Lithium ion storage between graphenes.
In this article, we investigate the storage of lithium ions between two parallel graphene sheets using the continuous approximation and the 6-12 Lennard-Jones potential. The continuous approximation assumes that the carbon atoms can be replaced by a uniform distribution across the surface of the graphene sheets so that the total interaction potential can be approximated by performing surface integrations. The number of ion layers determines the major storage characteristics of the battery, and our results show three distinct ionic configurations, namely single, double, and triple ion forming layers between graphenes. The number densities of lithium ions between the two graphenes are estimated from existing semi-empirical molecular orbital calculations, and the graphene sheets giving rise to the triple ion layers admit the largest storage capacity at all temperatures, followed by a marginal decrease of storage capacity for the case of double ion layers. These two configurations exceed the maximum theoretical storage capacity of graphite. Further, on taking into account the charge-discharge property, the double ion layers are the most preferable choice for enhanced lithium storage. Although the single ion layer provides the least charge storage, it turns out to be the most stable configuration at all temperatures. One application of the present study is for the design of future high energy density alkali batteries using graphene sheets as anodes for which an analytical formulation might greatly facilitate rapid computational results.


Targeting and extending the eukaryotic druggable genome with natural products: cytoskeletal targets of natural products.
Covering: 2014-2019We review recent progress on natural products that target cytoskeletal components, including microtubules, actin, intermediate filaments, and septins and highlight their demonstrated and potential utility in the treatment of human disease. The anticancer efficacy of microtubule targeted agents identified from plants, microbes, and marine organisms is well documented. We highlight new microtubule targeted agents currently in clinical evaluations for the treatment of drug resistant cancers and the accumulating evidence that the anticancer efficacy of these agents is not solely due to their antimitotic effects. Indeed, the effects of microtubule targeted agents on interphase microtubules are leading to their potential for more mechanistically guided use in cancers as well as neurological disease. The discussion of these agents as more targeted drugs also prompts a reevaluation of our thinking about natural products that target other components of the cytoskeleton. For instance, actin active natural products are largely considered chemical probes and non-selective toxins. However, studies utilizing these probes have uncovered aspects of actin biology that can be more specifically targeted to potentially treat cancer, neurological disorders, and infectious disease. Compounds that target intermediate filaments and septins are understudied, but their continued discovery and mechanistic evaluations have implications for numerous therapeutic indications.


Representation of eye movements and stimulus motion in topographically organized areas of human posterior parietal cortex.
Recent imaging studies have shown that the human posterior parietal cortex (PPC) contains four topographically organized areas along the intraparietal sulcus (IPS1-IPS4). Using a memory-guided saccade paradigm, we confirmed the locations and retinotopic organization of IPS1-IPS4 and identified two additional areas, IPS5 and superior parietal lobule 1 (SPL1). IPS5 is located at the intersection of the intraparietal and postcentral sulcus; SPL1 branches off the IPS and extends into the superior parietal lobule. Both areas, as well as IPS1-IPS4, each contain a representation of the contralateral visual hemifield. We then probed core functions of the dorsal pathway in these areas, that is, the representation of eye movements and visual motion, to compare the functional characteristics of human PPC to physiologically and anatomically defined areas in monkey PPC. First, as in monkey PPC, a gradient representation of eye movements was found along the IPS with decreasing responses for saccades and increasing responses for smooth pursuit eye movements from posterior/medial to anterior/lateral. The greatest preference for saccades was found in SPL1 and for smooth pursuit in IPS5. Second, and again similar to monkey PPC, all topographically organized PPC areas responded to different types of motion including planar, circular, and radial optic flow, as assessed using adaptation paradigms. Areas in posterior IPS preferred radial optic flow over planar motion, whereas areas in anterior PPC did not show preference for a particular motion type. Together, our results indicate strikingly similar characteristics in the general functional organization of human and monkey PPC, but also reveal some notable differences.


Cloning and expression of functional single-chain Fv antibodies directed against NIa and coat proteins of potato virus Y.
Three single-chain variable fragment (scFv) antibodies recognizing the nuclear inclusion a (NIa) and capsid proteins of potato virus Y were obtained from two mouse derived hybridoma clones secreting, respectively, an anti-NIa (22-1) and an anti-coat protein (136-13) monoclonal antibodies. The first monoclonal antibody was able to inhibit in vitro the PVY polyprotein cleavage by blocking the NIa protease activity. The amplified scFv cDNAs were first inserted into the TOPO vector and then sequenced. Several recombinant E. coli clones carrying the accurate scFv sequences were selected and the corresponding cDNAs were subcloned in pHEN phagemid and transferred in E. coli strain. The expressed scFv fragments showed an antibody activity that recognized the viral target proteins in infected tissues. Their activity was comparable to the parental monoclonal antibodies.


Family history of cancer and childhood rhabdomyosarcoma: a report from the Children's Oncology Group and the Utah Population Database.
Relatively little is known about the epidemiology and factors underlying susceptibility to childhood rhabdomyosarcoma (RMS). To better characterize genetic susceptibility to childhood RMS, we evaluated the role of family history of cancer using data from the largest case-control study of RMS and the Utah Population Database (UPDB). RMS cases (n = 322) were obtained from the Children's Oncology Group (COG). Population-based controls (n = 322) were pair-matched to cases on race, sex, and age. Conditional logistic regression was used to evaluate the association between family history of cancer and childhood RMS. The results were validated using the UPDB, from which 130 RMS cases were identified and matched to controls (n = 1300) on sex and year of birth. The results were combined to generate summary odds ratios (OR(s) ) and 95% confidence intervals (CI). Having a first-degree relative with a cancer history was more common in RMS cases than controls (OR(s) = 1.39, 95% CI: 0.97-1.98). Notably, this association was stronger among those with embryonal RMS (OR(s) = 2.44, 95% CI: 1.54-3.86). Moreover, having a first-degree relative who was younger at diagnosis of cancer (<30 years) was associated with a greater risk of RMS (OR(s) = 2.37, 95% CI: 1.34-4.18). In the largest analysis of its kind, we found that most children diagnosed with RMS did not have a family history of cancer. However, our results indicate an increased risk of RMS (particularly embryonal RMS) in children who have a first-degree relative with cancer, and among those whose relatives were diagnosed with cancer at <30 years of age.


Crystal structure of the RNA-dependent RNA polymerase from influenza C virus.
Negative-sense RNA viruses, such as influenza, encode large, multidomain RNA-dependent RNA polymerases that can both transcribe and replicate the viral RNA genome. In influenza virus, the polymerase (FluPol) is composed of three polypeptides: PB1, PB2 and PA/P3. PB1 houses the polymerase active site, whereas PB2 and PA/P3 contain, respectively, cap-binding and endonuclease domains required for transcription initiation by cap-snatching. Replication occurs through de novo initiation and involves a complementary RNA intermediate. Currently available structures of the influenza A and B virus polymerases include promoter RNA (the 5' and 3' termini of viral genome segments), showing FluPol in transcription pre-initiation states. Here we report the structure of apo-FluPol from an influenza C virus, solved by X-ray crystallography to 3.9 Å, revealing a new 'closed' conformation. The apo-FluPol forms a compact particle with PB1 at its centre, capped on one face by PB2 and clamped between the two globular domains of P3. Notably, this structure is radically different from those of promoter-bound FluPols. The endonuclease domain of P3 and the domains within the carboxy-terminal two-thirds of PB2 are completely rearranged. The cap-binding site is occluded by PB2, resulting in a conformation that is incompatible with transcription initiation. Thus, our structure captures FluPol in a closed, transcription pre-activation state. This reveals the conformation of newly made apo-FluPol in an infected cell, but may also apply to FluPol in the context of a non-transcribing ribonucleoprotein complex. Comparison of the apo-FluPol structure with those of promoter-bound FluPols allows us to propose a mechanism for FluPol activation. Our study demonstrates the remarkable flexibility of influenza virus RNA polymerase, and aids our understanding of the mechanisms controlling transcription and genome replication.


Inactivation of the phosphoinositide phosphatases Sac1p and Inp54p leads to accumulation of phosphatidylinositol 4,5-bisphosphate on vacuole membranes and vacuolar fusion defects.
Phosphoinositides direct membrane trafficking, facilitating the recruitment of effectors to specific membranes. In yeast phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) isproposed to regulate vacuolar fusion; however, in intact cells this phosphoinositide can only be detected at the plasma membrane. In Saccharomyces cerevisiae the 5-phosphatase, Inp54p, dephosphorylates PtdIns(4,5)P2 forming PtdIns(4)P, a substrate for the phosphatase Sac1p, which hydrolyzes (PtdIns(4)P). We investigated the role these phosphatases in regulating PtdIns(4,5)P2 subcellular distribution. PtdIns(4,5)P2 bioprobes exhibited loss of plasma membrane localization and instead labeled a subset of fragmented vacuoles in Deltasac1 Deltainp54 and sac1ts Deltainp54 mutants. Furthermore, sac1ts Deltainp54 mutants exhibited vacuolar fusion defects, which were rescued by latrunculin A treatment, or by inactivation of Mss4p, a PtdIns(4)P 5-kinase that synthesizes plasma membrane PtdIns(4,5)P2. Under these conditions PtdIns(4,5)P2 was not detected on vacuole membranes, and vacuole morphology was normal, indicating vacuolar PtdIns(4,5)P2 derives from Mss4p-generated plasma membrane PtdIns(4,5)P2. Deltasac1 Deltainp54 mutants exhibited delayed carboxypeptidase Y sorting, cargo-selective secretion defects, and defects in vacuole function. These studies reveal PtdIns(4,5)P2 hydrolysis by lipid phosphatases governs its spatial distribution, and loss of phosphatase activity may result in PtdIns(4,5)P2 accumulation on vacuole membranes leading to vacuolar fragmentation/fusion defects.


Unique membrane properties and enhanced signal processing in human neocortical neurons.
The advanced cognitive capabilities of the human brain are often attributed to our recently evolved neocortex. However, it is not known whether the basic building blocks of the human neocortex, the pyramidal neurons, possess unique biophysical properties that might impact on cortical computations. Here we show that layer 2/3 pyramidal neurons from human temporal cortex (HL2/3 PCs) have a specific membrane capacitance (Cm) of ~0.5 µF/cm2, half of the commonly accepted 'universal' value (~1 µF/cm2) for biological membranes. This finding was predicted by fitting in vitro voltage transients to theoretical transients then validated by direct measurement of Cm in nucleated patch experiments. Models of 3D reconstructed HL2/3 PCs demonstrated that such low Cm value significantly enhances both synaptic charge-transfer from dendrites to soma and spike propagation along the axon. This is the first demonstration that human cortical neurons have distinctive membrane properties, suggesting important implications for signal processing in human neocortex.


Photosensitization-induced retinopathy in the newborn beagle.
Photosensitization is a mechanism by which oxygen and light may interact to generate free radicals capable of tissue injury. It has been proposed as a possible etiologic mechanism in the development of retinopathy of prematurity. The authors report the effects of light exposure and a photosensitizer, rose bengal (RB), on the developing retina of the beagle puppy. Seven purebred beagle puppies (2 or 7 days old) were given RB (7.5 mg/ml) intravenously (0.9 ml bolus followed by a 74 microliters/min constant infusion), and one eye was exposed to filtered light delivered by a modified slit lamp at 30 mW/cm2 for 5, 15, 25, 35, and 45 minutes. The fellow eye was not irradiated and served as an RB-only control. Three beagles were exposed to light (one eye only) for 15 to 120 minutes in the absence of RB to provide light-only and no-treatment control eyes. Animals were followed clinically by indirect ophthalmoscopy and fluorescein angiography, and eyes were processed for light microscopy. Clinical and/or histologic abnormalities were found in all seven eyes exposed to light in the presence of rose bengal, as follows: vitreous hemorrhage in four eyes, incomplete peripheral retinal vascularization in four eyes, fibrovascular/fibrocellular proliferation with traction on the retina in two eyes (including preretinal neovascularization in one eye), total or partial retinal detachment in two eyes, dilated peripheral vessels compatible with shunt vessels in one eye, retinal dysplasia with loss of normal architecture and formation of rosettes in five eyes. All 13 control eyes showed normal, complete retinal vascularization. The failure to progress to the end-stage tractional retinal detachment seen in human infants is a shortcoming of existing animal models. Photosensitization injury to the developing retina in this animal model can produce a spectrum of retinal pathology that includes extraretinal vascularization and subsequent retinal detachment.


Major food sources of calories, added sugars, and saturated fat and their contribution to essential nutrient intakes in the U.S. diet: data from the National Health and Nutrition Examination Survey (2003-2006).
The risk of chronic disease cannot be predicted simply by the content of a single nutrient in a food or food group in the diet. The contribution of food sources of calories, added sugars and saturated fat (SFA) to intakes of dietary fiber and micronutrients of public health importance is also relevant to understanding the overall dietary impact of these foods. Identify the top food sources of calories, added sugars and SFA in the U.S. diet and quantify their contribution to fiber and micronutrient intakes. Single 24-hour dietary recalls (Day 1) collected from participants ≥2 years (n = 16,822) of the What We Eat in America, National Health and Nutrition Examination Survey (WWEIA/NHANES 2003-2006) were analyzed. All analyses included sample weights to account for the survey design. Calorie and nutrient intakes from foods included contributions from disaggregated food mixtures and tabulated by rank order. No one food category contributes more than 7.2% of calories to the overall U.S. diet, but half of the top 10 contribute 10% or more of total dietary fiber and micronutrients. Three of the top 10 sources of calories and SFA (beef, milk and cheese) contribute 46.3% of the calcium, 49.5% of the vitamin D, 42.3% of the vitamin B12 as well as other essential nutrients to the American diet. On the other hand, foods categorized as desserts, snacks, or beverages, contribute 13.6% of total calories, 83% of added sugar intake, and provide little or no nutritional value. Including food components of disaggregated recipes more accurately estimated the contribution of foods like beef, milk or cheese to overall nutrient intake compared to "as consumed" food categorizations. Some food sources of calories, added sugars and SFA make major contributions to American dietary fiber and micronutrient intakes. Dietary modifications targeting reductions in calories, added sugar, or SFA need to take these key micronutrient sources into account so as not to have the unintended consequence of lowering overall dietary quality.


Fit for life after cancer: does exercise timing matter?
To assess the effects of a single exercise session per week for 6 weeks on quality of life (QoL), fatigue and exercise participation in male and female cancer survivors with follow-up at 6 months. A secondary aim was to identify if the timing of exercise delivery determined its effect. An exploratory prospective cohort study design was implemented. Twenty-five patients undergoing or who had completed cancer treatment (11 active treatment; 14 completed treatment) undertook exercise and educational sessions (Fit for Life) 1×/week. The Brief Fatigue Inventory (BFI), the European Organisation for Research and Treatment of Cancer QoL C-30 (EORTC QLQ C-30) and the Godin Leisure Time Exercise Questionnaire (GLTEQ) were used to assess fatigue, QoL and exercise levels, respectively. Participants were evaluated before and after the intervention, and after 6 months. There was a significant group × time interaction for the GLTEQ at 6 months post in favour of exercising during active treatment (p=0.01). No other group × time interactions were observed across the EORTC QLQ C-30 or BFI. There was a significant main effect for time for EORTC QLQ C-30 Global with a significant increase observed between pre and 6 months post. Exercise 1×/week delivered during treatment may impact on long-term exercise participation in adult cancer survivors. This lower volume programme may improve QoL, but has minimal effect on fatigue suggesting an insufficient exercise dosage to impact this variable. This study generates interesting proof of concept results and may be helpful in the development of larger randomised controlled trials.


Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells.
Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate.


Intracellular precursors and secretion of alkaline extracellular protease of Yarrowia lipolytica.
Processing and secretion of the alkaline extracellular protease (AEP) from the yeast Yarrowia lipolytica was studied by pulse-chase and immunoprecipitation experiments. Over half of newly synthesized AEP was secreted by 6 min. Over 99% of AEP activity which was external to the cytoplasmic membrane was located in the supernatant medium. Polypeptides of 55, 52, 44, 36, and 32 kilodaltons (55K, 52K, 44K, 36K, and 32K polypeptides) were immunoprecipitated from [3H]leucine-labeled cell extracts by rabbit antibodies raised against mature, secreted AEP (32K polypeptide). Experiments with tunicamycin and endoglycosidase H indicated that the 55K, 52K, and 44K polypeptides contained about 2 kilodaltons of N-linked oligosaccharide and that the 36K and 32K polypeptides contained none. Results of pulse-chase experiments did not fit a simple precursor-product relationship of 55K----52K----44K----36K----32K. In fact, maximum labeling intensity of the 52K polypeptide occurred later than for the 44K and 36K polypeptides. Secretion of polypeptides of 19 and 20 kilodaltons derived from the proregion of AEP indicated that one major processing pathway was 55K----52K----32K. The gene coding for AEP (XPR2) was cloned and sequenced. The sequence and the immunoprecipitation results suggest that AEP is originally synthesized with an additional preproI-proII-proIII amino-terminal region. Processing definitely involves cleavage(s) after pairs of basic amino acids and the addition of one N-linked oligosaccharide. Signal peptidase cleavage, dipeptidyl aminopeptidase cleavages, and at least one additional proteolytic cleavage may also be involved.


Differing structures and dynamics of two photolesions portray verification differences by the human XPD helicase.
Ultraviolet light generates cyclobutane pyrimidine dimer (CPD) and pyrimidine 6-4 pyrimidone (6-4PP) photoproducts that cause skin malignancies if not repaired by nucleotide excision repair (NER). While the faster repair of the more distorting 6-4PPs is attributed mainly to more efficient recognition by XPC, the XPD lesion verification helicase may play a role, as it directly scans the damaged DNA strand. With extensive molecular dynamics simulations of XPD-bound single-strand DNA containing each lesion outside the entry pore of XPD, we elucidate strikingly different verification processes for these two lesions that have very different topologies. The open book-like CPD thymines are sterically blocked from pore entry and preferably entrapped by sensors that are outside the pore; however, the near-perpendicular 6-4PP thymines can enter, accompanied by a displacement of the Arch domain toward the lesion, which is thereby tightly accommodated within the pore. This trapped 6-4PP may inhibit XPD helicase activity to foster lesion verification by locking the Arch to other domains. Furthermore, the movement of the Arch domain, only in the case of 6-4PP, may trigger signaling to the XPG nuclease for subsequent lesion incision by fostering direct contact between the Arch domain and XPG, and thereby facilitating repair of 6-4PP.


Multiple roles of mouse Numb in tuning developmental cell fates.
Notch signaling regulates multiple differentiation processes and cell fate decisions during both invertebrate and vertebrate development. Numb encodes an intracellular protein that was shown in Drosophila to antagonize Notch signaling at binary cell fate decisions of certain cell lineages. Although overexpression experiments suggested that Numb might also antagonize some Notch activity in vertebrates, the developmental processes in which Numb is involved remained elusive. We generated mice with a homozygous inactivation of Numb. These mice died before embryonic day E11.5, probably because of defects in angiogenic remodeling and placental dysfunction. Mutant embryos had an open anterior neural tube and impaired neuronal differentiation within the developing cranial central nervous system (CNS). In the developing spinal cord, the number of differentiated motoneurons was reduced. Within the peripheral nervous system (PNS), ganglia of cranial sensory neurons were formed. Trunk neural crest cells migrated and differentiated into sympathetic neurons. In contrast, a selective differentiation anomaly was observed in dorsal root ganglia, where neural crest--derived progenitor cells had migrated normally to form ganglionic structures, but failed to differentiate into sensory neurons. Mouse Numb is involved in multiple developmental processes and required for cell fate tuning in a variety of lineages. In the nervous system, Numb is required for the generation of a large subset of neuronal lineages. The restricted requirement of Numb during neural development in the mouse suggests that in some neuronal lineages, Notch signaling may be regulated independently of Numb.


Brief interventions for obesity when patients are asked to pay for weight loss treatment: an observational study in primary care with an embedded randomised trial.
A brief intervention whereby GPs opportunistically facilitate an NHS-funded referral to a weight loss programme is clinically and cost-effective. To test the acceptability of a brief intervention and attendance at a weight loss programme when GPs facilitate a referral that requires patients to pay for the service. An observational study of the effect of a GP encouraging attendance at a weight loss programme requiring self-payment in the West Midlands from 16 October 2018 to 30 November 2018, to compare with a previous trial in England in which the service was NHS-funded. Sixty patients with obesity who consecutively attended primary care appointments received an opportunistic brief intervention by a GP to endorse and offer a referral to a weight loss programme at the patient's own expense. Participants were randomised to GPs who either stated the weekly monetary cost of the programme (basic cost) or who compared the weekly cost to an everyday discretionary item (cost comparison). Participants were subsequently asked to report whether they had attended a weight loss programme. Overall, 47% of participants (n = 28) accepted the referral; 50% (n = 15) in the basic cost group and 43% (n = 13) in the cost comparison group. This was significantly less than in a previous study when the programme was NHS-funded (77%, n = 722/940; P<0.0001). Most participants reported the intervention to be helpful/very helpful and appropriate/very appropriate (78%, n = 46/59 and 85%, n = 50/59, respectively) but scores were significantly lower than when the programme was NHS-funded (92% n = 851/922 and 88% n = 813/922, respectively; P = 0.004). One person (2%) attended the weight loss programme, which is significantly lower than the 40% of participants who attended when the programme was NHS-funded (P<0.0001). GP referral to a weight loss programme that requires patients to pay rather than offering an NHS-funded programme is acceptable; however, it results in almost no attendance.


Increasing sync rate of pulse-coupled oscillators via phase response function design: theory and application to wireless networks.
This paper addresses the synchronization rate of weakly connected pulse-coupled oscillators (PCOs). We prove that besides coupling strength, the phase response function is also a determinant of synchronization rate. Inspired by the result, we propose to increase the synchronization rate of PCOs by designing the phase response function. This has important significance in PCO-based clock synchronization of wireless networks. By designing the phase response function, synchronization rate is increased even under a fixed transmission power. Given that energy consumption in synchronization is determined by the product of synchronization time and transformation power, the new strategy reduces energy consumption in clock synchronization. QualNet experiments confirm the theoretical results.


Authorship ethics in global health research partnerships between researchers from low or middle income countries and high income countries.
Over the past two decades, the promotion of collaborative partnerships involving researchers from low and middle income countries with those from high income countries has been a major development in global health research. Ideally, these partnerships would lead to more equitable collaboration including the sharing of research responsibilities and rewards. While collaborative partnership initiatives have shown promise and attracted growing interest, there has been little scholarly debate regarding the fair distribution of authorship credit within these partnerships. In this paper, we identify four key authorship issues relevant to global health research and discuss their ethical and practical implications. First, we argue that authorship guidance may not adequately apply to global health research because it requires authors to write or substantially revise the manuscript. Since most journals of international reputation in global health are written in English, this would systematically and unjustly exclude non-English speaking researchers even if they have substantially contributed to the research project. Second, current guidance on authorship order does not address or mitigate unfair practices which can occur in global health research due to power differences between researchers from high and low-middle income countries. It also provides insufficient recognition of "technical tasks" such as local participant recruitment. Third, we consider the potential for real or perceived editorial bias in medical science journals in favour of prominent western researchers, and the risk of promoting misplaced credit and/or prestige authorship. Finally, we explore how diverse cultural practices and expectations regarding authorship may create conflict between researchers from low-middle and high income countries and contribute to unethical authorship practices. To effectively deal with these issues, we suggest: 1) undertaking further empirical and conceptual research regarding authorship in global health research; 2) raising awareness on authorship issues in global health research; and 3) developing specific standards of practice that reflect relevant considerations of authorship in global health research. Through review of the bioethics and global health literatures, and examination of guidance documents on ethical authorship, we identified a set of issues regarding authorship in collaborative partnerships between researchers from low-middle income countries and high income countries. We propose several recommendations to address these concerns.


Sleep disturbance during the menopausal transition in a multi-ethnic community sample of women.
Examine age-adjusted odds and racial/ethnic differences in self-reported difficulties falling and staying asleep and early morning awakening in midlife women to determine whether difficulty sleeping increased with progression through the menopausal transition. Longitudinal analysis. Community-based. 3,045 Caucasian, African American, Chinese, Japanese, and Hispanic women, aged 42-52 years and pre- or early peri-menopausal at baseline, participating in the Study of Women's Health Across the Nation (SWAN). None. Self-reported number of nights of difficulty falling asleep, staying asleep, and early morning awakening during the previous 2 weeks were obtained at baseline and 7 annual assessments. Random effects logistic regression was used to model associations between each of the 3 sleep measures and the menopausal transition, defined by bleeding patterns, vasomotor symptoms (VMS), and estradiol (E2) and follicle stimulating hormone (FSH) serum levels. Adjusted odds ratios (ORs) for difficulty falling asleep and staying asleep increased through the menopausal transition, but decreased for early morning awakening from late perimenopause to postmenopause. Naturally and surgically postmenopausal women using hormones, compared with those who were not, generally had lower ORs for disturbed sleep. More frequent VMS were associated with higher ORs of each sleep difficulty. Decreasing E2 levels were associated with higher ORs of trouble falling and staying asleep, and increasing FSH levels were associated with higher ORs of trouble staying asleep. Racial/ethnic differences were found for staying asleep and early morning awakening. Progression through the menopausal transition as indicated by 3 menopausal characteristics--symptoms, bleeding-defined stages, and endogenous hormone levels--is associated with self-reported sleep disturbances.


Updating Beliefs under Perceived Threat.
Humans are better at integrating desirable information into their beliefs than undesirable information. This asymmetry poses an evolutionary puzzle, as it can lead to an underestimation of risk and thus failure to take precautionary action. Here, we suggest a mechanism that can speak to this conundrum. In particular, we show that the bias vanishes in response to perceived threat in the environment. We report that an improvement in participants' tendency to incorporate bad news into their beliefs is associated with physiological arousal in response to threat indexed by galvanic skin response and self-reported anxiety. This pattern of results was observed in a controlled laboratory setting (Experiment I), where perceived threat was manipulated, and in firefighters on duty (Experiment II), where it naturally varied. Such flexibility in how individuals integrate information may enhance the likelihood of responding to warnings with caution in environments rife with threat, while maintaining a positivity bias otherwise, a strategy that can increase well-being.SIGNIFICANCE STATEMENT The human tendency to be overly optimistic has mystified scholars and lay people for decades: How could biased beliefs have been selected over unbiased beliefs? Scholars have suggested that although the optimism bias can lead to negative outcomes, including financial collapse and war, it can also facilitate health and productivity. Here, we demonstrate that a mechanism generating the optimism bias, namely asymmetric information integration, evaporates under threat. Such flexibility could result in enhanced caution in dangerous environments while supporting an optimism bias otherwise, potentially increasing well-being.


Clonal architectures and driver mutations in metastatic melanomas.
To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3' base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma.


Ultrahigh sensitivity polarimetric strain sensor based upon D-shaped optical fiber and surface plasmon resonance technology.
An ultrahigh sensitivity polarimetric strain sensor is proposed based upon a four-layer D-shaped optical fiber and surface plasmon resonance (SPR) technology. In contrast to existing SPR-based sensors, which are based on changes in the refractive index of the overlayer, the sensor proposed in this study is based on the change in the refractive index of the fiber core in response to the application of an axial load. Specifically, the phase difference between the P and S waves after passing through the sensor under SPR conditions is measured using a common-path heterodyne interferometer and is used to determine the corresponding change in the refractive index of the core, from which the strain is then inversely derived. The experimental results show that the sensitivity of the proposed sensor is around 2.19×10⁴ deg/ε, i.e., degree/strain. By contrast, that of a conventional (non-SPR) polarimetric fiber sensor is just 5.2×10² deg/ε. To the best of the authors' knowledge, the sensor proposed in this study represents the first reported attempt to exploit the refractive index change of the core of an SPR-based fiber sensor for strain measurement purposes.


Entropy- or enthalpy-driven collapse of strongly charged polymer chains in a one-component charged fluid of counterions or coions.
We applied a simulation method [T. Sumi and H. Sekino, J. Chem. Phys. 122, 194910 (2005)] to an infinitely dilute polyelectrolyte immersed in one-component charged fluids in order to investigate salt effects on its collapse. In this model system, the degree of freedom of the counterion (or the coion) is considered using a density-functional theory for polymer-solvent admixtures, while the oppositely charged ions are treated as a structureless background having the opposite charge. Results obtained by these simulations show that not only the counterion but also the coion makes the polymer chain collapsed. The effects by the coion are stronger than that by the counterion. Temperature variation of the gyration radius of the polymer chain immersed in the counterion is opposite to that in the coion: while the radius of gyration decreases as the temperature decreases in the case of the counterion, it decreases as the temperature increases in the case of the coion. From these results we conclude that the former is interpreted as an enthalpy-driven collapse caused by the screening effects of the counterion, whereas the latter is interpreted as an entropy-driven one due to the translational entropy of the coion.


Melatonin combined with endoplasmic reticulum stress induces cell death via the PI3K/Akt/mTOR pathway in B16F10 melanoma cells.
This study investigated B16F10 melanoma cell death induced by melatonin combined with endoplasmic reticulum (ER) stress through the PI3K/Akt/mTOR pathway. Cell viability was significantly decreased after treatment with melatonin combined with ER stress from thapsigargin or tunicamycin compared to no treatment or treatment with melatonin only. Combined melatonin and ER stress also significantly reduced expression of p85β, p-Akt (Ser473, Thr308), and p-mTOR (Ser2448, Ser2481) compared to treatment with melatonin only. The ER stress protein p-PERK and p-eIF2α were significantly increased under combined melatonin and ER stress treatment compared to no treatment or treatment with melatonin only. Combined melatonin and ER stress significantly reduced Bcl-2 protein and augmented Bax protein compared to melatonin-only treatment. Also, the combined treatment significantly lowered expression of catalase, Cu/Zn-SOD, and Mn-SOD proteins compared to melatonin only. Expression of p85β was significantly more decreased under treatment with melatonin and thapsigargin or tunicamycin plus the PI3K inhibitors LY294002 or wortmannin than under treatment with only melatonin or a PI3K inhibitor. The PI3K downstream target p-Akt (Ser473, Thr308) showed significantly decreased expression under treatment with melatonin and thapsigargin or tunicamycin plus PI3K inhibitors than under treatment with melatonin or PI3K inhibitors only. These results indicate that survival of B16F10 melanoma cells after combined treatment with melatonin and ER stress inducers is suppressed through regulation of the PI3K/Akt/mTOR pathway. Melatonin combined with thapsigargin or tunicamycin appears to be a promising strategy for effective melanoma treatment.


Activating HRAS mutation in agminated Spitz nevi arising in a nevus spilus.
Spitz nevi are benign melanocytic proliferations that can sometimes be clinically and histopathologically difficult to distinguish from melanoma. Agminated Spitz nevi have been reported to arise spontaneously, in association with an underlying nevus spilus, or after radiation or chemotherapy. However, to our knowledge, the genetic mechanism for this eruption has not been described. We report a case of agminated Spitz nevi arising in a nevus spilus and use exome sequencing to identify a clonal activating point mutation in HRAS (GenBank 3265) (c.37G→C) in the Spitz nevi and underlying nevus spilus. We also identify a secondary copy number increase involving HRAS on chromosome 11p, which occurs during the development of the Spitz nevi. Our results reveal an activating HRAS mutation in a nevus spilus that predisposes to the formation of Spitz nevi. In addition, we demonstrate a copy number increase in HRAS as a "second hit" during the formation of agminated Spitz nevi, which suggests that both multiple Spitz nevi and solitary Spitz nevi may arise through similar molecular pathways. In addition, we describe a unique investigative approach for the discovery of genetic alterations in Spitz nevi.


Ligand-receptor-mediated drug delivery: an emerging paradigm in cellular drug targeting.
Receptor-mediated cellular events have received major attention in the field of drug/gene delivery in the past few years. These events, which are mediated through the endogenous ligands/epitopes, could be exploited for designing site-specific and target-oriented delivery systems. The past decade has seen the development of endogenous ligands and their mimics of exogenous origins to selectively deliver the contained or immobilized moieties to the cellular interiors using a wide range of cell surface receptors/epitopes. Ligand-mediated active targeting has emerged as a novel paradigm in targeting either vascular compartment (first-order), cellular (second-order), or intracellular (third-order) levels. Most carrier systems or bioconjugates explored so far can be used as cargo units for the site-specific presentation and delivery of various bioactives using biorelevant ligands, including antibodies, polypeptides, oligosaccharides (carbohydrates), viral proteins, fusogenic residues, and molecules of endogenous origin. In this review, we describe various ligand-receptor systems that have been investigated to date for targeted or cellular drug delivery. These include blood carbohydrate (lectin) receptors, Fc receptors, complement receptors, interleukin receptors, lipoprotein receptors, transferin receptors, scavenger receptors, receptors/epitopes expressed on tumor cells, and cell adhesion receptors. The role of receptors as molecular target has opened new opportunities for cellular or intracellular targeting using carrier systems appended with targeting handles (ligands). Research in the field of ligand-receptor-based targeted system is expected to be an armamentarium and the focal point of research in the next millennium.


Characterization of a tobacco TPK-type K+ channel as a novel tonoplast K+ channel using yeast tonoplasts.
The tonoplast K(+) membrane transport system plays a crucial role in maintaining K(+) homeostasis in plant cells. Here, we isolated cDNAs encoding a two-pore K(+) channel (NtTPK1) from Nicotiana tabacum cv. SR1 and cultured BY-2 tobacco cells. Two of the four variants of NtTPK1 contained VHG and GHG instead of the GYG signature sequence in the second pore region. All four products were functional when expressed in the Escherichia coli cell membrane, and NtTPK1 was targeted to the tonoplast in tobacco cells. Two of the three promoter sequences isolated from N. tabacum cv. SR1 were active, and expression from these was increased approximately 2-fold by salt stress or high osmotic shock. To determine the properties of NtTPK1, we enlarged mutant yeast cells with inactivated endogenous tonoplast channels and prepared tonoplasts suitable for patch clamp recording allowing the NtTPK1-related channel conductance to be distinguished from the small endogenous currents. NtTPK1 exhibited strong selectivity for K(+) over Na(+). NtTPK1 activity was sensitive to spermidine and spermine, which were shown to be present in tobacco cells. NtTPK1 was active in the absence of Ca(2+), but a cytosolic concentration of 45 microM Ca(2+) resulted in a 2-fold increase in the amplitude of the K(+) current. Acidification of the cytosol to pH 5.5 also markedly increased NtTPK1-mediated K(+) currents. These results show that NtTPK1 is a novel tonoplast K(+) channel belonging to a different group from the previously characterized vacuolar channels SV, FV, and VK.


Improving philosophical dialogue interventions to better resolve problematic value pluralism in collaborative environmental science.
Environmental problems often outstrip the abilities of any single scientist to understand, much less address them. As a result, collaborations within, across, and beyond the environmental sciences are an increasingly important part of the environmental science landscape. Here, we explore an insufficiently recognized and particularly challenging barrier to collaborative environmental science: value pluralism, the presence of non-trivial differences in the values that collaborators bring to bear on project decisions. We argue that resolving the obstacles posed by value pluralism to collaborative environmental science requires detecting and coordinating the underlying problematic value differences. We identify five ways that a team might coordinate their problematic value differences and argue that, whichever mode is adopted, it ought to be governed by participatory virtues, pragmatic resolve, and moral concern. Relying on our experiences with the Toolbox Dialogue Initiative, as well as with other dialogical approaches that support team inquiry, we defend the claim that philosophical dialogue among collaborators can go a long way towards helping teams of environmental scientists and fellow travelers detect their problematic value differences. Where dialogical approaches fare less well is in helping teams coordinate these differences. We close by describing several principles for augmenting philosophical dialogue with other methods, and we list several of these methods in an appendix with brief descriptions and links for further learning. Overall, the article makes three main contributions to the research collaboration and values in science literatures: (1) It deepens our understanding of problematic value pluralism in team science; (2) It provides actionable guidance and methods for improving values-oriented philosophical dialogue interventions; and (3) It demonstrates one way of doing engaged philosophy.


Health Seeking Behaviour of Mothers of Under-Five-Year-Old Children in the Slum Communities of Nairobi, Kenya.
Prompt and appropriate health seeking is critical in the management of childhood illnesses. This paper examines the health seeking behaviour in under-five child morbidity. It explores in detail actions taken by 28 mothers when their children become sick. Sixty-two in-depth interviews with mothers were conducted from four study communities. The mothers were identified from a demographic surveillance system. The interviews were tape-recorded, transcribed and thematically analysed. The study shows that mothers classify childhood illnesses into four main categories: (1) not serious-coughs, colds, diarrhoea; (2) serious but not life-threatening-malaria; (3) sudden and serious-pneumonia; and (4) chronic and therefore not requiring immediate action-malnutrition, tuberculosis, chronic coughs. This classification is reflected in the actions taken and time it takes to act. Shops are used as the first source of healthcare, and when the care moves out of the home, private health facilities are used more compared to public health facilities, while even fewer mothers consult traditional healers. Consequently we conclude that there is a need to train mothers to recognize potentially life-threatening conditions and to seek appropriate treatment promptly. Drug vendors should be involved in intervention programs because they reach many mothers at the critical time of health seeking.


βENaC is required for whole cell mechanically gated currents in renal vascular smooth muscle cells.
Myogenic constrictor responses in small renal arteries and afferent arterioles are suppressed in mice with reduced levels of β-epithelial Na⁺ channel (βENaC(m/m)). The underlying mechanism is unclear. Decreased activity of voltage-gated calcium channels (VGCC) or mechanically gated ion channels and increased activity of large conductance calcium-activated potassium (BK) channels are a few possible mechanisms. The purpose of this study was to determine if VGCC, BK, or mechanically gated ion channel activity was altered in renal vascular smooth muscle cell (VSMC) from βENaC(m/m) mice. To address this, we used whole cell patch-clamp electrophysiological approaches in freshly isolated renal VSMCs. Compared with βENaC(+/+) controls, the current-voltage relationships for VGCC and BK activity are similar in βENaC(m/m) mice. These findings suggest neither VGCC nor BK channel dysfunction accounts for reduced myogenic constriction in βENaC(m/m) mice. We then examined mechanically gated currents using a novel in vitro assay where VSMCs are mechanically activated by stretching an underlying elastomer. We found the mechanically gated currents, predominantly carried by Na⁺, are observed with less frequency (87 vs. 43%) and have smaller magnitude (-54.1 ± 12.5 vs. -20.9 ± 4.9 pA) in renal VSMCs from βENaC(m/m) mice. Residual currents are expected in this model since VSMC βENaC expression is reduced by 50%. These findings suggest βENaC is required for normal mechanically gated currents in renal VSMCs and their disruption may account for the reduced myogenic constriction in the βENaC(m/m) model. Our findings are consistent with the role of βENaC as a VSMC mechanosensor and function of evolutionarily related nematode degenerin proteins.


Crocus sativus L. (saffron) for cancer chemoprevention: A mini review.
Cancer is one of the most feared diseases globally and there has been a sustained rise in its incidence in both developing and developed countries. Despite the growing therapeutic options for patients with cancer, their efficacy is time-limited and non-curative. Hence to overcome these drawbacks, an incessant screening for superior and safer drugs has been ongoing for numerous decades, resulting in the detection of anti-cancer properties of several phytochemicals. Chemoprevention using readily available natural substances from vegetables, fruits, herbs and spices is one of the significantly important approaches for cancer prevention in the present era. Among the spices, Crocus sativus L. (saffron; fān hóng huā) has generated interest because pharmacological experiments have established numerous beneficial properties including radical scavenging, anti-mutagenic and immuno-modulating effects. The more powerful components of saffron are crocin, crocetin and safranal. Studies in animal models and with cultured human malignant cell lines have demonstrated antitumor and cancer preventive activities of saffron and its main ingredients. This review provides a brief insight into the anticancer properties of saffron and its components.


Dispersion medium modulates oxidative stress response of human lung epithelial cells upon exposure to carbon nanomaterial samples.
Due to their large specific surface area, the potential of nanoparticles to be highly reactive and to induce oxidative stress is particularly high. In addition, some types of nanoparticles contain transition metals as trace impurities which are known to generate reactive oxygen species (ROS) in biological systems. This study investigates the potential of two types of single-walled carbon nanotube samples, nanoparticulate carbon black and crocidolite asbestos to induce ROS in lung epithelial cells in vitro. Carbon nanotube and carbon black samples were used as produced, without further purification or processing, in order to best mimic occupational exposure by inhalation of airborne dust particles derived from carbon nanomaterial production. Intracellular ROS were measured following short-term exposure of primary bronchial epithelial cells (NHBE) and A549 alveolar epithelial carcinoma cells using the redox sensitive probe carboxydichlorofluorescin (carboxy-DCFDA). The oxidative potential of agglomerated nanomaterial samples was compared following dispersion in cell culture medium with and without foetal calf serum (FCS) supplement. In addition, samples were dispersed in dipalmitoylphosphatidylcholine (DPPC), the major component of lung surfactant. It could be illustrated that in vitro exposure of lung epithelial cells to carbon nanomaterial samples results only in moderate or low oxidative stress under the exposure conditions employed. However, cell responses are strongly dependent on the vehicle used for dispersion. Whereas the presence of DPPC increased intracellular ROS formation, FCS seemed to protect the cells from oxidative insult.


Psychotherapy mediated by remote communication technologies: a meta-analytic review.
Access to psychotherapy is limited by psychopathology (e.g. agoraphobia), physical disability, occupational or social constraints and/or residency in under-served areas. For these populations, interventions delivered via remote communication technologies (e.g. telephone, internet) may be more appropriate. However, there are concerns that such delivery may influence the therapeutic relationship and thus reduce therapy effectiveness. This review aimed to determine the clinical effectiveness of remotely communicated, therapist-delivered psychotherapy. Systematic review (including electronic database searching and correspondence with authors) of randomised trials of individual remote psychotherapy. Electronic databases searched included MEDLINE (1966-2006), PsycInfo (1967-2006), EMBASE (1980-2006) and CINAHL databases (1982-2006). The Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDAN-CTR). All searches were conducted to include studies with a publication date to July 2006. Thirteen studies were identified, ten assessing psychotherapy by telephone, two by internet and one by videoconference. Pooled effect sizes for remote therapy versus control conditions were 0.44 for depression (95%CI 0.29 to 0.59, 7 comparisons, n = 726) and 1.15 for anxiety-related disorders (95%CI 0.81 to 1.49, 3 comparisons, n = 168). There were few comparisons of remote versus face-to-face psychotherapy. Remote therapy has the potential to overcome some of the barriers to conventional psychological therapy services. Telephone-based interventions are a particularly popular research focus and as a means of therapeutic communication may confer specific advantages in terms of their widespread availability and ease of operation. However, the available evidence is limited in quantity and quality. More rigorous trials are required to confirm these preliminary estimates of effectiveness. Future research priorities should include overcoming the methodological shortcomings of published work by conducting large-scale trials that incorporate both clinical outcome and more process-orientated measures.


Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial.
Autologous haemopoietic stem-cell transplantation (HSCT) improves survival in patients with multiple myeloma, but disease progression remains an issue. Allogeneic HSCT might reduce disease progression, but can be associated with high treatment-related mortality. Thus, we aimed to assess effectiveness of allogeneic HSCT with non-myeloablative conditioning after autologous HSCT compared with tandem autologous HSCT. In our phase 3 biological assignment trial, we enrolled patients with multiple myeloma attending 37 transplant centres in the USA. Patients (<70 years old) with adequate organ function who had completed at least three cycles of systemic antimyeloma therapy within the past 10 months were eligible for inclusion. We assigned patients to receive an autologous HSCT followed by an allogeneic HSCT (auto-allo group) or tandem autologous HSCTs (auto-auto group) on the basis of the availability of an HLA-matched sibling donor. Patients in the auto-auto group subsequently underwent a random allocation (1:1) to maintenance therapy (thalidomide plus dexamethasone) or observation. To avoid enrolment bias, we classified patients as standard risk or high risk on the basis of cytogenetics and β2-microglobulin concentrations. We used the Kaplan-Meier method to estimate differences in 3-year progression-free survival (PFS; primary endpoint) between patients with standard-risk disease in the auto-allo group and the best results from the auto-auto group (maintenance, observation, or pooled). This study is registered with ClinicalTrials.gov, number NCT00075829. Between Dec 17, 2003, and March 30, 2007, we enrolled 710 patients, of whom 625 had standard-risk disease and received an autologous HSCT. 156 (83%) of 189 patients with standard-risk disease in the auto-allo group and 366 (84%) of 436 in the auto-auto group received a second transplant. 219 patients in the auto-auto group were randomly assigned to observation and 217 to receive maintenance treatment, of whom 168 (77%) completed this treatment. PFS and overall survival did not differ between maintenance and observation groups and pooled data were used. Kaplan-Meier estimates of 3-year PFS were 43% (95% CI 36-51) in the auto-allo group and 46% (42-51) in the auto-auto group (p=0·671); overall survival also did not differ at 3 years (77% [95% CI 72-84] vs 80% [77-84]; p=0·191). Within 3 years, 87 (46%) of 189 patients in the auto-allo group had grade 3-5 adverse events as did 185 (42%) of 436 patients in the auto-auto group. The adverse events that differed most between groups were hyperbilirubinaemia (21 [11%] patients in the auto-allo group vs 14 [3%] in the auto-auto group) and peripheral neuropathy (11 [6%] in the auto-allo group vs 52 [12%] in the auto-auto group). Non-myeloablative allogeneic HSCT after autologous HSCT is not more effective than tandem autologous HSCT for patients with standard-risk multiple myeloma. Further enhancement of the graft versus myeloma effect and reduction in transplant-related mortality are needed to improve the allogeneic HSCT approach. US National Heart, Lung, and Blood Institute and the National Cancer Institute.


Comparison of an expert system with other clinical scores for the evaluation of severity of asthma.
"Asthmaexpert" was produced at the special request of several clinicians in order to obtain a better understanding of the medical decisions taken by clinical experts in the management of asthmatic patients. In order to assess the severity of asthma, a new score called Artificial Intelligence score (AI score), produced by Asthmaexpert, was compared with three other scores (Aas, Hargreave and Brooks). One hundred patients were enrolled prospectively in the study during their first consultation in the out-patient clinic. Distribution of severity level according to the different scores was studied, and the reliability between AI and other scores was evaluated by Kappa and MacNemar tests. Correlations with functional parameters were performed. The AI score assessed higher levels of severity than the other scores (Kappa = 18, 28 and 10% for Aas, Hargreave and Brooks, respectively) with significant MacNemar test in all cases. There was a significant correlation between AI score and forced expiratory volume in one second (FEV1) (r = 0.73). These data indicate that the AI score is a severity score which defines higher levels of severity than the chosen scores. Correlations for functional parameters are good. This score appears easy to use for the first consultation of an asthmatic patient.


Understanding public trust in water managers: Findings from the Netherlands.
Public trust in water managers is often considered an important precondition for the effective implementation of sustainable water-management practices. Although it is well known that general public trust in government institutions is under pressure, much less is known in the literature on water governance whether such distrust also affects general and task-specific trust of the wider public in water managers. In addition, empirical studies on the determinants of such trust seem to be scarce. To fill those gaps, this study aims to measure general and task-specific public trust in water managers in the Netherlands and to assess how a selected group of potential determinants is related to general- and task-specific trust in water managers. To this end, we employ an original survey among a representative sample of the Dutch population (N = 2262). We find that trust in water managers in the Netherlands is generally high, but that it also comes with some task-specific variations. People have more trust in the flood-protection capacities of the water managers than in the capacities to successfully manage surface-water quality, nature conservation, and drought management. Using linear regression models, we subsequently find that individual-level variations in trust in water managers are best explained by one's general level of political trust. Additionally, we also show that both risk perceptions and self-evaluations of how informed people feel themselves about water management are important factors with (curvilinear) relations with trust in water managers. Overall, we conclude that water managers are under specific conditions able to build themselves well-established reputations and relatively high trust levels based on their performances. Nevertheless, trust development is far from entirely in the hands of the water managers themselves as we also conclude that trust evaluations of water managers are not immune from negative generalized political evaluations and public perceptions on water related risks.


Interspecies transmission of the canine influenza H3N2 virus to domestic cats in South Korea, 2010.
In the past 4 years, incidences of endemic or epidemic respiratory diseases associated with canine influenza H3N2 virus in Asian dogs have been reported in countries such as South Korea and China. Canine species were considered to be the new natural hosts for this virus. However, at the beginning of 2010, influenza-like respiratory signs, such as dyspnoea, were also observed among cats as well as in dogs in an animal shelter located in Seoul, South Korea. The affected cats showed 100 % morbidity and 40 % mortality. We were able to isolate a virus from a lung specimen of a dead cat, which had suffered from the respiratory disease, in embryonated-chicken eggs. The eight viral genes isolated were almost identical to those of the canine influenza H3N2 virus, suggesting interspecies transmission of canine influenza H3N2 virus to the cat. Moreover, three domestic cats infected with intranasal canine/Korea/GCVP01/07 (H3N2) all showed elevated rectal temperatures, nasal virus shedding and severe pulmonary lesions, such as suppurative bronchopneumonia. Our study shows, for the first time, that cats are susceptible to canine influenza H3N2 infection, suggesting that cats may play an intermediate host role in transmitting the H3N2 virus among feline and canine species, which could lead to the endemic establishment of the virus in companion animals. Such a scenario raises a public health concern, as the possibility of the emergence of new recombinant feline or canine influenza viruses in companion animals with the potential to act as a zoonotic infection cannot be excluded.


Murine bilateral retinoblastoma exhibiting rapid-onset, metastatic progression and N-myc gene amplification.
Human retinoblastoma is a pediatric cancer initiated by RB gene mutations in the developing retina. We have examined the origins and progression of retinoblastoma in mouse models of the disease. Retina-specific inactivation of Rb on a p130-/- genetic background led to bilateral retinoblastoma with rapid kinetics, whereas on a p107-/- background Rb mutation caused predominantly unilateral tumors that arose with delayed kinetics and incomplete penetrance. In both models, retinoblastomas arose from cells at the extreme periphery of the murine retina. Furthermore, late retinoblastomas progressed to invade the brain and metastasized to the cervical lymph nodes. Metastatic tumors lacking Rb and p130 exhibited chromosomal changes revealed by representational oligonucleotide microarray analysis including high-level amplification of the N-myc oncogene. N-myc was found amplified in three of 16 metastatic retinoblastomas lacking Rb and p130 as well as in retinoblastomas lacking Rb and p107. N-myc amplification ranged from 6- to 400-fold and correlated with high N-myc-expression levels. These murine models closely resemble human retinoblastoma in their progression and secondary genetic changes, making them ideal tools for further dissection of steps to tumorigenesis and for testing novel therapies.


The nucleolar channel system of human endometrium is related to endoplasmic reticulum and R-rings.
The nucleolar channel system (NCS) is a well-established ultrastructural hallmark of the postovulation endometrium. Its transient presence has been associated with human fertility. Nevertheless, the biogenesis, composition, and function of these intranuclear membrane cisternae are unknown. Membrane systems with a striking ultrastructural resemblance to the NCS, termed R-rings, are induced in nuclei of tissue culture cells by overexpression of the central repeat domain of the nucleolar protein Nopp140. Here we provide a first molecular characterization of the NCS and compare the biogenesis of these two enigmatic organelles. Like the R-rings, the NCS consists of endoplasmic reticulum harboring the marker glucose-6-phosphatase. R-ring formation initiates at the nuclear envelope, apparently by a calcium-mediated Nopp140-membrane interaction, as supported by the calcium-binding ability of Nopp140, the inhibition of R-ring formation by calcium chelators, and the concentration of Nopp140 and complexed calcium in R-rings. Although biogenesis of the NCS may initiate similarly, the reduced presence of complexed calcium and Nopp140 suggests the involvement of additional factors.


Comparison of Videonystagmography and Audiological Findings after Stapedotomy; CO2 Laser vs Perforator.
Various types of laser, microdrill, and perforator are effectively used in the surgical treatment of otosclerosis. However, they have certain disadvantages along with advantages. The aim of this study was to evaluate the effects of carbon dioxide (CO2) laser and perforator stapedotomy techniques on audiological outcomes and postoperative vestibular functions via videonystagmography (VNG). This prospective and randomized clinical study was conducted in an academic tertiary medical center. Sixty-nine patients diagnosed with otosclerosis who underwent stapedotomy were enrolled in this study. Patients were divided into two groups based on the technique used in stapedotomy: CO2 laser and perforator. Postoperative hearing gain and VNG findings were the main outcome measures. Subsequently, the two study groups were compared for analysis. The preoperative air-bone gap was 32.7±8.9 decibel (dB) in the study population and it was improved to 12.9±8.4 dB after operation. There were no differences in VNG findings and vertigo symptoms between the laser and perforator groups at postoperative day 2. There was no significant gain difference regarding the air conduction, bone conduction, and air-bone gap between the two groups (p=0.294, p=0.57, and p=0.37, respectively). Both CO2 laser and perforator stapedotomy have successful audiological outcomes with no difference in postoperative vestibular disturbance.


Structural insight into how Streptomyces coelicolor maltosyl transferase GlgE binds α-maltose 1-phosphate and forms a maltosyl-enzyme intermediate.
GlgE (EC 188.8.131.52) is an α-maltose 1-phosphate:(1→4)-α-d-glucan 4-α-d-maltosyltransferase of the CAZy glycoside hydrolase 13_3 family. It is the defining enzyme of a bacterial α-glucan biosynthetic pathway and is a genetically validated anti-tuberculosis target. It catalyzes the α-retaining transfer of maltosyl units from α-maltose 1-phosphate to maltooligosaccharides and is predicted to use a double-displacement mechanism. Evidence of this mechanism was obtained using a combination of site-directed mutagenesis of Streptomyces coelicolor GlgE isoform I, substrate analogues, protein crystallography, and mass spectrometry. The X-ray structures of α-maltose 1-phosphate bound to a D394A mutein and a β-2-deoxy-2-fluoromaltosyl-enzyme intermediate with a E423A mutein were determined. There are few examples of CAZy glycoside hydrolase family 13 members that have had their glycosyl-enzyme intermediate structures determined, and none before now have been obtained with a 2-deoxy-2-fluoro substrate analogue. The covalent modification of Asp394 was confirmed using mass spectrometry. A similar modification of wild-type GlgE proteins from S. coelicolor and Mycobacterium tuberculosis was also observed. Small-angle X-ray scattering of the M. tuberculosis enzyme revealed a homodimeric assembly similar to that of the S. coelicolor enzyme but with slightly differently oriented monomers. The deeper understanding of the structure-function relationships of S. coelicolor GlgE will aid the development of inhibitors of the M. tuberculosis enzyme.


Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype.
Sickle cell disease (SCD) is caused by a single amino acid change in the adult hemoglobin (Hb) β chain that causes Hb polymerization and red blood cell (RBC) sickling. The co-inheritance of mutations causing fetal γ-globin production in adult life hereditary persistence of fetal Hb (HPFH) reduces the clinical severity of SCD. HPFH mutations in the HBG γ-globin promoters disrupt binding sites for the repressors BCL11A and LRF. We used CRISPR-Cas9 to mimic HPFH mutations in the HBG promoters by generating insertions and deletions, leading to disruption of known and putative repressor binding sites. Editing of the LRF-binding site in patient-derived hematopoietic stem/progenitor cells (HSPCs) resulted in γ-globin derepression and correction of the sickling phenotype. Xenotransplantation of HSPCs treated with gRNAs targeting the LRF-binding site showed a high editing efficiency in repopulating HSPCs. This study identifies the LRF-binding site as a potent target for genome-editing treatment of SCD.


Gait Stability Has Phase-Dependent Dual-Task Costs in Parkinson's Disease.
Dual-task (DT) paradigms have been used in gait research to assess the automaticity of locomotion, particularly in people with Parkinson's disease (PD). In people with PD, reliance on cortical control during walking leads to greater interference between cognitive and locomotor tasks. Yet, recent studies have suggested that even healthy gait requires cognitive control, and that these cognitive contributions occur at specific phases of the gait cycle. Here, we examined whether changes in gait stability, elicited by simultaneous cognitive DTs, were specific to certain phases of the gait cycle in people with PD. Phase-dependent local dynamic stability (LDS) was calculated for 95 subjects with PD and 50 healthy control subjects during both single task and DT gait at phases corresponding to (1) heel contact-weight transfer, (2) toe-off-early swing, and (3) single-support-mid swing. PD-related DT interference was evident only for the duration of late swing and LDS during the heel contact-weight transfer phase of gait. No PD-related DT costs were found in other traditional spatiotemporal gait parameters. These results suggest that PD-related DT interference occurs only during times where cortical activity is needed for planning and postural adjustments. These results challenge our understanding of DT costs while walking, particularly in people with PD, and encourage researchers to re-evaluate traditional concepts of DT interference.


Advances in electronic-nose technologies for the detection of volatile biomarker metabolites in the human breath.
Recent advancements in the use of electronic-nose (e-nose) devices to analyze human breath profiles for the presence of specific volatile metabolites, known as biomarkers or chemical bio-indicators of specific human diseases, metabolic disorders and the overall health status of individuals, are providing the potential for new noninvasive tools and techniques useful to point-of-care clinical disease diagnoses. This exciting new area of electronic disease detection and diagnosis promises to yield much faster and earlier detection of human diseases and disorders, allowing earlier, more effective treatments, resulting in more rapid patient recovery from various afflictions. E-nose devices are particularly suited for the field of disease diagnostics, because they are sensitive to a wide range of volatile organic compounds (VOCs) and can effectively distinguish between different complex gaseous mixtures via analysis of electronic aroma sensor-array output profiles of volatile metabolites present in the human breath. This review provides a summary of some recent developments of electronic-nose technologies, particularly involving breath analysis, with the potential for providing many new diagnostic applications for the detection of specific human diseases associated with different organs in the body, detectable from e-nose analyses of aberrant disease-associated VOCs present in air expired from the lungs.


The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.
Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.


International Charter of principles for sharing bio-specimens and data.
There is a growing international agreement on the need to provide greater access to research data and bio-specimen collections to optimize their long-term value and exploit their potential for health discovery and validation. This is especially evident for rare disease research. Currently, the rising value of data and bio-specimen collections does not correspond with an equal increase in data/sample-sharing and data/sample access. Contradictory legal and ethical frameworks across national borders are obstacles to effective sharing: more specifically, the absence of an integrated model proves to be a major logistical obstruction. The Charter intends to amend the obstacle by providing both the ethical foundations on which data sharing should be based, as well as a general Material and Data Transfer Agreement (MTA/DTA). This Charter is the result of a careful negotiation of different stakeholders' interest and is built on earlier consensus documents and position statements, which provided the general international legal framework. Further to this, the Charter provides tools that may help accelerate sharing. The Charter has been formulated to serve as an enabling tool for effective and transparent data and bio-specimen sharing and the general MTA/DTA constitutes a mechanism to ensure uniformity of access across projects and countries, and may be regarded as a consistent basic agreement for addressing data and material sharing globally. The Charter is forward looking in terms of emerging issues from the perspective of a multi-stakeholder group, and where possible, provides strategies that may address these issues.


Is there any way to protect from tacrolimus-induced renal and pancreas injury?
The aim of this study was to explore effects of erythropoietin and pentoxifylline in tacrolimus-induced pancreatic beta cell and renal injury in rats. Rats in group I were given saline; rats in group II were injected with tacrolimus; rats in group III were received erythropoietin (Epo) and tacrolimus; while rats in group IV were injected pentoxifylline (Ptx) plus tacrolimus for nine d. On 10th day, blood and tissue samples were taken for biochemical and pathological evaluations. Tacrolimus-injected animals exhibited significant elevation in blood urea nitrogen (BUN), and serum BUN levels were improved in rats pretreated with Ptx. Significantly more apoptotic nuclei were observed in kidneys of tacrolimus group. In rats subjected to tacrolimus and pretreated with Epo, there was significant decrease in apoptotic nuclei staining than those in tacrolimus group. Blood trough levels of tacrolimus were significantly higher in erythropoietin-pretreated group, although same amount of tacrolimus was injected with other groups. Results of our study demonstrated significant antiapoptotic effects of erythropoietin on renal tubules, increasing effect of erythropoietin on tacrolimus blood levels, and insignificant antioxidant effects of both erythropoietin and pentoxifylline on renal and pancreas tissues. Study with clinically greater tacrolimus levels may be useful to confirm these findings.


Conformational similarities in the beta-ionone ring region of the rhodopsin chromophore in its ground state and after photoactivation to the metarhodopsin-I intermediate.
High-resolution solid-state NMR methods have been used to analyze the conformation of the chromophore in the late photointermediate metarhodopsin-I, from observation of (13)C nuclei introduced into the beta-ionone ring (at the C16, C17, and C18 methyl groups) and into the adjoining segment of the polyene chain (at C8). Bovine rhodopsin in its native membrane was also regenerated with retinal that was (13)C-labeled close to the 11-Z bond (C20 methyl group) to provide a reporter for optimizing and quantifying the photoconversion to metarhodopsin-I. Indirect photoconversion via the primary intermediate, bathorhodopin, was adopted as the preferred method since approximately 44% conversion to the metarhodopsin-I component could be achieved, with only low levels (approximately 18%) of ground-state rhodopsin remaining. The additional photoproduct, isorhodopsin, was resolved in (13)C spectra from C8 in the chain, at levels of approximately 38%, and was shown using rotational resonance NMR to adopt the 6-s-cis conformation between the ring and the polyene chain. The C8 resonance was not shifted in the metarhodopsin-I spectral component but was strongly broadened, revealing that the local conformation had become less well defined in this segment of the chain. This line broadening slowed rotational resonance exchange with the C17 and C18 ring methyl groups but was accounted for to show that, despite the chain being more relaxed in metarhodopsin-I, its average conformation with respect to the ring was similar to that in the ground state protein. Conformational restraints are also retained for the C16 and C17 methyl groups on photoactivation, which, together with the largely preserved conformation in the chain, argues convincingly that the ring remains with strong contacts in its binding pocket prior to activation of the receptor. Previous conclusions based on photocrosslinking studies are considered in view of the current findings.


Pancreas Donor Risk Index but Not Pre-Procurement Pancreas Allocation Suitability Score Predicts Pancreas Graft Survival: A Cohort Study from a Large German Pancreas Transplantation Center.
BACKGROUND The pre-procurement pancreas allocation suitability score (P-PASS) was introduced to support clinical decision-making and ultimately expand the currently insufficient pancreas donor pool. The pancreas donor risk index (PDRI) can be used at the time of organ offering to predict one-year graft survival. Thus, this study aimed to analyze the validity of the PDRI and P-PASS in a large German transplant center. MATERIAL AND METHODS From 2002 to 2015, we performed 327 pancreas transplantations at our center. P-PASS and PDRI were calculated for 322 patients. To evaluate the pancreas graft survival, the patient cohort was divided into 2 P-PASS (<17, n=115 and ≥17, n=207) and 3 PDRI groups (<1, n=87; 1-1.5, n=133; and >1.5, n=102). Kaplan-Meier and Cox regression analyses were performed. We also examined differences regarding early pancreas graft failure for both scores using the chi-square test. RESULTS The PDRI was associated with pancreas graft survival in the univariate analysis (p=0.023). In the multivariate analysis, a PDRI >1.5 was associated with significantly decreased graft survival (hazard ratio=1.792, 95% confidence interval=1.10-2.90, p=0.018). The P-PASS showed no significant association (p=0.081) with pancreas graft survival in the Kaplan-Meier survival analysis. There were significantly more early pancreas graft losses in the P-PASS ≥17 group (p=0.025). CONCLUSIONS Our results showed an association between P-PASS ≥17 and early pancreas graft failure. However, this does not apply to long-term pancreas graft survival; the PDRI proved to be a better tool for this, and PDRI values >1.5 were associated with significantly worse outcomes after pancreas transplantation.


Heterogeneous decrease in malaria prevalence in children over a six-year period in south-western Uganda.
Malaria is a major public health problem, especially for children. However, recent reports suggest a decline in the malaria burden. The aim of this study was to assess the change in the prevalence of malaria infection among children below five years of age between 2004 and 2010 in a mesoendemic area of Uganda and to analyse the risk factors of malaria infection. Two cross-sectional surveys were conducted in 2004 and in 2010 at the end of the rainy and dry seasons to measure the prevalence of P. falciparum infection among children less than five years of age. Rapid diagnostic tests and blood smears were used to diagnose malaria infection. In 2010, sampling was stratified by urban and rural areas. In each selected household, knowledge of malaria and bed nets, and bed net ownership and use, were assessed. In 2004 and 2010, respectively, a total of 527 and 2,320 (999 in the urban area and 1,321 in rural areas) children less than five years old were enrolled. Prevalence of malaria infection declined from 43% (95% CI: 34-52) in 2004, to 23% (95% CI: 17-30) in rural areas in 2010 and 3% (95% CI: 2-5) in the urban area in 2010. From the rainy to dry season in 2010, prevalence decreased from 23% to 10% (95% CI: 6-14) in rural areas (P = 0.001) and remained stable from 3% to 4% (95% CI: 1-7) in the urban area (P = 0.9). The proportion of households reporting ownership and use of at least one bed net increased from 22.9% in 2004 to 64.7% in the urban area and 44.5% in rural areas in 2010 (P < 0.001). In 2010, the risk of malaria infection was consistently associated with child age and household wealth. In rural areas, malaria infection was also associated with geographic factors. This study reports a significant drop in the prevalence of malaria infection among children below five years of age, paralleled by an uptake in bed-net use. However, prevalence remains unacceptably high in rural areas and is strongly associated with poverty.


Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability.
Human gastric carcinoma shows a higher prevalence of microsatellite instability (MSI) than does any other type of sporadic human cancer. The reasons for this high frequency of MSI are not yet known. In contrast to endometrial and colorectal carcinoma, mutations of the DNA mismatch repair (MMR) genes hMLH1 or hMSH2 have not been described in gastric carcinoma. However, hypermethylation of the hMLH1 MMR gene promoter is quite common in MSI-positive endometrial and colorectal cancers. This hypermethylation has been associated with hMLH1 transcriptional blockade, which is reversible with demethylation, suggesting that an epigenetic mechanism underlies hMLH1 gene inactivation and MMR deficiency. Therefore, we studied the prevalence of hMLH1 promoter hypermethylation in a total of 65 gastric tumors: 18 with frequent MSI (MSI-H), 8 with infrequent MSI (MSI-L), and 39 that were MSI negative. We found a striking association between hMLH1 promoter hypermethylation and MSI; of 18 MSI-H tumors, 14 (77.8%) showed hypermethylation, whereas 6 of 8 MSI-L tumors (75%) were hypermethylated at hMLH1. In contrast, only 1 of 39 (2.6%) MSI-negative tumors demonstrated hMLH1 hypermethylation (P<0.0001 for MSI-H or MSI-L versus MSI-negative). Moreover, hypermethylated cancers demonstrated diminished expression of hMLH1 protein by both immunohistochemistry and Western blotting, whereas nonhypermethylated tumors expressed abundant hMLH1 protein. These data indicate that hypermethylation of hMLH1 is strongly associated with MSI in gastric cancers and suggest an epigenetic mechanism by which defective MMR occurs in this group of cancers.


Vibrational excitation induces double reaction.
Electron-induced reaction at metal surfaces is currently the subject of extensive study. Here, we broaden the range of experimentation to a comparison of vibrational excitation with electronic excitation, for reaction of the same molecule at the same clean metal surface. In a previous study of electron-induced reaction by scanning tunneling microscopy (STM), we examined the dynamics of the concurrent breaking of the two C-I bonds of ortho-diiodobenzene physisorbed on Cu(110). The energy of the incident electron was near the electronic excitation threshold of E0=1.0 eV required to induce this single-electron process. STM has been employed in the present work to study the reaction dynamics at the substantially lower incident electron energies of 0.3 eV, well below the electronic excitation threshold. The observed increase in reaction rate with current was found to be fourth-order, indicative of multistep reagent vibrational excitation, in contrast to the first-order rate dependence found earlier for electronic excitation. The change in mode of excitation was accompanied by altered reaction dynamics, evidenced by a different pattern of binding of the chemisorbed products to the copper surface. We have modeled these altered reaction dynamics by exciting normal modes of vibration that distort the C-I bonds of the physisorbed reagent. Using the same ab initio ground potential-energy surface as in the prior work on electronic excitation, but with only vibrational excitation of the physisorbed reagent in the asymmetric stretch mode of C-I bonds, we obtained the observed alteration in reaction dynamics.


[Survey of ants (Hymenoptera: Formicidae) in the urban area of Uberlândia, MG, Brazil].
Uberlândia, MG, Brazil, underwent an accelerated process of urbanization with a population growth of 3,54% each year, higher than the national average. One of the problems emergent from urbanization is the use of different habitats for a great variety of insects. The objective of this study was to identify species of house-invading ants that occur in the urban area of Uberlândia. The occurrence of the house-invading species in regard to the time of urbanization, neighborhood infrastructure, age and maintenance of private houses was also assessed. The ants were collected using bait-traps in 120 residences from 12 neighborhoods which were put in three groups. Fourteen species of ants were catalogued, with Camponotus (Mayr), Monomorium (Mayr) and Tapinoma (Foerster) being the most frequent genera. Only Camponotus vittatus (Forel), Monomorium pharaonis (L.), Tapinoma melanocephalum (Fabricius) and Brachymyrmex sp. (Mayr) were collected in all three groups. The relation between the ants collected and the age and maintenance of the private houses showed that Paratrechina longicornis (Latreille) was most frequent (60%) in poorly preserved or precarious constructions. Whereas, C. vittatus and Camonotus melanoticus (Emery) occurred in all categories of maintenance. Overall, C. vittatus which had not been found in any previously published survey of urban ants, was the most frequent species in urban areas of the Cerrado.


Neuronal Dystroglycan Is Necessary for Formation and Maintenance of Functional CCK-Positive Basket Cell Terminals on Pyramidal Cells.
Distinct types of GABAergic interneurons target different subcellular domains of pyramidal cells, thereby shaping pyramidal cell activity patterns. Whether the presynaptic heterogeneity of GABAergic innervation is mirrored by specific postsynaptic factors is largely unexplored. Here we show that dystroglycan, a protein responsible for the majority of congenital muscular dystrophies when dysfunctional, has a function at postsynaptic sites restricted to a subset of GABAergic interneurons. Conditional deletion of Dag1, encoding dystroglycan, in pyramidal cells caused loss of CCK-positive basket cell terminals in hippocampus and neocortex. PV-positive basket cell terminals were unaffected in mutant mice, demonstrating interneuron subtype-specific function of dystroglycan. Loss of dystroglycan in pyramidal cells had little influence on clustering of other GABAergic postsynaptic proteins and of glutamatergic synaptic proteins. CCK-positive terminals were not established at P21 in the absence of dystroglycan and were markedly reduced when dystroglycan was ablated in adult mice, suggesting a role for dystroglycan in both formation and maintenance of CCK-positive terminals. The necessity of neuronal dystroglycan for functional innervation by CCK-positive basket cell axon terminals was confirmed by reduced frequency of inhibitory events in pyramidal cells of dystroglycan-deficient mice and further corroborated by the inefficiency of carbachol to increase IPSC frequency in these cells. Finally, neurexin binding seems dispensable for dystroglycan function because knock-in mice expressing binding-deficient T190M dystroglycan displayed normal CCK-positive terminals. Together, we describe a novel function of dystroglycan in interneuron subtype-specific trans-synaptic signaling, revealing correlation of presynaptic and postsynaptic molecular diversity. Dystroglycan, an extracellular and transmembrane protein of the dystrophin-glycoprotein complex, is at the center of molecular studies of muscular dystrophies. Although its synaptic distribution in cortical brain regions is long established, function of dystroglycan in the synapse remained obscure. Using mice that selectively lack neuronal dystroglycan, we provide evidence that a subset of GABAergic interneurons requires dystroglycan for formation and maintenance of axonal terminals on pyramidal cells. As such, dystroglycan is the first postsynaptic GABAergic protein for which an interneuron terminal-specific function could be shown. Our findings also offer a new perspective on the mechanisms that lead to intellectual disability in muscular dystrophies without associated brain malformations.


Synergy of repression and silencing gradients along the chromosome.
The expression of a gene is determined by the transcriptional activators and repressors bound to its regulatory regions. It is not clear how these opposing activities are summed to define the degree of silencing of genes within a segment of the eukaryotic chromosome. We show that the general repressor Ssn6 and the silencing protein Sir3 generate inhibitory gradients with similar slopes over a transcribed gene, even though Ssn6 is considered a promoter-specific repressor of single genes, while Sir3 is a regional silencer. When two repression or silencing gradients flank a gene, they have a multiplicative effect on gene expression. A significant amplification of the interacting gradients distinguishes silencing from repression. When a silencing gradient is enhanced, the distance-dependence of the amplification changes and long-range effects are established preferentially. These observations reveal that repression and silencing proteins can attain different tiers in a hierarchy of conserved regulatory modes. The quantitative rules associated with these modes will help to explain the co-expression pattern of adjacent genes in the genome.


Alzheimer's disease: a correlative study.
In a study of 17 patients with histologically proven Alzheimer's disease the relationship between psychological, pathological and chemical measures of disorder was examined. Severity of dementia, determined by mental test performance, correlated highly with pathological change in large cortical neurons (cell loss and reduction in nuclear and nucleolar volume and cytoplasmic RNA content), to a lesser extent with cortical senile plaque and neurofibrillary tangle frequency and reduction in acetylcholine (ACh) synthesis, and not with reduction in choline acetyltransferase (CAT) activity. A strongly significant relationship was demonstrated between cell loss and reductions in nuclear and nucleolar volume and cytoplasmic RNA content. Reduction in CAT activity and senile plaque frequency were significantly correlated, thereby linking changes in the sub-cortical projection system of the nucleus basalis with the cortical pathology. The pattern of correlations suggests that the dementia of Alzheimer's disease is largely a reflection of the state of large cortical neurons, and it is argued that abnormalities in the latter may not be directly related to primary loss of cholinergic neurons in the subcortex.


Crenotherapy: a neglected resource for human health now re-emerging on sound scientific concepts.
Recent mechanistic evidence demonstrates that spa-based therapy (or, as we propose, crenotherapy from the Greek word kapparhoepsilonnueta, spring fountain) is indeed based on solid scientific data. This mini-review highlights the latest insights into the mechanisms of crenotherapy derived from in vitro experiments, studies on animal models, and carefully designed clinical trials. Although more basic and clinical data are still needed, crenotherapy is coming of age as a modern, scientifically sound therapy. As the underlying mechanisms are uncovered, it is becoming possible to choose the most appropriate applications of this centuries-old practice, possibly reducing medical costs, thus explaining the current worldwide renewed interest in crenotherapy.


Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy.
TRACK-HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3-Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross-sectional data from this large well-characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene-positive subjects (120 PreHD and 119 early HD) from the TRACK-HD study were included. Using voxel-based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti-saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD.