Real-Time Feedback on Mechanical Power Output: Facilitating Crew Rowers' Compliance With Prescribed Training Intensity.
Athletes require feedback in order to comply with prescribed training programs designed to optimize their performance. In rowing, current feedback parameters on intensity are inaccurate. Mechanical power output is a suitable objective measure for training intensity, but due to movement restrictions related to crew rowing, it is uncertain whether crew rowers are able to adjust their intensity based on power-output feedback. The authors examined whether rowers improve compliance with prescribed power-output targets when visual real-time feedback on power output is provided in addition to commonly used feedback. A total of 16 crew rowers rowed in 3 training sessions. During the first 2 sessions, they received commonly used feedback, followed by a session with additional power-output feedback. Targets were set by their coaches before the experiment. Compliance was operationalized as accuracy (absolute difference between target and delivered power output) and consistency (high- and low-frequency variations in delivered power output). Multilevel analyses indicated that accuracy and low-frequency variations improved by, respectively, 65% (P > .001) and 32% (P = .024) when additional feedback was provided. Compliance with power-output targets improved when crew rowers received additional feedback on power output. Two additional observations were made during the study that highlighted the relevance of power-output feedback for practice: There was a marked discrepancy between the prescribed targets and the actually delivered power output by the rowers, and coaches had difficulties perceiving improvements in rowers' compliance with power-output targets.


[Algorithm of inland water retrieval based on spectral matching].
This present paper presents a new inversion method of inland water based on spectral matching. First step of this method is using the known water surface measured hyperspectral and the absorption coefficient of each component, and obtaining backscattering coefficient of suspended matter with bio-optical model. The second step is calculation of the spectral reflectance of water bodies based on bio-optical model, through the cross-combination of inherent optical property of water components (chlorophyll, suspended matter, yellow substance), in order to create a look-up table of Rrs that corresponds to all combinations of water component. The third step is changing the look-up table data into MODIS spectral data using MODIS channel response function. The final study examined the applicability of the look-up table using the Hyperspectral and MODIS bands spectra, based on the minimum distance principle, to find the best matched spectra, thus it has found corresponding concentrations of three components. The average relative error of chlorophyll and suspended matter is 38.6% and 28% respectively. Optical properties of water components interfere with each other because of the complexity of inland water bodies, resulting in difficulty to extract the feature band for statistical model, and while it is hard for bio-optical model inversion method to solve the unstable problem of special inherent optical property with the seasons and regional issues, the method of this paper would have the advantages of bio-optical model, while eliminating instability of special inherent optical property, so it is a good approach to inland water retrieval.


Replacing β-mercaptoethanol in RNA extractions.
RNA extractions are potentially compromised in terms of both yield and quality by ribonucleases (RNases). The pungent and toxic reducing agent β-mercaptoethanol (β-ME), therefore, is commonly added to the biospecimen's lysis buffer to aid in RNase deactivation. Using different tissue types (liver tissue, kidney tissue, and cell pellets), extraction kits (RNeasy Mini Kit, Illustra RNA Spin Mini Kit, and PureLink Mini Kit), RNA quality assays (RNA integrity numbers [RINs] and quantitative real-time polymerase chain reaction [qRT-PCR]), yield assessments, and in vitro functional RNase assays (RNaseAlert Kit), we demonstrate that β-ME should be replaced by the less toxic dithiothreitol (DTT) alternative.


Prospective audit of adverse reactions occurring in 459 primary antibody-deficient patients receiving intravenous immunoglobulin.
Intravenous immunoglobulin (IVIG) is used as the standard replacement therapy for patients with primary antibody deficiencies. A previous study of adverse reactions in patients self-infusing at home over 1 year showed an overall reaction rate of 0.7%. A larger prospective study is reported here, involving a greater number of immunology centres and including children and adults who received infusions from medical or nursing staff as well as those self-infusing. Four hundred and fifty-nine patients were entered into this study and 13 508 infusions were given. The study showed that no severe reactions occurred and the reaction rate was low at 0.8%. This figure could have been lower, 0.5%, if predisposing factors responsible for some reactions had been considered before infusion. In conclusion, the study shows the importance of ongoing training for patients and staff to recognize the predisposing factors to prevent avoidable reactions. Because none of these reactions were graded as severe, the present guidance to prescribe self-injectable adrenaline for patients infusing outside hospital should be reviewed.


Relationships in pain: the experience of relationships to people living with chronic pain in rural areas.
The aim of the study was to develop new understanding of the lived experience of relationships for rural people living with chronic pain. Rural residents have greater difficulty accessing health services and providers. This is especially important to those living with chronic pain who often find themselves isolated from professionals who could potentially offer support. A phenomenological study with seven participants who had experienced chronic non-malignant pain for 2-29 years (Mean = 13) was recruited via a number of approaches and data analyzed using van Manen's framework. The themes that emerged from the analysis were as follows: pain as silence; privacy as a way of protection; no place out here to get support; and dealing with health-care professionals who do not understand. Lack of specialist services and support in rural areas means people with chronic pain are placed in even more vulnerable situations. Nurses remain at the forefront of service delivery in rural areas; hence, their role in management of people with chronic pain is vital in supporting them to maintain meaningful contact with others, including health professionals.


Efficacy of anti-VEGF and laser photocoagulation in the treatment of visual impairment due to diabetic macular edema: a systematic review and network meta-analysis.
Compare the efficacy of ranibizumab, aflibercept, laser, and sham in the first-line treatment of diabetic macular edema (DME) to inform technology assessments such as those conducted by the UK National Institute for Health and Care Excellence (NICE). MEDLINE, Embase, Cochrane Library, congress abstracts, ClinicalTrials.gov registry and Novartis data on file. Studies reporting 6- or 12-month results of randomized controlled trials (RCTs) evaluating at least two of ranibizumab 0.5 mg pro re nata, aflibercept 2.0 mg bi-monthly, laser photocoagulation or sham. Study quality was assessed based on likelihood of bias in selection, attrition, detection and performance. Improvement in best-corrected visual acuity (BCVA) measured as the proportion of patients gaining ≥10 letters on the Early Treatment Diabetic Retinopathy Study scale. The outcome was chosen following acceptance by NICE of a Markov model with 10-letter health states in the assessment of ranibizumab for DME. Bayesian network meta-analyses with fixed and random effects adjusted for differences in baseline BCVA or central retinal thickness. The analysis included 1,978 patients from eight RCTs. The random effects model adjusting for baseline BCVA was the best model based on total residual. The efficacy of ranibizumab was numerically, but not statistically, superior to aflibercept (odds ratio [OR] 1.59; 95% credible interval [CrI], 0.61-5.37). Ranibizumab and aflibercept were statistically superior to laser monotherapy with ORs of 5.50 (2.73-13.16) and 3.45 (1.62-6.84) respectively. The probability that ranibizumab is the most efficacious treatment was 73% compared with 14% for aflibercept, 12% for ranibizumab plus laser, and 0% for laser. Three of the eight RCTs included are not yet published. The models did not adjust for all potential effect modifiers. Ranibizumab was non-significantly superior to aflibercept and both anti-VEGF therapies had statistically superior efficacy to laser.


Late and very late stent thrombosis following drug-eluting stent implantation in unprotected left main coronary artery: a multicentre registry.
To evaluate the occurrence of late and very late stent thrombosis (ST) following elective drug-eluting stent (DES) implantation in unprotected left main coronary artery (LMCA) stenosis in a large multicentre registry. All 731 consecutive patients who had sirolimus- or paclitaxel-eluting stent electively implanted in de novo lesions on unprotected LMCA in five centres were included. ST was defined according to Academic Research Consortium definitions. Four (0.5%) patients had a definite ST: three early (two acute and one subacute) and one late ST, no cases of very late definite ST were recorded. All patients survived from the event. Three patients had a probable ST. Therefore, 7/731 (0.95%) patients had a definite or a probable ST and all were on dual antiplatelet therapy at the time of the event. Possible (eight late and 12 very late) ST occurred in 20 (2.7%) patients. At 29.5 ± 13.7 months follow-up, a total of 45 (6.2%) patients had died; 31 (4.2%) of cardiac death. Ninety five (12.9%) patients had a target-vessel and 76 (10.4%) a target-lesion revascularization. Angiographic follow-up was performed in 548 patients (75%): restenosis occurred in 77 (14.1%) patients. Elective treatment of LMCA stenosis with DES appears safe with a 0.9% incidence of definite and probable ST at 29.5 ± 13.7 months.


Raman scattering study of InAs nanowires under high pressure.
The pressure-dependent phonon modes of InAs nanowires have been investigated by Raman spectroscopy under high pressure up to ∼58 GPa. X-ray diffraction measurements show that InAs nanowires at 21 GPa exhibit a phase transition from a wurtzite to an orthorhombic crystal structure, with a corresponding drastic change in the first-order Raman spectra. In the low-pressure regime, a linear increase in phonon frequencies is observed, whereas splitting between longitudinal and transversal optical phonon modes decreases as a function of applied pressure. The calculated mode Grüneisen parameters and Born's transverse effective charge indicate that the wurtzite InAs nanowires exhibit a more covalent nature under compression.


Can Population Modelling Principles be Used to Identify Key PBPK Parameters for Paediatric Clearance Predictions? An Innovative Application of Optimal Design Theory.
Physiologically-based pharmacokinetic (PBPK) models are essential in drug development, but require parameters that are not always obtainable. We developed a methodology to investigate the feasibility and requirements for precise and accurate estimation of PBPK parameters using population modelling of clinical data and illustrate this for two key PBPK parameters for hepatic metabolic clearance, namely whole liver unbound intrinsic clearance (CLint,u,WL) and hepatic blood flow (Qh) in children. First, structural identifiability was enabled through re-parametrization and the definition of essential trial design components. Subsequently, requirements for the trial components to yield precise estimation of the PBPK parameters and their inter-individual variability were established using a novel application of population optimal design theory. Finally, the performance of the proposed trial design was assessed using stochastic simulation and estimation. Precise estimation of CLint,u,WL and Qh and their inter-individual variability was found to require a trial with two drugs, of which one has an extraction ratio (ER) ≤ 0.27 and the other has an ER ≥ 0.93. The proposed clinical trial design was found to lead to precise and accurate parameter estimates and was robust to parameter uncertainty. The proposed framework can be applied to other PBPK parameters and facilitate the development of PBPK models.


A chemotaxis-based explanation of spheroid formation in 3D cultures of breast cancer cells.
Three-dimensional cultures of cells are gaining popularity as an in vitro improvement over 2D Petri dishes. In many such experiments, cells have been found to organize in aggregates. We present new results of three-dimensional in vitro cultures of breast cancer cells exhibiting patterns. Understanding their formation is of particular interest in the context of cancer since metastases have been shown to be created by cells moving in clusters. In this paper, we propose that the main mechanism which leads to the emergence of patterns is chemotaxis, i.e., oriented movement of cells towards high concentration zones of a signal emitted by the cells themselves. Studying a Keller-Segel PDE system to model chemotactical auto-organization of cells, we prove that it admits Turing unstable solutions under a time-dependent condition. This result is illustrated by two-dimensional simulations of the model showing spheroidal patterns. They are qualitatively compared to the biological results and their variability is discussed both theoretically and numerically.


Possible role of cortisol and dehydroepiandrosterone in human development and psychopathology.
The characteristics of adrenal hormone secretion change markedly during infancy. Disturbances in basal levels may precipitate psychological dysfunction and are associated with psychopathology in young people. To relate three aspects of behavioural endocrinology: developmental changes in cortisol and dehydroepiandrosterone (DHEA), the role of these hormones in the psychopathology of young people, and the action of these steroids in the brain. A selective review from the human developmental, psychiatric and neurosciences literature. There are developmentally mediated changes in brain sensitivity following excess exposure to cortisol. This may result in impairments of mental and behavioural function. DHEA and gonadal steroids may modulate the actions of cortisol. Steroid hormones contribute to shaping behavioural function during early development and act as risk factors for psychopathology.


An SNMP-based solution to enable remote ISO/IEEE 11073 technical management.
This paper presents the design and implementation of an architecture based on the integration of simple network management protocol version 3 (SNMPv3) and the standard ISO/IEEE 11073 (X73) to manage technical information in home-based telemonitoring scenarios. This architecture includes the development of an SNMPv3-proxyX73 agent which comprises a management information base (MIB) module adapted to X73. In the proposed scenario, medical devices (MDs) send information to a concentrator device [designated as compute engine (CE)] using the X73 standard. This information together with extra information collected in the CE is stored in the developed MIB. Finally, the information collected is available for remote access via SNMP connection. Moreover, alarms and events can be configured by an external manager in order to provide warnings of irregularities in the MDs' technical performance evaluation. This proposed SNMPv3 agent provides a solution to integrate and unify technical device management in home-based telemonitoring scenarios fully adapted to X73.


Retroviral DNA integration: viral and cellular determinants of target-site selection.
Retroviruses differ in their preferences for sites for viral DNA integration in the chromosomes of infected cells. Human immunodeficiency virus (HIV) integrates preferentially within active transcription units, whereas murine leukemia virus (MLV) integrates preferentially near transcription start sites and CpG islands. We investigated the viral determinants of integration-site selection using HIV chimeras with MLV genes substituted for their HIV counterparts. We found that transferring the MLV integrase (IN) coding region into HIV (to make HIVmIN) caused the hybrid to integrate with a specificity close to that of MLV. Addition of MLV gag (to make HIVmGagmIN) further increased the similarity of target-site selection to that of MLV. A chimeric virus with MLV Gag only (HIVmGag) displayed targeting preferences different from that of both HIV and MLV, further implicating Gag proteins in targeting as well as IN. We also report a genome-wide analysis indicating that MLV, but not HIV, favors integration near DNase I-hypersensitive sites (i.e., +/- 1 kb), and that HIVmIN and HIVmGagmIN also favored integration near these features. These findings reveal that IN is the principal viral determinant of integration specificity; they also reveal a new role for Gag-derived proteins, and strengthen models for integration targeting based on tethering of viral IN proteins to host proteins.


The development of duodenal microadenomas in FAP patients: the human correlate of the Min mouse.
The morphological changes associated with the adenoma-carcinoma sequence are well documented in the colorectum. Small intestinal carcinogenesis is thought to progress through a similar adenoma-to-carcinoma pathway, but there is a relative dearth of studies examining the associated morphological changes. The best-known mouse model of intestinal neoplasia, the multiple intestinal neoplasia (Min) mouse, has been criticized as a genetic model of intestinal neoplasia, as the majority of its tumours occur in the small intestine. We examined pancreatico-duodenal resection specimens from seven familial adenomatous polyposis (FAP) patients. Serial sections of these were stained with haematoxylin and eosin for beta-catenin and its downstream target CD44, for BMPR1a, lysozyme, carbonic anhydrase II, and with MIB-1. Individual dysplastic crypts were isolated and mutations in the FAP (APC) gene compared between the top and bottom of the crypt. We found that: (a) duodenal microadenomas are extremely common in FAP patients; (b) these grow in the core of duodenal villi, forming lesions similar to those described in the Min mouse; (c) many lesions arise as monocryptal adenomas and grow by a process of crypt fission and branching; (d) migrating adenomatous cells lose their dysplastic phenotype as they migrate up the crypt villous axis; and (e) Paneth cells lose positional information. (a) the morphological similarity of adenomas in the Min mouse and human suggest the Min mouse is a good model of FAP; (b) duodenal adenomas in FAP originate in monocryptal adenomas and follow the 'bottom-up' rather than the 'top-down' model of morphogenesis; (c) early microadenomas show evidence of cellular differentiation; (d) defects in the positioning of Paneth cells suggests disruption of the EphB2:EphB3 receptor system.


Enhancing Resistance of Silk Fibroin Material to Enzymatic Degradation by Cross-Linking Both Crystalline and Amorphous Domains.
Silk fibroin (SF) membranes are finding widespread use as biomaterial scaffolds in a range of tissue engineering applications. The control over SF scaffold degradation kinetics is usually driven by the proportion of SF crystalline domains in the formulation, but membranes with a high β-sheet content are brittle and still contain amorphous domains, which are highly susceptible to enzymatic degradation. In this work, photo-cross-linking of SF using a ruthenium-based method, and with the addition of glycerol, was used to generate robust and flexible SF membranes for long-term tissue engineering applications requiring slow degradation of the scaffolds. The resulting mechanical properties, protein secondary structure, and degradation rate were investigated. In addition, the cytocompatibility and versatility of porous micropatterning of SF films were assessed. The photo-cross-linking reduced the enzymatic degradation of SF in vitro without interfering with the β-sheet content of the SF material, while adding glycerol to the composition grants flexibility to the membranes. By combining these methods, the membrane resistance to protease degradation was significantly enhanced compared to either method alone, and the SF mechanical properties were not impaired. We hypothesize that photo-cross-linking protects the SF amorphous regions from enzymatic degradation and complements the natural protection offered by β-sheets in the crystalline region. Overall, this approach presents broad utility in tissue engineering applications that require a long-term degradation profile and mechanical support.


Solar heating and cooling.
Data from a wide variety of sources reflect geographical, baccalaureate, and social class variations in the production of scientific and scholarly doctorates in the United States. To a significant extent, these variations are associated with the kind of religiousethnic group from which such persons come. Roman Catholics are extremely low producers of scientists and scholars, but fundamentalistic and traditional Protestant faiths (southern white Protestants, Lutherans) are also low producers. Liberal Protestant sects, such as Unitarians and Quakers, and secularized Jewish groups are highly productive, and less liberal faiths are moderately productive. Variations in productivity are reflective of differences in beliefs and values. Highly productive groups share a certain set of values, unproductive groups hold the antithesis of these, and those groups intermediate in productivity possess a mixed blend. Tentatively, the common beliefs and value systems of high producers seem to include naturalism; intrinsic valuation of learning and the individual quest for truth; emphasis on human dignity, goodness, and competence; a life pathway of serious dedication, of service to humanity, of continual striving; humanistic equalitarianism; a pragmatic search for better ways of doing things unfettered by traditional restraints; and a focus on the relatively immediate, foreseeable future which can be affected by personal effort. Historically, the scientists (or their immediate ancestors) have broken away from the traditional orthodoxy, broadened certain values, and retained others. For example, the children of Jewish immigrants to the United States departed from the traditional ritualism of the eastern European Jewish community, broadened the old value of scriptural erudition to include secular learning of all kinds, but maintained emphasis upon personal striving and social responsibility. Also, it appears that eminent scientists often emerge from devout Protestant homes emphasizing learning and responsibility but that such scientists frequently depart from the parental religious faith (31). Psychodynamically, this set of cultural values produces a person with an inquiring cognitive disposition, whose duty it is to strive diligently to improve the human condition. Given a certain level of intellectual talent, and cultural support in educational, scientific, and scholarly institutions, youth will frequently choose careers in scientific and scholarly professions. This same cultural milieu apparently also produces disproportionate numbers of inventors and entrepreneurs; historically, it produced those who activated the industrial revolution and those who generally were responsible for rapid economic growth. The data discussed herein extend only to about 1960, prior to the great social unrest of the 1960's and early 1970's. Speculatively, one might predict that productivity will diminish to the extent that current social movements stressing existential futility, goal attainment "now," or power relationships are successful in penetrating groups which have been highly productive, since these emphases undermine long longterm scholarly striving.


Use of electrolytes containing multiple co-anions in the analysis of anions by capillary electrophoresis using indirect absorbance detection.
Background electrolytes (BGEs) containing more than one UV-absorbing probe co-anion were investigated as possible means to control peak symmetries and improve the sensitivity of indirect detection in the separation of a mixture of inorganic and organic anions having a range of electrophoretic mobilities. In initial experiments, chloride and propanoate, which do not absorb at the detection wavelength, were added individually to a BGE containing phthalate as the UV-absorbing probe co-anion. The response ratios (i.e., the detector response for an analyte obtained with the BGE containing the probe and added co-anion divided by the response of the BGE containing the probe alone) were found to be dependent on the relative mobilities of the analyte, probe, and co-anion. In general, it was found that the analyte mainly displaced the BGE component to which its mobility was closest and exclusively displaced any BGE component having the same mobility. This behavior was utilized to design BGEs containing multiple probes to improve peak shapes by matching the mobilities of the BGE components with those of the analytes. A BGE comprising chromate and phthalate as probes was used to demonstrate the improvement in peak shapes when such an approach was used. This was further extended to a BGE containing three probes, namely, chromate, phthalate, and benzoate. System peaks were observed for each multiple-component BGE and for n BGE co-anions; n - 1 system peaks were induced. A simple linear function relating the mobility of the system peak for a two-co-anion BGE to the mobilities and relative concentrations of each of the co-anions was derived empirically. Finally, a series of probes was investigated to determine the optimum multiple BGE composition giving the best peak shapes and sensitivity in the separation of a mixture of 15 analytes. The best combination was a two-probe BGE consisting of chromate and 4-hydroxybenzenesulfonic acid.


Validation of the care transition measure in multi-ethnic South-East Asia in Singapore.
The 15-item Care Transition Measure (CTM-15) is a measure for assessing the quality of care during transition from the patients' perspective. The purpose of this study was to test the psychometric properties of the CTM-15 and CTM-3 (a 3-item version of the CTM-15) in Singapore, a multi-ethnic urban state in South-east Asia. A consecutive sample of patients was recruited from two tertiary hospitals. The subjects or their proxies were interviewed 3 weeks after discharge from hospital to home in English or Chinese using the CTM-15 questionnaire. Information about patients' visit to emergency department (ED), non-elective rehospitalisation for the condition of index hospitalisation, and care experience after discharge was also collected from respondents. Psychometric properties of CTM-15 and CTM-3 based on the five-point response scale (i.e. strongly disagree, disagree, neutral, agree, and strongly agree) and the three-point response scale (i.e. [strongly] agree, neutral, and [strongly] disagree) were tested for English and Chinese versions separately. Internal consistency reliability was assessed using Cronbach's alpha and construct validity was tested with T-test or Pearson's correlation by examining hypothesised association of CTM scores with ED visit, rehospitalisation, and experience with care after discharge. Exploratory factor analysis was performed to examine latent dimensions of CTM-15. A total of 414 (proxy: 96.1%) and 165 (proxy: 84.8%) subjects completed the interviews in English and Chinese, respectively. Cronbach's alpha values of the different CTM-15 versions ranged from 0.81 to 0.87. In contrast, Cronbach's alpha values of the CTM-3 ranged from 0.42 to 0.63. Both CTM-15 and CTM-3 were correlated with care experience after discharge regardless of survey language or response scale (Pearson's correlation coefficient: 0.36 to 0.46). Among the English-speaking respondents, the CTM-15 and CTM-3 scores based on both the three- and five-point response scales discriminated well between patients with and without ED visits or rehospitalisation for their index condition. Among Chinese-speaking respondents, no difference in CTM scores was observed between patients with and without ED visits or patients with and without rehospitalisation. The English and Chinese versions of the CTM-15 items demonstrated a similar 4-factor structure representing general care plan, medication, agreement on care plan, and specific care instructions. The care transition measure is a valid and reliable measure for quality of care transition in Singapore. Moreover, the care transition measure can be administered to proxies using a simpler response scale. The discriminatory power of the Chinese version of this instrument needs to be further tested in future studies.


Enantioselctive syntheses of sulfur analogues of flavan-3-Ols.
The first enantioselective syntheses of sulfur flavan-3-ol analogues 1-8 have been accomplished, whereby the oxygen atom of the pyran ring has been replaced by a sulfur atom. The key steps were: (a) Pd(0) catalyzed introduction of -S t-butyl group, (b) Sharpless enantioselective dihydroxylation of the alkene, (c) acid catalyzed ring closure to produce the thiopyran ring, and (d) removal of benzyl groups using N,N-dimethylaniline and AlCl(3). The compounds were isolated in high chemical and optical purity.


Identification of hypoxia in cells and tissues of epigastric 9L rat glioma using EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide].
One of the most sensitive hypoxia detection methods is based on the observation that binding of nitroimidazoles to cellular macromolecules occurs as a result of hypoxia-dependent bioreduction by cellular nitroreductases. Nitroimidazole-binding techniques provide measurements of hypoxia to virtually any degree of spatial resolution and with a multiplicity of techniques. This paper demonstrates hypoxia imaging using in vivo EF5 binding with detection by a fluorochrome-conjugated monoclonal antibody. We investigated these techniques in the 9L glioma tumour, in part because the exact nature of the hypoxia in this tumour system is controversial. Our results demonstrate that following intravenous injection of EF5, binding and detection using a monoclonal antibody in 9L gliomas is specific and oxygen dependent. Detection of binding using fluorescence microscopy can be performed on frozen tissues; tissue sections can be counterstained with haematoxylin and eosin for light microscopic analysis. Alternatively, the distribution of hypoxia in a tumour can be inferred by examining individual tumour cells using flow cytometric techniques. Based upon the results presented herein, the radiation-resistant phenotype of 9L epigastric tumours grown in our laboratories can be associated with the presence of hypoxic cells.


Value, search, persistence and model updating in anterior cingulate cortex.
Dorsal anterior cingulate cortex (dACC) carries a wealth of value-related information necessary for regulating behavioral flexibility and persistence. It signals error and reward events informing decisions about switching or staying with current behavior. During decision-making, it encodes the average value of exploring alternative choices (search value), even after controlling for response selection difficulty, and during learning, it encodes the degree to which internal models of the environment and current task must be updated. dACC value signals are derived in part from the history of recent reward integrated simultaneously over multiple time scales, thereby enabling comparison of experience over the recent and extended past. Such ACC signals may instigate attentionally demanding and difficult processes such as behavioral change via interactions with prefrontal cortex. However, the signal in dACC that instigates behavioral change need not itself be a conflict or difficulty signal.


Oviposition strategies, host coercion and the stable exploitation of figs by wasps.
A classic example of a mutualism is the one between fig plants (Ficus) and their specialized and obligate pollinating wasps. The wasps deposit eggs in fig ovules, which the larvae then consume. Because the wasps derive their fitness only from consumed seeds, this mutualism can persist only if the wasps are prevented from laying eggs in all ovules. The search for mechanisms that can limit oviposition and stabilize the wasp-seed conflict has spanned more than three decades. We use a simple foraging model, parameterized with data from two Ficus species, to show how fig morphology reduces oviposition rates and helps to resolve the wasp-seed conflict. We also propose additional mechanisms, based on known aspects of fig biology, which can prevent even large numbers of wasps from ovipositing in all ovules. It has been suggested that in mutualistic symbioses, the partner that controls the physical resources, in this case Ficus, ultimately controls the rate at which hosts are converted to visitors, regardless of relative evolutionary rates. Our approach provides a mechanistic implementation of this idea, with potential applications to other mutualisms and to theories of virulence.


An automated histological classification system for precision diagnostics of kidney allografts.
For three decades, the international Banff classification has been the gold standard for kidney allograft rejection diagnosis, but this system has become complex over time with the integration of multimodal data and rules, leading to misclassifications that can have deleterious therapeutic consequences for patients. To improve diagnosis, we developed a decision-support system, based on an algorithm covering all classification rules and diagnostic scenarios, that automatically assigns kidney allograft diagnoses. We then tested its ability to reclassify rejection diagnoses for adult and pediatric kidney transplant recipients in three international multicentric cohorts and two large prospective clinical trials, including 4,409 biopsies from 3,054 patients (62.05% male and 37.95% female) followed in 20 transplant referral centers in Europe and North America. In the adult kidney transplant population, the Banff Automation System reclassified 83 out of 279 (29.75%) antibody-mediated rejection cases and 57 out of 105 (54.29%) T cell-mediated rejection cases, whereas 237 out of 3,239 (7.32%) biopsies diagnosed as non-rejection by pathologists were reclassified as rejection. In the pediatric population, the reclassification rates were 8 out of 26 (30.77%) for antibody-mediated rejection and 12 out of 39 (30.77%) for T cell-mediated rejection. Finally, we found that reclassification of the initial diagnoses by the Banff Automation System was associated with an improved risk stratification of long-term allograft outcomes. This study demonstrates the potential of an automated histological classification to improve transplant patient care by correcting diagnostic errors and standardizing allograft rejection diagnoses.ClinicalTrials.gov registration: NCT05306795 .


JNK Inhibition Reduced Retinal Ganglion Cell Death after Ischemia/Reperfusion In Vivo and after Hypoxia In Vitro.
Mitogen-activated protein kinases (MAPKs) are key regulators that have been linked to cell survival and death. Among the main classes of MAPKs, c-jun N-terminal kinase (JNK) has been shown to mediate cell stress responses associated with apoptosis. In Vitro, hypoxia induced a significant increase in 661W cell death that paralleled increased activity of JNK and c-jun. 661W cells cultured in presence of the inhibitor of JNK (D-JNKi) were less sensitive to hypoxia-induced cell death. In vivo, elevation in intraocular pressure (IOP) in the rat promoted cell death that correlated with modulation of JNK activation. In vivo inhibition of JNK activation with D-JNKi resulted in a significant and sustained decrease in apoptosis in the ganglion cell layer, the inner nuclear layer and the photoreceptor layer. These results highlight the protective effect of D-JNKi in ischemia/reperfusion induced cell death of the retina.


Study and use of the probiotic Lactobacillus reuteri in pigs: a review.
Probiotics are living microorganisms that provide a wide variety of health benefits to the host when ingested in adequate amounts. The bacterial strains most frequently used as probiotic agents are lactic acid bacteria, such as Lactobacillus reuteri, which is one of the few endogenous Lactobacillus species found in the gastrointestinal tract of vertebrates, including humans, rats, pigs and chickens. L. reuteri is one of the most well documented probiotic species and has been widely utilized as a probiotic in humans and animals for many years. Initially, L. reuteri was used in humans to reduce the incidence and the severity of diarrhea, prevent colic and necrotic enterocolitis, and maintain a functional mucosal barrier. As interest in alternatives to in-feed antibiotics has grown in recent years, some evidence has emerged that probiotics may promote growth, improve the efficiency of feed utilization, prevent diarrhea, and regulate the immune system in pigs. In this review, the characteristics of L. reuteri are described, in order to update the evidence on the efficacy of using L. reuteri in pigs.


Antineoplastic Effects of PPARγ Agonists, with a Special Focus on Thyroid Cancer.
Peroxisome Proliferator-Activated Receptor-γ (PPARγ) is a ligand-activated nuclear hormone receptor that functions as transcription factor and plays an important role in lipid metabolism and insulin sensitization. Recent studies have shown that PPARγ is overexpressed in many tumor types, including cancers of breast, lung, pancreas, colon, glioblastoma, prostate and thyroid differentiated/anaplastic cancers. These data suggest a role of PPARγ in tumor development and/or progression. PPARγ is emerging as a growth-limiting and differentiation-promoting factor, and it exerts a tumor suppressor role. Moreover, naturally-occurring and synthetic PPARγ agonists promote growth inhibition and apoptosis. Thiazolidinediones (TZDs) are synthetic agonists of PPARγ that were developed to treat type II diabetes. These compounds also display anticancer effects which appear mainly to be independent of their PPARγ agonist activity. Various preclinical and clinical studies strongly suggest a role for TZDs both alone and in combination with existing chemotherapeutic agents, for the treatment of cancer. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells, targeting pathways capable of re-activating blocked terminal differentiation programs. PPARγ agonists have been shown to induce differentiation in solid tumors such as thyroid differentiated/ anaplastic cancers and sarcomas. However, emerging data suggest that chronic use of TZDs is associated with increased risk of adverse cardiovascular events. The exploration of newer PPARγ agonists can help in unveiling the underlying mechanisms of these drugs, providing new molecules that are able to treat cancer, without increasing the cardiovascular risk of neoplastic patients.


Population dynamics inferred from temporal variation at microsatellite loci in the selfing snail Bulinus truncatus.
We analyzed short-term forces acting on the genetics of subdivided populations based on a temporal survey of the microsatellite variability in the hermaphrodite freshwater snail Bulinus truncatus. This species inhabits temporary habitats, has a short generation time and exhibits variable rates of selfing. We studied the variability over three sampling dates in 12 Sahelian populations (1161 individuals). Classical genetic parameters (estimators of Ho, He, f, selfing rate and Fst) showed limited change over time whereas important temporal changes of allelic frequencies were detected for 10 of the ponds studied. These variations are not easily explained by selection, sampling drift and genetic drift alone and may be due to periodic migration. Indeed the habitats occupied by the populations studied are subject to large temporal fluctuations owing to annual cycles of drought and flood. In such ponds our results support a demographic model of population expansions and contractions under which available habitats, after the rainy season, are colonized by individuals originating from a smaller number of refuges (areas that never dry out in the deepest parts of the ponds). In contrast, selfing appeared to be an important force affecting the genetic structure in permanent ponds.


Kinetics and mechanisms of N-nitrosodimethylamine formation upon ozonation of N,N-dimethylsulfamide-containing waters: bromide catalysis.
N,N-Dimethylsulfamide (DMS), a newly identified, ubiquitous degradation product of the fungicide tolylfluanide, has been shown to be a N-nitrosodimethylamine (NDMA) precursor during ozonation. In this study, batch ozonation experiments in ultrapure buffered water, surface water, and tap water were performed to determine the kinetics and elucidate the mechanism of NDMA formation from DMS. It was found that at circumneutral pH, DMS reacts slowly with ozone (k approximately 20 M(-1) s(-1)) and moderately with hydroxyl radicals (k=1.5x10(9) M(-1)s(-1)). The reaction of DMS with these oxidants does not lead to NDMA. NDMA was only formed if bromide was present during ozonation of DMS-containing waters. Bromide is oxidized to hypobromous acid (HOBr) by ozone which then reacts with the primary amine of DMS to form a Br-DMS species. The rate limiting step of the formation of Br-DMS is the formation of HOBr. The reaction to form Br-DMS has an apparent second order rate constant at pH 8 of >3x10(4) M(-1)s(-1). The Br-DMS is transformed by ozone to NDMA and nitrate (k>or=5000 M(-1) s(-1)), with yields of 54% and 39%, respectively, based on the primary amine nitrogen of DMS. These reactions release bromide, making bromide a catalyst. NDMA is also formed during ozonation of DMS in the presence of hypochlorous acid (20-30% yield). The last step of NDMA formation is an intramolecular rearrangement with sulfur dioxide extrusion. On the basis of the mechanistic and kinetic information, it was possible to model NDMA formation in DMS-containing Lake Zurich water.


Emergency Medicine Resident Self-assessment of Clinical Teaching Compared to Student Evaluation Using a Previously Validated Rubric.
The quality of clinical teaching in the emergency department from the students' perspective has not been previously described in the literature. Our goals were to assess senior residents' teaching ability from the resident/teacher and student/learner viewpoints for any correlation, and to explore any gender association. The secondary goal was to evaluate the possible impact of gender on the resident/student dyad, an interaction that has previously been studied only in the faculty/student pairing. After approval by an institutional review board, a 1-year, grant-funded, single-site, prospective study was implemented at a regional medical campus that sponsors a 4-year dually approved emergency medicine residency. The residency hosts both medical school students (MSs) and physician's assistant students (PAs). Each student and senior resident working concurrently completed a previously validated ER Scale, which measured residents' teaching performance in 4 categories: Didactic, Clinical, Approachable, and Helpful. Students evaluated residents' teaching, while residents self-assessed their performance. The participants' demographic characteristics gathered included prior knowledge of or exposure to clinical teaching models. Gender was self-reported by participants. The analysis accounted for multiple observations by comparing participants' mean scores. Ninety-nine subjects were enrolled; none withdrew consent. Thirty-seven residents (11 women) and 62 students (39 women) from 25 MSs and 6 PA schools were enrolled, completing 517 teaching assessments. Students evaluated residents more favorably in all ER Scale categories than did residents on self-assessments (P < 0.0001). This difference was significant in all subgroup comparisons (types of school versus postgraduate years [PGYs]). Residents' evaluations by type of student (MS vs PA) did not show a significant difference. PGY 3 residents assessed themselves higher in all categories than did PGY 4 residents, with Approachability reaching significance (P = 0.0105). Male residents self-assessed their teaching consistently higher than did female residents, significantly so on Clinical (P = 0.0300). Students' evaluations of the residents' teaching skills by residents' gender did not reveal gender differences. MS and PA students evaluated teaching by EM senior residents statistically significantly higher than did EM residents on self-evaluation when using the ER Scale. Students did not evaluate residents' teaching with any difference by gender, although male residents routinely self-assessed their teaching abilities more positively than did female residents. These findings suggest that, if residency programs utilize resident self-evaluation for programmatic evaluation, the gender of the resident may impact self-scoring. This cohort may inform future study of resident teaching in the emergency department, such as the design of future resident-as-teacher curricula.


Contribution of mathematical modeling to the fight against bacterial antibiotic resistance.
Modeling of antibiotic resistance in pathogenic bacteria responsible for human disease has developed considerably over the last decade. Herein, we summarize the main published studies to illustrate the contribution of models for understanding both within-host and population-based phenomena. We then suggest possible topics for future studies. Model building of bacterial resistance has involved epidemiologists, biologists and modelers with two different objectives. First, modeling has helped largely in identifying and understanding the factors and biological phenomena responsible for the emergence and spread of resistant strains. Second, these models have become important decision support tools for medicine and public health. Major improvements of models in the coming years should take into account specific pathogen characteristics (resistance mechanisms, multiple colonization phenomena, cooperation and competition among species) and better description of the contacts associated with transmission risk within populations.


Educating the psychiatrist of the 21st century.
Psychiatry is under threat from developments within mental health care. In educating future psychiatrists, more emphasis should be placed upon: collaborative research; integrated teamwork, without interprofessional rivalry; work in primary care; the non-scientific components of psychiatry, centred upon relationships with patients; less dogmatic attitudes for or against psychoanalysis: psychiatry as a branch of medicine; and modern management and audit methods. Younger psychiatrists should be encouraged to take responsibility for shaping the future of the profession.


Dopamine signaling in C. elegans is mediated in part by HLH-17-dependent regulation of extracellular dopamine levels.
In Caenorhabditis elegans, the dopamine transporter DAT-1 regulates synaptic dopamine (DA) signaling by controlling extracellular DA levels. In dat-1(ok157) animals, DA is not taken back up presynaptically but instead reaches extrasynpatic sites, where it activates the dopamine receptor DOP-3 on choligeneric motor neurons and causes animals to become paralyzed in water. This phenotype is called swimming-induced paralysis (SWIP) and is dependent on dat-1 and dop-3. Upstream regulators of dat-1 and dop-3 have yet to be described in C. elegans. In our previous studies, we defined a role for HLH-17 during dopamine response through its regulation of the dopamine receptors. Here we continue our characterization of the effects of HLH-17 on dopamine signaling. Our results suggest that HLH-17 acts downstream of dopamine synthesis to regulate the expression of dop-3 and dat-1. First, we show that hlh-17 animals display a SWIP phenotype that is consistent with its regulation of dop-3 and dat-1. Second, we show that this behavior is enhanced by treatment with the dopamine reuptake inhibitor, bupropion, in both hlh-17 and dat-1 animals, a result suggesting that SWIP behavior is regulated via a mechanism that is both dependent on and independent of DAT-1. Third, and finally, we show that although the SWIP phenotype of hlh-17 animals is unresponsive to the dopamine agonist, reserpine, and to the antidepressant, fluoxetine, hlh-17 animals are not defective in acetylcholine signaling. Taken together, our work suggests that HLH-17 is required to maintain normal levels of dopamine in the synaptic cleft through its regulation of dop-3 and dat-1.


Hydroxychloroquine is associated with slower viral clearance in clinical COVID-19 patients with mild to moderate disease.
There are conflicting data regarding the use of hydroxychloroquine (HCQ) in COVID-19 hospitalized patients. The objective of this study was to assess the efficacy of HCQ in increasing SARS-CoV-2 viral clearance.Hospitalized adult patients with confirmed SARS-CoV-2 infection were retrospectively included in the study. The primary outcome was the time from a confirmed positive nasopharyngeal swab to turn negative. A negative nasopharyngeal swab conversion was defined as a confirmed SARS-CoV-2 case followed by 2 negative results using RT-PCR assay with samples obtained 24 hours apart. Multiple linear regression analysis was used to adjust for potential confounders.Thirty-four confirmed COVID-19 patients completed the study. Nineteen (55.9%) patients presented with symptoms, and 14 (41.2%) had pneumonia. Only 21 (61.8%) patients received HCQ. The time to SARS-CoV-2 negativity nasopharyngeal test was significantly longer in patients who received HCQ than those who did not receive HCQ [17 (13-21) vs 10 (4-13) days, P = .023]. HCQ was independently associated with time to negativity test after adjustment for potential confounders (symptoms, comorbidities, antiviral drugs, pneumonia, or oxygen therapy) in multivariable Cox proportional hazards regression analysis (hazard ratio = 0.33, 95% confidence interval: 0.13-0.9, P = .024). On day 14, 47.8% (14/23) patients tested negative in the HCQ group compared with 90.9% (10/11) patients who did not receive HCQ (P = .016).HCQ was associated with a slower viral clearance in COVID-19 patients with mild to moderate disease. Data from ongoing randomized clinical trials with HCQ should provide a definitive answer regarding the efficacy and safety of this treatment.


Synthesis of Mono- and Dinuclear Vanadium Complexes and Their Reactivity toward Dehydroperoxidation of Alkyl Hydroperoxides.
Several vanadium(V) complexes with either dipic-based or Schiff base ligands were synthesized. The complexes were fully characterized by elemental analysis, IR, 1H, 13C, and 51V NMR spectroscopy, as well as mass spectrometry and X-ray diffraction. Furthermore, they were tested toward their catalytic deperoxidation behavior and a significant difference between 4-heptyl hydroperoxide and cyclohexyl hydroperoxide was observed. In the case of 4-heptyl hydroperoxide, the selectivity toward the corresponding ketone was higher than with cyclohexyl hydroperoxide. DFT calculations performed on the vanadium complex showed that selective decomposition of secondary hydroperoxides with vanadium(V) to yield the corresponding ketone and water is indeed energetically feasible. The computed catalytic path, involving cleavage of the O-O bond, hydrogen transfer, release of ketone/water, and finally addition of hydroperoxide, can proceed without the generation of radical species.


The Indispensable Roles of Microglia and Astrocytes during Brain Development.
Glia are essential for brain functioning during development and in the adult brain. Here, we discuss the various roles of both microglia and astrocytes, and their interactions during brain development. Although both cells are fundamentally different in origin and function, they often affect the same developmental processes such as neuro-/gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis and synaptic pruning. Due to their important instructive roles in these processes, dysfunction of microglia or astrocytes during brain development could contribute to neurodevelopmental disorders and potentially even late-onset neuropathology. A better understanding of the origin, differentiation process and developmental functions of microglia and astrocytes will help to fully appreciate their role both in the developing as well as in the adult brain, in health and disease.


Prevalence of rubella and cytomegalovirus antibodies among pregnant women in northern Turkey.
Primary infections caused by rubella and cytomegalovirus (CMV) can lead to serious complications in pregnancy. Rubella and CMV screening of pregnant women is not routinely carried out in Turkey. The purpose of this study was to determine the prevalence of rubella and cytomegalovirus among pregnant women. The study was carried out in Samsun Maternity and Women's Disease and Pediatrics Hospital in Samsun province, Turkey. Between September 2004 and September 2005, 600 pregnant women aged 17-40 years were enrolled in this study. The results of the antenatal screening for rubella and CMV during the first trimester of pregnancy were evaluated. Anti-IgG against rubella seropositivity was found in 566 (94.3%) and rubella IgM seropositivity in 10 (1.7%). The positivity for anti-CMV IgG antibody was found in 584 (97.3%), while 6 (1.0%) were positive for the anti-CMV IgM antibody. Pregnant women seronegative for rubella and CMV are susceptible to rubella and CMV primary infections. Preventive measures must be taken to decrease the mortality and morbidity related to congenital rubella and CMV infections. The rubella status should be investigated before pregnancy and seronegative females can be advised vaccination.


The dynamic architecture of the metabolic switch in Streptomyces coelicolor.
During the lifetime of a fermenter culture, the soil bacterium S. coelicolor undergoes a major metabolic switch from exponential growth to antibiotic production. We have studied gene expression patterns during this switch, using a specifically designed Affymetrix genechip and a high-resolution time-series of fermenter-grown samples. Surprisingly, we find that the metabolic switch actually consists of multiple finely orchestrated switching events. Strongly coherent clusters of genes show drastic changes in gene expression already many hours before the classically defined transition phase where the switch from primary to secondary metabolism was expected. The main switch in gene expression takes only 2 hours, and changes in antibiotic biosynthesis genes are delayed relative to the metabolic rearrangements. Furthermore, global variation in morphogenesis genes indicates an involvement of cell differentiation pathways in the decision phase leading up to the commitment to antibiotic biosynthesis. Our study provides the first detailed insights into the complex sequence of early regulatory events during and preceding the major metabolic switch in S. coelicolor, which will form the starting point for future attempts at engineering antibiotic production in a biotechnological setting.


Induction of heat shock protein 60 expression in human monocytic cell lines infected with Mycobacterium leprae.
Monocytic cell lines (HL-60 and THP-1) were infected with viable Mycobacterium leprae. Levels of human hsp60 were estimated by Western blot (immunoblot) assay and a sandwich enzyme-linked immunosorbent assay. The results showed that infection of both of the cell lines induced the synthesis of human hsp60, which may be of significance in relation to autoimmune manifestations associated with mycobacterial infections.


Molecular phylogenetic insights into the evolution of Octocorallia: a review.
The anthozoan sub-class Octocorallia, comprising approximately 3000 species of soft corals, gorgonians, and sea pens, remains one of the most poorly understood groups of the phylum Cnidaria. Efforts to classify the soft corals and gorgonians at the suprafamilial level have long thwarted taxonomists, and the subordinal groups in current use are widely recognized to represent grades of colony forms rather than clades. Molecular phylogenetic analyses of the sub-class do not support either the current morphologically based subordinal or familial-level taxonomy. To date, however, the resolution necessary to propose an alternative, phylogenetic classification of Octocorallia or to elucidate patterns of morphological evolution within the group is lacking. Attempts to understand boundaries between species and interspecific or intraspecific phylogenetic relationships have been hampered by the very slow rate of mitochondrial gene evolution in Octocorallia, and a consequent dearth of molecular markers with variation sufficient to distinguish species (or sometimes genera). A review of the available ITS2 sequence data for octocorals, however, reveals a yet-unexplored phylogenetic signal both at sequence and secondary-structure levels. In addition, incongruence between mitochondrial and nuclear gene trees suggests that hybrid speciation and reticulate evolution may be an important mechanism of diversification in some genera. Emerging next-generation genomic-sequencing technologies offer the best hope for a breakthrough in our understanding of phylogenetic relationships and of evolution of morphological traits in Octocorallia. Genome and transcriptome sequencing may provide enough characters to resolve relationships at the deepest levels of the octocoral tree, while simultaneously offering an efficient means to screen for new genetic markers variable enough to distinguish species and populations.


The household costs of visceral leishmaniasis care in south-eastern Nepal.
Visceral leishmaniasis (VL) is an important public health problem in south-eastern Nepal affecting very poor rural communities. Since 2005, Nepal is involved in a regional initiative to eliminate VL. This study assessed the economic impact of VL on households and examined whether the intensified VL control efforts induced by the government resulted in a decrease in household costs. Between August and September 2010, a household survey was conducted among 168 patients that had been treated for VL within 12 months prior to the survey in five districts in south-eastern Nepal. We collected data on health-seeking behaviour, direct and indirect costs and coping strategies. The median total cost of one episode of VL was US$ 165 or 11% of annual household income. The median delay between the onset of symptoms and presentation to a qualified provider was 25 days. Once the patient presented to a qualified provider, the delay to correct diagnosis was minimal (median 3 days). Direct and indirect costs (income losses) represented 47% and 53% of total costs respectively. Households used multiple strategies to cope with the cost of illness, mainly mobilizing cash/savings (71%) or taking a loan (56%). The provision of free VL diagnosis and drugs by the Nepalese control programme has been an important policy measure to reduce the cost of VL to households. But despite the free VL drugs, the economic burden is still important for households. More effort should be put into reducing indirect costs, in particular the length of treatment, and preventing the transmission of VL through vector control.


Multidrug resistance conferred by novel DNA polymerase mutations in human cytomegalovirus isolates.
The emergence of antiviral-resistant cytomegalovirus (CMV) strains is a continuing clinical problem, with increased numbers of immunocompromised patients given longer-duration antiviral prophylaxis. Two previously unrecognized CMV DNA polymerase mutations (N408K and A834P) identified separately and together in at-risk lung and kidney transplant recipients and a third mutation (L737M) identified in a liver transplant recipient were characterized by marker transfer to antiviral-sensitive laboratory strains AD169 and Towne. Subsequent phenotypic analyses of recombinant strains demonstrated the ability of mutation N408K to confer ganciclovir (GCV) and cidofovir (CDV) resistance and of mutation A834P to confer GCV, foscarnet, and CDV resistance. Mutation L737M did not confer resistance to any of the antiviral agents tested. A recombinant strain containing both N408K and A834P demonstrated increased GCV and CDV resistance compared to the levels of resistance of the virus containing only the A834P mutation. The addition of mutation N408K in combination with A834P also partially reconstituted the replication impairment of recombinant virus containing only A834P. This suggests that perturbation of both DNA polymerization (A834P) and exonuclease (N408K) activities contributes to antiviral resistance and altered replication kinetics in these mutant strains. The identification of these multidrug-resistant CMV strains in at-risk seronegative recipients of organs from seropositive donors suggests that improved prophylactic and treatment strategies are required. The additive effect of multiple mutations on antiviral susceptibility suggests that increasing antiviral-resistant phenotypes can result from different virus-antiviral interactions.


Are we winning the war against posttraumatic stress disorder?
The most methodologically rigorous epidemiological study on American military personnel deployed to Iraq and Afghanistan found that 4.3% of troops developed posttraumatic stress disorder (PTSD). Among deployed combatants, 7.6% developed PTSD, whereas 1.4% of deployed noncombatants did so. The U.S. Department of Veterans Affairs has launched a program ensuring that all veterans with PTSD will receive evidence-based cognitive-behavioral therapy, and the Army has developed Battlemind postdeployment early interventions that reduce risk for the disorder.


Comparisons of clustered regularly interspaced short palindromic repeats and viromes in human saliva reveal bacterial adaptations to salivary viruses.
Explorations of human microbiota have provided substantial insight into microbial community composition; however, little is known about interactions between various microbial components in human ecosystems. In response to the powerful impact of viral predation, bacteria have acquired potent defences, including an adaptive immune response based on the clustered regularly interspaced short palindromic repeats (CRISPRs)/Cas system. To improve our understanding of the interactions between bacteria and their viruses in humans, we analysed 13 977 streptococcal CRISPR sequences and compared them with 2 588 172 virome reads in the saliva of four human subjects over 17 months. We found a diverse array of viruses and CRISPR spacers, many of which were specific to each subject and time point. There were numerous viral sequences matching CRISPR spacers; these matches were highly specific for salivary viruses. We determined that spacers and viruses coexist at the same time, which suggests that streptococcal CRISPR/Cas systems are under constant pressure from salivary viruses. CRISPRs in some subjects were just as likely to match viral sequences from other subjects as they were to match viruses from the same subject. Because interactions between bacteria and viruses help to determine the structure of bacterial communities, CRISPR-virus analyses are likely to provide insight into the forces shaping the human microbiome.


The counterbend phenomenon in flagellar axonemes and cross-linked filament bundles.
Recent observations of flagellar counterbend in sea urchin sperm show that the mechanical induction of curvature in one part of a passive flagellum induces a compensatory countercurvature elsewhere. This apparent paradoxical effect cannot be explained using the standard elastic rod theory of Euler and Bernoulli, or even the more general Cosserat theory of rods. Here, we develop a geometrically exact mechanical model to describe the statics of microtubule bundles that is capable of predicting the curvature reversal events observed in eukaryotic flagella. This is achieved by allowing the interaction of deformations in different material directions, by accounting not only for structural bending, but also for the elastic forces originating from the internal cross-linking mechanics. Large-amplitude static configurations can be described analytically, and an excellent match between the model and the observed counterbend deformation was found. This allowed a simultaneous estimation of multiple sperm flagellum material parameters, namely the cross-linking sliding resistance, the bending stiffness, and the sperm head junction compliance ratio. We further show that small variations on the empirical conditions may induce discrepancies for the evaluation of the flagellar material quantities, so that caution is required when interpreting experiments. Finally, our analysis demonstrates that the counterbend emerges as a fundamental property of sliding resistance in cross-linked filamentous polymer bundles, which also suggests that cross-linking proteins may contribute to the regulation of the flagellar waveform in swimming sperm via counterbend mechanics.


A simulation of cross-country skiing on varying terrain by using a mathematical power balance model.
The current study simulated cross-country skiing on varying terrain by using a power balance model. By applying the hypothetical inductive deductive method, we compared the simulated position along the track with actual skiing on snow, and calculated the theoretical effect of friction and air drag on skiing performance. As input values in the model, air drag and friction were estimated from the literature, whereas the model included relationships between heart rate, metabolic rate, and work rate based on the treadmill roller-ski testing of an elite cross-country skier. We verified this procedure by testing four models of metabolic rate against experimental data on the treadmill. The experimental data corresponded well with the simulations, with the best fit when work rate was increased on uphill and decreased on downhill terrain. The simulations predicted that skiing time increases by 3%-4% when either friction or air drag increases by 10%. In conclusion, the power balance model was found to be a useful tool for predicting how various factors influence racing performance in cross-country skiing.


Improved Social Interaction, Recognition and Working Memory with Cannabidiol Treatment in a Prenatal Infection (poly I:C) Rat Model.
Neuropsychiatric disorders such as schizophrenia are associated with cognitive impairment, including learning, memory and attention deficits. Antipsychotic drugs are limited in their efficacy to improve cognition; therefore, new therapeutic agents are required. Cannabidiol (CBD), the non-intoxicating component of cannabis, has anti-inflammatory, neuroprotective and antipsychotic-like properties; however, its ability to improve the cognitive deficits of schizophrenia remains unclear. Using a prenatal infection model, we examined the effect of chronic CBD treatment on cognition and social interaction. Time-mated pregnant Sprague-Dawley rats (n=16) were administered polyinosinic-polycytidilic acid (poly I:C) (POLY; 4 mg/kg) or saline (CONT) at gestation day 15. Male offspring (PN56) were injected twice daily with 10 mg/kg CBD (CONT+CBD, POLY+CBD; n=12 per group) or vehicle (VEH; CONT+VEH, POLY+VEH; n=12 per group) for 3 weeks. Body weight, food and water intake was measured weekly. The Novel Object Recognition and rewarded T-maze alternation tests assessed recognition and working memory, respectively, and the social interaction test assessed sociability. POLY+VEH offspring exhibited impaired recognition and working memory, and reduced social interaction compared to CONT+VEH offspring (p<0.01). CBD treatment significantly improved recognition, working memory and social interaction deficits in the poly I:C model (p<0.01 vs POLY+VEH), did not affect total body weight gain, food or water intake, and had no effect in control animals (all p>0.05). In conclusion, chronic CBD administration can attenuate the social interaction and cognitive deficits induced by prenatal poly I:C infection. These novel findings present interesting implications for potential use of CBD in treating the cognitive deficits and social withdrawal of schizophrenia.


Stressor-induced increase in muscle fatigability of young men and women is predicted by strength but not voluntary activation.
This study investigated mechanisms for the stressor-induced changes in muscle fatigability in men and women. Participants performed an isometric-fatiguing contraction at 20% maximal voluntary contraction (MVC) until failure with the elbow flexor muscles. Study one (n = 55; 29 women) involved two experimental sessions: 1) a high-stressor session that required a difficult mental-math task before and during a fatiguing contraction and 2) a control session with no mental math. For some participants (n = 28; 14 women), cortical stimulation was used to examine mechanisms that contributed to muscle fatigability during the high-stressor and control sessions. Study two (n = 23; nine women) determined the influence of a low stressor, i.e., a simple mental-math task, on muscle fatigability. In study one, the time-to-task failure was less for the high-stressor session than control (P < 0.05) for women (19.4%) and men (9.5%): the sex difference response disappeared when covaried for initial strength (MVC). MVC force, voluntary activation, and peak-twitch amplitude decreased similarly for the control and high-stressor sessions (P < 0.05). In study two, the time-to-task failure of men or women was not influenced by the low stressor (P > 0.05). The greater fatigability, when exposed to a high stressor during a low-force task, was not exclusive to women but involved a strength-related mechanism in both weaker men and women that accelerated declines in voluntary activation and slowing of contractile properties.


Multiparameter phenotypic screening for endogenous TFEB and TFE3 translocation identifies novel chemical series modulating lysosome function.
The accumulation of toxic protein aggregates in multiple neurodegenerative diseases is associated with defects in the macroautophagy/autophagy-lysosome pathway. The amelioration of disease phenotypes across multiple models of neurodegeneration can be achieved through modulating the master regulator of lysosome function, TFEB (transcription factor EB). Using a novel multi-parameter high-throughput screen for cytoplasmic:nuclear translocation of endogenous TFEB and the related transcription factor TFE3, we screened the Published Kinase Inhibitor Set 2 (PKIS2) library as proof of principle and to identify kinase regulators of TFEB and TFE3. Given that TFEB and TFE3 are responsive to cellular stress we have established assays for cellular toxicity and lysosomal function, critical to ensuring the identification of hit compounds with only positive effects on lysosome activity. In addition to AKT inhibitors which regulate TFEB localization, we identified a series of quinazoline-derivative compounds that induced TFEB and TFE3 translocation. A novel series of structurally-related analogs was developed, and several compounds induced TFEB and TFE3 translocation at higher potency than previously screened compounds. KINOMEscan and cell-based KiNativ kinase profiling revealed high binding for the PRKD (protein kinase D) family of kinases, suggesting good selectivity for these compounds. We describe and utilize a cellular target-validation platform using CRISPRi knockdown and orthogonal PRKD inhibitors to demonstrate that the activity of these compounds is independent of PRKD inhibition. The more potent analogs induced subsequent upregulation of the CLEAR gene network and cleared pathological HTT protein in a cellular model of proteinopathy, demonstrating their potential to alleviate neurodegeneration-relevant phenotypes. Abbreviations: AD: Alzheimer disease; AK: adenylate kinase; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; HD: Huntington disease; PD: Parkinson disease; PKIS2: Published Kinase Inhibitor Set 2; PRKD: protein kinase D; TFEB: transcription factor EB.


Health service utilisation during the COVID-19 pandemic in sub-Saharan Africa in 2020: a multicountry empirical assessment with a focus on maternal, newborn and child health services.
There are concerns about the impact of the COVID-19 pandemic on the continuation of essential health services in sub-Saharan Africa. Through the Countdown to 2030 for Women's, Children's and Adolescents' Health country collaborations, analysts from country and global public health institutions and ministries of health assessed the trends in selected services for maternal, newborn and child health, general service utilisation. Monthly routine health facility data by district for the period 2017-2020 were compiled by 12 country teams and adjusted after extensive quality assessments. Mixed effects linear regressions were used to estimate the size of any change in service utilisation for each month from March to December 2020 and for the whole COVID-19 period in 2020. The completeness of reporting of health facilities was high in 2020 (median of 12 countries, 96% national and 91% of districts ≥90%), higher than in the preceding years and extreme outliers were few. The country median reduction in utilisation of nine health services for the whole period March-December 2020 was 3.9% (range: -8.2 to 2.4). The greatest reductions were observed for inpatient admissions (median=-17.0%) and outpatient admissions (median=-7.1%), while antenatal, delivery care and immunisation services generally had smaller reductions (median from -2% to -6%). Eastern African countries had greater reductions than those in West Africa, and rural districts were slightly more affected than urban districts. The greatest drop in services was observed for March-June 2020 for general services, when the response was strongest as measured by a stringency index. The district health facility reports provide a solid basis for trend assessment after extensive data quality assessment and adjustment. Even the modest negative impact on service utilisation observed in most countries will require major efforts, supported by the international partners, to maintain progress towards the SDG health targets by 2030.


Suppression of Sproutys has a therapeutic effect for a mouse model of ischemia by enhancing angiogenesis.
Sprouty proteins (Sproutys) inhibit receptor tyrosine kinase signaling and control various aspects of branching morphogenesis. In this study, we examined the physiological function of Sproutys in angiogenesis, using gene targeting and short-hairpin RNA (shRNA) knockdown strategies. Sprouty2 and Sprouty4 double knockout (KO) (DKO) mice were embryonic-lethal around E12.5 due to cardiovascular defects. The number of peripheral blood vessels, but not that of lymphatic vessels, was increased in Sprouty4 KO mice compared with wild-type (WT) mice. Sprouty4 KO mice were more resistant to hind limb ischemia and soft tissue ischemia than WT mice were, because Sprouty4 deficiency causes accelerated neovascularization. Moreover, suppression of Sprouty2 and Sprouty4 expression in vivo by shRNA targeting accelerated angiogenesis and has a therapeutic effect in a mouse model of hind limb ischemia. These data suggest that Sproutys are physiologically important negative regulators of angiogenesis in vivo and novel therapeutic targets for treating peripheral ischemic diseases.


Armoring confined bubbles in the flow of colloidal suspensions.
We study the process of coating the interface of a long gas bubble, which is translating in a horizontal circular capillary tube filled with a colloidal suspension. A typical elongated confined bubble is comprised of three distinct regions: a spherical front cap, a central body that is separated from the tube wall by a thin liquid film, and a spherical cap at the back. These three regions are connected by transitional sections. Particles gradually coat the bubble from the back to the front. We investigate the mechanisms that govern the initial accumulation of the particles and the growth of the particle-coated area on the interface of the bubble. We show that the initial accumulation of particles starts at the stable stagnation ring on the rear cap of the bubble, and the particles will completely coat the spherical cap at the back of the bubble before accumulating on the central body. Armoring the central interface of the bubble with particles thickens the liquid film around the bubble relative to that around the particle-free interface. This effect creates a rather sharp step on the interface of the bubble in the central region, which separates the armored region from the particle-free region. After the bubble is completely coated, the liquid film around the body of the bubble will adjust again to an intermediate thickness. We show that the three distinct thicknesses that the liquid film acquires during the armoring process can be well described analytically.


Comparison of RT-qPCR and RT-dPCR Platforms for the Trace Detection of SARS-CoV-2 RNA in Wastewater.
We compared reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and RT digital PCR (RT-dPCR) platforms for the trace detection of SARS-CoV-2 RNA in low-prevalence COVID-19 locations in Queensland, Australia, using CDC N1 and CDC N2 assays. The assay limit of detection (ALOD), PCR inhibition rates, and performance characteristics of each assay, along with the positivity rates with the RT-qPCR and RT-dPCR platforms, were evaluated by seeding known concentrations of exogenous SARS-CoV-2 in wastewater. The ALODs using RT-dPCR were approximately 2-5 times lower than those using RT-qPCR. During sample processing, the endogenous (n = 96) and exogenous (n = 24) SARS-CoV-2 wastewater samples were separated, and RNA was extracted from both wastewater eluates and pellets (solids). The RT-dPCR platform demonstrated a detection rate significantly greater than that of RT-qPCR for the CDC N1 and CDC N2 assays in the eluate (N1, p = 0.0029; N2, p = 0.0003) and pellet (N1, p = 0.0015; N2, p = 0.0067) samples. The positivity results also indicated that for the analysis of SARS-CoV-2 RNA in wastewater, including the eluate and pellet samples may further increase the detection sensitivity using RT-dPCR.


Cross-sectional survey on prevalence of attention deficit hyperactivity disorder symptoms at a tertiary care health facility in Nairobi.
Attention deficit hyperactivity disorder is the most common childhood neurobehavioral disorder with well documented adverse consequences in adolescence and adulthood, yet 60-80% of cases go undiagnosed. Routine screening is not practiced in most pediatric outpatient services and little information exists on factors associated with the condition in developing countries. This was a questionnaire based cross-sectional survey whose primary objective was to determine prevalence of attention deficit hyperactivity disorder (ADHD) symptoms in children aged 6-12 years attending a tertiary care hospital Accidents and Emergency unit. Secondary objectives were to: (i) ascertain if physical injury and poor academic performance were associated with ADHD, (ii) compare diagnostic utility of parent-filled Vanderbilt Assessment Scale (VAS) against Statistical Manual of Mental Disorders-IV (DSM-IV) as the gold reference and (iii) establish if there exists an association between ADHD symptoms cluster and co-morbid conditions. Prevalence of cluster of symptoms consistent with ADHD was 6.3% (95% CI; 3.72-10.33) in 240 children studied. Those affected were more likely to repeat classes than the asymptomatic (OR 20.2; 95% CI 4.02-100.43). Additionally, 67% of the symptomatic had previously experienced burns and 37% post-traumatic open wounds. The odds of having an injury in the symptomatic was 2.9 (95% CI; 1.01-8.42) compared to the asymptomatic. Using DSM-IV as reference, VAS had a sensitivity of 66.7% (95%; CI 39.03-87.12) and specificity of 99.0% (95% CI; 96.1-99.2). Positive predictive value was 83.0% (95% CI; 50.4-97.3) and negative predictive value 98.0% (CI 95.1-99.1). Oppositional defiant disorder symptoms, anxiety, depression and conduct problems were not significantly associated with ADHD cluster of symptoms. The study found a relatively high prevalence of symptoms associated with ADHD. Symptomatic children experienced poor school performance. These findings support introduction of a policy on routine screening for ADHD in pediatric outpatient service. Positive history of injury and poor academic performance should trigger further evaluation for ADHD. Vanderbilt assessment scale is easier to administer than DSM-IV but has low sensitivity and high specificity that make it inappropriate for screening. It however provides a suitable alternative confirmatory test to determine who among clinically symptomatic patients requires referral to a psychiatrist.


What Causes Racial Health Care Disparities? A Mixed-Methods Study Reveals Variability in How Health Care Providers Perceive Causal Attributions.
Progress to address health care equity requires health care providers' commitment, but their engagement may depend on their perceptions of the factors contributing to inequity. To understand providers' perceptions of causes of racial health care disparities, a short survey was delivered to health care providers who work at 3 Veterans Health Administration sites, followed by qualitative interviews (N = 53). Survey data indicated that providers attributed the causes of disparities to social and economic conditions more than to patients' or providers' behaviors. Qualitative analysis revealed differences in the meaning that participants ascribed to these causal factors. Participants who believed providers contribute to disparities discussed race and racism more readily, identified the mechanisms through which disparities emerge, and contextualized patient-level factors more than those who believed providers contributed less to disparities. Differences in provider understanding of the underlying causal factors suggest a multidimensional approach to engage providers in health equity efforts.


Mesoaxial complete syndactyly and synostosis with hypoplastic thumbs: an unusual combination or homozygous expression of syndactyly type I?
Syndactyly type I is an autosomal dominant condition with complete or partial webbing between the third and fourth fingers or the second and third toes or both. We report here a previously undescribed phenotype of severe mesoaxial syndactyly and synostosis in patients born to affected parents. The characteristic features of these severe cases are (1) complete syndactyly and synostosis of the third and fourth fingers; (2) severe bone reduction in the proximal phalanges of the same fingers; (3) hypoplasia of the thumbs and halluces; (4) aplasia/hypoplasia of the middle phalanges of the second and fifth fingers; and (5) complete or partial soft tissue syndactyly of the toes. We report on three offspring with this phenotype from two different branches of a syndactyly type I family, suggesting that they may be homozygous for this condition. SSCP and linkage analysis indicated that neither HOXD13 nor other relevant genes in the chromosome 2q31 region was responsible for this phenotype.


Taq DNA polymerase slippage mutation rates measured by PCR and quasi-likelihood analysis: (CA/GT)n and (A/T)n microsatellites.
During microsatellite polymerase chain reaction (PCR), insertion-deletion mutations produce stutter products differing from the original template by multiples of the repeat unit length. We analyzed the PCR slippage products of (CA)n and (A)n tracts cloned in a pUC18 vector. Repeat numbers varied from two to 14 (CA)n and four to 12 (A)n. Data was generated on approximately 10 single molecules for each clone type using two rounds of nested PCR. The size and peak areas of the products were obtained by capillary electrophoresis. A quasi- likelihood approach to the analysis of the data estimated the mutation rate/repeat/PCR cycle. The rate for (CA)n tracts was 3.6 x 10(-3) with contractions 14 times greater than expansions. For (A)n tracts the rate was 1.5 x 10(-2) and contractions outnumbered expansions by 5-fold. The threshold for detecting 'stutter' products was computed to be four repeats for (CA)n and eight repeats for (A)n or approximately 8 bp in both cases. A comparison was made between the computationally and experimentally derived threshold values. The threshold and expansion to contraction ratios are explained on the basis of the active site structure of Taq DNA polymerase and models of the energetics of slippage events, respectively.


Kinesio Taping in Dysphonic Patients.
Kinesio taping (KT) is a method of elastic bandaging that produces a biomechanical effect on the organism. This study aims to evaluate its use in dysphonic patients tratment, as integrated part of speech therapy. Randomized controlled MATERIALS AND METHODS: Fifteen dysphonic patients were given the option to complement the speech therapy treatment with KT (DG1). 15 dysphonic patients suffering from similar conditions (DG2) who underwent traditional speech therapy were the control group. After treatment, both DG1 and DG2 obtained a statistically significant improvement for jitter and noise-to-harmonic ratio (P >0.05) and showed an improvement in Voice Handicap Index (VHI) total (VHIt), VHI functional (VHIf), VHI emotional (VHIe), and VHI physical (VHIp). However, the improvement was statistically significant for VHIt (P =0.0102), VHIe (P =0.0349), and VHIp (P =0.0366) in DG1, and only in VHIt (P =0.0466) in DG2. In DG1, P had a lower value than in DG2 for VHIt, VHIe, and VHIp. In DG2, there were a few patients who after therapy had a VHIt higher than before therapy, whereas this did not occur in DG1. As expected, this study confirms the benefits of speech therapy. Although KT is not a substitute for speech therapy, our preliminary results and patients' favorable response to KT encouraged us to continue with our studies on a larger scale. Further studies are required to better define the role of KT in speech therapy and evaluate its real effect over its placebo effect.


Effects of DNA damage induced by UV irradiation on gene expression in the protozoan parasite Entamoeba histolytica.
Previously, we provided evidence for the role of E. histolytica RAD52 epistasis group genes and the EhRAD51 recombinase in DNA damage response. To identify other genes participating in DNA repair in this protozoan parasite, here we analyzed the transcriptional response to genetic damage induced by ultraviolet light (UV) using cDNA microarrays. We found that 11.6% (350 ORFs) and 17.2% (522 ORFs) of genes were modulated at 5 min and 3h after UV irradiation, respectively. Most genes were less than 2-fold changed evidencing a weak transcriptional activation. The genes encoding so-called "classical" DNA repair proteins were slightly regulated in trophozoites submitted to UV irradiation. We also observed the over-expression of genes encoding for Fe-S clusters-containing proteins, potentially involved in the stress adaptation in response to DNA damage. Several genes encoding cytoskeleton proteins were repressed suggesting that actin dynamics was impaired after UV irradiation. Our analysis highlights novel genes potentially involved in DNA damage response, and these data will contribute to further elucidation of mechanisms regulating genome integrity in this early branch protozoan.


Magnetic vortex nucleation and annihilation in bi-stable ultra-small ferromagnetic particles.
Vortex-mediated magnetization reversal in individual ultra-small (∼100 nm) ferromagnetic particles at low temperatures is studied by nanoSQUID magnetometry. At zero applied bias field, the flux-closure magnetic state (vortex) and the quasi uniform configuration are bi-stable. This stems from the extremely small size of the nanoparticles that lies very close to the limit of single-domain formation. The analysis of the temperature-dependent (from 0.3 to 70 K) hysteresis of the magnetization allows us to infer the nature of the ground state magnetization configuration. The latter corresponds to a vortex state as also confirmed by electron holography experiments. Based on the simultaneous analysis of the vortex nucleation and annihilation data, we estimate the magnitude of the energy barriers separating the quasi single-domain and the vortex state and their field dependence. For this purpose, we use a modified power-law scaling of the energy barriers as a function of the applied bias field. These studies are essential to test the thermal and temporal stability of flux-closure states stabilized in ultra-small ferromagnets.


Qualitative Research for One Health: From Methodological Principles to Impactful Applications.
The One Health concept has inspired a rich vein of applied research and scholarly reflection over the past decade, yet with little influence from qualitative methodologists. With this overview, we describe the underpinning assumptions, purposes, and potential pitfalls of data collection techniques and methods of data analysis in key qualitative research methodologies. Our aim is to enhance One Health collaborations involving qualitative researchers, veterinary epidemiologists, and veterinary economists. There exist several distinct traditions of qualitative research, from which we draw selectively for illustrative purposes. Notwithstanding important distinctions, we emphasize commonalities and the potential for collaborative impact. The most important commonality is a shared focus on contextualizing human behavior and experience-culturally, economically, historically, and socially. We demonstrate that in-depth attention to context can assist veterinary economists and epidemiologists in drawing lessons from the implementation of policies and programs. In other words, qualitative researchers can assist One Health teams in distilling insights from "success stories," but also from adverse events and unintended consequences. As a result, qualitative researchers can contribute to One Health research and policy discussions by formulating more accurate and contextually-relevant parameters for future quantitative studies. When performed well, qualitative methodologies can help veterinary economists and epidemiologists to develop impactful research questions, to create more accurate and contextually-relevant parameters for quantitative studies, and to develop policy recommendations and interventions that are attuned to the political and socio-cultural context of their implementation. In sketching out the properties and features of influential methodologies, we underscore the value of working with seasoned qualitative researchers to incorporate questions about "what," "how," and "why" in mixed-methods research designs.


A comprehensive atlas of white matter tracts in the chimpanzee.
Chimpanzees (Pan troglodytes) are, along with bonobos, humans' closest living relatives. The advent of diffusion MRI tractography in recent years has allowed a resurgence of comparative neuroanatomical studies in humans and other primate species. Here we offer, in comparative perspective, the first chimpanzee white matter atlas, constructed from in vivo chimpanzee diffusion-weighted scans. Comparative white matter atlases provide a useful tool for identifying neuroanatomical differences and similarities between humans and other primate species. Until now, comprehensive fascicular atlases have been created for humans (Homo sapiens), rhesus macaques (Macaca mulatta), and several other nonhuman primate species, but never in a nonhuman ape. Information on chimpanzee neuroanatomy is essential for understanding the anatomical specializations of white matter organization that are unique to the human lineage.


Decreased 5-HT-mediated prolactin release in major depression.
The prolactin response to intravenous clomipramine, a 5-HT uptake inhibitor, was significantly attenuated in 12 patients with major depression. In contrast, in a further 12 depressed patients, the PRL responses to thyrotropin-releasing hormone, which acts directly on the pituitary to release PRL, were not reduced. These findings suggest that the reduction in 5-HT-mediated PRL release seen in depressed patients is due to an impairment of brain 5-HT function rather than a pituitary abnormality.


Patient-reported outcome (PRO) assessment in clinical trials: a systematic review of guidance for trial protocol writers.
Evidence suggests there are inconsistencies in patient-reported outcome (PRO) assessment and reporting in clinical trials, which may limit the use of these data to inform patient care. For trials with a PRO endpoint, routine inclusion of key PRO information in the protocol may help improve trial conduct and the reporting and appraisal of PRO results; however, it is currently unclear exactly what PRO-specific information should be included. The aim of this review was to summarize the current PRO-specific guidance for clinical trial protocol developers. We searched the MEDLINE, EMBASE, CINHAL and Cochrane Library databases (inception to February 2013) for PRO-specific guidance regarding trial protocol development. Further guidance documents were identified via Google, Google scholar, requests to members of the UK Clinical Research Collaboration registered clinical trials units and international experts. Two independent investigators undertook title/abstract screening, full text review and data extraction, with a third involved in the event of disagreement. 21,175 citations were screened and 54 met the inclusion criteria. Guidance documents were difficult to access: electronic database searches identified just 8 documents, with the remaining 46 sourced elsewhere (5 from citation tracking, 27 from hand searching, 7 from the grey literature review and 7 from experts). 162 unique PRO-specific protocol recommendations were extracted from included documents. A further 10 PRO recommendations were identified relating to supporting trial documentation. Only 5/162 (3%) recommendations appeared in ≥50% of guidance documents reviewed, indicating a lack of consistency. PRO-specific protocol guidelines were difficult to access, lacked consistency and may be challenging to implement in practice. There is a need to develop easily accessible consensus-driven PRO protocol guidance. Guidance should be aimed at ensuring key PRO information is routinely included in appropriate trial protocols, in order to facilitate rigorous collection/reporting of PRO data, to effectively inform patient care.


Distribution of olfactory receptor genes in the human genome.
We demonstrate that members of the olfactory receptor (OR) gene family are distributed on all but a few human chromosomes. Through FISH analysis, we show that OR sequences reside at more than 25 locations in the human genome. Their distribution is biased for terminal bands. Flow-sorted chromosomes were used to isolate 87 OR sequences derived from 16 chromosomes. Their sequence-relationships are indicative of the inter- and intrachromosomal duplications responsible for OR family expansion. The human genome has accumulated a striking number of dysfunctional copies: 72% of the sequences are pseudogenes. ORF-containing sequences predominate on chromosomes 7, 16 and 17.


Selective inhibition of HIV-1 reverse transcriptase-associated ribonuclease H activity by hydroxylated tropolones.
High-throughput screening of a National Cancer Institute library of pure natural products identified the hydroxylated tropolone derivatives beta-thujaplicinol (2,7-dihydroxy-4-1(methylethyl)-2,4,6-cycloheptatrien-1-one) and manicol (1,2,3,4-tetrahydro-5-7-dihydroxy-9-methyl-2-(1-methylethenyl)-6H-benzocyclohepten-6-one) as potent and selective inhibitors of the ribonuclease H (RNase H) activity of human immunodeficiency virus-type 1 reverse transcriptase (HIV-1 RT). beta-Thujaplicinol inhibited HIV-1 RNase H in vitro with an IC50 of 0.2 microM, while the IC50 for Escherichia coli and human RNases H was 50 microM and 5.7 microM, respectively. In contrast, the related tropolone analog beta-thujaplicin (2-hydroxy-4-(methylethyl)-2,4,6-cycloheptatrien-1-one), which lacks the 7-OH group of the heptatriene ring, was inactive, while manicol, which possesses a 7-OH group, inhibited HIV-1 and E.coli RNases H with IC50 = 1.5 microM and 40 microM, respectively. Such a result highlights the importance of the 2,7-dihydroxy function of these tropolone analogs, possibly through a role in metal chelation at the RNase H active site. Inhibition of HIV-2 RT-associated RNase H indirectly indicates that these compounds do not occupy the nonnucleoside inhibitor-binding pocket in the vicinity of the DNA polymerase domain. Both beta-thujaplicinol and manicol failed to inhibit DNA-dependent DNA polymerase activity of HIV-1 RT at a concentration of 50 microM, suggesting that they are specific for the C-terminal RNase H domain, while surface plasmon resonance studies indicated that the inhibition was not due to intercalation of the analog into the nucleic acid substrate. Finally, we have demonstrated synergy between beta-thujaplicinol and calanolide A, a nonnucleoside inhibitor of HIV-1 RT, raising the possibility that both enzymatic activities of HIV-1 RT can be simultaneously targeted.