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Trust is predictive of civic cooperation and economic growth. Recently, the U.S. public has demonstrated increased partisan division and a surveyed decline in trust in institutions. There is a need to quantify individual and community levels of trust unobtrusively and at scale. Using observations of language across more than 16,000 Facebook users, along with their self-reported generalized trust score, we develop and evaluate a language-based assessment of generalized trust. We then apply the assessment to more than 1.6 billion geotagged tweets collected between 2009 and 2015 and derive estimates of trust across 2,041 U.S. counties. We find generalized trust was associated with more affiliative words (love, we, and friends) and less angry words (hate and stupid) but only had a weak association with social words primarily driven by strong negative associations with general othering terms (“they” and “people”). At the county level, associations with the Centers for Disease Control and Prevention (CDC) and Gallup surveys suggest that people in high-trust counties were physically healthier and more satisfied with their community and their lives. Our study demonstrates that generalized trust levels can be estimated from language as a low-cost, unobtrusive method to monitor variations in trust in large populations.

Abstract Background Early blood transfusion improves survival in patients with life-threatening bleeding, but the optimal transfusion strategy in the pre-hospital setting has yet to be established. Although there is some evidence of benefit with the use of whole blood, there have been no randomised controlled trials exploring the clinical and cost effectiveness of pre-hospital administration of whole blood versus component therapy for trauma patients with life-threatening bleeding. The aim of this trial is to determine whether pre-hospital leukocyte-depleted whole blood transfusion is better than standard care (blood component transfusion) in reducing the proportion of participants who experience death or massive transfusion at 24 h. Methods This is a multi-centre, superiority, open-label, randomised controlled trial with internal pilot and within-trial cost-effectiveness analysis. Patients of any age will be eligible if they have suffered major traumatic haemorrhage and are attended by a participating air ambulance service. The primary outcome is the proportion of participants with traumatic haemorrhage who have died (all-cause mortality) or received massive transfusion in the first 24 h from randomisation. A number of secondary clinical, process, and safety endpoints will be collected and analysed. Cost (provision of whole blood, hospital, health, and wider care resource use) and outcome data will be synthesised to present incremental cost-effectiveness ratios for the trial primary outcome and cost per quality-adjusted life year at 90 days after injury. We plan to recruit 848 participants (a two-sided test with 85% power, 5% type I error, 1-1 allocation, and one interim analysis would require 602 participants—after allowing for 25% of participants in traumatic cardiac arrest and an additional 5% drop out, the sample size is 848). Discussion The SWiFT trial will recruit 848 participants across at least ten air ambulances services in the UK. It will investigate the clinical and cost-effectiveness of whole blood transfusion versus component therapy in the management of patients with life-threatening bleeding in the pre-hospital setting. Trial registration ISRCTN: 23657907; EudraCT: 2021-006876-18; IRAS Number: 300414; REC: 22/SC/0072, 21 Dec 2021.

This paper presents a study of the experiences of five individuals who explore their unique relationship between music and spirituality. Each participant critically narrates their faith and beliefs and explores how these relate to their experiences with music. The paper begins with a brief exposition of the literature concerning music and spirituality and the linkages between the two. The methodology combines narrative and auto-ethnography, underpinned by a phenomenological approach to reflection on experiences. Using deep self-analysis, the five authors derive and discover lessons concerning their own relationship between faith, spirituality, and music. These are then analysed to produce common themes concerning the intertwining of spirituality with music. Finally, the conclusions present a novel contribution which includes lessons on how through self-exploration, one can use music and spirituality to repair and ultimately enrich the soul. The paper exposes the interplay between faith, spirituality and music, which will be of general interest and provide inspiration to those who intend to use music to enrich their lives and heal themselves.

Electroencephalography (EEG) has shown potential for identifying early-stage biomarkers of neurocognitive dysfunction associated with dementia due to Alzheimer's disease (AD). A large body of evidence shows that, compared to healthy controls (HC), AD is associated with power increases in lower EEG frequencies (delta and theta) and decreases in higher frequencies (alpha and beta), together with slowing of the peak alpha frequency. However, the pathophysiological processes underlying these changes remain unclear. For instance, recent studies have shown that apparent shifts in EEG power from high to low frequencies can be driven either by frequency specific periodic power changes or rather by non-oscillatory (aperiodic) changes in the underlying 1/f slope of the power spectrum. Hence, to clarify the mechanism(s) underlying the EEG alterations associated with AD, it is necessary to account for both periodic and aperiodic characteristics of the EEG signal. Across two independent datasets, we examined whether resting-state EEG changes linked to AD reflect true oscillatory (periodic) changes, changes in the aperiodic (non-oscillatory) signal, or a combination of both. We found strong evidence that the alterations are purely periodic in nature, with decreases in oscillatory power at alpha and beta frequencies (AD < HC) leading to lower (alpha + beta) / (delta + theta) power ratios in AD. Aperiodic EEG features did not differ between AD and HC. By replicating the findings in two cohorts, we provide robust evidence for purely oscillatory pathophysiology in AD and against aperiodic EEG changes. We therefore clarify the alterations underlying the neural dynamics in AD and emphasize the robustness of oscillatory AD signatures, which may further be used as potential prognostic or interventional targets in future clinical investigations.

Summary: Understanding the memory substrates underlying substance abuse requires the permanent tagging and manipulation of drug-recruited neural ensembles. Here, we present a protocol for activity-dependent labeling and chemogenetic manipulation of fentanyl-activated striatal ensembles using the ArcTRAP approach. We outline the necessary steps to breed ArcTRAP mice, prepare drugs and reagents, conduct behavioral training, and perform tagging and manipulation. This approach can be adapted to investigate drug-recruited ensembles in other brain regions, providing a versatile tool for exploring the neural mechanisms underlying addiction.For complete details on the use and execution of this protocol, please refer to Wang et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Aflatoxins are toxic secondary metabolites of fungi that colonize staple food crops, such as maize and groundnut, frequently used in complementary feeding. In preparation for a large trial, this pilot study examined if provision of a low‐aflatoxin infant porridge flour made from local maize and groundnuts reduced the prevalence of a urinary aflatoxin biomarker in infants. Thirty‐six infants aged 6–18 months were included from four villages in Kongwa District, Tanzania. The study was conducted over 12 days with a three‐day baseline period and a 10 days where low‐AF porridge flour was provided. Porridge intake of infants was assessed using quantitative 24‐h recalls by mothers. Household food ingredients used in infant porridge preparation and urine samples were collected on Days 1–3 (baseline) and 10–12 (follow‐up). Aflatoxins were measured in household foods, and AFM1 was measured in urine. At baseline and follow‐up, 78% and 97%, respectively, of the infants consumed porridge in the previous 24 h, with a median volume of 220 mL (interquartile range [IQR]: 201, 318) and 460 mL (IQR: 430, 563), respectively (p

Cities across Canada are aging—fast. As the “baby boom” generation enters older adulthood, cities are facing a dramatic demographic shift. However, it is unclear whether cities in Canada are prepared to meet the needs of the growing older adult population. Through the case study of one of Canada’s demographically oldest cities, Victoria, BC, we assess the age-friendliness of local plans and policies. Specifically, we conduct a plan evaluation content analysis to assess the city’s Official Community Plan and supporting statutory plans to determine whether the city is truly planning for an age-friendly environment. We find that while the city is aware of the aging population, it fails to explicitly mention or provide targeted policies for older adults in its planning documents. We unpack the practical challenges of planning for an aging population and provide targeted recommendations for municipalities to incorporate age-friendly elements within their statutory plans.

Abstract Background Cognitive problems affect up to 70% of people with multiple sclerosis (MS), which can negatively impact mood, ability to work, and quality of life. Addressing cognitive problems is a top 10 research priority for people with MS. Our ongoing research has systematically developed a cognitive screening and management pathway (NEuRoMS) tailored for people with MS, involving a brief cognitive evaluation and rehabilitation intervention. The present study aims to assess the feasibility of delivering the pathway and will inform the design of a definitive randomised controlled trial (RCT) to investigate the clinical and cost-effectiveness of the intervention and eventually guide its clinical implementation. Methods The feasibility study is in three parts. Part 1 involves an observational study of those who receive screening and support for cognitive problems, using routinely collected clinical data. Part 2 is a two-arm, parallel group, multicentre, feasibility RCT with a nested fidelity evaluation. This part will evaluate the feasibility of undertaking a definitive trial comparing the NEuRoMS intervention plus usual care to usual care only, amongst people with MS with mild cognitive problems (n = 60). In part 3, semi-structured interviews will be undertaken with participants from part 2 (n = 25), clinicians (n = 9), and intervention providers (n = 3) involved in delivering the NEuRoMS cognitive screening and management pathway. MS participants will be recruited from outpatient clinics at three UK National Health Service hospitals. Discussion Timely screening and effective management of cognitive problems in MS are urgently needed due to the detrimental consequences of cognitive problems on people with MS, the healthcare system, and wider society. The NEuRoMS intervention is based on previous and extant literature and has been co-constructed with relevant stakeholders. If effective, the NEuRoMS pathway will facilitate timely identification and management of cognitive problems in people with MS. Trial registration ISRCTN11203922 . Prospectively registered on 09.02.2021.

Healthcare continues toward team-based approaches in which multiple disciplines collaborate to ensure holistic patient care. National standards for intraprofessional collaboration guide curriculum design for entry-level occupational therapy (OT) and occupational therapy assistant (OTA) programs to ensure students acquire specific skills and knowledge needed for current OT practices. Effective intraprofessional collaboration includes effective communication, respect, trust, and understanding of role delineation, which students prefer to learn in experiential, face-to-face formats. The purpose of this study was to examine OT and OTA students’ perspectives of participating in an educational escape room (EER) as a novel experience for intraprofessional education. Investigators created an EER with a healthcare plot and conducted it at two sites with 76 students, who had 60 minutes to solve puzzles based on OT/OTA knowledge to “escape” the room. Seventy-five students provided feedback on the EER in an online survey. Participants enjoyed working together in the EER, and felt it was a fun way to apply learned skills. They reported that collaboration was a key benefit and that this learning approach made them feel like equal contributors and created a sense of accomplishment. OT educators should consider including novel game-based learning activities such as EERs in their programs and in collaboration with other programs.

This semester-long study explores the under-researched topic of mental labour among middle-aged Belgian mothers in the context of the coronavirus crisis’ lockdowns. Mental labour refers to the presence of a cognitive burden induced by familial responsibilities, and it is often more prevalent in women than in men. By means of one focus group and six in-depth individual interviews, this research uncovers the different mechanisms that Belgian mothers developed during the first two coronavirus crisis lockdowns to better cope with their mental labour. Through this research, we hope to raise awareness of the mental labour experienced by mothers and highlight the different ways in which gender inequalities are perpetuated in the household, as well as envision how a better balance of tasks performed by men and women can be achieved.

Hunter syndrome is a neurodegenerative lysosomal storage disorder with limited treatment options to halt the progressive neurocognitive decline. Whilst Intravenous enzyme replacement therapy (ERT) does not cross the blood brain barrier; Intrathecal ERT, in clinical studies, did not demonstrate significant effect on cognition, despite having better CNS delivery. Hematopoietic stem cell transplantation (HSCT) has the potential to treat CNS disease. We reviewed the literature and outline our experience of treating two siblings with severe Hunter syndrome: ‘Sibling A' with intravenous and intrathecal ERT and ‘Sibling B' with Early HSCT. A literature review identified 8 articles reporting on the comparative efficacy of both treatments. Our clinical outcomes indicate that Sibling B performed better than Sibling A in relation to early developmental milestones as well as neurocognition, activities of daily living, quality of life and neurophysiological outcomes in mid childhood. Sibling A's developmental trajectory fell within the extremely low range and Sibling B's development trajectory fell within the low-average to average range. This suggests HSCT had a disease modifying effect and highlights the efficacy of early HSCT in moderating the CNS progression in Hunter syndrome. Long term follow up is needed to elucidate the efficacy of HSCT on neurological progression.

Abstract Endothelial hemoglobin (Hb)α regulates endothelial nitric oxide synthase (eNOS) biochemistry. We hypothesized that Hb could also be expressed and biochemically active in the ciliated human airway epithelium. Primary human airway epithelial cells, cultured at air–liquid interface (ALI), were obtained by clinical airway brushings or from explanted lungs. Human airway Hb mRNA data were from publically available databases; or from RT-PCR. Hb proteins were identified by immunoprecipitation, immunoblot, immunohistochemistry, immunofluorescence and liquid chromatography- mass spectrometry. Viral vectors were used to alter Hbβ expression. Heme and nitrogen oxides were measured colorimetrically. Hb mRNA was expressed in human ciliated epithelial cells. Heme proteins (Hbα, β, and δ) were detected in ALI cultures by several methods. Higher levels of airway epithelial Hbβ gene expression were associated with lower FEV1 in asthma. Both Hbβ knockdown and overexpression affected cell morphology. Hbβ and eNOS were apically colocalized. Binding heme with CO decreased extracellular accumulation of nitrogen oxides. Human airway epithelial cells express Hb. Higher levels of Hbβ gene expression were associated with airflow obstruction. Hbβ and eNOS were colocalized in ciliated cells, and heme affected oxidation of the NOS product. Epithelial Hb expression may be relevant to human airways diseases.

The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA-associated PD is identical to sporadic PD, aside from the earlier age at onset (AAO), more frequent cognitive impairment and more rapid progression. Mutations in GBA can be associated with loss- and gain-of-function mechanisms. A key hallmark of PD is the presence of intraneuronal proteinaceous inclusions named Lewy bodies, which are made up primarily of alpha-synuclein. Mutations in the GBA gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism. Models of GCase deficiency demonstrate dysfunction of the autophagic-lysosomal pathway and subsequent accumulation of alpha-synuclein. This dysfunction can also lead to aberrant lipid metabolism, including the accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine. Certain mutations cause GCase to be misfolded and retained in the endoplasmic reticulum (ER), activating stress responses including the unfolded protein response (UPR), which may contribute to neurodegeneration. In addition to these mechanisms, a GCase deficiency has also been associated with mitochondrial dysfunction and neuroinflammation, which have been implicated in the pathogenesis of PD. This review discusses the pathways associated with GBA-PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration.

S-nitroso-l-cysteine (L-CSNO) behaves as a ligand. Its soluble guanylate cyclase–independent (sGC-independent) effects are stereoselective — that is, not recapitulated by S-nitroso-d-cysteine (D-CSNO) — and are inhibited by chemical congeners. However, candidate L-CSNO receptors have not been identified. Here, we have used 2 complementary affinity chromatography assays — followed by unbiased proteomic analysis — to identify voltage-gated K+ channel (Kv) proteins as binding partners for L-CSNO. Stereoselective L-CSNO–Kv interaction was confirmed structurally and functionally using surface plasmon resonance spectroscopy; hydrogen deuterium exchange; and, in Kv1.1/Kv1.2/Kvβ2-overexpressing cells, patch clamp assays. Remarkably, these sGC-independent L-CSNO effects did not involve S-nitrosylation of Kv proteins. In isolated rat and mouse respiratory control (petrosyl) ganglia, L-CSNO stereoselectively inhibited Kv channel function. Genetic ablation of Kv1.1 prevented this effect. In intact animals, L-CSNO injection at the level of the carotid body dramatically and stereoselectively increased minute ventilation while having no effect on blood pressure; this effect was inhibited by the L-CSNO congener S-methyl-l-cysteine. Kv proteins are physiologically relevant targets of endogenous L-CSNO. This may be a signaling pathway of broad relevance.

Online, social media communication is often ambiguous, and it can encourage speed and inattentiveness. We investigated whether Actively Open Minded Thinking (AOT), a dispositional willingness to seek out new or potentially threatening information, may help users avoid these pitfalls. In Study 1, we determined that correctly assessing social media authors’ traits was positively predicted by raters’ AOT. In Study 2, we used data-driven methods to devise a three-dimensional picture of online behaviors of people high or low in AOT, finding that AOT is associated with thoughtful, nuanced, idiosyncratic actions and with resisting the typically fast pace of online interactions. AOT may be an important factor in accurate, socially responsible online behavior.

Context: Exogenous nitrogen oxides must be made bioavailable to sustain normal physiology because nitric oxide synthase (NOS) deficient mice are viable. In the stomach, S-nitrosoglutathione (GSNO) is formed from ingested nitrite and high levels of airway glutathione (GSH) that are cleared and swallowed. However, gastric GSNO may be broken down by nutrients like ascorbic acid (AA) before it is absorbed. Objective: To study the effect of AA on GSNO formation and stability. Materials and methods: GSH and nitrite were reacted with or without 5 mM AA or Resiston (5 mM AA with retinoic acid and α-tocopherol). GSNO was measured by reduction/chemiluminescence and HPLC. AA and reduced thiols were measured colorimetrically. O-Nitrosoascorbate and AA were measured by gas chromatography–mass spectrometry (GC–MS). Results: GSNO was formed in saline and gastric samples (pH ∼4.5) from physiological levels of GSH and nitrite. Neither AA nor Resiston decreased [GSNO] at pH >3; rather, they increased [GSNO] (0.12 ± 0.19 μM without AA; 0.42 ± 0.35 μM with AA; and 0.43 ± 0.23 μM with Resiston; n = 4 each; p ≤ 0.05). However, AA compounds decreased [GSNO] at lower pH and with incubation >1 h. Mechanistically, AA, but not dehydroascorbate, increased GSNO formation; and the O-nitrosoascorbate intermediate was formed. Conclusions: AA, with or without other antioxidants, did not deplete GSNO formed from physiological levels of GSH and nitrite at pH >3. In fact, it favoured GSNO formation, likely through O-nitrosoascorbate. Gastric GSNO could be a NOS-independent source of bioavailable nitrogen oxides.

The misalignment between internal circadian rhythm and the day-night cycle can be caused by genetic, behavioural and environmental factors, and may have a profound impact on human physiology. Here West et al. show that desynchrony between the internal clock and the external environment alter metabolic parameters and cardiac function in mice.

Political scientist Stephen Skowronek defines transformational presidents as those who altered the political system and the nation. Voters’ dissatisfaction with Barack Obama, the backlash evident in the election of Donald Trump and analysis of his presidency thus far raises two important questions. Firstly, can there be a transformational presidency in the twenty-first century? Secondly, have transformational presidential elections replaced the transformational presidency? Utilizing news media sources, this article demonstrates that the twenty-first century can best be described as the era of post-nationalism, with globalization providing a check on presidential power. It is now nearly impossible for a transformational candidate to become a transformational president.

Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and in vitro studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation in vivo in mammals remains unknown. To address this, we generated a Parkin Ser65Ala (S65A) knock-in mouse model. We observe endogenous Parkin Ser65 phosphorylation and activation in mature primary neurons following mitochondrial depolarization and reveal this is disrupted in ParkinS65A/S65A neurons. Phenotypically, ParkinS65A/S65A mice exhibit selective motor dysfunction in the absence of any overt neurodegeneration or alterations in nigrostriatal mitophagy. The clinical relevance of our findings is substantiated by the discovery of homozygous PARKIN (PARK2) p.S65N mutations in two unrelated patients with PD. Moreover, biochemical and structural analysis demonstrates that the ParkinS65N/S65N mutant is pathogenic and cannot be activated by PINK1. Our findings highlight the central role of Parkin Ser65 phosphorylation in health and disease.

PSMD9 was first characterized as a component of the PA700 proteasomal regulator, and was found to stimulate association of PA700 with the catalytic 20S proteasomal core to form the active 26S proteasome. It was also independently identified under the name “bridge-1” as a transcriptional co-activator that modulates function of the transcription factors PDX-1, E12, and E47, and interacts with the co-activator histone acetyltransferase p300. Here, we discuss the molecular and genetic data linking PSMD9 to a diverse range of conditions including diabetes, cancer, mental health problems, polycystic ovary syndrome and neurodegenerative diseases, and thereby highlight its potential as a therapeutic target in these multiple settings.

Emerging evidence suggests that dopamine may modulate learning and memory with important implications for understanding the neurobiology of memory and future therapeutic targeting. An influential hypothesis posits that dopamine biases reinforcement learning. More recent data also suggest an influence during both consolidation and retrieval. Eighteen Parkinson’s disease patients learned through feedback ON or OFF medication, with memory tested 24 hr later ON or OFF medication (4 conditions, within-subjects design with matched healthy control group). Patients OFF medication during learning decreased in memory accuracy over the following 24 hr. In contrast to previous studies, however, dopaminergic medication during learning and testing did not affect expression of positive or negative reinforcement. Two further experiments were run without the 24 hr delay, but they too failed to reproduce effects of dopaminergic medication on reinforcement learning. While supportive of a dopaminergic role in consolidation, this study failed to replicate previous findings on reinforcement learning.

In the last two decades, online learning has transformed the field of higher education. Also during this time, institutions of higher education have seen increases in their adult learner populations. The flexibility and accessibility of an online education model is often particularly appealing to adult learners, who bring unique needs, expectations, and learning styles to their educational experiences. Using Kolb’s Learning Style Inventory and Knowles’ andragogy model as theoretical frameworks, this study evaluates an online graduate course in epidemiology in terms of the demographics, learning styles, satisfaction, and achievement of students. Comparing the online course to the same, land-based course that was offered concurrently, we found no differences between students’ learning styles, satisfaction, and overall achievement. However, students in the land-based class were more likely to be matriculated into a degree program (p

The Convention on the Rights of Persons with Disabilities (CRPD) creates duties for States Parties and UN agencies to ensure that individuals under their protection have equal enjoyment of the full range of human rights. This includes the Article 25 right to enjoy ‘the highest attainable standard of health without discrimination on the basis of disability.’ However, refugees, who are forced to seek protection outside their state, face particular obstacles to maintaining an adequate level of wellbeing and accessing services to meet their health needs. Among this group, those who have a disability may confront multiple intersecting challenges. This paper draws on the findings of research across countries that play host to significant refugee populations. It explores the contribution of the CRPD to the international human rights framework for refugees, with particular attention to the right to health. Incorporating evidence from the field, it discusses the implementation of these rights and related duties in humanitarian responses across the world. This article discusses common barriers to health services for refugees with disabilities in six host countries. Based on the broad conceptualization of health and wellbeing established in the international legal framework, it also examines the relationship between the fulfilment of Article 25 and other basic socioeconomic rights. It provides examples of good practice and identifies strategies to better ensure the rights set out in Article 25 of the CRPD.

Background. To characterize participant reasons for withdrawing from a diabetes focused longitudinal clinical observational trial (TEDDY) during the first three study years. Methods. 8677 children were recruited into the TEDDY study. At participant withdrawal staff recorded any reason parents provided for withdrawal. Reasons were categorized into (1) family characteristics and (2) protocol reasons. Families who informed staff of their withdrawal were classified as active withdrawals (AW); families without a final contact were considered passive withdrawals (PW). Results. Withdrawal was highest during the first study year (n=1220). Most families were AW (n=1549; 73.4%). PW was more common in the United States (n=1001; 37.8%) and among young mothers (p=0.001). The most frequent protocol characteristic was blood draw (55%) and the most common family reason was not having enough time (66%). The blood draw was more common among female participants; being too busy was more common among males. Both reasons were associated with study satisfaction. Conclusions. Results suggest that, for families of children genetically at risk for diabetes, procedures that can be painful/frightening should be used with caution. Study procedures must also be considered for the demands placed on participants. Study satisfaction should be regularly assessed as an indicator of risk for withdrawal.

PURPOSE: We aimed to identify putative predictive protein biomarkers of radioresistance. EXPERIMENTAL DESIGN: Three breast cancer cell lines (MCF7, MDA-MB-231, and T47D) were used as in vitro models to study radioresistance. Inherent radiosensitivities were examined using a clonogenic survival assay. It was revealed that each cell line differed in their response to radiotherapy. These parental breast cancer cell lines were used to establish novel derivatives (MCF7RR, MDA-MB-231RR, and T47DRR) displaying significant resistance to ionizing radiation. Derivative cells were compared with parental cells to identify putative biomarkers associated with the radioresistant phenotype. To identify these biomarkers, complementary proteomic screening approaches were exploited encompassing two-dimensional gel electrophoresis in combination with mass spectrometry, liquid chromatography coupled with tandem mass spectrometry and quantitative proteomics using iTRAQ technology. RESULTS: A large number of potential biomarkers were identified, and several of these were confirmed using Western blot analysis. In particular, a decrease in the expression of the 26S proteasome was found in all radioresistant derivatives when compared with the respective parent cells. Decreased expression of this target was also found to be associated with radioresistant laryngeal tumors (P = .05) in a small pilot immunohistochemical study. CONCLUSIONS: These findings suggest that the 26S proteasome may provide a general predictive biomarker for radiotherapy outcome.

In this work, we developed the first study in Colombia to obtain and evaluate syngas compositions derived from asphaltenes gasification. These asphaltenes came from the implementation of a Deasphalting process to San Fernando crude oil, with the purpose of looking for technological options for their utilization. We performed the design, installation and commissioning of facilities for the gasification of asphaltenes at laboratory scale, it following an experimental methodology, performing nine tests and considering temperature and agent gasification quantity (oxygen) as independent variables. The syngas derived from gasification was analyzed by two chromatographic techniques, which reported the presence of refinery gases and sulfur. We evidenced a growth tendency of CO, H2 and sulfur composition and a decrease in CH4 and CO2 composition with temperature. The composition of the syngas was evaluated with different quantities of gasification agent (33%, 40% and 47% the amount of oxygen theoretically required for complete combustion) at each temperature levels operated. It was established that when using a 40% of gasification agent, you get greater average content of CO and H2, which are the interest gases in the gasification process.En este trabajo se desarrolló el primer estudio en el país de la obtención y evaluación de las composiciones del syngas a partir de la gasificación de asfaltenos provenientes de la aplicación del proceso de Desasfaltado al crudo San Fernando, con el objeto de evaluar opciones tecnológicas para su utilización. Para ello se realizó el diseño y puesta en marcha de un sistema de gasificación de asfaltenos a escala de laboratorio, donde se empleó una metodología experimental, realizando nueve pruebas y tomando como variables independientes la temperatura y el agente gasificante (oxígeno). El syngas obtenido de la gasificación fue analizado por dos técnicas de cromatografía, las cuales reportaron la presencia de gases de refinería y azufrados. De estos resultados experimentales se evidencia una tendencia de crecimiento en la composición del CO, H2 y azufrados, y una disminución en la composición del CH4 y CO2 con la temperatura. Se evaluó la composición del syngas con la variación del agente gasificante (33%, 40% y 47% del oxígeno teórico requerido en una combustión total) en cada uno de los niveles de temperatura operados y se estableció que al utilizar un 40% de agente gasificante, se obtienen en promedio los mejores resultados en las composiciones del CO y H4, siendo estos los gases de interés en el proceso de gasificación.Neste trabalho desenvolveuse o primeiro estudo no país da obtenção e avaliação das composições do syngas a partir da gaseificação de asfaltenos provenientes da aplicação do processo de Desasfaltado ao cru São Fernando, com o objeto de avaliar opções tecnológicas para a sua utilização. Para tal realizou-se o desenho e posta em marcha de um sistema de gaseificação de asfaltenos a escala de laboratório, onde se empregou uma metodologia experimental, realizando nove provas e tomando como variáveis independentes a temperatura e o agente gaseificante (oxigênio). O syngas obtido da gaseificação foi analisado por duas técnicas de cromatografia, as quais reportaram a presença de gases de refinaria e enxofrados. Destes resultados experimentais evidenciase uma tendência de crescimento na composição do CO, H2 e enxofrados, e uma diminuição na composição do CH4 e CO2 com a temperatura. Avaliouse a composição do syngas com a variação do agente gaseificante (33%, 40% e 47% do oxigênio teórico requerido em uma combustão total) em cada um dos níveis de temperatura operados e estabeleceuse que ao utilizar um 40% de agente gaseificante, obtém-se em média os melhores resultados nas composições do CO e H4, sendo estes os gases de interesse no processo de gaseificação.

MicroRNA (miR) expression is commonly dysregulated in many cancers, including breast. MiR-92 is one of six miRs encoded by the miR-17-92 cluster, one of the best-characterised oncogenic miR clusters. We examined expression of miR-92 in the breast epithelium and stroma during breast cancer progression. We also investigated the role of miR-92 in fibroblasts in vitro and showed that down-regulation in normal fibroblasts enhances the invasion of breast cancer epithelial cells.We used laser microdissection (LMD) to isolate epithelial cells from matched normal, DCIS and invasive tissue from 9 breast cancer patients and analysed miR-92 expression by qRT-PCR. Expression of ERβ1, a direct miR-92 target, was concurrently analysed for each case by immunohistochemistry. LMD was also used to isolate matched normal (NFs) and cancer-associated fibroblasts (CAFs) from 14 further cases. Effects of miR-92 inhibition in fibroblasts on epithelial cell invasion in vitro was examined using a Matrigel™ assay. miR-92 levels decreased in microdissected epithelial cells during breast cancer progression with highest levels in normal breast epithelium, decreasing in DCIS (p

Abstract This Critical Synthesis Package contains: (1) a Critical Analysis of the psychometric properties and application to health sciences education for the Scientific Misconduct Questionnaire-Revised (SMQ-R), and (2) a copy of the SMQ-R instrument developed by Marion Broome, PhD. The SMQ-R is a survey instrument that includes 68 closed-choice items and 12 open-ended questions designed to examine aspects of scientific misconduct as reported by research coordinators. The survey includes items assessing the following categories: demographics and work setting characteristics, perception of workplace environment, prevalence of scientific misconduct, awareness of scientific misconduct, reporting scientific misconduct, attitudes and beliefs, behavioral influences, and experiences with scientific misconduct in research. A validation study demonstrated validity for one of four subscales. Although this version has been used to assist in the development of similar tools for other audiences, further psychometric evaluation of the tool, or a modified version, would increase its utility in medical education.

Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART.In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4

The postmodernist re-evaluation of historical study has led to an awareness of the value of the moving image to the historian. Film can present us with glimpses of a past independent of discourse and its unique link with reality carries with it inevitable assumptions of authenticity. Yet the selection and manipulation of material by the filmmaker, and the dependence on causality or the establishment of ‘fact’, makes historical documentary as problematic as any other mode of historiography. National history is shaped as national identity, and, ultimately, acts of commemoration say as much about the present as the past.

Trypanosoma brucei spp. develop into mammalian-infectious metacyclic trypomastigotes inside tsetse salivary glands. Besides acquiring a variant surface glycoprotein (VSG) coat, little is known about the metacyclic expression of invariant surface antigens. Proteomic analyses of saliva from T. brucei-infected tsetse flies identified, in addition to VSG and Brucei Alanine-Rich Protein (BARP) peptides, a family of glycosylphosphatidylinositol (GPI)-anchored surface proteins herein named as Metacyclic Invariant Surface Proteins (MISP) because of its predominant expression on the surface of metacyclic trypomastigotes. The MISP family is encoded by five paralog genes with >80% protein identity, which are exclusively expressed by salivary gland stages of the parasite and peak in metacyclic stage, as shown by confocal microscopy and immuno-high resolution scanning electron microscopy. Crystallographic analysis of a MISP isoform (MISP360) and a high confidence model of BARP revealed a triple helical bundle architecture commonly found in other trypanosome surface proteins. Molecular modelling combined with live fluorescent microscopy suggests that MISP N-termini are potentially extended above the metacyclic VSG coat, and thus could be tested as a transmission-blocking vaccine target. However, vaccination with recombinant MISP360 isoform did not protect mice against a T. brucei infectious tsetse bite. Lastly, both CRISPR-Cas9-driven knock out and RNAi knock down of all MISP paralogues suggest they are not essential for parasite development in the tsetse vector. We suggest MISP may be relevant during trypanosome transmission or establishment in the vertebrate's skin.

The article offers information on suggested practices for managing online reputation for new graduates. Topics include the use importance of using the professional networking site, LinkedIn in promoting online reputation and self promotion and offers information on how to build a branded LinkedIn profile. Also presented are suggested keywords that can be used to increase chances of full-time employment.

Although ERs (oestrogen receptors) mediate breast tumour behaviour, the precise role of ERβ remains unclear. This is mainly because analyses have been complicated by the presence in breast tissue of three ERβ protein variants (ERβ1, ERβ2 and ERβ5) that derive from differential 3′ splicing. We have recently identified the first known mechanisms responsible for the differential control of isoform expression, involving regulation of translation via 5′-UTRs (untranslated regions). In the present study, we have uncovered further complexity involving the influence of multiple promoters and cross-talk between 5′- and 3′-UTRs. We demonstrate that full-length ERβ mRNAs are transcribed from three separate promoters; two promoters are well-established within the literature, whereas the third represents a novel finding. Each promoter produces transcripts with distinct 5′-UTRs. The differential 3′ splicing that produces transcripts coding for the ERβ isoforms also defines isoform-specific 3′-UTRs. We identified exact 3′-UTR sequences for each isoform, and have shown that alternative polyadenylation sites are used in a cell-type specific manner to produce transcripts with 3′-UTRs of different lengths. Critically, we show that 5′- and 3′-UTRs combine to specify the efficiencies with which individual transcripts are translated, with 3′-UTR length having a key influence. In addition, we demonstrate how 17β-oestradiol, a key driver of breast cancer development, affects the regulation of ERβ expression at both transcriptional and translational levels. [ABSTRACT FROM AUTHOR]

Post-transcriptional regulation, via 5′-UTRs (5′-untranslated regions), plays an important role in the control of eukaryotic gene expression. Recent analyses of the mammalian transcriptome suggest that most of the genes express multiple alternative 5′-UTRs and inappropriate expression of these regions has been shown to contribute to the development of carcinogenesis. The present review will focus on the complex post-transcriptional regulation of ERβ (oestrogen receptor β) expression. In particular, results from our laboratory suggest that the expression of alternative 5′-UTRs plays a key role in determining the level of ERβ protein expression. We have also shown that these alternative ERβ 5′-UTRs have a tissue-specific distribution and are differentially expressed between various normal and tumour tissues. Our results also suggest that alternative 5′-UTRs can influence downstream splicing events, thereby perhaps affecting ERβ function. These results suggest that alternative 5′-UTRs may have an overall influence on ER activity and this may have important implications for our understanding of cancer biology and treatment. [ABSTRACT FROM AUTHOR]

Thirteen patients who experienced problems with irritability and aggression following closed head injury CHI participated in a non blind, 8 week open trial of sertraline Hcl. Significant reduction in irritability and aggressive outbursts was observed. No significant changes were observed in depressive symptomatology. Results suggest that serotonergic agents may be useful in treating aggression and irritability after head injury. Further placebo controlled studies using serotonergic agents are indicated. [ABSTRACT FROM AUTHOR]

Describes the knowledge of physical therapists in the United States regarding battered women. Recognition by physical therapists of battered women in clinical settings; Need for education in the detection of signs of abuse; Initiation of physical therapy research in domestic violence identification and education.

Objective: To describe and explore relationships between social demographic factors and incidence or worsening of pressure ulcer scores among post-acute care (PAC) settings., Design: The authors present the incidence of new or worsening pressure ulcers stratified by self-reported patient race and sex. Investigators used logistic regression modeling to examine relative risk of developing new or worsened pressure ulcers by sociodemographic status and multiple regression modeling to estimate the relative contribution of facility-level factors on rates of new or worsening pressure ulcers., Setting: Three PAC settings: long-term care hospitals, inpatient rehabilitation facilities, and skilled nursing facilities., Participants: Medicare Part A residents and patients with complete stays in PAC facilities during 2015., Main Outcome Measure: The incidence of new or worsened pressure ulcers as calculated using the specifications of the National Quality Forum-endorsed pressure ulcer quality measure #0678., Main Results: The sample included 1,566,847 resident stays in 14,822 skilled nursing facilities, 478,292 patient stays in 1,132 inpatient rehabilitation facilities, and 121,834 patient stays in 397 long-term care hospitals. Significant differences in new or worsened pressure ulcer incidence rates by sociodemographic factors were found in all three settings. Black race, male sex, and advanced age were significant predictors of new or worsened ulcers, although controlling for health conditions reduced the racial disparity. The authors noted significant differences among facilities based on ownership type, urban/rural location, and sociodemographic makeup of facilities' residents/patients., Conclusions: There is evidence of disparities in the incidence of new or worsened pressure ulcers across PAC settings, suggesting publicly available quality data may be used to identify and ameliorate these problems.

Experts evaluating evidence of the occurrence and effects of abuse before, during, and after pregnancy have called for research on the context within which violence occurs. This study elicited postpartum mothers' perceptions of roles and conflict in their abusive intimate relationships. Thirty newly delivered African-, Anglo-, and Hispanic-American abused mothers consented to be interviewed. While ethnicity, cultural norms, and economic issues framed their descriptions, more than half (57%) described their relationships as not abusive even though they reported experiencing behaviors defined as abuse on standardized abuse screening instruments. Several women found ways to take care of themselves within the abusive relationship. The concerns that these diverse abused postpartum mothers expressed can serve as a foundation for the development of culturally sensitive interventions.