Frequency dependent hub role of the dorsal and ventral right anterior insula.
The right anterior insula (rAI) plays a crucial role in generating adaptive behavior by orchestrating multiple brain networks. Based on functional separation findings of the insula and spectral fingerprints theory of cognitive functions, we hypothesize that the hub role of the rAI is region and frequency dependent. Using the Human Connectome Project dataset and backtracking approach, we segregate the rAI into dorsal and ventral parts at frequency bands from slow 6 to slow 3, indicating the frequency dependent functional separation of the rAI. Functional connectivity analysis shows that, within lower than 0.198 Hz frequency range, the dorsal and ventral parts of rAI form a complementary system to synchronize with externally and internally-oriented networks. Moreover, the relationship between the dorsal and ventral rAIs predicts the relationship between anti-correlated networks associated with the dorsal rAI at slow 6 and slow 5, suggesting a frequency dependent regulation of the rAI to brain networks. These findings could improve our understanding of the rAI by supporting the region and frequency dependent function of rAI and its essential role in coordinating brain systems relevant to internal and external environments.


Learning Invariant Patterns Based on a Convolutional Neural Network and Big Electroencephalography Data for Subject-Independent P300 Brain-Computer Interfaces.
A brain-computer interface (BCI) measures and analyzes brain activity and converts this activity into computer commands to control external devices. In contrast to traditional BCIs that require a subject-specific calibration process before being operated, a subject-independent BCI learns a subject-independent model and eliminates subject-specific calibration for new users. However, building subject-independent BCIs remains difficult because electroencephalography (EEG) is highly noisy and varies by subject. In this study, we propose an invariant pattern learning method based on a convolutional neural network (CNN) and big EEG data for subject-independent P300 BCIs. The CNN was trained using EEG data from a large number of subjects, allowing it to extract subject-independent features and make predictions for new users. We collected EEG data from 200 subjects in a P300-based spelling task using two different types of amplifiers. The offline analysis showed that almost all subjects obtained significant cross-subject and cross-amplifier effects, with an average accuracy of more than 80%. Furthermore, more than half of the subjects achieved accuracies above 85%. These results indicated that our method was effective for building a subject-independent P300 BCI, with which more than 50% of users could achieve high accuracies without subject-specific calibration.


A continuous morphological approach to study the evolution of pollen in a phylogenetic context: An example with the order Myrtales.
The study of pollen morphology has historically allowed evolutionary biologists to assess phylogenetic relationships among Angiosperms, as well as to better understand the fossil record. During this process, pollen has mainly been studied by discretizing some of its main characteristics such as size, shape, and exine ornamentation. One large plant clade in which pollen has been used this way for phylogenetic inference and character mapping is the order Myrtales, composed by the small families Alzateaceae, Crypteroniaceae, and Penaeaceae (collectively the "CAP clade"), as well as the large families Combretaceae, Lythraceae, Melastomataceae, Myrtaceae, Onagraceae and Vochysiaceae. In this study, we present a novel way to study pollen evolution by using quantitative size and shape variables. We use morphometric and morphospace methods to evaluate pollen change in the order Myrtales using a time-calibrated, supermatrix phylogeny. We then test for conservatism, divergence, and morphological convergence of pollen and for correlation between the latitudinal gradient and pollen size and shape. To obtain an estimate of shape, Myrtales pollen images were extracted from the literature, and their outlines analyzed using elliptic Fourier methods. Shape and size variables were then analyzed in a phylogenetic framework under an Ornstein-Uhlenbeck process to test for shifts in size and shape during the evolutionary history of Myrtales. Few shifts in Myrtales pollen morphology were found which indicates morphological conservatism. Heterocolpate, small pollen is ancestral with largest pollen in Onagraceae. Convergent shifts in shape but not size occurred in Myrtaceae and Onagraceae and are correlated to shifts in latitude and biogeography. A quantitative approach was applied for the first time to examine pollen evolution across a large time scale. Using phylogenetic based morphometrics and an OU process, hypotheses of pollen size and shape were tested across Myrtales. Convergent pollen shifts and position in the latitudinal gradient support the selective role of harmomegathy, the mechanism by which pollen grains accommodate their volume in response to water loss.


Motor Imagery Training on Muscle Strength and Gait Performance in Ambulant Stroke Subjects-A Randomized Clinical Trial.
The ultimate goal of physiotherapy in stroke rehabilitation is focused towards physical independence and to restore their functional ability during activities of daily living (ADLs). Motor imagery (MI) is an active process during which a specific action is reproduced within working memory without any actual movements. MI training enhances motor learning, neural reorganization and cortical activation in stroke. The efficacy of MI training involving lower extremity mobility tasks need to be assessed. To evaluate the effects of combining motor imagery with physical practice in paretic Lower Extremity Muscles Strength and Gait Performance in Ambulant Stroke subjects. A Randomized Clinical Trial was conducted in Department of Physical Therapy, Tertiary Care Hospitals, Mangalore, India which includes 40 hemi paretic subjects (>3 months post-stroke) who were ambulant with good imagery ability in both KVIQ-20 ≥ 60 and Time dependent MI screening test were recruited and randomly allocated into task-oriented training group (n=20) and task-oriented training group plus MI group (n=20). Subjects in both groups underwent task orientated training for lower extremity 45-60 minutes, 4 days per week for 3 weeks. In addition, the experimental group received 30 minutes of audio-based lower extremity mobility tasks for MI practice. Isometric muscle strength of Hip, Knee and Ankle using a hand-held dynamometer and self-selected 10 m gait speed were assessed before and after 3 weeks of intervention. Both the groups had found a significant change for all the outcome measures following 3 weeks of interventions with p <.05. The experimental group had shown a significant improvement in paretic hip muscles (both flexors and extensors), knee extensors and ankle dorsiflexors and gait speed compare to control group with p < .05 between group analyses. Additional task specific MI training improves paretic muscle strength and gait performance in ambulant stroke patients.


MicroRNA‑543 inhibits proliferation, invasion and induces apoptosis of glioblastoma cells by directly targeting ADAM9.
Glioma is the most common type of malignant brain tumor in humans and accounts for 81% of all malignant brain tumor cases in adults. The abnormal expression of microRNAs (miRs) has been reported to be important in the formation and progression of various types of human cancer, including glioblastoma (GBM). Therefore, studies into the expression, and roles of microRNAs as diagnostic and prognostic markers, as well as their therapeutic value for patients with GBM are warranted. The expression and roles of miR‑543 have been reported in several types of human cancer. However, the role of miR‑543 in GBM remains unclear. In the current study, the expression pattern of miR‑543 in GBM, the effects of miR‑543 on GBM cells and the underlying molecular mechanism was determined. The results of the present study demonstrated that miR‑543 was significantly downregulated in GBM tissue samples and cell lines. Furthermore, the upregulation of miR‑543 inhibited GBM cell proliferation and invasion, as well as promoted cell apoptosis. In addition, a disintegrin and metalloproteinase 9 (ADAM9) was identified to be a direct target gene of miR‑543. Furthermore, ADAM9 was significantly upregulated in GBM tissue samples and its expression was inversely correlated with miR‑543 expression in GBM tissue, suggesting that miR‑543 downregulation may contribute to ADAM9 upregulation in GBM. Finally, the results of the rescue experiment indicated that ADAM9 overexpression significantly reversed the effects of miR‑543 on the proliferation, invasion and apoptosis of GBM cells, suggesting that miR‑543 serves as a tumor suppressor in GBM through ADAM9 regulation. Overall, these findings indicate that the miR‑543/ADAM9 signaling pathway may provide as a potential therapeutic strategy for GBM.


Division of the momentum of electromagnetic waves in linear media into electromagnetic and material parts.
It is proposed a natural and consistent division of the momentum of electromagnetic waves in linear, non-dispersive and non-absorptive dielectric and magnetic media into material and electromagnetic parts. The material part is calculated using directly the Lorentz force law and the electromagnetic momentum density has the form epsilon(0)E x B, without an explicit dependence on the properties of the media. The consistency of the treatment is verified through the obtention of a correct momentum balance equation in many examples and showing the compatibility of the division with the Einstein's theory of relativity by the use of a gedanken experiment. An experimental prediction for the radiation pressure on mirrors immersed in linear dielectric and magnetic media is also made.


Structural basis for anticodon recognition by methionyl-tRNA synthetase.
In the 2.7-A resolution crystal structure of methionyl-tRNA synthetase (MetRS) in complex with tRNA(Met) and a methionyl-adenylate analog, the tRNA anticodon loop is distorted to form a triple-base stack comprising C34, A35 and A38. A tryptophan residue stacks on C34 to extend the triple-base stack. In addition, C34 forms Watson-Crick-type hydrogen bonds with Arg357. This structure resolves the longstanding question of how MetRS specifically recognizes tRNA(Met).


The perfect storm: incarceration and the high-risk environment perpetuating transmission of HIV, hepatitis C virus, and tuberculosis in Eastern Europe and Central Asia.
Despite global reductions in HIV incidence and mortality, the 15 UNAIDS-designated countries of Eastern Europe and Central Asia (EECA) that gained independence from the Soviet Union in 1991 constitute the only region where both continue to rise. HIV transmission in EECA is fuelled primarily by injection of opioids, with harsh criminalisation of drug use that has resulted in extraordinarily high levels of incarceration. Consequently, people who inject drugs, including those with HIV, hepatitis C virus, and tuberculosis, are concentrated within prisons. Evidence-based primary and secondary prevention of HIV using opioid agonist therapies such as methadone and buprenorphine is available in prisons in only a handful of EECA countries (methadone or buprenorphine in five countries and needle and syringe programmes in three countries), with none of them meeting recommended coverage levels. Similarly, antiretroviral therapy coverage, especially among people who inject drugs, is markedly under-scaled. Russia completely bans opioid agonist therapies and does not support needle and syringe programmes-with neither available in prisons-despite the country's high incarceration rate and having the largest burden of people with HIV who inject drugs in the region. Mathematical modelling for Ukraine suggests that high levels of incarceration in EECA countries facilitate HIV transmission among people who inject drugs, with 28-55% of all new HIV infections over the next 15 years predicted to be attributable to heightened HIV transmission risk among currently or previously incarcerated people who inject drugs. Scaling up of opioid agonist therapies within prisons and maintaining treatment after release would yield the greatest HIV transmission reduction in people who inject drugs. Additional analyses also suggest that at least 6% of all incident tuberculosis cases, and 75% of incident tuberculosis cases in people who inject drugs are due to incarceration. Interventions that reduce incarceration itself and effectively intervene with prisoners to screen, diagnose, and treat addiction and HIV, hepatitis C virus, and tuberculosis are urgently needed to stem the multiple overlapping epidemics concentrated in prisons.


Natural and anthropogenic ethanol sources inNorth America and potential atmospheric impacts of ethanol fuel use.
We used an ensemble of aircraft measurements with the GEOS-Chem chemical transport model to constrain present-day North American ethanol sources, and gauge potential long-range impacts of increased ethanol fuel use. We find that current ethanol emissions are underestimated by 50% in Western North America, and overestimated by a factor of 2 in the east. Our best estimate for year-2005 North American ethanol emissions is 670 GgC/y, with 440 GgC/y from the continental U.S. We apply these optimized source estimates to investigate two scenarios for increased ethanol fuel use in the U.S.: one that assumes a complete transition from gasoline to E85 fuel, and one tied to the biofuel requirements of the U.S. Energy Indepence and Security Act (EISA). For both scenarios, increased ethanol emissions lead to higher atmospheric acetaldehyde concentrations (by up to 14% during winter for the All-E85 scenario and 2% for the EISA scenario) and an associated shift in reactive nitrogen partitioning reflected by an increase in the peroxyacetyl nitrate (PAN) to NO(y) ratio. The largest relative impacts occur during fall, winter, and spring because of large natural emissions of ethanol and other organic compounds during summer. Projected changes in atmospheric PAN reflect a balance between an increased supply of peroxyacetyl radicals from acetaldehyde oxidation, and the lower NO(x) emissions for E85 relative to gasoline vehicles. The net effect is a general PAN increase in fall through spring, and a weak decrease over the U.S. Southeast and the Atlantic Ocean during summer. Predicted NO(x) concentrations decrease in surface air over North America (by as much 5% in the All-E85 scenario). Downwind of North America this effect is counteracted by higher NO(x) export efficiency driven by increased PAN production and transport. From the point of view of NO(x) export from North America, the increased PAN formation associated with E85 fuel use thus acts to offset the associated lower NO(x) emissions.


Interactions of pre-symbolic children with developmental disabilities with their mothers and siblings.
Depending on the severity of their disabilities, children with Down syndrome (DS) and with cerebral palsy (CP) may remain pre-symbolic for prolonged periods of time. When interacting with pre-symbolic children, communication partners have a role in identifying which of their behaviours are communicative, to be able to respond to those behaviours and maintain reciprocal interaction. To date, most research on these children's communication development has been conducted within the context of mother-child interaction. Seldom have they been observed interacting with other family members, and in interactions other than dyadic, despite these interactions also occurring daily. To explore and compare the interaction of mothers and siblings with pre-symbolic children with DS and with CP in dyadic and triadic contexts. Twelve pre-symbolic children with DS (aged 1;10-5;04 years) and 12 with CP (aged 1;09-5;07 years), and their mothers and siblings participated in this study. They were recruited from early intervention centres from the West Coast of Peninsular Malaysia. Children were observed as they engaged in three play interactions: mother-child, sibling-child and mother-sibling-child (triadic). Children produced the most pre-symbolic communicative behaviours during mother-child, followed by triadic and lastly sibling-child interaction, suggesting that the mother's presence encouraged children to communicate. Mothers created a more facilitative communication environment for the children than did siblings, by directing high rates of initiations towards them and by taking turns that paved the way for the child's next turn. Although siblings' low rates of interaction did not provide children with as many opportunities to produce communicative behaviours, it encouraged them to produce high proportions of initiations. During triadic interaction, mothers and siblings had to direct interaction towards two communication partners, causing them to direct less interaction towards the children with DS or CP. There was no significant difference in mother and sibling responsiveness to children's communicative behaviours across interactions and disability types, suggesting that mothers and siblings might have adapted to the children's various early communicative behaviours. From this study, it was evident that mothers and siblings of pre-symbolic children with DS and with CP engaged them in reciprocal interaction. Findings on how mothers and siblings influence pre-symbolic children's communication suggest the need to involve them in assessment and intervention for these children.


Attending Emergency Physicians' Perceptions of a Programmatic Workplace-Based Assessment System: The McMaster Modular Assessment Program (McMAP).
Construct: The McMaster Modular Assessment Program (McMAP) is a programmatic workplace-based assessment (WBA) system that provides emergency medicine trainees with competency judgments through frequent task-specific and global daily assessments. Background: The longevity of McMAP relative to other programmatic WBA systems affords a unique view that precedes large-scale transitions to competency-based medical education (CBME), particularly in North America. Although prior work has described the perspective of residents using this system, the in-depth experiences of assessors using the system have yet to be explored. This perspective is important for understanding the validity of the competency judgments the system produces. Approach: We conducted a qualitative study that used semi-structured interviews analyzed using interpretive description (Thorne) to explore 16 attending physicians' experiences using McMAP. Data analysis was completed independently by 2 researchers, who met regularly to discuss codes and resolve any disagreements. Results: Having a structured assessment framework for a range of clinical tasks has helped encourage what attendings perceived to be more frequent and better-quality assessments, with the added advantages of being holistic, flexible, and learner-driven. However, attendings also perceived a number of challenges of McMAP and programmatic WBA more broadly. These included a reluctance to give and to document negative feedback, "gaming" of the system by both attendings and residents, and a variety of logistic and technology-related concerns. Conclusions: Based on our findings, we offer several key recommendations that can help programs maximize the benefits of programmatic WBA as they transition to CBME.


Pentameric assembly of a neuronal glutamate transporter.
Freeze-fracture electron microscopy was used to study the structure of a human neuronal glutamate transporter (EAAT3). EAAT3 was expressed in Xenopus laevis oocytes, and its function was correlated with the total number of transporters in the plasma membrane of the same cells. Function was assayed as the maximum charge moved in response to a series of transmembrane voltage pulses. The number of transporters in the plasma membrane was determined from the density of a distinct 10-nm freeze-fracture particle, which appeared in the protoplasmic face only after EAAT3 expression. The linear correlation between EAAT3 maximum carrier-mediated charge and the total number of the 10-nm particles suggested that this particle represented functional EAAT3 in the plasma membrane. The cross-sectional area of EAAT3 in the plasma membrane (48 +/- 5 nm(2)) predicted 35 +/- 3 transmembrane alpha-helices in the transporter complex. This information along with secondary structure models (6-10 transmembrane alpha-helices) suggested an oligomeric state for EAAT3. EAAT3 particles were pentagonal in shape in which five domains could be identified. They exhibited fivefold symmetry because they appeared as equilateral pentagons and the angle at the vertices was 110 degrees. Each domain appeared to contribute to an extracellular mass that projects approximately 3 nm into the extracellular space. Projections from all five domains taper toward an axis passing through the center of the pentagon, giving the transporter complex the appearance of a penton-based pyramid. The pentameric structure of EAAT3 offers new insights into its function as both a glutamate transporter and a glutamate-gated chloride channel.


A cAMP-regulatory sequence (CRS1) of CYP17 is a cellular target for the homeodomain protein Pbx1.
Cytochrome P450c17 encoded by CYP17, whose expression is regulated by peptide hormones via cAMP, is required for cortisol and sex hormone biosynthesis thereby playing a key role in biological processes including sexual differentiation. Utilizing the cAMP-regulatory sequence CRS1 of the bovine CYP17 gene as an affinity ligand, four CRS1-binding proteins have been purified from nuclear extracts of mouse adrenocortical Y1 cells and shown to enhance the in vitro transcription of a reporter gene promoted by CRS1. Microsequencing of these four proteins established two of them to be the homeodomain proteins Pbx1a and Pbx1b, originally discovered by their involvement in the t(1;19) chromosomal translocation in pre-B-cell acute lymphoblastic leukemias. Overexpression of Pbx1 in Y1 cells enhances cAMP-dependent transcription of the CRS1-dependent reporter gene. These results identify the CRS1 of bovine CYP17 as a cellular target for Pbx1 and suggest that one role of this homeodomain protein is in the regulation of steroidogenesis and subsequently sexual development.


Mechanical equivalence of spin and orbital angular momentum of light: an optical spanner.
We use a Laguerre-Gaussian laser mode within an optical tweezers arrangement to demonstrate the transfer of the orbital angular momentum of a laser mode to a trapped particle. The particle is optically confined in three dimensions and can be made to rotate; thus the apparatus is an optical spanner. We show that the spin angular momentum of +/-?per photon associated with circularly polarized light can add to, or subtract from, the orbital angular momentum to give a total angular momentum. The observed cancellation of the spin and orbital angular momentum shows that, as predicted, a Laguerre-Gaussian mode with an azimuthal mode index l=1 has a well-defined orbital angular momentum corresponding to ? per photon.


Distribution and Characteristics of Groundnut Rosette Disease in Kenya.
Groundnut rosette is a major virus disease of peanut in sub-Saharan Africa. The disease is caused by a complex of three agents: GRAV (groundnut rosette assistor luteovirus), GRV (groundnut rosette umbravirus), and the associated satellite RNA (Sat-RNA). During the 1997 to 1998 crop season, the incidence of rosette in farmers' fields was estimated at 24 to 40% in western Kenya and 30% in the Rift Valley. Sequence analysis of Kenyan isolates revealed that GRAV-CP sequences shared 97 to 100% and 95 to 98% sequence homology at nucleotide and amino acid levels, respectively, amongst themselves and with the Malawian and Nigerian isolates. The ORFs 3 and 4 of GRV were similar, with a homology of 99% at the nucleotide and amino acid levels among Kenyan isolates. The GRV sequences of Kenyan isolates were closer to the Malawian (95 to 96%) than to the Nigerian (87 to 88%) isolates. Sat-RNA shared 89 to 94% nucleotide identity with those from Malawi and Nigeria. A closer sequence relationship was observed between Kenyan and Malawian isolates in all regions compared. This is the first report on the distribution and molecular characterization of groundnut rosette disease complex in East Africa.


Orthostatic hypotension-related hospitalizations in the United States.
Orthostatic hypotension has been commonly described in elderly persons and is associated with an increased risk of falls, syncope, and cerebrovascular events. Nevertheless, the precise burden of this condition in the US is currently unknown. We analyzed discharge data from the Nationwide Inpatient Sample to identify orthostatic hypotension-related hospitalizations and associated comorbidities after excluding acute causes of this condition. National hospitalization rates were estimated using US census population estimates, and the medical conditions most frequently associated with orthostatic hypotension were assessed. In 2004, there were an estimated 80,095 orthostatic hypotension-related hospitalizations, yielding an overall rate of 36 (95% confidence interval, 34 to 38) hospitalizations per 100,000 US adults. Orthostatic hypotension was the primary diagnosis in 35% of these hospitalizations. The number of orthostatic hypotension-related hospitalizations increased steadily with age, and patients aged 75 years or older had the highest annual hospitalization rate, 233 per 100,000 (95% confidence interval, 217 to 249). The median length of hospital stay was 3 days (IQR 2-6) and the overall in-hospital mortality was 0.9%. Caucasian males were most likely to be hospitalized with orthostatic hypotension. Syncope was the most common comorbid condition reported among orthostatic hypotension patients. Orthostatic hypotension is a relatively common condition among hospitalized US elderly patients. In light of the progressive aging of the US population, the contribution of orthostatic hypotension to morbidity and mortality is likely to increase, and deserves further scrutiny.


Inconsistent fertility motivations and contraceptive use behaviors among women in Honduras.
Recent studies have demonstrated that it is common for women to report inconsistent fertility motivations and family planning behaviors. This study examines these inconsistencies among urban Honduran women interviewed at two points in time and presents reasons for inconsistent fertility motivations and contraceptive behaviors at follow-up. Data come from a one-year panel study conducted in Honduras from October 2006 to December 2007. A total of 633 women aged 15-44 years were interviewed at baseline and follow-up and have non-missing information on the key variables of interest. At baseline and follow-up, women were asked how much of a problem it would be (no problem/small problem/big problem) if they got pregnant in the next couple of weeks. At follow-up, women were asked an open-ended question on reasons it would be no problem, a small problem, or a big problem. The open-ended question was recoded into a smaller set of response categories. Univariate and bivariate analyses are presented to examine inconsistencies and reasons for stated inconsistencies. At follow-up, over half the women using a contraceptive method said that it would be no problem if they got pregnant. Nearly half of the women changed their perceptions between baseline and follow-up. Common reasons for reporting no problem among contraceptive users were that they accepted a child as God's will or that children are a blessing, their last child was old enough and they wanted another child. Common reasons for reporting a big/small problem among non-users of family planning (who have an unmet need for family planning) were that they were not in a stable relationship, the husband was not present, and they would expect a negative response from their family. Inconsistent fertility motivations and contraceptive behaviors are common among effective contraceptive users. Women who are using contraception and become pregnant will not necessarily report the pregnancy as unintended, given the widespread acceptance of unintended pregnancies in Honduras. Family planning providers need to recognize that fertility motivations vary over time and that women may not have firm motivations to avoid a pregnancy.


Human RECQ5beta helicase promotes strand exchange on synthetic DNA structures resembling a stalled replication fork.
The role of the human RECQ5beta helicase in the maintenance of genomic stability remains elusive. Here we show that RECQ5beta promotes strand exchange between arms of synthetic forked DNA structures resembling a stalled replication fork in a reaction dependent on ATP hydrolysis. BLM and WRN can also promote strand exchange on these structures. However, in the presence of human replication protein A (hRPA), the action of these RecQ-type helicases is strongly biased towards unwinding of the parental duplex, an effect not seen with RECQ5beta. A domain within the non-conserved portion of RECQ5beta is identified as being important for its ability to unwind the lagging-strand arm and to promote strand exchange on hRPA-coated forked structures. We also show that RECQ5beta associates with DNA replication factories in S phase nuclei and persists at the sites of stalled replication forks after exposure of cells to UV irradiation. Moreover, RECQ5beta is found to physically interact with the polymerase processivity factor proliferating cell nuclear antigen in vitro and in vivo. Collectively, these findings suggest that RECQ5beta may promote regression of stalled replication forks to facilitate the bypass of replication-blocking lesions by template-switching. Loss of such activity could explain the elevated level of mitotic crossovers observed in RECQ5beta-deficient cells.


Tobacco use, cessation advice to patients and attitudes to tobacco control among physicians in Ukraine.
To examine the relationship between physicians' smoking behaviors and their attitudes toward tobacco use by their patients and tobacco control in the Ukraine, a 70-item questionnaire was administered to 799 general practitioners (287 men and 512 women) working in both rural (278 physicians) and urban (521 physicians) areas of three regions of Ukraine. In all, 13.9% of physicians were current smokers and 21.6% reported being past smokers, with significantly (P<0.001) more men than women being current or past smokers. Odds ratios from logistic regression analysis reveal that physicians who are heavy smokers are 26% less likely to record tobacco use by patients than medium smokers. Heavy smokers devote significantly less effort to providing cessation information to patients and are 36% less likely to support the complete prohibition of smoking in the physician's workplace. Older physicians, female physicians and physicians working in urban areas are significantly more likely than younger, male and rural physicians to advise their patients on smoking. The provision of smoking cessation to patients by general practitioners in Ukraine is influenced by several factors, a major one being the smoking status of the physician. If smoking among physicians declines, this will encourage the patient to consider a serious quit attempt in several ways, most notably: (1) physicians act as societal role models and can promote non-smoking as a norm and (2) the likelihood that a patient will be provided smoking cessation counseling increases.


Hydride oxidation from a titanium-aluminum bimetallic complex: insertion, thermal and electrochemical reactivity.
We report the synthesis and reactivity of paramagnetic heterometallic complexes containing a Ti(iii)-μ-H-Al(iii) moiety. Combining different stoichiometries amounts of Cp2TiCl and KH3AlC(TMS)3 (Cp = cyclopentadienyl, TMS = trimethylsilyl) resulted in the formation of either bimetallic Cp2Ti(μ-H)2(H)AlC(TMS)3 (2) or trimetallic (Cp2Ti)2(μ-H)3(H)AlC(TMS)3 (3) via salt metathesis pathways. While these complexes were indefinitely stable at room temperature, the bridging hydrides were readily activated upon exposure to heteroallenes, heating, or electrochemical oxidation. In each case, formal hydride oxidation occurred, but the isolated product maintained the +3 oxidation state at both metal centers. The nature of this reactivity was explored using deuterium labelling experiments and Density Functional Theory (DFT) calculations. It was found that while C-H activation from the Ti(iii) bimetallic may occur through a σ-bond metathesis pathway, chemical oxidation to Ti(iv) promotes bimolecular reductive elimination of dihydrogen to form a Ti(iii) product.


Determinants of survival in progressive multifocal leukoencephalopathy.
We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML). We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood. Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/microL at PML diagnosis compared to 67% in those with CD4 >200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival. The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.


Chimpanzees and bonobos differ in intrinsic motivation for tool use.
Tool use in nonhuman apes can help identify the conditions that drove the extraordinary expansion of hominin technology. Chimpanzees and bonobos are our closest living relatives. Whereas chimpanzees are renowned for their tool use, bonobos use few tools and none in foraging. We investigated whether extrinsic (ecological and social opportunities) or intrinsic (predispositions) differences explain this contrast by comparing chimpanzees at Kalinzu (Uganda) and bonobos at Wamba (DRC). We assessed ecological opportunities based on availability of resources requiring tool use. We examined potential opportunities for social learning in immature apes. Lastly, we investigated predispositions by measuring object manipulation and object play. Extrinsic opportunities did not explain the tool use difference, whereas intrinsic predispositions did. Chimpanzees manipulated and played more with objects than bonobos, despite similar levels of solitary and social play. Selection for increased intrinsic motivation to manipulate objects likely also played an important role in the evolution of hominin tool use.


Characterization of Drosophila GDNF receptor-like and evidence for its evolutionarily conserved interaction with neural cell adhesion molecule (NCAM)/FasII.
Glial cell line-derived neurotrophic factor (GDNF) family ligands are secreted growth factors distantly related to the TGF-β superfamily. In mammals, they bind to the GDNF family receptor α (Gfrα) and signal through the Ret receptor tyrosine kinase. In order to gain insight into the evolution of the Ret-Gfr-Gdnf signaling system, we have cloned and characterized the first invertebrate Gfr-like cDNA (DmGfrl) from Drosophila melanogaster and generated a DmGfrl mutant allele. We found that DmGfrl encodes a large GPI-anchored membrane protein with four GFR-like domains. In line with the fact that insects lack GDNF ligands, DmGfrl mediated neither Drosophila Ret phosphorylation nor mammalian RET phosphorylation. In situ hybridization analysis revealed that DmGfrl is expressed in the central and peripheral nervous systems throughout Drosophila development, but, surprisingly, DmGfrl and DmRet expression patterns were largely non-overlapping. We generated a DmGfrl null allele by genomic FLP deletion and found that both DmGfrl null females and males are viable but display fertility defects. The female fertility defect manifested as dorsal appendage malformation, small size and reduced viability of eggs laid by mutant females. In male flies DmGfrl interacted genetically with the Drosophila Ncam (neural cell adhesion molecule) homolog FasII to regulate fertility. Our results suggest that Ret and Gfrl did not function as an in cis receptor-coreceptor pair before the emergence of GDNF family ligands, and that the Ncam-Gfr interaction predated the in cis Ret-Gfr interaction in evolution. The fertility defects that we describe in DmGfrl null flies suggest that GDNF receptor-like has an evolutionarily ancient role in regulating male fertility and a previously unrecognized role in regulating oogenesis. These results shed light on the evolutionary aspects of the structure, expression and function of Ret-Gfrα and Ncam-Gfrα signaling complexes.


Engineered Reversal of Function in Glycolytic Yeast Promoters.
Promoters are key components of cell factory design, allowing precise expression of genes in a heterologous pathway. Several commonly used promoters in yeast cell factories belong to glycolytic genes, highly expressed in actively growing yeast when glucose is used as a carbon source. However, their expression can be suboptimal when alternate carbon sources are used, or if there is a need to decouple growth from production. Hence, there is a need for alternate promoters for different carbon sources and production schemes. In this work, we demonstrate a reversal of regulatory function in two glycolytic yeast promoters by replacing glycolytic regulatory elements with ones induced by the diauxic shift. We observe a shift in induction from glucose-rich to glucose-poor medium without loss of regulatory activity, and strong ethanol induction. Applications of these promoters were validated for expression of the vanillin biosynthetic pathway, reaching production of vanillin comparable to pathway designs using strong constitutive promoters.


Anticoagulant treatment and survival in cancer patients. The evidence from clinical studies.
The association between cancer and an increased incidence of venous thromboembolism (Trousseau syndrome) is well characterized and recent studies have shown that the hemostatic system plays a key role at different stages in the process of tumorigenesis. Anticoagulant drugs therefore appear to be an attractive strategy in cancer therapy, with an effect that would surpass the benefit of preventing thrombosis. This hypothesis was initially supported by the post-hoc analysis of clinical trials not primarily designed to evaluate the effect of anticoagulants, mainly low molecular weight heparins (LMWH), on cancer survival. Other studies regarding the addition of unfractionated heparin or oral anticoagulants to standard cancer treatment offered controversial results. However, recent investigations among cancer patients without deep venous thrombosis, with cancer-related mortality as the primary end point, suggest that at least in some patients LMWH may exert an antineoplastic effect in vivo and alter the natural history of malignant disease by increasing the response rates and, therefore, improving survival. Additional research on this field is needed to clarify the biological mechanisms involved and to answer yet unsolved questions such as the types of tumor and stages of disease most suitable for this treatment as well as how to optimize treatment regimens.


Physiological responses of bacteria in biofilms to disinfection.
In situ enumeration methods using fluorescent probes and a radioisotope labelling technique were applied to evaluate physiological changes of Klebsiella pneumoniae within biofilms after disinfection treatment. Chlorine (0.25 mg of free chlorine per liter [pH 7.2]) and monochloramine (1 mg/liter [pH 9.0]) were employed as disinfectants in the study. Two fluorgenic compounds, 5-cyano-2,3-ditolyl tetrazolium chloride and rhodamine 123, and tritiated uridine incorporation were chosen for assessment of physiological activities. Results obtained by these methods were compared with those from the plate count and direct viable count methods. 5-Cyano-2,3-ditolyl tetrazolium chloride is an indicator of bacterial respiratory activity, rhodamine 123 is incorporated into bacteria in response to transmembrane potential, and the incorporation of uridine represents the global RNA turnover rate. The results acquired by these methods following disinfection exposure showed a range of responses and suggested different physiological reactions in biofilms exposed to chlorine and monochloramine. The direct viable count response and respiratory activity were affected more by disinfection than were the transmembrane potential and RNA turnover rate on the basis of comparable efficiency as evaluated by plate count enumeration. Information revealed by these approaches can provide different physiological insights that may be used in evaluating the efficacy of biofilm disinfection.


Cognitive disorganization in hippocampus: a physiological model of the disorganization in psychosis.
Cognitive coordination refers to processes that organize the timing of activity among neurons without altering individual discharge properties. Coordinating processes allow neural networks to coactivate related representations and prevent the coactivation of unrelated representations. Impaired cognitive coordination, also called cognitive disorganization, is hypothesized to be the core deficit in the disorganized syndrome of schizophrenia (Phillips and Silverstein, 2003), a condition characterized by hallucinations, disorganization, and thought disorder. This disorganization hypothesis is based on the observation that schizophrenic subjects are impaired at segregating relevant and irrelevant stimuli and selectively using associations between relevant cues. We report that injecting the neural activity blocker tetrodotoxin (TTX) into one hippocampus persistently coactivated pyramidal cells in the uninjected hippocampus that initially discharged independently. In accord with the definition of cognitive disorganization, pyramidal cell firing rates only changed for 15 min and did not accompany the coactivation. The TTX-induced coactivity was maximal at gamma periods, consistent with altered gamma oscillations and disorganization in schizophrenia. A network model confirmed that increasing the coupling of weakly associated cells impairs the selective activation and inhibition of stored spatial representations. This TTX-induced cognitive disorganization correctly predicted that the same TTX injection selectively impaired the ability of rats to segregate relevant associations among distal spatial stimuli from irrelevant local stimuli (Wesierska et al., 2005). The TTX-induced coactivity of hippocampal pyramidal cell discharge has construct and predictive validity as a physiological model of psychosis-related disorganization.


Cardiovascular risk factors associated with polymyalgia rheumatica and giant cell arteritis in a prospective cohort: EPIC-Norfolk Study.
PMR and GCA are associated with increased risk of vascular disease. However, it remains unclear whether this relationship is causal or reflects a common underlying propensity. The aim of this study was to identify whether known cardiovascular risk factors increase the risk of PMR and GCA. Clinical records were examined using key word searches to identify cases of PMR and GCA, applying current classification criteria in a population-based cohort. Associations between cardiovascular risk factors and incident PMR and GCA were analysed using Cox proportional hazards. In 315 022 person years of follow-up, there were 395 incident diagnoses of PMR and 118 incident diagnoses of GCA that met the clinical definition. Raised diastolic blood pressure (>90 mmHg) at baseline/recruitment was associated with subsequent incident PMR [hazard ratio=1.35 (95% CI 1.01, 1.80) P=0.045], and ever-smoking was associated with incident GCA [hazard ratio=2.01 (95% CI 1.26, 3.20) P=0.003]. Estimates were similar when the analysis was restricted to individuals whose diagnoses satisfied the current classification criteria sets. PMR and GCA shares common risk factors with vascular disease onset, suggesting a common underlying propensity. This may indicate a potential for disease prevention strategies through modifying cardiovascular risk.


Outcomes of faecal occult blood tests requested outside the UK National Bowel Cancer Screening Programme.
Faecal occult blood test (FOBt) is commonly requested by clinicians in both primary and secondary care. The aim of this study was to examine the use and outcomes of clinician-requested FOB testing in a single Trust taking part in the National Bowel Cancer Screening Programme pilots. Data from a single Trust was used. The Trust's pathology reporting system was searched retrospectively for all FOBt study requests in 1 year. In patients with a positive test, the Trust's clinical results reporting system was searched to determine the type and outcome of any investigations. Patients with positive tests were cross-matched with the Trust's colorectal cancer database to detect interval cancers. 1363 FOB tests were requested during the calendar year. 715 (52.5%) were completed. Mean age was 60.6 years, 30.7% of patients were in the screening age group. 60 (4.4%) patients were FOBt positive. Total colonic imaging was performed in only 22% of those who were FOBt positive. Significant pathology was detected in five patients (0.4%) including three colonic carcinomas. There were no interval cancers in the FOBt-positive group. The number of FOBt requests has increased with the introduction of a colorectal cancer screening programme. The FOBt completion rate and colonic imaging rate in FOBt-positive patients outside the national screening programme was low. Guidelines for the use of FOBt outside of screening are needed.


How common are polycystic ovaries and the polycystic ovarian syndrome in women with Cushing's syndrome?
Women with Cushing's syndrome (CS) may present with menstrual irregularity and symptoms/signs of hyperandrogenism, a phenotype similar to that of the polycystic ovarian syndrome (PCOS); however, currently there are no data on the prevalence of either polycystic ovaries (PCO) and/or PCOS in patients with CS. The aim of this study was to investigate their presence among women of reproductive age presenting with CS by analysing clinical, endocrinological and ultrasonographic features. Prospective study of all women within the reproductive age (range 18-40 years) who presented with CS between August 1994 and January 2000. Thirteen women (median age 32 years, range 18-39 years) with CS were evaluated. The diagnosis of CS was based on the presence of appropriate clinical features and an elevated serum midnight cortisol with failure to suppress 0900 hours serum cortisol to less than 50 nmol/l following a formal low-dose dexamethasone suppression test (LDDST). All women had their clinical features relevant to possible hyperandrogenism, menstrual disorder and infertility recorded, and circulating gonadotrophins, oestradiol, androgens and SHBG levels measured; ovarian ultrasonography was performed during their initial assessment. Relevant MR/CT imaging of the pituitary and/or adrenal glands was performed. Eleven women had ACTH-dependent CS [nine Cushing's disease (CD), one ectopic ACTH syndrome due to a bronchial carcinoid, one periodic CS of unknown origin); two patients had ACTH-independent CS (adrenal adenomas). All women with CS had at least one symptom/sign of hyperandrogenism (13 hirsutism, seven acne, five male-pattern alopecia). Nine women (70%) had menstrual disturbances (four oligomenorrhoea, four amenorrhoea, one polymenorrhoea) while four women (30%) had a normal menstrual pattern. Serum oestradiol levels for the group as a whole were similar to those observed in the early follicular phase of normally menstruating women; however, seven women had low oestradiol, LH and FSH levels suggestive of hypogonadotrophic hypogonadism. Serum androgen levels (testosterone, androstendione and DHEAS), even in the presence of symptoms/signs of hyperandrogenism, were within the normal reference range but SHBG levels were uniformly decreased even in women with normal menstrual cycles. There was a negative correlation between urinary free cortisol, but not mean serum cortisol, and serum oestradiol, testosterone and SHBG levels (r = - 0.8, r = - 0.86 and r = - 0.66, P<0.02, P<0.01 and P<0.05, respectively), but not LH or FSH levels. Despite the fact that seven of these 13 patients lacked normal gonadotrophin stimulation, ovarian volumes of both ovaries were relatively preserved: right 7.3 ml, range 2.8-12.8 ml, and left 5.3 ml, range 2.3-13 ml. Women who were defined as oestrogen sufficient (E2 > 140 pmol/l) had higher serum androstenedione, and lower urinary free cortisol levels, than women who were oestrogen deficient (E2 < 140 pmol/l). Six of the 13 women (46%) had ovarian morphology suggestive of PCO, four of six oestrogen sufficient women and two of seven oestrogen deficient women. The results did not differ according to the underlying cause of CS. PCO and PCOS are common in women with Cushing's syndrome; women with Cushing's syndrome and only moderately elevated cortisol secretion maintain gonadotrophin stimulation to the ovary with normal oestradiol levels, in contrast to women with Cushing's syndrome and higher cortisol secretion who develop hypogonadotrophic hypogonadism. However, even in the latter group, high ovarian volumes were maintained and some had ovarian morphology suggestive of PCO.


Collective action for implementation: a realist evaluation of organisational collaboration in healthcare.
Increasingly, it is being suggested that translational gaps might be eradicated or narrowed by bringing research users and producers closer together, a theory that is largely untested. This paper reports a national study to fill a gap in the evidence about the conditions, processes and outcomes related to collaboration and implementation. A longitudinal realist evaluation using multiple qualitative methods case studies was conducted with three Collaborations for Leadership in Applied Health Research in Care (England). Data were collected over four rounds of theory development, refinement and testing. Over 200 participants were involved in semi-structured interviews, non-participant observations of events and meetings, and stakeholder engagement. A combined inductive and deductive data analysis process was focused on proposition refinement and testing iteratively over data collection rounds. The quality of existing relationships between higher education and local health service, and views about whether implementation was a collaborative act, created a path dependency. Where implementation was perceived to be removed from service and there was a lack of organisational connections, this resulted in a focus on knowledge production and transfer, rather than co-production. The collaborations' architectures were counterproductive because they did not facilitate connectivity and had emphasised professional and epistemic boundaries. More distributed leadership was associated with greater potential for engagement. The creation of boundary spanning roles was the most visible investment in implementation, and credible individuals in these roles resulted in cross-boundary work, in facilitation and in direct impacts. The academic-practice divide played out strongly as a context for motivation to engage, in that 'what's in it for me' resulted in variable levels of engagement along a co-operation-collaboration continuum. Learning within and across collaborations was patchy depending on attention to evaluation. These collaborations did not emerge from a vacuum, and they needed time to learn and develop. Their life cycle started with their position on collaboration, knowledge and implementation. More impactful attempts at collective action in implementation might be determined by the deliberate alignment of a number of features, including foundational relationships, vision, values, structures and processes and views about the nature of the collaboration and implementation.


Effectiveness of statin intensive therapy in type 2 diabetes mellitus with high visit-to-visit blood pressure variability.
Intensive lipid-lowering therapy is recommended in type 2 diabetes mellitus (T2DM) patients with target organ damage. However, the evidence is insufficient to stratify the patients who will benefit from the intensive therapy among them. High visit-to-visit variability in systolic blood pressure (SBP) is associated with increased risk of cardiovascular events. We investigated the effectiveness of intensive versus standard statin therapy in the primary prevention of cardiovascular events among T2DM patients with retinopathy stratified by visit-to-visit SBP variability. The standard versus intensive statin therapy for hypercholesterolemic patients with diabetic retinopathy study was the first trial comparing statin intensive therapy targeting low-density lipoprotein cholesterol (LDL-C) <70 mg/dl and standard therapy targeting LDL-C ≥100 to <120 mg/dl in T2DM patients with retinopathy without known cardiovascular disease. Using this dataset, we divided the patients into two subpopulations based on standard deviation (SD) and average real variability (ARV) of clinic SBP within the initial 6 months. In a total of 4899 patients, 240 composite cardiovascular events were observed during a median follow-up of 37.3 months. In multivariable-adjusted model comparing intensive versus standard therapy, the hazard ratios for composite cardiovascular events were 0.64 (95% CI 0.45-0.90) and 1.21 (95% CI 0.82-1.80) in patients with high and low SBP variability as defined by SD, respectively. Interaction between SBP variability and statin therapy was significant (P = 0.018). The analysis using ARV of SBP showed similar results. Statin intensive therapy targeting LDL-C <70 mg/dl had benefits in primary prevention of cardiovascular events compared with standard therapy among T2DM patients with retinopathy having high, but not low, visit-to-visit SBP variability.


Molecular classification of cutaneous malignant melanoma by gene expression profiling.
The most common human cancers are malignant neoplasms of the skin. Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease. Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm. Accordingly, though melanoma is thought to present with different 'taxonomic' forms, these are considered part of a continuous spectrum rather than discrete entities. Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro, a feature of some highly aggressive metastatic melanomas. Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression.


Effects of an experimental calcium aluminosilicate cement on the viability of murine odontoblast-like cells.
Quick-setting calcium aluminosilicate cement with improved washout resistance is a potential substitute for calcium silicate cements in endodontics. This study examined the effect of an experimental calcium aluminosilicate cement (Quick-Set; Primus Consulting, Bradenton, FL) on the viability of odontoblast-like cells. The biocompatibility of Quick-Set and white ProRoot MTA (WMTA; Dentsply Tulsa Dental Specialties, Tulsa, OK) cements and their eluents was evaluated using a murine dental papilla-derived odontoblast-like cell line (MDPC-23); 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to examine the effects of the 2 hydraulic cements on mitochondrial metabolic activity. Flow cytometry and confocal laser scanning microscopy were used to identify the effects of the 2 cements on cell death-induced plasma membrane permeability to fluorescent dyes and DNA stains. After the first week of immersion in culture medium, Quick-Set and WMTA were more cytotoxic than the Teflon-negative control (P < .05), and the cells exhibited more apoptosis/necrosis than Teflon (P < .05). After the second week of immersion, the 2 cements were as biocompatible as Teflon (P > .05), with cells exhibiting minimal apoptosis/necrosis. Eluents from the set cements at 1:1 dilution were significantly more cytotoxic that eluents at 1:10 or 1:100 dilution (P < .05). Quick-Set and WMTA exhibited similar cytotoxicity profiles. They possess negligible in vitro toxicologic risks after time-dependent elution of toxic components.


Enzootic activity of Rift Valley fever virus in Senegal.
In two areas of Senegal where previous evidence of Rift Valley fever (RVF) virus circulation was detected, Barkedji in the Sahelian bioclimatic zone and Kedougou in the Sudano-Guinean zone, a longitudinal study of the enzootic maintenance of RVF virus was undertaken from 1991 to 1993. Mosquitoes, sand flies, and ticks were collected and domestic ungulates were monitored with serologic surveys. Rift Valley fever virus was not isolated in Kedougou. In Barkedji, RVF virus was isolated from Aedes vexans and Ae. ochraceus mosquitoes collected in traps near ground pools and cattle droves and from one health sheep. Sand flies were not involved in the maintenance cycle. Seroconversions were recorded in three (1.9%) of 160 monitored sheep and goats. The interepizootic vectors appeared to belong to the Aedes subgenus Neomelaniconion in East Africa, and to the subgenus Aedimorphus in West Africa. Epizootics in East Africa are associated with an increase in rainfall. However, factors associated with epizootics remain unknown for West Africa.


The neural underpinnings of an optimal exploitation of social information under uncertainty.
Social information influences decision-making through an integration of information derived from individual experience with that derived from observing the actions of others. This raises the question as to which extent one should utilize social information. One strategy is to make use of uncertainty estimates, leading to a copy-when-uncertain strategy that weights information from individual and social sources based on their respective reliabilities. Here, we investigate this integration process by extending models of Bayes optimal integration of sensory information to a social decision context. We then use a key parameter of our behavioral model in conjunction with functional magnetic resonance imaging to identify the neural substrate that is specifically linked to the fidelity of this integration process. We show that individuals behave near Bayes optimal when integrating two distinct sources of social information but systematically deviate from Bayes optimal choice when integrating individual with social information. This systematic behavioral deviation from optimality is linked to activity of left inferior frontal gyrus. Thus, an ability to optimally exploit social information depends on processes that overcome an egocentric bias, and this regulatory role involves the left inferior prefrontal cortex. The findings provide a mechanistic explanation for observations wherein individuals neglect the benefits from exploiting social information.


The proteolytic cleavage of eukaryotic initiation factor (eIF) 4G is prevented by eIF4E binding protein (PHAS-I; 4E-BP1) in the reticulocyte lysate.
A common feature of viral infection is the subversion of the host cell machinery towards the preferential translation of viral products. In some instances, this is partly mediated by the expression of virally encoded proteases which lead to the cleavage of initiation factor eIF4G. The foot-and-mouth disease virus encodes two forms of a cysteine proteinase (L protease) which bisects the eIF4G polypeptide into an N-terminal fragment containing the eIF4E binding site, and a C-terminal fragment which contains binding sites for eIF4A and eIF3 and which associates with the 40S ribosomal subunit. Previously, we have demonstrated that the cleavage of eIF4G by L protease stimulates the translation of uncapped transcripts encoding cellular proteins and supports internal initiation driven by picornavirus internal ribosome entry segment (IRES) elements. Use of reticulocyte lysates manipulated to deplete them of eIF4E and the N-terminal fragment suggests that the C-terminal fragment of eIF4G is responsible for these effects, and we have now confirmed this by purifying the C-terminal fragment and analysing its effects directly in the absence of L protease. Interestingly, we find that pre-incubation of reticulocyte lysates or ribosomal salt wash fractions with the specific eIF4E binding protein, PHAS-I (eIF4E-BP1), blocks the proteolytic cleavage of eIF4G by L protease. This effect can be reversed by addition of recombinant eIF4E. These data are consistent with a model whereby the L protease cleavage site in eIF4G is inaccessible until a change in conformation is induced by the binding of eIF4E. This may have implications for a role for eIF4E binding in triggering changes that expose other domains in the eIF4G molecule during initiation of translation.


The persistence of induced abortion in Cuba: exploring the notion of an "abortion culture".
Cuba's annual induced abortion rate persistently ranks among the highest in the world, and abortion plays a prominent role in Cuban fertility regulation despite widespread contraceptive prevalence and state promotion of modern contraceptives. We explore this phenomenon using the concept of an "abortion culture," typically used in reference to Soviet and post-Soviet countries. We synthesize existing literature to provide a historical account of abortion and contraception in Cuba. We also provide a qualitative analysis of abortion and contraceptive use based on in-depth interviews conducted in 2005 in Havana with 24 women who have had an abortion and 10 men whose partners have had an abortion. Information gained from a focus-group discussion with medical professionals also informed the study. Our four principal findings are: (a) longstanding awareness of abortion, (b) the view of abortion as a personal decision, (c) the influence of economic constraints on the decision to induce an abortion, and (d) general skepticism toward contraceptives. We discuss our results on abortion in Cuba in relation to the notion of social diffusion, an approach commonly used to explain the spread of fertility control throughout a population.


The development of the Quality Indicator for Rehabilitative Care (QuIRC): a measure of best practice for facilities for people with longer term mental health problems.
Despite the progress over recent decades in developing community mental health services internationally, many people still receive treatment and care in institutional settings. Those most likely to reside longest in these facilities have the most complex mental health problems and are at most risk of potential abuses of care and exploitation. This study aimed to develop an international, standardised toolkit to assess the quality of care in longer term hospital and community based mental health units, including the degree to which human rights, social inclusion and autonomy are promoted. The domains of care included in the toolkit were identified from a systematic literature review, international expert Delphi exercise, and review of care standards in ten European countries. The draft toolkit comprised 154 questions for unit managers. Inter-rater reliability was tested in 202 units across ten countries at different stages of deinstitutionalisation and development of community mental health services. Exploratory factor analysis was used to corroborate the allocation of items to domains. Feedback from those using the toolkit was collected about its usefulness and ease of completion. The toolkit had excellent inter-rater reliability and few items with narrow spread of response. Unit managers found the content highly relevant and were able to complete it in around 90 minutes. Minimal refinement was required and the final version comprised 145 questions assessing seven domains of care. Triangulation of qualitative and quantitative evidence directed the development of a robust and comprehensive international quality assessment toolkit for units in highly variable socioeconomic and political contexts.


Addressing a systematic vibration artifact in diffusion-weighted MRI.
We have identified and studied a pronounced artifact in diffusion-weighted MRI on a clinical system. The artifact results from vibrations of the patient table due to low-frequency mechanical resonances of the system which are stimulated by the low-frequency gradient switching associated with the diffusion-weighting. The artifact manifests as localized signal-loss in images acquired with partial Fourier coverage when there is a strong component of the diffusion-gradient vector in the left-right direction. This signal loss is caused by local phase ramps in the image domain which shift the apparent k-space center for a particular voxel outside the covered region. The local signal loss masquerades as signal attenuation due to diffusion, severely disrupting the quantitative measures associated with diffusion-tensor imaging (DTI). We suggest a way to improve the interpretation of affected DTI data by including a co-regressor which accounts for the empirical response of regions affected by the artifact. We also demonstrate that the artifact may be avoided by acquiring full k-space data, and that subsequent increases in TE can be avoided by employing parallel acceleration.


The Evolving Role of Multivitamin/Multimineral Supplement Use among Adults in the Age of Personalized Nutrition.
Micronutrient deficiencies occur in segments of the adult population in the United States. Multivitamin/multimineral supplements (MVMS) are widely used by this population, which reduces inadequacies in micronutrient intake, but the potential for exceeding tolerable upper intake levels in others should be considered. There are concerns associated with the excessive intake of certain nutrients, particularly folic acid, and potential untoward consequences. The advent of nutrigenomics and the enhanced ability to directly study the interactions between nutrition and genetic variants and expression will allow for the conduct of more targeted studies with specific endpoints and may ultimately lead to progress in the field of personalized nutrition. The role of MVMS in health maintenance and chronic disease prevention remains controversial. Conducting studies in this area has been hampered by, among other factors, inconsistent definitions of MVMS, ranging from as few as three vitamins to broad-spectrum products containing more than two dozen vitamins and minerals. Results from some observational studies and large-scale, randomized, controlled trials suggest that MVMS may reduce the risk of some forms of cancer and, potentially, cardiovascular disease. The ongoing COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is expected to build on this research and provide additional insights into these areas.


Using patient-reported outcomes in clinical practice: challenges and opportunities.
Introduce and explore issues at an international conference about the use of patient-reported outcomes (PROs) in clinical practice. Review of salient literature, clinical and personal experiences, conference presentations and discussions, and post-conference comments from outside experts. PROs (information from patients about a health condition and its management) have been assessed through self-reports for at least four decades. Traditional applications are in clinical and health services research. Uses in clinical practice, although increasing, are less common and more challenging. PROs can enhance the understanding of patients' experiences and responses to therapy and inform clinical practice. We pose and discuss four main questions: (1) Will clinicians accept PRO measures? (2) Will clinicians use PRO measures? (3) Will measuring PROs actually improve those outcomes? (4) Will PROs be perceived as having other, less salutary purposes? A patient-centered perspective on PRO measurement presents issues about the extent to which PROs can accurately capture patient experiences and assess psychosocial and environmental factors that influence communication with clinicians and eventual outcomes. We end with comments about the intersection of PROs and bioethics, noting contributions that PROs may make to beneficence, patient autonomy, and distributive justice.


Determination of left ventricular volumes by Simpson's rule in infants and children with congenital heart disease.
Regression equations were developed from left ventricular casts of known volumes to calculate left ventricular volumes from biplane cineangiography obtained in non-standard views. Volumes were calculated by Simpson's rule from casts of postmortem specimens from patients with congenital heart disease. The casts were divided into two groups: those that came from patients with abnormal right ventricular haemodynamic function (group 1, n = 11) and those that came from patients in which it was normal (group 2, n = 9). Biplane cinegrams were taken in conventional (anteroposterior/lateral, right anterior oblique/left anterior oblique) and non-conventional (long axis oblique, hepatoclavicular, and sitting up) projections. The true volume of each cast was determined from its weight and specific gravity. Correlations between measured and true volumes (r = 0.96 to 0.99) were excellent in all projections, although each projection overestimated the true volumes (slope = 0.72 to 0.94). The regression equations obtained from conventional views were significantly different from those from the non-conventional views; however, the regression slopes in group 1 were not different from those in group 2 in any view. Regression equations obtained by Simpson's rule do not seem to be affected by the haemodynamic state of the right ventricle. Different regression equations are required to measure left ventricular volumes from non-conventional angiograms.


When a Family Seeks to Exclude Residents From Their Child's Care.
A primary goal of our medical education system is to produce physicians qualified to promote health, prevent and treat disease, and relieve suffering. Although some aspects of the practice of medicine can be learned in classrooms, from textbooks, or with simulators, other aspects can only be learned through the direct provision of patient care. Residency programs therefore offer essential educational experiences that support residents' acquisition of knowledge, skills, and professional judgment through the assumption of progressive responsibility under an appropriate level of supervision. Yet, ethical questions can arise when medical education is integrated with patient care. How should we balance the educational needs of residents and the social benefits of medical education against obligations to patients and families? In this article, we present the case of a child whose family requests that residents not be allowed to perform any procedures on their child and then ask experts (a pediatric residency program director, a pediatrics resident, and an ethicist) to comment.


Neuroprotective effect of an antioxidant, lutein, during retinal inflammation.
Lutein has been the focus of recent study as a possible therapeutic approach for retinal diseases, but the molecular mechanism of its neuroprotective effect remains to be elucidated. The aim of this study was to investigate, with the use of a mouse endotoxin-induced uveitis (EIU) model, the neuroprotective effects of lutein against retinal neural damage caused by inflammation. EIU was induced by intraperitoneal injection of lipopolysaccharide (LPS). Each animal was given a subcutaneous injection of lutein or vehicle three times: concurrently with and 3 hours before and after the LPS injection. Analysis was carried out 24 hours after EIU induction. Levels of rhodopsin protein and STAT3 activation were analyzed by immunoblotting. Lengths of the outer segments of the photoreceptor cells were measured. Dark-adapted full-field electroretinograms were recorded. Oxidative stress in the retina was analyzed by dihydroethidium and fluorescent probe. Expression of glial fibrillary acidic protein (GFAP) was shown immunohistochemically. The EIU-induced decrease in rhodopsin expression followed by shortening of the outer segments and reduction in a-wave amplitude were prevented by lutein treatment. Levels of STAT3 activation, downstream of inflammatory cytokine signals, and reactive oxygen species (ROS), which are both upregulated during EIU, were reduced by lutein. Pathologic change of Müller glial cells, represented by GFAP expression, was also prevented by lutein. The present data revealed that the antioxidant lutein was neuroprotective during EIU, suggesting a potential approach for suppressing retinal neural damage during inflammation.


Structural and functional abnormalities in the spleen of an mFtz-F1 gene-disrupted mouse.
The spleen has two main functions. The first is to provide a proper microenvironment to lymphoid and myeloid cells, whereas the second involves clearance of abnormal erythrocytes. Ad4BP/SF-1, a product of the mammalian FTZ-F1 gene (mFTZ-F1), was originally identified as a steroidogenic, tissue-specific transcription factor. Immunohistochemical examination of the mammalian spleens confirmed the expression of Ad4BP/SF-1 in endothelial cells of the splenic venous sinuses and pulp vein. In mFtz-F1 gene-disrupted (KO) mice, several structural abnormalities were detected in the spleen, including underdevelopment and nonuniform distribution of erythrocytes. Examination of the spleen of KO fetuses showed failure of development of certain tubular structures during embryogenesis. These structures are normally assembled by Ad4BP/SF-1 immunoreactive cells, and most likely form the vascular system during later stages of development. Other structural abnormalities in the spleen of the KO mice included defects in the tissue distribution of type-IV collagen, laminin, c-kit, and vimentin. These morphologic defects in the vascular system were associated with a decrease in the proportion of hematopoietic cells, although differentiation of these cells was not affected significantly. A high number of abnormal red blood cells containing Howell-Jolly bodies were noted in the KO mice, indicating impaired clearance by the splenic vascular system. We also detected the presence of an mRNA-encoding cholesterol side-chain cleavage P450 in the spleen, resembling the findings in steroidogenic tissues such as the gonads and adrenal cortex. The mRNA transcript was not involved in splenic structural defects as it was detected in the spleens of both normal and KO mice, indicating that the regulatory mechanism of the P450 gene in the spleen is different from that in steroidogenic tissues. Our results indicate that a lack of the mFtz-F1 gene in mice is associated with structural and functional abnormalities of the splenic vascular system.


Three Principles to REVISE People's Unethical Behavior.
Dishonesty and unethical behavior are widespread in the public and private sectors and cause immense annual losses. For instance, estimates of U.S. annual losses indicate $1 trillion paid in bribes, $270 billion lost due to unreported income, and $42 billion lost in retail due to shoplifting and employee theft. In this article, we draw on insights from the growing fields of moral psychology and behavioral ethics to present a three-principle framework we call REVISE. This framework classifies forces that affect dishonesty into three main categories and then redirects those forces to encourage moral behavior. The first principle, reminding, emphasizes the effectiveness of subtle cues that increase the salience of morality and decrease people's ability to justify dishonesty. The second principle, visibility, aims to restrict anonymity, prompt peer monitoring, and elicit responsible norms. The third principle, self-engagement, increases people's motivation to maintain a positive self-perception as a moral person and helps bridge the gap between moral values and actual behavior. The REVISE framework can guide the design of policy interventions to defeat dishonesty.


Latent and subclinical tuberculosis in HIV infected patients: a cross-sectional study.
HIV and tuberculosis (TB) are commonly associated. Identifying latent and asymptomatic tuberculosis infection in HIV-positive patients is important in preventing death and morbidity associated with active TB. Cross-sectional study of one time use of an interferon-gamma release assay (T-SPOT.TB - immunospot) to detect tuberculosis infection in patients in a UK inner city HIV clinic with a large sub-Saharan population. 542 patient samples from 520 patients who disclosed their symptoms of TB were tested. Median follow-up was 35 months (range 27-69). More than half (55%) originated from countries with medium or high tuberculosis burden and 57% were women. Antiretroviral therapy was used by 67%; median CD4 count at test was 458 cells/μl. A negative test was found in 452 samples and an indeterminate results in 40 (7.4%) but neither were associated with a low CD4 count. A positive test was found in 10% (50/502) individuals. All patients with positive tests were referred to the TB specialist, 47 (94%) had a chest radiograph and 46 (92%) attended the TB clinic. Two had culture-positive TB and a third individual with features of active TB was treated. 40 started and 38 completed preventive treatment. One patient who completed preventive treatment with isoniazid monotherapy subsequently developed isoniazid-resistant pulmonary tuberculosis. No patient with a negative test has developed TB. We found an overall prevalence of latent TB infection of 10% through screening for TB in those with HIV infection and without symptoms, and a further 1% with active disease, a yield greater than typically found in contact tracing. Acceptability of preventive treatment was high with 85% of those with latent TB infection eventually completing their TB chemotherapy regimens. IGRA-based TB screening among HIV-infected individuals was feasible in the clinical setting and assisted with appropriate management (including preventive treatment and therapy for active disease). Follow-up of TB incidence in this group is needed to assess the long-term effects of preventive treatment.


Tacrolimus Improves Symptoms of Children With Myasthenia Gravis Refractory to Prednisone.
Myasthenia gravis tends to affect children in China. Oral pyridostigmine and prednisone could effectively improve the symptoms, but multiple side effects become a major concern after long-term oral prednisone. To avoid the long-term complications of prednisone therapy and to obtain more satisfactory improvement, we tested the efficacy and safety of tacrolimus in children with myasthenia gravis. Children with myasthenia gravis who had not achieved satisfactory improvement or who experienced severe side effects after prednisone therapy were recruited between January 2015 and December 2016 at Tongji Hospital. All the children were treated with tacrolimus 1 mg to 2 mg daily and the dose was adjusted on the basis of the clinical response and the serum concentration. The dosage of prednisone, the severity of symptoms, blood samples, the serum concentration of tacrolimus, and titers of antiacetylcholine receptor antibodies were evaluated every four weeks. Fourteen children were enrolled. One child withdrew two weeks after the enrollment. Thirteen children have completed the therapy for one year. At the end point, the dosage of prednisone was significantly decreased (P < 0.05), the symptoms were evaluated by the quantitative myasthenia gravis score, and myasthenia gravis-specific manual muscle testing and myasthenia gravis-activities of daily living scores were significantly improved (P < 0.05, P < 0.05, and P < 0.01, respectively). More importantly, ten (76.9%) patients had completely discontinued prednisone, and the major side effects were nearly reversed. The mean titer of antiacetylcholine receptor antibodies significantly dropped from 1.96±2.62 nmol/L to 0.70±1.04 nmol/L (P < 0.05). No severe adverse events were reported. Our results suggest that tacrolimus is a promising agent for children with refractory myasthenia gravis. Randomized clinical trials are needed to confirm the observation.


Oxytocin and vasopressin are dysregulated in Williams Syndrome, a genetic disorder affecting social behavior.
The molecular and neural mechanisms regulating human social-emotional behaviors are fundamentally important but largely unknown; unraveling these requires a genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a condition caused by deletion of ~28 genes, is associated with a gregarious personality, strong drive to approach strangers, difficult peer interactions, and attraction to music. WS provides a unique opportunity to identify endogenous human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and arginine vasopressin (AVP) regulate reproductive and social behaviors in mammals, and we reasoned that these might mediate the features of WS. Here we established blood levels of OT and AVP in WS and controls at baseline, and at multiple timepoints following a positive emotional intervention (music), and a negative physical stressor (cold). We also related these levels to standardized indices of social behavior. Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP. Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors. These results indicate that WS deleted genes perturb hypothalamic-pituitary release not only of OT but also of AVP, implicating more complex neuropeptide circuitry for WS features and providing evidence for their roles in endogenous regulation of human social behavior. The data suggest a possible biological basis for amygdalar involvement, for increased anxiety, and for the paradox of increased approach but poor social relationships in WS. They also offer insight for translating genetic and neuroendocrine knowledge into treatments for disorders of social behavior.


Urinary ADAM12 and MMP-9/NGAL complex detect the presence of gastric cancer.
Although the early diagnosis of gastric cancer provides the opportunity for curative endoscopic resection, comprehensive screening endoscopy would be invasive and expensive. To date, there is a complete absence of clinically useful gastric cancer biomarkers. With the goal of discovering noninvasive biomarkers for the early diagnosis of gastric cancer, we have conducted a case-control study using urine samples from individuals with gastric cancer versus healthy control samples. Of the enrolled 106 patients from September, 2012 to April, 2013, a cohort of 70 patients composed of 35 patients with gastric cancer and 35 age- and sex-matched healthy controls was analyzed. The gastric cancer group was composed of stage IA of 62.9% (22/35). The urinary levels of MMP-9/NGAL complex (uMMP-9/NGAL) and ADAM12 (uADAM12) were significantly higher in the gastric cancer group compared with the healthy control group as determined by monospecific ELISAs (uMMP-9/NGAL: median, 85 pg/mL vs. 0 pg/mL; P = 0.020; uADAM12: median, 3.35 ng/mL vs. 1.44 ng/mL; P < 0.001). Multivariate analysis demonstrated that both uMMP-9/NGAL and uADAM12 were significant, independent diagnostic biomarkers for gastric cancer. Moreover, MMP-9/NGAL activity was significantly elevated as determined by gelatin zymography. The combination of uMMP-9/NGAL with uADAM12 distinguished between control samples and gastric cancer samples with an AUC of 0.825 (P < 0.001) in an ROC analysis. Significantly, immunohistochemical analyses demonstrated a high coexpression of MMP-9 and NGAL (P < 0.001) and high expression of ADAM12 (P < 0.001) in gastric cancer tissues compared with adjacent normal tissues (N = 35). In summary, uMMP-9/NGAL and uADAM12 are potential noninvasive biomarkers for gastric cancer, including early-stage disease.


Possible roles for the hominoid-specific DSCR4 gene in human cells.
Down syndrome in humans is caused by trisomy of chromosome 21. DSCR4 (Down syndrome critical region 4) is a de novo-originated protein-coding gene present only in human chromosome 21 and its homologous chromosomes in apes. Despite being located in a medically critical genomic region and an abundance of evidence indicating its functionality, the roles of DSCR4 in human cells are unknown. We used a bioinformatic approach to infer the biological importance and cellular roles of this gene. Our analysis indicates that DSCR4 is likely involved in the regulation of interconnected biological pathways related to cell migration, coagulation and the immune system. We also showed that these predicted biological functions are consistent with tissue-specific expression of DSCR4 in migratory immune system leukocyte cells and neural crest cells (NCCs) that shape facial morphology in the human embryo. The immune system and NCCs are known to be affected in Down syndrome individuals, who suffer from DSCR4 misregulation, which further supports our findings. Providing evidence for the critical roles of DSCR4 in human cells, our findings establish the basis for further experimental investigations that will be necessary to confirm the roles of DSCR4 in the etiology of Down syndrome.


Dwarfism with joint laxity in Friesian horses is associated with a splice site mutation in B4GALT7.
Inbreeding and population bottlenecks in the ancestry of Friesian horses has led to health issues such as dwarfism. The limbs of dwarfs are short and the ribs are protruding inwards at the costochondral junction, while the head and back appear normal. A striking feature of the condition is the flexor tendon laxity that leads to hyperextension of the fetlock joints. The growth plates of dwarfs display disorganized and thickened chondrocyte columns. The aim of this study was to identify the gene defect that causes the recessively inherited trait in Friesian horses to understand the disease process at the molecular level. We have localized the genetic cause of the dwarfism phenotype by a genome wide approach to a 3 Mb region on the p-arm of equine chromosome 14. The DNA of two dwarfs and one control Friesian horse was sequenced completely and we identified the missense mutation ECA14:g.4535550C > T that cosegregated with the phenotype in all Friesians analyzed. The mutation leads to the amino acid substitution p.(Arg17Lys) of xylosylprotein beta 1,4-galactosyltransferase 7 encoded by B4GALT7. The protein is one of the enzymes that synthesize the tetrasaccharide linker between protein and glycosaminoglycan moieties of proteoglycans of the extracellular matrix. The mutation not only affects a conserved arginine codon but also the last nucleotide of the first exon of the gene and we show that it impedes splicing of the primary transcript in cultured fibroblasts from a heterozygous horse. As a result, the level of B4GALT7 mRNA in fibroblasts from a dwarf is only 2 % compared to normal levels. Mutations in B4GALT7 in humans are associated with Ehlers-Danlos syndrome progeroid type 1 and Larsen of Reunion Island syndrome. Growth retardation and ligamentous laxity are common manifestations of these syndromes. We suggest that the identified mutation of equine B4GALT7 leads to the typical dwarfism phenotype in Friesian horses due to deficient splicing of transcripts of the gene. The mutated gene implicates the extracellular matrix in the regular organization of chrondrocyte columns of the growth plate. Conservation of individual amino acids may not be necessary at the protein level but instead may reflect underlying conservation of nucleotide sequence that are required for efficient splicing.


Repair of senescent myocardium by mesenchymal stem cells is dependent on the age of donor mice.
Myocardial infarction is one of the leading causes of mortality in aged people. Whether age of donors of mesenchymal stem cells (MSCs) affects its ability to repair the senescent heart tissue is unknown. In the present study, MSCs from young (2 months) and aged (18 months) green fluorescent protein expressing C57BL/6 mice were characterized with p16(INK4a) and β-gal associated senescence. Myocardial infarction was produced in 18-month-old wild-type C57BL/6 mice transplanted with MSCs from young and aged animals in the border of the infarct region. Expression of p16(INK4a) in MSCs from aged animals was significantly higher (21.5%± 1.2, P < 0.05) as compared to those from young animals (9.2%± 2.8). A decline in the tube-forming ability on Matrigel was also observed in aged MSCs as well as down-regulation of insulin-like growth factor-1, fibroblast growth factor (FGF-2), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) compared to young cells. Mice transplanted with young MSCs exhibited significant improvement in their left ventricle (LV) systolic and diastolic function as demonstrated by dp/dt(max) , dp/dt(min) , P(max) . Reduction in the LV fibrotic area was concomitant with neovascularization as demonstrated by CD31 and smooth muscle actin (SMA) expression. Real-time RT-PCR analysis for VEGF, stromal cell derived factor (SDF-1α) and GATA binding factor 4 (GATA-4) genes further confirmed the effect of age on MSC differentiation towards cardiac lineages and enhanced angiogenesis. These studies lead to the conclusion that repair potential of MSCs is dependent on the age of donors and the repair of senescent infarcted myocardium requires young healthy MSCs.


Evolution of Multiple Sensory Systems Drives Novel Egg-Laying Behavior in the Fruit Pest Drosophila suzukii.
The rise of a pest species represents a unique opportunity to address how species evolve new behaviors and adapt to novel ecological niches [1]. We address this question by studying the egg-laying behavior of Drosophila suzukii, an invasive agricultural pest species that has spread from Southeast Asia to Europe and North America in the last decade [2]. While most closely related Drosophila species lay their eggs on decaying plant substrates, D. suzukii oviposits on ripening fruit, thereby causing substantial economic losses to the fruit industry [3-8]. D. suzukii has evolved an enlarged, serrated ovipositor that presumably plays a key role by enabling females to pierce the skin of ripe fruit [9]. Here, we explore how D. suzukii selects oviposition sites, and how this behavior differs from that of closely related species. We have combined behavioral experiments in multiple species with neurogenetics and mutant analysis in D. suzukii to show that this species has evolved a specific preference for oviposition on ripe fruit. Our results also establish that changes in mechanosensation, olfaction, and presumably gustation have contributed to this ecological shift. Our observations support a model in which the emergence of D. suzukii as an agricultural pest is the consequence of the progressive modification of several sensory systems, which collectively underlie a radical change in oviposition behavior.


An optical window into brain function in children and adolescents: A systematic review of functional near-infrared spectroscopy studies.
Despite decades of research, our understanding of functional brain development throughout childhood and adolescence remains limited due to the challenges posed by certain neuroimaging modalities. Recently, there has been a growing interest in using functional near-infrared spectroscopy (fNIRS) to elucidate the neural basis of cognitive and socioemotional development and identify the factors shaping these types of development. This article, focusing on the fNIRS methods, presents an up-to-date systematic review of fNIRS studies addressing the effects of age and other factors on brain functions in children and adolescents. Literature searches were conducted using PubMed and PsycINFO. A total of 79 fNIRS studies involving healthy individuals aged 3-17 years that were published in peer-reviewed journals in English before July 2020 were included. Six methodological aspects of these studies were evaluated, including the research design, experimental paradigm, fNIRS measurement, data preprocessing, statistical analysis, and result presentation. The risk of bias, such as selective outcome reporting, was assessed throughout the review. A qualitative synthesis of study findings in terms of the factor effects on changes in oxyhemoglobin concentration was also performed. This unregistered review highlights the strengths and limitations of the existing literature and suggests directions for future research to facilitate the improved use of fNIRS in developmental cognitive neuroscience research.


Thermosensory Perceptual Learning Is Associated with Structural Brain Changes in Parietal-Opercular (SII) Cortex.
The location of a sensory cortex for temperature perception remains a topic of substantial debate. Both the parietal-opercular (SII) and posterior insula have been consistently implicated in thermosensory processing, but neither region has yet been identified as the locus of fine temperature discrimination. Using a perceptual learning paradigm in male and female humans, we show improvement in discrimination accuracy for subdegree changes in both warmth and cool detection over 5 d of repetitive training. We found that increases in discriminative accuracy were specific to the temperature (cold or warm) being trained. Using structural imaging to look for plastic changes associated with perceptual learning, we identified symmetrical increases in gray matter volume in the SII cortex. Furthermore, we observed distinct, adjacent regions for cold and warm discrimination, with cold discrimination having a more anterior locus than warm. The results suggest that thermosensory discrimination is supported by functionally and anatomically distinct temperature-specific modules in the SII cortex.SIGNIFICANCE STATEMENT We provide behavioral and neuroanatomical evidence that perceptual learning is possible within the temperature system. We show that structural plasticity localizes to parietal-opercular (SII), and not posterior insula, providing the best evidence to date resolving a longstanding debate about the location of putative "temperature cortex." Furthermore, we show that cold and warm pathways are behaviorally and anatomically dissociable, suggesting that the temperature system has distinct temperature-dependent processing modules.


Effects of ascorbic acid and α-lipoic acid on performance and meat quality of broilers subjected to heat stress.
1. The present study was aimed to investigate the effect of adding ascorbic acid or α-lipoic acid to to the diet of broilers exposed to heat stress on performance and meat quality. 2. Heat stress caused a decrease in final body weight and feed consumption, whilst ascorbic acid (AA) and α-lipoic acid (ALA) partly prevented the decrease in final body weight of males. 3. While heat stress increased the pH values of broiler drumsticks and breast meat, AA and ALA partly reduced this increase. For meat quality, AA and ALA reduced the adverse effects on the relative yellowness value, particularly on d 14 of storage. 4. It was determined that heat stress affected the microbiological quality of meat adversely, and that AA and ALA alleviated this effect to a certain extent. 5. In conclusion, while heat stress affected body weight gain and meat quality adversely, the supplementation of the ration with AA and ALA partly alleviated these adverse effects.