Musculoskeletal overuse injuries and heart rate variability: Is there a link?
Accurate detection and prevention of overuse musculoskeletal injuries is limited by the nature of somatic tissue injury. In the pathogenesis of overuse injuries, it is well recognized that an abnormal inflammatory response occurs within somatic tissue before pain is perceived which can disrupt the normal remodeling process and lead to subsequent degeneration. Current overuse injury prevention methods focused on biomechanical faults or performance standards lack the sensitivity needed to identify the status of tissue injury or repair. Recent evidence has revealed an apparent increase in the prevalence and impact of overuse musculoskeletal injuries in athletics. When compared to acute injuries, overuse injuries have a potentially greater negative impact on athletes' overall health burden. Further, return to sport rehabilitation following overuse injury is complicated by the fact that the absence of pain does not equate to complete physiological healing of the injured tissue. Together, this highlights the need for exercise monitoring and injury prevention methods which incorporate assessment of somatic tissue response to loading. One system primarily involved in the activation of pathways and neuromediators responsible for somatic tissue repair is the autonomic nervous system (ANS). Although not completely understood, emerging research supports the critical importance of peripheral ANS activity in the health and repair of somatic tissue injury. Due to its significant contributions to cardiac function, ANS activity can be measured indirectly with heart rate monitoring. Heart rate variability (HRV) is one index of ANS activity that has been used to investigate the relationship between athletes' physiological response to accumulating training load. Research findings indicated that HRV may provide a reflection of ANS homeostasis, or the body's stress-recovery status. This noninvasive marker of the body's primary driver of recovery has the potential to incorporate important and as yet unmonitored physiological mechanisms involved in overuse injury development. We hypothesize that abnormal somatic tissue response to accumulating microtrauma may modulate ANS activity at the level of HRV. Exploring the link between HRV modulation and somatic tissue injury has the potential to reveal the putative role of ANS homeostasis on overuse musculoskeletal injury development.


Are sleep difficulties associated with migraine attributable to anxiety and depression?
To examine whether sleep complaints reported by migraineurs can be attributed to comorbid anxiety and/or depression. A consistent association between migraine and sleep complaints has been reported in community and clinical studies. However, anxiety and depression are often comorbid with migraine. Thus, it may be possible that the increased prevalence of sleep problems in migraineurs is attributable to comorbid anxiety and depression. To our knowledge, no previous studies have demonstrated that the associations are not solely attributed to comorbid anxiety and depression. Controlled family study of anxiety disorders and substance use disorders in a community in New Haven County, CT. The sample included 221 probands (41 migraineurs) and their 261 directly interviewed first-degree relatives (39 migrainuers), including parents, siblings, and offspring over age 18. A lifetime history of migraine was obtained using the Diagnostic Interview for Headache Syndromes. A lifetime history of psychiatric disorders was obtained using the semi-structured Schedule for Affective Disorders and Schizophrenia which was modified to incorporate Diagnostic and Statistical Manual diagnostic criteria. Several sleep items on current and lifetime sleep complaints were included as a subset of the interview. There was a significant association between migraine and the number of sleep problems as well as several specific sleep symptoms among probands and their adult relatives. Adults with migraine reported having significantly more lifetime sleep problems (OR [CI] = 2.3 [1.1-4.6]), and more current sleep difficulties, specifically, inadequate sleep (2.5 [1.2-5.0]), difficulty falling asleep (3.0 [1.5-6.3]), and persistent nightmares of childhood onset (4.3 [1.8-9.9]) than those without migraine. The associations between sleep problems and migraine persisted after controlling for both lifetime and current anxiety and mood disorders. The association between sleep problems and migraine that is not solely explained by comorbid anxiety disorders or depression suggests that sleep problems should be evaluated among people with migraine.


Mammalian proliferating cell nuclear antigen stimulates the processivity of two wheat embryo DNA polymerases.
Multiple DNA polymerases have been described in all organisms studied to date. Their specific functions are not easy to determine, except when powerful genetic and/or biochemical tools are available. However, the processivity of a DNA polymerase could reflect the physiological role of the enzyme. In this study, analogies between plant and animal DNA polymerases have been investigated by analyzing the size of the products synthesized by wheat DNA polymerases A, B, CI, and CII as a measure of their processivity. Thus, incubations have been carried out with poly(dA)-oligo(dT) as a template-primer under varying assay conditions. In the presence of MgCl2, DNA polymerase A was highly processive, whereas DNA polymerases B, CI, and CII synthesized much shorter products. With MnCl2 instead of MgCl2, DNA polymerase A was highly processive, DNA polymerases B and CII were moderately processive, and DNA polymerase CI remained strictly distributive. The effect of calf thymus proliferating cell nuclear antigen (PCNA) on wheat polymerases was studied as described for animal DNA polymerases. The high processivity of DNA polymerase A was PCNA independent, whereas both enzyme activity and processivity of wheat DNA polymerases B and CII were significantly stimulated by PCNA. On the other hand, DNA polymerase CI was not stimulated by PCNA and, like animal DNA polymerase beta, was distributive in all cases. From these results, we propose that wheat DNA polymerase A could correspond to a DNA polymerase alpha, DNA polymerases B and CII could correspond to the delta-like enzyme, and DNA polymerase CI could correspond to DNA polymerase beta.


O-GlcNAcylation regulates dopamine neuron function, survival and degeneration in Parkinson disease.
The dopamine system in the midbrain is essential for volitional movement, action selection, and reward-related learning. Despite its versatile roles, it contains only a small set of neurons in the brainstem. These dopamine neurons are especially susceptible to Parkinson's disease and prematurely degenerate in the course of disease progression, while the discovery of new therapeutic interventions has been disappointingly unsuccessful. Here, we show that O-GlcNAcylation, an essential post-translational modification in various types of cells, is critical for the physiological function and survival of dopamine neurons. Bidirectional modulation of O-GlcNAcylation importantly regulates dopamine neurons at the molecular, synaptic, cellular, and behavioural levels. Remarkably, genetic and pharmacological upregulation of O-GlcNAcylation mitigates neurodegeneration, synaptic impairments, and motor deficits in an animal model of Parkinson's disease. These findings provide insights into the functional importance of O-GlcNAcylation in the dopamine system, which may be utilized to protect dopamine neurons against Parkinson's disease pathology.


Experiences of caregivers of children with inherited metabolic diseases: a qualitative study.
We sought to understand the experiences of parents/caregivers of children with inherited metabolic diseases (IMD) in order to inform strategies for supporting patients and their families. We investigated their experiences regarding the management of disease, its impact on child and family life, and interactions with the health care system. From four Canadian centres, we conducted semi-structured telephone interviews with parents/caregivers of children with an IMD who were born between 2006 and 2015 and who were participating in a larger cohort study. Participants were selected with the aim of achieving a diverse sample with respect to treatment centre, IMD, and age of the child. Interviews emphasized the impacts of the disease and its treatment on the child and family and explicitly queried perceptions of interactions with the health care system. We identified emergent themes from the interview data. We completed interviews with 21 parents/caregivers. The 21 children were aged <1 to 7 years old with IMD that included amino acid disorders, urea cycle disorders, fatty acid oxidation disorders, and organic acid disorders or 'other' IMD. Most parents reported that they and their families had adapted well to their child's diagnosis. Parents used proactive coping strategies to integrate complex disease management protocols into routine family life. An important source of stress was concern about the social challenges faced by their children. Participants reported positive interactions with their most involved health care providers within the metabolic clinic. However, they reported challenges associated with the health care system outside of disease-specific metabolic care, when encountering systems and providers unfamiliar with the child's disease. The successful use of proactive coping strategies among parents of children with IMD in this study suggests the potential value of promoting positive coping and is an important direction for future study. Parents' social concerns for their children were important stressors that warrant consideration by health care providers positioned to support families. Our results with respect to experiences with care highlight the important role of specialized metabolic clinics and point to a need for better coordination of the care that takes place outside the disease-specific management of IMD.


Acute maternal infection and risk of pre-eclampsia: a population-based case-control study.
Infection in pregnancy may be involved in the aetiology of pre-eclampsia. However, a clear association between acute maternal infection and pre-eclampsia has not been established. We assessed whether acute urinary tract infection, respiratory tract infection, and antibiotic drug prescriptions in pregnancy (a likely proxy for maternal infection) are associated with an increased risk of pre-eclampsia. We used a matched nested case-control design and data from the UK General Practice Research Database to examine the association between maternal infection and pre-eclampsia. Primiparous women aged at least 13 years and registered with a participating practice between January 1987 and October 2007 were eligible for inclusion. We selected all cases of pre-eclampsia and a random sample of primiparous women without pre-eclampsia (controls). Cases (n=1533) were individually matched with up to ten controls (n=14236) on practice and year of delivery. We calculated odds ratios and 95% confidence intervals for pre-eclampsia comparing women exposed and unexposed to infection using multivariable conditional logistic regression. After adjusting for maternal age, pre-gestational hypertension, diabetes, renal disease and multifetal gestation, the odds of pre-eclampsia were increased in women prescribed antibiotic drugs (adjusted odds ratio 1.28;1.14-1.44) and in women with urinary tract infection (adjusted odds ratio 1.22;1.03-1.45). We found no association with maternal respiratory tract infection (adjusted odds ratio 0.91;0.72-1.16). Further adjustment for maternal smoking and pre-pregnancy body mass index made no difference to our findings. Women who acquire a urinary infection during pregnancy, but not those who have a respiratory infection, are at an increased risk of pre-eclampsia. Maternal antibiotic prescriptions are also associated with an increased risk. Further research is required to elucidate the underlying mechanism of this association and to determine whether, among women who acquire infections in pregnancy, prompt treatment or prophylaxis against infection might reduce the risk of pre-eclampsia.


Do patients consistently report comorbid conditions over time?: results from the prostate cancer outcomes study.
Comorbidity is an important dimension of patient health status. However, limited attention has been given to assessing the reliability of patient-reported data on comorbid conditions. We sought to evaluate the consistency of self-report of 12 comorbid conditions at 3 distinct time points and examine the sociodemographic, clinical, health status, and survey factors associated with reliability. We undertook a longitudinal cohort analysis of survey and medical record abstract data obtained from a population-based sample of 3095 prostate cancer survivors. Consistent and inconsistent response patterns were assessed using descriptive statistics and regression modeling. More than half of the cohort demonstrated consistent responses to all comorbid condition questionnaire items. Arthritis had the highest (13%) and liver disease the lowest (1%) proportion of inconsistent responses. Older age, lower income, and poorer general and mental health status were significant predictors of inconsistent responses. Subset analyses of the 4 most prevalent comorbid conditions (ie, arthritis, diabetes, hypertension, and depression) showed that respondents who reported that they were limited by, or taking prescription medicine for, the condition were more likely to provide consistent responses than those neither limited nor taking medicine. Response consistencies of 92% or better were obtained for 11 of the 12 conditions. Men with a relatively recent prostate cancer diagnosis are generally able to provide reliable reports of their concomitant health conditions. To increase the likelihood of obtaining reliable data, investigators should consider ascertaining condition severity and current medical management when querying subjects about comorbid conditions in surveys.


Ursodeoxycholic acid decreases age-related adiposity and inflammation in mice.
Ursodeoxycholic acid (UDCA), a natural, hydrophilic nontoxic bile acid, is clinically effective for treating cholestatic and chronic liver diseases. We investigated the chronic effects of UDCA on age-related lipid homeostasis and underlying molecular mechanisms. Twenty-week-old C57BL/6 male and female mice were fed a diet with or without 0.3% UDCA supplementation for 25 weeks. UDCA significantly reduced weight gain, adiposity, hepatic triglyceride, and hepatic cholesterol without incidental hepatic injury. UDCA-mediated hepatic triglyceride reduction was associated with downregulated hepatic expression of peroxisome proliferator-activated receptor-γ, and of other genes involved in lipogenesis (Chrebp, Acaca, Fasn, Scd1, and Me1) and fatty acid uptake (Ldlr, Cd36). The inflammatory cytokines Tnfa, Ccl2, and Il6 were significantly decreased in liver and/or white adipose tissues of UDCA-fed mice. These data suggest that UDCA exerts beneficial effects on age-related metabolic disorders by lowering the hepatic lipid accumulation, while concurrently reducing hepatocyte and adipocyte susceptibility to inflammatory stimuli. [BMB Reports 2016; 49(2): 105-110].


Invasive squamous-cell cervical carcinoma and combined oral contraceptives: results from a multinational study. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.
Data from a hospital-based case-control study collected in 11 participating centers in 9 countries were analyzed to determine whether use of combined oral contraceptives alters risk of invasive squamous-cell cervical cancer. Information on prior use of oral contraceptives, screening for cervical cancer, and suspected risk factors for this disease were ascertained from interviews of 2361 cases and 13,644 controls. A history of smoking and anal and genital warts was obtained, and blood specimens were collected for measurement of antibodies against herpes simplex and cytomegaloviruses, from selected sub-sets of these women, as was a sexual history from interviews of husbands. The relative risk of invasive squamous-cell cervical carcinoma was estimated to be 1.31, with a 95% confidence interval that excluded one, in women who ever used combined oral contraceptives. Risk of this disease increased significantly with duration of use after 4 to 5 years from first exposure, and declined with the passage of time after cessation of use to that of non-users in about 8 years. No sources of bias or confounding were identified that offered plausible explanations for these findings. The strength of these results, and their consistency with those from other studies, suggest that a causal relationship may exist between use of combined oral contraceptives and squamous-cell cervical carcinoma. Women who have used these products for 4 or more years, and who most recently used them within the past 8 years, should receive high priority for cervical cytologic screening.


Endocrine effects of examination stress.
1. We have studied endocrine function in nine healthy young men 16 weeks before and immediately after Final degree examinations. Factors other than psychological stress which might have affected hormone levels were excluded. 2. The presence of psychological stress at the time of examinations was confirmed by finding increased values for two self-rating anxiety scales. 3. Urine metadrenaline excretion was increased in all subjects at the time of examination. Serum and early morning urine cortisol as well as pituitary-testicular and pituitary-thyroid function and prolactin levels were unaffected by examination stress. 4. This study questions the popular belief that psychological stress stimulates prolactin secretion and suppresses pituitary-testicular function.


Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders.
Involvement of the olfactory bulb by Lewy-type alpha-synucleinopathy (LTS) is known to occur at an early stage of Parkinson's disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical alpha-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included alpha-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer's disease with LTS (ADLS), Alzheimer's disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the Unified Parkinson's Disease Rating Scale (Spearman R -0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.


Exploring activity levels in physical education lessons in the UK: a cross-sectional examination of activity types and fitness levels.
To establish pupil fitness levels, and the relationship to global norms and physical education (PE) enjoyment. To measure and describe physical activity (PA) levels during secondary school PE lessons, in the context of recommended levels, and how levels vary with activity and lesson type. A cross-sectional design; 10 697 pupils aged 12.5 (SD 0.30) years; pupils who completed a multistage fitness test and wore accelerometers to measure PA during PE lessons. Multilevel models estimated fitness and PE activity levels, accounting for school and class-level clustering. Cardiorespiratory fitness was higher in boys than girls (ß=-0.48; 95% CI -0.56 to -0.39, p<0.001), within absolute terms 51% of boys and 54% of girls above the 50th percentile of global norms. On average, pupils spent 23.8% of PE lessons in moderate-to-vigorous PA (MVPA), and 7.1% in vigorous PA (VPA). Fitness-focused lessons recorded most VPA in co-educational (ß=1.09; 95% CI 0.43 to 1.74) and boys-only lessons (ß=0.32; 95% CI -0.21 to 0.85). In girls-only lessons, track athletics recorded most VPA (ß=0.13; 95% CI -0.50 to 0.75) and net/wall/racket games (ß=0.97; 95% CI 0.12 to 1.82) the most MVPA. For all lesson types, field athletics was least active (ß=-0.85; 95% CI -1.33 to -0.36). There was a relationship of enjoyment of PE to fitness (ß=1.03; 95% CI 0.83 to 1.23), and this relationship did not vary with sex (ß=-0.14 to 0.23; 95% CI -0.16 to 0.60). PE lessons were inactive compared with current guidelines. We propose that if we are to continue to develop a range of sporting skills in schools at the same time as increasing levels of fitness and PA, there is a need to introduce additional sessions of PE activity focused on increasing physical activity. NCT03286725.


Murine cytomegalovirus infection causes apoptosis of uninfected retinal cells.
To determine the role of apoptosis in prevention and/or exacerbation of retinal disease in a mouse model of cytomegalovirus retinitis. Immunocompetent or T-cell- depleted BALB/c mice were injected with murine cytomegalovirus (MCMV) by supraciliary injection. On sequential days after infection, mice were killed, and eyes were harvested for cryosectioning or for DNA extraction. Ocular sections were stained with monoclonal antibodies specific for MCMV or for T cells or used in the TdT-dUTP terminal nick-end labeling (TUNEL) assay to detect apoptotic cells. In immunocompetent BALB/c mice, TUNEL assays revealed that a large area of the retina was apoptotic in relation to the relatively small number of MCMV-infected cells that were observed in the subjacent choroid and/or retinal pigment epithelium. In infected eyes from T-cell- depleted mice, there were more TUNEL-positive cells, and the areas of apoptosis were more extensive than in immunocompetent mice. These observations correlated with the increased extent of MCMV infection that is observed in the eyes of T-cell- depleted mice. However, irrespective of immune status, TUNEL-positive apoptotic cells were present mainly in areas of the retina overlying areas of MCMV-infected choroid and/or retinal pigment epithelium. More intense DNA laddering, indicative of increased apoptosis, was observed in the posterior segments of the eyes of T-cell- depleted mice after supraciliary inoculation with murine cytomegalovirus compared with less intense DNA laddering in the posterior segments of eyes of immunocompetent MCMV-infected mice. The ability of the mouse's immune system to control MCMV infections in some tissues depends on induction of apoptosis in virus-infected cells. However, in the retina, cells undergoing apoptosis were not virus-infected, a finding that suggests that apoptosis of uninfected retinal cells may play a role in the pathogenesis of MCMV retinitis.


Community treatment orders increase community care and delay readmission while in force: Results from a large population-based study.
There is debate about the effectiveness of community treatment orders in the management of people with a severe mental illness. While some case-control studies suggest community treatment orders reduce hospital readmissions, three randomised controlled trials find no effects. These randomised controlled trials measure outcomes over a longer period than the community treatment order duration and assess the combined effectiveness of community treatment orders both during and after the intervention. This study examines the effectiveness of community treatment orders in a large population-based sample, restricting observation to the period under a community treatment order. All persons ( n = 5548) receiving a community treatment order in New South Wales, Australia, over the period 2004-2009 were identified. Controls were matched using a propensity score based on demographic, clinical and prior care variables. A baseline period equal to each case's duration of treatment was constructed. Treatment effects were compared using zero-inflated negative binomial regression, adjusting for demographics, clinical characteristics and pre-community treatment order care. Compared to matched controls, people on community treatment orders were less likely to be readmitted (odds ratio = 0.90, 95% confidence interval = [0.84, 0.97]) and had a significantly longer time to their first readmission (incidence rate ratio = 1.47, 95% confidence interval = [1.36, 1.58]), fewer hospital admissions (incidence rate ratio = 0.90, 95% confidence interval = [0.84, 0.96]) and more days of community care (incidence rate ratio = 1.55, 95% confidence interval = [1.51, 1.59]). Increased community care and delayed first admission were found for all durations of community treatment order care. Reduced odds of readmission were limited to people with 6 months or less of community treatment order care, and reduced number of admissions and days in hospital to people with prolonged (>24 months) community treatment order care. In this large population-based study, community treatment orders increase community care and delay rehospitalisation while they are in operation. Some negative findings in this field may reflect the use of observation periods longer than the period of active intervention.


Guidelines for the prevention of intravascular catheter-related infections. Centers for Disease Control and Prevention.
These guidelines have been developed for practitioners who insert catheters and for persons responsible for surveillance and control of infections in hospital, outpatient, and home health-care settings. This report was prepared by a working group comprising members from professional organizations representing the disciplines of critical care medicine, infectious diseases, health-care infection control, surgery anesthesiology interventional radiology pulmonary medicine, pediatric medicine, and nursing. The working group was led by the Society of Critical Care Medicine (SCCM), in collaboration with the Infectious Disease Society of America (IDSA), Society for Healthcare Epidemiology ofAmerica (SHEA), Surgical Infection Society (SIS), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), American Society of Critical Care Anesthesiologists (ASCCA), Association for Professionals in Infection Control and Epidemiology (APIC), Infusion Nurses Society (INS), Oncology Nursing Society (ONS), Society of Cardiovascular and Interventional Radiology (SCVIR), American Academy of Pediatrics (AAP), and the Healthcare Infection Control Practices Advisory Committee (HICPAC) of the Centers for Disease Control and Prevention (CDC) and is intended to replace the Guideline for Prevention of Intravascular Device-Related Infections published in 1996 These guidelines are intended to provide evidence-based recommendations for preventing catheter-related infections. Major areas of emphasis include 1) educating and training health-care providers who insert and maintain catheters; 2) using maximal sterile barrier precautions during central venous catheter insertion; 3) using a 2% chlorhexidine preparation for skin antisepsis; 4) avoiding routine replacement of central venous catheters as a strategy to prevent infection; and 5) using antiseptic/antibiotic impregnated short-term central venous catheters if the rate of infection is high despite adherence to other strategies (i.e., education and training, maximal sterile barrier precautions, and 2% chlorhexidine for skin antisepsis). These guidelines also identify performance indicators that can be used locally by health-care institutions or organizations to monitor their success in implementing these evidence-based recommendations.


Temperature dependence of band gaps and conformational disorder in PEDOT and its selenium and tellurium derivatives: Density functional calculations.
The conducting polymer poly(3,4-ethylenedioxythiophene), or PEDOT, is an attractive material for flexible electronics. We present combined molecular dynamics and quantum chemical calculations, based on density functional theory, of EDOT oligomers and isoelectronic selenium and tellurium derivatives (EDOS and EDOTe) to address the effect of temperature on the geometrical and electronic properties of these systems. With finite size scaling, we also extrapolate our results to the infinite polymers, i.e., PEDOT, PEDOS, and PEDOTe. Our computations indicate that the most favourable oligomer conformations at finite temperature are conformations around the flat trans-conformation and a non-flat conformation around 45° from the cis-conformation. Also, the dihedral stiffness increases with the atomic number of the heteroatom. We find excellent agreement with experimentally measured gaps for PEDOT and PEDOS. For PEDOT, the gap does not increase with temperature, whereas this is the case for its derivatives. The conformational disorder and the choice of the basis set both significantly affect the calculated gaps.


Tumor targeting of functionalized quantum dot-liposome hybrids by intravenous administration.
A strategy to target functionalized quantum dot-liposome (f-QD-L) hybrid vesicles in the solid tumor tissue of tumor-bearing mice is explored. Functionalized polyethylene glycol (PEG)-lipid coated QD (f-QD) were encapsulated into the aqueous core of 100 nm cationic (DOPC:Chol: DOTAP); sterically stabilized, fluid-phase (DOPC:Chol:DSPE-PEG2000); and sterically stabilized, gel-phase (DSPC:Chol:DSPE-PEG2000) liposome vesicles. Double tracking of f-QD-L in blood was performed at different time points after intravenous administration in B16F10 melanoma tumor-bearing C57BL6 mice. Cholesteryl [-1-14C] oleate lipids probed the vesicle membrane were followed by liquid scintillation counting while QD were determined independently by elemental (Cd2+) analysis using inductively coupled plasma mass spectrometry (ICP-MS). Rapid blood clearance was observed following intravenous administration of the cationic hybrid vesicles, while incorporation of PEG at the surface of zwitterionic vesicles dramatically prolonged their blood circulation half-life after systemic administration. The "rigid" PEGylated f-QD-L (DSPC:Chol:DSPE-PEG2000) hybrid vesicles led to rapid tumor accumulation of peak values (approximately 5% of injected dose per gram tissue) of QD compared to long-circulating f-QD that accumulated in the tumor tissue at longer time points. More interestingly, this hybrid vesicle tumor retention persisted for at least 24 h. For almost all types of systems, a preferential cadmium uptake by liver and spleen was obtained. Overall, f-QD-L hybrid vesicles offer great potential for tumor imaging applications due to their rapid accumulation and prolonged retention within the tumor. Furthermore, f-QD-L offer many opportunities for the development of combinatory therapeutic and imaging (theranostic) modalities by incorporating both drug molecules and QD within the different compartments of a single vesicle.


[Application of vestibular rehabilitation with an introduction session in patients with chronic dizziness].
Pharmacological and non-pharmacological approaches are the treatment options for dizzy patients. Vestibular exercises are a potential treatment option for intractable dizzy patients who do not respond to conventional drug therapy. The retention rate of exercises is quite important for a successful outcome. We organized vestibular exercise courses to improve the retention rate in the outpatient groups; these courses comprised introduction sessions with a clinical psychologist and rehabilitation sessions with a clinical technologist. It is unclear whether the effects of vestibular rehabilitation are based on the improvement of the psychological parameters of vestibular function. Therefore, we evaluated the functional mechanism of vestibular rehabilitation by using questionnaires and balance function tests. Our study comprised 16 patients with chronic dizziness. The patients performing the self-administered home-based vestibular exercise courses were supervised in small groups. The patients were taught that the exercises were to be performed 4 times a day at their respective homes. The symptoms of dizziness were evaluated using the Japanese version of the dizziness handicap inventory (DHI). Anxiety and depression levels were assessed using a set of psychological questionnaires. The static and dynamic balance function was assessed using static posturography and foam posturography and by measuring the time required for performing a certain series of eye-head movement protocols at the initial visit, before rehabilitation, and 2 and 3 months after rehabilitation. Of 16 patients, 15 could successfully complete the study (93.8%). The DHI score significantly improved 1 month after the rehabilitation, whereas anxiety and depression levels did not improve. The results of static and foam posturography as well as the time required for the eye-head movements also significantly improved. The improvement in the DHI scores was not associated with psychological changes, but with the improvement in the static and dynamic balance function.


Mobile DNA elements in T4 and related phages.
Mobile genetic elements are common inhabitants of virtually every genome where they can exert profound influences on genome structure and function in addition to promoting their own spread within and between genomes. Phage T4 and related phage have long served as a model system for understanding the molecular mechanisms by which a certain class of mobile DNA, homing endonucleases, promote their spread. Homing endonucleases are site-specific DNA endonucleases that initiate mobility by introducing double-strand breaks at defined positions in genomes lacking the endonuclease gene, stimulating repair and recombination pathways that mobilize the endonuclease coding region. In phage T4, homing endonucleases were first discovered as encoded within the self-splicing td, nrdB and nrdD introns of T4. Genomic data has revealed that homing endonucleases are extremely widespread in T-even-like phage, as evidenced by the astounding fact that ~11% of the T4 genome encodes homing endonuclease genes, with most of them located outside of self-splicing introns. Detailed studies of the mobile td intron and its encoded endonuclease, I-TevI, have laid the foundation for genetic, biochemical and structural aspects that regulate the mobility process, and more recently have provided insights into regulation of homing endonuclease function. Here, we summarize the current state of knowledge regarding T4-encoded homing endonucleases, with particular emphasis on the td/I-TevI model system. We also discuss recent progress in the biology of free-standing endonucleases, and present areas of future research for this fascinating class of mobile genetic elements.


Interorganelle interactions and inheritance patterns of nuclei and vacuoles in budding yeast meiosis.
Many of the mechanisms by which organelles are inherited by spores during meiosis are not well understood. Dramatic chromosome motion and bouquet formation are evolutionarily conserved characteristics of meiotic chromosomes. The budding yeast bouquet genes (NDJ1, MPS3, CSM4) mediate these movements via telomere attachment to the nuclear envelope (NE). Here, we report that during meiosis the NE is in direct contact with vacuoles via nucleus-vacuole junctions (NVJs). We show that in meiosis NVJs are assembled through the interaction of the outer NE-protein Nvj1 and the vacuolar membrane protein Vac8. Notably, NVJs function as diffusion barriers that exclude the nuclear pore complexes, the bouquet protein Mps3 and NE-tethered telomeres from the outer nuclear membrane and nuclear ER, resulting in distorted NEs during early meiosis. An increase in NVJ area resulting from Nvj1-GFP overexpression produced a moderate bouquet mutant-like phenotype in wild-type cells. NVJs, as the vacuolar contact sites of the nucleus, were found to undergo scission alongside the NE during meiotic nuclear division. The zygotic NE and NVJs were partly segregated into 4 spores. Lastly, new NVJs were also revealed to be synthesized de novo to rejoin the zygotic NE with the newly synthesized vacuoles in the mature spores. In conclusion, our results revealed that budding yeast nuclei and vacuoles exhibit dynamic interorganelle interactions and different inheritance patterns in meiosis, and also suggested that nvj1Δ mutant cells may be useful to resolve the technical challenges pertaining to the isolation of intact nuclei for the biochemical study of meiotic nuclear proteins.


Quantitative and time-resolved nanoparticle composition measurements during new particle formation.
The chemical composition of 20 nm diameter particles was measured with the Nano Aerosol Mass Spectrometer (NAMS) in a rural/coastal environment during days when new particle formation (NPF) occurred and days when NPF did not occur. NAMS provides a quantitative measure of nanoparticle elemental composition with high time resolution. These measurements show that nanoparticle chemical composition is dynamic on both types of days and that changes in nanoparticle chemical composition do not necessarily correlate with changes in aerosol mass or number concentration. On NPF days, NAMS can distinguish between elements associated with particle formation and early mass growth from those associated with later mass growth. In the early stage of NPF, the particle phase sulphur mole fraction (S) increases simultaneously with the increase in gas phase sulphuric acid. This composition change occurs before the mode diameter has grown into the NAMS-measured size range and is quantitatively described by sulphuric acid condensation. The nitrogen mole fraction (N) also increases during this time period. The N/S mole ratio is approximately 2, indicating that particulate sulphate is fully neutralized. As the mode diameter passes into and through the NAMS-measured size range, N increases at a faster rate than S (N/S mole ratio increases above 2), indicating that a separate, nitrogen-based growth process exists, possibly involving aminium salts, inorganic nitrate and/or organonitrates. Carbonaceous matter is the most abundant component (-50% by mass) of the growing nanoparticles, but it is the inorganic species that are preferentially enhanced during NPF relative to other times of day. Concurrent measurements of cloud condensation nucleation activity during NPF events suggest that these newly formed particles are hygroscopic. Nanoparticle composition on non-NPF days also shifts toward a more inorganic composition during the daytime, but the chemical species are different from NPF days and the particles are less hygroscopic. Incorporation of S into growing nanoparticles is adequately explained by existing models, but currently no models exist to satisfactorily explain incorporation of nitrogen-containing species or carbonaceous matter.


Weakened Cholinergic Blockade of Inflammation Associates with Diabetes-Related Depression.
Emerging evidence demonstrates association of depression with both immune malfunctioning and worsened course of diverse aging-related diseases, but there is no explanation for the pathway(s) controlling this dual association. Here, we report that in post-reproductive and evolutionarily -blind" years, depression may weaken pathogen-host defense, compatible with the antagonistic pleiotropy hypothesis. In 15,532 healthy volunteers, depression scores associated with both inflammatory parameters and with increased circulation cholinesterase activities, implicating debilitated cholinergic blockade of inflammation as an underlying mechanism; furthermore, depression, inflammation and cholinesterase activities all increased with aging. In the entire cohort, combined increases in inflammation and the diabetic biomarker hemoglobin A1c associated with elevated depression. Moreover, metabolic syndrome patients with higher risk of diabetes showed increased cholinesterase levels and pulse values, and diabetic patients presented simultaneous increases in depression, inflammation and circulation cholinesterase activities, suggesting that cholinergic impairment precedes depression. Our findings indicate that dysfunctioning cholinergic regulation weakens the otherwise protective link between depression and pathogen-host defense, with global implications for aging-related diseases.


Pre-morbid IQ in mental disorders: a Danish draft-board study of 7486 psychiatric patients.
Longitudinal studies indicate that future schizophrenia patients exhibit lower IQ than healthy controls. Recent studies suggest that future patients with other mental illnesses obtain lower pre-morbid IQ. The aims of this study were to compare pre-morbid IQ among five diagnostic categories and normal controls, to examine the distribution of pre-morbid IQ, and to investigate the relationship between pre-morbid IQ and risk of mental illness. A total of 7486 individuals hospitalized with psychiatric disease and 20 531 controls. IQ was measured at the draft board and hospital diagnoses [schizophrenia (Sz), non-schizophrenic, non-affective psychoses (NSAP), affective (AD), personality (PD) and neurotic/stress disorders (ND)] were followed up to ages 43-54 years. Individuals hospitalized < or = 1 year after appearing before the draft board were excluded. All future patients obtained significantly lower pre-morbid IQ than controls (3-7 IQ points), AD had the highest IQ and PD the lowest. In each diagnostic category, decreasing IQ was associated with an increasing risk of becoming a patient [odds ratios (ORs) 0.5-2.5 over the full IQ spectrum]. IQ distributions was nearly normal and uni-modal. IQ deficits in each diagnostic category may reflect different functional patterns and temporal vicissitudes of the specific pathogenetic processes involved in different mental disorders.


Uptake of Nutri-Score during the first year of implementation in Belgium.
Front-of-pack (FOP) nutrition labeling has been recommended by the World Health Organization (WHO) as one of a suite of measures needed to improve population diets. The voluntary Nutri-Score FOP labeling system, which was first implemented in France, was approved for implementation in Belgium by the Minister of Public Health in August 2018 and has been officially adopted in Belgium since April 1st 2019. We assessed the uptake of Nutri-Score by food retailers and manufacturers during the first year of implementation in Belgium. In November-December 2019, pictures for 1781 products displaying Nutri-Score on the FOP were collected from the five biggest retailers, representing about 10% of products on the market in Belgium. About 90% of products displaying Nutri-Score on the FOP in 2019 were own-brand products from two major food retailers, while the few remainder were branded products. About 56% of products displayed Nutri-Score A or B while 26% of products displayed Nutri-Score D or E. During the first year of implementation, > 1700 food products displayed Nutri-Score on the FOP in Belgium. While the majority of those products were healthier foods (Nutri-Score A&B), about one quarter of less healthy products (Nutri-Score D&E) already displayed Nutri-Score as well. In the meantime, all five biggest retailers, including discounters, have committed to display Nutri-Score on the FOP from 2020 onwards, which may increase pressure on other food manufacturers to improve uptake of Nutri-Score for branded products.


Complications and risk factors for severe outcome in children with measles.
Risk factors for severe measles are poorly investigated in high-income countries. The Italian Society for Paediatric Infectious Diseases conducted a retrospective study in children hospitalised for measles from January 2016 to August 2017 to investigate the risk factors for severe outcome defined by the presence of long-lasting sequelae, need of intensive care or death. Nineteen hospitals enrolled 249 children (median age 14.5 months): 207 (83%) children developed a complication and 3 (1%) died. Neutropaenia was more commonly reported in children with B3-genotype compared with other genotypes (29.5% vs 7.7%, p=0.01). Pancreatitis (adjusted OR [aOR] 9.19, p=0.01) and encephalitis (aOR 7.02, p=0.04) were related to severe outcome in multivariable analysis, as well as C reactive protein (CRP) (aOR 1.1, p=0.028), the increase of which predicted severe outcome (area under the receiver operating characteristic curve 0.67, 95% CI 0.52 to 0.82). CRP values >2 mg/dL were related to higher risk of complications (OR 2.0, 95% CI 1.15 to 3.7, p=0.01) or severe outcome (OR 4.13, 95% CI 1.43 to 11.8, p<0.01). The risk of severe outcome in measles is independent of age and underlying conditions, but is related to the development of organ complications and may be predicted by CRP value.


Leucine-rich repeat kinase 2 exacerbates neuronal cytotoxicity through phosphorylation of histone deacetylase 3 and histone deacetylation.
Parkinson's disease (PD) is characterized by slow, progressive degeneration of dopaminergic neurons in the substantia nigra. The cause of neuronal death in PD is largely unknown, but several genetic loci, including leucine-rich repeat kinase 2 (LRRK2), have been identified. LRRK2 has guanosine triphosphatase (GTPase) and kinase activities, and mutations in LRRK2 are the major cause of autosomal-dominant familial PD. Histone deacetylases (HDACs) remove acetyl groups from lysine residues on histone tails, promoting transcriptional repression via condensation of chromatin. Here, we demonstrate that LRRK2 binds to and directly phosphorylates HDAC3 at Ser-424, thereby stimulating HDAC activity. Specifically, LRRK2 promoted the deacetylation of Lys-5 and Lys-12 on histone H4, causing repression of gene transcription. Moreover, LRRK2 stimulated nuclear translocation of HDAC3 via the phoshorylation of karyopherin subunit α2 and α6. HDAC3 phosphorylation and its nuclear translocation were increased in response to 6-hydroxydopamine (6-OHDA) treatment. LRRK2 also inhibited myocyte-specific enhancer factor 2D activity, which is required for neuronal survival. LRRK2 ultimately promoted 6-OHDA-induced cell death via positive modulation of HDAC3. These findings suggest that LRRK2 affects epigenetic histone modification and neuronal survival by facilitating HDAC3 activity and regulating its localization.


Manual Versus Robotic Catheter Ablation for the Treatment of Atrial Fibrillation: The Man and Machine Trial.
Circumferential pulmonary vein isolation (CPVI) using irrigated radiofrequency is the most frequently used ablation technique for the treatment of atrial fibrillation worldwide. To date, no large randomized multicenter trials have evaluated the efficacy and safety of CPVI using robotic navigation (RN) systems compared with the current gold standard of manual ablation (MN). In this prospective, international multicenter noninferiority trial, 258 patients with paroxysmal or persistent atrial fibrillation were randomized for CPVI using either RN (RN group, n = 131) or manual ablation (MN group, n = 127). In all patients, CPVI was performed using irrigated radiofrequency ablation in combination with a 3-dimensional mapping system. The primary endpoint was the absence of atrial arrhythmia recurrence on or off antiarrhythmic drugs during a 12-month follow-up period. Secondary endpoints were the evaluation of periprocedural complications and procedural data such as procedure time, fluoroscopy time, and incidence of esophageal injury. Baseline characteristics were comparable between the RN group and MN group. Procedure time was significantly shorter in the MN group (129.3 ± 43.1 min vs. 140.9 ± 36.5 min; p = 0.026). 247 patients completed the 12-month follow-up (RN group, n = 123; MN group, n = 124). Recurrence rate was comparable between the RN and MN groups (n = 29 of 123 [23.6%] vs. 25 of 124 [20.2%]). The incidence of procedure-related major complications did not differ significantly between ablation arms (RN group, n = 8 [6.1%] vs. MN group, n = 6 [4.7%]; p = 0.62). One patient from the RN group developed a fatal atrioesophageal fistula. This study demonstrated that robotic ablation is noninferior to the current gold standard of manual ablation for CPVI with respect to success and complication rates. Procedure times were significantly longer in the RN group. (Alster Man and Machine: Comparison of Manual and Mechanical Remote Robotic Catheter Ablation for Drug-Refractory Atrial Fibrillation; NCT00982475).


Blood pressure, lanthanum-, and norepinephrine-induced mechanical response in thoracic aortic tissue.
The responses of isolated thoracic aortic rings to 10(-5) M norepinephrine (NE) and 5 mM lanthanum chloride (La3+) were compared in tissues from 6- to 8-week-old and 12- to 16-week-old rats. Twelve strains of rats were selected: spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), genetically related outcross F1 and F2, backcross BC1(S) and BC1(W), and Wistar, SHR/Wistar, and Wistar/WKY crosses, Sprague-Dawley (SD), and also Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The La3+ response, expressed as the percentage of the maximal response to NE, demonstrated both age and blood pressure (BP) components in the SHR, WKY, F1, F2, and BC rats; however, when the La3+ response was expressed as mg force/mg tissue, no significant differences within these same groups were noted. The magnitude of the NE response in the same group of rats was inversely related to the BP of the 12- to 16-week-old animals (r = -0.45), and was not affected by treatment of the animal from conception with alpha-methyldopa. Aortic tissues from DS, but not DR or SD rats, demonstrated a response to La3+ which increased with the BP of the rat. This was not observed in prehypertensive DS rats and was prevented by the control of hypertension with either hydrochlorothiazide or MK-421 (a converting-enzyme inhibitor). We conclude that the reduced NE response in aortic tissues from SHR and related hypertensive rats reflects an inherent defect in the vascular smooth cell of the rat and is unaffected by BP control with antihypertensive drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)


Propionate metabolism in the rat heart by 13C n.m.r. spectroscopy.
High-resolution 13C n.m.r. spectroscopy has been used to examine propionate metabolism in the perfused rat heart. A number of tricarboxylic acid (TCA) cycle intermediates are observable by 13C n.m.r. in hearts perfused with mixtures of pyruvate and propionate. When the enriched 13C-labelled nucleus originates with pyruvate, the resonances of the intermediates appear as multiplets due to formation of multiply-enriched 13C-labelled isotopomers, whereas when the 13C-labelled nucleus originates with propionate, these same intermediates appear as singlets in the 13C spectrum since entry of propionate into the TCA cycle occurs via succinyl-CoA. An analysis of the isotopomer populations in hearts perfused with [3-13C]pyruvate plus unlabelled propionate indicates that about 27% of the total pyruvate pool available to the heart is derived directly from unlabelled propionate. This was substantiated by perfusing a heart for 2 h with [3-13C]propionate as the only available exogenous substrate. Under these conditions, all of the propionate consumed by the heart, as measured by conventional chemical analysis, ultimately entered the oxidative pathway as [2-13C] or [3-13C]pyruvate. This is consistent with entry of propionate into the TCA cycle intermediate pools as succinyl-CoA and concomitant disposal of malate to pyruvate via the malic enzyme. 13C resonances arising from enriched methylmalonate and propionylcarnitine are also detected in hearts perfused with [3-13C] or [1-13C]propionate which suggests that 13C n.m.r. may be useful as a non-invasive probe in vivo of metabolic abnormalities involving the propionate pathway, such as methylmalonic aciduria or propionic acidaemia.


Closing the gender gap in competitiveness through priming.
Men have been observed to have a greater willingness to compete compared to women, and it is possible that this contributes to gender differences in wages and career advancement. Policy interventions such as quotas are sometimes used to remedy this but these may cause unintended side-effects. Here, we present experimental evidence that a simple and practically costless tool-priming subjects with power-can close the gender gap in competitiveness. While in a neutral as well as in a low-power priming situation men are much more likely than women to choose competition, this gap vanishes when subjects are primed with a high-power situation. We show that priming with high power makes competition entry decisions more realistic and also that it reduces the level of risk tolerance among male participants, which can help explain why it leads to a closing down of the gender gap in competitiveness.


A dynamic model of some malaria-transmitting anopheline mosquitoes of the Afrotropical region. II. Validation of species distribution and seasonal variations.
The first part of this study aimed to develop a model for Anopheles gambiae s.l. with separate parametrization schemes for Anopheles gambiae s.s. and Anopheles arabiensis. The characterizations were constructed based on literature from the past decades. This part of the study is focusing on the model's ability to separate the mean state of the two species of the An. gambiae complex in Africa. The model is also evaluated with respect to capturing the temporal variability of An. arabiensis in Ethiopia. Before conclusions and guidance based on models can be made, models need to be validated. The model used in this paper is described in part one (Malaria Journal 2013, 12:28). For the validation of the model, a data base of 5,935 points on the presence of An. gambiae s.s. and An. arabiensis was constructed. An additional 992 points were collected on the presence An. gambiae s.l.. These data were used to assess if the model could recreate the spatial distribution of the two species. The dataset is made available in the public domain. This is followed by a case study from Madagascar where the model's ability to recreate the relative fraction of each species is investigated. In the last section the model's ability to reproduce the temporal variability of An. arabiensis in Ethiopia is tested. The model was compared with data from four papers, and one field survey covering two years. Overall, the model has a realistic representation of seasonal and year to year variability in mosquito densities in Ethiopia. The model is also able to describe the distribution of An. gambiae s.s. and An. arabiensis in sub-Saharan Africa. This implies this model can be used for seasonal and long term predictions of changes in the burden of malaria. Before models can be used to improving human health, or guide which interventions are to be applied where, there is a need to understand the system of interest. Validation is an important part of this process. It is also found that one of the main mechanisms separating An. gambiae s.s. and An. arabiensis is the availability of hosts; humans and cattle. Climate play a secondary, but still important, role.


Grxcr1 Promotes Hair Bundle Development by Destabilizing the Physical Interaction between Harmonin and Sans Usher Syndrome Proteins.
Morphogenesis and mechanoelectrical transduction of the hair cell mechanoreceptor depend on the correct assembly of Usher syndrome (USH) proteins into highly organized macromolecular complexes. Defects in these proteins lead to deafness and vestibular areflexia in USH patients. Mutations in a non-USH protein, glutaredoxin domain-containing cysteine-rich 1 (GRXCR1), cause non-syndromic sensorineural deafness. To understand the deglutathionylating enzyme function of GRXCR1 in deafness, we generated two grxcr1 zebrafish mutant alleles. We found that hair bundles are thinner in homozygous grxcr1 mutants, similar to the USH1 mutants ush1c (Harmonin) and ush1ga (Sans). In vitro assays showed that glutathionylation promotes the interaction between Ush1c and Ush1ga and that Grxcr1 regulates mechanoreceptor development by preventing physical interaction between these proteins without affecting the assembly of another USH1 protein complex, the Ush1c-Cadherin23-Myosin7aa tripartite complex. By elucidating the molecular mechanism through which Grxcr1 functions, we also identify a mechanism that dynamically regulates the formation of Usher protein complexes.


Biological activity of interleukin-2 bound to Candida albicans.
The lymphokine interleukin-2 (IL-2), which is necessary for the generation of an optimal cell-mediated immune response, has recently been shown to have lectinlike properties, with specificity for high-mannose groups. Therefore, the ability of IL-2 to bind to the mannose-rich fungus Candida albicans was examined. Heat-killed fungi preincubated with IL-2 stimulated, in a dose-dependent manner, proliferation of the IL-2-dependent cell line CTLL20. Soluble mannan, which is rich in exposed mannose groups, inhibited binding of IL-2 to C. albicans by approximately 60%, suggesting that the lectinlike properties of IL-2 are partially responsible for its fungal binding capacity. Binding of IL-2 to fungi appeared to be reversible, as C. albicans preincubated with IL-2 stimulated CTLL20 proliferation even when the fungi and cells were separated by an 0.4-microns-pore-size membrane. The lymphoproliferative response of normal human peripheral blood mononuclear cells to C. albicans was augmented when the fungus was preincubated with IL-2. Binding of 125I-IL-2 could not be inhibited by unlabeled IL-2, suggesting the absence of high-affinity receptors on C. albicans for IL-2. While the in vivo relevance remains to be determined, these data demonstrate that IL-2 can bind to C. albicans in vitro and thereby influence the host response to this medically important fungus.


A Stat3-interacting protein (StIP1) regulates cytokine signal transduction.
Genetic and biochemical studies have led to the identification of the Stat3-Interacting Protein StIP1. The preferential association of StIP1 with inactive (i.e., unphosphorylated) Stat3 suggests that it may contribute to the regulation of Stat3 activation. Consistent with this possibility, StIP1 also exhibits an affinity for members of the Janus kinase family. Overexpression of the Stat3-binding domain of StIP1 blocks Stat3 activation, nuclear translocation, and Stat3-dependent induction of a reporter gene. These studies indicate that StIP1 regulates the ligand-dependent activation of Stat3, potentially by serving as a scaffold protein that promotes the interaction between Janus kinases and their Stat3 substrate. The ability of StIP1 to associate with several additional members of the signal transducer and activator of transcription family suggests that StIP1 may serve a broader role in cytokine-signaling events.


Experimental systemic amyloidosis induced by immunization with syngeneic organ extracts in mice.
Systemic amyloidosis was induced consistently in mice by intramuscular injection of syngeneic organ (liver and kidney) extracts mixed with CFA six times at weekly intervals. Syngeneic organ extract with CFA also induced amyloidosis of a lesser degree. All three strains of mice (C57BL/6, C3H/He, and BALB/c) injected with a syngeneic liver extract mixed with CFA developed systemic amyloidosis; the most prominent amyloid deposition occurred in C57BL/6 (B6) mice, followed by C3H/He and BALB/c. The amyloid substance deposited in these animals was identified as mouse amyloid A protein (AA). Furthermore, an organ specificity of the immunogen in inducing amyloidosis was suggested with liver and kidney extracts. Primed spleen cells of the immunized B6 mice were fractionated by a nylon-wool column and injected to normal recipient mice via the tail vein. Organs of the recipient mice developed systemic amyloidosis 8 wk after the transfer, and the most prominent histological changes occurred in the recipient mice given nylon-wool column adherent spleen cells. Using anti-Thy-1,2; Ly-1; Ly-2, antibody and complement, it was suggested that T cells, especially Ly-1,2,3+ T cell populations in the primed nylon-wool adherent cells, play an important role in the induction of systemic amyloidosis. It was shown further that the amyloidosis-inducing substance in liver extract was composed of unstable proteins or protein-bound substance.


Specific harm reduction strategies employed by 3,4-methylenedioxymethamphetmine/ ecstasy users in the United States and the United Kingdom.
Both recreational and problematic MDMA/ecstasy users could benefit from employing harm reduction interventions intended to preserve health and prevent negative consequences. To evaluate whether use of such interventions varied by country of residence and frequency of ecstasy use, we used web-based surveys to assess how often 104 lower-frequency and higher-frequency American ecstasy users and 80 lower-frequency and higher-frequency British ecstasy users employed each of 19 self-initiated harm reduction strategies when they used ecstasy during a two-month period. Several significant differences notwithstanding, at least 75% of participants had used 11 of the 19 strategies one or more times during the two-month assessment period, regardless of whether they lived in the United States or United Kingdom and whether they were lower-frequency or higher-frequency ecstasy users. When proportions of American and British participants using a strategy differed significantly, it was typically larger proportions of Americans using those strategies. Many of the less frequently employed strategies are not applicable on every occasion of ecstasy use. However, because ecstasy is not a diverted pharmaceutical of known quality/potency, testing for the presence of MDMA, other stimulants, and adulterants is a strategy that everyone should employ, regardless of country of residence or how frequently one consumes ecstasy.


Working effectively with clients who self-injure using a solution focused approach.
In Australia, the most common service used by self-injurers is the emergency department. Even though nurses are the key clinician available to such patients, nurses have usually received no special training to identify and address the needs of these clients. Building on the knowledge that emergency nurses feel ill-prepared, lack clear frameworks for practice and are thus vulnerable to subtle discourse tensions such as managing versus caring, and diagnosing versus understanding, an intervention was conducted and evaluated to enhance understanding and build proactive nursing skills. It was centred on a nursing philosophy known as solution focused nursing (SFN) - a model of care developed by author to orient care away from a deficit model. Deficit models tend to be reactive and centred on presenting problems. SFN is designed to move nurses' perspective towards a proactive, strengths orientation, the aim of which is to assist them to instill hope in the client and motivate him/her to take the next steps needed for change and recovery. Nurses in two Australian emergency departments completed questionnaires before and after participating in SFN training focused on working with complex clients who self-harm. A comparison group of nurses also completed questionnaires. Results indicated some benefits of the intervention; there were improvements in participants' perception that nursing is strengths oriented and in nurses' satisfaction with their skills. Yet, there were no significant improvement in nurses' reports of their professional self-concept. There is merit in: broadening access to the intervention, so that more nurses in other contexts can learn a strengths model of care and apply it to their practice; and extending the research to measure sustained learning outcomes and improvements to practice.


Experimental evolution of bet hedging under manipulated environmental uncertainty in Neurospora crassa.
All organisms are faced with environmental uncertainty. Bet-hedging theory expects unpredictable selection to result in the evolution of traits that maximize the geometric-mean fitness even though such traits appear to be detrimental over the shorter term. Despite the centrality of fitness measures to evolutionary analysis, no direct test of the geometric-mean fitness principle exists. Here, we directly distinguish between predictions of competing fitness maximization principles by testing Cohen's 1966 classic bet-hedging model using the fungus Neurospora crassa. The simple prediction is that propagule dormancy will evolve in proportion to the frequency of 'bad' years, whereas the prediction of the alternative arithmetic-mean principle is the evolution of zero dormancy as long as the expectation of a bad year is less than 0.5. Ascospore dormancy fraction in N. crassa was allowed to evolve under five experimental selection regimes that differed in the frequency of unpredictable 'bad years'. Results were consistent with bet-hedging theory: final dormancy fraction in 12 genetic lineages across 88 independently evolving samples was proportional to the frequency of bad years, and evolved both upwards and downwards as predicted from a range of starting dormancy fractions. These findings suggest that selection results in adaptation to variable rather than to expected environments.


Altitudinal distribution and body resource allocation in a high mountain social wasp (Hymenoptera: Vespidae).
Jame's rule proposes a direct relationship between body size and altitude. There are several studies about this rule; however, few studies analyze proportional changes in body parts along gradients. The morphological variation of Agelaia pallipes (Olivier) in five sites along an altitudinal gradient (2600-3380 m) in the Santuario de Iguaque, Colombia, were studied in order to test whether or not the species follows Jame's rule, and whether body parts follow a homogeneous variation. Body variation analysis was conducted through multivariate analysis of variance (MANOVA) and the relationship between altitude and each morphometric measurement was studied through regression analyses. The MANOVA indicated significant differences among sites. An increase in altitude leads to a reduction in body size, especially in hind femur length and head width. However, measurements linked to flight such as mesosoma height, mesoscutum width, and fore wing size showed a reverse tendency. Possibly all described changes are consequence of both reduction on food availability and lower atmospheric pressure. The low temperature of high areas may strongly limit foraging and thus food availability. Lower atmospheric pressure reduces flight potential and may result in an increase in size of both wings and flight muscles. This paper underscores the need to study in detail the changes in body proportions in species with wide distribution ranges in latitude and altitude.


Recorded Mental Health Recovery Narratives as a Resource for People Affected by Mental Health Problems: Development of the Narrative Experiences Online (NEON) Intervention.
The internet enables sharing of narratives about health concerns on a substantial scale, and some digital health narratives have been integrated into digital health interventions. Narratives describing recovery from health problems are a focus of research, including those presented in recorded (eg, invariant) form. No clinical trial has been conducted on a web-based intervention providing access to a collection of Recorded Recovery Narratives (RRNs). This study presents knowledge produced through the development of the Narrative Experiences Online (NEON) Intervention, a web-based intervention incorporating the algorithmic recommendation of RRNs. Knowledge was gathered through knowledge integration (KI) activities. KI1 synthesized previous studies to produce the NEON Impact Model describing how accessing RRNs produces health-related outcomes. KI2 developed curation principles for the NEON Collection of RRNs through consultation with the NEON Lived Experience Advisory Panel and the curation of a preliminary collection. KI3 identified harm minimization strategies for the NEON Intervention through consultation with the NEON International Advisory Board and Lived Experience Advisory Panel. The NEON Intervention was finalized through 2 research studies (RS). In RS1, mental health service users (N=40) rated the immediate impact of randomly presented narratives to validate narrative feedback questions used to inform the recommendation algorithm. In RS2, mental health service users (n=25) were interviewed about their immediate response to a prototype of the NEON Intervention and trial procedures and then were interviewed again after 1 month of use. The usability and acceptability of the prototype and trial procedures were evaluated and refinements were made. KI1 produced the NEON Impact Model, which identifies moderators (recipient and context), mechanisms of connection (reflection, comparison, learning, and empathy), processes (identification of change from narrative structure or content and internalization of observed change), and outcomes (helpful and unhelpful). KI2 identified 22 curation principles, including a mission to build a large, heterogeneous collection to maximize opportunities for connection. KI3 identified seven harm minimization strategies, including content warnings, proactive and reactive blocking of narratives, and providing resources for the self-management of emotional distress. RS1 found variation in the impact of narratives on different participants, indicating that participant-level feedback on individual narratives is needed to inform a recommender system. The order of presentation did not predict narrative feedback. RS2 identified amendments to web-based trial procedures and the NEON Intervention. Participants accessed some narratives multiple times, use reduced over the 4-week period, and narrative feedback was provided for 31.8% (105/330) of narrative accesses. RRNs can be integrated into web-based interventions. Evaluating the NEON Intervention in a clinical trial is feasible. The mixed methods design for developing the NEON Intervention can guide its extension to other clinical populations, the design of other web-based mental health interventions, and the development of narrative-based interventions in mental health.


The effect of light regimen and melatonin on the development of spontaneous mammary tumors in HER-2/neu transgenic mice is related to a downregulation of HER-2/neu gene expression.
The effect and the mechanism of light regimen and melatonin on the development of mammary tumors in HER2/neu transgenic mice were investigated. Female HER-2/neu mice starting from the age of 2 months were kept under standard light/dark regimen (LD) or constant light illumination (LL) and a part of each group was given melatonin (20 mg/l) during the night time. The exposure to LL failed to change the incidence of spontaneous mammary adenocarcinoma development, the size of mammary tumors, as well as the incidence and size of lung metastases. However, the number of tumors per mouse was significantly increased in the LL group as compared to the LD group. The number of mice bearing 4 and more tumors was higher in the LL group than in the LD group, whereas the number of mice bearing 1 to 3 tumors was lower in the LL group in comparison with the LD group. Melatonin decreased the incidence and size of mammary adenocarcinomas, and the incidence of lung metastases in the LD group but not in the LL group. The mean number of tumors per mouse was not changed by melatonin treatment in both light regimens. The number of mice bearing 4 and more tumors was reduced by melatonin more significantly in the LL group than in LD group. Melatonin treatment resulted in a 2.5-fold reduction in the expression of HER-2/neu mRNA in mammary tumors from HER-2 /neu transgenic mice. The data demonstrate the influence of the LD light regiment and melatonin treatment in the development of spontaneous mammary tumors in HER-2/neu mice suggesting a melatonin-dependent modulation of HER-2/neu gene expression in mammary adenocarcinoma.


Deep Learning for Accelerometric Data Assessment and Ataxic Gait Monitoring.
Ataxic gait monitoring and assessment of neurological disorders belong to important multidisciplinary areas that are supported by digital signal processing methods and machine learning tools. This paper presents the possibility of using accelerometric data to optimise deep learning convolutional neural network systems to distinguish between ataxic and normal gait. The experimental dataset includes 860 signal segments of 16 ataxic patients and 19 individuals from the control set with the mean age of 38.6 and 39.6 years, respectively. The proposed methodology is based upon the analysis of frequency components of accelerometric signals simultaneously recorded at specific body positions with a sampling frequency of 60 Hz. The deep learning system uses all of the frequency components in a range of 〈0,30 〉 Hz. Our classification results are compared with those obtained by standard methods, which include the support vector machine, Bayesian methods, and the two-layer neural network with features estimated as the relative power in selected frequency bands. Our results show that the appropriate selection of sensor positions can increase the accuracy from 81.2% for the foot position to 91.7% for the spine position. Combining the input data and the deep learning methodology with five layers increased the accuracy to 95.8%. Our methodology suggests that artificial intelligence methods and deep learning are efficient methods in the assessment of motion disorders and they have a wide range of further applications.


Proteomic analysis of laser microdissected melanoma cells from skin organ cultures.
Gaining insights into the molecular events that govern the progression from melanoma in situ to advanced melanoma and understanding how the local microenvironment at the melanoma site influences this progression are two clinically pivotal aspects that to date are largely unexplored. In an effort to identify key regulators of the crosstalk between melanoma cells and the melanoma-skin microenvironment, primary and metastatic human melanoma cells were seeded into skin organ cultures (SOCs) and grown for two weeks. Melanoma cells were recovered from SOCs by laser microdissection and whole-cell tryptic digests were analyzed by nanoflow liquid chromatography-tandem mass spectrometry. The differential protein abundances were calculated by spectral counting, the results of which provides evidence that cell-matrix and cell-adhesion molecules that are upregulated in the presence of these melanoma cells recapitulate proteomic data obtained from comparative analysis of human biopsies of invasive melanoma and a tissue sample of adjacent, noninvolved skin. This concordance demonstrates the value of SOCs for conducting proteomic investigations of the melanoma microenvironment.


Optical Control of Dopamine Receptors Using a Photoswitchable Tethered Inverse Agonist.
Family A G protein-coupled receptors (GPCRs) control diverse biological processes and are of great clinical relevance. Their archetype rhodopsin becomes naturally light sensitive by binding covalently to the photoswitchable tethered ligand (PTL) retinal. Other GPCRs, however, neither bind covalently to ligands nor are light sensitive. We sought to impart the logic of rhodopsin to light-insensitive Family A GPCRs in order to enable their remote control in a receptor-specific, cell-type-specific, and spatiotemporally precise manner. Dopamine receptors (DARs) are of particular interest for their roles in motor coordination, appetitive, and aversive behavior, as well as neuropsychiatric disorders such as Parkinson's disease, schizophrenia, mood disorders, and addiction. Using an azobenzene derivative of the well-known DAR ligand 2-(N-phenethyl-N-propyl)amino-5-hydroxytetralin (PPHT), we were able to rapidly, reversibly, and selectively block dopamine D1 and D2 receptors (D1R and D2R) when the PTL was conjugated to an engineered cysteine near the dopamine binding site. Depending on the site of tethering, the ligand behaved as either a photoswitchable tethered neutral antagonist or inverse agonist. Our results indicate that DARs can be chemically engineered for selective remote control by light and provide a template for precision control of Family A GPCRs.


Managing water to protect fish: a review of California's Environmental Water Account, 2001-2005.
The Sacramento-San Joaquin Delta, the landward reach of the San Francisco Estuary, provides habitat for threatened delta smelt, endangered winter-run Chinook salmon, and other species of concern. It is also the location of huge freshwater diversion facilities that entrain large numbers of fish. Reducing the entrainment of listed fishes into these facilities has required curtailment of pumping, reducing the reliability of water deliveries. We reviewed the first 5 years (2001-2005) of the Environmental Water Account (EWA), a program instituted to resolve conflicts between protecting listed fishes and providing a reliable water supply. The EWA provided fishery agencies with control over 0.2-0.4 km(3) of water to be used for fish protection at no cost to users of exported water, and fish agencies guaranteed no disruption of water supply for fish protection. The EWA was successful in reducing uncertainty in water supply; however, its contribution to the recovery of listed fishes was unclear. We estimated the effectiveness of the EWA to be modest, increasing the survival of winter-run Chinook salmon by 0-6% (dependent on prescreen mortality), adult delta smelt by 0-1%, and juvenile delta smelt by 2-4%. Allocating EWA water for a single life stage of one species could provide larger gains in survival. An optimally allocated EWA of equal size to the median of the first 5 years could increase abundance of juvenile delta smelt up to 7% in the springs of dry years. If the EWA is to become a long-term program, estimates of efficacy should be refined. If the program is to be held accountable for quantitative increases in fish populations, it will be necessary to integrate scientific, possibly experimental, approaches.


Nonadditivity Analysis.
We introduce the statistics behind a novel type of SAR analysis named "nonadditivity analysis". On the basis of all pairs of matched pairs within a given data set, the approach analyzes whether the same transformations between related molecules have the same effect, i.e., whether they are additive. Assuming that the experimental uncertainty is normally distributed, the additivities can be analyzed with statistical rigor and sets of compounds can be found that show significant nonadditivity. Nonadditivity analysis can not only detect nonadditivity, potential SAR outliers, and sets of key compounds but also allow estimating an upper limit of the experimental uncertainty in the data set. We demonstrate how complex SAR features that inform medicinal chemistry can be found in large SAR data sets. Finally, we show how the upper limit of experimental uncertainty for a given biochemical assay can be estimated without the need for repeated measurements of the same protein-ligand system.


Efficacy of hydroxypropyl cellulose ophthalmic inserts (LACRISERT) in subsets of patients with dry eye syndrome: findings from a patient registry.
To determine acceptability and efficacy of hydroxypropyl cellulose ophthalmic inserts in patients with dry eye syndrome (DES) and additional comorbidities. A multicenter, 2-visit, open-label, 4-week registry study. Five hundred twenty patients were recruited to the intent-to-treat group. Four hundred eighteen patients completed the study including 86 contact lens wearers, 79 with cataract diagnosis, 52 with prior cataract surgery, 22 with prior laser-assisted in situ keratomileusis, and 15 with glaucoma. Patient questionnaires were completed at baseline and after 4 weeks of treatment to assess mean change in severity of DES symptoms, ocular surface disease index (OSDI) scores, frequency of occurrence of DES symptoms, occurrence of difficulty when performing activities of daily living (ADLs), and frequency of discomfort in various environmental conditions. Mean change was measured from visit 1 to visit 2. Symptoms, OSDI scores, and measure of degree of difficulty when performing ADLs. Four hundred eighteen patients completed the study. Compared with baseline, this population of patients demonstrated statistically significant improvements in mean OSDI scores (P = 0.0215) and symptoms of discomfort, burning, dryness, grittiness, stinging, and light sensitivity (P < 0.05). Mean improvement in OSDI scores of patients in the 5 identified subsets of patients with comorbid conditions were significant for patients using contact lenses (P < 0.025), who had undergone prior cataract surgery (P < 0.04), and with prior laser-assisted in situ keratomileusis surgery (P < 0.05). Patients diagnosed with cataracts or glaucoma did not show significant changes in any measures in this study. Patients with DES and comorbid conditions experienced relief of symptoms and benefit to ADLs and quality of life similar to patients without comorbid conditions. In subsets of patients with moderate to severe DES and comorbid conditions, hydroxypropyl cellulose ophthalmic inserts improve the symptoms of DES, ability to perform ADLs, and quality of life. The reported benefits may be additive to those seen with patients' existing therapies.


Daylio: mood-quantification for a less stressful you.
Moods are emotional states that can last from short to long periods of times. However, if moods are negative for long durations, people's quality of life can deteriorate significantly. Daylio is a simple, easy to use mobile application that can help people track their moods and activities to identify triggers to disorders.


Bridging a yawning chasm: EEG investigations into the debate concerning the role of the human mirror neuron system in contagious yawning.
Ongoing debate in the literature concerns whether there is a link between contagious yawning and the human mirror neuron system (hMNS). One way of examining this issue is with the use of the electroencephalogram (EEG) to measure changes in mu activation during the observation of yawns. Mu oscillations are seen in the alpha bandwidth of the EEG (8-12 Hz) over sensorimotor areas. Previous work has shown that mu suppression is a useful index of hMNS activation and is sensitive to individual differences in empathy. In two experiments, we presented participants with videos of either people yawning or control stimuli. We found greater mu suppression for yawns than for controls over right motor and premotor areas, particularly for those scoring higher on traits of empathy. In a third experiment, auditory recordings of yawns were compared against electronically scrambled versions of the same yawns. We observed greater mu suppression for yawns than for the controls over right lateral premotor areas. Again, these findings were driven by those scoring highly on empathy. The results from these experiments support the notion that the hMNS is involved in contagious yawning, emphasise the link between contagious yawning and empathy, and stress the importance of good control stimuli.


Factors controlling the spread of HIV in heterosexual communities in developing countries: patterns of mixing between different age and sexual activity classes.
The paper describes the development and analysis of a mathematical model of the spread and demographic impact of HIV in heterosexual communities in developing countries. The model extends previous work in this area by the representation of patterns of mixing between and within different age and sexual activity classes in a two sex structure. Summary parameters are derived to represent different mixing patterns, ranging from assortative via random to disassortative, as are methods to ensure that particular mixing patterns between different age and sexual classes (stratified on the basis of rates of sexual partner change) meet constraints that balance the supply and demand for sexual partners as AIDS induced mortality influences the demographic structure of a population. Analyses of model behaviour rely on numerical methods due to the complexity of the mathematical framework, and sensitivity analyses are conducted to assess the significance of different assumptions and different parameter assignments. Simulated patterns of HIV spread across the two sexes and various age classes are compared with observed patterns in Uganda. The principle conclusion of the study is that the pattern of mixing between age and sexual activity classes, combined with the assumptions made to balance supply and demand between the sexes have a very major influence on the predicted pattern of HIV spread and the demographic impact of AIDS. The paper ends with a discussion of future needs in model development and data acquisition.


Predictors of 16-year mortality among individuals initiating help-seeking for an alcoholic use disorder.
We examined rates and predictors of mortality in individuals (47% women) who had just initiated help-seeking for their alcohol use disorders (AUDs) at the start of the study (n=628) and were followed for 16 years. For both women and men, the observed-to-expected mortality ratio (1.4) was lower than rates found in samples of treated individuals with AUDs, suggesting that those initiating help-seeking careers have better chances of long-term survival. Of the individuals for whom cause of death was known, 68% died of alcohol-related causes. Men were more likely to die than were women. When gender was controlled, individuals who were older and unmarried and had more alcohol dependence symptoms at baseline were more likely to die over the 16-year period. When these baseline characteristics were controlled, better drinking outcomes at 1 year were associated with a lower likelihood of subsequent death. The combination of a shorter duration of inpatient/residential care and better drinking outcomes at 1 year was related to a lower probability of death, as was the combination of a longer duration of outpatient care or Alcoholics Anonymous attendance and better drinking outcomes at 1 year. Efforts should be made to help providers identify individuals who are not responding positively to inpatient or residential treatment and intervene to motivate participation in continuing outpatient care and community 12-step self-help groups to reduce the likelihood of a chronic and fatal AUD course.


Testing a social-cognitive model of intimate abusiveness among substance-dependent males.
Throughout history, the human race has been characterized by the use of physical and emotional aggression by individuals, particularly males, in their intimate relationships. Intimate abusiveness is particularly common among substance-dependent males. As a result of male intimate abusiveness, victims suffer a variety of problems, ranging from emotional trauma to death due to physical injury. Despite increased attention to this problem, our understanding of the process leading to intimate abusiveness is far from comprehensive. The primary purpose of the present study was to expand our understanding of intimate abusiveness through the application of a social-cognitive model of intimate abusiveness among substance-dependent males. Participants were 57 males from an inpatient substance abuse treatment program. Subjects completed questionnaires indicating their level of intimate abusiveness. In addition, they completed partner-related attribution measures, as well as coping response measures indicating how they would interpret and handle five ambiguous vignettes involving their partner. It was hypothesized that violent men would attribute greater negative intent and responsibility to their partner, and that they would choose to handle the ambiguous vignettes in less competent ways compared with nonviolent men. Further, it was predicted that the association between intimate abusiveness and competency of coping responses would be mediated by attributions made about the partner. Results of the study generally supported predictions. The implications of the results are discussed, and suggestions are made for future research.


Multiplexed Detection of Epigenetic Markers Using Quantum Dot (QD)-Encoded Hydrogel Microparticles.
Epigenetic alterations in gene expression are influenced by experiences and environment, resulting in significant variation of epigenetic markers from individual to individual. Therefore, it is imperative to measure various epigenetic markers simultaneously from samples of individual subjects to accurately analyze the epigenetic markers in biological samples. Moreover, the individualized genome-wide analysis has become a critical technology for recent trends in clinical applications such as early diagnosis and personalized medicine screening of numerous diseases. The array-based detection of modified histones, conventionally used for multiplexed analysis of epigenetic changes, requires pooling of samples from many subjects to analyze population-wise differences in the expression of histone markers and does not permit individualized analysis. Here, we report multiplexed detection of genome-wide changes in various histone modifications at a single-residue resolution using quantum dot (QD)-encoded polyethylene glycol diacrylate (PEGDA) hydrogel microparticles. To demonstrate the potential of our methodology, we present the simultaneous detection of (1) acetylation of lysine 9 of histone 3 (Ac-H3K9), (2) dimethylation of H3K9 (2Me-H3K9), and (3) trimethylation of H3K9 (3Me-H3K9) from three distinct regions in the brain [nucleus accumbens (NAc), dorsal striatum (DSt), and cerebellum (Cbl)] of cocaine-exposed mice. Our hydrogel-based epigenetic assay enabled relative quantification of the three histone variants from only 10 μL of each brain lysate (protein content = ∼ 1 μg/μL) per mouse. We verified that the exposure to cocaine induced a significant increase of acetylation while a notable decrease in methylation in NAc.


Identification and Description of the Key Molecular Components of the Egg Strings of the Salmon Louse (Lepeophtheirus salmonis).
The salmon louse Lepeophtheirus salmonis is a parasite of Atlantic salmon and other salmonids. Every year, it causes high costs for the Norwegian aquaculture industry. While the morphology of the female genital tract has been described, knowledge of the molecular basis of reproduction is very limited. We identified nine genes which are expressed exclusively in the female cement gland, the organ responsible for cement production, which is used to hold the eggs together and keep them attached to their mother in egg strings. Six of these genes encode proteins with signal peptides and probably form the main component of the cement. Two other genes are peroxidases, which are probably important in the cement formation. The last gene is not similar to any known protein, but contains a transmembrane domain. A knockdown of all these genes leads to missing or deformed egg strings, preventing reproduction of the lice. The correct assemblage of the cement in the cement gland is essential for successful reproduction of salmon lice. Similar proteins seem to be present in other copepod species, as well.


The Gcd10p/Gcd14p complex is the essential two-subunit tRNA(1-methyladenosine) methyltransferase of Saccharomyces cerevisiae.
The modified nucleoside 1-methyladenosine (m(1)A) is found at position 58 in the TPsiC loop of many eukaryotic tRNAs. The absence of m(1)A from all tRNAs in Saccharomyces cerevisiae mutants lacking Gcd10p elicits severe defects in processing and stability of initiator methionine tRNA (tRNA(i)(Met)). Gcd10p is found in a complex with Gcd14p, which contains conserved motifs for binding S-adenosylmethionine (AdoMet). These facts, plus our demonstration that gcd14Delta cells lacked m(1)A, strongly suggested that Gcd10p/Gcd14p complex is the yeast tRNA(m(1)A)methyltransferase [(m(1)A)MTase]. Supporting this prediction, affinity-purified Gcd10p/Gcd14p complexes used AdoMet as a methyl donor to synthesize m(1)A in either total tRNA or purified tRNA(i)(Met) lacking only this modification. Kinetic analysis of the purified complex revealed K(M) values for AdoMet or tRNA(i)(Met) of 5.0 microM and 2.5 nM, respectively. Mutations in the predicted AdoMet-binding domain destroyed GCD14 function in vivo and (m(1)A)MTase activity in vitro. Purified Flag-tagged Gcd14p alone had no enzymatic activity and was severely impaired for tRNA-binding compared with the wild-type complex, suggesting that Gcd10p is required for tight binding of the tRNA substrate. Our results provide a demonstration of a two-component tRNA MTase and suggest that binding of AdoMet and tRNA substrates depends on different subunits of the complex.


Nongynecologic Findings Seen at Pelvic US.
Ultrasonography (US) is frequently the first imaging modality used to examine women with symptoms involving the pelvis. It is widely available and involves no exposure to ionizing radiation. Images can be acquired with a transabdominal, endovaginal, or translabial approach, and the use of video clips and three-dimensional reconstructions can be helpful. US is excellent for assessment of the uterus, ovaries, and adnexa. Occasionally, nongynecologic pelvic diseases arising from the gastrointestinal, genitourinary, and musculoskeletal systems and the pelvic peritoneal and extraperitoneal spaces may be detected and can be a source of diagnostic dilemma. US can be helpful not only in the detection but also occasionally in the characterization of such entities. Computed tomography and magnetic resonance imaging are useful in complicated cases. In this article, the normal US appearance of the bowel and US signs of bowel disease and specific entities, including appendicitis, diverticular disease, bowel obstruction, appendiceal mucocele, and intestinal tumors, are reviewed. The lower urinary tract is included in the field of view in every pelvic US examination; commonly encountered entities related to the urinary bladder, distal ureter, and urethra are illustrated. In addition to arising in the gastrointestinal and genitourinary tracts, pathologic conditions in the pelvis can arise in the peritoneal or extraperitoneal space. Although conditions of the pelvic peritoneal and extraperitoneal spaces are rare, it is important to recognize these entities and distinguish them from the more common gynecologic diseases. Owing to the implications for diagnosis and management, radiologists and other physicians who perform pelvic US should be aware of the spectrum of nongynecologic pathologic entities that can be detected. ©RSNA, 2017.


Spectral properties of hyperbolic nanonetworks with tunable aggregation of simplexes.
Cooperative self-assembly is a ubiquitous phenomenon found in natural systems which is used for designing nanostructured materials with new functional features. Its origin and mechanisms, leading to improved functionality of the assembly, have attracted much attention from researchers in many branches of science and engineering. These complex structures often come with hyperbolic geometry; however, the relation between the hyperbolicity and their spectral and dynamical properties remains unclear. Using the model of aggregation of simplexes introduced by Šuvakov et al. [Sci. Rep. 8, 1987 (2018)2045-232210.1038/s41598-018-20398-x], here we study topological and spectral properties of a large class of self-assembled structures or nanonetworks consisting of monodisperse building blocks (cliques of size n=3,4,5,6) which self-assemble via sharing the geometrical shapes of a lower order. The size of the shared substructure is tuned by varying the chemical affinity ν such that for significant positive ν sharing the largest face is the most probable, while for ν<0, attaching via a single node dominates. Our results reveal that, while the parameter of hyperbolicity remains δ_{max}=1 across the assemblies, their structure and spectral dimension d_{s} vary with the size of cliques n and the affinity when ν≥0. In this range, we find that d_{s}>4 can be reached for n≥5 and sufficiently large ν. For the aggregates of triangles and tetrahedra, the spectral dimension remains in the range d_{s}∈[2,4), as well as for the higher cliques at vanishing affinity. On the other end, for ν<0, we find d_{s}≂1.57 independently on n. Moreover, the spectral distribution of the normalized Laplacian eigenvalues has a characteristic shape with peaks and a pronounced minimum, representing the hierarchical architecture of the simplicial complexes. These findings show how the structures compatible with complex dynamical properties can be assembled by controlling the higher-order connectivity among the building blocks.