Hemodynamic responses in human multisensory and auditory association cortex to purely visual stimulation.
Recent findings of a tight coupling between visual and auditory association cortices during multisensory perception in monkeys and humans raise the question whether consistent paired presentation of simple visual and auditory stimuli prompts conditioned responses in unimodal auditory regions or multimodal association cortex once visual stimuli are presented in isolation in a post-conditioning run. To address this issue fifteen healthy participants partook in a "silent" sparse temporal event-related fMRI study. In the first (visual control) habituation phase they were presented with briefly red flashing visual stimuli. In the second (auditory control) habituation phase they heard brief telephone ringing. In the third (conditioning) phase we coincidently presented the visual stimulus (CS) paired with the auditory stimulus (UCS). In the fourth phase participants either viewed flashes paired with the auditory stimulus (maintenance, CS-) or viewed the visual stimulus in isolation (extinction, CS+) according to a 5:10 partial reinforcement schedule. The participants had no other task than attending to the stimuli and indicating the end of each trial by pressing a button. During unpaired visual presentations (preceding and following the paired presentation) we observed significant brain responses beyond primary visual cortex in the bilateral posterior auditory association cortex (planum temporale, planum parietale) and in the right superior temporal sulcus whereas the primary auditory regions were not involved. By contrast, the activity in auditory core regions was markedly larger when participants were presented with auditory stimuli. These results demonstrate involvement of multisensory and auditory association areas in perception of unimodal visual stimulation which may reflect the instantaneous forming of multisensory associations and cannot be attributed to sensation of an auditory event. More importantly, we are able to show that brain responses in multisensory cortices do not necessarily emerge from associative learning but even occur spontaneously to simple visual stimulation.


'Localimania' revisited: guidelines for the formation of specific epithets for names of prokaryotes based on names of institutions or their acronyms. A proposal for emendation of Appendix 9 to the International Code of Nomenclature of Prokaryotes.
We here present a survey of the increasing use of the -ensis (-ense) ending for the formation of specific epithets that do not refer to geographical locations but to names of research institutes or their acronyms. To our opinion the use of the -ensis (-ense) ending must be discouraged for such purposes, the formation of nouns in the genitive case being preferred for the formation of such arbitrary epithets. Emendation of Appendix 9 - Orthography to the International Code of Nomenclature of Prokaryotes is proposed with guidelines for the formation of such names.


Microplankton life histories revealed by holographic microscopy and deep learning.
The marine microbial food web plays a central role in the global carbon cycle. However, our mechanistic understanding of the ocean is biased toward its larger constituents, while rates and biomass fluxes in the microbial food web are mainly inferred from indirect measurements and ensemble averages. Yet, resolution at the level of the individual microplankton is required to advance our understanding of the microbial food web. Here, we demonstrate that, by combining holographic microscopy with deep learning, we can follow microplanktons throughout their lifespan, continuously measuring their three-dimensional position and dry mass. The deep-learning algorithms circumvent the computationally intensive processing of holographic data and allow rapid measurements over extended time periods. This permits us to reliably estimate growth rates, both in terms of dry mass increase and cell divisions, as well as to measure trophic interactions between species such as predation events. The individual resolution provides information about selectivity, individual feeding rates, and handling times for individual microplanktons. The method is particularly useful to detail the rates and routes of organic matter transfer in micro-zooplankton, the most important and least known group of primary consumers in the oceans. Studying individual interactions in idealized small systems provides insights that help us understand microbial food webs and ultimately larger-scale processes. We exemplify this by detailed descriptions of micro-zooplankton feeding events, cell divisions, and long-term monitoring of single cells from division to division.


19-core MCF transmission system using EDFA with shared core pumping coupled via free-space optics.
We report the development of a space division multiplexed (SDM) transmission system consisting of a 19-core fiber and 19-core Erbium-doped fiber amplifier (EDFA). A new 19-core fiber with an improved core arrangement was employed to achieve a low aggregated inter-core crosstalk of -42 dB at 1550 nm over 30 km. The EDFA uses shared free-space optics for pump beam combining and isolation, thus is SDM transparent and has some potential for cost reduction. 19.6 dB to 23.3 dB gain and 6.0 dB to 7.0 dB noise figure were obtained for each SDM channel at 1550 nm. System feasibility for SDM transmission over 1200 km was demonstrated with 100 Gb/s PDM-QPSK signals.


Single-molecule visualization of human RECQ5 interactions with single-stranded DNA recombination intermediates.
RECQ5 is one of five RecQ helicases found in humans and is thought to participate in homologous DNA recombination by acting as a negative regulator of the recombinase protein RAD51. Here, we use kinetic and single molecule imaging methods to monitor RECQ5 behavior on various nucleoprotein complexes. Our data demonstrate that RECQ5 can act as an ATP-dependent single-stranded DNA (ssDNA) motor protein and can translocate on ssDNA that is bound by replication protein A (RPA). RECQ5 can also translocate on RAD51-coated ssDNA and readily dismantles RAD51-ssDNA filaments. RECQ5 interacts with RAD51 through protein-protein contacts, and disruption of this interface through a RECQ5-F666A mutation reduces translocation velocity by ∼50%. However, RECQ5 readily removes the ATP hydrolysis-deficient mutant RAD51-K133R from ssDNA, suggesting that filament disruption is not coupled to the RAD51 ATP hydrolysis cycle. RECQ5 also readily removes RAD51-I287T, a RAD51 mutant with enhanced ssDNA-binding activity, from ssDNA. Surprisingly, RECQ5 can bind to double-stranded DNA (dsDNA), but it is unable to translocate. Similarly, RECQ5 cannot dismantle RAD51-bound heteroduplex joint molecules. Our results suggest that the roles of RECQ5 in genome maintenance may be regulated in part at the level of substrate specificity.


A Treatment Algorithm for Moderate to Severe Atopic Dermatitis in Adults.
Atopic dermatitis (AD) is a common and chronic inflammatory skin disease. Approximately 10% of adults with AD do not respond adequately to topical therapies and require phototherapy and/or systemic therapy. To provide a patient-focused approach to the identification and management of adults with AD who require systemic treatment. A working group of clinicians experienced in managing AD was convened to review and discuss current evidence on the identification and clinical management of adults with moderate to severe AD. We propose a set of simple and practical clinical criteria for selecting candidates for systemic treatment of AD based on their response to first-line topical therapy and 4 clinical measures that are easily incorporated into routine practice. We also suggest a framework for evaluating systemic treatments according to attributes that are important from both a clinician's and a patient's perspective. An algorithm was developed proposing a pathway for treatment of moderate to severe AD in adults. Adults with moderate to severe AD that does not respond adequately to topical therapies currently have few safe and effective treatment options. A clinical algorithm could help guide treatment decisions.


How would case managers' practice change in a consumer-directed care environment in Australia?
The aim of this study was to explore case managers' perceived changes in their practice in the future when consumer-directed care (CDC) is widely implemented in Australia's community aged care system. Purposeful sampling was used and semi-structured individual and group interviews were conducted between September 2012 and March 2013. Participants were drawn from a list of all case managers who administered publicly funded community aged care packages in Victoria, Australia. Empowerment theory was used to guide the analysis and interpretation of the data. The thematic analysis revealed that case managers had mixed views about CDC. They also perceived changes in case managers' practice in the future when CDC is widely implemented. These might specifically include: first, case managers would not directly manage clients' budgets. While some case managers were concerned about losing power for this change, others believed that they would still have important financial roles to perform, such as setting rules, providing financial support and monitoring clients' use of budgets. Second, case managers would focus on performing roles in providing information, and empowering, facilitating and educating clients. These would help to strengthen clients' capacities and assist them to self-manage their care. Third, case managers would work in partnership with clients through frequent or skilful communication, mutual goal setting and goal facilitation. Fourth, case managers would manage more clients. In addition, they would provide less support to each individual client and perform less care co-ordination role. The findings suggest case managers paying attention to power balance regarding budget management in a CDC environment. Furthermore, they might frequently or skilfully communicate with, empower, facilitate and educate clients; work together with them to set up goals; and facilitate them to achieve goals. New research using empowerment theory to examine the actual practice of case managers in a well-established CDC system is warranted.


Cognitive enhancement mediated through postsynaptic actions of norepinephrine on ongoing cortical activity.
We propose two distinct types of norepinephrine (NE)-neuromodulatory systems: an enhanced-excitatory and enhanced-inhibitory (E-E/E-I) system and a depressed-excitatory and enhanced-inhibitory (D-E/E-I) system. In both systems, inhibitory synaptic efficacies are enhanced, but excitatory ones are modified in a contradictory manner: the E-E/E-I system enhances excitatory synaptic efficacies, whereas the D-E/E-I system depresses them. The E-E/E-I and D-E/E-I systems altered the dynamic property of ongoing (background) neuronal activity and greatly influenced the cognitive performance (S/N ratio) of a cortical neural network. The E-E/E-I system effectively enhanced S/N ratio for weaker stimuli with lower doses of NE, whereas the D-E/E-I system enhanced stronger stimuli with higher doses of NE. The neural network effectively responded to weaker stimuli if brief gamma-bursts were involved in ongoing neuronal activity that is controlled under the E-E/E-I neuromodulatory system. If the E-E/E-I and the D-E/E-I systems interact within the neural network, depressed neurons whose activity is depressed by NE application have bimodal property. That is, S/N ratio can be enhanced not only for stronger stimuli as its original property but also for weaker stimuli, for which coincidental neuronal firings among enhanced neurons whose activity is enhanced by NE application are essential. We suggest that the recruitment of the depressed neurons for the detection of weaker (subthreshold) stimuli might be advantageous for the brain to cope with a variety of sensory stimuli.


Surgical treatment of epilepsy in Vietnam: program development and international collaboration.
The purpose of this report was to describe an international collaboration model to facilitate the surgical treatment of children with epilepsy in Vietnam. This model uses three complementary methods to achieve a meaningful expansion in epilepsy surgery capacity: US-based providers visiting Hanoi, Vietnam; Vietnamese providers visiting the US; and ongoing telecollaboration, including case review and real-time mentorship using internet-based communication platforms. Introductions took place during a US neurosurgeon's visit to Vietnam in 2014. Given the Vietnamese surgeon's expertise in intraventricular tumor surgery, the focus of the initial visit was corpus callosotomy. After two operations performed jointly, the Vietnamese surgeon went on to perform 10 more callosotomy procedures in the ensuing 6 months with excellent results. The collaborative work grew and matured in 2016-2017, with 40 pediatric epilepsy surgeries performed from 2015 through 2017. Because pediatric epilepsy care requires far more than neurosurgery, teams traveling to Vietnam included a pediatric neurologist and an electroencephalography (EEG) technologist. Also, in 2016-2017, a neurosurgeon, two neurologists, and an EEG nurse from Vietnam completed 2- to 3-month fellowships at Children's of Alabama (COA) in the US. These experiences improved EEG capabilities and facilitated the development of intraoperative electrocorticography (ECoG), making nonlesional epilepsy treatment more feasible. The final component has been ongoing, i.e., regular communication. The Vietnamese team regularly sends case summaries for discussion to the COA epilepsy conference. Three patients in Vietnam have undergone resection guided by ECoG without the US team present, although there was communication via internet-based telecollaboration tools between Vietnamese and US EEG technologists. To date, two of these three patients remain seizure free. The Vietnamese team has presented the results of their epilepsy experience at two international functional and epilepsy surgery scientific meetings. Ongoing international collaboration has improved the surgical care of epilepsy in Vietnam. Experience suggests that the combination of in-country and US-based training, augmented by long-distance telecollaboration, is an effective paradigm for increasing the capacity for highly subspecialized, multidisciplinary neurosurgical care.


A hub-attachment based method to detect functional modules from confidence-scored protein interactions and expression profiles.
Many research results show that the biological systems are composed of functional modules. Members in the same module usually have common functions. This is useful information to understand how biological systems work. Therefore, detecting functional modules is an important research topic in the post-genome era. One of functional module detecting methods is to find dense regions in Protein-Protein Interaction (PPI) networks. Most of current methods neglect confidence-scores of interactions, and pay little attention on using gene expression data to improve their results. In this paper, we propose a novel hub-attachment based method to detect functional modules from confidence-scored protein interactions and expression profiles, and we name it HUNTER. Our method not only can extract functional modules from a weighted PPI network, but also use gene expression data as optional input to increase the quality of outcomes. Using HUNTER on yeast data, we found it can discover more novel components related with RNA polymerase complex than those existed methods from yeast interactome. And these new components show the close relationship with polymerase after functional analysis on Gene Ontology. A C++ implementation of our prediction method, dataset and supplementary material are available at http://hub.iis.sinica.edu.tw/Hunter/. Our proposed HUNTER method has been applied on yeast data, and the empirical results show that our method can accurately identify functional modules. Such useful application derived from our algorithm can reconstruct the biological machinery, identify undiscovered components and decipher common sub-modules inside these complexes like RNA polymerases I, II, III.


Patients' self-evaluation of symptoms, signs and compliance to therapy for heart failure surveillance: A pilot study on identification of worsening heart failure.
In patients with chronic heart failure (HF), it is unclear whether self-evaluation of HF-related symptoms and signs may contribute to the surveillance of clinical stability over time or the early identification of worsening HF. Therefore, HF-related symptoms and signs, and compliance to therapy were investigated by a self-administrated questionnaire in patients hospitalized due to worsening HF (cases) as well in those with stable HF (controls). The temporal interval of interest for the questionnaire focused on 2 to 7 days before the hospitalization of the control visit. A method called "classic" extrapolated a surveillance score by 4 questions revealing HF-related symptoms or signs (higher score indicative of more symptoms or sings reported). Alternatively, 3 additional questions enriched the "classic" questionnaire, including one on whether the health status was perceived as stable, improved or worsening. The score from "perceived health status" inquiry was used as "conditional factor" to computed the surveillance score as: conditional factor + [conditional factor X (the sum of the points yielded by the responses to each question on symptoms, sings and compliance to therapy)]. Among 51 patients hospitalized due to worsening HF and 104 with chronic HF (retrospective study), the area under the curve (receiver operating characteristic) discriminating worsening HF was 0.90 by the classic, and 0.96 by the conditional method (both p<0.001), yielding error rates of 2 in 10 by the classic and 1 in 10 by the conditional method. In a pilot longitudinal study in 37 ambulatory HF patients from a different population source, predicting worsening HF by alternative questionnaires within 12 weeks from the visit yielded consistent results. In conclusion, patients' self-monitoring symptoms, signs and compliance by a standardized questionnaire and a conditional method for generating relative a score, may be a promising method for HF stability surveillance.


A population-based survey on family intentions and fertility awareness in women and men in the United Kingdom and Denmark.
Across several European countries family formation is increasingly postponed. The aims of the study were to investigate the desire for family building and fertility awareness in the UK and Denmark. A population-based internet survey was used among women (n = 1,000) and men (n = 237) from the UK (40%) and Denmark (60%). Data covered socio-demographics, family formation, and awareness of female age-related fertility. Data analysis used descriptive statistics and logistic regression analysis for studying associations between low fertility awareness and desired family formation. The majority of all participants desired two or three children. Two-thirds of the childless participants desired a first child at 30+ years, and one-fifth of the women and one-third of the men desired a last child at age 40. Overall, 83% of women and 73% of men were aware that female fertility starts to decline around 25-30 years. Men had significantly lower fertility awareness. Women who underestimated the impact of age on female fertility were significantly more likely to have a desire or attempted their first child at a higher age. Even though the majority were aware of the age-related decrease in female fertility, most desired having children at an age when female fertility has declined. Women who were not sufficiently aware of the impact of advanced age were significantly more likely to have their first child at a higher age. There is a need for developing educational programs for women and men in order to increase the population's knowledge of fertility and risk factors for infertility.


Effect of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in patients with type 2 diabetes.
We are aware of no study that has indicated the effects of daily consumption of multispecies probiotic supplements on metabolic profiles, high-sensitivity C-reactive protein (hs-CRP), and oxidative stress in diabetic patients. This study was designed to determine the effects of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in diabetic patients. This randomized double-blind placebo-controlled clinical trial was performed on 54 diabetic patients aged 35-70 years. Subjects were randomly assigned to take either a multispecies probiotic supplement (n = 27) or placebo (n = 27) for 8 weeks. The multispecies probiotic supplement consisted of 7 viable and freeze-dried strains: Lactobacillus acidophilus (2 × 10(9) CFU), L. casei (7 × 10(9) CFU), L. rhamnosus (1.5 × 10(9) CFU), L. bulgaricus (2 × 10(8) CFU), Bifidobacterium breve (2 × 10(10) CFU), B. longum (7 × 10(9) CFU), Streptococcus thermophilus (1.5 × 10(9) CFU), and 100 mg fructo-oligosaccharide. Fasting blood samples were taken at baseline and after intervention to measure metabolic profiles, hs-CRP, and biomarkers of oxidative stress including plasma total antioxidant capacity and total glutathione (GSH). Between-group comparisons of fasting plasma glucose (FPG) revealed that consumption of probiotic supplements prevented a rise in FPG (+28.8 ± 8.5 for placebo vs. +1.6 ± 6 mg/dl for probiotic group, p = 0.01). Although a significant within-group increase in serum insulin and low-density lipoprotein cholesterol levels was found in both the probiotic group and the placebo group, the changes were similar between the two groups. We observed a significant increase in HOMA-IR (homeostasis model of assessment-insulin resistance) in both the probiotic group (p = 0.02) and the placebo group (p = 0.001); however, the increase in the placebo group was significantly higher than that in the probiotic group (+2.38 vs. +0.78, p = 0.03). Mean changes in serum hs-CRP were significantly different between the two groups (-777.57 for the probiotic group vs. +878.72 ng/ml for the placebo group, p = 0.02). Probiotic supplementation led to a significant increase in plasma GSH levels compared to placebo (240.63 vs. -33.46 µmol/l, p = 0.03). In conclusion, multispecies probiotic supplementation, compared with placebo, for 8 weeks in diabetic patients prevented a rise in FPG and resulted in a decrease in serum hs-CRP and an increase in plasma total GSH.


Ovulation after glucocorticoid suppression of adrenal androgens in the polycystic ovary syndrome is not predicted by the basal dehydroepiandrosterone sulfate level.
Adrenal androgen (AA) excess, primarily in the form of dehydroepiandrosterone sulfate (DHEAS), affects over 50% of women with the polycystic ovary syndrome (PCOS). Nonetheless, it is unclear what role AA excess plays in the PCOS-associated oligo-ovulation. We have hypothesized that AAs are important in the maintenance of the ovulatory dysfunction of women with PCOS and AA excess, which can be improved by glucocorticoid suppression. To test our hypothesis we prospectively studied 36 unselected women, ages 18-40 yr, with PCOS; i.e. oligomenorrhea (cycles > 35 days in length), and clinical/ biochemical evidence of hyperandrogenism (i.e. hirsutism and/or hyperandrogenemia), after the exclusion of related disorders. After informed consent, all patients underwent an acute ACTH-(1-24) stimulation test, measuring androstenedione, dehydroepiandrosterone (DHEA) and cortisol (F), and were then treated with dexamethasone 0.5 mg/day for four cycles. Ovulatory function was assessed before and during treatment using a basal body temperature calendar and day 22-24 progesterone (P4) levels. If patients were anovulatory (P4 < 4 ng/mL), a withdrawal bleed was induced by the administration of 100 mg P4 in oil i.m. Before and during treatment the levels of total and free testosterone (T), sex hormone-binding globulin, androstenedione, DHEA, DHEAS, cortisol, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were monitored. With therapy, all patients demonstrated a significant decrease in all androgens (-40-60%), a 24% increase in sex hormone-binding globulin, and no change in LH/FSH. Mean body weight increased by over 4 kg (4.4%) during treatment. Of the 138 cycles monitored, 78% remained anovulatory. Twenty-five percent, 17%, 14%, and 20% of the first, second, third, and fourth treatment cycles, were ovulatory, respectively (P = 0.381). Of the 36 patients studied, 18 (50%) did not demonstrate a single ovulatory cycle (i.e. a day 22-24 P4 level > 4 ng/mL); and of the remaining, 10 (28%) had only one, five (14%) had two, and three (8%) had three ovulatory cycles. There were no significant differences either in physical features, basal hormones, adrenal response to ACTH stimulation, or hormonal levels at the end of treatment, between those women ovulating and those not. Finally, there were no differences in ovulatory response to dexamethasone therapy between women with (n = 14) and without (n = 22) DHEAS excess (i.e. DHEAS > 2750 ng/mL). In conclusion, the data from this prospective study do not suggest that continuous dexamethasone suppression results in consistent ovulation in any PCOS patient, regardless of basal DHEAS levels. Furthermore, this treatment is associated with significant side-effects, notably weight gain. Finally, these data suggest that, while AA may be an important risk factor for PCOS, once the syndrome is established, they play a limited role in the associated ovulatory dysfunction.


Exogenous peptides compete for the presentation of endogenous antigens to major histocompatibility complex class II-restricted T cells.
Antigen-presenting cells (APC) transfected with a construct encoding the hen egg-white lysozyme (HEL) amino acid sequence 1-80 constitutively present HEL peptides complexed to major histocompatibility complex (MHC) class II molecules to specific T cell hybridomas, indicating that endogenous cellular antigens can be efficiently presented to class II-restricted T cells. Here we show that exogenous peptide competitors added to HEL-transfected APC can inhibit the presentation of endogenous HEL peptides to class II-restricted T cells. The inhibition is specific for the class II molecule binding the competitor peptide, and it affects to the same extent presentation of exogenous or endogenous HEL peptides. These results, demonstrating that an exogenous competitor can inhibit class II-restricted T cell activation induced by endogenous as well as exogenous antigen, suggest lack of strict compartmentalization between endogenous and exogenous pathways of antigen presentation. Since autoreactive T cells may recognize endogenous, as well as exogenous antigens, the results have implications for the treatment of autoimmune diseases by MHC blockade.


Predictors of Drinking Water Boiling and Bottled Water Consumption in Rural China: A Hierarchical Modeling Approach.
Approximately two billion people drink unsafe water. Boiling is the most commonly used household water treatment (HWT) method globally and in China. HWT can make water safer, but sustained adoption is rare and bottled water consumption is growing. To successfully promote HWT, an understanding of associated socioeconomic factors is critical. We collected survey data and water samples from 450 rural households in Guangxi Province, China. Covariates were grouped into blocks to hierarchically construct modified Poisson models and estimate risk ratios (RR) associated with boiling methods, bottled water, and untreated water. Female-headed households were most likely to boil (RR = 1.36, p < 0.01), and among boilers those using electric kettles rather than pots had higher income proxies (e.g., per capita TV ownership RR = 1.42, p < 0.01). Higher-income households with younger, literate, and male heads were more likely to purchase (frequently contaminated) bottled water, or use electric kettles if they boiled. Our findings show that boiling is not an undifferentiated practice, but one with different methods of varying effectiveness, environmental impact, and adoption across socioeconomic strata. Our results can inform programs to promote safer and more efficient boiling using electric kettles, and suggest that if rural China's economy continues to grow then bottled water use will increase.


Disruption of the dorsolateral prefrontal cortex facilitates the consolidation of procedural skills.
In explicit sequence learning tasks, an improvement in performance (skill) typically occurs after sleep-leading to the recent literature on sleep-dependent motor consolidation. Consolidation can also be facilitated during wakefulness if declarative knowledge for the sequence is reduced through a secondary cognitive task. Accordingly, declarative and procedural consolidation processes appear to mutually interact. Here we used TMS to test the hypothesis that functions in the dorsolateral prefrontal cortex (DLPFC) that support declarative memory formation indirectly reduce the formation of procedural representations. We hypothesize that disrupting the DLPFC immediately after sequence learning would degrade the retention or the consolidation of the sequence within the declarative memory system and thus facilitate consolidation within procedural memory systems, evident as wakeful off-line skill improvement. Inhibitory theta-burst TMS was applied to the left DLPFC (n = 10), to the right DLPFC (n = 10), or to an occipital cortical control site (n = 10) immediately after training on the serial reaction time task (SRTT). All groups were retested after eight daytime hours without sleep. TMS of either left or right DLPFC lead to skill improvements on the SRTT. Increase in skill was greater following right DLPFC stimulation than left DLPFC stimulation; there was no improvement in skill for the control group. Across all participants, free recall of the sequence was inversely related to the improvements in performance on the SRTT. These results support the hypothesis of interference between declarative and procedural consolidation processes and are discussed in the framework of the interactions between memory systems.


Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding.
Cellular prion protein (PrP(C)) is a glycosyl-phosphatidylinositol-anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrP(SC)) induces transmissible spongiform encephalopathies. In contrast, PrP(C) has a number of physiological functions in several neural processes. Several lines of evidence implicate PrP(C) in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrP(C) has been implicated in the inhibition of N-methyl-d-aspartic acid (NMDA)-mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnp(o/o)Jnk3(o/o) mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrP(C)-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrP(C) with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6-PSD-95 interaction after KA injections was favored by the absence of PrP(C). Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrP(C) against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.


Antimalarial combination therapies increase gastric ulcers through an imbalance of basic antioxidative-oxidative enzymes in male Wistar rats.
Antimalarials are globally used against plasmodium infections, however, information on the safety of new antimalarial combination therapies on the gastric mucosa is scarce. The aim of this study was to investigate the effects of Artesunate-Amodiaquine and Artemether-Lumefantrine on ulcer induction. Malondialdehyde (MDA), reduced glutathione (GSH) and major histological changes in male Wistar rats following ulcer induction using Indomethacin were investigated. Gastric ulcers were in four groups; Group I was administered Artesunate, group II received Artesunate-Amodiaquine, group III received Artemether-Lumefantrine, and group IV was a positive control (normal saline). Group V was the negative control consisting of healthy rats. Antimalarial combination therapies were associated with a high gastric ulcer index than a single antimalarial agent, Artesunate. In addition, levels of MDA were significantly higher in the combination of therapies while levels of GSH were lower in comparison to Artesunate and the negative control. Microscopically, antimalarial combination therapies were associated with severe inflammation and tissue damage than Artesunate in the gastric mucosa showing that antimalarial combination therapies exert their toxic effects through oxidative stress mechanisms, and this leads to cellular damage. Findings in this study demonstrate a need to revisit information on the pharmacodynamics of major circulating antimalarial agents in developing countries.


Clinical applications of bone morphogenetic proteins: current evidence.
Bone morphogenetic proteins (BMPs) were first described by Dr. Marshall Urist in 1965. Since 1988 a series of clinical studies and randomized clinical trials have evaluated the application of these molecules in humans. A comprehensive review of 30 clinical studies was performed to elicit the existing evidence of the English orthopaedic literature. BMPs appear to be efficacious as the reported success rates are equivalent and perhaps superior to those achieved with the gold standard methods of autografting. Clinical safety assessments have been even more encouraging with just a few reports of adverse events related to their use in clinical practice. There are certain controversies on the presented results of all the reviewed clinical series, which reflect the complexity of the osteoinductive and osteoconductive role of the BMPs, the ongoing quest for optimization of the dosing schemes and delivery carriers, as well as the multifactorial interactions during bone formation and remodeling.


The measurement and prevalence of an ideational model of family and economic development in Nepal.
Developmental idealism (DI) is a system of beliefs and values that endorses modern societies and families and sees them as occurring together, with modern families as causes and consequences of societal development. This study was motivated by the belief that the population of Nepal has absorbed these ideas and that the ideas affect their family behaviour. We use data collected in Nepal in 2003 to show that Nepalis discuss ideas about development and its relationship to family life and that DI has been widely accepted. It is related in predictable ways to education, paid employment, rural-urban residence, and mass media exposure. Although it would be useful to know its influence on demographic decision-making and behaviour, we cannot evaluate this with our one-time cross-sectional survey. Our data and theory suggest that this influence may be substantial.


Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL.
The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.


Perturbed upper limb movements cause short-latency postural responses in trunk muscles.
Addition of a load to a moving upper limb produces a perturbation of the trunk due to transmission of mechanical forces. This experiment investigated the postural response of the trunk muscles in relation to unexpected limb loading. Subjects performed rapid, bilateral shoulder flexion in response to a stimulus. In one third of trials, an unexpected load was added bilaterally to the upper limbs in the first third of the movement. Trunk muscle electromyography, intra-abdominal pressure and upper limb and trunk motion were measured. A short-latency response of the erector spinae and transversus abdominis muscles occurred approximately 50 ms after the onset of the limb perturbation that resulted from addition of the load early in the movement and was coincident with the onset of the observed perturbation at the trunk. The results provide evidence of initiation of a complex postural response of the trunk muscles that is consistent with mediation by afferent input from a site distant to the lumbar spine, which may include afferents of the upper limb.


Structured Caregiver Feedback Enhances Engagement and Impact of Mobile Health Support: A Randomized Trial in a Lower-Middle-Income Country.
Patients' engagement in mobile health (m-health) interventions using interactive voice response (IVR) calls is less in low- and middle-income countries (LMICs) than in industrialized ones. We conducted a study to determine whether automated telephone feedback to informal caregivers ("CarePartners") increased engagement in m-health support among diabetes and hypertension patients in Bolivia. Patients with diabetes and/or hypertension were identified through ambulatory clinics affiliated with four hospitals. All patients enrolled with a CarePartner. Patients were randomized to weekly IVR calls including self-management questions and self-care education either alone ("standard m-health") or with automated feedback about health and self-care needs sent to their CarePartner after each IVR call ("m-health+CP"). The 72 participants included 39 with diabetes and 53 with hypertension, of whom 19 had ≤6 years of education. After 1,225 patient-weeks of attempted IVR assessments, the call completion rate was higher among patients randomized to m-health+CP compared with standard m-health (62.0% versus 44.9%; p < 0.047). CarePartner feedback more than tripled call completion rates among indigenous patients and patients with low literacy (p < 0.001 for both). M-health+CP patients were more likely to report excellent health via IVR (adjusted odds ratio [AOR] = 2.60; 95% confidence interval [CI], 1.07, 6.32) and less likely to report days in bed due to illness (AOR = 0.42; 95% CI, 0.19, 0.91). In this study we found that caregiver feedback increased engagement in m-health and may improve patients' health status relative to standard approaches. M-health+CP represents a scalable strategy for increasing the reach of self-management support in LMICs.


Charging and supercharging of proteins for mass spectrometry: recent insights into the mechanisms of electrospray ionization.
Electrospray ionization (ESI) is an essential technique for transferring proteins from solution into the gas phase for mass spectrometry and ion mobility spectrometry. The mechanisms whereby [M + zH]z+ protein ions are released from charged nanodroplets during ESI have been controversial for many years. Here we discuss recent computational and experimental studies that have shed light on many of the mysteries in this area. Four types of protein ESI experiments can be distinguished, each of which appears to be associated with a specific mechanism. (i) Native ESI proceeds according to the charged residue model (CRM) that entails droplet evaporation to dryness, generating compact protein ions in low charge states. (ii) Native ESI supercharging is also a CRM process, but the dried-out proteins accumulate additional charge because supercharging agents such as sulfolane interfere with the ejection of small ions (Na+, NH4+, etc.) from the shrinking droplets. (iii) Denaturing ESI follows the chain ejection model (CEM), where protein ions are gradually expelled from the droplet surface. H+ equilibration between the droplets and the protruding chains culminates in highly charged gaseous proteins, analogous to the collision-induced dissociation of multi-protein complexes. (iv) Denatured ESI supercharging also generates protein ions via the CEM. Supercharging agents stabilize protonated sites on the protein tail via charge-dipole interactions, causing the chain to acquire additional charge. There will likely be scenarios that fall outside of these four models, but it appears that the framework outlined here covers most of the experimentally relevant conditions.


Cellular pharmacology of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in mouse resident peritoneal macrophages, Kupffer cells, and hepatocytes.
The in vitro and in vivo interaction of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ + (II) (L-NDDP) with mouse resident peritoneal macrophages (RPM), Kupffer cells (KC), and hepatocytes was studied. The peak in vitro uptake of L-NDDP by RPM was 12.5 ng elemental platinum/100 micrograms cell protein and constituted 0.2% of the platinum available for phagocytosis. The subsequent release of platinum by RPM was rapid initially, with a 20-fold increase over the first 4 h, followed by a plateau; ultrafilterable (free) platinum constituted 50% of the total platinum released at 24 h. The retained intracellular platinum in RPM at 24 h was close to 50% of that initially present. The peak in vitro uptake of L-NDDP by KC was 11.3 ng platinum/100 micrograms cell protein and amounted to 0.2% of the platinum available for phagocytosis. The release of platinum by KC was detectable only after 4 h of incubation and increased 3-fold over the next 14 h. The ultrafilterable platinum released by KC at 18 h was 40% of the total platinum released. The retained intracellular platinum in KC at 18 h was 33% of that initially present. The peak in vitro uptake of L-NDDP by hepatocytes was almost 50 ng platinum/100 micrograms cell protein and constituted 0.8% of the platinum available for intake. Following the i.v. injection of L-NDDP, hepatocytes contained up to 6-fold higher platinum concentrations than KC. This observation was supported by transmission electron microscopy showing a higher concentration of multilamellar vesicles within hepatocytes than in KC, 5 min after i.v. injection of L-NDDP. These findings suggest that L-NDDP becomes available to the liver following i.v. injection, that both macrophages and hepatocytes play a role in the metabolism of L-NDDP, and that Kupffer cells could mediate a sustained release of platinum in the liver following the interaction with L-NDDP, indicating the potential of L-NDDP for the treatment of tumors in the liver.


Characterization of starch-debranching enzymes in pea embryos
Two distinct types of debranching enzymes have been identified in developing pea (Pisum sativum L.) embryos using native gel analysis and tests of substrate preference on purified or partially purified activities. An isoamylase-like activity capable of hydrolyzing amylopectin and glycogen but not pullulan is present throughout development and is largely or entirely confined to the plastid. Activities capable of hydrolyzing pullulan are present both inside and outside of the plastid, and extraplastidial activity increases relative to the plastidial activity during development. Both types of debranching enzyme are also present in germinating embryos. We argue that debranching enzymes are likely to have a role in starch metabolism in the plastid of the developing embryo and in starch degradation during germination.


Transtheoretical model stages of change for dietary and physical exercise modification in weight loss management for overweight and obese adults.
Obesity is a global public health threat. The transtheoretical stages of change (TTM SOC) model has long been considered a useful interventional approach in lifestyle modification programmes, but its effectiveness in producing sustainable weight loss in overweight and obese individuals has been found to vary considerably. To assess the effectiveness of dietary intervention or physical activity interventions, or both, and other interventions based on the transtheoretical model (TTM) stages of change (SOC) to produce sustainable (one year and longer) weight loss in overweight and obese adults. Studies were obtained from searches of multiple electronic bibliographic databases. We searched The Cochrane Library, MEDLINE, EMBASE and PsycINFO. The date of the last search, for all databases, was 17 December 2013. Trials were included if they fulfilled the criteria of randomised controlled clinical trials (RCTs) using the TTM SOC as a model, that is a theoretical framework or guideline in designing lifestyle modification strategies, mainly dietary and physical activity interventions, versus a comparison intervention of usual care; one of the outcome measures of the study was weight loss, measured as change in weight or body mass index (BMI); participants were overweight or obese adults only; and the intervention was delivered by healthcare professionals or trained lay people at the hospital and community level, including at home. Two review authors independently extracted the data, assessed studies for risk of bias and evaluated overall study quality according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). We resolved disagreements by discussion or consultation with a third party. A narrative, descriptive analysis was conducted for the systematic review. A total of three studies met the inclusion criteria, allocating 2971 participants to the intervention and control groups. The total number of participants randomised to the intervention groups was 1467, whilst 1504 were randomised to the control groups. The length of intervention was 9, 12 and 24 months in the different trials. The use of TTM SOC in combination with diet or physical activity, or both, and other interventions in the included studies produced inconclusive evidence that TTM SOC interventions led to sustained weight loss (the mean difference between intervention and control groups varied from 2.1 kg to 0.2 kg at 24 months; 2971 participants; 3 trials; low quality evidence). Following application of TTM SOC there were improvements in physical activity and dietary habits, such as increased exercise duration and frequency, reduced dietary fat intake and increased fruit and vegetable consumption (very low quality evidence). Weight gain was reported as an adverse event in one of the included trials. None of the trials reported health-related quality of life, morbidity, or economic costs as outcomes. The small number of studies and their variable methodological quality limit the applicability of the findings to clinical practice. The main limitations include inadequate reporting of outcomes and the methods for allocation, randomisation and blinding; extensive use of self-reported measures to estimate the effects of interventions on a number of outcomes, including weight loss, dietary consumption and physical activity levels; and insufficient assessment of sustainability due to lack of post-intervention assessments. The evidence to support the use of TTM SOC in weight loss interventions is limited by risk of bias and imprecision, not allowing firm conclusions to be drawn. When combined with diet or physical activity, or both, and other interventions we found very low quality evidence that it might lead to better dietary and physical activity habits. This systematic review highlights the need for well-designed RCTs that apply the principles of the TTM SOC appropriately to produce conclusive evidence about the effect of TTM SOC lifestyle interventions on weight loss and other health outcomes.


Survey on current cognitive practices within the European Low-Grade Glioma Network: towards a European assessment protocol.
The European Low-Grade Glioma network indicated a need to better understand common practices regarding the managing of diffuse low-grade gliomas. This area has experienced great advances in recent years. A general survey on the managing of diffuse low-grade gliomas was answered by 21 centres in 11 European countries. Here we focused on specific questions regarding perioperative and intraoperative cognitive assessments. More centres referred to the same speech and language therapist and/or neuropsychologist across all assessments; a core of assessment tools was routinely used across centres; fluency tasks were commonly used in the perioperative stages, and object naming during surgery; tasks that tapped on attention, executive functions, visuospatial awareness, calculation and emotions were sparsely administered; preoperative assessments were performed 1 month or 1 week before surgery; timing for postoperative assessments varied; finally, more centres recommended early rehabilitation, whenever needed. There is an emerging trend towards following similar practices for the management of low-grade gliomas in Europe. Our results are descriptive and formalise current discussions in our group. Also, they contribute towards the development of a European assessment protocol.


Concurrent and prospective associations among biological maturation, and physical activity at 11 and 13 years of age.
This study examined concurrent and prospective associations between objective measures of biological maturation, body composition and physical activity (PA) in adolescent males (n = 671) and females (n = 680). Participants born to women recruited to the Avon Longitudinal Study of Parents and Children birth cohort study were assessed at 11 and 13 years. Percentage of predicted adult stature was used as an estimate of biological maturation. PA and time sedentary was assessed over 7 consecutive days using Actigraph accelerometers. Body composition was assessed using whole-body DXA scans. At 11 and 13 years, maturity in males was inversely associated with accelerometer counts-per-minute (CPM) and time engaged in light PA, and positively associated with time sedentary. In females, maturity was inversely associated with accelerometer (CPM) at 11 but not 13 years. Adjusting for accelerometer wear times and corresponding activity levels at 11 years, maturity and percentage fat mass at 11 years did not predict any indices of PA or sedentary behavior in males or females at 13 years. Whereas advanced maturation in males is associated with less PA and more sedentary behavior at 11 and 13 years, maturity at 11 does not predict PA or sedentary behavior at 13 years in either sex.


The CNS-specific hyaluronan-binding protein BEHAB is expressed in ventricular zones coincident with gliogenesis.
Hyaluronan (HA) is a ubiquitous component of extracellular matrices, and in several systems it plays a central role in regulating cellular proliferation and differentiation. Cell, or tissue,-specific functions of HA are likely to be mediated by cell, or tissue,-specific HA-binding proteins. We previously hyaluronan-binding protein from rat and cat (Jaworski et al., 1994). In view of the potential role of HA in neural differentiation, we examined the expression of BEHAB during late embryonic and early postnatal development of the rat. BEHAB is expressed at very high levels in ventricular zones throughout the neuraxis. Expression is first detected at embryonic day 15 (E15) in the spinal cord, and is detected at progressively more rostral levels at later ages. BEHAB expression, like other features of neural development, follows both caudal-to-rostral and ventral-to-dorsal gradients. The timing of BEHAB expression parallels the timing of the generation of glial cells. In all areas of the CNS examined, BEHAB expression begins after the peak of neurogenesis and coincident with gliogenesis. The regulation of proliferation and differentiation by HA in other tissues, together with the expression of BEHAB in zones of mitotic activity coincident with the generation of glia, suggests that the extracellular matrix protein encoded by BEHAB could play a role in the generation or differentiation of CNS glia.


Vagus Nerve Stimulation (VNS) and Treatment of Depression: To the Brainstem and Beyond.
Neuromodulation appears to be emerging gradually as a new therapeutic field in psychiatric treatment. It encompasses neuropsychiatric medical devices, such as vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and electroconvulsive therapy (ECT). As a therapeutic approach to affective disorders, neuromodulation shifts the focus from the monoamine synapse to neural circuitry of the brain, which is dysregulated in depression. This neural circuitry has been elaborated on over the course of 15 years of neuroimaging research in mood disorders and is now believed to encompass disturbances in a frontolimbic network. These include reduced metabolism and blood flow in the prefrontal cortex and anterior cingulate and pathologically increased activity in the subgenual cingulate and amygdala.VNS is an implanted device that has established efficacy in pharmaco-resistant epilepsy. It was approved by the FDA for the treatment of severe, recurrent unipolar and bipolar depression in July of 2005. VNS adopts a bottom-up approach to modulating the neural circuitry of depression by stimulating vagal afferent fibers in the neck, which carry impulses to the brain stem to target there the locus ceruleus and dorsal raphe nucleus. Now that VNS has moved beyond the experimental phase and into the clinic, psychiatrists are faced with deciding who is an appropriate patient for this surgical implant and how to integrate VNS into existing treatment in order to optimize both efficacy and safety.This review of VNS will assess the efficacy and safety data that led to the FDA approval. We will also review for the busy clinician how VNS is likely to translate into clinical practice as a treatment option for patients in need who are suffering from severe depression.


p53 gene mutations and protein nuclear accumulation are early events in intestinal type gastric cancer but late events in diffuse type.
We screened for p53 alterations in 71 early gastric cancers of differing histological types and growth patterns, 18 advanced cancers of diffuse type, 19 dysplastic lesions, and 12 extensive intestinal metaplasia cases. Tumors were investigated for gene mutations (exons 5-8) with PCR-based denaturing gradient gel electrophoresis and sequencing techniques, and for protein accumulation with immunohistochemical methods. Nontumor samples were studied with immunohistochemistry alone. Of the early cancers, intestinal tumors showed a much higher p53 mutation frequency (41%) than did diffuse cancers (4%). When comparing early and advanced tumors of the same type, we observed a similarity in mutation frequency (41 versus about 50%) for intestinal tumors, and a significant increase for diffuse tumors (from 4 to 33%). Immunopositive case distribution between tumor types and stages paralleled that of mutated cases. Immunohistochemical and genetic analysis gave concordant results for all samples with gene mutations. Eighteen of the 65 (28%) nonmutated tumors displayed significant immunoreactivity. Early tumors that massively penetrated the submucosa, i.e., the early tumors for which prognosis is worst, showed the highest frequency both of p53 gene mutation and of nonmutated protein accumulation. Twelve of 19 dysplastic lesions showed significant immunoreactivity, whereas intestinal metaplasias proved unreactive in all but a few cells. Our results yield two implications: that p53 alterations have a crucial and early role in gastric carcinogenesis of intestinal type, likely acting at the transition step between metaplasia and dysplasia; and that the alterations are mainly associated with tumor progression in cancer of diffuse type.


Traumatic shoulder dislocation in the adolescent athlete: advances in surgical treatment.
The shoulder joint has the greatest range of motion of any joint in the body and as a result is particularly susceptible to dislocation and subluxation. Recurrent instability is a common complication after traumatic shoulder dislocation in young people, with rates as high as 100% in skeletally immature patients and 96% in for adolescents. Treatment for shoulder dislocation has traditionally involved immobilization followed by a rehabilitation program. Recent studies have reported decreased rates of recurrent instability and improved outcomes in patients treated with surgical stabilization of acute, traumatic shoulder dislocation. The purpose of this review is to review recent publications concerning the treatment of traumatic shoulder dislocations in adolescents. Lawton et al. retrospectively reviewed 70 shoulders in 66 patients 16 years old or younger treated for shoulder instability with follow-up more than 2 years. Forty-two shoulders were successfully treated with physical therapy, whereas 28 eventually required surgery. Subsequently, Deitch et al. retrospectively identified 32 patients between 11 and 18 years of age with radiographically documented traumatic anterior shoulder dislocation. Instability recurred in 75% of patients and 50% eventually required surgical stabilization. Bottoni et al. reported results of a prospective randomized trial comparing arthroscopic stabilization to nonoperative treatment of acute, traumatic shoulder dislocations in patients aged 18 to 26 years. Recurrent instability developed in 75% of patients treated conservatively versus 11% in those treated with surgery. DeBerardino et al. prospectively evaluated arthroscopic stabilization of acute shoulder dislocations in 48 young athletes with an average follow-up of 37 months and reported a 12% rate of recurrent instability. All patients with stable shoulders were able to return to their previous levels of activity. Conservative management of traumatic shoulder dislocations in young patients is associated with high rates of recurrent instability. Recent studies have demonstrated improved results and significant reduction in recurrent instability in patients treated with surgical stabilization when compared with nonoperative treatment.


Structural basis of 7SK RNA 5'-γ-phosphate methylation and retention by MePCE.
Among RNA 5'-cap structures, γ-phosphate monomethylation is unique to a small subset of noncoding RNAs, 7SK and U6 in humans. 7SK is capped by methylphosphate capping enzyme (MePCE), which has a second nonenzymatic role as a core component of the 7SK ribonuclear protein (RNP), an essential regulator of RNA transcription. We report 2.0- and 2.1-Å X-ray crystal structures of the human MePCE methyltransferase domain bound to S-adenosylhomocysteine (SAH) and uncapped or capped 7SK substrates, respectively. 7SK recognition is achieved by protein contacts to a 5'-hairpin-single-stranded RNA region, thus explaining MePCE's specificity for 7SK and U6. The structures reveal SAH and product RNA in a near-transition-state geometry. Unexpectedly, binding experiments showed that MePCE has higher affinity for capped versus uncapped 7SK, and kinetic data support a model of slow product release. This work reveals the molecular mechanism of methyl transfer and 7SK retention by MePCE for subsequent assembly of 7SK RNP.


Investigating genetic diversity of Brucella abortus and Brucella melitensis in Italy with MLVA-16.
Despite the eradication of brucellosis from most of Europe, the disease remains relatively common in a variety of livestock in southern European countries. It is therefore surprising that with such high prevalence rates, there have been few genetic characterizations of brucellosis outbreaks in this region. We conducted a genetic assessment of 206 isolates of Brucella abortus and B. melitensis from Italy using Variable Number Tandem Repeats (VNTRs). We determined genetic diversity and geographic distribution of these Brucella VNTR genotypes from 160 farms in eight regions of Southern Italy in a fine-scale analysis using 16 VNTR loci in a MLVA-16 methodology. In a broad scale analysis, we then used a reduced dataset of 11 VNTR loci (MLVA-11) to compare genotypes from Italy to a global database. In the 84 isolates of B. melitensis, there were 56 genotypes using MLVA-16; 43 of these genotypes were found only once. At a broad scale, 81 of these isolates were part of an Italian sub-group within the West Mediterranean group. One of the two B. melitensis isolates from a human patient shared the same genotype as a livestock isolate, suggesting a possible epidemiological connection. In 122 B. abortus isolates, there were 34 genotypes by MLVA-16; 16 of these genotypes were found only once. At a broad scale with MLVA-11, one genotype was predominant, comprising 77.8% of the isolates and was distributed throughout Southern Italy. These data on the current lineages of Brucella present in Italy should form the basis for epidemiological studies of Brucella throughout the country, while placing these strains in a global context.


Human Early Life Exposome (HELIX) study: a European population-based exposome cohort.
Essential to exposome research is the collection of data on many environmental exposures from different domains in the same subjects. The aim of the Human Early Life Exposome (HELIX) study was to measure and describe multiple environmental exposures during early life (pregnancy and childhood) in a prospective cohort and associate these exposures with molecular omics signatures and child health outcomes. Here, we describe recruitment, measurements available and baseline data of the HELIX study populations. The HELIX study represents a collaborative project across six established and ongoing longitudinal population-based birth cohort studies in six European countries (France, Greece, Lithuania, Norway, Spain and the UK). HELIX used a multilevel study design with the entire study population totalling 31 472 mother-child pairs, recruited during pregnancy, in the six existing cohorts (first level); a subcohort of 1301 mother-child pairs where biomarkers, omics signatures and child health outcomes were measured at age 6-11 years (second level) and repeat-sampling panel studies with around 150 children and 150 pregnant women aimed at collecting personal exposure data (third level). Cohort data include urban environment, hazardous substances and lifestyle-related exposures for women during pregnancy and their offspring from birth until 6-11 years. Common, standardised protocols were used to collect biological samples, measure exposure biomarkers and omics signatures and assess child health across the six cohorts. Baseline data of the cohort show substantial variation in health outcomes and determinants between the six countries, for example, in family affluence levels, tobacco smoking, physical activity, dietary habits and prevalence of childhood obesity, asthma, allergies and attention deficit hyperactivity disorder. HELIX study results will inform on the early life exposome and its association with molecular omics signatures and child health outcomes. Cohort data are accessible for future research involving researchers external to the project.


Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop.
Coordinated regulation of the ubiquitin-proteasome system (UPS) is crucial for the cell to adjust its protein degradation capacity to changing proteolytic requirements. We have shown previously that mammalian cells upregulate proteasome gene expression in response to proteasome inhibition. Here, we report the identification of the transcription factor TCF11 (long isoform of Nrf1) as a key regulator for 26S proteasome formation in human cells to compensate for reduced proteolytic activity. Under noninducing conditions, TCF11 resides in the endoplasmic reticulum (ER) membrane. There, TCF11 is targeted to ER-associated protein degradation requiring the E3 ubiquitin ligase HRD1 and the AAA ATPase p97. Proteasome inhibitors trigger the accumulation of oxidant-damaged proteins and promote the nuclear translocation of TCF11 from the ER, permitting activation of proteasome gene expression by binding to antioxidant response elements in their promoter regions. Thus, we uncovered the transcriptional control loop regulating human proteasome-dependent protein degradation to counteract proteotoxic stress caused by proteasome inhibition.


Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial.
To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy. Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial. 862 centres in 43 countries. 5216 (28%) of 18,624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management. Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615). Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year. 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel. In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy. Clinical trials NCT00391872.


The Impact of Structural Heterogeneity on Excitation-Inhibition Balance in Cortical Networks.
Models of cortical dynamics often assume a homogeneous connectivity structure. However, we show that heterogeneous input connectivity can prevent the dynamic balance between excitation and inhibition, a hallmark of cortical dynamics, and yield unrealistically sparse and temporally regular firing. Anatomically based estimates of the connectivity of layer 4 (L4) rat barrel cortex and numerical simulations of this circuit indicate that the local network possesses substantial heterogeneity in input connectivity, sufficient to disrupt excitation-inhibition balance. We show that homeostatic plasticity in inhibitory synapses can align the functional connectivity to compensate for structural heterogeneity. Alternatively, spike-frequency adaptation can give rise to a novel state in which local firing rates adjust dynamically so that adaptation currents and synaptic inputs are balanced. This theory is supported by simulations of L4 barrel cortex during spontaneous and stimulus-evoked conditions. Our study shows how synaptic and cellular mechanisms yield fluctuation-driven dynamics despite structural heterogeneity in cortical circuits.


Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins block distinct steps in transendothelial migration of effector memory CD4+ T cells by targeting different endothelial proteins.
ORFK3 (K3) and ORFK5 (K5) are Kaposi's sarcoma-associated herpesvirus-encoded E3 ubiquitin ligases that differentially reduce surface expression of various proteins in infected cells. In this study, we describe their effects on human dermal microvascular endothelial cells (ECs), a natural target of Kaposi's sarcoma-associated herpesvirus infection. TNF-treated human dermal microvascular ECs transduced to express K5 show reduced capacity to capture effector memory (EM) CD4+ T cells under conditions of venular shear stress. K5 but not K3 transduction significantly reduces ICAM-1 expression and the inhibition of T cell capture was phenocopied by small interfering RNA knockdown of ICAM-1 and by anti-ICAM-1 Ab blocking. Cotransduction with an ICAM-1 truncated construct not subject to K5 ubiquitylation restored EM CD4+ T cell capture. K3 transductants effectively capture EM CD4+ T cells, but fail to support their transendothelial migration (TEM) in response to TCR engagement by superantigen presented by the ECs, leaving intact chemokine-dependent TEM. K3 but not K5 transduction significantly reduces PECAM-1 expression, and the effect on TCR-induced TEM is phenocopied by small interfering RNA knockdown of PECAM-1 and by anti-PECAM-1 Ab blocking. TCR-dependent TEM was restored in K3 transductants cotransduced to express a mutant of PECAM-1 not subject to K3-induced ubiquitylation. EM CD4+ T cells lack any known PECAM-1 counter receptor, but heterophilic engagement of PECAM-1 can involve glycosaminoglycans. In addition, TCR-induced TEM, but not chemokine-induced TEM, appears to involve a heparan- or chondroitin-like molecule on T cells. These results both identify specific roles of K5 and K3 in immune evasion and further differentiate the processes of inflammatory chemokine- versus TCR-dependent recruitment of human EM CD4+ T cells.


Short-term and long-term outcomes of minimally invasive and open transforaminal lumbar interbody fusions: is there a difference?
Previous studies comparing minimally invasive transforaminal lumbar interbody fusion (MITLIF) with open TLIF have demonstrated that MITLIF reduces blood loss and decreases postoperative pain while preserving fusion rates and reducing complications. In this study, the authors wanted to compare outcomes of MITLIF with those of open TLIF to determine whether MITLIF also improves postoperative functional mobility and decreases the usage of pain medication. In total, 75 consecutive patients who underwent either single-level open TLIF or MITLIF at the University of California, San Francisco, between 2006 and 2011 were included, and patients were followed up for an average of 5.05 years. Fifty patients underwent MITLIF and 25 underwent open TLIF. Primary outcomes included administration of morphine-equivalent narcotics and functional status on postoperative Day 1. Secondary outcomes included operative characteristics, complications, long-term fusion rates, and visual analog scale (VAS) scores. No statistically significant differences in age, sex, body mass index (BMI), level of disease, or surgical indication were detected between the open TLIF and MITLIF groups. Similarly, preoperative medication usage did not significantly differ between these groups. Intraoperatively, compared with TLIF, MITLIF resulted in decreased lengths of operation, lower blood loss, and fewer complications (p < 0.05). Total administration of morphine-equivalent pain medication in the hospital also tended to be lower in the MITLIF than in the TLIF group. Functional assessment by physical therapy on postoperative Day 1 demonstrated higher function in the MITLIF patients for transfer-related tasks, ambulatory ability, and distance walked than in the TLIF patients (p < 0.05). This translated to shorter inpatient hospitalizations (6.05 vs 4.8 days for open TLIF vs MITLIF patients, respectively, p = 0.006) and an average cost reduction of $3885 per MITLIF patient. Long-term fusion rates were 92% in the MITLIF group and 100% in the open TLIF group (p = 0.09). Preoperative VAS pain scores were 7.1 for the MITLIF patients and 7.6 for the TLIF patients (p = 0.26). At the last follow-up, the reported VAS pain score was 2.9 in the MITLIF patients and 3.5 in the open TLIF patients, but this difference was not statistically significant (p = 0.25). There was also no statistically significant difference in the degree change in this score (p = 0.44). The MITLIF approach achieves improved functional mobility, decreases the usage of postoperative pain medication, and significantly reduces cost compared with open TLIF while preserving long-term fusion rates. To the authors' knowledge, this is the first study comparing the postoperative usage of pain medication between treatments in the postoperative period before discharge.


Lobectomy, sublobar resection, and stereotactic ablative radiotherapy for early-stage non-small cell lung cancers in the elderly.
The incidence of early-stage non-small cell lung cancer (NSCLC) among the elderly is expected to rise dramatically owing to demographic trends and increased computed tomographic screening. However, to our knowledge, no modern trials have compared the most common treatments for NSCLC. To determine clinical characteristics and survival outcomes associated with the 3 most commonly used definitive therapies for early-stage NSCLC in the elderly. The Surveillance, Epidemiology, and End Results database linked to Medicare was used to determine the baseline characteristics and outcomes of 9093 patients with early-stage, node-negative NSCLC who underwent definitive treatment consisting of lobectomy, sublobar resection, or stereotactic ablative radiotherapy (SABR) from January 1, 2003, through December 31, 2009. Overall and lung cancer-specific survival were compared using Medicare claims through December 31, 2012. We used proportional hazards regression and propensity score matching to adjust outcomes for key patient, tumor, and practice environment factors. The median age was 75 years, and treatment distribution was 79.3% for lobectomy, 16.5% for sublobar resection, and 4.2% for SABR. Unadjusted 90-day mortality was highest for lobectomy (4.0%) followed by sublobar resection (3.7%; P = .79) and SABR (1.3%; P = .008). At 3 years, unadjusted mortality was lowest for lobectomy (25.0%), followed by sublobar resection (35.3%; P < .001) and SABR (45.1%; P < .001). Proportional hazards regression demonstrated that sublobar resection was associated with worse overall survival (adjusted hazard ratio [AHR], 1.32 [95% CI, 1.20-1.44]; P < .001) and lung cancer-specific survival (AHR, 1.50 [95% CI, 1.29-1.75]; P < .001) compared with lobectomy. Propensity score-matching analysis reiterated these findings for overall survival (AHR, 1.36 [95% CI, 1.17-1.58]; P < .001) and lung cancer-specific survival (AHR, 1.46 [95% CI, 1.13-1.90]; P = .004). In proportional hazards regression, SABR was associated with better overall survival than lobectomy in the first 6 months after diagnosis (AHR, 0.45 [95% CI, 0.27-0.75]; P < .001) but worse survival thereafter (AHR, 1.66 [95% CI, 1.39-1.99]; P < .001). Propensity score-matching analysis of well-matched SABR and lobectomy cohorts demonstrated similar overall survival in both groups (AHR, 1.01 [95% CI, 0.74-1.38]; P = .94). Lobectomy was associated with better outcomes than sublobar resection in elderly patients with early-stage NSCLC. Propensity score matching suggests that SABR may be a good option among patients with very advanced age and multiple comorbidities.


Predicting changing malaria risk after expanded insecticide-treated net coverage in Africa.
The Roll Back Malaria (RBM) partnership has established goals for protecting vulnerable populations with locally appropriate vector control. In many places, these goals will be achieved by the mass distribution of insecticide treated bednets (ITNs). Mathematical models can forecast an ITN-driven realignment of malaria endemicity, defined by the Plasmodium falciparum parasite rate (PfPR) in children, to predict PfPR endpoints and appropriate program timelines for this change in Africa. The relative ease of measuring PfPR and its widespread use make it particularly suitable for monitoring and evaluation. This theory provides a method for context-dependent evaluation of ITN programs and a basis for setting rational ITN coverage targets over the next decade.


A family history of smoking predicts heightened levels of stress-induced cigarette craving.
Individuals with histories of smoking in first-degree relatives are significantly more likely to be persistent smokers themselves. The mechanisms underlying this relationship are unknown. Considerable research has demonstrated that smokers display heightened levels of cigarette craving after being exposed to stressful situations, and the magnitude of these craving responses is thought to be predictive of later cessation failure. Based on this research, we tested experimentally the hypothesis that smokers with two or more first-degree relatives who smoked (FH+) would exhibit stronger craving reactions following stressful stimuli than smokers without such family histories (FH-). We recruited 83 smokers by advertisement (mean age = 41.2 years, 57% female, 41% completed some college, 59% African American). The study was conducted in an interview room in an urban medical center. Participants were exposed to a neutral situation (changing a lightbulb) and a stressful situation (dental work) using script-guided imagery. Participants completed background measures of demographics, distress and smoking behavior. In addition, participants completed cigarette craving and anxiety questionnaires immediately before and after each condition. Supporting the study hypothesis, FH+ smokers (n = 39) selectively displayed stronger craving reactions to dental imagery (P < 0.03) than did FH- smokers (n = 44). The higher levels of stress-induced cigarette craving demonstrated experimentally for individuals with family histories of smoking suggest one mechanism for their poorer cessation success.


Comprehensive RNA-Sequencing Analysis in Serum and Muscle Reveals Novel Small RNA Signatures with Biomarker Potential for DMD.
Extracellular small RNAs (sRNAs), including microRNAs (miRNAs), are promising biomarkers for diseases such as Duchenne muscular dystrophy (DMD), although their biological relevance is largely unknown. To investigate the relationship between intracellular and extracellular sRNA levels on a global scale, we performed sRNA sequencing in four muscle types and serum from wild-type, dystrophic mdx, and mdx mice in which dystrophin protein expression was restored by exon skipping. Differentially abundant sRNAs were identified in serum (mapping to miRNA, small nuclear RNA [snRNA], and PIWI-interacting RNA [piRNA] loci). One novel candidate biomarker, miR-483, was increased in both mdx serum and muscle, and also elevated in DMD patient sera. Dystrophin restoration induced global shifts in miRNA (including miR-483) and snRNA-fragment abundance toward wild-type levels. Specific serum piRNA-like sRNAs also responded to exon skipping therapy. Absolute miRNA expression in muscle was positively correlated with abundance in the circulation, although multiple highly expressed miRNAs in muscle were not elevated in mdx serum, suggesting that both passive and selective release mechanisms contribute to serum miRNA levels. In conclusion, this study has revealed new insights into the sRNA biology of dystrophin deficiency and identified novel DMD biomarkers.


Proposals for the mitigation of the environmental impact of clinical laboratories.
Laboratories should be aware of the carbon footprint resulting from their activities and take steps to mitigate it as part of their societal responsibilities. Once committed to a mitigation programme, they should announce an environmental policy, secure the support of senior management, initiate documentation, institute a staff training programme, schedule environmental audits and appoint an environmental manager. Laboratories may aspire to be accredited to one of the standards for environmental management, such as the ISO 14000. As environmental and quality issues are linked, the improvement in the environmental management of an organisation will ultimately lead to improved quality system performance. Indeed, environmental management could conceivably come under overall quality management. Although there will be initial costs, good environmental practices can bring savings. Environmental improvement should be based on the 3R concept to reduce, reuse and recycle. Several policy initiatives may be introduced. These include a green purchasing policy for equipment, laboratory furniture and reagents as well as the management of packaging wastes. There are several ways to reduce energy, water usage and wastage. A reduction of test numbers and collection tubes should be attempted. Paper management involves all aspects of 3R. The recycling of solvents and general wastes should be practised where feasible. The construction new laboratories or renovations to existing ones are opportunities to make them more environmentally-friendly. The advocacy of policies to associates and the inclusion of environmentally-friendly conditions on contractors are integral parts of the programme.


A herbal antifungal formulation of Thymus serpillum, Origanum vulgare and Rosmarinus officinalis for treating ovine dermatophytosis due to Trichophyton mentagrophytes.
A number of herbal products with anti-inflammatory, antiseptic and antimycotic properties are available for dermatological usage. The successful treatment of 13 sheep affected by ringworm due to Trichophyton mentagrophytes with a mixture consisting of essential oils (EOs) of Thymus serpillum 2%, Origanum vulgare 5% and Rosmarinus officinalis 5% in sweet almond (Prunus dulcis) oil. The effectiveness of EOs and of the major components of the mixture (thymol, carvacrol, 1,8 cineole, α-pinene, p-cymene, γ-terpinene) against the fungal clinical isolate was evaluated by a microdilution test. Thirteen animals were topically administered with the mixture twice daily for 15 days. The other sheep were administered with a conventional treatment (seven animals) or left untreated (two animals). Minimum inhibitory concentration (MIC) values were 0.1% for T. serpillum, 0.5% for O. vulgare, 2.5% for I. verum and 5% for both R. officinalis and C. limon. Thymol and carvacrol showed MICs of 0.125% and 0.0625%. A clinical and aetiological cure was obtained at the end of each treatment regimen in only the treated animals. Specific antimycotic drugs licenced for food-producing sheep are not available within the European Community. The mixture tested here appeared to be a versatile tool for limiting fungal growth.


Playing catch-up with Escherichia coli: using yeast to increase success rates in recombinant protein production experiments.
Several host systems are available for the production of recombinant proteins, ranging from Escherichia coli to mammalian cell-lines. This article highlights the benefits of using yeast, especially for more challenging targets such as membrane proteins. On account of the wide range of molecular, genetic, and microbiological tools available, use of the well-studied model organism, Saccharomyces cerevisiae, provides many opportunities to optimize the functional yields of a target protein. Despite this wealth of resources, it is surprisingly under-used. In contrast, Pichia pastoris, a relative new-comer as a host organism, is already becoming a popular choice, particularly because of the ease with which high biomass (and hence recombinant protein) yields can be achieved. In the last few years, advances have been made in understanding how a yeast cell responds to the stress of producing a recombinant protein and how this information can be used to identify improved host strains in order to increase functional yields. Given these advantages, and their industrial importance in the production of biopharmaceuticals, I argue that S. cerevisiae and P. pastoris should be considered at an early stage in any serious strategy to produce proteins.


Rationale and Approaches to Phosphate and Fibroblast Growth Factor 23 Reduction in CKD.
Patients with CKD often progress to ESRD and develop cardiovascular disease (CVD), yet available therapies only modestly improve clinical outcomes. Observational studies report independent associations between elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels and risks of ESRD, CVD, and death. Phosphate excess induces arterial calcification, and although elevated FGF23 helps maintain serum phosphate levels in the normal range in CKD, it may contribute mechanistically to left ventricular hypertrophy (LVH). Consistent epidemiologic and experimental findings suggest the need to test therapeutic approaches that lower phosphate and FGF23 in CKD. Dietary phosphate absorption is one modifiable determinant of serum phosphate and FGF23 levels. Limited data from pilot studies in patients with CKD stages 3-4 suggest that phosphate binders, low phosphate diets, or vitamin B3 derivatives, such as niacin or nicotinamide, may reduce dietary phosphate absorption and serum phosphate and FGF23 levels. This review summarizes current knowledge regarding the deleterious systemic effects of phosphate and FGF23 excess, identifies questions that must be addressed before advancing to a full-scale clinical outcomes trial, and presents a novel therapeutic approach to lower serum phosphate and FGF23 levels that will be tested in the COMBINE Study: The CKD Optimal Management With BInders and NicotinamidE study.


Are unimanual movements bilateral?
Motor control is a fundamental challenge for the central nervous system. In this review, we show that unimanual movements involve bi-hemispheric activation patterns that resemble the bilateral neural activation typically observed for bimanual movements. For unimanual movements, the activation patterns in the ipsilateral hemisphere arguably entail processes that serve to suppress interhemispheric cross-talk through transcallosal tracts. Improper suppression may cause involuntary muscle co-activation and as such it comes as no surprise that these processes depend on the motor task. Identifying the detailed contributions of local and global excitatory and inhibitory cortical processes to this suppression calls for integrating findings from various behavioral paradigms and imaging modalities. Doing so systematically highlights that lateralized activity in left (pre)motor cortex modulates with task complexity, independently of the type of task and the end-effector involved. Despite this lateralization, however, our review supports the idea of bi-hemispheric cortical activation being a fundamental mode of upper extremity motor control.


Polydentate chalcogen reagents for the facile preparation of Pd2 and Pd4 complexes.
The silylated organochalcogen reagents 1,2-(Me3SiSCH2)2C6H4, and 1,2-(Me3SiSeCH2)2C6H4, were prepared from the corresponding organobromides and lithium trimethylsilanechalcogenolate Li[ESiMe3] (E = S, Se). They have been characterized by multinuclear NMR spectroscopy ((1)H, (13)C, (77)Se) and electrospray ionization mass spectrometry. and react under mild conditions with (1,3-bis(diphenylphosphino)propane)palladium(ii) chloride, [PdCl2(dppp)], to provide the dinuclear organochalcogenolate-bridged complexes [(dppp)2Pd2-μ-κ(2)S-{1,2-(SCH2)2C6H4}]X2, []X2 and [(dppp)2Pd2-μ-κ(2)Se-{1,2-(SeCH2)2C6H4}]X2, []X2 (X = Cl, Br) in good yield, respectively. Furthermore, the tetranuclear palladium complex [(dppp)4Pd4-μ-κ(4)S-{1,2,4,5-(SCH2)4C6H2}]X4, []X4 (X = Cl, Br) can be synthesized from the reaction of the tetrathiotetrasilane 1,2,4,5-(Me3SiSCH2)4C6H2, and [PdCl2(dppp)]. The structures of []X2, []X2 and []X4 were determined by single crystal X-ray diffraction methods. A variety of NMR experiments including two-dimensional homonuclear and heteronuclear correlated spectra were used to probe the solution behaviour of the dinuclear complexes in more detail. These complexes were further characterized by electrospray ionization (ESI) mass spectrometry, and for []X2 and []X2, UV-Vis absorption spectroscopy.


Consumption and its discontents: addiction, identity and the problems of freedom.
The focus of this paper is on the notion of 'addictive consumption', conceived as a set of discourses that are embedded within wider socio-historical processes of governance and control. It examines the discursive convergences and conflicts between practices of consumption and notions of addiction, which it notes are consistently represented in terms of the oppositional categories of self-control vs. compulsion and freedom vs. determinism. These interrelations are explored with reference to the development of notions of addiction, and their relation to shifting configurations of identity, subjectivity and governance. Finally, it suggests that the notion of 'addiction' has particular valence in advanced liberal societies, where an unprecedented emphasis on the values of freedom, autonomy and choice not only encourage the conditions for its proliferation into ever wider areas of social life, but also reveal deep tensions within the ideology of consumerism itself.


The failure to show a necessary role for C3 in the in vitro antibody response.
The in vitro antibody response of mouse spleen cells to TNP coupled to both T-dependent and T-independent carriers as well as to sheep erythrocytes has been studied to investigate the possible role of complement activation in the induction of antibody formation. The following has been found. (1) In vitro responses of both IgM and IgG can be obtained to both T-dependent and T-independent antigens in serum-free media, although they are smaller than those found in serum-containing media. This shows that no exogenous source of complement is necessary for in vitro antibody formation by spleen cells. (2) Similarly, normal antibody responses are obtained if the cultures are grown in human serum depleted of C3b-inactivator, which contains high concentrations of C3b. (3) In the presence of antibody to mouse C3 the response to the T-independent antigen is reduced, the IgM responses being more affected than the IgG. However, purified F(ab')2 anti-C3 has no inhibitory effect and it therefore seems likely that it is the formation of intact immune complexes containing Fc rather than the interference with C3 function that is responsible for the inhibition seen. (4) The conventionally purified anti-complementary factor from cobra venom has no effect on the antibody response in serum-free culture or when human or fetal calf sera are used. In no experiment was any potentiation of T-dependent responses observed. However, the presence of quite small concentrations (2%) of cobra veno


The microbe-derived short chain fatty acid butyrate targets miRNA-dependent p21 gene expression in human colon cancer.
Colonic microbiota ferment non-absorbed dietary fiber to produce prodigious amounts of short chain fatty acids (SCFAs) that benefit the host through a myriad of metabolic, trophic, and chemopreventative effects. The chemopreventative effects of the SCFA butyrate are, in part, mediated through induction of p21 gene expression. In this study, we assessed the role of microRNA(miRNA) in butyrate's induction of p21 expression. The expression profiles of miRNAs in HCT-116 cells and in human sporadic colon cancers were assessed by microarray and quantitative PCR. Regulation of p21 gene expression by miR-106b was assessed by 3' UTR luciferase reporter assays and transfection of specific miRNA mimics. Butyrate changed the expression of 44 miRNAs in HCT-116 cells, many of which were aberrantly expressed in colon cancer tissues. Members of the miR-106b family were decreased in the former and increased in the latter. Butyrate-induced p21 protein expression was dampened by treatment with a miR-106b mimic. Mutated p21 3'UTR-reporter constructs expressed in HCT-116 cells confirmed direct miR-106b targeting. Butyrate decreased HCT-116 proliferation, an effect reversed with the addition of the miR-106b mimic. We conclude that microbe-derived SCFAs regulate host gene expression involved in intestinal homeostasis as well as carcinogenesis through modulation of miRNAs.


Comprehensive review of the impact of direct oral anticoagulants on thrombophilia diagnostic tests: Practical recommendations for the laboratory.
There is a laboratory and clinical need to know the impact of direct oral anticoagulants (DOACs) on diagnostic tests to avoid misinterpretation of results. Although the regulatory labelling documents provide some information about the influences of each DOAC on diagnostic tests, these are usually limited to some of the most common tests and no head to head comparison is available. In this paper, we report the impact of DOACs on several thrombophilia tests, including assessment of antithrombin, protein S and protein C activity assays, detection of activated protein C resistance and assays used for lupus anticoagulant. Results are compared and discussed with data obtained from literature. The final goal of this comprehensive review is to provide practical recommendations for laboratories to avoid misdiagnosis due to oral direct factor Xa (FXa) or IIa (FIIa) inhibitors. Overall, oral direct FXa (apixaban, betrixaban, edoxaban and rivaroxaban) and FIIa (dabigatran) antagonists may affect clot-based thrombophilia diagnostic tests resulting in false-positive or false-negative results. An effect on FIIa-based thrombophilia diagnostic tests is observed with dabigatran but not with anti-FXa DOACs and conversely for FXa-based thrombophilia diagnostic tests. No impact was observed with antigenic/chromogenic methods for the assessment of protein S and C activity. In conclusion, interpretation of thrombophilia diagnostic tests results should be done with caution in patients on DOACs. The use of a device/chemical compound able to remove or antagonize the effect of DOACs or the development of new diagnostic tests insensitive to DOACs should be considered to minimize the risk of false results.


Corrosion monitoring with speckle correlation.
The changes in the microtopography of a metal surface during a corrosion process are measured by decorrelation of the scattered speckle fields under coherent illumination. For that purpose a quantitative relation between the decorrelation of the scattered light fields and the rate of corrosion is established in a theoretical model, based on the statistics of phase and reflectivity changes of point scatterers at the surface. The speckle fields are recorded by a CCD camera and processed numerically in a computer, yielding the standard deviation of the topography changes with nanometer sensitivity. From the analysis of a series of images taken at equal time intervals during the corrosion process, the degree of interrelation among subsequent topography changes is calculated.


Is the Returning Farmland to Forest Program a Success? Three Case Studies from Sichuan.
China's tuigeng huanlin or "Returning Farmland to Forest" (RFFP) program has been widely praised as the world's largest and most successful payment for ecosystem services program, as well as a major contributor to China's dramatic increase in forest cover from perhaps as low as 8% in 1960 to about 21% today. By compensating rural households for the conversion of marginal farmland to forestland and financing the afforestation of barren mountainsides, the program, in addition to expanding forestland, aims to reduce soil erosion and alleviate poverty. This paper presents qualitative and quantitative studies conducted on the local implementation of RFFP in three diverse townships in Sichuan. We find the actual results to be more mixed than the official figures would indicate. Though there have been some positive results, we identify problems with site and species selection, compensation for land taken out of cultivation, shift of labor to off-farm activities, and monitoring of replanted sites, which challenge the ecological and economic impacts of these programs and reveal much of the effort of the program has been misdirected. We suggest that efforts are misplaced because of the top-down, panacea nature of the program, which in turn is a feature of Chinese bureaucratic management.