Automating the assignment of diagnosis codes to patient encounters using example-based and machine learning techniques.
Human classification of diagnoses is a labor intensive process that consumes significant resources. Most medical practices use specially trained medical coders to categorize diagnoses for billing and research purposes. We have developed an automated coding system designed to assign codes to clinical diagnoses. The system uses the notion of certainty to recommend subsequent processing. Codes with the highest certainty are generated by matching the diagnostic text to frequent examples in a database of 22 million manually coded entries. These code assignments are not subject to subsequent manual review. Codes at a lower certainty level are assigned by matching to previously infrequently coded examples. The least certain codes are generated by a naïve Bayes classifier. The latter two types of codes are subsequently manually reviewed. Standard information retrieval accuracy measurements of precision, recall and f-measure were used. Micro- and macro-averaged results were computed. RESULTS At least 48% of all EMR problem list entries at the Mayo Clinic can be automatically classified with macro-averaged 98.0% precision, 98.3% recall and an f-score of 98.2%. An additional 34% of the entries are classified with macro-averaged 90.1% precision, 95.6% recall and 93.1% f-score. The remaining 18% of the entries are classified with macro-averaged 58.5%. Over two thirds of all diagnoses are coded automatically with high accuracy. The system has been successfully implemented at the Mayo Clinic, which resulted in a reduction of staff engaged in manual coding from thirty-four coders to seven verifiers.


Measuring Compassion in Healthcare: A Comprehensive and Critical Review.
There is international concern about the lack of compassion in healthcare systems. A valid and reliable tool for measuring compassion in healthcare systems and educational institutions is required. This comprehensive and critical narrative synthesis identified and compared existing measures of compassionate care in clinical settings. PubMed, MEDLINE, CINAHL and PsycINFO databases and grey literature were searched to identify studies that report information on instruments that measure compassion or compassionate care in clinicians, nurses, healthcare students and patients. Textual qualitative descriptions of included studies were prepared. Instruments were evaluated using the Evaluating Measures of Patient-Reported Outcomes (EMPRO) tool. Nine studies containing information on the Compassion Competence Scale, a self-report instrument that measures compassion competence among Korean nurses; the Compassion Scale, the Compassionate Care Assessment Tool©, and the Schwartz Center Compassionate Care Scale™, patient-reported instruments that measure the importance of healthcare provider compassion; the Compassion Practices Scale, an instrument that measures organisational support for compassionate care; and instruments that measure compassion in educational institutions (instructional quality and a Geriatric Attitudes Scale), were included. Each instrument is associated with significant limitations. Most only measure certain aspects of compassion and lack evidence of adaptability to diverse practice settings. The EMPRO of self-report instruments revealed a lack of psychometric information on measurement reliability, validity, responsiveness and interpretability, respondent, administrative and scoring burden, and use in subpopulations. The findings of this narrative synthesis identified an unmet need for a psychometrically validated instrument that comprehensively measures the construct of compassion in healthcare settings.


Prolactin and proinflammatory cytokine expression at the fetomaternal interface in first trimester miscarriage.
To investigate the expression of prolactin (PRL), PRL-receptor (PRL-R), and the TH1 cytokines interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) at the maternofetal interface. Case-control study. University hospital unit of gynecology and obstetrics and research laboratories. Women undergoing suction curettage for spontaneous miscarriage (study group) and voluntary termination of pregnancy (control group) in the first trimester. Samples of decidua and villi collected and histologically examined at the time of suction curettage. Evaluation of all villous samples for karyotype with only euploid cases included; detection of transcripts of PRL, PRL-R, TNF-α, IFN-γ, and IL-2 by qualitative reverse-transcriptase-polymerase chain reaction (RT-PCR); investigation of pattern and site of expression by immunohistochemistry. In both groups, PRL-R and IFN-γ were broadly expressed. The expression of PRL was impaired or absent in the villi of the study group compared with controls. Expression of TNF-α was reduced, although not statistically significantly, in both decidual and villous samples of the study group. Immunohistochemical analysis showed the lack of IL-2 expression in decidual specimens of the control group versus the full expression shown in the study group. Our results highlight the correspondence between PRL expression and vital pregnancy and the involvement of the TH1 cytokines with different specific roles at the implantation site. Prolactin and IL-2 may reciprocally influence expression.


DNA methylation analysis on purified neurons and glia dissects age and Alzheimer's disease-specific changes in the human cortex.
Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer's disease (AD). However, strong variation of cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues. We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as CLU, SYNJ2 and NCOR2 or in glia RAI1,CXXC5 and INPP5A. Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as MCF2L, ANK1, MAP2, LRRC8B, STK32C and S100B. A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., HOXA3 or glia (ANK1). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes APP and ADAM17. Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.


Use of drug-eluting stents versus bare-metal stents in Korea: a cost-minimization analysis using population data.
The goal of this study was to perform an economic analysis of a primary stenting with drug-eluting stents (DES) compared with bare-metal stents (BMS) in patients with acute myocardial infarction (AMI) admitted through an emergency room (ER) visit in Korea using population-based data. We employed a cost-minimization method using a decision analytic model with a two-year time period. Model probabilities and costs were obtained from a published systematic review and population-based data from which a retrospective database analysis of the national reimbursement database of Health Insurance Review and Assessment covering 2006 through 2010 was performed. Uncertainty was evaluated using one-way sensitivity analyses and probabilistic sensitivity analyses. Among 513 979 cases with AMI during 2007 and 2008, 24 742 cases underwent stenting procedures and 20 320 patients admitted through an ER visit with primary stenting were identified in the base model. The transition probabilities of DES-to-DES, DES-to-BMS, DES-to-coronary artery bypass graft, and DES-to-balloon were 59.7%, 0.6%, 4.3%, and 35.3%, respectively, among these patients. The average two-year costs of DES and BMS in 2011 Korean won were 11 065 528 won/person and 9 647 647 won/person, respectively. DES resulted in higher costs than BMS by 1 417 882 won/person. The model was highly sensitive to the probability and costs of having no revascularization. Primary stenting with BMS for AMI with an ER visit was shown to be a cost-saving procedure compared with DES in Korea. Caution is needed when applying this finding to patients with a higher level of severity in health status.


Refining ensembles of predicted gene regulatory networks based on characteristic interaction sets.
Different ensemble voting approaches have been successfully applied for reverse-engineering of gene regulatory networks. They are based on the assumption that a good approximation of true network structure can be derived by considering the frequencies of individual interactions in a large number of predicted networks. Such approximations are typically superior in terms of prediction quality and robustness as compared to considering a single best scoring network only. Nevertheless, ensemble approaches only work well if the predicted gene regulatory networks are sufficiently similar to each other. If the topologies of predicted networks are considerably different, an ensemble of all networks obscures interesting individual characteristics. Instead, networks should be grouped according to local topological similarities and ensemble voting performed for each group separately. We argue that the presence of sets of co-occurring interactions is a suitable indicator for grouping predicted networks. A stepwise bottom-up procedure is proposed, where first mutual dependencies between pairs of interactions are derived from predicted networks. Pairs of co-occurring interactions are subsequently extended to derive characteristic interaction sets that distinguish groups of networks. Finally, ensemble voting is applied separately to the resulting topologically similar groups of networks to create distinct group-ensembles. Ensembles of topologically similar networks constitute distinct hypotheses about the reference network structure. Such group-ensembles are easier to interpret as their characteristic topology becomes clear and dependencies between interactions are known. The availability of distinct hypotheses facilitates the design of further experiments to distinguish between plausible network structures. The proposed procedure is a reasonable refinement step for non-deterministic reverse-engineering applications that produce a large number of candidate predictions for a gene regulatory network, e.g. due to probabilistic optimization or a cross-validation procedure.


Advances in digital CBT: where are we now, and where next?
Digital CBT refers to the use of digital tools, platforms or devices to deliver or enhance cognitive behavioural therapy assessment, formulation, treatment, training and supervision. The 'Advances in Digital CBT' special issue aimed to document examples of innovative digital CBT practice in this rapidly developing field. In this paper, we have briefly summarised and synthesised the advances demonstrated in this group of articles. These include developments in our understanding of mental health apps, the use of digital tools as an adjunct to therapy, the effectiveness of remotely delivered CBT in routine clinical practice, our understanding of user experiences and involvement, and in digital CBT research methods. We consider the extent of current knowledge in these areas and identify where gaps in evidence lie and how the field could be taken forward to address these. Lastly, we reflect on the broader digital CBT picture and offer our suggestions of six key directions for future research: using robust study designs to evaluate and optimise digital tools; translating and culturally adapting digital tools and practices; understanding and addressing digital exclusion; exploring, reporting and addressing possible negative effects; improving user involvement in design and evaluation; and addressing the implementation gap for digital tools. We suggest that further advances in these areas would be of particular benefit to the digital CBT field.


Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture.
Apoptosis occurs during the isolation and even short-term storage and culture of hepatocytes, and in the pathogenesis of liver diseases, such as hepatic failure and hepatitis. Therapeutic hypothermia has beneficial effects in experimental models of fulminant hepatic failure. The mechanisms underlying the potential benefits of mild hypothermia on the liver have not been well investigated. We examined the effects of temperature on soluble Fas ligand-induced apoptosis in freshly isolated mouse hepatocytes. Decreasing the culture temperature from 37 degrees C to 32 degrees C produced significant suppression of Fas-mediated apoptosis in cultured hepatocytes over a 12-h period. This observation was supported by cell morphology, flow cytometry analysis of cellular DNA content, and Annexin V-FITC staining of membrane phosphatidylserine translocation. In hypothermic conditions, Fas-mediated cytochrome c release from mitochondria of hepatocytes and the proximate downstream activation of caspase-9 were suppressed under mild hypothermic conditions. Effector caspase-7 activity was also inhibited at 32 degrees C. In contrast, the activation of initiator caspase-8 and cleavage of Bid were not affected after Fas-ligand stimulation. These findings suggest that mild hypothermia suppresses Fas-mediated apoptosis of liver cells by the partial inhibition of signaling events including mitochondrial damage, cytochrome c release, and subsequent apoptosome formation and effector caspase activation.


FEESST: a new bedside endoscopic test of the motor and sensory components of swallowing.
We here introduce an office or bedside method of evaluating both the motor and sensory components of swallowing, called fiberoptic endoscopic evaluation of swallowing with sensory testing (FEESST). FEESST combines the established endoscopic evaluation of swallowing with a technique that determines laryngopharyngeal (LP) sensory discrimination thresholds by endoscopically delivering air pulse stimuli to the mucosa innervated by the superior laryngeal nerve. Endoscopic assessment of LP sensory capacity followed by endoscopic visualization of deglutition was prospectively performed 148 times on 133 patients with dysphagia over an 8-month period. The patients had a variety of underlying diagnoses, with stroke and chronic neurologic disease predominating (n = 94). Subsequent to LP sensory testing, a complete dysphagia evaluation was conducted. Various food and liquid consistencies were dyed green, and attention was paid to their management throughout the pharyngeal stage of swallowing. Evidence of latent swallow initiation, pharyngeal pooling and/or residue, laryngeal penetration, laryngeal aspiration, and/or reflux was noted. Recommendations for therapeutic intervention were based on information obtained during the FEESST and often involved the employment of compensatory swallowing strategies, modification of the diet or its presentation, placement on non-oral feeding status, and/or referral to other related specialists. All patients successfully completed the examination. In 111 of the evaluations (75%), severe (>6.0 mm Hg air pulse pressure [APP]) unilateral or bilateral LP sensory deficits were found. With puree consistencies, 31% of evaluations with severe deficits, compared to 5% of evaluations with either normal sensitivity or moderate (4.0 to 6.0 mm Hg APP) LP sensory deficits, displayed aspiration (p < .001, chi2 test). With puree consistencies, 69% of evaluations with severe deficits, compared to 24% with normal or moderate deficits, displayed laryngeal penetration (p < .001, chi2 test). FEESST allows the clinician to obtain a comprehensive bedside assessment of swallowing that is performed as the initial swallowing evaluation for the patient with dysphagia.


Operator induced variability in left ventricular measurements with cardiovascular magnetic resonance is improved after training.
Accurate and reproducible measurement of left ventricular (LV) mass and function is a significant strength of Cardiovascular Magnetic Resonance (CMR). Reproducibility and accuracy of these measurements is usually reported between experienced operators. However, an increasing number of inexperienced operators are now training in CMR and are involved in post-processing analysis. The aim of the study was to assess the interobserver variability of the manual planimetry of LV contours amongst two experienced and six inexperienced operators before and after a two months training period. Ten healthy normal volunteers (5 men, mean age 34+/-14 years) comprised the study population. LV volumes, mass, and ejection fraction were manually evaluated using Argus software (Siemens Medical Solutions, Erlangen, Germany) for each subject, once by the two experienced and twice by the six inexperienced operators. The mean values of experienced operators were considered the reference values. The agreement between operators was evaluated by means of Bland-Altman analysis. Training involved standardized data acquisition, simulated off-line analysis and mentoring. The trainee operators demonstrated improvement in the measurement of all the parameters compared to the experienced operators. The mean ejection fraction variability improved from 7.2% before training to 3.7% after training (p=0.03). The parameter in which the trainees showed the least improvement was LV mass (from 7.7% to 6.7% after training). The basal slice selection and contour definition were the main sources of errors. An intensive two month training period significantly improved the accuracy of LV functional measurements. Adequate training of new CMR operators is of paramount importance in our aim to maintain the accuracy and high reproducibility of CMR in LV function analysis.


Curcuma longa (turmeric). Monograph.
Curcuma longa, a perennial herb, is a member of the Zingiberaceae (ginger) family. The plant grows to a height of three to five feet, and is cultivated extensively in Asia, India, China, and other countries with a tropical climate. It has oblong, pointed leaves and bears funnel-shaped yellow flowers. The rhizome is the portion of the plant used medicinally; it is usually boiled, cleaned, and dried, yielding a yellow powder. Dried Curcuma longa is the source of the spice turmeric, the ingredient that gives curry powder its characteristic yellow color. Turmeric is used extensively in foods for both its flavor and color. Turmeric has a long tradition of use in the Chinese and Ayurvedic systems of medicine, particularly as an anti-inflammatory agent, and for the treatment of flatulence, jaundice, menstrual difficulties, hematuria, hemorrhage, and colic. Turmeric can also be applied topically in poultices to relieve pain and inflammation. Current research has focused on turmeric's antioxidant, hepatoprotective, anti-inflammatory, anticarcinogenic, and antimicrobial properties, in addition to its use in cardiovascular disease and gastrointestinal disorders.


Looking at both sides of the invasion: patterns of colonization in the violet tunicate Botrylloides violaceus.
Understanding the ecological and evolutionary forces that shape the genetic structure of invasive populations and facilitate their expansion across a large spectrum of environments is critical for the prediction of spread and management of ongoing invasions. Here, we study the dynamics of postestablishment colonization in the colonial ascidian Botrylloides violaceus, a notorious marine invader. After its initial introduction from the Northwest Pacific, B. violaceus spread rapidly along the Pacific and Atlantic coasts of North America, impacting both aquaculture facilities and natural ecosystems. We compare genetic diversity and patterns of gene flow among 25 populations (N=679) from the West and East coasts, and evaluate the contribution of sexual vs. asexual reproduction to this species' invasion success using data from the mitochondrial cytochrome c oxidase subunit I (COI) gene and 13 nuclear polymorphic microsatellite loci. Our results reveal contrasting patterns of spread in the coastal waters of North America. While the West coast was colonized by noncontiguous (long-distance) dispersal, the East coast invasion appears to have occurred through contiguous (stepping-stone) spread. Molecular data further indicate that although dispersal in colonial ascidians is predominantly achieved through sexually produced propagules, aquaculture practices such as high-pressure washing can facilitate fragmentation and potentially exacerbate infestations and spread via asexual propagules. The results presented here suggest that caution should be used against the general assumption that all invasions, even within a single species, exhibit similar patterns of colonization, as highly contrasting dynamics may transpire in different invaded ranges.


Tendon functional extracellular matrix.
This article is one of a series, summarizing views expressed at the Orthopaedic Research Society New Frontiers in Tendon Research Conference. This particular article reviews the three workshops held under the "Functional Extracellular Matrix" stream. The workshops focused on the roles of the tendon extracellular matrix, such as performing the mechanical functions of tendon, creating the local cell environment, and providing cellular cues. Tendon is a complex network of matrix and cells, and its biological functions are influenced by widely varying extrinsic and intrinsic factors such as age, nutrition, exercise levels, and biomechanics. Consequently, tendon adapts dynamically during development, aging, and injury. The workshop discussions identified research directions associated with understanding cell-matrix interactions to be of prime importance for developing novel strategies to target tendon healing or repair.


In vitro biotransformation of an arsenosugar by mouse anaerobic cecal microflora and cecal tissue as examined using IC-ICP-MS and LC-ESI-MS/MS.
This investigation examined chemical and microbiological transformations of an arsenosugar by mouse cecum. To mimic the low oxygen environment in the mammalian gastrointestinal tract, reaction mixtures were incubated under anaerobic conditions. An arsenosugar extracted from ribbon kelp, 3-[5'-deoxy-5-(dimethylarsinoyl)-beta-ribofuranosyloxy]-2-hydroxypropanesulfonic acid, As392, was added to reaction mixtures that contained either cecal microflora or cecal tissue homogenate. These reaction mixtures were incubated at 0 or 37 degrees C for up to 48 hours to monitor biotransformation of the arsenosugar. Analysis of the reaction mixtures by IC-ICP-MS and LC-ESI-MS/MS indicated that the arsenosugar was converted primarily (95%) to its sulfur analog in less than 1 h at 37 degrees C. Conversion of As392 to its sulfur analog was much slower at 0 degrees C (21% conversion after 48 h). In reaction mixtures with cecal tissue homogenate, conversion of As392 to its sulfur analog was slower (77% conversion after 48 h at 37 degrees C). A good mass balance was found in all reaction mixtures between the amount of arsenosugar added and the sum of all detected arsenic-containing products. LC-ESI-MS/MS spectra of the sulfur-containing arsenosugar formed in all reaction mixtures containing cecal microflora compared well with those of a synthetic standard. These results suggest that the anaerobic microflora of the gastrointestinal tract can rapidly convert ingested arsenosugars to sulfur analogs. This biotransformation may affect the subsequent absorption, metabolism, and disposition of arsenic present in arsenosugars.


Omalizumab in patients with NSAIDs-exacerbated respiratory disease.
The association of acetylsalicylic acid (ASA) intolerance, chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, or chronic urticaria is known as NSAID-exacerbated respiratory disease (N-ERD). N-ERD patients often suffer from recurrent nasal polyps, severe asthma or also from urticaria. The aim of the present study was to retrospectively analyze the clinical efficacy of anti-IgE antibody treatment with omalizumab in patients with confirmed N-ERD. In the open trial with patients receiving verum patients with CRSwNP, confirmed N-ERD by oral or nasal ASA challenges, asthma or chronic urticaria were included in the study. Rhinological and pulmonary parameters were evaluated before and after 3, 6 and 9 months of therapy by rhinological questionnaires (CRS VAS-scores and RSOM-31), nasal polyp (NP)-, ACT-scores and FEV1 values. Urticaria activity was monitored clinically. N-ERD patients with aspirin desensitization were included as control group (follow-up 9 months). In the omalizumab group 16 patients were included (10 female, 6 male, mean age 51 yrs). CRS symptoms, RSOM-31- and NP-score decreased significantly following omalizumab therapy compared to baseline. The ACT-score (MV 16.5 to 20.6) and FEV1values (MV 80 % to 89 %) improved significantly. No urticaria symptoms were reported after 3 months. Oral prednisolone therapy was required in one case and a repeated nasal sinus surgery in an additional case due to progression of NP. In the control group (8 female, 8 male, mean age 45 yrs) the NP-score was unchanged. Omalizumab is an effective therapy option in N-ERD patients in a 9 month study period.


Summary and comparison of myeloid growth factor guidelines in patients receiving cancer chemotherapy.
Three different practice guidelines for the myeloid growth factors were recently published by major professional organizations. A comprehensive review and comparison of the guidelines using a priori structured content criteria and a previously validated quality appraisal tool are reported. The final recommendations from these guidelines are consistent for primary prophylaxis with the colony-stimulating factors (CSFs) when the risk of febrile neutropenia is in the range of 20% or greater. All 3 guidelines also recommend prophylactic use of myeloid growth factors in patients with important factors increasing individual risk of neutropenic complications. The recommendation that patients receiving regimens associated with lower risk should have CSF use guided by individual risk assessment is also consistent. Critical quality appraisal indicates that the scope, purpose, stakeholder involvement, and applicability of these guidelines differ little. The American Society of Clinical Oncology and European Organization for Research and Treatment of Cancer guidelines place more emphasis on comprehensive literature reviews, and the National Comprehensive Cancer Network guidelines are more current based on systematic annual updates. Presentation clarity also favors National Comprehensive Cancer Network guidelines, with recommendations generally presented as both text and algorithmic diagram.


Mechanisms of foot and ankle injuries in soccer.
Although player-to-player contact is a risk factor in the majority of soccer injuries, the mechanisms leading to these injuries have not been analyzed. To assess the relationships between foot/ankle injuries and foul play and tackle type, and to identify the position of the foot and ankle at the time of injury. Prospective cohort study. Team physicians prospectively recorded each injury in four world soccer competitions, and the videotaped incident leading to the injury was retrospectively analyzed. Of 76 foot and ankle injuries (52 contusions, 20 sprains, 4 fractures), direct contact occurred between players in 72. Significantly more injuries involved a tackle from the side and a lateral or medial tackle force. The injured limb was weightbearing in 41 and nonweightbearing in 35 of the incidents. Significantly more injuries resulted in time lost from soccer when the limb was weightbearing. The most common foot and ankle positions at the time of injury were pronated/neutral in the sagittal plane for weightbearing limbs, and plantar flexed/neutral in the coronal plane for nonweightbearing limbs. The most common foot and ankle rotations at the time of injury were external (23) and eversion (28). The majority of injuries were caused by tackles involving lateral or medial forces that created a corresponding eversion or inversion rotation of the foot or ankle. The weightbearing status of the injured limb was a significant risk factor.


A unified survey of Si-H and H-H bond activation catalysed by electron-deficient boranes.
The bond activation chemistry of B(C6F5)3 and related electron-deficient boranes is currently experiencing a renaissance due to the fascinating development of frustrated Lewis pairs (FLPs). B(C6F5)3's ability to catalytically activate Si-H bonds through η(1) coordination opened the door to several unique reduction processes. The ground-breaking finding that the same family of fully or partially fluorinated boron Lewis acids allows for the related H-H bond activation, either alone or as a component of an FLP, brought considerable momentum into the area of transition-metal-free hydrogenation and, likewise, hydrosilylation. This review comprehensively summarises synthetic methods involving borane-catalysed Si-H and H-H bond activation. Systems corresponding to an FLP-type situation are not covered. Aside from the broad manifold of C=X bond reductions and C=X/C-X defunctionalisations, dehydrogenative (oxidative) Si-H couplings are also included.


Enhancing workplace wellness efforts to reduce obesity: a qualitative study of low-wage workers in St Louis, Missouri, 2013-2014.
The objective of this study was to examine workplace determinants of obesity and participation in employer-sponsored wellness programs among low-wage workers. We conducted key informant interviews and focus groups with 2 partner organizations: a health care employer and a union representing retail workers. Interviews and focus groups discussed worksite factors that support or constrain healthy eating and physical activity and barriers that reduce participation in workplace wellness programs. Focus group discussions were transcribed and coded to identify main themes related to healthy eating, physical activity, and workplace factors that affect health. Although the union informants recognized the need for workplace wellness programs, very few programs were offered because informants did not know how to reach their widespread and diverse membership. Informants from the health care organization described various programs available to employees but noted several barriers to effective implementation. Workers discussed how their job characteristics contributed to their weight; irregular schedules, shift work, short breaks, physical job demands, and food options at work were among the most commonly discussed contributors to poor eating and exercise behaviors. Workers also described several general factors such as motivation, time, money, and conflicting responsibilities. The workplace offers unique opportunities for obesity interventions that go beyond traditional approaches. Our results suggest that modifying the physical and social work environment by using participatory or integrated health and safety approaches may improve eating and physical activity behaviors. However, more research is needed about the methods best suited to the needs of low-wage workers.


In-line and selective phase separation of medium-chain carboxylic acids using membrane electrolysis.
We had extracted n-caproate from bioreactor broth. Here, we introduced in-line membrane electrolysis that utilized a pH gradient between two chambers to transfer the product into undissociated n-caproic acid without chemical addition. Due to the low maximum solubility of this acid, selective phase separation occurred, allowing simple product separation into an oily liquid containing ∼90% n-caproic and n-caprylic acid.


Increased bacterial translocation in gluten-sensitive mice is independent of small intestinal paracellular permeability defect.
We investigated whether treatment with gliadin induces a paracellular permeability defect that enhances bacterial translocation to mesenteric lymph nodes (MLN) via resident dendritic cells (DC) expressing TLR-2 or 4 in HCD4/HLA-DQ8 transgenic mice. HLA-DQ8 transgenic mice were sensitized and subsequently gavaged with gliadin, in the presence or absence of AT1001 (paracellular permeability inhibitor). Non-sensitized mice were gavaged with indomethacin (permeability inducer) or rice cereal. CD11c and CD103 (DC markers) and TLR-2 and 4 were investigated by immunostaining. Intestinal permeability was assessed by paracellular flux of (51)Cr-EDTA in Ussing chambers. Bacterial translocation to MLN was performed by plate counting on aerobic and anaerobic conditions. In gliadin-treated mice, both (51)Cr-EDTA flux in jejunal mucosa and aerobic and anaerobic bacterial counts in MLN were increased (p < 0.05) compared to indomethacin-treated mice and controls. The inhibitor AT1001 normalized (51)Cr-EDTA flux, but had no effect on bacterial translocation in gliadin-treated mice. In addition, changes in mucosal DC marker distribution such as increased (p < 0.05) trans-epithelial CD103(+) cells and reduction (p < 0.05) of CD11c immunostaining were detected in gliadin-treated mice. Moreover, changes in DC markers and TLR-2 or 4 immunophenotypes were not associated. Pharmacological restoration of paracellular permeability was not sufficient to prevent bacterial translocation in gluten-sensitive mice. We hypothesize that transcellular mechanisms involving CD103(+)DC and CD11c(+)DC may explain in gluten-sensitive HCD4/HLA-DQ8 transgenic mice the sustained increased bacterial translocation observed in the absence of a significant inflammatory response.


Endoplasmic Reticulum Stress Predicts Clinical Response to Cyclosporine Treatment in Primary Membranous Nephropathy.
Little is known about the endoplasmic reticulum stress (ERS) marker glucose regulated protein 78 (GRP78) and calcineurin in the kidney in primary membranous nephropathy (PMN) and if they could predict post-cyclosporine treatment outcome. This is a retrospective study using a dataset of biopsy-confirmed PMN from Peking Union Medical College Hospital from 1996 to 2014. Seventy-six adult patients treated with cyclosporine as primary immunosuppression for at least 6 months were studied. Immunohistochemistry was used to detect GRP78 and calcineurin in the kidney. Serum calcineurin was assayed by ELISA. Patients were grouped into no-remission (NR, n = 17), partial remission (PR, n = 39), or complete remission (CR, n = 20) at the end of 6 months of treatment. There was no difference of initial dose of cyclosporine among NR, PR, and CR groups. Kidney calcineurin expression in PMN was significantly increased compared to that in controls (p < 0.0083). The glomerular GRP78 in NR PMN was higher than that in control, CR and PR patients (p < 0.0083). Kidney calcineurin expression and GRP78 expression was positively correlated. However, there were no differences in either serum calcineurin levels or kidney calcineurin expressions among NR, PR or CR groups. There was a negative correlation between serum calcineurin activity and whole kidney calcineurin expression (p = 0.034) or glomerular calcineurin expression (p = 0.007). Neither kidney calcineurin nor GRP78 expression was correlated with proteinuria. ERS marker GRP78 in the glomeruli but not serum or kidney calcineurin expression could be a useful marker in PMN to negatively predict the response to cyclosporine treatment at the sixth month.


Interleukin-6 deletion stimulates revascularization and new bone formation following ischemic osteonecrosis in a murine model.
Legg-Calvé-Perthes disease (LCPD) is a childhood form of ischemic osteonecrosis of the femoral head which can produce a permanent femoral head deformity and early osteoarthritis. The femoral head deformity results from increased bone resorption and decreased bone formation during repair and remodeling of the necrotic femoral head. A recent study showed that a pro-inflammatory cytokine, interleukin-6 (IL-6), is significantly elevated in the synovial fluid of patients with LCPD. We hypothesized that IL-6 elevation decreases bone formation during the repair process following ischemic osteonecrosis and that IL-6 depletion will increase new bone formation. To test this hypothesis, we surgically induced ischemic osteonecrosis in the wild-type (n = 29) and IL-6 knockout (KO) mice (n = 25). The animals were assessed at 48 h, 2 weeks and 4 weeks following the induction of ischemic osteonecrosis using histologic, histomorphometric and micro-CT methods. IL-6 immunohistochemistry showed high expression of IL-6 in the osteonecrotic side of the wild-type mice at 48 h and 4 weeks following ischemic osteonecrosis, but not in the IL-6 KO mice. We also confirmed an undetectable level of IL-6 expression in the primary osteoblasts of the IL-6 KO mice compared to the readily detectable level in the wild-type mice. Furthermore, we confirmed that IL-6 deletion did not affect the extent of bone necrosis in the IL-6 KO mice compared to the wild-type mice by performing histologic and terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) assessments at 2 weeks following the induction of ischemia. Both groups had the same extent of ischemic osteonecrosis and absence of repair at 2 weeks. At 4 weeks, the necrotic epiphyses showed a significant increase in the extent of revascularization in the IL-6 KO mice compared to the wild-type mice (p = 0.001). In addition, a significantly greater recovery of the hematopoietic bone marrow was observed in the osteonecrotic side of the IL-6 KO mice compared to the wild-type mice (p < 0.01). Vascular endothelial growth factor (VEGF) immunohistochemistry showed regionally increased staining in the areas of repair in the osteonecrosis side of IL-6 KO mice compared to the wild-type mice at 4 weeks following ischemic osteonecrosis. Micro-CT assessment of the wild-type mice at 4 weeks showed a significant decrease in the percent bone volume (p < 0.01) in the osteonecrotic side compared to the control side. In contrast, IL-6 KO mice showed significantly increased bone volume in the osteonecrotic side compared to the osteonecrotic side of WT mice (p < 0.001). No significant difference in the bone volume percentage was found between the control side of the wild-type and the IL-6 KO mice. Histomorphometric analysis at 4 weeks revealed increased osteoblast number/bone surface (p < 0.001), bone formation rate (BFR) (p = 0.0001), and mineral apposition rate (MAR) (p < 0.0001) in the osteonecrotic side of the IL-6 KO mice compared to the wild-type mice. The number of osteoclast/bone surface was also increased in the IL-6 KO mice compared to the wild-type mice (p < 0.0001). No significant difference was observed between the control side of the wild-type and IL-6 KO mice with regards to the number of osteoblast or osteoclast/bone surface, BFR, and MAR. We next obtained primary osteoblasts from IL-6 KO mice and showed they expressed a significantly higher level of RANKL/OPG than wild-type mice (p = 0.001) in hypoxia culture condition. Taken together, the findings indicate that IL-6 deletion stimulates revascularization and new bone formation following ischemic osteonecrosis. This study provides new evidence that therapeutic strategies to block IL-6 may be beneficial for bone healing following ischemic osteonecrosis.


Registration uncertainty quantification via low-dimensional characterization of geometric deformations.
This paper presents an efficient approach to quantifying image registration uncertainty based on a low-dimensional representation of geometric deformations. In contrast to previous methods, we develop a Bayesian diffeomorphic registration framework in a bandlimited space, rather than a high-dimensional image space. We show that a dense posterior distribution on deformation fields can be fully characterized by much fewer parameters, which dramatically reduces the computational complexity of model inferences. To further avoid heavy computation loads introduced by random sampling algorithms, we approximate a marginal posterior by using Laplace's method at the optimal solution of log-posterior distribution. Experimental results on both 2D synthetic data and real 3D brain magnetic resonance imaging (MRI) scans demonstrate that our method is significantly faster than the state-of-the-art diffeomorphic registration uncertainty quantification algorithms, while producing comparable results.


Vegetation feedbacks of nutrient addition lead to a weaker carbon sink in an ombrotrophic bog.
To study vegetation feedbacks of nutrient addition on carbon sequestration capacity, we investigated vegetation and ecosystem CO2 exchange at Mer Bleue Bog, Canada in plots that had been fertilized with nitrogen (N) or with N plus phosphorus (P) and potassium (K) for 7-12 years. Gross photosynthesis, ecosystem respiration, and net CO2 exchange were measured weekly during May-September 2011 using climate-controlled chambers. A substrate-induced respiration technique was used to determine the functional ability of the microbial community. The highest N and NPK additions were associated with 40% less net CO2 uptake than the control. In the NPK additions, a diminished C sink potential was due to a 20-30% increase in ecosystem respiration, while gross photosynthesis rates did not change as greater vascular plant biomass compensated for the decrease in Sphagnum mosses. In the highest N-only treatment, small reductions in gross photosynthesis and no change in ecosystem respiration led to the reduced C sink. Substrate-induced microbial respiration was significantly higher in all levels of NPK additions compared with control. The temperature sensitivity of respiration in the plots was lower with increasing cumulative N load, suggesting more labile sources of respired CO2 . The weaker C sink potential could be explained by changes in nutrient availability, higher woody : foliar ratio, moss loss, and enhanced decomposition. Stronger responses to NPK fertilization than to N-only fertilization for both shrub biomass production and decomposition suggest that the bog ecosystem is N-P/K colimited rather than N-limited. Negative effects of further N-only deposition were indicated by delayed spring CO2 uptake. In contrast to forests, increased wood formation and surface litter accumulation in bogs seem to reduce the C sink potential owing to the loss of peat-forming Sphagnum.


CT and MRI of hepatic abscess in patients with chronic granulomatous disease.
We describe the spectrum of radiologic appearances of hepatic abscesses in patients with chronic granulomatous disease (CGD), a hereditary immunodeficiency presenting in childhood that occurs at a rate of 1 in 200,000-250,000 live births and predisposes patients to infection with catalase-positive organisms. Hepatic abscesses in patients with CGD show an atypical radiologic appearance compared with sporadic hepatic abscesses, and they are characterized by homogeneous enhancement and multiseptal enhancement. In the appropriate clinical setting, the appearance of an enhancing mass should suggest the possibility of a CGD-related hepatic abscess.


School Day Energy Expenditure in Elementary School Children.
The purpose was to characterize energy expenditure (EE) during academic subjects and activities during an elementary school day. Children in 2nd to 4th grades (N = 33) wore the SenseWear Armband (SWA) for 5 school days to measure EE. Teachers' logs were compared with SWA data to extract information about EE throughout the day. Energy expenditure was also compared among grades. After controlling for body mass, grade level was not a significant predictor of average daily caloric expenditure, F (2, 17.58) = .29, P = .75, ω(2) = .05. When comparing activities throughout the day, relative rates of EE differed significantly, Wilks' F (7, 23) = 52.2, P = .00, ηp(2) = .94, with PE and recess having higher EE. When academic subjects were compared (math, science, language arts), relative rate of EE was also significantly different, Wilks' F (2, 30) = 4.31, P = .02, ηp(2) = .22. For the full sample, relative rate EE was higher in science than in language arts. The school day provides opportunity for EE for children. These data support the potential benefit of active instruction in language arts as a method to increase school day EE.


Unusual case of venous thrombosis.
A young woman developed a line-associated deep vein thrombosis (DVT), which was treated with low molecular weight heparin (dalteparin). 8 days later, the DVT had significantly extended-in spite of therapeutic heparin levels. A diagnosis of heparin-induced thrombocytopenia and thrombosis (HITT) was considered, but the platelet count had not dropped. Nevertheless, a HITT assay was carried out which came back positive, with a repeat assay confirming the result. Dalteparin was stopped and apixaban treatment started, with symptomatic recovery over the following days and weeks.


Multi-channel Bragg gratings based on nonuniform amplitude-only sampling.
A novel technique to implement a Bragg grating with multi-channel and high channel-count response based on nonuniform amplitude-only sampling is proposed. Thanks to the nonuniform sampling, a sophisticated phase modulation for the generation of multi-channel spectral response can be equivalently achieved, while the pitch of the Bragg grating is maintained uniform. The principle is presented. Two design examples with two Bragg gratings for multi-channel filtering and for multi-channel chromatic dispersion compensation are provided.


Use of precisely sculptured thin film (STF) substrates with generalized ellipsometry to determine spatial distribution of adsorbed fibronectin to nanostructured columnar topographies and effect on cell adhesion.
Sculptured thin film (STF) substrates consist of nanocolumns with precise orientation, intercolumnar spacing, and optical anisotropy, which can be used as model biomaterial substrates to study the effect of homogenous nanotopogrophies on the three-dimensional distribution of adsorbed proteins. Generalized ellipsometry was used to discriminate between the distributions of adsorbed FN either on top of or within the intercolumnar void spaces of STFs, afforded by the optical properties of these precisely crafted substrates. Generalized ellipsometry indicated that STFs with vertical nanocolumns enhanced total FN adsorption two-fold relative to flat control substrates and the FN adsorption studies demonstrate different STF characteristics influence the degree of FN immobilization both on top and within intercolumnar spaces, with increasing spacing and surface area enhancing total protein adsorption. Mouse fibroblasts or mouse mesenchymal stem cells were subsequently cultured on STFs, to investigate the effect of highly ordered and defined nanotopographies on cell adhesion, spreading, and proliferation. All STF nanotopographies investigated in the absence of adsorbed FN were found to significantly enhance cell adhesion relative to flat substrates; and the addition of FN to STFs was found to have cell-dependent effects on enhancing cell-material interactions. Furthermore, the amount of FN adsorbed to the STFs did not correlate with comparative enhancements of cell-material interactions, suggesting that nanotopography predominantly contributes to the biocompatibility of homogenous nanocolumnar surfaces. This is the first study to correlate precisely defined nanostructured features with protein distribution and cell-nanomaterial interactions. STFs demonstrate immense potential as biomaterial surfaces for applications in tissue engineering, drug delivery, and biosensing.


Cervical spondylotic myelopathy: patterns of neurological deficit and recovery after anterior cervical decompression.
We evaluated the specific pattern of pre- and postoperative neurological signs and symptoms and functional results in patients with cervical spondylotic myelopathy who underwent anterior decompressive operations. Additionally, we sought to determine which findings had predictive value for surgical outcome. We retrospectively reviewed the records of 76 patients with cervical spondylotic myelopathy caused by osteophytic ridge or intervertebral disc herniation who underwent anterior cervical decompression and fusion performed by one surgeon. The patients were evaluated postoperatively by office visits and/or telephone interviews. Outcome was assessed by objective neurological examination and scoring with multiple functional rating scales. The most common preoperative symptoms were deterioration of hand use (75%), upper extremity sensory complaints (82.9%), and gait difficulties (80.3%). In the upper extremities, preoperative weakness was most common in the hand intrinsic muscles (56.6%) and triceps (28.9%), and in the lower extremities, preoperative weakness was most common in the iliopsoas (38.8%) and quadriceps (26.3%). In the lower extremities, individual muscle groups had strength improvement rates from 79.1 to 88.1 %; somewhat higher rates, from 81.3 to 90.9%, were observed in the upper extremities. When evaluated by using the Cooper myelopathy scale, lower extremity functional improvement occurred in 46.7% of the patients and upper extremity functional improvement in 75.4%. Overall functional improvement, evaluated by using a modification of the Japanese Orthopedic Association Scale, was noted in 79.7% of the patients who had abnormal scores preoperatively. Strength improved at rates of approximately 80 to 90% in individual muscle groups after anterior cervical decompression. However, fewer than half of all patients experienced functional improvement in the lower extremities, a discrepancy that was probably caused by persistent spasticity rather than muscle weakness. Postoperative dysfunction in the upper extremities was caused by residual weakness as well as sensory loss. Recurrent symptomatic spondylosis at unoperated levels was calculated to occur at an incidence of 2% per year.


PASS2: an automated database of protein alignments organised as structural superfamilies.
The functional selection and three-dimensional structural constraints of proteins in nature often relates to the retention of significant sequence similarity between proteins of similar fold and function despite poor sequence identity. Organization of structure-based sequence alignments for distantly related proteins, provides a map of the conserved and critical regions of the protein universe that is useful for the analysis of folding principles, for the evolutionary unification of protein families and for maximizing the information return from experimental structure determination. The Protein Alignment organised as Structural Superfamily (PASS2) database represents continuously updated, structural alignments for evolutionary related, sequentially distant proteins. An automated and updated version of PASS2 is, in direct correspondence with SCOP 1.63, consisting of sequences having identity below 40% among themselves. Protein domains have been grouped into 628 multi-member superfamilies and 566 single member superfamilies. Structure-based sequence alignments for the superfamilies have been obtained using COMPARER, while initial equivalencies have been derived from a preliminary superposition using LSQMAN or STAMP 4.0. The final sequence alignments have been annotated for structural features using JOY4.0. The database is supplemented with sequence relatives belonging to different genomes, conserved spatially interacting and structural motifs, probabilistic hidden markov models of superfamilies based on the alignments and useful links to other databases. Probabilistic models and sensitive position specific profiles obtained from reliable superfamily alignments aid annotation of remote homologues and are useful tools in structural and functional genomics. PASS2 presents the phylogeny of its members both based on sequence and structural dissimilarities. Clustering of members allows us to understand diversification of the family members. The search engine has been improved for simpler browsing of the database. The database resolves alignments among the structural domains consisting of evolutionarily diverged set of sequences. Availability of reliable sequence alignments of distantly related proteins despite poor sequence identity and single-member superfamilies permit better sampling of structures in libraries for fold recognition of new sequences and for the understanding of protein structure-function relationships of individual superfamilies. PASS2 is accessible at http://www.ncbs.res.in/~faculty/mini/campass/pass2.html


Diffusion of residual monomer in polymer resins.
A simplified mathematical model which made use of Fick's laws of diffusion written in spherical coordinates was developed to describe the rate of diffusion of residual monomers from polymer resins. The properties of the monomer-polymer system which influenced the amount of monomer remaining in the polymer as a function of time were the diffusivity and solubility of the monomer in the polymer, and the particle size of the polymer resin. This model was used to analyze literature data on the diffusion of residual vinyl chloride monomer in polyvinyl chloride resins made by the suspension process. It was concluded that particle size of the resin was a significant parameter which should be taken advantage of in process equipment designed to remove residual monomer from PVC resins. The diffusivity of the monomer in the polymer was a function of the solubility of the monomer in the polymer. Monomer solubility can be determined from Henry's law. It was suggested that this model could be adapted to describe diffusion of monomers from any monomer-polymer system, and would be a useful approach to modeling the transport of nonreactive chemical additives from plastics.


The impact of acute and chronic graft-versus-host disease on normal and malignant B-lymphoid precursors after allogeneic stem cell transplantation for B-lineage acute lymphoblastic leukemia.
The development of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (SCT) for B-lineage acute lymphoblastic leukemia (B-ALL) is associated with a lower probability of leukemia relapse. However, mechanisms by which this GVHD-associated graft-versus-leukemia effect is exerted are poorly understood. In this study, we simultaneously traced the kinetics of normal donor-derived and leukemic recipient-derived B-lymphopoiesis comparing patients with or without GVHD. We used multiparameter flow-cytometry to quantify pro-B (CD19+CD10+CD34+), pre-B (CD19+CD10+CD34-) precursors and malignant lymphoblasts identified by leukemia-associated markers in 161 prospective marrow samples from 39 consecutive B-ALL patients after allogeneic SCT. Chimerism analysis was performed by quantitative real-time polymerase chain reaction of null alleles and insertion/deletion (indel) polymorphisms. Acute GVHD of grades II-IV is associated with a strong inhibition of normal donor-derived pro-B and pre-B precursors at days +30 and +60 post-SCT. Patients who develop chronic GVHD have lower percentages of marrow B-cell precursors during the first year after SCT. Likewise, recipient-derived leukemia B cells were absent at days +30 and +60 in patients with acute GVHD grades II-IV and were less likely to be detected in patients with chronic GVHD. Induction of GVHD as treatment of increasing amounts of leukemia cells causes inhibition of both normal and malignant B compartments even in the absence of steroid therapy. We conclude that the development of GVHD after allogeneic SCT is associated with a non-specific inhibition of B-lymphopoiesis.


Ion-induced molecular growth in clusters of small hydrocarbon chains.
We report on studies of collisions between 3 keV Ar+ projectile ions and neutral targets of isolated 1,3-butadiene (C4H6) molecules and cold, loosely bound clusters of these molecules. We identify molecular growth processes within the molecular clusters that appears to be driven by knockout processes and that could result in the formation of (aromatic) ring structures. These types of reactions are not unique to specific projectile ions and target molecules, but will occur whenever atoms or ions with suitable masses and kinetic energies collide with aggregates of matter, such as carbonaceous grains in the interstellar medium or aerosol nanoparticles in the atmosphere.


Tensile and shear mechanical properties of rotator cuff repair patches.
Augmentation of rotator cuff tears aims to strengthen the repair and reduce rerupture, yet studies still report high failure rates. This study determines key mechanical properties of rotator cuff repair patches, including establishing values for toughness and measuring the shear properties of repair patches and human rotator cuff tendons. We hypothesized that different repair grafts would (1) have varying material parameters, and (2) not all have mechanical properties similar to human rotator cuff tendons. Eight specimens each from the Restore, GraftJacket, Zimmer Collagen Repair, and SportsMesh repair patches were tested to failure in tension and for suture pullout. We assessed ultimate tensile strength, tensile (Young's) modulus, and failure strain. This study also established toughness values and shear data. Storage modulus was calculated using dynamic shear analysis for the patches and 18 samples of normal rotator cuff tendon. We report significant variability in important mechanical properties of repair patches, with the mechanical parameters of the patches diverting variously-and often significantly-from values for human rotator cuff tendon. The repair grafts tested all displayed significant variation in their mechanical properties and had at least some reduced parameters compared with human rotator cuff tendons. This study offers experimentally derived information of value to surgeons when selecting rotator cuff repair grafts. A better understanding of the mechanical suitability of repair grafts for supporting human rotator cuffs is needed if repair patches are to provide a solution for the clinical problem of failure of rotator cuff repairs.


One-dimensional photonic crystal optical limiter.
We explore a new passive optical limiter design using transverse modulation instability in the one-dimensional photonic crystal (PC) using x(3) materials. The performance of PC optical limiters strongly depends on the choice of the materials and the geometry and it improves as the duration of the incident pulse is extended. PC optical limiter performance is compared with that of a device made from homogeneous material. We identify three criteria for benchmarking the PC optical limiter. We also include a discussion of the advantages and disadvantages of PC optical limiters for real world applications.


Alpha-MSH regulates intergenic splicing of MC1R and TUBB3 in human melanocytes.
Alternative splicing enables higher eukaryotes to increase their repertoire of proteins derived from a restricted number of genes. However, the possibility that functional diversity may also be augmented by splicing between adjacent genes has been largely neglected. Here, we show that the human melanocortin 1 receptor (MC1R) gene, a critical component of the facultative skin pigmentation system, has a highly complex and inefficient poly(A) site which is instrumental in allowing intergenic splicing between this locus and its immediate downstream neighbour tubulin-β-III (TUBB3). These transcripts, which produce two distinct protein isoforms localizing to the plasma membrane and the endoplasmic reticulum, seem to be restricted to humans as no detectable chimeric mRNA could be found in MC1R expressing mouse melanocytes. Significantly, treatment with the MC1R agonist α-MSH or activation of the stress response kinase p38-MAPK, both key molecules associated with ultraviolet radiation dermal insult and subsequent skin tanning, result in a shift in expression from MC1R in favour of chimeric MC1R-TUBB3 isoforms in cultured melanocytes. We propose that these chimeric proteins serve to equip melanocytes with novel cellular phenotypes required as part of the pigmentation response.


Nonalcoholic steatohepatitis: the new frontier for liver transplantation.
Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease globally and nonalcoholic steatohepatitis is projected to become the most common indication for liver transplantation. The purpose of this review is to highlight key issues surrounding NAFLD as an indication for liver transplantation, including its increasing prevalence, outcomes related to liver transplantation, development of post liver transplant NAFLD and NAFLD in the liver donor pool. With the advent of direct-acting antiviral therapies, the proportion of patients on the liver transplant list or undergoing liver transplant for chronic hepatitis C infection is steadily decreasing. In contrast, the number transplants performed for NAFLD is increasing. By 2030, it is estimated that the incidence of decompensated cirrhosis and hepatocellular carcinoma will increase by 168 and 137%, respectively, and the number of deaths will increase by 178%. Liver transplantation cures cirrhosis but does not treat the underlying metabolic disease associated with NAFLD. Thus, strategies to control comorbidities in patients with NAFLD prior to transplant are needed to decrease waitlist mortality and the recurrence of NAFLD after liver transplant. NAFLD in the donor pool is also a growing concern. Strategies to minimize steatosis and expand the number of donors are critical to meet the growing demand for liver transplantation.


A quantitative description of dendritic conductances and its application to dendritic excitation in layer 5 pyramidal neurons.
Postsynaptic integration is a complex function of passive membrane properties and nonlinear activation of voltage-gated channels. Some cortical neurons express many voltage-gated channels, with each displaying heterogeneous dendritic conductance gradients. This complexity has hindered the construction of experimentally based mechanistic models of cortical neurons. Here we show that it is possible to overcome this obstacle. We recorded the membrane potential from the soma and apical dendrite of layer 5 (L5) pyramidal neurons of the rat somatosensory cortex. A combined experimental and numerical parameter peeling procedure was implemented to optimize a detailed ionic mechanism for the generation and propagation of dendritic spikes in neocortical L5 pyramidal neurons. In the optimized model, the density of voltage-gated Ca(2+) channels decreased linearly from the soma, and leveled at the distal apical dendrite. The density of the small-conductance Ca(2+)-activated channel decreased along the apical dendrite, whereas the density of the large-conductance Ca(2+)-gated K(+) channel was uniform throughout the apical dendrite. The model predicted an ionic mechanism for the generation of a dendritic spike, the interaction of this spike with the backpropagating action potential, the mechanism responsible for the ability of the proximal apical dendrite to control the coupling between the axon and the dendrite, and the generation of NMDA spikes in the distal apical tuft. Moreover, in addition to faithfully predicting many experimental results recorded from the apical dendrite of L5 pyramidal neurons, the model validates a new methodology for mechanistic modeling of neurons in the CNS.


Gut microbiome analysis by post: Evaluation of the optimal method to collect stool samples from infants within a national cohort study.
Understanding the role of the gut microbiome is pivotal for the future development of therapies for the prevention and management of autoimmune conditions such as type 1 diabetes when sampling during early life may be particularly important. The current standard methods for collecting gut microbiome samples for research is to extract fresh samples or freeze samples immediately after collection. This is often impractical however for population-based studies. The aim of this study was to determine the optimal method for the stabilization of stool bacterial DNA obtained from nappies and transported by post in ambient conditions to the research centre for a national birth cohort study. Four methods to collect samples were compared to immediate freezing of samples: 1) collecting faeces onto a swab which was immediately frozen, 2) using a commercially available kit with stabilisation solution (OMNIgene•GUT kit) at ambient temperature, 3) collecting onto a swab and 4) collecting into a sterile plain tube. Samples 3) and 4) were returned to the laboratory by post at ambient temperatures. A Bland Altman analysis was used to assess the agreement between the different methods and the frozen standard. Stool samples were collected by parents. For samples transported in ambient conditions, the limits of agreement showed that the OMNIgene•GUT kit had the narrowest 95% limits of agreement with the frozen standard as measured by the number of operational taxonomic units and the Shannon diversity index. All methods assessed for preserving samples collected from nappies at a distance and delivered by post for gut microbiome analysis showed variation / disagreement from the frozen standard. Overall, the OMNIgene•GUT kit preserved the samples with minimal changes compared to other methods and was practical for parents to use.


Biogenic porous silica and silicon sourced from Mexican Giant Horsetail (Equisetum myriochaetum) and their application as supports for enzyme immobilization.
Porous silica-based materials are attractive for biomedical applications due to their biocompatibility and biodegradable character. In addition, inorganic supports such as porous silicon are being developed due to integrated circuit chip compatibility and tunable properties leading to a wide range of multidisciplinary applications. In this contribution, biosilica extracted from a rarely studied plant material (Equisetum Myriochaetum), its conversion to silicon and the potential for both materials to be used as supports for enzyme immobilization are investigated. E. myriochaetum was subject to conventional acid digestion to extract biogenic silica with a% yield remarkably higher (up to 3 times) than for other Equisetum sp. (i.e. E. Arvense). The surface area of the isolated silica was ∼400 m2/g, suitable for biotechnological applications. Biogenic silicon was obtained by magnesiothermic reduction. The materials were characterized by SEM-EDX, XRD, FT-IR, ICP-OES, TGA and BET analysis and did not contain significant levels of class 1 heavy elements (such as Pb, Cd, Hg and As). Two commercial peroxidases, horseradish peroxidase (HRP) and Coprinus cinereus peroxidase (CiP) were immobilized onto the biogenic materials using three different functionalization routes: (A) carbodiimide, (B) amine + glutaraldehyde and (C) amine + carbodiimide. Although both biogenic silica and porous silicon could be used as supports differences in behaviour were observed for the two enzymes. For HRP, loading onto biogenic silica via the glutaraldehyde immobilization technique (route B) was most effective. The loading of CiP showed a much higher peroxidase activity onto porous silicon than silica functionalized by the carbodiimide method (route A). From the properties of the extracted materials obtained from Equisetum Myriochaetum and the immobilization results observed, these materials appear to be promising for industrial and biomedical applications.


Astaxanthin reduces oxidative stress, but not aortic damage in atherosclerotic rabbits.
We evaluated whether carotenoid astaxanthin (ASX) could prevent oxidative and atherosclerotic damage in rabbits. Rabbits received regular chow (control) or an atherogenic diet (1% cholesterol) alone or supplemented with 50, 100, and 500 mg% ASX for 60 days (n = 5-9 per group). The atherogenic diet increased the serum cholesterol levels and the ratio of the intima/media area in the aortic arch. These changes were not prevented by ASX. Atherosclerotic rabbits showed increased aortic lipid peroxidation and nonprotein thiol group (NPSH) levels along with inhibition of glutathione peroxidase (GSH-Px). All ASX doses attenuated lipid peroxidation and the increase in NPSH but not the inhibition of GSH-Px. Aortic superoxide dismutase (SOD), catalase (CAT), and thioredoxin reductase (TrxR) activities were enhanced in atherosclerotic rabbits. Although all ASX doses prevented the increase in SOD activity, only 100 and 500 mg% ASX prevented the increase in CAT activity. Furthermore, these same doses partially prevented the increase in TrxR activity, while 50 mg% ASX completely prevented the effects of the atherogenic diet on this enzyme. However, ASX did not attenuate the hypercholesterolemia or the atherosclerotic lesions caused by the atherogenic diet at any of the doses evaluated. Our results indicate that although ASX did not prevent hypercholesterolemia or atherosclerotic lesions, it could play a beneficial role by preventing lipid peroxidation and changes in antioxidant enzyme activities.


Spatially resolved quantum nano-optics of single photons using an electron microscope.
We report on the experimental demonstration of single-photon state generation and characterization in an electron microscope. In this aim we have used low intensity relativistic (energy between 60 and 100 keV) electrons beams focused in a ca. 1 nm probe to excite diamond nanoparticles. This triggered individual neutral nitrogen-vacancy centers to emit photons which could be gathered and sent to a Hanbury Brown-Twiss intensity interferometer. The detection of a dip in the correlation function at small time delays clearly demonstrates antibunching and thus the creation of nonclassical light states. Specifically, we have also demonstrated single-photon states detection. We unveil the mechanism behind quantum states generation in an electron microscope, and show that it clearly makes cathodoluminescence the nanometer scale analog of photoluminescence. By using an extremely small electron probe size and the ability to monitor its position with subnanometer resolution, we also show the possibility of measuring the quantum character of the emitted beam with deep subwavelength resolution.


Compartmentalized innervation of primate lateral rectus muscle.
Skeletal and craniofacial muscles are frequently composed of multiple neuromuscular compartments that serve different physiological functions. Evidence of possible regional selectivity in LR intramuscular innervation was sought in a study of the anatomic potential of lateral rectus (LR) muscle compartmentalization. Whole orbits of two humans and five macaque monkeys were serially sectioned at 10-microm thickness and stained with Masson trichrome. The abducens nerve (CN6) was traced anteriorly from the deep orbit as it branched to enter the LR and arborized among extraocular muscle (EOM) fibers. Three-dimensional reconstruction was performed in human and monkey orbits. Findings were in concordance in the monkey and human orbits. External to the LR global surface, CN6 bifurcated into approximately equal-sized trunks before entering the global layer. Subsequent arborization showed a systematic topography, entering a well-defined inferior zone 0.4 to 2.5 mm more posteriorly than branches entering the largely nonoverlapping superior zone. Zonal innervation remained segregated anteriorly and laterally within the LR. Consistent segregation of intramuscular CN6 arborization in humans and monkeys suggests functionally distinct superior and inferior zones for the LR. Since the LR is shaped as a broad vertical strap, segregated control of the two zones could activate them separately, potentially mediating previously unappreciated but substantial torsional and vertical oculorotary LR actions.


Characterization of bacteria causing acute otitis media using Raman microspectroscopy.
Otitis media (OM) is a prevalent disease that is the most frequent cause of physician visits and prescription of antibiotics for children. Current methods to diagnose OM and differentiate between the two main types of OM, acute otitis media (AOM) and otitis media with effusion (OME), rely on interpreting symptoms that may overlap between them. Since AOM requires antibiotic treatment and OME does not, there is a clinical need to distinguish between AOM and OME to determine whether antibiotic treatment is necessary and guide future prescriptions. We used an optical spectroscopy technique, Raman spectroscopy (RS), to identify and characterize the biochemical features of the three main pathogens that cause AOM in vitro. A Renishaw inVia confocal Raman microscope at 785 nm was used to spectrally investigate the Raman signatures of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Biochemical features or biomarkers important for classification of each bacterial species were identified and yielded a 97% accuracy of discrimination. To test the effectiveness of Raman-based bacterial classification in a clinical sample, human middle ear effusion (MEE) from patients affected by recurrent AOM was collected, cultured, and measured using RS. The probability of bacterial involvement from each of the three main bacteria that cause AOM was determined from the clinical MEE samples. These results suggest the potential of utilizing RS to aid in accurately diagnosing AOM and providing physicians with bacterial identification to guide treatment.


Exercise might be good for me, but I don't feel good about it: do automatic associations predict exercise behavior?
Models employed in exercise psychology highlight the role of reflective processes for explaining behavior change. However, as discussed in social cognition literature, information-processing models also consider automatic processes (dual-process models). To examine the relevance of automatic processing in exercise psychology, we used a priming task to assess the automatic evaluations of exercise stimuli in physically active sport and exercise majors (n = 32), physically active nonsport majors (n = 31), and inactive students (n = 31). Results showed that physically active students responded faster to positive words after exercise primes, whereas inactive students responded more rapidly to negative words. Priming task reaction times were successfully used to predict reported amounts of exercise in an ordinal regression model. Findings were obtained only with experiential items reflecting negative and positive consequences of exercise. The results illustrate the potential importance of dual-process models in exercise psychology.


Request a woman scientist: A database for diversifying the public face of science.
A global online register of women scientists, ready to share their science, was established by a cohort of volunteer women from the grassroots organization 500 Women Scientists on January 17th, 2018. In less than one year, the database "Request a Woman Scientist" comprised over 7,500 women from 174 scientific disciplines and 133 countries. The database is built upon a voluntary questionnaire regarding career stage, degree, scientific discipline, geographic location, and other self-identifying dimensions of representation. The information was visualized using the software platform Tableau, with dropdown menus that help query the database and output a list of names, email addresses, and websites. The biological sciences and women scientists from the United States of America were best represented in the database. A survey of women in the database conducted in November 2018 showed that of 1,278 respondents, 11% had been contacted since signing up for a variety of engagements, including media, peer review, panel participation, educational outreach, and professional/research connections. These engagements resulted in consultations for articles, video chats with students, and speaking opportunities at conferences and events. With improved functionality and marketing, outreach in the global south, and future translation in other languages, this database will further promote the profile and participation of women scientists across society, which in turn will benefit the advancement of science.


Automatic control during hand reaching at undetected two-dimensional target displacements.
1. The aim of this study was to demonstrate that goal-directed pointing movements, executed at normal speed to a small visual target, but without vision of the movement, do not rely on preprogrammed commands (open-loop process); by contrast these responses are under the control of a feedback loop, which compares the ongoing response and the goal (or its internal representation). When the location of this goal is changed at the onset of the movement, an automatic correction of the path occurs. Modification of the goal was obtained by presenting a target in the peripheral visual field that the subject had to look at and point at as quickly and accurately as possible. When the orienting ocular saccade reached its peak velocity, statistically corresponding to the hand movement onset, the target was suddenly shifted 10 degrees in a random direction. This perturbation was undetected by the subject because of the absence of perception during the saccade. For the compensation to occur, the initial orientation of the movement and also its extent had to be modified. The results revealed 1) a nearly complete compensation of the movement path and a 66- to 80-ms duration lengthening; 2) relatively short reaction times to the perturbations (from 145 to 174 ms, with effective reaction times even 40 ms shorter); 3) nearly identical spatiotemporal movement characteristics to the perturbations, regardless of whether vision of the hand was allowed, suggesting that corrections were subserved by the same mechanisms. 2. The spatiotemporal characteristics of these unconscious corrections were similar to those observed in the classical double-step experiments investigating the intentional modifications of ongoing movements and suggest that they might share some common low-level mechanisms. That is, they could rely on visuokinesthetic feedback loops, which compare the updated information provided by the eye at the end of the saccade and the proprioceptive information of the end point effector (the fingertip here); they could also rely on feed-forward processes detecting the discrepancy between an efference copy of the movement and the new goal; or they could rely on a combination of those two main processes.


Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage.
To test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH. We performed sequencing across 559 Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in United States-based and 1,381 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling. We identified 107 rare nonsynonymous variants in sporadic ICH, of which 2 missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the United States-based cohort. The minor allele of rs201716258 was also present in Scottish patients with ICH, and rs138269346 was observed in 2 ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with nonlobar ICH risk (p = 0.05), but not with lobar ICH (p = 0.08), while associations between rs201716258 and ICH subtypes were nonsignificant (p > 0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in European populations), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen). We identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.


Tackling obesity in adult primary care.
Obesity is a growing problem. In England in 2008, 66% of men and 57% of women had a BMI >25 kg/m2; within this 24% of men and 25% of women were obese with a BMI >30 kg/m2. Obesity is a major contributing cause of disease. The relative risk (RR) of diabetes in overweight men is 2.40 and in obese men 6.74 compared with men with a BMI in the normal range. The respective RR values in women are 3.92 and 12.41. There is a 40% increased risk of death from CVD for every 5 kg/m2 increase in BMI above 25 kg/m2. Obesity is also associated with a raised risk of: fertility problems, cirrhosis, osteoarthritis, pregnancy complications, obstructive sleep apnoea and asthma. Patients should be offered advice on dietary change and increasing physical activity which includes behavioural components. Encouragement to make small changes in a sustained way can make significant differences to energy balance. Physical activity should be of moderate intensity (increased heart rate and breathing but still able to converse). Drug treatment is a useful addition when lifestyle measures alone are not effective. Evidence is increasing for the effectiveness of bariatric surgery in treating obesity-related disease, particularly diabetes.


Pulmonary vascular anatomy & anatomical variants.
The vessels supplying the lungs include the pulmonary arteries, pulmonary veins, and bronchial arteries. The segmental and sub segmental pulmonary arteries parallel the bronchi and are named according to the bronchopulmonary segments they supply. There are however considerable anatomic variations, particularly in the upper lobes with variations in number or presence of accessory arteries from adjacent segments. The subsegmental pulmonary vein branches, run within interlobular septa and do not parallel the segmental or sub segmental pulmonary artery branches and bronchi. They converge to form right and left superior and inferior pulmonary veins which drain into the left atrium. Knowledge of normal and variant anatomy on cross-sectional and angiographic images is essential for accurate diagnosis of vascular pathology and aids planning of interventional procedures.


Thymic Function Associated With Cancer Development, Relapse, and Antitumor Immunity - A Mini-Review.
The thymus is the central lymphoid organ for T cell development, a cradle of T cells, and for central tolerance establishment, an educator of T cells, maintaining homeostatic cellular immunity. T cell immunity is critical to control cancer occurrence, relapse, and antitumor immunity. Evidence on how aberrant thymic function influences cancer remains largely insufficient, however, there has been recent progress. For example, the involuted thymus results in reduced output of naïve T cells and a restricted T cell receptor (TCR) repertoire, inducing immunosenescence and potentially dampening immune surveillance of neoplasia. In addition, the involuted thymus relatively enhances regulatory T (Treg) cell generation. This coupled with age-related accumulation of Treg cells in the periphery, potentially provides a supportive microenvironment for tumors to escape T cell-mediated antitumor responses. Furthermore, acute thymic involution from chemotherapy can create a tumor reservoir, resulting from an inflammatory microenvironment in the thymus, which is suitable for disseminated tumor cells to hide, survive chemotherapy, and become dormant. This may eventually result in cancer metastatic relapse. On the other hand, if thymic involution is wisely taken advantage of, it may be potentially beneficial to antitumor immunity, since the involuted thymus increases output of self-reactive T cells, which may recognize certain tumor-associated self-antigens and enhance antitumor immunity, as demonstrated through depletion of autoimmune regulator (AIRE) gene in the thymus. Herein, we briefly review recent research progression regarding how altered thymic function modifies T cell immunity against tumors.


Evidence for genetic transmission of thyroid peroxidase autoantibody epitopic "fingerprints".
Autoimmune thyroid disease is characterized by the tendency to cluster in families and by IgG class autoantibodies to antigens such as thyroid peroxidase (TPO). The epitopes recognized by polyclonal serum autoantibodies can be quantitatively fingerprinted using four recombinant human TPO autoantibodies (expressed as Fab) that define A and B domain epitopes in an immunodominant region. To determine whether these fingerprints are genetically transmitted, we analyzed fingerprints of 63 members of 7 multiplex Old Order Amish families and 17 individuals from 4 Hashimoto thyroiditis families. Inhibition of serum autoantibody binding to [125I]TPO by the recombinant Fab was used to assess recognition of the TPO immunodominant region (4 Fab combined) and recognition of domain A or B (individual Fab). Complex segregation analysis was performed using a unified model (POINTER). For the 4 Fab combined inhibition phenotype, the no transmission model was rejected (chi2(4) = 20.67; P < 0.0032), and the most parsimonious model includes a major gene effect. More importantly, evidence for genetic transmission was obtained for the phenotype defined by the ratio of inhibition by subdomain Fab B1:B2. Thus, for this ratio (reflecting recognition of the B domain), the no transmission model was rejected chi2(4) = 63.59; P < 0.000008). Moreover, the polygenic hypothesis could be rejected, but not the major locus hypothesis, suggesting that major genes might be involved in familial transmission of this trait. In conclusion, our findings suggest that autoantibody recognition of the TPO immunodominant region and the TPO B domain is genetically transmitted. These data may open the way to the identification by candidate analysis or positional cloning of at least one gene responsible for the development of Hashimoto's thyroiditis.


Experimental reconstruction of an abdominal wall defect with electrospun polycaprolactone-ureidopyrimidinone mesh conserves compliance yet may have insufficient strength.
Electrospun meshes mimic the extracellular matrix, which may improve their integration. We aimed to compare polycaprolactone (PCL) modified with ureidopyrimidinone (UPy) electrospun meshes with ultra-lightweight polypropylene (PP; Restorelle) reference textile meshes for in vivo compliance. We chose UPy-PCL because we have shown it does not compromise biomechanical properties of native tissue, and because it potentially can be bioactivated. We performed ex vivo biomechanical cyclic loading in wet conditions and in vivo overlay of full-thickness abdominal wall defects in rats and rabbits. Animals were sacrificed at 7, 42 and 54 days (rats; n = 6/group) and 30 and 90 days (rabbits; n = 3/group). Outcomes were herniation, mesh degradation and mesh dimensions, explant compliance and histology. High failure rates prompted us to provide additional material strength by increasing fiber diameter and mesh thickness, which was further tested in rabbits as a biomechanically more challenging model. Compliance was tested in animals without herniation. In both species, UPy-PCL-explants were as compliant as native tissue. In rats, PP-explants were stiffer. Contraction was similar in UPy-PCL and PP-explants. However, UPy-PCL-meshes macroscopically degraded from 30 days onwards, coinciding with herniation in up to half of animals. Increased fiber and mesh thickness did not improve outcome. Degradation of UPy-PCL is associated with an abundance of foreign body giant cells until UPy-PCL disappears. Abdominal wall reconstruction with electrospun UPy-PCL meshes failed in 50%. Degradation coincided with a transient vigorous foreign body reaction. Non-failing UPy-PCL-explants were as compliant as native tissue. Despite that, the high failure rate forces us to explore electrospun meshes based on other polymers.


Sodium hydrosulfide induces systemic thermotolerance to strawberry plants through transcriptional regulation of heat shock proteins and aquaporin.
Temperature extremes represent an important limiting factor to plant growth and productivity. The present study evaluated the effect of hydroponic pretreatment of strawberry (Fragaria x ananassa cv. 'Camarosa') roots with an H2S donor, sodium hydrosulfide (NaHS; 100 μM for 48 h), on the response of plants to acute heat shock treatment (42°C, 8 h). Heat stress-induced phenotypic damage was ameliorated in NaHS-pretreated plants, which managed to preserve higher maximum photochemical PSII quantum yields than stressed plants. Apparent mitigating effects of H2S pretreatment were registered regarding oxidative and nitrosative secondary stress, since malondialdehyde (MDA), H2O2 and nitric oxide (NO) were quantified in lower amounts than in heat-stressed plants. In addition, NaHS pretreatment preserved ascorbate/glutathione homeostasis, as evidenced by lower ASC and GSH pool redox disturbances and enhanced transcription of ASC (GDH) and GSH biosynthetic enzymes (GS, GCS), 8 h after heat stress imposition. Furthermore, NaHS root pretreatment resulted in induction of gene expression levels of an array of protective molecules, such as enzymatic antioxidants (cAPX, CAT, MnSOD, GR), heat shock proteins (HSP70, HSP80, HSP90) and aquaporins (PIP). Overall, we propose that H2S root pretreatment activates a coordinated network of heat shock defense-related pathways at a transcriptional level and systemically protects strawberry plants from heat shock-induced damage.


Ursolic Acid Inhibits Collective Cell Migration and Promotes JNK-Dependent Lysosomal Associated Cell Death in Glioblastoma Multiforme Cells.
Ursolic acid (UA) is a bioactive compound which has demonstrated therapeutic efficacy in a variety of cancer cell lines. UA activates various signalling pathways in Glioblastoma multiforme (GBM) and offers a promising starting point in drug discovery; however, understanding the relationship between cell death and migration has yet to be elucidated. UA induces a dose dependent cytotoxic response demonstrated by flow cytometry and biochemical cytotoxicity assays. Inhibitor and fluorescent probe studies demonstrate that UA induces a caspase independent, JNK dependent, mechanism of cell death. Migration studies established that UA inhibits GBM collective cell migration in a time dependent manner that is independent of the JNK signalling pathway. Cytotoxicity induced by UA results in the formation of acidic vesicle organelles (AVOs), speculating the activation of autophagy. However, inhibitor and spectrophotometric analysis demonstrated that autophagy was not responsible for the formation of the AVOs. Confocal microscopy and isosurface visualisation determined co-localisation of lysosomes with the previously identified AVOs, thus providing evidence that lysosomes are likely to be playing a role in UA induced cell death. Collectively, our data identify that UA rapidly induces a lysosomal associated mechanism of cell death in addition to UA acting as an inhibitor of GBM collective cell migration.


The competition-colonization trade-off is dead; long live the competition-colonization trade-off.
When applied at the individual patch level, the classic competition-colonization models of species coexistence assume that propagules of superior competitors can displace adults of inferior competitors (displacement competition). But if adults are invulnerable to displacement by propagules (as trees are to seeds), and propagules compete to replace adults that die for reasons independent of the outcome of juvenile competition (a lottery system), a competition-colonization trade-off alone is not able to produce coexistence. However, we show that coexistence is possible if patch density varies spatially, such that it becomes a niche axis. We also show how a dispersal-fecundity trade-off can partition variation in patch density. We discuss the application of these models to empirical systems. An important implication of communities coexisting via variation in patch density is that the amount of habitat loss necessarily interacts with the pattern of loss in affecting extinctions, invasions, and coexistence, in contrast to displacement competition models, for which the spatial pattern of loss is not important or is less important. Finally, with respect to mechanisms promoting coexistence, we suggest that trade-offs between different stages of colonization could be far more common in nature than a trade-off between competitive ability and colonization ability.


The possibility of left dominant activation of the sensorimotor cortex during lip protrusion in men.
Lip protrusion requires bilateral symmetrical movements of the facial muscles, but the laterality of the activated sensorimotor cortex corresponding to the area of the face activated during lip protrusion remains under discussion. In this study, blood-oxygenation-level-dependent (BOLD) responses in the sensorimotor cortex during non-verbal lip protrusion were evaluated in a 3T magnetic field in twenty healthy right-handed subjects. The results showed that the activated sensorimotor area on the left side was larger than that on the right side, and there was a statistically significant difference in the number of activated voxels between the left and right sensorimotor cortex in an individual study of the male group, although approximately symmetrical motor action potentials of facial muscles were recorded during lip protrusion. There was a statistically significant difference in interaction between the hemisphere (right and left) and sex (men and women) and multiple comparison test showed statistical significant differences between "men and right" and "men and left", and between "men and left" and "women and left". The peak value of the percent changes in BOLD signal responses on the left side was approximately twice as high as that on the right side in the males of the group, though the bilateral sensorimotor cortex was almost equally activated in the females in the group. In addition, the left primary sensory area related to the face area was significantly activated as a region where Male was more active than Female in a general linear model (multi-study, multisubject) analysis. This study revealed the possibility that the left sensorimotor cortex was more closely involved in non-verbal mouth movement in men, suggesting sex-related differences in sensorimotor cortex activation.


Diffusion tensor imaging detects treatment effects of FTY720 in experimental autoimmune encephalomyelitis mice.
Fingolimod (FTY720) is an orally available sphingosine-1-phosphate (S1P) receptor modulator reducing relapse frequency in patients with relapsing-remitting multiple sclerosis (RRMS). In addition to immunosuppression, neuronal protection by FTY720 has also been suggested, but remains controversial. Axial and radial diffusivities derived from in vivo diffusion tensor imaging (DTI) were employed as noninvasive biomarkers of axonal injury and demyelination to assess axonal protection by FTY720 in experimental autoimmune encephalomyelitis (EAE) mice. EAE was induced through active immunization of C57BL/6 mice using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55)). We evaluated both the prophylactic and therapeutic treatment effect of FTY720 at doses of 3 and 10 mg/kg on EAE mice by daily clinical scoring and end-point in vivo DTI. Prophylactic administration of FTY720 suppressed the disease onset and prevented axon and myelin damage when compared with EAE mice without treatment. Therapeutic treatment by FTY720 did not prevent EAE onset, but reduced disease severity, improving axial and radial diffusivity towards the control values without statistical significance. Consistent with previous findings, in vivo DTI-derived axial and radial diffusivity correlated with clinical scores in EAE mice. The results support the use of in vivo DTI as an effective outcome measure for preclinical drug development.


Identification of ubiquitin ligases required for skeletal muscle atrophy.
Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.


Defence in Depth Against Human Extinction: Prevention, Response, Resilience, and Why They All Matter.
We look at classifying extinction risks in three different ways, which affect how we can intervene to reduce risk. First, how does it start causing damage? Second, how does it reach the scale of a global catastrophe? Third, how does it reach everyone? In all of these three phases there is a defence layer that blocks most risks: First, we can prevent catastrophes from occurring. Second, we can respond to catastrophes before they reach a global scale. Third, humanity is resilient against extinction even in the face of global catastrophes. The largest probability of extinction is posed when all of these defences are weak, that is, by risks we are unlikely to prevent, unlikely to successfully respond to, and unlikely to be resilient against. We find that it's usually best to invest significantly into strengthening all three defence layers. We also suggest ways to do so tailored to the classes of risk we identify. Lastly, we discuss the importance of underlying risk factors - events or structural conditions that may weaken the defence layers even without posing a risk of immediate extinction themselves.