Facilitating factors in overcoming barriers to cataract surgical services among the bilaterally cataract blind in Southern India: A cross-sectional study.
To effectively address cataract blindness, increasing sight-restoring surgeries among the bilaterally blind are essential. To improve uptake of surgical services among this group, evidence regarding the problems of access is vital. Barriers in accessing eye care services have previously been reported but not specific to bilaterally cataract blind patients. Further, there is a gap in knowledge regarding factors facilitating access to eye care. Our aims were to (1) report proportion of bilaterally cataract blind patients undergoing surgery and sight restoration rate (SRR) and (2) analyze barriers and factors enabling access to eye care services among bilaterally cataract blind patients. Retrospective analysis of interview and clinical data of bilaterally cataract blind patients undergoing surgery through outreach services at the base hospital, from June 2015 to May 2016, was performed. Demographic data, vision, postoperative visual outcomes, barriers, and facilitating factors in accessing cataract surgical services were obtained. Bilateral cataract blindness was present in 196/3178 (6.2%, 95% confidence interval 5.4-7.06) patients. SRR was 6.5%. Fear of surgery (24.2%) and lack of family support/escort (22.9%) were the most common barriers. Neighbors and acquaintances (28.6%), general health workers (20.2%), and persons who had undergone cataract surgery (19.6%) were the most common facilitating factors. Proportion of bilaterally cataract blind people undergoing surgery and consequently SRR were low. The most common barriers were at the individual level while facilitating factors at the community level were instrumental in promoting uptake of services. Interventions involving community-based support for the blind may be useful in overcoming barriers to eye care.


Patient safety: moving the bar in prison health care standards.
Improvements in community health care quality through error reduction have been slow to transfer to correctional settings. We convened a panel of correctional experts, which recommended 60 patient safety standards focusing on such issues as creating safety cultures at organizational, supervisory, and staff levels through changes to policy and training and by ensuring staff competency, reducing medication errors, encouraging the seamless transfer of information between and within practice settings, and developing mechanisms to detect errors or near misses and to shift the emphasis from blaming staff to fixing systems. To our knowledge, this is the first published set of standards focusing on patient safety in prisons, adapted from the emerging literature on quality improvement in the community.


Rehospitalization for childhood asthma: timing, variation, and opportunities for intervention.
To assess the timing of pediatric asthma rehospitalization, variation in rate of rehospitalization across hospitals, and factors associated with rehospitalization at different intervals. Retrospective cohort analysis of 44,204 hospitalizations for children with asthma within 42 children's hospitals between July 2008 and June 2011. The main outcome measures were rehospitalization for asthma within 7, 15, 30, 60, 180, and 365 days of an index asthma admission. The rate of asthma rehospitalization ranged from 0.5% (n = 208) at 7 days to 17.2% (n = 7603) at 365 days. Black patients and patients with public insurance had higher odds of rehospitalization at 60 days and beyond (P ≤ .01 for both). Adolescents (12- to 18-year-old), patients with a diagnosis of a complex chronic condition, and patients with a prior year asthma admission had higher odds of rehospitalization at every time interval (P ≤ .001 for all). Significant hospital variation in case-mix adjusted rates of rehospitalization existed at each time interval (P ≤ .01 for all). Rates at 365 days were ≤ 10.9% for the top 10% of hospitals; if all hospitals achieved this rate, 36.6% of rehospitalizations might have been avoided. Significant variation in asthma rehospitalization rates exists across children's hospitals from 7 to 365 days after an index admission. Racial/ethnic and economic disparities emerge at 60 days. By 1 year, rehospitalizations account for 1 in 6 hospitalizations. Assessing asthma rehospitalizations at longer intervals may augment our current understanding of and approach to post-hospitalization care improvement.


Endogeneous sources of infection in transplant recipients.
The mammal organisms carry on their surfaces and in their tissues cohorts of microorganisms of various nature. There is a balance of interests and profits between the host and microbial inhabitants. The bacteria and fungi behave like comensals, colonizers, dormants, however, under certain, mostly unknown, conditions may evoke reaction of the host. This process is damaging both for the host and microbes. Large surgical trauma and allograft itself, as well as, immunosuppression create favorable conditions for imbalance between inhabiting microorganism and the recipient. The host flora and that transplanted with the organ graft become activated. Active combating of the proliferating bacteria with antibiotics becomes necessary. Our knowledge of the bacterial flora of the so called "sterile" tissues remains rudimentary. There is still a great deal of prejudice on the sterility of deep tissues e.g. muscles, fat tissue, etc. This review cumulates pertinent literature data on the microorganisms-host interactions. Our own findings on colonization of arteries and adjacent tissues are discussed in the context of atherosclerosis and grafting.


Liquid index matching for 2D and 3D terahertz imaging.
Two-dimensional (2D) terahertz imaging and 3D visualization suffer from severe artifacts since an important part of the terahertz beam is reflected, diffracted, and refracted at each interface. These phenomena are due to refractive index mismatch and reflection in the case of non-orthogonal incidence. This paper proposes an experimental procedure that reduces these deleterious optical refraction effects for a cylinder and a prism made with polyethylene material. We inserted these samples in a low absorption liquid medium to match the sample index. We then replaced the surrounding air with a liquid with an optimized refractive index, with respect to the samples being studied. Using this approach we could more accurately recover the original sample shape by time-of-flight tomography.


Activation of the renin-angiotensin system in mice aggravates mechanical loading-induced knee osteoarthritis.
Epidemiological studies have shown an association between hypertension and knee osteoarthritis (OA). The purpose of this study was to investigate whether activation of the renin-angiotensin system (RAS) can aggravate mechanical loading-induced knee OA in mice. Eight-week-old male Tsukuba hypertensive mice (THM) and C57BL/6 mice were divided into running and non-running groups. Mice in the running group were forced to run (25 m/min, 30 min/day, 5 days/week) on a treadmill. All mice in the four groups (n=10 in each group) were euthanized after 0, 2, 4, 6, or 8 weeks of running or natural breeding. Cartilage degeneration in the left knees was histologically evaluated using the modified Mankin score. Expression of Col X, MMP-13, angiotensin type 1 receptor (AT1R), and AT2R was examined immunohistochemically. To study the effects of stimulation of the AT1R in chondrocytes by mechanical loading and/or Angiotensin II (AngII) on transduction of intracellular signals, phosphorylation levels of JNK and Src were measured in bovine articular chondrocytes cultured in three-dimensional agarose scaffolds. After 4 weeks, the mean Mankin score for the lateral femoral condylar cartilage was significantly higher in the THM running group than in the C57BL/6 running group and non-running groups. AT1R and AT2R expression was not detected at 0 weeks in any group but was noted after 4 weeks in the THM running group. AT1R expression was also noted at 8 weeks in the C57BL/6 running group. The expression levels of AT1R, COL X, and MMP-13 in chondrocytes were significantly higher in the THM running group than in the control groups. Positive significant correlations were noted between the Mankin score and the rate of AT1R-immunopositive cells, between the rates of AT1R- and Col X-positive cells, and between the rates of AT1R- and AT2R-positive cells. The phosphorylation level of JNK was increased by cyclic compression loading or addition of AngII to the cultured chondrocytes and was reversed by pretreatment with an AT1R blocker. A synergistic effect on JNK phosphorylation was observed between compression loading and AngII addition. Transgene activation of renin and angiotensinogen aggravated mechanical load-induced knee OA in mice. These findings suggest that AT1R expression in chondrocytes is associated with early knee OA and plays a role in the progression of cartilage degeneration. The RAS may be a common molecular mechanism involved in the pathogenesis of hypertension and knee OA.


Magnetic-composite-modified polycrystalline silicon nanowire field-effect transistor for vascular endothelial growth factor detection and cancer diagnosis.
This study proposes a vascular endothelial growth factor (VEGF) biosensor for diagnosing various stages of cervical carcinoma. In addition, VEGF concentrations at various stages of cancer therapy are determined and compared to data obtained by computed tomography (CT) and cancer antigen 125 (CA-125). The increase in VEGF concentrations during operations offers useful insight into dosage timing during cancer therapy. This biosensor uses Avastin as the biorecognition element for the potential cancer biomarker VEGF and is based on a n-type polycrystalline silicon nanowire field-effect transistor (poly-SiNW-FET). Magnetic nanoparticles with poly[aniline-co-N-(1-one-butyric acid) aniline]-Fe3O4 (SPAnH-Fe3O4) shell-core structures are used as carriers for Avastin loading and provide rapid purification due to their magnetic properties, which prevent the loss of bioactivity; furthermore, the high surface area of these structures increases the quantity of Avastin immobilized. Average concentrations in human blood for species that interfere with detection specificity are also evaluated. The detection range of the biosensor for serum samples covers the results expected from both healthy individuals and cancer patients.


Differences between sexually victimized and nonsexually victimized male adolescent sexual abusers: developmental antecedents and behavioral comparisons.
This study compares sexually victimized and nonsexually victimized male adolescent sexual abusers on a number of variables. Self-report measures were administered to 325 male sexually abusive youth (average age 16) in six residential facilities in the Midwest, 55% of whom reported sexual victimization. The results indicate that the sexually victimized sexual abusers have more severe developmental antecedents (trauma, family characteristics, early exposure to pornography and personality) and recent behavioral difficulties (characteristics of sexual aggression, sexual arousal, use of pornography, and nonsexual criminal behavior) than the nonsexually victimized group. Results are contrasted with recent typological research, which found no relationship between sexual victimization and subtype membership. Treatment, research, and theoretical implications are discussed.


Monophyletic origin and unique dispersal patterns of domestic fowls.
With the aim of elucidating in greater detail the genealogical origin of the present domestic fowls of the world, we have determined mtDNA sequences of the D-loop regions for a total of 21 birds, of which 12 samples belong to red junglefowl (Gallus gallus) comprising three subspecies (six Gallus gallus gallus, three Gallus gallus spadiceus, and three Gallus gallus bankiva) and nine represent diverse domestic breeds (Gallus gallus domesticus). We also sequenced four green junglefowl (Gallus varius), two Lafayette's junglefowl (Gallus lafayettei), and one grey junglefowl (Gallus sonneratii). We then constructed a phylogenetic tree for these birds by the use of nucleotide sequences, choosing the Japanese quail (Coturnix coturnix japonica) as an outgroup. We found that a continental population of G. g. gallus was the real matriarchic origin of all the domestic poultries examined in this study. It is also of particular interest that there were no discernible differences among G. gallus subspecies; G. g. bankiva was a notable exception. This was because G. g. spadiceus and a continental population of G. g. gallus formed a single cluster in the phylogenetic tree. G. g. bankiva, on the other hand, was a distinct entity, thus deserving its subspecies status. It implies that a continental population of G. g. gallus sufficed as the monophyletic ancestor of all domestic breeds. We also discussed a possible significance of the initial dispersal pattern of the present domestic fowls, using the phylogenetic tree.


Prostate specific antigen at the initial diagnosis of metastasis to bone in patients after radical prostatectomy.
Among men with biochemical progression after radical prostatectomy little is known about prostate specific antigen at the time of metastasis to bone in hormone naïve patients. This information would be useful in determining when to initiate androgen deprivation therapy. From a large radical prostatectomy series we identified 193 hormone naïve men in whom bone metastases developed at a mean of 6 years postoperatively. We examined the prostate specific antigen distribution at bone scan conversion by time from radical prostatectomy to metastasis. ANOVA and linear regression were also used to examine the association of clinicopathological tumor features with prostate specific antigen at bone metastasis. Median prostate specific antigen was 31.9 ng/ml at the initial diagnosis of metastatic disease. Bone scan conversion occurred at a prostate specific antigen of less than 10, 10 to 100 and greater than 100 ng/ml in 50 (25.9%), 98 (50.8%) and 45 (23.3%) men, respectively. Lower prostate specific antigen at diagnosis, higher prostatectomy Gleason scores and shorter time to metastasis were associated with lower prostate specific antigen at bone metastasis, whereas prostate specific antigen at metastasis was not significantly associated with other clinicopathological features. Prostate specific antigen at the time of bone scan detected metastasis is highly variable. Unlike the pretreatment setting when metastases are rare at a prostate specific antigen of less than 10 ng/ml, 25.9% of bone metastases after radical prostatectomy occurred at a prostate specific antigen of less than 10 ng/ml. Because metastasis may occur at a low prostate specific antigen, patients with biochemical progression managed expectantly need regular bone scans even if prostate specific antigen is low to detect metastasis before symptoms.


Laparoscopic herniorrhaphy in children.
The authors report their experience in laparoscopic repair of inguinal hernias in children. From May 2010 to November 2013, 122 patients with inguinal hernia underwent laparoscopic herniorrhaphy (92 males and 30 females). Telescope used was 5 mm, while trocars for the operative instruments were 3 or 2 mm. After introducing the camera at the umbilical level and trocars in triangulation, a 4-0 nonabsorbable monofilament suture was inserted directly through the abdominal wall. The internal inguinal ring was then closed by N or double N suture. All operations were performed in one-day surgery setting. In the case of association of inguinal and umbilical hernia an original technique was performed for positioning and fixing the umbilical trocar and for the primary closure of the abdominal wall defect. The postoperative follow-up consisted of outpatient visits at 1 week and 1, 3, and 6 months. The mean age of patients was 38.5 months. Of all patients, 26 were also suffering from umbilical hernia (19 males and 7 females). A total of 160 herniorrhaphies were performed; 84 were unilateral (66 inguinal hernia, 18 inguinal hernia associated with umbilical hernia), 38 bilateral (30 inguinal hernia, 8 inguinal hernia associated with umbilical hernia). Nine of 122 patients (6 males and 3 females) were operated in emergency for incarcerated hernia. A pre-operative diagnosis of unilateral inguinal hernia was performed in 106 cases. Of these patients, laparoscopy revealed a controlateral open internal inguinal ring in 22 cases (20.7%). The mean operative time was 29.9±15.9 min for the monolateral herniorrhaphies, while in case of bilateral repair the mean operative time was 41.5±10.4 min. The mean operative time for the repair of unilateral inguinal hernia associated with umbilical hernia was 30.1±7.4 while for the correction of bilateral inguinal hernia associated with umbilical hernia 39.5±10.6 min. There were 3 recurrences (1.8%): 2 cases in unilateral repair and 1 case a unilateral recurrence in a bilateral repair. No other complications were seen. Laparoscopic repair of inguinal hernia in children performed in this experience resulted a safe and effective procedure.


Comparison of the behavioral and neurochemical effects of the two optical enantiomers of medetomidine, a selective alpha-2-adrenoceptor agonist.
Medetomidine (MED) is a veterinary sedative whose mode of action is activation of alpha-2 adrenoceptors. Because the carbon atom which separates the two ring systems is methylated, there is a center of stereochemical asymmetry in the molecule. The resulting enantiomers, d-MED and l-MED have recently become available for study. The biological activity of MED, as is now demonstrated in rats in vivo, seems to reside almost exclusively in the d-MED form. Only at extremely high doses (e.g., 10 mg/kg) does l-MED exert any effects, interpreted as alpha-2 adrenoceptor antagonism. In contrast, doses of d-MED as low as 30 micrograms/kg cause sedation, hypothermia and induce neurochemical changes in norepinephrine and 5-hydroxytryptamine metabolism in brain characteristic of alpha-2-agonists (decreases in concentrations of biogenic amine metabolites, turnover and increases in concentration of parent amine). The most sensitive neurochemical indicator of the alpha-2-agonist action of d-MED was the concentration of unconjugated 3-methoxy-4-hydroxy-phenyethylene glycol in rat cerebral spinal fluid, doses of d-MED as low as 10 micrograms/kg caused a significant reduction in this norepinephrine metabolite. Simultaneous administration of the specific alpha-2 adrenoceptor antagonist, atipamezole (1 mg/kg), effectively inhibited the behavioral and most of the neurochemical actions of d-MED (100 micrograms/kg). It is concluded that the enantiomers of MED may be extremely useful in elucidating structure action relationships at alpha-2 adrenoceptors.


Setting priorities for mental health care in Nepal: a formative study.
There is an urgent need to address the massive treatment gap for mental health problems, especially in low income settings. Packages of care integrated in routine primary health care are posited as a strategy to scale-up mental health care, yet more needs to be known about the most feasible and effective way to go about this. The study follows a combined methods design that includes engaging an expert panel in a priority setting exercise, running workshops to develop a Theory of Change and conducting in-depth qualitative interviews and focus group discussions with key stakeholders. The results of each research step were taken forward to inform the subsequent one. There was strong endorsement for a system of care that encompasses both the perspectives of health facility and the community. Issues related to increasing access and demand, guaranteeing a sustainable supply of psychotropic medicine, adequate human resourcing, and ensuring positive family involvement came up as priority areas of attention. The study underlines many of the known barriers in developing mental health services. At the same time it provides a distinct pathway and concrete recommendations for overcoming these challenges in Nepal.


Intercomparison of phenological transition dates derived from the PhenoCam Dataset V1.0 and MODIS satellite remote sensing.
Phenology is a valuable diagnostic of ecosystem health, and has applications to environmental monitoring and management. Here, we conduct an intercomparison analysis using phenological transition dates derived from near-surface PhenoCam imagery and MODIS satellite remote sensing. We used approximately 600 site-years of data, from 128 camera sites covering a wide range of vegetation types and climate zones. During both "greenness rising" and "greenness falling" transition phases, we found generally good agreement between PhenoCam and MODIS transition dates for agricultural, deciduous forest, and grassland sites, provided that the vegetation in the camera field of view was representative of the broader landscape. The correlation between PhenoCam and MODIS transition dates was poor for evergreen forest sites. We discuss potential reasons (including sub-pixel spatial heterogeneity, flexibility of the transition date extraction method, vegetation index sensitivity in evergreen systems, and PhenoCam geolocation uncertainty) for varying agreement between time series of vegetation indices derived from PhenoCam and MODIS imagery. This analysis increases our confidence in the ability of satellite remote sensing to accurately characterize seasonal dynamics in a range of ecosystems, and provides a basis for interpreting those dynamics in the context of tangible phenological changes occurring on the ground.


Fifteen-year trend in treatment outcomes among patients with pulmonary smear-positive tuberculosis and its determinants in Arsi Zone, Central Ethiopia.
Directly Observed Treatment Short course (DOTS) strategy is aimed at diagnosing 70% of infectious tuberculosis (TB) and curing 85% of it. Arsi Zone of Ethiopia piloted DOTS strategy in 1992. Since then, the trend in treatment outcomes in general and at district-level in particular has not been assessed. The aim of this study was to analyse the trend in TB treatment outcomes and audit district-level treatment outcomes in the 25 districts of Arsi Zone. A retrospective cohort study design was employed to audit pulmonary smear-positive (PTB + ) patients registered between 1997 and 2011. Demographic and related data were collected from the TB unit registers between January and March 2013. The 15-year trend in treatment outcomes among PTB+ patients and district-level treatment outcomes was computed. From 14,221 evaluated PTB+ cases, 11,888 (83.6%) were successfully treated. The treatment success rate (TSR) varied from 69.3 to 92.5%, defaulter rate from 2.5 to 21.6%, death rate from 1.6 to 11.1%, and failure rate from 0 to 3.6% across the 25 districts of the zone. The trend in TSR increased from 61 to 91% with the increase of population DOTS coverage from 18 to 70%. There was a declining trend in defaulter rate from 29.9 to 2.1% and death rate from 8.8 to 5.4% over 15 years. Patients aged 25-49 years (Adjusted Odd Ratio (AOR), 0.23; 95% CI: 0.21-0.26) and ≥50 years (AOR, 0.43; 95% CI: 0.32-0.59), re-treatment cases (AOR, 0.61; 0.41, 0.67), and TB/HIV co-infection cases (AOR, 0.45; 95% CI: 0.31-0.53) were associated with unsuccessful treatment outcomes. DOTS expansion and improving population DOTS coverage in Arsi has led to a significant increase in treatment success and decrease in death and defaulter rates. However, there is a major variation in treatment outcomes across the 25 districts of the zone, so district-specific intervention strategy needs to be considered. The low TSR among re-treatment cases might be due to the high rate of MDR-TB among this group, and the issue needs to be further investigated to identify the extent of the problem.


Magnitude and causes of socioeconomic differentials in mortality: further evidence from the Whitehall Study.
The aim was to explore the magnitude and causes of the differences in mortality rates according to socioeconomic position in a cohort of civil servants. This was a prospective observational study of civil servants followed up for 10 years after baseline data collection. Civil service offices in London. 11,678 male civil servants were studied, aged 40-64 at baseline screening between 1967 and 1969. Two indices of socioeconomic position were available on these participants--employment grade (categorised into four levels), and ownership of a car. Main outcome measures were all cause and cause specific mortality, with cause of death taken from death certificates coded according to the eighth revision of the ICD. Employment grade and car ownership were independently related to total mortality and to mortality from the major cause groups. Combining the indices further improved definition of mortality risk and the age adjusted relative rate between the highest grade car owners and the lowest grade non-owners of 4.3 is considerably larger than the social class differentials seen in the British population. Factors potentially involved in the production of these mortality differentials were examined. Smoking, plasma cholesterol concentration, blood pressure, and glucose intolerance did not appear to account for them. The pattern of differentials was the same in the group who reported no ill health at baseline as it was in the whole sample, which suggests that health selection associated with frank illness was not a major determinant. The contribution of height, a marker for environmental factors acting in early life, was also investigated. Whereas adjustment for employment grade and car ownership attenuated the association between short stature and mortality, height differences within employment grade and car ownership groups explained little of the differential mortality. The use of social class as an index of socioeconomic position leads to underestimation of the association between social factors and mortality, which may be reflected in public health initiatives and priorities. Known risk factors could not be shown to account for the differentials in mortality, although the degree to which this can be explored with single measurements is limited.


Sortilin regulates progranulin action in castration-resistant prostate cancer cells.
The growth factor progranulin is as an important regulator of transformation in several cellular systems. We have previously demonstrated that progranulin acts as an autocrine growth factor and stimulates motility, proliferation, and anchorage-independent growth of castration-resistant prostate cancer cells, supporting the hypothesis that progranulin may play a critical role in prostate cancer progression. However, the mechanisms regulating progranulin action in castration-resistant prostate cancer cells have not been characterized. Sortilin, a single-pass type I transmembrane protein of the vacuolar protein sorting 10 family, binds progranulin in neurons and negatively regulates progranulin signaling by mediating progranulin targeting for lysosomal degradation. However, whether sortilin is expressed in prostate cancer cells and plays any role in regulating progranulin action has not been established. Here, we show that sortilin is expressed at very low levels in castration-resistant PC3 and DU145 cells. Significantly, enhancing sortilin expression in PC3 and DU145 cells severely diminishes progranulin levels and inhibits motility, invasion, proliferation, and anchorage-independent growth. In addition, sortilin overexpression negatively modulates Akt (protein kinase B, PKB) stability. These results are recapitulated by depleting endogenous progranulin in PC3 and DU145 cells. On the contrary, targeting sortilin by short hairpin RNA approaches enhances progranulin levels and promotes motility, invasion, and anchorage-independent growth. We dissected the mechanisms of sortilin action and demonstrated that sortilin promotes progranulin endocytosis through a clathrin-dependent pathway, sorting into early endosomes and subsequent lysosomal degradation. Collectively, these results point out a critical role for sortilin in regulating progranulin action in castration-resistant prostate cancer cells, suggesting that sortilin loss may contribute to prostate cancer progression.


Nicotine modulates contextual fear extinction through changes in ventral hippocampal GABAergic function.
Numerous studies have attributed the psychopathology of anxiety and stress disorders to maladaptive behavioral responses such as an inability to extinguish fear. Therefore, understanding neural substrates of fear extinction is imperative for developing more effective therapies for anxiety and stress disorders. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs in the fear extinction process. In the present study, we first examined the involvement of several brain regions essential for fear extinction (i.e., dorsal and ventral hippocampus, dHPC and vHPC; infralimbic, IL, and prelimbic, PL of the medial prefrontal cortex, mPFC; basolateral nucleus of the amygdala, BLA) in the impairing effects of a nAChR agonist, nicotine, on contextual fear extinction in mice. Our results showed that systemic administration of nicotine during contextual fear extinction increased c-fos expression in the vHPC and BLA while not affecting dHPC, IL or PL. In line with these results, local nicotine infusions into the vHPC, but not dHPC, resulted in impaired contextual fear extinction. Interestingly, we found that local nicotine infusions into the PL also resulted in impairment of contextual fear extinction. Second, we measured the protein levels of the GABA synthesizing enzymes GAD65 and GAD67 in the dHPC and vHPC during contextual fear extinction. Our results showed that in the group that received acute nicotine, both GAD65 and GAD67 protein levels were downregulated in the vHPC, but not in dHPC. This effect was negatively correlated with the level of freezing response during fear extinction suggesting that the downregulated GAD65/67 levels were associated with disrupted fear extinction. Finally, using c-fos/GAD65/67 double immunofluorescence, we showed that nicotine mainly increased c-fos expression in non-GABAergic ventral hippocampal cells, indicating that acute nicotine increases vHPC excitability. Overall, our results suggest that acute nicotine's impairing effects on fear extinction are associated with ventral hippocampal disinhibition. Therefore, these results further our understanding of the interaction between nicotine addiction and anxiety and stress disorders by describing novel neural mechanisms mediating fear extinction.


Practitioner Review: Differential susceptibility theory: might it help in understanding and treating mental health problems in youth?
Diathesis-stress models conceptualise individual differences in propensity for psychopathology as an interaction between environmental risk factors and intra-individual vulnerabilities. In contrast, the differential susceptibility theory and related frameworks view intra-individual differences as variations in sensitivity to the environments rather than merely vulnerability to them. Specifically, they suggest that more sensitive individuals are more affected by the quality of their context, whether positive or negative, than others who are less sensitive. Empirical research over the last two decades has found support for this notion in that greater sensitivity is associated with a greater risk of psychopathology in adverse contexts, but also with lower risk in positive environments. However, despite growing academic and public interest in this field, it is currently unclear to what extent the differential susceptibility model is relevant, or applicable, to clinical practice. The purpose of this review is to focus on the differential susceptibility theory as an alternative explanation of individual differences in mental health and examine its relevance in the treatment of mental health problems in young people. We provide an overview of differential susceptibility and related theories, and current relevant research in the field. We identify potential implications of differential susceptibility models for understanding and treating mental health problems in young people, whilst also highlighting important gaps in research that limit their application at present. Finally, we suggest directions for future research that will assist in the translation of differential susceptibility theories into clinical practice.


Cognitive Function and Falls in Older Adults With Type 2 Diabetes Mellitus.
Cognitive impairments have been reported in older adults with type 2 diabetes (T2DM), which subsequently increases the risk of falling. However, the relationship between specific cognitive processes and falls has not been reported. Therefore, the purpose of this study was to describe the contribution of cognitive function to falls in older adults with T2DM and to describe any differences by age group. A cross-sectional analysis was conducted of 1171 older adult respondents with T2DM from the 2010 wave of the Health and Retirement Study. Group assignment was based on age: younger group 65 to 74 years (N = 662) or older group (N = 509). Groupwise comparisons of demographic, cognitive, and mobility variables were completed, followed by logistic regression analyses to examine the contribution of specific cognitive processes to falls for the sample and then by group after controlling for demographic and mobility-related variables. Significant differences existed between groups in demographic, cognitive, and mobility variables and falls. Executive function was consistently identified as a predictor of falls in the whole sample (odds ratio [OR] = 1.06; 95% CI, 1.02-1.09) and within groups: younger group (OR = 1.06; 95% CI, 1.01-1.11) and older group (OR = 1.07; 95% CI, 1.01-1.13), while delayed recall was a much stronger predictor of falls in the older group (OR = 1.28; 95% CI, 1.03-1.59). Orientation and immediate recall were not predictors of falls. Executive function and delayed recall, 2 cognitive domains reported to influence glycemic control and disease management in those with T2DM, are associated with an increased fall risk and should be included in the assessment of fall risk in this population.


Microplastic contamination of intertidal sediments of Scapa Flow, Orkney: A first assessment.
The concentration of microplastic particles and fibres was determined in the intertidal sediments at selected sites in Scapa Flow, Orkney, using a super-saturated NaCl flotation technique to extract the plastic and FT-IR spectroscopy to determine the polymer types. Mean concentrations were 730 and 2300kg-1 sediment (DW), respectively. Detailed spatial and quantitative analysis revealed that their distribution was a function of proximity to populated areas and associated wastewater effluent, industrial installations, degree of shore exposure and complex tidal flow patterns. Sediment samples from Orkney showed similar levels of microplastic contamination as in two highly populate industrialized mainland UK areas, The Clyde and the Firth of Forth. It was concluded that relative remoteness and a comparative small island population are not predictors of lower microplastic pollution. Furthermore, a larger concerted effort across Scotland and the UK is required to establish a baseline microplastic database for the evaluation of future policy measures.


Mandibular and dental characteristics of Late Triassic mammaliaform Haramiyavia and their ramifications for basal mammal evolution.
As one of the earliest-known mammaliaforms, Haramiyavia clemmenseni from the Rhaetic (Late Triassic) of East Greenland has held an important place in understanding the timing of the earliest radiation of the group. Reanalysis of the type specimen using high-resolution computed tomography (CT) has revealed new details, such as the presence of the dentary condyle of the mammalian jaw hinge and the postdentary trough for mandibular attachment of the middle ear-a transitional condition of the predecessors to crown Mammalia. Our tests of competing phylogenetic hypotheses with these new data show that Late Triassic haramiyids are a separate clade from multituberculate mammals and are excluded from the Mammalia. Consequently, hypotheses of a Late Triassic diversification of the Mammalia that depend on multituberculate affinities of haramiyidans are rejected. Scanning electron microscopy study of tooth-wear facets and kinematic functional simulation of occlusion with virtual 3D models from CT scans confirm that Haramiyavia had a major orthal occlusion with the tallest lingual cusp of the lower molars occluding into the lingual embrasure of the upper molars, followed by a short palinal movement along the cusp rows alternating between upper and lower molars. This movement differs from the minimal orthal but extensive palinal occlusal movement of multituberculate mammals, which previously were regarded as relatives of haramiyidans. The disparity of tooth morphology and the diversity of dental functions of haramiyids and their contemporary mammaliaforms suggest that dietary diversification is a major factor in the earliest mammaliaform evolution.


Sociodemographic characteristics of tobacco consumers in a rural area of Bangladesh.
Bangladesh typifies many developing countries experiencing an increasing trend in tobacco consumption. However, little is known about the general pattern of tobacco consumption and about population groups who are more prone to tobacco consumption. This paper aimed at generating knowledge on tobacco consumption, especially emphasizing the identification of sociodemographic groups who are more prone to tobacco consumption vis-à-vis tobacco-related health consequences in a remote rural area in Bangladesh. Information on the tobacco consumption status of 6,618 individuals (52.1% males, 47.9% females), aged over 15 years, was collected in 1994. Both univariate and multivariate analyses were done. Individuals were categorized as consumers if they consumed tobacco in any form at all, i.e. smoke or chew. The independent variables included various characteristics of individuals and households. Overall, 43.4% of the study subjects consumed tobacco. Males were 9.38 times more likely to consume tobacco than their female counterparts. Individuals with no education were 3.62 times more likely to consume tobacco than those who had completed six or more years of schooling, and the poor were almost twice as likely to consume tobacco than the rich. Tobacco consumption in both smoke and chewing form has been a part of household consumption in Bangladesh from time immemorial. Only aggressive anti-tobacco programmes on various fronts may salvage the vulnerable groups from the menace of tobacco consumption in Bangladesh.


Cellular membranes function as a storage compartment for celecoxib.
Celecoxib is a selective cyclooxygenase-2-(COX-2)-inhibitor used to treat inflammation and pain and prevents colorectal cancer in patients at high doses by affecting several non-COX-2 proteins. However, celecoxib concentrations appropriate to inhibit proliferation or to induce apoptosis in cell culture (up to 100 microM) clearly exceed those in human plasma (up to 10 microM). Therefore, we speculated that celecoxib might accumulate in human cells, which may facilitate the drug's interaction with non-COX-2 proteins. Determination of intracellular celecoxib concentrations by liquid chromatography tandem mass spectrometry gave five- to tenfold higher levels as compared to other coxibs (etoricoxib, valdecoxib, lumiracoxib, and rofecoxib) in different tumor cell types, including human HCA-7 and HCT-116 colon carcinoma cells, BL-41 B lymphocytes, Mono Mac 6 monocytes, and in mouse NIH-3T3 non-tumor fibroblasts. This intracellular accumulation of celecoxib was due to an integration of the drug into cellular phospholipid membranes as demonstrated by nuclear Overhauser spectroscopy/nuclear magnetic resonance. Consequently, celecoxib disturbed the plasma membrane integrity of HCT-116 cells and displayed an increased COX-2-inhibitory potency in HCA-7 cells. The use of other coxibs demonstrated that intracellular accumulation is peculiar of celecoxib. Accumulation of celecoxib in human cells may provide a novel molecular basis for the ability of the drug to interact with non-COX-2 targets in vivo despite comparatively low plasma concentrations.


Simulation Study of cDNA Dataset to Investigate Possible Association of Differentially Expressed Genes of Human THP1-Monocytic Cells in Cancer Progression Affected by Bacterial Shiga Toxins.
Shiga toxin (Stxs) is a family of structurally and functionally related bacterial cytotoxins produced by Shigella dysenteriae serotype 1 and shigatoxigenic group of Escherichia coli that cause shigellosis and hemorrhagic colitis, respectively. Until recently, it has been thought that Stxs only inhibits the protein synthesis and induces expression to a limited number of genes in host cells, but recent data showed that Stxs can trigger several signaling pathways in mammalian cells and activate cell cycle and apoptosis. To explore the changes in gene expression induced by Stxs that have been shown in other systems to correlate with cancer progression, we performed the simulated analysis of cDNA dataset and found differentially expressed genes (DEGs) of human THP1-monocytic cells treated with Stxs. In this study, the entire data (treated and untreated replicates) was analyzed by statistical algorithms implemented in Bioconductor packages. The output data was validated by the k-fold cross technique using generalized linear Gaussian models. A total of 50 DEGs were identified. 7 genes including TSLP, IL6, GBP1, CD274, TNFSF13B, OASL, and PNPLA3 were considerably (<0.00005) related to cancer proliferation. The functional enrichment analysis showed 6 down-regulated and 1 up-regulated genes. Among these DEGs, IL6 was associated with several cancers, especially with leukemia, lymphoma, lungs, liver and breast cancers. The predicted regulatory motifs of these genes include conserved RELA, STATI, IRFI, NF-kappaB, PEND, HLF, REL, CEBPA, DI_2, and NFKB1 transcription factor binding sites (TFBS) involved in the complex biological functions. Thus, our findings suggest that Stxs has the potential as a valuable tool for better understanding of treatment strategies for several cancers.


Deferred cord clamping, cord milking, and immediate cord clamping at preterm birth: a systematic review and individual participant data meta-analysis.
Umbilical cord clamping strategies at preterm birth have the potential to affect important health outcomes. The aim of this study was to compare the effectiveness of deferred cord clamping, umbilical cord milking, and immediate cord clamping in reducing neonatal mortality and morbidity at preterm birth. We conducted a systematic review and individual participant data meta-analysis. We searched medical databases and trial registries (from database inception until Feb 24, 2022; updated June 6, 2023) for randomised controlled trials comparing deferred (also known as delayed) cord clamping, cord milking, and immediate cord clamping for preterm births (<37 weeks' gestation). Quasi-randomised or cluster-randomised trials were excluded. Authors of eligible studies were invited to join the iCOMP collaboration and share individual participant data. All data were checked, harmonised, re-coded, and assessed for risk of bias following prespecified criteria. The primary outcome was death before hospital discharge. We performed intention-to-treat one-stage individual participant data meta-analyses accounting for heterogeneity to examine treatment effects overall and in prespecified subgroup analyses. Certainty of evidence was assessed with Grading of Recommendations Assessment, Development, and Evaluation. This study is registered with PROSPERO, CRD42019136640. We identified 2369 records, of which 48 randomised trials provided individual participant data and were eligible for our primary analysis. We included individual participant data on 6367 infants (3303 [55%] male, 2667 [45%] female, two intersex, and 395 missing data). Deferred cord clamping, compared with immediate cord clamping, reduced death before discharge (odds ratio [OR] 0·68 [95% CI 0·51-0·91], high-certainty evidence, 20 studies, n=3260, 232 deaths). For umbilical cord milking compared with immediate cord clamping, no clear evidence was found of a difference in death before discharge (OR 0·73 [0·44-1·20], low certainty, 18 studies, n=1561, 74 deaths). Similarly, for umbilical cord milking compared with deferred cord clamping, no clear evidence was found of a difference in death before discharge (0·95 [0·59-1·53], low certainty, 12 studies, n=1303, 93 deaths). We found no evidence of subgroup differences for the primary outcome, including by gestational age, type of delivery, multiple birth, study year, and perinatal mortality. This study provides high-certainty evidence that deferred cord clamping, compared with immediate cord clamping, reduces death before discharge in preterm infants. This effect appears to be consistent across several participant-level and trial-level subgroups. These results will inform international treatment recommendations. Australian National Health and Medical Research Council.


Activation of Nrf2 in keratinocytes causes chloracne (MADISH)-like skin disease in mice.
The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/"metabolizing acquired dioxin-induced skin hamartomas" (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.


On estimating the directionality distribution in pedicle trabecular bone from micro-CT images.
Our interest in the trabecular alignment within bone stems from the need to better understand the manner in which it can affect ultrasound propagation, particularly in pedicles. Within long bones it is well established that trabecular structures are aligned in an organized manner associated with the direction of load distribution; however, for smaller bones there are limited alignment studies. To investigate the directionality distribution in a quantitative manner we used a micro-CT to obtain three-dimensional (3D) structural data and developed analytical methods based on the special properties of Gabor filters. Implementation of these techniques has been developed and tested on a variety of simulated images as well as on 3D structures whose geometry is well-defined. To test the use of this technique we compared the results obtained on vertebral body trabecular bone with visual directionality and previous measurements by others. The method has been applied to six human pedicle samples in two orthogonal planes with results that provide reasonable proof-of-principle evidence that the method is well suited for estimating the directionality distribution within pedicle bones.


Molecular and biochemical responses of hypoxia exposure in Atlantic croaker collected from hypoxic regions in the northern Gulf of Mexico.
A major impact of global climate change has been the marked increase worldwide in the incidence of coastal hypoxia (dissolved oxygen, DO<2.0 mg l-1). However, the extent of hypoxia exposure to motile animals such as fish collected from hypoxic waters as well as their molecular and physiological responses to environmental hypoxia exposure are largely unknown. A suite of potential hypoxia exposure biomarkers was evaluated in Atlantic croaker collected from hypoxic and normoxic regions in the northern Gulf of Mexico (nGOM), and in croaker after laboratory exposure to hypoxia (DO: 1.7 mg l-1). Expression of hypoxia-inducible factor-α, hif-α; neuronal nitric oxide synthase, nNOS; and insulin-like growth factor binding protein, igfbp mRNAs and protein carbonyl (PC, an oxidative stress indicator) content were elevated several-fold in brain and liver tissues of croaker collected from nGOM hypoxic sites. All of these molecular and biochemical biomarkers were also upregulated ~3-10-fold in croaker brain and liver tissues within 1-2 days of hypoxia exposure in controlled laboratory experiments. These results suggest that hif-αs, nNOS and igfbp-1 transcripts and PC contents are useful biomarkers of environmental hypoxia exposure and some of its physiological effects, making them important components for improved assessments of long-term impacts of environmental hypoxia on fish populations.


A DSM-5 to-do list for adult psychiatry residency directors.
A small study within the author's department, comparing resident and faculty attitudes toward the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), revealed that the DSM-5 transition process is starting from a point in which neither faculty nor residents are optimistic that the new DSM will result in improved diagnosis or treatment. However, the publication of DSM-5 presents training directors with opportunities to engage trainees in the study of the evolution of psychiatric nosology and the evidence for core psychiatric diagnoses. Residents should be encouraged to become familiar with both DSM-5 and National Institute of Mental Health Research Domain Criteria (NIMH RDoC) categories in their study of the neurobiology of psychiatric disorders. Department chairs are encouraged to establish timelines for the DSM-5 transition for faculty, residents, medical student teaching, medical record keeping, and billing for services. Training directors should be aware that national examinations for trainees will transition gradually between 2014 and 2017, so comparisons should be made whenever possible between DSM-IV-TR and DSM-5. To minimize trainee confusion, departments should attend to the coherence of transition timelines among faculty, resident, and medical student training.


Derivatives of spin dynamics simulations.
We report analytical equations for the derivatives of spin dynamics simulations with respect to pulse sequence and spin system parameters. The methods described are significantly faster, more accurate, and more reliable than the finite difference approximations typically employed. The resulting derivatives may be used in fitting, optimization, performance evaluation, and stability analysis of spin dynamics simulations and experiments.


Urinary miRNA Biomarkers of Drug-Induced Kidney Injury and Their Site Specificity Within the Nephron.
Drug-induced kidney injury (DIKI) is a major concern in both drug development and clinical practice. There is an unmet need for biomarkers of glomerular damage and more distal renal injury in the loop of Henle and the collecting duct (CD). A cross-laboratory program to identify and characterize urinary microRNA (miRNA) patterns reflecting tissue- or pathology-specific DIKI was conducted. The overall goal was to propose miRNA biomarker candidates for DIKI that could supplement information provided by protein kidney biomarkers in urine. Rats were treated with nephrotoxicants causing injury to distinct nephron segments: the glomerulus, proximal tubule, thick ascending limb (TAL) of the loop of Henle and CD. Meta-analysis identified miR-192-5p as a potential proximal tubule-specific urinary miRNA candidate. This result was supported by data obtained in laser capture microdissection nephron segments showing that miR-192-5p expression was enriched in the proximal tubule. Discriminative miRNAs including miR-221-3p and -222-3p were increased in urine from rats treated with TAL versus proximal tubule toxicants in accordance with their expression localization in the kidney. Urinary miR-210-3p increased up to 40-fold upon treatment with TAL toxicants and was also enriched in laser capture microdissection samples containing TAL and/or CD versus proximal tubule. miR-23a-3p was enriched in the glomerulus and was increased in urine from rats treated with doxorubicin, a glomerular toxicant, but not with toxicants affecting other nephron segments. Taken together these results suggest that urinary miRNA panels sourced from specific nephron regions may be useful to discriminate the pathology of toxicant-induced lesions in the kidney, thereby contributing to DIKI biomarker development needs for industry, clinical, and regulatory use.


The organization of the brainstem nuclei associated with the vagus nerve in the Agouti (Dasyprocta leporina). A neurohistological study.
A total of six adult animals were used for the study. Following anaesthesia via intraperitoneal injection of a mixture of ketamin and bombazine in ratio 2:1, thoracotomy was performed to exteriorize the heart for intracardial perfusion. The perfusion canular was inserted into the left ventricle and animal perfused sequentially with normal saline and 10% formal saline. Following perfusion, craniotomy was performed to remove the entire brain along with the upper segments of the spinal cord. The brain specimen was then dehydrated, cleared and infiltrated with paraffin wax. The specimen was then cut in 15 micron thick serial sections. The sections were then processed for neurohistological analyses using a Nikon microscope to which was attached Nikon camera. Analyses of the sections revealed bilateral representation of the dorsal motor nucleus of the vagus nerve in the medulla oblongata. The nucleus ambiguus, nucleus of the tractus solitarius, hypoglossal nucleus and the area postrema were also identified in the medulla oblongata. The implications of our findings are discussed in the text of the article.


Nuclear morphology and deformation in engineered cardiac myocytes and tissues.
Cardiac tissue engineering requires finely-tuned manipulation of the extracellular matrix (ECM) microenvironment to optimize internal myocardial organization. The myocyte nucleus is mechanically connected to the cell membrane via cytoskeletal elements, making it a target for the cellular response to perturbation of the ECM. However, the role of ECM spatial configuration and myocyte shape on nuclear location and morphology is unknown. In this study, printed ECM proteins were used to configure the geometry of cultured neonatal rat ventricular myocytes. Engineered one- and two-dimensional tissue constructs and single myocyte islands were assayed using live fluorescence imaging to examine nuclear position, morphology and motion as a function of the imposed ECM geometry during diastolic relaxation and systolic contraction. Image analysis showed that anisotropic tissue constructs cultured on microfabricated ECM lines possessed a high degree of nuclear alignment similar to that found in vivo; nuclei in isotropic tissues were polymorphic in shape with an apparently random orientation. Nuclear eccentricity was also increased for the anisotropic tissues, suggesting that intracellular forces deform the nucleus as the cell is spatially confined. During systole, nuclei experienced increasing spatial confinement in magnitude and direction of displacement as tissue anisotropy increased, yielding anisotropic deformation. Thus, the nature of nuclear displacement and deformation during systole appears to rely on a combination of the passive myofibril spatial organization and the active stress fields induced by contraction. Such findings have implications in understanding the genomic consequences and functional response of cardiac myocytes to their ECM surroundings under conditions of disease.


Analytical and numerical stability analysis of Soret-driven convection in a horizontal porous layer: The effect of vertical vibrations.
The authors studied the effect of vertical high-frequency and small-amplitude vibrations on the separation of a binary mixture saturating a porous cavity. The horizontal bottom plate was submitted to constant uniform heat flux and the top one was maintained at constant temperature while no mass flux was imposed. The influence of vertical vibrations on the onset of convection and on the stability of the unicellular flow was investigated for positive separation ratio [Formula: see text]. The case of high-frequency and small-amplitude vibrations was considered so that a formulation using time averaged equations could be used. For an infinite horizontal porous layer, the equilibrium solution was found to lose its stability via a stationary bifurcation leading to unicellular flow or multicellular one depending on the value of [Formula: see text]. The analytical solution of the unicellular flow was obtained and separation was expressed in terms of Lewis number, separation ratio and thermal Rayleigh number. The direct numerical simulations using the averaged governing equations and analytical stability analysis showed that the unicellular flow loses its stability via oscillatory bifurcation. The vibrations decrease the value of [Formula: see text], which allows species separation for a wide variety of binary mixtures. The vibrations can be used to maintain the unicellular flow and allow species separation over a wider range of Rayleigh numbers. The results of direct numerical simulations and analytical model are in good agreement.


A fibril-based structural constitutive theory reveals the dominant role of network characteristics on the mechanical behavior of fibroblast-compacted collagen gels.
In this paper, we present a general, fibril-based structural constitutive theory which accounts for three material aspects of crosslinked filamentous materials: the single fibrillar force response, the fibrillar network model, and the effects of alterations to the fibrillar network. In the case of the single fibrillar response, we develop a formula that covers the entropic and enthalpic deformation regions, and introduce the relaxation phase to explain the observed force decay after crosslink breakage. For the filamentous network model, we characterize the constituent element of the fibrillar network in terms its end-to-end distance vector and its contour length, then decompose the vector orientation into an isotropic random term and a specific alignment, paving the way for an expanded formalism from principal deformation to general 3D deformation; and, more important, we define a critical core quantity over which macroscale mechanical characteristics can be integrated: the ratio of the initial end-to-end distance to the contour length (and its probability function). For network alterations, we quantitatively treat changes in constituent elements and relate these changes to the alteration of network characteristics. Singular in its physical rigor and clarity, this constitutive theory can reproduce and predict a wide range of nonlinear mechanical behavior in materials composed of a crosslinked filamentous network, including: stress relaxation (with dual relaxation coefficients as typically observed in soft tissues); hysteresis with decreasing maximum stress under serial cyclic loading; strain-stiffening under uniaxial tension; the rupture point of the structure as a whole; various effects of biaxial tensile loading; strain-stiffening under simple shearing; the so-called "negative normal stress" phenomenon; and enthalpic elastic behaviors of the constituent element. Applied to compacted collagen gels, the theory demonstrates that collagen fibrils behave as enthalpic elasticas with linear elasticity within the gels, and that the macroscale nonlinearity of the gels originates from the curved fibrillar network. Meanwhile, the underlying factors that determine the mechanical properties of the gels are clarified. Finally, the implications of this study on the enhancement of the mechanical properties of compacted collagen gels and on the cellular mechanics with this model tissue are discussed.


Silence is golden: The effect of verbalization on group performance.
Contrary to the popular belief that collaboration brings better problem solutions, empirical studies have revealed that interacting groups often performed worse than noninteracting "nominal" groups. Past studies mainly examined how overhearing others' ideas impacts group performance. This study investigated the impact of another essential but overlooked group communicative process-verbalizing ideas to others-on group performance. Participants (N = 156) solved 20 verbal puzzles either alone quietly, alone thinking-aloud, or in verbalizing pairs. Participants in the same working-alone condition were randomly paired to form nominal pairs and their pooled performance was treated as nominal group performance. Relative to the quiet nominal group, the performance of the thinking-aloud nominal and interacting groups were impaired to similar extents. These two groups also demonstrated a similar limited capacity to expand the search scope. The equivalency of the interacting and thinking-aloud nominal group results suggest that verbalization is a key factor in groups' inferior performance. (PsycINFO Database Record


Diffusion tensor imaging shows mechanism-specific differences in injury pattern and progression in rat models of acute spinal cord injury.
We investigate the ability of diffusion tensor imaging (DTI) to distinguish between three experimental rat models of spinal cord injury mechanism - contusion, dislocation, and distraction. Ex vivo DTI scans were performed on cord specimens that were preserved at different time points of the acute injury (3 hr, 24 hr, and 7 days post-injury) across all three injury mechanisms. White matter was classified as abnormal if their DTI metric was substantially different from regional values measured from a set of uninjured controls, thus allowing generation of binary "white matter damage maps" which categorizes each pixel in the DTI image as "normal" or "damaged". Damage classification was most robust using thresholds in the longitudinal diffusivity, which supports previous studies that show that longitudinal diffusivity is the most robust DTI metric in depicting damage in SCI. Furthermore, the spatial damage patterns from all subjects in the same group were consolidated into a "damage occurrence ratio map", which illustrates an average damage shape that characterizes the injury mechanism. Our analysis has yielded a dataset which highlights the differences in injury pattern due to the initial mode of mechanical injury. For example, contusion produced an initial injury that emanated radially outward from the central canal, with subsequent damage along the caudal corticospinal tract and rostral gracile fasciculus; dislocation injuries showed a high level of involvement in the lateral and ventral white matter which became less apparent by 7 days post-injury, and distraction injuries were found to be less focal and more distributed rostrocaudally. This work represents a first step in adopting the use of the primary injury mechanism as a clinical prognostic factor in SCI, which may help to inform the trialing of existing neuroprotective treatment candidates, the development of new therapies as well as personalize the management of SCI for the individual patient.


Blood concentrations of estradiol and sex hormone-binding globulin in relation to age at menarche in premenopausal British and Japanese women.
In a cross-sectional study, serum estradiol (E2) and sex hormone-binding globulin (SHBG) concentrations were not significantly related to age at menarche in premenopausal British women in the luteal or follicular phases of the cycle. In Japanese subjects in the luteal phase, a marginally higher concentration of E2 was observed in those who had undergone an early rather than a late menarche. In British women, previous oral contraceptive users had significantly lower luteal phase E2 concentrations than never users.


Trial effects in single-trial ERP components and autonomic responses at very long ISIs.
Single-trial data from autonomic and ERP measures were used to capture the rapidly decreasing initial responses characteristic of the orienting reflex (OR) to repeated stimuli. Stimulus-response patterns were compared to determine central analogues of autonomic indices of processes leading to the OR, and the OR itself. Participants were presented with 12 indifferent tones in an auditory dishabituation paradigm. Temporal principal component analysis (PCA) decomposed EOG-corrected ERP data for 16 subjects. Response patterns of ERPs, cardiac, and respiratory responses were compared to the phasic skin conductance response (SCR). SCR decremented over trials, recovered on the change trial, and dishabituated to the representation of the standard, meeting the formal definition of habituation required of the OR. The evoked cardiac response showed no trial effects. Respiratory pause (RP) decreased linearly over trials, recovering marginally on the change trial. Nine identifiable ERP components were extracted: P1, N1-3, N1-1, processing negativity (PN), P2, P3a, P3b, a novelty-sensitive P3 component (labelled HabP3), and the slow wave (SW). P3b and SW showed decrement over trials, but with no recovery, HabP3 showed decrement and increased response on the change trial, while the P1, N1 subcomponents, P2 and P3a were insensitive to novelty. Stimulus-response patterns of the RP and HabP3 suggest sensitivity to novelty processing, while the P1, N1-3, N-1, PN, P2, P3a and cardiac deceleration appear to mark processing prior to novelty, such as stimulus transient detection (cardiac deceleration) and/or intensity processing. This study supports predictions of preliminary process theory, demonstrating fractionation of 3 autonomic and 9 ERP components to novelty, and disconfirming the unitary nature of the OR.


Incentivising doctor attendance in rural Bangladesh: a latent class analysis of a discrete choice experiment.
Doctor absenteeism is widespread in Bangladesh, and the perspectives of the actors involved are insufficiently understood. This paper sought to elicit preferences of doctors over aspects of jobs in rural areas in Bangladesh that can help to inform the development of packages of policy interventions that may persuade them to stay at their posts. We conducted a discrete choice experiment with 308 doctors across four hospitals in Dhaka, Bangladesh. Four attributes of rural postings were included based on a literature review, qualitative research and a consensus-building workshop with policymakers and key health-system stakeholders: relationship with the community, security measures, attendance-based policies and incentive payments. Respondents' choices were analysed with mixed multinomial logistic and latent class models and were used to simulate the likely uptake of jobs under different policy packages. All attributes significantly impacted doctor choices (p<0.01). Doctors strongly preferred jobs at rural facilities where there was a supportive relationship with the community (β=0.93), considered good attendance in education and training (0.77) or promotion decisions (0.67), with functional security (0.67) and higher incentive payments (0.5 per 10% increase of base salary). Jobs with disciplinary action for poor attendance were disliked by respondents (-0.63). Latent class analysis identified three groups of doctors who differed in their uptake of jobs. Scenario modelling identified intervention packages that differentially impacted doctor behaviour and combinations that could feasibly improve doctors' attendance. Bangladeshi doctors have strong but varied preferences over interventions to overcome absenteeism. We generated evidence suggesting that interventions considering the perspective of the doctors themselves could result in substantial reductions in absenteeism. Designing policy packages that take account of the different situations facing doctors could begin to improve their ability and motivation to be present at their job and generate sustainable solutions to absenteeism in rural Bangladesh.


Cytoplasmic sequestration of the RhoA effector mDiaphanous1 by Prohibitin2 promotes muscle differentiation.
Muscle differentiation is controlled by adhesion and growth factor-dependent signalling through common effectors that regulate muscle-specific transcriptional programs. Here we report that mDiaphanous1, an effector of adhesion-dependent RhoA-signalling, negatively regulates myogenesis at the level of Myogenin expression. In myotubes, over-expression of mDia1ΔN3, a RhoA-independent mutant, suppresses Myogenin promoter activity and expression. We investigated mDia1-interacting proteins that may counteract mDia1 to permit Myogenin expression and timely differentiation. Using yeast two-hybrid and mass-spectrometric analysis, we report that mDia1 has a stage-specific interactome, including Prohibitin2, MyoD, Akt2, and β-Catenin, along with a number of proteosomal and mitochondrial components. Of these interacting partners, Prohibitin2 colocalises with mDia1 in cytoplasmic punctae in myotubes. We mapped the interacting domains of mDia1 and Phb2, and used interacting (mDia1ΔN3/Phb2 FL or mDia1ΔN3/Phb2-Carboxy) and non-interacting pairs (mDia1H + P/Phb2 FL or mDia1ΔN3/Phb2-Amino) to dissect the functional consequences of this partnership on Myogenin promoter activity. Co-expression of full-length as well as mDia1-interacting domains of Prohibitin2 reverse the anti-myogenic effects of mDia1ΔN3, while non-interacting regions do not. Our results suggest that Prohibitin2 sequesters mDia1, dampens its anti-myogenic activity and fine-tunes RhoA-mDia1 signalling to promote differentiation. Overall, we report that mDia1 is multi-functional signalling effector whose anti-myogenic activity is modulated by a differentiation-dependent interactome. The data have been deposited to the ProteomeXchange with identifier PXD012257.


Using functional neuroimaging to investigate the mechanisms of action of selective serotonin reuptake inhibitors (SSRIs).
Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of depression and a range of anxiety disorders [1;2]. Preclinical models have been relatively successful at elucidating the key neurochemical effects of these serotonergic agents; however, a lack of understanding exists of the functional mechanisms by which these drugs exert their effects on mood and anxiety. Elucidating the link between the neurochemical effects of these drugs and their therapeutic action is an essential step in further understanding some of the current limitations of SSRIs, and in developing novel agents that are more selectively designed to target the symptoms they treat. An increasingly popular experimental method within psychopharmacological research is the use of functional neuroimaging techniques to investigate the pharmacological modulation of task-induced brain activity by psychoactive drugs. Such an approach offers an exciting opportunity to investigate the mechanisms of drug action and, in this way, bridge the gap between preclinical and clinical studies. Applying this approach to the study of SSRIs has highlighted that direct modulation of activity in neural areas involved in emotional processing may represent a key functional mechanism through which these agents exert their antidepressant clinical effects. This review summarises the cognitive and neuroimaging evidence suggesting the critical role that disruptions in emotion-related processing play in depression and anxiety disorders. It then examines the functional neuroimaging evidence, from both patient and healthy volunteer studies, to suggest that the amelioration of such disruptions is a key mechanism through which SSRIs exert their therapeutic effects.


A Multilayer Microfluidic Platform for the Conduction of Prolonged Cell-Free Gene Expression.
The limitations of cell-based synthetic biology are becoming increasingly apparent as researchers aim to develop larger and more complex synthetic genetic regulatory circuits. The analysis of synthetic genetic regulatory networks in vivo is time consuming and suffers from a lack of environmental control, with exogenous synthetic components interacting with host processes resulting in undesired behavior. To overcome these issues, cell-free characterization of novel circuitry is becoming more prevalent. In vitro transcription and translation (IVTT) mixtures allow the regulation of the experimental environment and can be optimized for each unique system. The protocols presented here detail the fabrication of a multilayer microfluidic device that can be utilized to sustain IVTT reactions for prolonged durations. In contrast to batch reactions, where resources are depleted over time and (by-) products accumulate, the use of microfluidic devices allows the replenishment of resources as well as the removal of reaction products. In this manner, the cellular environment is emulated by maintaining an out-of-equilibrium environment in which the dynamic behavior of gene circuits can be investigated over extended periods of time. To fully exploit the multilayer microfluidic device, hardware and software have been integrated to automate the IVTT reactions. By combining IVTT reactions with the microfluidic platform presented here, it becomes possible to comprehensively analyze complex network behaviors, furthering our understanding of the mechanisms that regulate cellular processes.


Applying unmixing to gene expression data for tumor phylogeny inference.
While in principle a seemingly infinite variety of combinations of mutations could result in tumor development, in practice it appears that most human cancers fall into a relatively small number of "sub-types," each characterized a roughly equivalent sequence of mutations by which it progresses in different patients. There is currently great interest in identifying the common sub-types and applying them to the development of diagnostics or therapeutics. Phylogenetic methods have shown great promise for inferring common patterns of tumor progression, but suffer from limits of the technologies available for assaying differences between and within tumors. One approach to tumor phylogenetics uses differences between single cells within tumors, gaining valuable information about intra-tumor heterogeneity but allowing only a few markers per cell. An alternative approach uses tissue-wide measures of whole tumors to provide a detailed picture of averaged tumor state but at the cost of losing information about intra-tumor heterogeneity. The present work applies "unmixing" methods, which separate complex data sets into combinations of simpler components, to attempt to gain advantages of both tissue-wide and single-cell approaches to cancer phylogenetics. We develop an unmixing method to infer recurring cell states from microarray measurements of tumor populations and use the inferred mixtures of states in individual tumors to identify possible evolutionary relationships among tumor cells. Validation on simulated data shows the method can accurately separate small numbers of cell states and infer phylogenetic relationships among them. Application to a lung cancer dataset shows that the method can identify cell states corresponding to common lung tumor types and suggest possible evolutionary relationships among them that show good correspondence with our current understanding of lung tumor development. Unmixing methods provide a way to make use of both intra-tumor heterogeneity and large probe sets for tumor phylogeny inference, establishing a new avenue towards the construction of detailed, accurate portraits of common tumor sub-types and the mechanisms by which they develop. These reconstructions are likely to have future value in discovering and diagnosing novel cancer sub-types and in identifying targets for therapeutic development.


Respiratory and circulatory control at high altitudes.
Hyperventilation is one of the most important features of acclimatization to high altitude. Resting ventilation at extreme altitudes increases up to fourfold and exercise ventilation for a given work level increases to the same extent. Hypoxic stimulation of the peripheral chemoreceptors is the chief mechanism for the hyperventilation but there is also evidence that central sensitization of the respiratory centres occurs. Permanent residents of high altitude have a blunted hypoxic ventilatory response compared to acclimatized lowlanders. Cardiac output increases in responses to acute hypoxia but returns to normal in acclimatized lowlanders. Oxygen uptake at extreme altitudes is markedly limited by the diffusion properties of the blood gas barrier. As a consequence the maximal oxygen consumption of a climber near the summit of Mount Everest is near his basal oxygen requirements. Maximal oxygen consumption is so sensitive to barometric pressure that it may be that day-to-day variations will affect the chances of a climber reaching the summit without supplementary oxygen.


FNTM: a server for predicting functional networks of tissues in mouse.
Functional Networks of Tissues in Mouse (FNTM) provides biomedical researchers with tissue-specific predictions of functional relationships between proteins in the most widely used model organism for human disease, the laboratory mouse. Users can explore FNTM-predicted functional relationships for their tissues and genes of interest or examine gene function and interaction predictions across multiple tissues, all through an interactive, multi-tissue network browser. FNTM makes predictions based on integration of a variety of functional genomic data, including over 13 000 gene expression experiments, and prior knowledge of gene function. FNTM is an ideal starting point for clinical and translational researchers considering a mouse model for their disease of interest, researchers already working with mouse models who are interested in discovering new genes related to their pathways or phenotypes of interest, and biologists working with other organisms to explore the functional relationships of their genes of interest in specific mouse tissue contexts. FNTM predicts tissue-specific functional relationships in 200 tissues, does not require any registration or installation and is freely available for use at http://fntm.princeton.edu.


Graded activity: legacy of the sanatorium.
Occupational therapists in all areas of practice grade therapeutic activities to help patients progress toward their goals. It is proposed in this paper that the concept of graded activity originated in German tuberculosis sanatoria in the late 1800s, when patients were required to walk on graded (sloped) land for exercise. British physician Marcus Paterson included work, as well as walking, in his graduated exercise program for tuberculosis patients and was honored for this innovation at the founding meeting of the National Society for the Promotion of Occupational Therapy (NSPOT). George Barton, Susan Tracy, and Herbert Hall were among the NSPOT members who contributed to the development of graded activity as a principle in occupational therapy intervention. The military rehabilitation programs established during World War I provided additional impetus, and by the mid-1920s, graded activity was recognized as central to the profession.


Methods of identifying delirium: A research protocol.
Delirium is an acute disorder affecting up to 80% of intensive care unit (ICU) patients. It is associated with a 10-fold increase in cognitive impairment, triples the rate of in-hospital mortality, and costs $164 billion annually. Delirium acutely affects attention and global cognitive function with fluctuating symptoms caused by underlying organic etiologies. Early detection is crucial because the longer a patient experiences delirium the worse it becomes and the harder it is to treat. Currently, identification is through intermittent clinical assessment using standardized tools, like the Confusion Assessment Method for ICU. Such tools work well in clinical research but do not translate well into clinical practice because they are subjective, intermittent and have low sensitivity. As such, healthcare providers using these tools fail to recognize delirium symptoms as much as 80% of the time. Delirium-related biochemical derangement leads to electrical changes in electroencephalographic (EEG) patterns followed by behavioral signs and symptoms. However, continuous EEG monitoring is not feasible due to cost and need for skilled interpretation. Studies using limited-lead EEG show large differences between patients with and without delirium while discriminating delirium from other causes. The Ceribell is a limited-lead device that analyzes EEG. If it is capable of detecting delirium, it would provide an objective physiological monitor to identify delirium before symptom onset. This pilot study was designed to explore relationships between Ceribell and delirium status. Completion of this study will provide a foundation for further research regarding delirium status using the Ceribell data.


Contrasting effects of untreated textile wastewater onto the soil available nitrogen-phosphorus and enzymatic activities in aridisol.
Water shortage and soil qualitative degradation are significant environmental problems in arid and semi-arid regions of the world. The increasing demand for water in agriculture and industry has resulted in the emergence of wastewater use as an alternative in these areas. Textile wastewater is produced in surplus amounts which poses threat to the environment as well as associated flora and fauna. A 60-day incubation study was performed to assess the effects of untreated textile wastewater at 0, 25, 50, 75, and 100% dilution levels on the physico-chemical and some microbial and enzymatic properties of an aridisol soil. The addition of textile wastewater provoked a significant change in soil pH and electrical conductivity and soil dehydrogenase and urease activities compared to the distilled-water treated control soil. Moreover, compared to the control treatment, soil phosphomonoesterase activity was significantly increased from 25 to 75% application rates, but decreased at 100% textile wastewater application rate. Total and available soil N contents increased significantly in response to application of textile wastewater. Despite significant increases in the soil total P contents after the addition of textile wastewater, soil available P content decreased with increasing concentration of wastewater. Changes in soil nutrient contents and related enzymatic activities suggested a dynamic match between substrate availability and soil N and P contents. Aridisols have high fixation and low P availability, application of textile wastewater to such soils should be considered only after careful assessment.


Bulk segregant analysis using single nucleotide polymorphism microarrays.
Bulk segregant analysis (BSA) using microarrays, and extreme array mapping (XAM) have recently been used to rapidly identify genomic regions associated with phenotypes in multiple species. These experiments, however, require the identification of single feature polymorphisms (SFP) between the cross parents for each new combination of genotypes, which raises the cost of experiments. The availability of the genomic polymorphism data in Arabidopsis thaliana, coupled with the efficient designs of Single Nucleotide Polymorphism (SNP) genotyping arrays removes the requirement for SFP detection and lowers the per array cost, thereby lowering the overall cost per experiment. To demonstrate that these approaches would be functional on SNP arrays and determine confidence intervals, we analyzed hybridizations of natural accessions to the Arabidopsis ATSNPTILE array and simulated BSA or XAM given a variety of gene models, populations, and bulk selection parameters. Our results show a striking degree of correlation between the genotyping output of both methods, which suggests that the benefit of SFP genotyping in context of BSA can be had with the cheaper, more efficient SNP arrays. As a final proof of concept, we hybridized the DNA from bulks of an F2 mapping population of a Sulfur and Selenium ionomics mutant to both the Arabidopsis ATTILE1R and ATSNPTILE arrays, which produced almost identical results. We have produced R scripts that prompt the user for the required parameters and perform the BSA analysis using the ATSNPTILE1 array and have provided them as supplemental data files.


WorldSID Dummy Head-Neck Biofidelity Response.
Accident studies indicate that serious neck injuries are generally infrequent in side crashes. However, given the rapid changes in side impact protection technology, such as side airbags and curtain systems, the nature of head-neck interactions is likely to change. Consequently, the newest generation of anthropomorphic test devices for side impact should provide realistic prediction of the head-neck kinematics and include meaningful measurements related to risk of head and neck injury. The WorldSID dummy has been assessed against a set of five test conditions that have been used to define biofidelity impact response targets. Three of the five test conditions are recommended by ISO TR9790 (ISO 1997), the NBDL 7.2 G, 6.9 m/s lateral sled impact reported by Ewing et al. (1977) and Wismans et al. (1986) , the Patrick and Chou lateral, 6.7 G 5.8 m/s (1976) and Tarriere lateral 12.2 g, 6,1 m/s sled impact (ISO 1997). Due to its expected loading environment, the dummy neck performance has also been evaluated for neck bending in frontal flexion and extension (Mertz and Patrick, 1971). The 5th test condition is the NBDL 45 degrees frontal-oblique sled test (Wismans 1986, Philippens 2004). The latter and two of the ISO TR9790 test conditions form the basis of the draft IHRA requirements for evaluating side impact dummy biomechanical responses. The paper reports on the findings of the assessment of the WorldSID pre-production dummy. The Mertz and Patrick OC moment-head angle corridor is used as supplemental requirement for frontal flexion-extension. The biofidelity requirements contain both kinematic and dynamic response targets. The neck has a good performance for NBDL lateral and Tarriere requirements, and the Mertz OC moment-flexion angle. The performance for the Patrick and Chou, the NBDL oblique test conditions and the Mertz OC moment extension angle are fair to marginal. The repeatability performance of the dummy was found to be good for all lateral and most oblique test parameters. The neck design does not allow much more further optimization without fundamental changes.


Regulation of Dense-Core Granule Replenishment by Autocrine BMP Signalling in Drosophila Secondary Cells.
Regulated secretion by glands and neurons involves release of signalling molecules and enzymes selectively concentrated in dense-core granules (DCGs). Although we understand how many secretagogues stimulate DCG release, how DCG biogenesis is then accelerated to replenish the DCG pool remains poorly characterised. Here we demonstrate that each prostate-like secondary cell (SC) in the paired adult Drosophila melanogaster male accessory glands contains approximately ten large DCGs, which are loaded with the Bone Morphogenetic Protein (BMP) ligand Decapentaplegic (Dpp). These DCGs can be marked in living tissue by a glycophosphatidylinositol (GPI) lipid-anchored form of GFP. In virgin males, BMP signalling is sporadically activated by constitutive DCG secretion. Upon mating, approximately four DCGs are typically released immediately, increasing BMP signalling, primarily via an autocrine mechanism. Using inducible knockdown specifically in adult SCs, we show that secretion requires the Soluble NSF Attachment Protein, SNAP24. Furthermore, mating-dependent BMP signalling not only promotes cell growth, but is also necessary to accelerate biogenesis of new DCGs, restoring DCG number within 24 h. Our analysis therefore reveals an autocrine BMP-mediated feedback mechanism for matching DCG release to replenishment as secretion rates fluctuate, and might explain why in other disease-relevant systems, like pancreatic β-cells, BMP signalling is also implicated in the control of secretion.


Firearm availability and suicide, homicide, and unintentional firearm deaths among women.
In the United States, more than 45,000 women died from gun violence over the last decade. To determine whether measures of firearm availability are related to rates of suicide, homicide, and unintentional firearm deaths among women in the United States. Pooled cross-sectional time series data on suicide, homicide, and unintentional firearm deaths (1988-1997) were used to estimate the association between the rate of violent death among women and four proxies of firearm availability. Two proxies came from survey reports of household firearm ownership rates; two were derived from mortality statistics. United States, 1988-1997. The increased rate of suicide and homicide in states with high gun levels was accounted for primarily by significantly elevated firearm suicide and firearm homicide rates. Unintentional firearm death rates were also increased in states with more guns. At the regional level, qualitatively similar results were obtained. Between 1988 and 1997, the suicide, homicide, and unintentional firearm death rates among women were disproportionately higher in states where guns were more prevalent. The elevated rates of violent death in states with more guns was not entirely explained by a state's poverty or urbanization and was driven primarily by lethal firearm violence, not by lethal nonfirearm violence.


Verbal and visual problems in reading disability.
Most individuals interested in reading disability favor the view that disordered language processing is the main cause of children's reading problems and that visual problems are seldom, if ever, responsible. Nevertheless, in a preliminary study (Eden, Stein, & Wood, 1993) we showed that visuospatial and oculomotor tests can be used to differentiate children with reading disabilities from nondisabled children. In the present study we investigated a larger sample of children to see if these findings held true. Using 93 children from the Bowman Gray Learning Disability Project (mean age = 11.3 years; 54 boys, 39 girls), we compared the phonological and visuospatial abilities of nondisabled children (children whose reading at fifth grade rated a Woodcock-Johnson reading standardized score between 85 and 115), and children with reading disability (whose reading standardized score was below 85 on the Woodcock-Johnson). In addition to performing poorly on verbal tests, the children with reading disability were significantly worse than nondisabled children at many visual and eye-movement tasks. A high proportion of the variance (68%) in reading ability of both the nondisabled children and those with reading disability could be predicted by combining visual and phonological scores in a multiple regression. These results provide further support for the hypothesis that reading disability may, to some extent, result from dysfunction of the visual and oculomotor systems.


Neurocomputational mechanisms underlying subjective valuation of effort costs.
In everyday life, we have to decide whether it is worth exerting effort to obtain rewards. Effort can be experienced in different domains, with some tasks requiring significant cognitive demand and others being more physically effortful. The motivation to exert effort for reward is highly subjective and varies considerably across the different domains of behaviour. However, very little is known about the computational or neural basis of how different effort costs are subjectively weighed against rewards. Is there a common, domain-general system of brain areas that evaluates all costs and benefits? Here, we used computational modelling and functional magnetic resonance imaging (fMRI) to examine the mechanisms underlying value processing in both the cognitive and physical domains. Participants were trained on two novel tasks that parametrically varied either cognitive or physical effort. During fMRI, participants indicated their preferences between a fixed low-effort/low-reward option and a variable higher-effort/higher-reward offer for each effort domain. Critically, reward devaluation by both cognitive and physical effort was subserved by a common network of areas, including the dorsomedial and dorsolateral prefrontal cortex, the intraparietal sulcus, and the anterior insula. Activity within these domain-general areas also covaried negatively with reward and positively with effort, suggesting an integration of these parameters within these areas. Additionally, the amygdala appeared to play a unique, domain-specific role in processing the value of rewards associated with cognitive effort. These results are the first to reveal the neurocomputational mechanisms underlying subjective cost-benefit valuation across different domains of effort and provide insight into the multidimensional nature of motivation.


Thermally Conductive Polyethylene/Expanded Graphite Composites as Heat Transfer Surface: Mechanical, Thermo-Physical and Surface Behavior.
Composites of high-density polyethylene (HDPE) and expanded graphite (EG) are prepared for heat exchangers in multi-effect distillation (MED) desalination. At 50 wt.% EG loading, the thermal conductivity of HDPE was increased by 372%. Moreover, the surface wettability of the HDPE/EG composite was enhanced by corona and RF plasma treatment as demonstrated by the increase in surface free energy from 28.5 mJ/m2 for untreated HDPE/EG to 55.5 and 54.5 mJ/m2 for HDPE/EG treated by corona and RF plasma, respectively. This enhanced surface wettability was retained over a long time with only a 9% and 18% decrease in RF and corona plasma-treated samples' surface energy after two months. The viscoelastic moduli and the complex viscosity profiles indicated that EG content dictates the optimum processing technique. At loading below 30 wt.%, the extrusion process is preferred, while above 30 wt.% loading, injection molding is preferred. The plasma treatment also improved the HDPE/EG composite overall heat transfer coefficient with an overall heat transfer coefficient of the composite reaching about 98% that of stainless steel. Moreover, the plasma-treated composite exhibited superior resistance to crystallization fouling in both CaSO4 solution and artificial seawater compared to untreated composites and stainless-steel surfaces.


A semi-automated luminescence based standard membrane feeding assay identifies novel small molecules that inhibit transmission of malaria parasites by mosquitoes.
Current first-line treatments for uncomplicated falciparum malaria rapidly clear the asexual stages of the parasite, but do not fully prevent parasite transmission by mosquitoes. The standard membrane feeding assay (SMFA) is the biological gold standard assessment of transmission reducing activity (TRA), but its throughput is limited by the need to determine mosquito infection status by dissection and microscopy. Here we present a novel dissection-free luminescence based SMFA format using a transgenic Plasmodium falciparum reporter parasite without resistance to known antimalarials and therefore unrestricted in its utility in compound screening. Analyses of sixty-five compounds from the Medicines for Malaria Venture validation and malaria boxes identified 37 compounds with high levels of TRA (>80%); different assay modes allowed discrimination between gametocytocidal and downstream modes of action. Comparison of SMFA data to published assay formats for predicting parasite infectivity indicated that individual in vitro screens show substantial numbers of false negatives. These results highlight the importance of the SMFA in the screening pipeline for transmission reducing compounds and present a rapid and objective method. In addition we present sixteen diverse chemical scaffolds from the malaria box that may serve as a starting point for further discovery and development of malaria transmission blocking drugs.


Matrix metalloproteinase 9 promoter activity is induced coincident with invasion during tumor progression.
Matrix metalloproteinase 9 (MMP-9, also known as gelatinase B or 92-kd Type IV collagenase) is overexpressed in many human and murine cancers. We induced carcinomas in mice carrying a transgene that links the MMP-9 promoter to the reporter ss-galactosidase so that activation of the MMP-9 promoter would be indicated by ss-galactosidase. Mammary carcinomas were induced by mating the MMP-9 promoter reporter transgenic mice with mice carrying a transgene for murine mammary tumor virus promoter linked to polyoma middle T antigen, a transgene that leads to rapid development of mammary tumors in female mice. None of the hyperplastic mammary glands and none of the carcinomas in situ expressed ss-galactosidase. However, all invasive tumors had evidence of ss-galactosidase expression. In addition to the breast carcinomas, a malignant teratoma in a female and a papillary adenocarcinoma in the pelvic region of a male arose and were also ss-galactosidase positive. We also induced skin tumors in the mice with the MMP-9 reporter transgene with 7, 12-dimethylbenz[a]anthracene (DMBA) treatment followed by phorbol 12 myristate 13-acetate (TPA). None of the papillomas or in situ carcinomas showed any ss-galactosidase expression, but expression was seen in invasive carcinoma. Although normal skin epithelial cells did not express ss-galactosidase, we did find staining in a few cells at the duct of the sebaceous gland at the base of the hair follicles. The MMP-9 reporter transgene did not lead to expression in the alveolar macrophages, confirming that additional upstream sequences are required for expression in macrophages. These experiments have revealed that MMP-9 promoter activity is induced coincident with invasion during tumor progression. Furthermore, this indicates that the more proximal upstream elements of the promoter are sufficient for MMP-9 transcription during tumor progression.