuclei to nonspecific thalamic nuclei and then to layer 4 of neocortical areas via layers 1-to-5-to-6-to-4.


An analysis of orientation and ocular dominance patterns in the visual cortex of cats and ferrets.
We report an analysis of orientation and ocular dominance maps that were recorded optically from area 17 of cats and ferrets. Similar to a recent study performed in primates (Obermayer & Blasdel, 1997), we find that 80% (for cats and ferrets) of orientation singularities that are nearest neighbors have opposite sign and that the spatial distribution of singularities deviates from a random distribution of points, because the average distances between nearest neighbors are significantly larger than expected for a random distribution. Orientation maps of normally raised cats and ferrets show approximately the same typical wavelength; however, the density of singularities is higher in ferrets than in cats. Also, we find the well-known overrepresentation of cardinal versus oblique orientations in young ferrets (Chapman & Bonhoeffer, 1998; Coppola, White, Fitzpatrick, & Purves, 1998) but only a weak, not quite significant overrepresentation of cardinal orientations in cats, as has been reported previously (Bonhoeffer & Grinvald, 1993). Orientation and ocular dominance slabs in cats exhibit a tendency of being orthogonal to each other (Hubener, Shoham, Grinvald, & Bonhoeffer, 1997), albeit less pronounced, as has been reported for primates (Obermayer & Blasdel, 1993). In chronic recordings from single animals, a decrease of the singularity density and an increase of the ocular dominance wavelength with age but no change of the orientation wavelengths were found. Orientation maps are compared with two pattern models for orientation preference maps: bandpass-filtered white noise and the field analogy model. Bandpass-filtered white noise predicts sign correlations between orientation singularities, but the correlations are significantly stronger (87% opposite sign pairs) than what we have found in the data. Also, bandpass-filtered noise predicts a deviation of the spatial distribution of singularities from a random dot pattern. The field analogy model can account for the structure of certain local patches but not for the whole orientation map. Differences between the predictions of the field analogy model and experimental data are smaller than what has been reported for primates (Obermayer & Blasdel, 1997), which can be explained by the smaller size of the imaged areas in cats and ferrets.


Wildfire and drought dynamics destabilize carbon stores of fire-suppressed forests.
Widespread fire suppression and thinning have altered the structure and composition of many forests in the western United States, making them more susceptible to the synergy of large-scale drought and fire events. We examine how these changes affect carbon storage and stability compared to historic fire-adapted conditions. We modeled carbon dynamics under possible drought and fire conditions over a 300-year simulation period in two mixed-conifer conditions common in the western United States: (1) pine-dominated with an active fire regime and (2) fir-dominated, fire suppressed forests. Fir-dominated stands, with higher live- and dead-wood density, had much lower carbon stability as drought and fire frequency increased compared to pine-dominated forest. Carbon instability resulted from species (i.e., fir's greater susceptibility to drought and fire) and stand (i.e., high density of smaller trees) conditions that develop in the absence of active management. Our modeling suggests restoring historic species composition and active fire regimes can significantly increase carbon stability in fire-suppressed, mixed-conifer forests. Long-term management of forest carbon should consider the relative resilience of stand structure and composition to possible increases in disturbance frequency and intensity under changing climate.


Photoactive platinum(iv) complex conjugated to a cancer-cell-targeting cyclic peptide.
A conjugate of cancer-cell targeting cyclic disulphide nona-peptide c(CRWYDENAC) consisting of nine l-amino acids with the photoactive succinate platinum(iv) complex trans,trans-[Pt(N3)2(py)2(OH)(succinate)] (Pt-cP) has been synthesised and characterised. The conjugate was stable in dark, but released succinate-peptide and Pt(ii) species upon irradiation with visible light, and formed photoproducts with guanine. Conjugate Pt-cP exhibited higher photocytotoxicity than parent complex trans,trans,trans-[Pt(N3)2(OH)2(py)2] (FM-190) towards cancer cells, including ovarian A2780, lung A549 and prostate PC3 human cancer cells upon irradiation with blue light (465 nm, 17.28 J cm-2) with IC50 values of 2.8-22.4 μM and the highest potency for A549 cells. Even though the dark cellular accumulation of Pt-cP in A2780 cells was lower than that of parent FM-190, Pt from Pt-cP accumulated in cancer cells upon irradiation to a level >3× higher than that from FM-190. In addition, the cellular accumulation of Pt from Pt-cP was enhanced ca. 47× after irradiation.


Quantitative epistasis analysis and pathway inference from genetic interaction data.
Inferring regulatory and metabolic network models from quantitative genetic interaction data remains a major challenge in systems biology. Here, we present a novel quantitative model for interpreting epistasis within pathways responding to an external signal. The model provides the basis of an experimental method to determine the architecture of such pathways, and establishes a new set of rules to infer the order of genes within them. The method also allows the extraction of quantitative parameters enabling a new level of information to be added to genetic network models. It is applicable to any system where the impact of combinatorial loss-of-function mutations can be quantified with sufficient accuracy. We test the method by conducting a systematic analysis of a thoroughly characterized eukaryotic gene network, the galactose utilization pathway in Saccharomyces cerevisiae. For this purpose, we quantify the effects of single and double gene deletions on two phenotypic traits, fitness and reporter gene expression. We show that applying our method to fitness traits reveals the order of metabolic enzymes and the effects of accumulating metabolic intermediates. Conversely, the analysis of expression traits reveals the order of transcriptional regulatory genes, secondary regulatory signals and their relative strength. Strikingly, when the analyses of the two traits are combined, the method correctly infers ~80% of the known relationships without any false positives.


K-Pax2: Bayesian identification of cluster-defining amino acid positions in large sequence datasets.
The recent growth in publicly available sequence data has introduced new opportunities for studying microbial evolution and spread. Because the pace of sequence accumulation tends to exceed the pace of experimental studies of protein function and the roles of individual amino acids, statistical tools to identify meaningful patterns in protein diversity are essential. Large sequence alignments from fast-evolving micro-organisms are particularly challenging to dissect using standard tools from phylogenetics and multivariate statistics because biologically relevant functional signals are easily masked by neutral variation and noise. To meet this need, a novel computational method is introduced that is easily executed in parallel using a cluster environment and can handle thousands of sequences with minimal subjective input from the user. The usefulness of this kind of machine learning is demonstrated by applying it to nearly 5000 haemagglutinin sequences of influenza A/H3N2.Antigenic and 3D structural mapping of the results show that the method can recover the major jumps in antigenic phenotype that occurred between 1968 and 2013 and identify specific amino acids associated with these changes. The method is expected to provide a useful tool to uncover patterns of protein evolution.


Mining phenotypes for gene function prediction.
Health and disease of organisms are reflected in their phenotypes. Often, a genetic component to a disease is discovered only after clearly defining its phenotype. In the past years, many technologies to systematically generate phenotypes in a high-throughput manner, such as RNA interference or gene knock-out, have been developed and used to decipher functions for genes. However, there have been relatively few efforts to make use of phenotype data beyond the single genotype-phenotype relationships. We present results on a study where we use a large set of phenotype data - in textual form - to predict gene annotation. To this end, we use text clustering to group genes based on their phenotype descriptions. We show that these clusters correlate well with several indicators for biological coherence in gene groups, such as functional annotations from the Gene Ontology (GO) and protein-protein interactions. We exploit these clusters for predicting gene function by carrying over annotations from well-annotated genes to other, less-characterized genes in the same cluster. For a subset of groups selected by applying objective criteria, we can predict GO-term annotations from the biological process sub-ontology with up to 72.6% precision and 16.7% recall, as evaluated by cross-validation. We manually verified some of these clusters and found them to exhibit high biological coherence, e.g. a group containing all available antennal Drosophila odorant receptors despite inconsistent GO-annotations. The intrinsic nature of phenotypes to visibly reflect genetic activity underlines their usefulness in inferring new gene functions. Thus, systematically analyzing these data on a large scale offers many possibilities for inferring functional annotation of genes. We show that text clustering can play an important role in this process.


Color-coded imaging of spontaneous vessel anastomosis in vivo.
Vessel anastomosis is important in tumor angiogenesis as well as for vascularization therapy for ischemia and other diseases. We report here the development of a color-coded imaging model that can visualize the anastomosis between blood vessels of red fluorescent protein (RFP)-expressing vessels in vascularized Gelfoam® previously transplanted into RFP transgenic mice and then re-transplanted into nestin-driven green fluorescent protein (ND-GFP) mice where nascent blood vessels express GFP. Gelfoam® was initially transplanted subcutaneously in the flank of transgenic RFP nude mice. Skin flaps were made at 14 days after transplantation of Gelfoam® to allow observation of vascularization of the Gelfoam® using confocal fluorescence imaging. The implanted Gelfoam® became highly vascularized with RFP vessels. Fourteen days after transplantation into RFP transgenic nude mice, the Gelfoam® was removed and re-transplanted into the subcutis on the flank of ND-GFP transgenic nude mice in which nascent blood vessels express GFP. Skin flaps were made and anastomosis between the GFP-expressing nascent blood vessels of ND-GFP transgenic nude mice and RFP blood vessels in the Gelfoam® was imaged 14 and 21 days after re-transplantation. The results presented in this report indicate a possible mechanism for tumor angiogenesis and suggest a new paradigm of therapeutic revascularization of ischemic organs requiring new blood vessels and in other diseases.


High performance of Ga-doped ZnO transparent conductive layers using MOCVD for GaN LED applications.
High performance of Ga-doped ZnO (GZO) prepared using metalorganic chemical vapor deposition (MOCVD) was employed in GaN blue light-emitting diodes (LEDs) as transparent conductive layers (TCL). By the post-annealing process, the annealed 800°C GZO films exhibited a high transparency above 97% at wavelength of 450 nm. The contact resistance of GZO decreased with the annealing temperature increasing. It was attributed to the improvement of the GZO crystal quality, leading to an increase in electron concentration. It was also found that some Zn atom caused from the decomposition process diffused into the p-GaN surface of LED, which generated a stronger tunneling effect at the GZO/p-GaN interface and promoted the formation of ohmic contact. Moreover, contrast to the ITO-LED, a high light extraction efficiency of 77% was achieved in the GZO-LED at injection current of 20 mA. At 350 mA injection current, the output power of 256.51 mW of GZO-LEDs, corresponding to a 21.5% enhancement as compared to ITO-LEDs was obtained; results are promising for the development of GZO using the MOCVD technique for GaN LED applications.


Quantitive studies of the reactions to horizontal angular accelerations in axolotls. II. head-turning reflexes in animals with a supernumerary pair of labyrinths.
In axolotls (Ambystoma mexicanun) the labyrinths and the associated parts of the medulla were doubled artificially. In these so-called tandem-heads the vestibular afferent fibres from both labyrinths on one side united within the medulla to form common bundles. The head-turning reflexes following impulse acceleration and during long-lasting acceleration were measured quantitatively and compared with those for normal animals. The form and the time-course of the reactions were almost identical in both groups. Tandem-heads showed a linear relationship between stimulus intensity and reaction strength, parallel to that in normal animals but with a greater reaction for a given stimulus. Consequent to this shift in the relationship, there was a significant decrease in the reaction threshold. The removal of one horizontal semicircular canal in tandem-heads proved that both pairs of labyrinths were functionally connected with the brain. It was suggested that during ontogenesis there exists a kind of specificity in the connexion of vestibular fibres. From the parallel shift of the intensity functions it was concluded that the input from both pairs of labyrinths in tandem-heads is not simply accumulate but compared with a reference parameter, which is also double in tandem-heads.


The Story of #GetMePPE and GetUsPPE.org to Mobilize Health Care Response to COVID-19 : Rapidly Deploying Digital Tools for Better Health Care.
Physicians, nurses, and other health care providers initiated the #GetMePPE movement on Twitter to spread awareness of the shortage of personal protective equipment (PPE) during the coronavirus disease (COVID-19) pandemic. Dwindling supplies, such as face masks, gowns and goggles, and inadequate production to meet increasing demand have placed health care workers and patients at risk. The momentum of the #GetMePPE Twitter hashtag resulted in the creation of a petition to urge public officials to address the PPE shortage through increased funding and production. Simultaneously, the GetUsPPE.org website was launched through the collaboration of physicians and software engineers to develop a digital platform for the donation, request, and distribution of multi-modal sources of PPE. GetUsPPE.org and #GetMePPE were merged in an attempt to combine public engagement and advocacy on social media with the coordination of PPE donation and distribution. Within 10 days, over 1800 hospitals and PPE suppliers were registered in a database that enabled the rapid coordination and distribution of scarce and in-demand materials. One month after its launch, the organization had distributed hundreds of thousands of PPE items and had built a database of over 6000 PPE requesters. The call for action on social media and the rapid development of this digital tool created a productive channel for the public to contribute to the health care response to COVID-19 in meaningful ways. #GetMePPE and GetUsPPE.org were able to mobilize individuals and organizations outside of the health care system to address the unmet needs of the medical community. The success of GetUsPPE.org demonstrates the potential of digital tools as a platform for larger health care institutions to rapidly address urgent issues in health care. In this paper, we outline this process and discuss key factors determining success.


Association of Coffee Intake With Survival in Patients With Advanced or Metastatic Colorectal Cancer.
Several compounds found in coffee possess antioxidant, anti-inflammatory, and insulin-sensitizing effects, which may contribute to anticancer activity. Epidemiological studies have identified associations between increased coffee consumption and decreased recurrence and mortality of colorectal cancer. The association between coffee consumption and survival in patients with advanced or metastatic colorectal cancer is unknown. To evaluate the association of coffee consumption with disease progression and death in patients with advanced or metastatic colorectal cancer. This prospective observational cohort study included 1171 patients with previously untreated locally advanced or metastatic colorectal cancer who were enrolled in Cancer and Leukemia Group B (Alliance)/SWOG 80405, a completed phase 3 clinical trial comparing the addition of cetuximab and/or bevacizumab to standard chemotherapy. Patients reported dietary intake using a semiquantitative food frequency questionnaire at the time of enrollment. Data were collected from October 27, 2005, to January 18, 2018, and analyzed from May 1 to August 31, 2018. Consumption of total, decaffeinated, and caffeinated coffee measured in cups per day. Overall survival (OS) and progression-free survival (PFS). Among the 1171 patients included in the analysis (694 men [59%]; median age, 59 [interquartile range, 51-67] years). The median follow-up time among living patients was 5.4 years (10th percentile, 1.3 years; IQR, 3.2-6.3 years). A total of 1092 patients (93%) had died or had disease progression. Increased consumption of coffee was associated with decreased risk of cancer progression (hazard ratio [HR] for 1-cup/d increment, 0.95; 95% CI, 0.91-1.00; P = .04 for trend) and death (HR for 1-cup/d increment, 0.93; 95% CI, 0.89-0.98; P = .004 for trend). Participants who consumed 2 to 3 cups of coffee per day had a multivariable HR for OS of 0.82 (95% CI, 0.67-1.00) and for PFS of 0.82 (95% CI, 0.68-0.99), compared with those who did not drink coffee. Participants who consumed at least 4 cups of coffee per day had a multivariable HR for OS of 0.64 (95% CI, 0.46-0.87) and for PFS of 0.78 (95% CI, 0.59-1.05). Significant associations were noted for both caffeinated and decaffeinated coffee. Coffee consumption may be associated with reduced risk of disease progression and death in patients with advanced or metastatic colorectal cancer. Further research is warranted to elucidate underlying biological mechanisms.


A potential field model using generalized sigmoid functions.
The lack of a potential field model capable of providing accurate representations of objects of arbitrary shapes is considered one major limitation in applying the artificial potential field method in many practical applications. In this correspondence, we propose a potential function based on generalized sigmoid functions. The generalized sigmoid model can be constructed from combinations of implicit primitives or from sampled surface data. The constructed potential field model can achieve an accurate analytic description of objects in two or three dimensions and requires very modest computation at run time. In this correspondence, applications of the generalized sigmoid model in path-planning tasks for mobile robots and in haptic feedback tasks are presented. The validation results in this correspondence show that the model can effectively allow the user or mobile robot to avoid penetrations of obstacles while successfully accomplishing the task.


Ethical dilemmas of social science research on AIDS and orphanhood in Western Kenya.
This paper is based on the experiences drawn from a long-term social science research programme on the impact of the AIDS pandemic on orphanhood in western Kenya. It discusses the ethical dilemma of maintaining a delicate balance between research ethics, the expectations of the study population and negotiating the community's vested interests in a health related research project in a low-income society. I argue that informed consent and the intended benefits of the study to the participants continue to be major challenges facing the justification of social research with people affected by or living with AIDS in low-income societies. The paper underscores the importance of community feedback sessions as a way of enhancing chances of acceptability of research efforts and obtaining informed consent. It further shows how community feedback sessions contribute to local knowledge of the problem being studied, creating opportunities for advocacy. This discussion adds to the existing ethical debate on the wider contexts within which research on vulnerable people affected by AIDS is conducted by arguing that research practice is inseparable from epistemological concerns of knowledge production. I suggest that ethnographers should enhance efforts to innovatively design action research projects to serve the twin purposes of data collection and deal with ethical challenges that are experienced when doing long-term research on vulnerable groups.


Role of DNA repair in the protection against genotoxic stress.
The genome of all organisms is constantly attacked by a variety of environmental and endogenous mutagens that cause cell death, apoptosis, senescence, genetic diseases and cancer. To mitigate these deleterious endpoints of genotoxic reactions, living organisms have evolved one or more mechanisms for repairing every type of naturally occurring DNA lesion. For example, double-strand breaks are rapidly religated by non-homologous end-joining. Homologous recombination is used for the high-fidelity repair of interstrand cross-links, double-strand breaks and other DNA injuries that disrupt the replication fork. Some genotoxic lesions inflicted by alkylating agents can be repaired by direct reversal of DNA damage. The base excision repair pathway takes advantage of multiple DNA glycosylases to remove modified or incorrect bases. Finally, the nucleotide excision repair machinery provides a versatile strategy to monitor DNA quality and eliminate all forms of helix-distorting DNA lesions, including a wide diversity of carcinogen adducts. The efficiency of DNA repair responses is enhanced by their coupling to transcription and coordination with the cell cycle circuit.


Coat color alterations over the years and their association with growth performances in the Menz sheep central nucleus and community-based breeding programs.
In the traditional Menz sheep breeding, communities select against black coat color and therefore its frequency is declining over time. We hypothesize that this exercise is causing the loss of an important gene pool. Data collected from on-station Menz sheep nucleus (n = 1992) and community-based breeding program (CBBP) (n = 5578) were analyzed to (1) assess color proportion dynamics over years and (2) associate phenotypic performances and estimated breeding values (EBVs) for growth traits with coat color of the animals. The on-station nucleus considered growth trait as selection criteria, while CBBP focused on a combination of growth and morphological characters. The results showed that the proportion of black coat color increased across years in the on-station nucleus flock (2.1% per year). However, in the CBBP, flocks' proportion of black coat color declined over time (1.03-1.05% per year). Birth and growth traits of black-colored sheep were consistently superior (P < 0.05) to white-colored sheep. Mean yearling weight and EBV of black rams used in the on-station flock was 24.3 kg and 3.7 kg, respectively, while the values for white-colored sheep were 19.7 kg and 1.6 kg, respectively. This variation in growth performances of Menz sheep among different colors may be due to the linkage between color and growth performance genes. Thus, selection against black coat color in the CBBPs seems to have an adverse effect on the genetic progress of growth traits in the Menz sheep. Understanding the core reasons behind the prevailing selection against black coat color and devising measures to address them should be considered. Developing a black line targeting specific markets might also be worthy to maximize production as well as maintain qualities associated with black color.


Deep brain stimulation as a treatment for neuropathic pain: a longitudinal study addressing neuropsychological outcomes.
Deep brain stimulation (DBS) of the periventricular/periaqueductal gray area and sensory thalamus can reduce pain intensity in patients with neuropathic pain. However, little is known about its impact on quality of life, emotional well-being, and cognition. This study followed up 18 patients who had received DBS for neuropathic pain. Each participant had previously undergone psychometric evaluation of each of the above areas as part of a routine presurgical neuropsychological assessment. Commensurate measures were employed at a follow-up assessment at least 6 months postsurgery. DBS significantly improved mood, anxiety, and aspects of quality of life. Improvements correlated with reduced pain severity. However, the sample continued to show impairments in most areas when compared against normative data published on nonclinical samples. There was little change in general cognitive functioning, aside from deterioration in spatial working memory. However, improvements in pain severity were associated with less improvement (and even deterioration) on measures of executive cognitive functioning. Improvements in emotional well-being also were correlated with changes in cognition. These results suggest that DBS of the periventricular/periaqueductal gray and/or sensory thalamus improves quality of life and emotional well-being in sufferers, although there is some indication of executive dysfunction, particularly among those reporting greatest pain alleviation. This article examines the neuropsychological outcomes of DBS surgery as a treatment for neuropathic pain. This intervention was found to improve pain severity, emotional well-being, and quality of life, although such benefits may be accompanied by reduced ability on tasks measuring executive functioning.


Reflecting on 20 years of breast cancer modeling in CISNET: Recommendations for future cancer systems modeling efforts.
Since 2000, the National Cancer Institute's Cancer Intervention and Surveillance Modeling Network (CISNET) modeling teams have developed and applied microsimulation and statistical models of breast cancer. Here, we illustrate the use of collaborative breast cancer multilevel systems modeling in CISNET to demonstrate the flexibility of systems modeling to address important clinical and policy-relevant questions. Challenges and opportunities of future systems modeling are also summarized. The 6 CISNET breast cancer models embody the key features of systems modeling by incorporating numerous data sources and reflecting tumor, person, and health system factors that change over time and interact to affect the burden of breast cancer. Multidisciplinary modeling teams have explored alternative representations of breast cancer to reveal insights into breast cancer natural history, including the role of overdiagnosis and race differences in tumor characteristics. The models have been used to compare strategies for improving the balance of benefits and harms of breast cancer screening based on personal risk factors, including age, breast density, polygenic risk, and history of Down syndrome or a history of childhood cancer. The models have also provided evidence to support the delivery of care by simulating outcomes following clinical decisions about breast cancer treatment and estimating the relative impact of screening and treatment on the United States population. The insights provided by the CISNET breast cancer multilevel modeling efforts have informed policy and clinical guidelines. The 20 years of CISNET modeling experience has highlighted opportunities and challenges to expanding the impact of systems modeling. Moving forward, CISNET research will continue to use systems modeling to address cancer control issues, including modeling structural inequities affecting racial disparities in the burden of breast cancer. Future work will also leverage the lessons from team science, expand resource sharing, and foster the careers of early stage modeling scientists to ensure the sustainability of these efforts.


Frizzled regulates localization of cell-fate determinants and mitotic spindle rotation during asymmetric cell division.
Cell-fate diversity is generated in part by the unequal segregation of cell-fate determinants during asymmetric cell divisions. In the Drosophila pupa, the pI sense organ precursor cell is polarized along the anterior-posterior axis of the fly and divides asymmetrically to generate a posterior pIIa cell and an anterior pIIb cell. The anterior pIIb cell specifically inherits the determinant Numb and the adaptor protein Partner of Numb (Pon). By labelling both the Pon crescent and the microtubules in living pupae, we show that determinants localize at the anterior cortex before mitotic-spindle formation, and that the spindle forms with random orientation and rotates to line up with the Pon crescent. By imaging living frizzled (fz) mutant pupae we show that Fz regulates the orientation of the polarity axis of pI, the initiation of spindle rotation and the unequal partitioning of determinants. We conclude that Fz participates in establishing the polarity of pI.