Surgical management of meningiomas involving the optic nerve sheath.
The management of optic nerve sheath meningiomas (ONSMs) remains controversial but includes surgery, radiotherapy, and plain observation. Surgery is often thought to result in postoperative blindness. The authors report on a large series of patients surgically treated for ONSM, with an emphasis on the visual outcome. Seventy-three patients with ONSMs who had undergone surgery between 1991 and 2002 were retrospectively analyzed. The standard surgical approach consisted of pterional craniotomy, intradural (54 patients) or extradural (10 patients) unroofing of the optic canal, or a combined procedure (seven patients). Thirty-two tumors demonstrated extension through the optic canal. Twenty-nine tumors reached the chiasm or contralateral side. Patients with intraorbital flat tumors should undergo radiotherapy instead of surgery. Those with a large intraorbital mass and no useful vision should undergo surgery. Tumors extending intracranially through the optic canal are amenable to decompression of the optic canal and resection of the intracranial portion. The follow-up period was a mean 45.4 months (range 6-144 months). Ten patients underwent postoperative radiotherapy. Visual acuity was not significantly influenced by surgery but did become worse with a longer duration of preoperative symptoms and a longer follow-up period. A tumor location in the optic canal was another negative factor. Radiotherapy preserved vision in five of 10 cases. The loss of vision in patients with ONSM is only a matter of time. In patients with good vision the role of radiotherapy becomes more important. Surgery is recommended for intracranial tumors to prevent contralateral extension.


Further experience with epigastric pain reproduction test in duodenal ulceration.
Further evidence is presented that the epigastric pain of duodenal ulceration, situated between the rib margins and just below the xiphisternum, arises from the lower oesophagus.One-hundred patients with duodenal ulceration were divided into those with epigastric pain (61) and those with pain in the upper abdomen but not in the epigastrium (39). Perfusion of 0.1 N HCl into the lower oesophagus reproduced epigastric pain in 53 of the 61 with epigastric pain (mean 37 ml) but in none of the 39 without (mean 125 ml). All those who had been woken by epigastric pain at night in the previous four weeks had a positive test.In five the test remained positive even though the acid was neutralized by a continuous perfusion of alkali just below the gastro-oesophageal junction. In another five 200 ml 0.1 N HCl instilled into the stomach for 21 minutes did not reproduce epigastric pain, even though 30 ml perfused for three minutes into the lower oesophagus did.


Vital signs as physiomarkers of neonatal sepsis.
Neonatal sepsis accounts for significant morbidity and mortality, particularly among premature infants in the Neonatal Intensive Care Unit. Abnormal vital sign patterns serve as physiomarkers of sepsis and provide early warning of illness before overt clinical decompensation. The systemic inflammatory response to pathogens signals the autonomic nervous system, leading to changes in temperature, respiratory rate, heart rate, and blood pressure. In infants with comorbidities of prematurity, vital sign abnormalities often occur in the absence of infection, which confounds sepsis diagnosis. This review will cover the mechanisms of vital sign changes in neonatal sepsis, including the cholinergic anti-inflammatory pathway mediated by the vagus nerve, which is critical to the host response to infectious and inflammatory insults. We will also review the clinical implications of vital sign changes in neonatal sepsis, including their use in early warning scores and systems to direct clinicians to the bedside of infants with physiologic changes that might be due to sepsis. IMPACT: This manuscript summarizes and reviews the relevant literature on the physiological manifestations of neonatal sepsis and how we monitor and analyze these through vital signs and advanced analytics.


Digit ratio (2D:4D) and performance in Indian swimmers.
It has been suggested that achievement in sports is correlated with a putative measure of prenatal testosterone the 2nd to 4th digit ratio (2D:4D). It has been shown that digit ratio (2D:4D) is negatively associated with prenatal testosterone, and it is also negatively associated with ability in sports. This study examined associations between 2D:4D and performance of both male and female National level Indian swimmers. Age matched non-sports personnel formed the control. Lengths of second and fourth digits were measured after scanning both hands and their ratio calculated. Our results show lower 2D:4D values in males compared to females (P < 0.05). Among male, but not female, swimmers had significantly (P < 0.05) lower 2D:4D ratio. Low 2D:4D in male swimmers suggests they are more prenatally programmed via long-lasting extra genital effects of testosterone. 2D:4D ratio could be used to identify young sports personnel who have potential to reach high levels of performance.


Humic-like substances in cigarette smoke condensate and lung tissue of smokers.
Deposition of pigmented matter in the lower respiratory tract correlates with the extent of emphysema in smokers as well as with free radical generation and iron accumulation. Pulmonary emphysema is postulated to be mediated by free radical generation which is either directly or indirectly associated with cigarette smoke exposure. The hypothesis was tested that 1) incomplete combustion of tobacco yields humic-like substances (HLS) which 2) deposit in the lung as pigmented particulates, 3) complex iron cations in vitro and in vivo, and 4) have a capacity to catalyze oxidant formation. HLS, isolated by alkali extraction of cigarette smoke condensate (CSC) (Tobacco Health Research Institute, University of Kentucky), demonstrated a high carbon and low carboxylate content on elemental and functional group analyses, respectively, compared with values for HLS sequestered from soils. The HLS isolated from CSC had a capacity to complex iron in vitro and accumulated the metal in vivo after intratracheal instillation in an animal model. Both HLS and its iron complex generated free radicals, and some portion of this oxidant generation was metal dependent. Lung tissue collected at autopsy from smokers contained HLS with an infrared spectrum almost identical to that of the material isolated from CSC. Associations between particulate deposition, metal accumulation, and free radical generation suggest a possible role of HLS in the induction of lung disease following cigarette exposure.


Patient perspectives of successful adalimumab biosimilar transitioning in Crohn's disease: an interview study.
Transition from originator biological medicines to their biosimilar equivalents is now part of routine clinical practice, but there is little understanding of patient experiences, which influence adherence and overall satisfaction with care. Understanding this will help ensure future switches adequately address patients' concerns and expectations leading to better outcomes for all stakeholders. 35 patients participating in a clinical trial including an open-label transition event from originator to biosimilar adalimumab, mimicking what would be encountered in a real-world setting, took part in semi-structured interviews exploring their experience of biosimilar transition. Opinions expressed were often heterogeneous, but common experiences and themes were identified. Five themes were identified following thematic analysis. (1) Understanding and awareness of biosimilars: prior awareness of biosimilars and knowledge of the biosimilar concept was low, indicating a disparity between healthcare professionals and patients. (2) Motivation to undertake transition: patients accept a biosimilar transition to minimise drug expenditure. (3) Initial concerns: before undertaking biosimilar transition away from the brand they had experienced, anticipated loss of efficacy and adverse effects from the biosimilar were common concerns for patients. (4) Reassuring factors: trust in the healthcare team is critical to patient acceptance of biosimilars. Important reassurances include a point of contact, education about biosimilars and monitoring. (5) Experiences during the transition: on reflection, participants described consistent efficacy and tolerability (although 22 participants specifically mentioned injection pain) following brand transition. The majority of patients felt comfortable with future transition to another adalimumab biosimilar. Injection experience was an important component of patient satisfaction.


Comparison of fecal indicator bacterial populations in surface waters of the Kalamazoo River, USA.
Surface waters along the Kalamazoo River, USA, were examined for occurrence and population trends of fecal indicator bacteria (FIB) with culture-based and culture-independent methods. The two methods recorded discrepancies in FIB counts, with the culture-independent method revealing more consistent numbers between the river sites. FIB cells that hybridized with the ECO1482 probe were highest in the downstream site, while the upstream site recorded higher ENF343 hybridized cells. Spatial and temporal differences in FIB populations were probably attributable to contrasting fecal pollution influences, vegetation type, varying environmental conditions as well as several in-stream factors between the two river sites.


Head and Neck Cancer: A Study on the Complex Relationship between QoL and Swallowing Function.
Head and neck squamous cell carcinoma (HNSCC) is linked to significant morbidity, adversely affecting survival and functional capacity. Post-treatment challenges such as pain, dysphonia, and dysphagia are common, prompting increased attention in survivorship research. Quality of Life (QoL) questionnaires, especially the MD Anderson Dysphagia Inventory (MDADI), are prevalent outcome measures in clinical studies but often lack parallel objective swallowing function evaluations, leading to potential outcome discrepancies. This study aimed to illuminate the relationship between subjective QoL (EQ-5D-5L and MDADI) measures and objective swallowing function (evaluated via Fiberoptic Endoscopic Evaluation of Swallowing, FEES) in patients with HNSCC. The analysis revealed a notable discordance between objective measures of swallowing function, such as the Penetration-Aspiration Scale (PAS) and residue ratings in the vallecula or piriform sinus, and patients' subjective QoL assessments (p = 0.21). Despite the lack of correlation, swallowing-related QoL, as measured by the MDADI, was more indicative of disease severity than generic QoL assessments. Generic QoL scores did not demonstrate substantial variation between patients. In contrast, MDADI scores significantly declined with advancing tumor stage, multimodal therapy, and reliance on feeding tubes. However, the clinical significance of this finding was tempered by the less than 10-point difference in MDADI scores. The findings of this study underline the limitations of QoL measures as standalone assessments in patients with HNSCC, given their reliance on patient-perceived impairment. While subjective QoL is a crucial aspect of evaluating therapeutic success and patient-centric outcomes, it may fail to capture critical clinical details such as silent aspirations. Consequently, QoL assessments should be augmented by objective evaluations of swallowing function in clinical research and practice to ensure a holistic understanding of patient well-being and treatment impact.


"Music Therapy Was Never on the Table": Perspectives of Parents of Young Autistic Children.
Parent coaching of music interventions is emerging as a viable model for families with young autistic children, yet recruitment difficulties have been apparent in previous studies. Understanding parent perspectives of early intervention services is critical to ensure that interventions are acceptable, feasible, and effective for all family members. In order to understand possible parental resistance to this type of parent education, we explored perspectives regarding music therapy, research, and parent coaching in parents of young autistic children. Fourteen parents attended virtual focus groups to discuss their experiences. We used a descriptive phenomenological approach to uncover the essence of their experience. Our findings indicate that, contrary to our preconceptions, participants did not show negative dispositions towards music therapy, research, or parent coaching. Instead, most participants had very little or no knowledge of music therapy services. They had limited experience with research in general, and only two participants had experienced music therapy directly. Several participants had varying amounts of experience with parent participation or parent coaching outside of music therapy and shared positive experiences with it. Parents seemed willing and eager to learn music strategies to support their children and saw value in the use of music for their child's development. First-contact providers (i.e., early interventionists and diagnosticians) and social media seem influential in parents' decision-making as they navigate early intervention services soon after diagnosis. Music therapy organizations are encouraged to design targeted efforts to make information on music therapy available through these sources.


Utility of Epstein-Barr Virus DNA in Nasopharynx Swabs as a Reflex Test to Triage Seropositive Individuals in Nasopharyngeal Carcinoma Screening Programs.
Epstein-Barr virus (EBV) DNA detection in the nasopharynx is considered a biomarker for nasopharyngeal carcinoma (NPC). We evaluated its performance as a reflex test to triage EBV seropositives within an NPC screening program in China. The study population was embedded within an ongoing NPC screening trial and included 1111 participants who screened positive for anti-EBV VCA (antibodies against EBV capsid antigens)/EBNA1 (EBV nuclear antigen1)-IgA antibodies (of 18 237 screened). Nasopharynx swabs were collected/tested for EBNA1 gene EBV DNA load. We evaluated performance of EBV DNA in the nasopharynx swab as a reflex test to triage EBV serological high-risk (those referred to endoscopy/MRI) and medium-risk (those referred to accelerated screening) individuals. By the end of 2019, we detected 20 NPC cases from 317 serological high-risk individuals and 4 NPC cases from 794 medium-risk individuals. When used to triage serological high-risk individuals, nasopharynx swab EBV DNA was detected in 19/20 cases (positivity rate among cases: 95.0%; 95% CI, 75.1%-99.9%), with a referral rate of 63.4% (201/317, 95% CI, 57.8%-68.7%) and NPC detection rate among positives of 9.5% (19/201, 95% CI, 5.8%-14.4%). The performance of an algorithm that combined serology with triage of serology high-risk individuals using EBV DNA testing yielded a sensitivity of 72.4% (95% CI, 3.0%-81.4%) and specificity of 97.6% (95% CI, 97.2%-97.9%). When used to triage EBV serological medium-risk individuals, the positivity rate among cases was 75.0% (95% CI, 19.4%-99.4%), with a referral rate of 61.8% (95% CI, 58.4%-65.2%) and NPC detection rate among positives of 0.6% (95% CI, 0.1%-1.8%). Nasopharynx swab EBV DNA showed promise as a reflex test to triage serology high-risk individuals, reducing referral by ca. 40% with little reduction in sensitivity compared to a serology-only screening program.


Distress among hospitalized pediatric cancer patients modified by pet-therapy intervention to improve quality of life.
This state of the science, integrative literature review focuses on animal-facilitated therapy (AFT) and the benefits provided to quality of life in hospitalized pediatric oncology patients. Results showed physiological and psychological benefits in pediatric inpatients settings. AFT has been shown to decrease pain, change vital signs, provide distraction, decrease fear, increase socialization, increase pleasure and decrease emotional distress in hospitalized pediatric patients. AFT needs to be implemented with appropriate medical discretion, but for the appropriate high-risk patients, AFT can improve quality of life. Pain, adjustment difficulties, mood changes and symptom management can be improved in inpatient pediatric cancer patients receiving AFT, thus improving overall quality of life.


Effect of Kinesio taping on Y-balance test performance and the associated leg muscle activation patterns in children with developmental coordination disorder: A randomized controlled trial.
Children with developmental coordination disorder (DCD) have leg muscular deficits which negatively affects their dynamic postural stability. Kinesio tape (KT) could enhance muscle activation, postural control and functional activities in healthy individuals. Therefore, we hypothesized that the usage of KT may address the postural instability problem of children with DCD. To investigate the immediate effect of KT on dynamic postural stability and the associated lower limb muscle activity in children with DCD. Forty-nine children with DCD were recruited where twenty-five children were randomly assigned to the KT group (mean age = 8.18 ± 1.16 years) and twenty-four to the control group (mean age = 8.06 ± 0.93 years). KT group received KT application to the rectus femoris and gastrocnemius muscles whereas the control group received no intervention. Measurements were taken before and after the application of KT. Dynamic balance performance was measured using a lower quartile Y-balance test (YBT-LQ). Leg muscle peak activation and time-to-peak muscle activation of the dominant lower limb during YBT-LQ were measured by surface electromyography. YBT-LQ composite score increased by 6.3% in the KT group at posttest (95% CI: -7.308, -2.480). In addition, a higher rectus femoris peak activation was illustrated for YBT-LQ anterior (32.5%; 95% CI: -48.619, -16.395) and posteromedial (24.6%; 95% CI: -42.631, -6.591) reach directions from pretest values in the KT group. Moreover, KT group exhibited a 38% (95% CI: 0.015, 2.983) longer gastrocnemius medialis time-to-peak duration for YBT-LQ posteromedial reach direction when compared to the control group. KT revealed an immediate beneficial effect on YBT-LQ performance. Application of KT also increased rectus femoris peak activation and lengthened the muscle time-to-peak duration for specific reach directions. Incorporating KT as an adjunct with dynamic balance training programme could be beneficial for children with DCD.


Cloning of major histocompatibility complex (Mhc) genes from threespine stickleback, Gasterosteus aculeatus.
The threespine stickleback Gasterosteus aculeatus is an important model in evolutionary and ethologic studies. Its utility would greatly be increased by the availability of molecular markers distinguishing individuals and populations. Such markers can be provided by the major histocompatibility complex (Mhc) genes, which are well known for their extensive polymorphism. In the present study, both class I and class II B Mhc genes have been identified and sequenced. Fifteen distinct class I exon 2 and exon 3 sequences were obtained and assigned to 12 loci on the basis of intron 2 length differences. Some of the loci appear to be related to class I loci identified previously in cichlid fish. The intron 2 sequences and insertions/deletions in exon 2 group the loci into three families (with one family divided further into two subfamilies) derived from different ancestral genes. The ancestors presumably diverged from one another before the divergence of Gasterosteiformes from Perciformes. The 12 distinct class II B sequences may be derived from six loci, which are, however, closely related to one another in both exonic and intronic parts and may have diverged from a single common ancestor after the divergence of Gasterosteiformes from Perciformes. The intron 2 of some of the class I genes contains two microsatellites that can be used as markers, in addition to the polymorphism of the Mhc genes in their exonic regions.


Sale of cigarettes to children in Exeter.
The sale of cigarettes to children in Exeter was investigated. Thirty-seven local shops were visited and the salespeople interviewed: 28 incorrectly understood the relevant law and seven had no knowledge of it. Only seven people said they tried to keep within the law. Only two of the 37 shops were displaying the Tobacco Advisory Council's explanatory notice sent to every cigarette retailer in the United Kingdom in 1981. Every shop sold cigarettes. It is proposed that: a notice explaining the law be displayed in all cigarette retailing shops; the tobacconist's licence (abolished in 1963) be reintroduced; and local civic and health authorities combine to educate retailers, their staff and the public.


Interleukin-15 in autoimmunity.
Interleukin-15 (IL-15) is a member of the IL-2 family of cytokines, which use receptor complexes containing the common gamma (γc) chain for signaling. IL-15 plays important roles in innate and adaptative immune responses and is implicated in the pathogenesis of several immune diseases. The IL-15 receptor consists of 3 subunits namely, the ligand-binding IL-15Rα chain, the β chain (also used by IL-2) and the γc chain. IL-15 uses a unique signaling pathway whereby IL-15 associates with IL-15Rα during biosynthesis, and this complex is 'trans-presented' to responder cells that expresses the IL-2/15Rβγc receptor complex. IL-15 is subject to post-transcriptional and post-translational regulation, and evidence also suggests that IL-15 cis-signaling can occur under certain conditions. IL-15 has been implicated in the pathology of various autoimmune diseases such as rheumatoid arthritis, autoimmune diabetes, inflammatory bowel disease, coeliac disease and psoriasis. Studies with pre-clinical models have shown the beneficial effects of targeting IL-15 signaling in autoimmunity. Unlike therapies targeting other cytokines, anti-IL-15 therapies have not yet been successful in humans. We discuss the complexities of IL-15 signaling in autoimmunity and explore potential immunotherapeutic approaches to target the IL-15 signaling pathway.


Impacts of fertilization on water quality of a drained pine plantation: a worst case scenario.
Intensive plantation forestry will be increasingly important in the next 50 yr to meet the high demand for domestic wood in the United States. However, forest management practices can substantially influence downstream water quality and ecology. This study analyses, the effect of fertilization on effluent water quality of a low gradient drained coastal pine plantation in Carteret County, North Carolina using a paired watershed approach. The plantation consists of three watersheds, two mature (31-yr) and one young (8-yr) (age at treatment). One of the mature watersheds was commercially thinned in 2002. The mature unthinned watershed was designated as the control. The young and mature-thinned watersheds were fertilized at different rates with Arborite (Encee Chemical Sales, Inc., Bridgeton, NC), and boron. The outflow rates and nutrient concentrations in water drained from each of the watersheds were measured. Nutrient concentrations and loadings were analyzed using general linear models (GLM). Three large storm events occurred within 47 d of fertilization, which provided a worst case scenario for nutrient export from these watersheds to the receiving surface waters. Results showed that average nutrient concentrations soon after fertilization were significantly (alpha = 0.05) higher on both treatment watersheds than during any other period during the study. This increase in nutrient export was short lived and nutrient concentrations and loadings were back to prefertilization levels as soon as 3 mo after fertilization. Additionally, the mature-thinned watershed presented higher average nutrient concentrations and loadings when compared to the young watershed, which received a reduced fertilizer rate than the mature-thinned watershed.


3-year clinical evaluation of a compomer, a resin-modified glass ionomer and a resin composite in Class III restorations.
To evaluate and compare intra-individually a polyacid-modified resin composite, commonly called compomer (Dyract), a resin-modified glass ionomer cement (RM GIC)(Fuji II LC) and a resin composite (Pekafill) in Class III cavities. In 50 patients, 154 Class III restorations were placed. Most patients received one of each of the experimental materials. At baseline, 6 months, 1, 2 and 3 years the restorations were evaluated by slightly modified USPHS criteria. At 3 years, 152 restorations were evaluated. Two restorations were replaced, one due to fracture and one due to secondary caries. The resin composite showed significantly better color match. A slight but still acceptable color shift and increased surface roughness was seen for the RM GIC. The compomer and the resin composite performed significantly better than the RM GIC. No postoperative sensitivity was reported and no loss of vitality was seen after use of the three different total etch techniques.


The application of visible wavelength reflectance hyperspectral imaging for the detection and identification of blood stains.
Current methods of detection and identification of blood stains rely largely on visual examination followed by presumptive tests such as Kastle-Meyer, Leuco-malachite green or luminol. Although these tests are useful, they can produce false positives and can also have a negative impact on subsequent DNA tests. A novel application of visible wavelength reflectance hyperspectral imaging has been used for the detection and positive identification of blood stains in a non contact and non destructive manner on a range of coloured substrates. The identification of blood staining was based on the unique visible absorption spectrum of haemoglobin between 400 and 500 nm. Images illustrating successful discrimination of blood stains from nine red substances are included. It has also been possible to distinguish between blood and approximately 40 other reddish stains. The technique was also successfully used to detect latent blood stains deposited on white filter paper at dilutions of up to 1 in 512 folds and on red tissue at dilutions of up to 1 in 32 folds. Finally, in a blind trial, the method successfully detected and identified a total of 9 blood stains on a red T-shirt.


Cervical cancer prevention in reproductive health services: knowledge, attitudes and practices of midwives in Côte d'Ivoire, West Africa.
Cervical cancer is the most common cancer among women and the leading cause of cancer deaths in women in Côte d'Ivoire. Low resource countries can now prevent this cancer by using HPV vaccine and effective and affordable screening tests. However the implementation of these prevention strategies needs well-trained human resources. Part of the solution could come from midwives by integrating cervical cancer prevention into reproductive health services. The aim of this survey was to assess knowledge, attitudes and practices of midwives towards cervical cancer prevention in Abidjan, Côte d'Ivoire, and to find out factors associated with appropriate knowledge. A cross-sectional survey was conducted among midwives in the urban district of Abidjan, using a self-administered questionnaire. Knowledge was assessed by two scores. Factors associated with appropriate knowledge were determined using a logistic regression analysis. Attitudes and practices were described and compare using the Chi2 test. A total of 592 midwives were enrolled, including 24.5% of final-year students. 55.7% of midwives had appropriate knowledge on cervical cancer, and 42.4% of them had appropriate knowledge on cervical cancer prevention strategies. Conferences, courses taken at school of midwifery and special training sessions on cervical cancer (OR = 4.9, 95% CI [1.9 to 12.6], p <0.01) were associated with good knowledge on the management of this disease. Among these midwives, 18.4% had already benefited from a screening test for themselves, 37.7% had already advised screening to patients and 8.4% were able to perform a visual inspection. 50.3% of midwives knew HPV vaccine as a preventive method; among them 70.8% usually recommended it to young girls. Despite sufficient knowledge about cervical cancer prevention, attitudes and practices of midwives should be improved by organizing capacity building activities. This would ensure the success of integration of cervical cancer prevention into reproductive health services in countries like Côte d'Ivoire.


Transcriptional Regulation in Archaea: From Individual Genes to Global Regulatory Networks.
Archaea are major contributors to biogeochemical cycles, possess unique metabolic capabilities, and resist extreme stress. To regulate the expression of genes encoding these unique programs, archaeal cells use gene regulatory networks (GRNs) composed of transcription factor proteins and their target genes. Recent developments in genetics, genomics, and computational methods used with archaeal model organisms have enabled the mapping and prediction of global GRN structures. Experimental tests of these predictions have revealed the dynamical function of GRNs in response to environmental variation. Here, we review recent progress made in this area, from investigating the mechanisms of transcriptional regulation of individual genes to small-scale subnetworks and genome-wide global networks. At each level, archaeal GRNs consist of a hybrid of bacterial, eukaryotic, and uniquely archaeal mechanisms. We discuss this theme from the perspective of the role of individual transcription factors in genome-wide regulation, how these proteins interact to compile GRN topological structures, and how these topologies lead to emergent, high-level GRN functions. We conclude by discussing how systems biology approaches are a fruitful avenue for addressing remaining challenges, such as discovering gene function and the evolution of GRNs.


A novel retroviral mutagenesis screen identifies prognostic genes in RUNX1 mediated myeloid leukemogenesis.
Using a novel retroviral shuttle vector approach we identified genes that collaborate with a patient derived RUNX1 (AML1) mutant. RUNX1 mutations occurs in 40% of myelodysplastic syndromes (MDS). MDS are a group of hematopoietic stem cell disorders that are characterized by dysplasia that often progress to acute myeloid leukemia (AML). Our goal was to identify genes dysregulated by vector-mediated genotoxicity that may collaborate with the RUNX1 mutant (D171N). D171N expressing cells have a survival and engraftment disadvantage and require additional genetic lesions to survive and persist. By dysregulating genes near the integrated vector provirus, the shuttle vector can promote transformation of D171N cells and tag the nearby genes that collaborate with D171N. In our approach, a gammaretroviral shuttle vector that expresses D171N is used to transduce CD105+, Sca-1+ mouse bone marrow. Mutagenized cells are expanded in liquid culture and vector integration sites from surviving cells are then identified using a retroviral shuttle vector approach. We repeatedly recovered integrated vector proviruses near genes (Itpkb, Ccdc12, and Nbeal2). To assess the prognostic significance of the genes identified we examined differential expression, overall survival, and relapse free survival of AML patients with alteration in the genes identified using The Cancer Genome Atlas (TCGA) AML data set. We found that ITPKB functions as an independent factor for poor prognoses and RUNX1 mutations in conjunction with ITPKB, CCDC12, and NBEAL2 have prognostic potential in AML.


Redundancy in aromatic O-demethylation and ring opening reactions in Novosphingobium aromaticivorans and their impact in the metabolism of plant derived phenolics.
Lignin is a plant heteropolymer composed of phenolic subunits. Because of its heterogeneity and recalcitrance, the development of efficient methods for its valorization still remains an open challenge. One approach to utilize lignin is its chemical deconstruction into mixtures of monomeric phenolic compounds followed by biological funneling into a single product. Novosphingobium aromaticivorans DSM12444 has been previously engineered to produce 2-pyrone-4,6-dicarboxylic acid (PDC) from depolymerized lignin by simultaneously metabolizing multiple aromatics through convergent routes involving the intermediates 3-methoxygallic acid (3-MGA) and protocatechuic acid (PCA). We investigated enzymes predicted to be responsible for O-demethylation and oxidative aromatic ring opening, two critical reactions involved in the metabolism of phenolics compounds by N. aromaticivorans The results showed the involvement of DesA in O-demethylation of syringic and vanillic acids, LigM in O-demethylation of vanillic acid and 3-MGA, and a new O-demethylase, DmtS, in the conversion of 3-MGA into gallic acid (GA). In addition, we found that LigAB was the main aromatic ring opening dioxygenase involved in 3-MGA, PCA, and GA metabolism, and that a previously uncharacterized dioxygenase, LigAB2, had high activity with GA. Our results indicate a metabolic route not previously identified in N. aromaticivorans that involves O-demethylation of 3-MGA to GA. We predict this pathway channels ∼15% of the carbon flow from syringic acid, with the rest following ring opening of 3-MGA. The new knowledge obtained in this study allowed for the creation of an improved engineered strain for the funneling of aromatic compounds that exhibits stoichiometric conversion of syringic acid into PDC.IMPORTANCE For lignocellulosic biorefineries to effectively contribute to reduction of fossil fuel use, they need to become efficient at producing chemicals from all major components of plant biomass. Making products from lignin will require engineering microorganisms to funnel multiple phenolic compounds to the chemicals of interest, and N. aromaticivorans is a promising chassis for this technology. The ability of N. aromaticivorans to efficiently and simultaneously degrade many phenolic compounds may be linked to having functionally redundant aromatic degradation pathways and enzymes with broad substrate specificity. A detailed knowledge of aromatic degradation pathways is thus essential to identify genetic engineering targets to maximize product yields. Furthermore, knowledge of enzyme substrate specificity is critical to redirect flow of carbon to desired pathways. This study described an uncharacterized pathway in N. aromaticivorans and the enzymes that participate in this pathway, allowing the engineering of an improved strain for production of PDC from lignin.


Quantifying the consequences of measles-induced immune modulation for whooping cough epidemiology.
Measles, an acute viral disease, continues to be an important cause of childhood mortality worldwide. Infection with the measles virus is thought to be associated with a transient but profound period of immune suppression. Recently, it has been claimed that measles-induced immune manipulation lasts for about 30 months and results in increased susceptibility to other co-circulating infectious diseases and more severe disease outcomes upon infection. We tested this hypothesis using model-based inference applied to parallel historical records of measles and whooping cough mortality and morbidity. Specifically, we used maximum likelihood to fit a mechanistic transmission model to incidence data from three different eras, spanning mortality records from 1904 to 1912 and 1922 to 1932 and morbidity records from 1946 to 1956. Our aim was to quantify the timing, severity and pathogenesis impacts of measles-induced immune modulation and their consequences for whooping cough epidemiology across a temporal gradient of measles transmission. We identified an increase in susceptibility to whooping cough following recent measles infection by approximately 85-, 10- and 36-fold for the three eras, respectively, although the duration of this effect was variable. Overall, while the immune impacts of measles may be strong and clearly evident at the individual level, their epidemiological signature in these data appears both modest and inconsistent. This article is part of the theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes'. This issue is linked with the subsequent theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control'.


Accuracy of CT-guided needle biopsy of musculoskeletal neoplasms.
The purpose of our study was to assess the accuracy of CT-guided biopsy of musculoskeletal neoplasms with respect to technique, anatomic site, and histology. During a 3-year period (January 1992 to December 1994), 176 core needle biopsies and 45 fine-needle aspirations were performed under CT guidance on patients with musculoskeletal neoplasms. To assess the accuracy of these procedures, we compared the diagnosis at biopsy with the final diagnosis as determined at the time of definitive treatment of the lesion. All biopsy findings were categorized as a primary malignancy (excluding round cell lesions), round cell lesion, local recurrence, or metastatic carcinoma. In addition, each lesion was analyzed according to which biopsy technique was used, whether frozen tissue section or rapid cytologic evaluation was used, and at which anatomic site the mass was found. The accuracy for needle biopsy was 93% and that for fine-needle aspiration was 80%. The complication rate for both techniques was less than 1%. Accuracy rates for the four categories of primary malignancy, round cell lesion, local recurrence, and metastatic carcinoma were 87%, 75%, 94%, and 100%, respectively. The mismatch rates were similar in soft-tissue lesions (5/52) and bone lesions (16/169). Diminished accuracy was associated with round cell lesions (20%) and lesions located in the spine or the perivertebral region (20%). Nondiagnostic and insufficient specimens were found in 18 (8%) of the 221 patients. CONCLUSION. CT-guided biopsy of musculoskeletal malignancies is a safe and effective procedure if performed by a team of clinicians, pathologists, and radiologists who possess subspecialty expertise.


Non-protected areas demanding equitable conservation strategies as of protected areas in the Central Himalayan region.
The present study aims to explore the mammalian diversity of Darjeeling district using camera traps along with questionnaire survey in protected area (PA) and non- protected area (Non-PA). We also attempted to understand the influence of habitat variables on mammalian species richness using the generalized linear mixed models (GLMM). A total of 30 mammal species were recorded of which 21 species were detected through camera trapping with the most abundant records of barking deer (Muntiacus muntjak) and least of the elusive Chinese pangolin (Manis pentadactyla) and red panda (Ailurus fulgens). Additionally, melanistic forms of four mammals were also recorded. The mammalian species richness, their capture rate and naïve occupancy did not differ significantly among the PA and Non-PA. The GLMM revealed that the proportions of oak and bamboo in the forest, percentage canopy cover and camera trap operational days (wAICc = 0.145, wBIC = 0.603) were significant predictors of species richness in the study. We suggest Non-PA forest of Darjeeling should be given equal conservation importance as to the PA. Landscape based conservation planning will be imperative for achieving long term conservation goals in the study area.


Psychometric properties of the WHOQOL-BREF in citizens from a disadvantaged neighborhood in Southern Sweden.
Citizens living in disadvantaged neighborhoods experience poorer health than the majority, and this inequality is a public health problem even in a welfare state such as Sweden. Numerous initiatives aimed at improving health and quality of life in these populations are being implemented and evaluated. Given that these populations are predominantly multicultural and multilingual, an instrument such as the WHOQOL-BREF, which is cross-culturally validated and available in multiple languages, may be appropriate. However, this cannot be ascertained since the psychometric properties of WHOQOL-BREF have never been assessed in the Swedish context. Thus, the current study aimed at assessing the psychometric properties of the WHOQOL-BREF questionnaire in citizens from a disadvantaged neighborhood in Southern Sweden. The respondents in this study were 103 citizens who participated in the health promotional activities of a Health promotional program and also responded to the 26-item, WHOQOL-BREF questionnaire as a part of an evaluation to assess the impact of the activities on the health-related quality of life of citizens. A Rasch model using WINSTEP 4.5.1 was used to assess the psychometric properties in this study. Five of the 26 items, including pain and discomfort, dependence on medical substances, physical environment, social support, and negative feelings did not display acceptable goodness-of-fit to the Rasch model. On removing these items, the 21-item WHOQOL-BREF scale had an improved internal scale validity and person-separation reliability than the original 26-item version for this group of citizens from the neighborhood. When assessing the individual domains, three of the five items that were misfits on analyzing the full model also showed misfits in relation to two respective domains. When these items were removed, the internal scale validity of the domains also improved. WHOQOL-BREF seemed to be psychometrically inadequate when used in the original form due to internal scale validity problems, while the modified 21-item scale seemed better at measuring the health-related quality of life of citizens living in socially disadvantaged neighborhoods in Sweden. Omission of items shall be done but with caution. Alternatively, future studies may also consider rephrasing the items with misfits and further testing the instrument with larger samples exploring the associations between subsamples and specific item misfit responses.


Babesia microti and Malaria Infection in Africa: A Pilot Serosurvey in Kilosa District, Tanzania.
Babesia is a tick-borne intraerythrocytic parasite that is clinically and diagnostically similar to malaria parasite, conferring risk of misdiagnosis in areas where both parasites are endemic. Data on Babesia in humans in Africa are lacking, despite evidence that it is present in regional animal populations. Samples that were collected in November 2014 to July 2015 in Kilosa district, Tanzania, were evaluated for evidence of malaria and Babesia infection. Clinical data and laboratory samples (i.e., hemoglobin, rapid diagnostic testing [RDT] for malaria, peripheral blood smear, and dried blood spots) from a routine survey were available for analysis. Dried blood spots were tested using an investigational enzyme linked immunosorbent assay (ELISA) against Babesia microti. A total of 1,030 children aged 1 month to < 5 years were evaluated; 186 (18.1%) were malaria RDT positive, 180 (96.8%) of whom had peripheral smears reviewed; 70/180 (38.9%) were smear positive for parasites. The median (inter quartile range) and range of B. microti ELISA signal to cutoff (S/C) ratio was 0.10 (0.06-0.15) and 0.01-1.65, respectively; the S/C ratios were significantly higher in subjects ≥ 1 year as compared with those < 1 year old (P < 0.001). There was also a statistically significant association between a positive RDT for malaria and the Babesia S/C (median 0.09 versus 0.13 in RDT negative versus RDT positive, respectively; P < 0.001). The highest S/C ratios were disproportionately clustered in a few hamlets. The findings suggest that Babesia may be present in Kilosa district, Tanzania. However, serological cross-reactivity and false positivity, notably between Babesia and Plasmodium spp., cannot be definitively excluded and have implications for testing in other settings.


Genetically encoded optical activation of DNA recombination in human cells.
We developed two tightly regulated, light-activated Cre recombinase enzymes through site-specific incorporation of two genetically-encoded photocaged amino acids in human cells. Excellent optical off to on switching of DNA recombination was achieved. Furthermore, we demonstrated precise spatial control of Cre recombinase through patterned illumination.


Brain edema in acute liver failure: inhibition by L-histidine.
Brain edema and the associated increase in intracranial pressure are potentially lethal complications of acute liver failure (ALF). Astrocyte swelling (cytotoxic edema) represents a significant component of the brain edema in ALF, and elevated blood and brain ammonia levels have been strongly implicated in its formation. We earlier showed in cultured astrocytes that oxidative stress (OS) and the mitochondrial permeability transition (mPT) play major roles in the mechanism of ammonia-induced astrocyte swelling. Glutamine, a byproduct of ammonia metabolism, has also been shown to induce OS, the mPT, and astrocyte swelling. Such effects of glutamine were suggested to be mediated by its hydrolysis in mitochondria, potentially yielding high levels of ammonia in this organelle and leading to OS and the mPT. L-histidine, an inhibitor of mitochondrial glutamine transport, was recently shown to mitigate OS, mPT, and cell swelling in cultured astrocytes treated with ammonia. The present study examined whether L-histidine similarly abolishes OS, the mPT, and brain edema in a rat model of ALF. Treatment of rats with thioacetamide caused a significant degree of brain edema, which was associated with induction of OS and the mPT. These changes were completely abolished by L-histidine, supporting a key role of mitochondrial glutamine transport and hydrolysis in the mechanism of the brain edema associated with ALF.


Congenital NOS2 deficiency prevents impairment of hypoxic pulmonary vasoconstriction in murine ventilator-induced lung injury.
Hypoxic pulmonary vasoconstriction (HPV) preserves systemic arterial oxygenation during lung injury by diverting blood flow away from poorly ventilated lung regions. Ventilator-induced lung injury (VILI) is characterized by pulmonary inflammation, lung edema, and impaired HPV leading to systemic hypoxemia. Studying mice congenitally deficient in inducible nitric oxide synthase (NOS2) and wild-type mice treated with a selective NOS2 inhibitor, L-N(6)-(1-iminoethyl)lysine (L-NIL), we investigated the contribution of NOS2 to the impairment of HPV in anesthetized mice subjected to 6 h of either high tidal volume (HV(T)) or low tidal volume (LV(T)) ventilation. HPV was estimated by measuring the changes of left lung pulmonary vascular resistance (LPVR) in response to left mainstem bronchus occlusion (LMBO). LMBO increased the LPVR similarly in wild-type, NOS2(-/-), and wild-type mice treated with L-NIL 30 min before commencing 6 h of LV(T) ventilation (96% +/- 30%, 103% +/- 33%, and 80% +/- 16%, respectively, means +/- SD). HPV was impaired in wild-type mice subjected to 6 h of HV(T) ventilation (23% +/- 16%). In contrast, HPV was preserved after 6 h of HV(T) ventilation in NOS2(-/-) and wild-type mice treated with L-NIL either 30 min before or 6 h after commencing HV(T) ventilation (66% +/- 22%, 82% +/- 29%, and 85% +/- 16%, respectively). After 6 h of HV(T) ventilation and LMBO, systemic arterial oxygen tension was higher in NOS2(-/-) than in wild-type mice (192 +/- 11 vs. 171 +/- 17 mmHg; P < 0.05). We conclude that either congenital NOS2 deficiency or selective inhibition of NOS2 protects mice from the impairment of HPV occurring after 6 h of HV(T) ventilation.


Synthesis and secretion of tobacco neutral PR-5 protein by transgenic tobacco and yeast.
Tobacco neutral osmotin-like protein was expressed in both homologous and heterologous expression systems. Osmotin-like protein was retained in tobacco cells when expressed as the prepro-form, whereas deletion of the carboxyl-terminal propeptide of 22 amino acids induced its secretion into the extracellular fluid. Without the amino-terminal signal peptide, there was no accumulation of osmotin-like protein. When the construct with both the amino- and carboxyl-terminal peptides was introduced to methylotrophic yeast, divergent osmotin-like protein forms were found in the cell and medium. Results suggest that the amino-terminal signal of the osmotin-like protein is essential for the transport of protein to the endoplasmic reticulum both in tobacco and yeasts but that the carboxyl-terminal propeptide signal is effective only for intracellular retention in tobacco.


Prevalence of Financial Fraud and Scams Among Older Adults in the United States: A Systematic Review and Meta-Analysis.
The financial exploitation of older adults was recently recognized by the Centers for Disease Control and Prevention as a serious public health problem. Knowledge of the prevalence of elder financial exploitation is mostly limited to the category of financial abuse, which occurs in relationships involving an expectation of trust. Little is known about the other major category of elder financial exploitation-elder financial fraud and scams, which is perpetrated by strangers. A valid estimate of elder financial fraud-scam prevalence is necessary as a foundation for research and prevention efforts. To estimate the prevalence of elder financial fraud-scam victimization in the United States based on a systematic review and meta-analysis. Multiple investigators independently screened titles and abstracts and reviewed relevant full-text records from PubMed, Medline, PsycINFO, Criminal Justice Abstracts, Social Work Abstracts, and AgeLine databases. To maximize the validity and generalizability of prevalence estimation, we restricted eligibility to general population-based studies (English speaking, 1990 onward) using state- or national-level probability sampling and collecting data directly from older adults. Information on elder financial fraud-scam prevalence and study-level characteristics was extracted independently by 2 investigators. Meta-analysis of elder financial fraud-scam prevalence used generalized mixed models with individual studies as levels of a random classification factor. We included 12 studies involving a total of 41 711 individuals in the meta-analysis. Overall pooled elder financial fraud-scam prevalence (up to 5-year period) across studies was 5.6% (95% confidence interval [CI] = 4.0%, 7.8%), with a 1-year period prevalence of 5.4% (95% CI = 3.2%, 7.6%). Studies using a series of questions describing specific fraud-scam events to measure victimization found a significantly higher prevalence (7.1%; 95% CI = 4.8%, 9.4%) than studies using a single, general-question self-report assessment approach (3.6%; 95% CI = 1.8%, 5.4%). Elder financial fraud and scams is a common problem, affecting approximately 1 of every 18 cognitively intact, community-dwelling older adults each year; it requires further attention from researchers, clinicians, and policymakers. Elder financial fraud-scam prevalence findings in this study likely underestimate the true population prevalence. We provide methodological recommendations to limit older adult participation and reporting bias in future population-based research. Public Health Implications. Elder financial exploitation victimization is associated with mortality, hospitalization, and poor physical and mental health. Health care professionals working with older adults likely routinely encounter patients who are fraud-scam victims. Validation of instruments to screen for elder financial fraud and scams in clinical settings is an important area of future research. Without effective primary prevention strategies, the absolute scope of this problem will escalate with the growing population of older adults.


Xenopus Cdc6 performs separate functions in initiating DNA replication.
Cdc6 performs an essential role in the initiation of eukaryotic DNA replication by recruiting the minichromosome maintenance (MCM) complex onto DNA. Using immunodepletion/add-back experiments in Xenopus egg extracts, we have determined that both Walker A (ATP binding) and Walker B (ATP hydrolysis) motifs of Xenopus Cdc6 (Xcdc6) are essential, but have distinct functional roles. Although Walker B mutant protein binds chromatin well, Walker A mutant protein binds chromatin poorly. Neither Walker A nor Walker B mutant protein, however, load appreciable MCM onto DNA. Herein, we provide evidence that Cdc6 functions as a multimer: 1) mutant and wild-type Xcdc6 form multimers; 2) either mutant protein is dominant negative when added before wild-type Xcdc6, but stimulates DNA replication when added simultaneously with wild-type Xcdc6; and 3) the two mutants restore DNA replication when added together, in the absence of wild-type Xcdc6. Our findings suggest that ATP may play a key regulatory role within this multimer: its binding to Cdc6 promotes chromatin association and its hydrolysis facilitates MCM loading. Moreover, ATP binding and hydrolysis may occur in trans between Cdc6 subunits within the complex.


Biotin labelling of chicken antibodies and their subsequent use in ELISA and immunohistochemistry.
Avian antibodies have many advantages to mammalian antibodies due to the phylogenetic differences between birds and mammals, resulting in an increased sensitivity and a decreased background in many immunological assays. Since the avidin-biotin system is an efficient detection system for antibodies with a high sensitivity, we wanted to investigate the activity and unspecific binding of optimally biotin labelled chicken antibodies in ELISA and immunohistochemistry. We report on the conditions for biotinylation of chicken antibodies and that optimally biotinylated antibodies show a high activity and a low background in both ELISA and immunohistochemistry.


Reference values for standardized tests of walking speed and distance: a systematic review.
To provide an overview of the reference values and methodology used to obtain them for time- and distance-limited walk tests. We performed a systematic review and searched PubMed, MEDLINE (Ovid), EMBASE, CINAHL, Scopus, PEDro, and The Cochrane Library from 1946 to May 2013. Full-text peer-reviewed articles written in English, French or Spanish were considered eligible. Two authors independently screened titles and abstracts. One author determined eligibility of full-text articles, appraised methodological quality, and extracted data. A second author independently verified the accuracy of extracted data. Of the 41 eligible studies reviewed, 25 failed to describe the method used to select participants and 10 had an inadequate sample size. Twenty-five studies provided reference values for one time-limited walk test (6-min walk test (6 MWT)) and 18 studies provided reference values for 15 distance-limited walk tests. Across studies, walk test distances ranged from 3m to 40m. Descriptive values and reference equations for the 6 MWT were reported in 15 and 20 studies, respectively. Across 43 regression equations (median R(2)=0.46), age (98%) and sex (91%) were most frequently included. The equation yielding the maximum R(2) value (0.78) included age, height, weight and percentage of predicted maximum heart rate. Among six unique regression equations for distance-limited walk tests (median R(2)=0.17), sex (83%), age (67%) and weight (67%) were most frequently included. The equation yielding the maximum R(2) value (0.25) included age and sex. Reference values reported for these tests provide a basis for classifying walking capacity as within normal limits, determining the magnitude of deficit, educating clients, setting rehabilitation goals, and planning studies.


Functional expression of TRPV channels in T cells and their implications in immune regulation.
The importance of Ca(2+) signalling and temperature in the context of T cell activation is well known. However, the molecular identities of key players involved in such critical regulations are still unknown. In this work we explored the endogenous expression of transient receptor potential vanilloid (TRPV) channels, a group of thermosensitive and non-selective cation channels, in T cells. Using flow cytometry and confocal microscopy, we demonstrate that members belonging to the TRPV subfamily are expressed endogenously in the human T cell line Jurkat, in primary human T cells and in primary murine splenic T cells. We also demonstrate that TRPV1- and TRPV4-specific agonists, namely resiniferatoxin and 4α-phorbol-12,13-didecanoate, can cause Ca(2+) influx in T cells. Moreover, our results show that expression of these channels can be upregulated in T cells during concanavalin A-driven mitogenic and anti-CD3/CD28 stimulated TCR activation of T cells. By specific blocking of TRPV1 and TRPV4 channels, we found that these TRPV inhibitors may regulate mitogenic and T cell receptor mediated T cell activation and effector cytokine(s) production by suppressing tumour necrosis factor, interleukin-2 and interferon-γ release. These results may have broad implications in the context of cell-mediated immunity, especially T cell responses and their regulations, neuro-immune interactions and molecular understanding of channelopathies.


Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response.
It is widely believed that protection against acquisition of HIV or SIV infection requires anti-envelope (anti-Env) antibodies, and that cellular immunity may affect viral loads but not acquisition, except in special cases. Here we provide evidence to the contrary. Mucosal immunization may enhance HIV vaccine efficacy by eliciting protective responses at portals of exposure. Accordingly, we vaccinated macaques mucosally with HIV/SIV peptides, modified vaccinia Ankara-SIV (MVA-SIV), and HIV-gp120-CD4 fusion protein plus adjuvants, which consistently reduced infection risk against heterologous intrarectal SHIVSF162P4 challenge, both high dose and repeated low dose. Surprisingly, vaccinated animals exhibited no anti-gp120 humoral responses above background and Gag- and Env-specific T cells were induced but failed to correlate with viral acquisition. Instead, vaccine-induced gut microbiome alteration and myeloid cell accumulation in colorectal mucosa correlated with protection. Ex vivo stimulation of the myeloid cell-enriched population with SHIV led to enhanced production of trained immunity markers TNF-α and IL-6, as well as viral coreceptor agonist MIP1α, which correlated with reduced viral Gag expression and in vivo viral acquisition. Overall, our results suggest mechanisms involving trained innate mucosal immunity together with antigen-specific T cells, and also indicate that vaccines can have critical effects on the gut microbiome, which in turn can affect resistance to infection. Strategies to elicit similar responses may be considered for vaccine designs to achieve optimal protective efficacy.


Chimeric influenza virus induces neutralizing antibodies and cytotoxic T cells against human immunodeficiency virus type 1.
Expression vectors based on DNA or plus-stranded RNA viruses are being developed as vaccine carriers directed against various pathogens. Less is known about the use of negative-stranded RNA viruses, whose genomes have been refractory to direct genetic manipulation. Using a recently described reverse genetics method, we investigated whether influenza virus is able to present antigenic structures from other infectious agents. We engineered a chimeric influenza virus which expresses a 12-amino-acid peptide derived from the V3 loop of gp120 of human immunodeficiency virus type 1 (HIV-1) MN. This peptide was inserted into the loop of antigenic site B of the influenza A/WSN/33 virus hemagglutinin (HA). The resulting chimeric virus was recognized by specific anti-V3 peptide antibodies and a human anti-gp120 monoclonal antibody in both hemagglutination inhibition and neutralization assays. Mice immunized with the chimeric influenza virus produced anti-HIV antibodies which were able to bind to synthetic V3 peptide, to precipitate gp120, and to neutralize MN virus in human T-cell culture system. In addition, the chimeric virus was also capable of inducing cytotoxic T cells which specifically recognize the HIV sequence. These results suggest that influenza virus can be used as an expression vector for inducing both B- and T-cell-mediated immunity against other infectious agents.


Associations between physical activity, sedentary behaviour and left ventricular structure and function from the Echocardiographic Study of Latinos (ECHO-SOL).
The cross-sectional association between accelerometer-measured physical activity (PA), sedentary behaviour (SB) and cardiac structure and function is less well described. This study's primary aim was to compare echocardiographic measures of cardiac structure and function with accelerometer measured PA and SB. Participants included 1206 self-identified Hispanic/Latino men and women, age 45-74 years, from the Echocardiographic Study of Latinos. Standard echocardiographic measures included M-mode, two-dimensional, spectral, tissue Doppler and myocardial strain. Participants wore an Actical accelerometer at the hip for 1 week. The mean±SE age for the cohort was 56±0.4 years, 57% were women. Average moderate to vigorous PA (MVPA) was 21±1.1 min/day, light PA was 217±4.2 min/day and SB was 737±8.1 min/day. Both higher levels of light PA and MVPA (min/day) were associated with lower left ventricular (LV) mass index (LVMI)/end-diastolic volume and a lower E/e' ratio. Higher levels of MVPA (min/day) were associated with better right ventricular systolic function. Higher levels of SB were associated with increased LVMI. In a multivariable linear regression model adjusted for demographics and cardiovascular disease modifiable factors, every 10 additional min/day of light PA was associated with a 0.03 mL/m2 increase in left atrial volume index (LAVI) (p<0.01) and a 0.004 cm increase in tricuspid annular plane systolic excursion (p<0.01); every 10 additional min/day of MVPA was associated with a 0.18 mL/m2 increase in LAVI (p<0.01) and a 0.24% improvement in global circumferential strain (p<0.01). Our findings highlight the potential positive association between the MVPA and light PA on cardiac structure and function.


Labeled Oxygen: Increased Diffusion Rate through Soil Containing Growing Corn Roots.
The diffusion of oxygen labeled with oxygen-18 through cores of wet soil increased significantly when roots of growing corn seedlings penetrated the cores. The increase was small or absent when roots grew through a layer of soft wax or a layer of water-saturated 0.5-mm glass beads, indicating that the diffusion increase was a joint effect of the roots and airfilled pores in the soil. A possible mechanism is suggested.


Further evidence for links between facial width-to-height ratio and fighting success: Commentary on Zilioli et al. (2014).
Recent research has reported an association between facial width-to-height ratio (fWHR) and both fighting performance and judgments of formidability in a sample of mixed martial arts (MMA) combatants. The results provide evidence of fWHR being associated with sporting performance and aggression in men. However, it has been argued that the effect of fWHR might be a by-product of associations between body size and behavioral measures. Here we tested whether fWHR is associated with perceived aggressiveness, fighting ability and success in physical confrontation, while controlling for body size, also in a sample of MMA fighters. We found that perceived fighting ability was predicted by weight but not by fWHR. In contrast, both fWHR and body weight independently predicted perceived aggressiveness. Furthermore, we found positive associations between fWHR and fighting performance which appear to be independent of body size. Our findings provide further support for the proposal that fWHR is associated with fighting ability and perceived aggression, and that these effects are independent of body size. Therefore, fWHR might be considered as a viable and reliable marker for inference of success in male intra-sexual competition.


Effects of treatment with metformin on TSH levels: a meta-analysis of literature studies.
Some data suggest that metformin affects the thyroid profile in patients with type 2 diabetes, but contrasting results are reported in different settings. The aim of this meta-analysis was to assess the effect of metformin treatment on TSH in subjects with or without thyroid dysfunction. We performed a systematic search of articles evaluating changes in TSH levels in patients receiving metformin. Studies evaluating TSH levels before and after metformin treatment were included. Clinical data, demographic variables, and TSH levels before and after treatment with metformin were extracted. Data were analyzed according to the underlying thyroid disease. A total of 7 datasets (206 patients) were included in the final analysis. After metformin treatment, a slight but significant reduction in TSH levels was found in 4 datasets on 119 patients with overt hypothyroidism receiving l-T4 replacement (mean difference, 1.08; 95% confidence interval [CI], 0.50, 1.65; P=.0003). Similarly, in 2 datasets reporting on a total of 33 patients with subclinical hypothyroidism not receiving treatment with l-T4, a significant reduction in TSH levels was reported (mean difference, 1.59; 95% CI, 1.32, 1.87; P<.00001) after treatment with metformin. In 1 dataset, including 54 euthyroid patients not receiving l-T4, no changes in TSH levels were reported after treatment with metformin (mean difference, 0.18; 95% CI, -0.20, 0.56; P=.35). Metformin induces a reduction in TSH levels both in overt and in subclinical hypothyroidism. In contrast, no change in TSH levels is found in euthyroid patients.


Pathogenic aspects of pyogenic liver abscess associated with experimental schistosomiasis.
Schistosomiasis mansoni infection that occurs concurrently with Staphylococcus aureus bacteremia favors the formation of pyogenic liver abscess. The present experimental study in mice evaluated the following aspects of the relationship between infection with Schistosoma mansoni and liver abscess caused by S. aureus: a) the role of the eggs of S. mansoni in the genesis of the abscesses; b) the influence of different phases of schistosomiasis in the development of liver abscesses; and c) the effect of the treatment of schistosomiasis on the development of the abscesses. Macroscopic and histopathological study showed multiple liver abscesses around granulomas of S. mansoni in the acute and chronic phases of schistosomiasis. Treatment of acute schistosomiasis before experimentally-induced bacteremia did not prevent the formation of liver abscess. The study findings indicate that granulomas around S. mansoni eggs and worms lodged in the liver provide a focus and substrate for pyogenic abscesses caused by S. aureus.


BEAUTY: an enhanced BLAST-based search tool that integrates multiple biological information resources into sequence similarity search results.
BEAUTY (BLAST enhanced alignment utility) is an enhanced version of the NCBI's BLAST data base search tool that facilitates identification of the functions of matched sequences. We have created new data bases of conserved regions and functional domains for protein sequences in NCBI's Entrez data base, and BEAUTY allows this information to be incorporated directly into BLAST search results. A Conserved Regions Data Base, containing the locations of conserved regions within Entrez protein sequences, was constructed by (1) clustering the entire data base into families, (2) aligning each family using our PIMA multiple sequence alignment program, and (3) scanning the multiple alignments to locate the conserved regions within each aligned sequence. A separate Annotated Domains Data Base was constructed by extracting the locations of all annotated domains and sites from sequences represented in the Entrez, PROSITE, BLOCKS, and PRINTS data bases. BEAUTY performs a BLAST search of those Entrez sequences with conserved regions and/or annotated domains. BEAUTY then uses the information from the Conserved Regions and Annotated Domains data bases to generate, for each matched sequence, a schematic display that allows one to directly compare the relative locations of (1) the conserved regions, (2) annotated domains and sites, and (3) the locally aligned regions matched in the BLAST search. In addition, BEAUTY search results include World-Wide Web hypertext links to a number of external data bases that provide a variety of additional types of information on the function of matched sequences. This convenient integration of protein families, conserved regions, annotated domains, alignment displays, and World-Wide Web resources greatly enhances the biological informativeness of sequence similarity searches. BEAUTY searches can be performed remotely on our system using the "BCM Search Launcher" World-Wide Web pages (URL is < http:/ /gc.bcm.tmc.edu:8088/ search-launcher/launcher.html > ).


Sympathetic neural responses to induced ventricular tachycardia.
Although sympathetic mechanisms play a major role in buffering abrupt arterial pressure reductions, including those that occur during tachyarrhythmias, human sympathetic nervous system responses to ventricular tachycardia have not been measured. Muscle sympathetic nerve activity was recorded directly from the peroneal nerve in 16 patients during diagnostic induction of 19 episodes of sustained monomorphic ventricular tachycardia (average rate 189 beats/min, range 130 to 250). Average systolic and diastolic pressures decreased from 149/78 to 61/49 mm Hg by 10 s and increased toward baseline levels to 88/64 mm Hg by 1 min of ventricular tachycardia. Average sympathetic nerve activity increased by 92% at 10 s in direct proportion to arterial pressure reductions and in inverse proportion to ventricular rate and remained 83% above baseline levels at 1 min. The late recovery of arterial pressure during ventricular tachycardia was related significantly to the magnitude of early sympathetic responses. Sympathetic activity tended to lose its discrete bursting pattern during ventricular tachycardia, and power spectral analysis showed that the large sympathetic peaks at the heart rate frequency present during sinus rhythm are absent during ventricular tachycardia. This study is the first to delineate human sympathetic nervous system responses to ventricular tachycardia. The results suggest that in the patients studied, large early sympathetic surges differed from those that occur during sinus rhythm and contributed to hemodynamic stability during ventricular tachycardia.


Exploring the comparative responsiveness of a core set of outcome measures in a school-based conductive education programme.
Conductive education (CE) is a holistic educational system that uses an active cognitive approach to teach individuals with motor disorders to become more functional participants in daily activities. While CE's popularity continues to grow in North America and Europe, its effectiveness has not been established. The lack of definition of responsive outcome measures for evaluation of CE programmes has limited the interpretability of conclusions from earlier studies evaluating effectiveness. To determine which measures from a core set were most responsive to physical, functional and psychosocial changes associated with a school-based CE programme. This was a one-group before and after data collection design using an 8-month follow-up period. We enrolled a referral sample of nine children with cerebral palsy in Kindergarten or Grade 1 (Gross Motor Function Classification System levels 3, 4 or 5). The study took place within a school-based CE programme at a Canadian children's rehabilitation centre. Children participated in a CE full-day class for an entire school year. Physical, functional, psychosocial and participation measures included: Gross Motor Function Measure (GMFM), Quality of Upper Extremity Skills Test (QUEST), Peabody Developmental Motor Scales, Paediatric Evaluation of Disability Inventory (PEDI), Pictorial Scale of Perceived Competence and Social Acceptance for Young Children, Individualized Educational Plan, and Goal Attainment Scaling (GAS). Four children from the study's second year were also evaluated on the Impact on Family Scale (IFS), GAS and School Function Assessment. The Gross Motor Function Measure, QUEST, PEDI (Caregiver Assistance) and IFS were most responsive to change. GAS was useful in documenting and quantifying goals. Problems were encountered in evaluating self-esteem and school participation. Several strong measures of outcome were identified. Further work is needed to find valid and sensitive psychosocial and school participation measures for these young children.


Lymphocyte subpopulations in patients with primary fibromyalgia.
Fibromyalgia (FM) is a clinical entity of unknown etiology frequently diagnosed in rheumatology. The potential involvement of the immune system in its pathogenesis has been suggested. Studies of abnormal T cell subpopulations often have been inconclusive. We attempted to clear this point by comparing lymphocyte subpopulations, including some of the newer activation markers, in patients with FM and healthy controls. Sixty-five patients with FM and 56 healthy controls were studied. Flow cytometry was used as a quantification technique to measure lymphocyte subpopulations, CD3 (T cells), CD19 (B cells), CD16 (natural killer cells), CD4 (T helper/inducer cells), CD8 (T cytotoxic/suppressor cell), CD25 (interleukin 2 receptor), CD69 (activation inducer molecule marker), CD71 (transferrin receptor) and CD54 (ICAM-1); CD4/CD8 ratios were also estimated. The number of T cells expressing activation markers CD69 and CD25 was decreased in patients with FM; the other subpopulations were similar in patients and controls. Our results suggest a defect in T cell activation in patients with FM.


Rates of divergence in gene expression profiles of primates, mice, and flies: stabilizing selection and variability among functional categories.
The extent to which natural selection shapes phenotypic variation has long been a matter of debate among those studying organic evolution. We studied the patterns of gene expression polymorphism and divergence in several datasets that ranged from comparisons between two very closely related laboratory strains of mice to comparisons across a considerably longer time scale, such as between humans and chimpanzees, two species of mice, and two species of Drosophila. The results were analyzed and interpreted in view of neutral models of phenotypic evolution. Our analyses used a number of metrics to show that most mRNA levels are evolutionary stable, changing little across the range of taxonomic distances compared. This implies that, overall, widespread stabilizing selection on transcription levels has prevented greater evolutionary changes in mRNA levels. Nevertheless, the range of rates of divergence is large with highly significant differences in the rate and patterns of transcription divergence across functional classes defined on the basis of the gene ontology annotation (primates and mice datasets) or on the basis of the pattern of sex-biased gene expression (Drosophila). Moreover, rates of divergence of sex-biased genes in the contrast between Drosophila species show a distinct pattern from that observed in the contrast between populations of D. melanogaster. Hence, we discuss the time scale of the changes observed and its consequences for the relationship between variation in gene expression within and between species. Finally, we argue that differences in mRNA levels of the magnitudes observed herein could be explained by a remarkably small number of generations of directional selection.


The NAC transcription factor FaRIF controls fruit ripening in strawberry.
In contrast to climacteric fruits such as tomato, the knowledge on key regulatory genes controlling the ripening of strawberry, a nonclimacteric fruit, is still limited. NAC transcription factors (TFs) mediate different developmental processes in plants. Here, we identified and characterized Ripening Inducing Factor (FaRIF), a NAC TF that is highly expressed and induced in strawberry receptacles during ripening. Functional analyses based on stable transgenic lines aimed at silencing FaRIF by RNA interference, either from a constitutive promoter or the ripe receptacle-specific EXP2 promoter, as well as overexpression lines showed that FaRIF controls critical ripening-related processes such as fruit softening and pigment and sugar accumulation. Physiological, metabolome, and transcriptome analyses of receptacles of FaRIF-silenced and overexpression lines point to FaRIF as a key regulator of strawberry fruit ripening from early developmental stages, controlling abscisic acid biosynthesis and signaling, cell-wall degradation, and modification, the phenylpropanoid pathway, volatiles production, and the balance of the aerobic/anaerobic metabolism. FaRIF is therefore a target to be modified/edited to control the quality of strawberry fruits.


Human myocardial pericytes: multipotent mesodermal precursors exhibiting cardiac specificity.
Perivascular mesenchymal precursor cells (i.e., pericytes) reside in skeletal muscle where they contribute to myofiber regeneration; however, the existence of similar microvessel-associated regenerative precursor cells in cardiac muscle has not yet been documented. We tested whether microvascular pericytes within human myocardium exhibit phenotypes and multipotency similar to their anatomically and developmentally distinct counterparts. Fetal and adult human heart pericytes (hHPs) express canonical pericyte markers in situ, including CD146, NG2, platelet-derived growth factor receptor (PDGFR) β, PDGFRα, alpha-smooth muscle actin, and smooth muscle myosin heavy chain, but not CD117, CD133, and desmin, nor endothelial cell (EC) markers. hHPs were prospectively purified to homogeneity from ventricular myocardium by flow cytometry, based on a combination of positive- (CD146) and negative-selection (CD34, CD45, CD56, and CD117) cell lineage markers. Purified hHPs expanded in vitro were phenotypically similar to human skeletal muscle-derived pericytes (hSkMPs). hHPs express mesenchymal stem/stromal cell markers in situ and exhibited osteo-, chondro-, and adipogenic potentials but, importantly, no ability for skeletal myogenesis, diverging from pericytes of all other origins. hHPs supported network formation with/without ECs in Matrigel cultures; hHPs further stimulated angiogenic responses under hypoxia, markedly different from hSkMPs. The cardiomyogenic potential of hHPs was examined following 5-azacytidine treatment and neonatal cardiomyocyte coculture in vitro, and intramyocardial transplantation in vivo. Results indicated cardiomyocytic differentiation in a small fraction of hHPs. In conclusion, human myocardial pericytes share certain phenotypic and developmental similarities with their skeletal muscle homologs, yet exhibit different antigenic, myogenic, and angiogenic properties. This is the first example of an anatomical restriction in the developmental potential of pericytes as native mesenchymal stem cells.


Interplay between social media use, sleep quality, and mental health in youth: A systematic review.
Social media applications are increasingly prominent among youth. This systematic review provides a comprehensive assessment of the literature on the relationship between active social media use, sleep quality, and common mental health outcomes (anxiety, depression, and psychological distress) among youth. MEDLINE, PsychINFO, EMBASE and Scopus were searched for observational studies investigating this relationship among youth (aged 16-25). Thirty-six cross-sectional studies and six prospective cohort studies met the inclusion criteria. Among cross-sectional studies, significant associations between excessive social media use with poor mental health outcomes (n = 33), poor sleep quality (n = 24), and significant associations between poor sleep quality and negative mental health (n = 16) were found. In longitudinal studies, frequent social media use was a risk factor for both poor mental health (n = 6) and poor sleep outcomes (n = 5). Some studies showed sleep quality mediating the relationship between social media use and negative mental health outcomes in youth. Overall, included evidence links excessive social media use to poor sleep quality and negative mental health in youth. Given the public health implications of sleep problems, excessive social media use warrants further investigation to clarify the directionality and strength of their associations with poor sleep quality and negative mental health outcomes.


Gastroenterology research in the United Kingdom: funding sources and impact.
To determine the sources of founding for UK gastroenterology research papers and the relative impact of papers funded by different groups and of unfunded ones. UK gastroenterology papers from 1988-94 were selectively retrieved from the Science Citation Index by means of a specially constructed filter based on their title keywords and journal names. They were looked up in libraries to determine their funding sources and these, together with their numbers of authors, numbers of addresses, and research category (clinical/basic) were considered as input parameters to the research. Output parameters analysed were mean journal impact category, citation counts by papers, and the frequency of citation by a US patient. Gastroenterology papers comprise about 7% of all UK biomedical research and 46% of them have no acknowledged funding source. One quarter of the papers acknowledged government support, and a similar fraction a private, non-profit source; 11% were funded by the pharmaceutical industry. The papers acknowledging funding had significantly more impact than the others on all three measures. The citing patents had six times more UK inventors than the average for all US Patent and Trademark Office patents in the relevant classes and were mostly generic in application. The variation in impact of papers funded by different sources can mostly be explained by a simple model based on the input factors (numbers of funding bodies, numbers of authors, numbers of addresses, and research type). The national science base in gastroenterology is important for the underpinning of UK invented patents citing to it.


Histamine inhibition of neutrophil lysosomal enzyme release: an H2 histamine receptor response.
Human polymorphonuclear leukocytes treated with cytochalasin B release the lysosomal enzyme beta glucuronidase during contact with serum-activated zymosan particles. Histamine increases intracellular cyclic adenosine monophosphate and inhibits release of this enzyme. The H2 antihistamine metiamide blocks the histamine inhibition of lysosomal enzyme release and the increase in the intracellular adenoisine 3,5'-monophosphate of granulocytes. Chlorpheniramine, an H1 antihistamine, did not block the histamine inhibition of granulocyte lysosomal enzyme release.


A Reappraisal of Dependency Length Minimization as a Linguistic Universal.
Dependency length minimization is widely regarded as a cross-linguistic universal reflecting syntactic complexity in natural languages. A typical way to operationalize dependency length in corpus-based studies has been to count the number of words between syntactically related words. However, such a formulation ignores the syntactic nature of the linguistic material that intervenes a dependency. In this work, we investigate if the number of syntactic heads (rather than the number of words) that intervene a dependency better captures the syntactic complexity across languages. We demonstrate that the dependency length minimization constraint in terms of the number of words could arise as a consequence of constraints on the intervening heads and the tree properties such as node arity. The current study highlights the importance of syntactic heads as central regions of structure building during processing. The results show that when syntactically related words are nonadjacent, increased structure building in the intervening region is avoided.


[Fragmentation of DNA of monkey adenovirus type 7 by specific endonucleases R. SalI and R. BamI].
The effect of restrictive endonucleases R. Ecor I, R. Bam I, and R. Sal I on simian adenovirus type 7 (SA7) genome was studied. Because of the occurrence of the only recognition site, the R. EcoR I enzyme cuts SA7 DNA into two fragments with molecular mass of 12 and 10 X 10(6) daltons. R. Ram I cuts this DNA in 6 sites producing 7 fragments with molecular mass 6.6, 5.9, 3.8, 2.7, 1.3, 0.7 and 0.6 X 10(6) daltons. Treatment with R. Sal I gives 6 fragments with molecular mass of 8.1, 5.5, 4.3, 2.45, 1.2, and 0.6 X 10(6) daltons R. Bam I and R. Sal I fragments form the sequence E--A--D--F--C--G--B and A--B--D--F--E--C, respectively. The only recognition site of R. EcoR I is localized in the C fragment of R. Bam I and B fragment of R. Sal I.


Patients with symptoms of delayed gastric emptying have a high prevalence of oesophageal dysmotility, irrespective of scintigraphic evidence of gastroparesis.
Patients with symptoms suggestive of gastroparesis exhibit several symptoms, such as epigastric pain, postprandial fullness, bloating and regurgitation. It is uncertain if such symptoms reflect underlying oesophageal motor disorder. To examine whether patients with epigastric pain and postprandial distress syndrome suggestive of functional dyspepsia and/or gastroparesis also have concomitant oesophageal motility abnormalities and, if so, whether there are any associations between these disturbances. In this retrospective cohort study, consecutive patients with functional gastrointestinal symptoms suggestive of gastric neuromuscular dysfunction (gastroparesis or functional dyspepsia) underwent clinical assessment, gastric scintigraphy, oesophageal high-resolution manometry and ambulatory pH monitoring using standard protocols. We studied 61 patients with various functional upper gastrointestinal symptoms who underwent gastric scintigraphy, oesophageal high-resolution manometry and ambulatory pH monitoring. Forty-four patients exhibited gastroparesis by gastric scintigraphy. Oesophageal motility disorders were found in 68% and 42% of patients with or without scintigraphic evidence of gastroparesis respectively, suggesting of overlapping gastric and oesophageal neuromuscular disorder. Forty-three per cent of patients with gastroparesis had abnormal oesophageal acid exposure with mean % pH <4.0 of 7.5 in contrast to 38% of those symptomatic controls with normal gastric emptying, with mean %pH <4.0 of 5.4 (NS). Symptoms of epigastric pain, heartburn/regurgitation, bloating, nausea, vomiting, dysphagia, belching and weight loss could not distinguish patients with or without gastroparesis, although weight loss was significantly more prevalent and severe (p<0.002) in patients with gastroparesis. There was no relationship between oesophageal symptoms and motor or pH abnormalities in either groups. Irrespective of gastric emptying delay by scintigraphy, patients with symptoms suggestive of gastric neuromuscular dysfunction have a high prevalence of oesophageal motor disorder and pathological oesophageal acid exposure that may contribute to their symptoms and may require therapy. High-resolution oesophageal manometry and pH monitoring are non-invasive and potentially useful in the assessment and management of these patients.


An Efficient Cancer Classification Model Using Microarray and High-Dimensional Data.
Cancer can be considered as one of the leading causes of death widely. One of the most effective tools to be able to handle cancer diagnosis, prognosis, and treatment is by using expression profiling technique which is based on microarray gene. For each data point (sample), gene data expression usually receives tens of thousands of genes. As a result, this data is large-scale, high-dimensional, and highly redundant. The classification of gene expression profiles is considered to be a (NP)-Hard problem. Feature (gene) selection is one of the most effective methods to handle this problem. A hybrid cancer classification approach is presented in this paper, and several machine learning techniques were used in the hybrid model: Pearson's correlation coefficient as a correlation-based feature selector and reducer, a Decision Tree classifier that is easy to interpret and does not require a parameter, and Grid Search CV (cross-validation) to optimize the maximum depth hyperparameter. Seven standard microarray cancer datasets are used to evaluate our model. To identify which features are the most informative and relative using the proposed model, various performance measurements are employed, including classification accuracy, specificity, sensitivity, F1-score, and AUC. The suggested strategy greatly decreases the number of genes required for classification, selects the most informative features, and increases classification accuracy, according to the results.


Deletion of JEN1 and ADY2 reduces lactic acid yield from an engineered Saccharomyces cerevisiae, in xylose medium, expressing a heterologous lactate dehydrogenase.
Microorganisms have evolved to produce specific end products for many reasons, including maintaining redox balance between NAD+ and NADH. The yeast Saccharomyces cerevisiae, for example, produces ethanol as a primary end product from glucose for the regeneration of NAD+. Engineered S. cerevisiae strains have been developed to ferment lignocellulosic sugars, such as xylose, to produce lactic acid by expression of a heterologous lactate dehydrogenase (ldhA from Rhizopus oryzae) without genetic perturbation to the native ethanol pathway. Surprisingly, the engineered yeast strains predominantly produce ethanol from glucose, but produce lactic acid as the major product from xylose. Here, we provide initial evidence that the shift in product formation from ethanol to lactic acid during xylose fermentation is at least partially dependent on the presence of functioning monocarboxylate transporter genes/proteins, including JEN1 and ADY2, which are downregulated and unstable in the presence of glucose, but upregulated/stable on xylose. Future yeast metabolic engineering studies may find the feedstock/carbon selection, such as xylose, an important step toward improving the yield of target end products.


Oxidative stress enzyme status and frequency of micronuclei in heroin addicts in Turkey.
Heroin is among the most widely used and dangerous addictive opiate. The World Health Organization (WHO) estimated that more than 15 million people are under the influence of opiate addiction. The aim of this study was to investigate copper zinc-superoxide dismutase (Cu,Zn-SOD), catalase (CAT) and selenium-dependent glutathione peroxidase (Se-GPx) antioxidant enzyme activities, malondialdehyde (MDA) levels and the frequency of micronuclei (MN) in addicts using heroin, the most commonly abused opiate in Turkey. Addicts were defined as individuals diagnosed according to "Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)" criteria by the "Alcohol and Substance Abuse Treatment and Education Centre-Ankara (AMATEM)". The control group had no addiction. In comparisons between the groups, a significant decrease in Cu,Zn-SOD activity and increases in MDA levels and MN frequency were observed in addicts. It can be concluded that opiates may cause oxidative stress and that antioxidant supplementation, in addition to pharmacological and psychiatric approaches, can reduce the toxicological effects of these opiates.


HIV Protease Inhibitor Ritonavir Impairs Endothelial Function Via Reduction in Adipose Mass and Endothelial Leptin Receptor-Dependent Increases in NADPH Oxidase 1 (Nox1), C-C Chemokine Receptor Type 5 (CCR5), and Inflammation.
Background Cardiovascular disease is currently the leading cause of death in patients with human immunodeficiency virus on combination antiretroviral therapy. Although the use of the protease inhibitor ritonavir has been associated with increased prevalence of cardiovascular disease, the underlying mechanisms remain ill-defined. Herein, we tested the hypothesis that ritonavir-mediated lipoatrophy causes endothelial dysfunction via reducing endothelial leptin signaling. Methods and Results Long-term (4 weeks) but not short-term (3 days) treatment with ritonavir reduced body weight, fat mass, and leptin levels and induced endothelial dysfunction in mice. Moreover, ritonavir increased vascular NADPH oxidase 1, aortic H2O2 levels as well as interleukin-1β, GATA3 (GATA binding protein 3), the macrophage marker (F4/80), and C-C chemokine receptor type 5 (CCR5) expression. Reactive oxygen species scavenging with tempol restored endothelial function, and both NADPH oxidase 1 and CCR5 deletion in mice protected from ritonavir-mediated endothelial dysfunction and vascular inflammation. Remarkably, leptin infusion markedly improved endothelial function and significantly reduced vascular NADPH oxidase 1, interleukin-1β, GATA3, F4/80, and CCR5 levels in ritonavir-treated animals. Selective deficiency in endothelial leptin receptor abolished the protective effects of leptin infusion on endothelial function. Conversely, selective increases in endothelial leptin signaling with protein tyrosine phosphatase deletion blunted ritonavir-induced endothelial dysfunction. Conclusions All together, these data indicate that ritonavir-associated endothelial dysfunction is a direct consequence of a reduction in adiposity and leptin secretion, which decreases endothelial leptin signaling and leads to a NADPH oxidase 1-induced, CCR5-mediated reduction in NO bioavailability. These latter data also introduce leptin deficiency as an additional contributor to cardiovascular disease and leptin as a negative regulator of CCR5 expression, which may provide beneficial avenues for limiting human immunodeficiency virus infection.


Construct Validity of the Children's Coping Strategies Scale (CCSS): A Bifactor Model Approach.
There has been debate regarding the factor structure of the Children's Coping Strategies Scale (CCSS); in most previous studies there were different subscales, representing coping strategies. However, according to the theoretically multidimensional construct of coping, coping consists of an adaptive process and uses the lowest possible level of coping strategy. Accordingly, this study applies a new method of multidimensional item response theory (MIRT) to testing the latent structure of teenagers' coping strategies and to improve the construct validity of the CCSS. The participants were 1,138 16-year-old high school students (48.2% female, 51.8% male) studying arts and science. This study compares three different model types: a unidimensional model, a simple multidimensional construct model, and a bifactor model. The results indicate that the latent structure of CCSS is not only described by specific coping strategies (e.g., rumination) but also by a general adaptation process, which is consistent with theoretical understandings of coping. Furthermore, the five-factor model, which contains a "reflection" dimension, is more suitable for Chinese teenagers.


Detection of transcriptional triggers in the dynamics of microbial growth: application to the respiratorily versatile bacterium Shewanella oneidensis.
The capacity of microorganisms to respond to variable external conditions requires a coordination of environment-sensing mechanisms and decision-making regulatory circuits. Here, we seek to understand the interplay between these two processes by combining high-throughput measurement of time-dependent mRNA profiles with a novel computational approach that searches for key genetic triggers of transcriptional changes. Our approach helped us understand the regulatory strategies of a respiratorily versatile bacterium with promising bioenergy and bioremediation applications, Shewanella oneidensis, in minimal and rich media. By comparing expression profiles across these two conditions, we unveiled components of the transcriptional program that depend mainly on the growth phase. Conversely, by integrating our time-dependent data with a previously available large compendium of static perturbation responses, we identified transcriptional changes that cannot be explained solely by internal network dynamics, but are rather triggered by specific genes acting as key mediators of an environment-dependent response. These transcriptional triggers include known and novel regulators that respond to carbon, nitrogen and oxygen limitation. Our analysis suggests a sequence of physiological responses, including a coupling between nitrogen depletion and glycogen storage, partially recapitulated through dynamic flux balance analysis, and experimentally confirmed by metabolite measurements. Our approach is broadly applicable to other systems.


[Simplified indicator of socioeconomic status in short surveys: a proposal based on assets and services].
To develop a socioeconomic index for brief surveys that allows a classification in relation to a reference population with a parsimonious approach. A socioeconomic index was created using assets and use of services indicators to predict income level within a national representative survey of income (ENIGH, National Survey of Households Income and Expenditures) and then tested with data from a survey among key populations (men who have sex with men/transvestite, transgender, transsexual/female sex workers) and compared to an already published indicator. The concordance for quintiles 1, 2, 3, 4, and 5 between the two indexes were 94, 94, 82, 83, and 89%, respectively. The Spearman's rank correlation coefficient was 0.85. The proposed parsimonious index captures the socioeconomic level heterogeneity in the MSM/TTT/FSW survey. The use of this index is suggested for short surveys because of the next advantages: a) it uses dichotomic variables; b) the variables used do not imply the fulfillment of any statistical assumption; c) it is easily calculated; d) it can be used for comparing groups.