Phylogeographic analysis delimits three evolutionary significant units of least chipmunks in North America and identifies unique genetic diversity within the imperiled Peñasco population.
Although least chipmunks (Neotamias minimus) are a widely distributed North American species of least concern, the southernmost population, N. m. atristriatus (Peñasco least chipmunk), is imperiled and a candidate for federal listing as a subspecies. We conducted a phylogeographic analysis across the N. minimus range to assess genomic differentiation and distinctiveness of the N. m. atristriatus population. Additionally, we leveraged the historical component of sampling to conduct a temporal analysis of N. minimus genetic diversity and also considered climate change effects on range persistence probability by projecting a species distribution model into the IPCC5 RCP 2.6 and 8.5 scenarios. We identified three geographically structured groups (West, North, and South) that were supported by both mitochondrial and nuclear data. N. m. atristriatus grouped within a unique South subclade but were not reciprocally monophyletic from N. m. operarius, and nuclear genome analyses did not separate N. m. atristriatus, N. m. caryi, and N. m. operarius. Thus, while least chipmunks in the Southwest represent an evolutionary significant unit, subspecies distinctions were not supported and listing of the Peñasco population as a Distinct Population Segment of N. m. operarius may be warranted. Our results also support consideration of populations with North and West mitogenomes as two additional evolutionary significant units. We found that N. minimus genetic diversity declined by ~87% over the last century, and our models predicted substantial future habitat contraction, including the loss of the full contemporary ranges of N. m. atristriatus, N. m. arizonensis, and N. m. chuskaensis.


Identification of a new small ubiquitin-like modifier (SUMO)-interacting motif in the E3 ligase PIASy.
Small ubiquitin-like modifier (SUMO) conjugation is a reversible post-translational modification process implicated in the regulation of gene transcription, DNA repair, and cell cycle. SUMOylation depends on the sequential activities of E1 activating, E2 conjugating, and E3 ligating enzymes. SUMO E3 ligases enhance transfer of SUMO from the charged E2 enzyme to the substrate. We have previously identified PIASy, a member of the Siz/protein inhibitor of activated STAT (PIAS) RING family of SUMO E3 ligases, as essential for mitotic chromosomal SUMOylation in frog egg extracts and demonstrated that it can mediate effective SUMOylation. To address how PIASy catalyzes SUMOylation, we examined various truncations of PIASy for their ability to mediate SUMOylation. Using NMR chemical shift mapping and mutagenesis, we identified a new SUMO-interacting motif (SIM) in PIASy. The new SIM and the currently known SIM are both located at the C terminus of PIASy, and both are required for the full ligase activity of PIASy. Our results provide novel insights into the mechanism of PIASy-mediated SUMOylation. PIASy adds to the growing list of SUMO E3 ligases containing multiple SIMs that play important roles in the E3 ligase activity.


Bone morphogenetic protein signal transduction in bone.
Bone morphogenetic proteins (BMPs) promote bone formation by stimulating the proliferation and differentiation of osteoblasts. It has been suggested that non-union of the bone, and delayed healing, may be the result of decreased levels of BMP activity. Activation of BMP receptors initiates phosphorylation of the downstream effector proteins, known as receptor-regulated Smads, leading to signal transduction. Receptor-regulated Smads form a hetero-oligomeric complex with a common mediator Smad, which translocates into the nucleus and regulates target gene transcription. The BMP signalling cascade is closely regulated, with the inhibitory Smads blocking the intracellular signal cascade. Extracellular antagonists, such as noggin, inhibit binding to BMP receptors. BMP-2 and BMP-7 have demonstrated clinical utility for bone regeneration, and are commercially available through the use of recombinant DNA technology.


Wilks' Λ dissimilarity measures for gene clustering: an approach based on the identification of transcription modules.
Clustering methods are widely used in the analysis of microarray data for their ability to uncover coordinated expression profiles. One important goal of clustering is to discover coregulated genes because it has been postulated that genes targeted by the same transcription factors tend to show similar expression patterns. We focus on agglomerative hierarchical clustering and consider the problem of choosing a dissimilarity measure on the basis of its ability to identify functional modules consisting of a transcription factor and the associated target genes. We first propose two criteria that constitute a theoretical framework for assessing the adequacy and comparing different dissimilarity measures. We show that the proposed criteria allow one to gain insight into the behavior of dissimilarity measures and lead to a ranking of some of the most commonly used dissimilarity measures. Next, we introduce two dissimilarity measures based on the Wilks' Λ statistic and show that, according to the above criteria, they have better performance than the other considered measures. The theoretical results are supported by an applied analysis on both simulated and real data.


Applications of GeneMark in multispecies environments.
This paper is supposed to bridge the gap between practical experience in using GeneMark for a rapidly widening repertoire of genomes, and the available publications that determine and compare the gene prediction accuracy of the GeneMark method for different genomes. Here we focus on the genome-specific variability of prediction error rates and their sources. DNA sequence inhomogeneity is present both in training and control sets of coding and non-coding regions. Coding region inhomogeneity, caused by differences in sequence composition between "native" and horizontally transferred genes or between genes expressed at different levels, contributes to the false negative error rate. Inhomogeneity of non-coding region may frequently be caused by the presence of unnoticed genes and contributes to the false positive error rate. We have documented such unnoticed genes in GenBank sequences for several species Some of protein products of these genes have been characterized by similarity search methods. For others, which we call "pioneer genes", no significant similarity has been found at a protein sequence level although the confidence of GeneMark prediction is high. For instance, to date a majority of those pioneer gene predictions made for E. coli now show strong similarity to more recently characterized proteins that have been added to protein sequence database. Another practical question is related to genomic sequence inhomogeneity at interspecies level: if GeneMark has not been trained for a particular species, is it possible to apply models derived for phylogenetically close genomes? The answer is, yes. The results of cross-species gene prediction experiments show that cross-species prediction can often be reasonably accurate.


Mass Spectrometry-Based Fast Photochemical Oxidation of Proteins (FPOP) for Higher Order Structure Characterization.
Assessment of protein structure and interaction is crucial for understanding protein structure/function relationships. Compared to high-resolution structural tools, including X-ray crystallography, nuclear magnetic resonance (NMR), and cryo-EM, and traditional low-resolution methods, such as circular dichroism, UV-vis, and florescence spectroscopy, mass spectrometry (MS)-based protein footprinting affords medium-to-high resolution (i.e., regional and residue-specific insights) by taking advantage of proteomics methods focused on the primary structure. The methodology relies on "painting" the reactive and solvent-exposed amino acid residues with chemical tags and using the pattern of modifications as footprints from analysis by bottom-up MS-based proteomics to deduce protein higher order structures. The outcome can refer to proteins in solution or even in cells and is complementary to those of X-ray crystallography and NMR. It is particularly useful in mapping protein-ligand interfaces and conformational changes resulting from ligand binding, mutation, and aggregation. Fast photochemical oxidation of proteins (FPOP), in its original conception, is a type of hydroxyl-radical-based protein footprinting that utilizes a pulsed KrF laser (248 nm) to trigger hydrolysis of hydrogen peroxide to produce solution hydroxyl radicals, which subsequently modify the protein in situ. The platform is expanding to adopt other reactive species including carbenes. The reactivity of the probe depends on the intrinsic reactivity of the radical with the residue side chain and the solvent accessibility of the residue as a function of the tertiary/quaternary structures. By introducing an appropriate scavenger to compete with hydroxyl radical self-quenching, the lifetime of the primary radicals is remarkably shortened to approximately microsecond. Thus, the sampling time scale of FPOP is much faster than hydrogen-deuterium exchange and other covalent labeling methods relying on nonradical reactions. The short footprinting time scale of FPOP offers two major advantages for protein structure elucidation: (1) it allows the protein to be interrogated in its native or near-native state with minimum structural perturbation; (2) it exhibits high sensitivity toward alterations in protein higher order structures because its sampling time is short with respect to protein conformational changes and dynamic motion. In addition, the covalent and irreversible oxidation by the hydroxyl radical provides more flexibility in the downstream proteomics workflow and MS analysis, permitting high spatial resolution with residue-specific information. Since its invention in 2005 by Hambly and Gross, FPOP has developed from proof-of-concept to a valuable biophysical tool for interrogating protein structure. In this Account, we summarize the principles and experimental design of FPOP that enable its fast labeling and describe the current and unique capabilities of the technique in protein higher order structure elucidation. Application examples include characterization of amyloid β self-assembly, protein-ligand interactions with a special emphasis on epitope mapping for protein therapeutics (e.g., antibody, Fab, and adnectin), protein folding detailed to residue-specific folding kinetics, and protein flexibility/dynamics. Additionally, the utility of FPOP-based oxidative footprinting should grow with our continuing developments of novel reagents (e.g., sulfate radical anion, carbene diradical, and trifluoromethyl radical). These reactive reagents are compatible with the current FPOP platform and offer different reactivity and selectivity toward various types of amino acid residues, providing complementary insights into protein higher order structures for soluble proteins and ultimately for membrane-bound proteins.


CD56 Expression Is an Important Prognostic Factor in Multiple Myeloma Even with Bortezomib Induction.
In this retrospective study, we evaluated the impact of CD56, CD117, and CD28 expression on clinical characteristics and survival in newly diagnosed myeloma patients treated with bortezomib-based induction therapy. We analyzed 110 myeloma patients. Immunophenotype was determined using panels consisting of CD19/CD38/CD45/CD56/CD138 and CD20, CD28, and CD117 were used additionally. All samples were tested for recurrent chromosomal aberrations. CD56, CD117, and CD28 expression rates were 71, 6, and 68%, respectively. The lack of CD56 expression was associated with light chain myeloma. The lack of CD117 expression was associated with elevated creatinine levels (p = 0.037). We discovered the correlation between CD 28 expression and female gender. The median progression-free survival (PFS) for patients with revised International Staging System stage 2 disease with CD56 expression or the lack of CD56 expression was 20.5 vs. 13.8 months (p = 0.03). In patients undergoing autologous hematopoietic stem cell transplantation (aHSCT), we found no difference in PFS and overall survival regarding the CD56 expression. We found no impact of CD117 and CD28 expression on PFS in patients regarding aHSCT. Induction treatment incorporating bortezomib diminishes the negative impact of the lack of CD117 expression and aberrancy of CD28 but does not overcome the negative impact of the lack of CD56 expression.


Global transcriptome analysis of Borrelia burgdorferi during association with human neuroglial cells.
As adherence and entry of a pathogen into a host cell are key components to an infection, identifying the molecular mechanisms responsible for cellular association will provide a better understanding of a microbe's pathogenesis. We previously established an in vitro model for Borrelia burgdorferi infection of human neuroglial cells. To expand on our earlier study, we performed B. burgdorferi whole-genome expression analysis following a 20-hour infection of human neuroglial cells to identify borrelial genes that were differentially regulated during host-cell association compared with cultured Borrelia in cell-free medium. This study identifies several regulated genes, the products of which may be important mediators of cellular pathogenesis.


Fourth International Conference: Modern Vaccines/Adjuvants Formulation--Impact on Future Development: May 15-17 2013, CHUV, Lausanne, Switzerland.
On the 15-17th of May 2013, about 120 scientists, postdoctoral fellows and professors representing renowned academic institutes and senior scientists and executives from small biotechs, contract research organizations (CROs) and Big Pharma companies, gathered at the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland for the 4th international conference on Modern Vaccines and Adjuvants Formulation. Despite this relative small number, the speakers and attendees covered together a very broad field of expertise. Indeed, experts in microbiology, immunology, biochemistry, formulation, virus and nanoparticle characterization, vaccine production, quality control as well as regulatory professionals attended the conference and were able to present their works and discuss new developments within the field of vaccine and adjuvant development, characterization and approval process. This broad diversity was a highpoint of the conference and allowed for a stimulating environment and underlined the complexity of the challenges that the field currently faces in order to develop better or completely new vaccines and adjuvants.


The PreDoc Program: Pipeline Healthcare Apprenticeship Program through the Lens of a Neurologist.
This article was migrated. The article was marked as recommended. Objective: The PreDoc program is a longitudinal apprenticeship aimed at increasing college student interest in pursuing a healthcare career. This program offers the continuity of clinical, research, and educational exposure in academic medicine utilizing a career immersion approach that allows a graduated level of responsibility, experience, and leadership opportunities. Methods: Students get an asynchronous/synchronous curriculum under the direction of academic physicians committed to boosting the pipeline. Training in critical career development skills including "goal setting," professionalism, communication, and time management are provided to Pre-Docs by their senior peers and program leaders. Results: Since the implementation of the PreDoc program in 2013, 28 students have enrolled in the program. Twenty-three students completed the survey; 100% ranked the program quality as good/excellent. Students reported more interest in academic medicine (n=19, 83%), neurology (n=18, 78%), and sleep medicine (n=18, 78%). A majority of the students reported that they were extremely likely to pursue a medical career (n=20, 87%). All students have completed or are in the process of completing at least one scholarly product. Conclusions: The PreDoc program has been successful in promoting college student scholarly productivity in healthcare and in garnering student interest in academic medicine, particularly in neurology.


Effect of heating temperature and time on the phosphate adsorption capacity of thermally modified copper tailings.
In the present study, copper tailings were treated at different temperatures (50-650 °C) and for various times (0.5-6 hours) and their phosphate adsorption capacity was investigated. The results showed that heating temperature significantly affected adsorption capacity. The highest capacity was observed in treatments at 310-350 °C. Heating time did not influence phosphate adsorption ability of copper tailings. Scanning electron microscopy, Barrett-Joyner-Halenda (BJH), and Fourier transform infrared spectroscopy (FTIR) were employed to characterize untreated copper tailings (raw CT) and copper tailings heated at 340 °C (CT340). The results showed that CT340 had a rougher surface, more and smaller pores, a larger surface area and higher FTIR transmittance than raw CT. These changes in texture might explain the increased phosphate adsorption of thermally modified copper tailings. Mathematical modeling showed that the Langmuir nonlinear model was the best fit to the current data. The maximum adsorption capacities of raw CT and CT340 were predicted as 2.08 mg/g and 14.25 mg/g at 298 K, pH 6.0, respectively.


[Diagnosis and treatment of vascular erectile dysfunction with the vibration-vacuum penis stimulator "Sanos"].
The paper describes a new device for treatment of vascular erectile dysfunction--the vibrovacuum fallostimulator "Sanos". This method differs from conventional local decompression in a dynamic regimen of vacuum effect on the penis in the presence of vibration. The resultant reduced exposure of the organ to vacuum prevents such serious complications as edema, hemorrhages and necrosis of penile skin. The dynamic vacuum regimen is also effective in restoring erectile activity of the penis producing erection similar to physiological. A 10-15-day course of vibrovacuum fallostimulation was conducted in 330 patients with vascular erectile dysfunction. Recovery of arteriocavernous blood flow was registered in 92.1%. No complications occurred. The above method can be also applied for diagnosis of both insufficient arterial circulation in the penis and defects in venoocclusive mechanism of erection.


Involvement of miR-495 in the skin pigmentation of rainbow trout (Oncorhynchus mykiss) through the regulation of mc1r.
MicroRNAs (miRNAs) play crucial roles in skin pigmentation in animals. Rainbow trout (Oncorhynchus mykiss) is a key economic fish species worldwide, and skin color directly affects its economic value. However, the functions of miRNAs in rainbow trout skin pigmentation remain largely unknown. Herein, we overexpressed and silenced miR-495 in vitro and in vivo to investigate its functions. The analysis of spatial and temporal expression patterns suggested that miR-495 is a potential regulator during the process of skin pigmentation. In vitro, mc1r was validated as a direct target for miR-495 by dual-luciferase reporter assay, and overexpression of miR-495 significantly inhibited mc1r expression; in contrast, mc1r and its downstream gene mitf levels were markedly upregulated by decreased miR-495. In vivo, overexpressed miR-495 by injecting agomiR-495 led to a substantial decrease in the expression of mc1r and mitf in dorsal skin and liver, while the opposite results were obtained after miR-495 silencing by antagomiR-495. These findings suggested that miR-495 can target mc1r to regulate rainbow trout skin pigmentation, which provide a potential basis for using miRNAs as target drugs to treat pigmentation disorders and melanoma.


Studies of cell adhesion and flow cytometric analyses of degranulation, surface phenotype, and viability using human eosinophils, basophils, and mast cells.
Products derived from eosinophils, basophils, and mast cells are considered critical to the development of allergic diseases. Studies of the selective recruitment, accumulation, and/or activation of these cells during human allergic inflammatory reactions in vitro and in vivo have been facilitated by a wide variety of methods. Some have been developed to identify and isolate these cells from a variety of sites, including blood, airway secretions, and surgical or autopsy tissues. Once enriched in purity, assays of cell adhesion to endothelium, epithelium, matrix proteins, and purified, immobilized counterligands for integrins, selectins, or immunoglobulin gene superfamily structures can be performed in vitro under both static and flow conditions. Techniques involving flow cytometry, utilizing characteristics of cellular light scatter and immunofluorescence, have permitted the elucidation of cell surface phenotype and have aided in quantification of cellular degranulation and viability. These approaches have yielded new information on the function of human eosinophils, basophils, and mast cells and have suggested unique cell-specific pathways of cell recruitment, activation, and survival that may contribute to the pathogenesis of allergic diseases.


Incidence and Persistence of Viral Shedding in COVID-19 Post-acute Patients With Negativized Pharyngeal Swab: A Systematic Review.
After the global spread of a severe acute respiratory syndrome caused by a coronavirus (SARS-CoV-2), factors that influence viral diffusion have gained great attention. Human-to-human transmission mainly occurs through droplets, but viral RNA clearance in different biological fluids in coronavirus disease 2019 (COVID-19) remains unclear. We aimed to correlate the presence and the relevant temporal patterns of SARS-CoV-2 viral RNA in biological specimens (stool, urine, blood, and tears) of the transmission with clinical/epidemiological features in patients with COVID-19. We focused on the time window between the positivity of reverse transcriptase-polymerase chain reaction (RT-PCR) tests from different specimens. We used the Mantel-Cox log rank test to verify the differences in terms of viral shedding duration, while we employed the Mann-Whitney U-test for subgroup analysis. This review protocol was registered with PROSPERO number: CRD42020183629. We identified 147 studies; we included 55 (1,348 patients) for epidemiological analysis, of which we included 37 (364 patients) for statistical analysis. The most frequently used specimens other than respiratory tract swabs were stool samples (or anal/rectal swabs), with a positivity rate of 48.8%, followed by urine samples, with a positivity rate of 16.4%; blood samples showed a positivity rate of 17.5%. We found that fecal positivity duration (median 19 days) was significantly (p < 0.001) longer than respiratory tract positivity (median 14 days). Limited data are available about the other specimens. In conclusion, medical and social communities must pay close attention to negativization criteria for COVID-19, because patients could have longer alternative viral shedding.


The winners know how to change--do you?
Major change is always costly, but when maintaining the status quo is even more expensive, a strategic imperative for change has been created. The process of managing change is not focused on what to change, but how change decisions can be implemented successfully. Successful organizations achieve their change objectives (human and technical) on time and within budget. Unsuccessful organizations either never accomplish what they plan or do so only after consuming a great deal more time and money than they anticipated. This article introduces an abbreviated review of the ten best practices associated with change management. The reader will recognize the multitude of variables that can be relevant to any change effort and begin to assess the matrix relationship between these interdependent variables.


Neuromuscular electrical stimulation as an adjunct to endurance and resistance training during pulmonary rehabilitation in stable chronic obstructive pulmonary disease.
The purpose of this study was to investigate whether adding neuromuscular electrical stimulation (NMES) to a comprehensive pulmonary rehabilitation (cPR) program would have additive effects on clinical-functional outcomes. Twenty-seven chronic obstructive pulmonary disease patients participating in a 10-week cPR program were randomly allocated to NMES + cPR (n = 13) or Sham + cPR (n = 14) groups. Quadriceps strength, exercise capacity, symptoms, mood, activities of daily living and quality of life were evaluated pre- and post-interventions. There were no significant differences in any of the physiological and subjective improvements induced by NMES + cPR versus Sham + cPR (p > 0.05). In fact, the NMES + cPR group showed lower increases in incremental shuttle walk test (ISWT) distance (38.4 vs 69.2 m, respectively) and %ISWT distance (5.1 vs 9%, respectively) compared with the Sham + cPR group (p < 0.05). The increase in exercise capacity is less important when NMES is used as an adjunct to the cPR.


A cohort study of banana plantation workers in the French West Indies: first mortality analysis (2000-2015).
Chlordecone, an organochlorine insecticide, was widely used in the French West Indies banana plantations. We set up a cohort of banana plantation workers who worked between 1973 and 1993, the period of authorized use of chlordecone. Vital status and causes of death were collected from French national registries. Workers were followed up from 1 January 2000 to 31 December 2015. Cause-specific mortality in the cohort was compared to that of the general population of the French West Indies by computing standardized mortality ratios (SMRs). A total of 11,112 workers (149,526 person-years, 77% men) were included in the mortality analysis, and 3647 deaths occurred over the study period. There was a slight deficit in all-cause mortality, which was statistically significant in men (SMR = 0.93, 95% CI 0.89-0.96), but not in women (SMR = 0.96, 95% CI 0.89-1.04). All-cancer mortality did not differ significantly from that of the general population (men: SMR = 0.96, 95% CI 0.90-1.03; women: SMR = 1.04, 95% CI 0.89-1.21). Significant excesses of deaths were observed for stomach cancer in women (SMR = 1.94, 95% CI 1.24-2.89) and pancreatic cancer in women farm owners (SMR = 2.31, 95% CI 1.06-4.39). Mortality from prostate cancer was similar to that of the general population in the whole cohort (SMR = 1.00; 95% CI 0.89-1.13) and non-significantly elevated among farm workers (SMR = 1.10, 95% CI 0.87-1.36). Non-significant increases in mortality were also observed for lung cancer in women, leukemia in men, and non-Hodgkin lymphoma in both genders.


High-resolution mapping of genomic imbalance and identification of gene expression profiles associated with differential chemotherapy response in serous epithelial ovarian cancer.
Array comparative genomic hybridization (aCGH) and microarray expression profiling were used to subclassify DNA and RNA alterations associated with differential response to chemotherapy in ovarian cancer. Two to 4 Mb interval arrays were used to map genomic imbalances in 26 sporadic serous ovarian tumors. Cytobands 1p36, 1q42-44, 6p22.1-p21.2, 7q32.1-q34 9q33.3-q34.3, 11p15.2, 13q12.2-q13.1, 13q21.31, 17q11.2, 17q24.2-q25.3, 18q12.2, and 21q21.2-q21.3 were found to be statistically associated with chemotherapy response, and novel regions of loss at 15q11.2-q15.1 and 17q21.32-q21.33 were identified. Gene expression profiles were obtained from a subset of these tumors and identified a group of genes whose differential expression was significantly associated with drug resistance. Within this group, five genes (GAPD, HMGB2, HSC70, GRP58, and HMGB1), previously shown to form a nuclear complex associated with resistance to DNA conformation-altering chemotherapeutic drugs in in vitro systems, may represent a novel class of genes associated with in vivo drug response in ovarian cancer patients. Although RNA expression change indicated only weak DNA copy number dependence, these data illustrate the value of molecular profiling at both the RNA and DNA levels to identify small genomic regions and gene subsets that could be associated with differential chemotherapy response in ovarian cancer.


Octadecaneuropeptide (ODN) Induces N2a Cells Differentiation through a PKA/PLC/PKC/MEK/ERK-Dependent Pathway: Incidence on Peroxisome, Mitochondria, and Lipid Profiles.
Neurodegenerative diseases are characterized by oxidative stress, mitochondrial damage, and death of neuronal cells. To counteract such damage and to favor neurogenesis, neurotrophic factors could be used as therapeutic agents. Octadecaneuropeptide (ODN), produced by astrocytes, is a potent neuroprotective agent. In N2a cells, we studied the ability of ODN to promote neuronal differentiation. This parameter was evaluated by phase contrast microscopy, staining with crystal violet, cresyl blue, and Sulforhodamine 101. The effect of ODN on cell viability and mitochondrial activity was determined with fluorescein diacetate and DiOC6(3), respectively. The impact of ODN on the topography of mitochondria and peroxisomes, two tightly connected organelles involved in nerve cell functions and lipid metabolism, was evaluated by transmission electron microscopy and fluorescence microscopy: detection of mitochondria with MitoTracker Red, and peroxisome with an antibody directed against the ABCD3 peroxisomal transporter. The profiles in fatty acids, cholesterol, and cholesterol precursors were determined by gas chromatography, in some cases coupled with mass spectrometry. Treatment of N2a cells with ODN (10-14 M, 48 h) induces neurite outgrowth. ODN-induced neuronal differentiation was associated with modification of topographical distribution of mitochondria and peroxisomes throughout the neurites and did not affect cell viability and mitochondrial activity. The inhibition of ODN-induced N2a differentiation with H89, U73122, chelerythrine and U0126 supports the activation of a PKA/PLC/PKC/MEK/ERK-dependent signaling pathway. Although there is no difference in fatty acid profile between control and ODN-treated cells, the level of cholesterol and some of its precursors (lanosterol, desmosterol, lathosterol) was increased in ODN-treated cells. The ability of ODN to induce neuronal differentiation without cytotoxicity reinforces the interest for this neuropeptide with neurotrophic properties to overcome nerve cell damage in major neurodegenerative diseases.


Floral Induction in the Short-Day Plant Chrysanthemum Under Blue and Red Extended Long-Days.
Shorter photoperiod and lower daily light integral (DLI) limit the winter greenhouse production. Extending the photoperiod by supplemental light increases biomass production but inhibits flowering in short-day plants such as Chrysanthemum morifolium. Previously, we reported that flowering in growth-chamber grown chrysanthemum with red (R) and blue (B) LED-light could also be induced in long photoperiods by applying only blue light during the last 4h of 15h long-days. This study investigates the possibility to induce flowering by extending short-days in greenhouses with 4h of blue light. Furthermore, flower induction after 4h of red light extension was tested after short-days RB-LED light in a growth-chamber and after natural solar light in a greenhouse. Plants were grown at 11h of sole source RB light (60:40) in a growth-chamber or solar light in the greenhouse (short-days). Additionally, plants were grown under long-days, which either consisted of short-days as described above extended with 4h of B or R light to long-days or of 15h continuous RB light or natural solar light. Flower initiation and normal capitulum development occurred in the blue-extended long-days in the growth-chamber after 11h of sole source RB, similarly as in short-days. However, when the blue extension was applied after 11h of full-spectrum solar light in a greenhouse, no flower initiation occurred. With red-extended long-days after 11h RB (growth-chamber) flower initiation occurred, but capitulum development was hindered. No flower initiation occurred in red-extended long-days in the greenhouse. These results indicate that multiple components of the daylight spectrum influence different phases in photoperiodic flowering in chrysanthemum in a time-dependent manner. This research shows that smart use of LED-light can open avenues for a more efficient year-round cultivation of chrysanthemum by circumventing the short-day requirement for flowering when applied in emerging vertical farm or plant factories that operate without natural solar light. In current year-round greenhouses' production, however, extension of the natural solar light during the first 11 h of the photoperiod with either red or blue sole LED light, did inhibit flowering.


Ambient fine particulate matter air pollution and the risk of hospitalization among COVID-19 positive individuals: Cohort study.
Ecologic analyses suggest that living in areas with higher levels of ambient fine particulate matter air pollution (PM2.5) is associated with higher risk of adverse COVID-19 outcomes. Studies accounting for individual-level health characteristics are lacking. We leveraged the breadth and depth of the US Department of Veterans Affairs national healthcare databases and built a national cohort of 169,102 COVID-19 positive United States Veterans, enrolled between March 2, 2020 and January 31, 2021, and followed them through February 15, 2021. Annual average 2018 PM2.5 exposure, at an approximately 1 km2 resolution, was linked with residential street address at the year prior to COVID-19 positive test. COVID-19 hospitalization was defined as first hospital admission between 7 days prior to, and 15 days after, the first COVID-19 positive date. Adjusted Poisson regression assessed the association of PM2.5 with risk of hospitalization. There were 25,422 (15.0%) hospitalizations; 5,448 (11.9%), 5,056 (13.0%), 7,159 (16.1%), and 7,759 (19.4%) were in the lowest to highest PM2.5 quartile, respectively. In models adjusted for State, demographic and behavioral factors, contextual characteristics, and characteristics of the pandemic a one interquartile range increase in PM2.5 (1.9 µg/m3) was associated with a 10% (95% CI: 8%-12%) increase in risk of hospitalization. The association of PM2.5 and risk of hospitalization among COVID-19 individuals was present in each wave of the pandemic. Models of non-linear exposure-response suggested increased risk at PM2.5 concentrations below the national standard 12 µg/m3. Formal effect modification analyses suggested higher risk of hospitalization associated with PM2.5 in Black people compared to White people (p = 0.045), and in those living in socioeconomically disadvantaged neighborhoods (p < 0.001). Exposure to higher levels of PM2.5 was associated with increased risk of hospitalization among COVID-19 infected individuals. The risk was evident at PM2.5 levels below the regulatory standards. The analysis identified those of Black race and those living in disadvantaged neighborhoods as population groups that may be more susceptible to the untoward effect of PM2.5 on risk of hospitalization in the setting of COVID-19.


Building and benchmarking the motivated deception corpus: Improving the quality of deceptive text through gaming.
When one studies fake news or false reviews, the first step to take is to find a corpus of text samples to work with. However, most deceptive corpora suffer from an intrinsic problem: there is little incentive for the providers of the deception to put their best effort, which risks lowering the quality and realism of the deception. The corpus described in this project, the Motivated Deception Corpus, aims to rectify this problem by gamifying the process of deceptive text collection. By having subjects play the game Two Truths and a Lie, and by rewarding those subjects that successfully fool their peers, we collect samples in such a way that the process itself improves the quality of the text. We have amassed a large corpus of deceptive text that is strongly incentivized to be convincing, and thus more reflective of real deceptive text. We provide results from several configurations of neural network prediction models to establish machine learning benchmarks on the data. This new corpus is demonstratively more challenging to classify with the current state of the art than previous corpora.


HIV-1-specific cytotoxicity is preferentially mediated by a subset of CD8(+) T cells producing both interferon-gamma and tumor necrosis factor-alpha.
CD8(+) T cells play a crucial role in the control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. Recent data suggest that HIV-1-specific CD8(+) T cell subsets may differ in their ability to exert these effector functions. Here, we directly compared the cytokine secretion patterns and cytotoxic capacity of HIV-1-specific CD8(+) T cells, using a flow-cytometric cytotoxicity assay based on caspase-3 activation in dying target cells. These experiments revealed considerable intraindividual and interindividual differences among epitope-specific T-cell effector functions: while the frequency of HIV-1-specific CD8(+) T cells secreting interferon-gamma but no tumor necrosis factor-alpha (TNF-alpha) following antigenic stimulation was only weakly correlated to their cytotoxic activity (R = 0.05, P =.57), a subset of CD8(+) T cells secreting both inter-feron-gamma and TNF-alpha was substantially more strongly associated with cytotoxicity (R = 0.67, P <.001). This subset of CD8(+) T cells also exhibited stronger intracellular perforin expression and more pronounced direct ex vivo HIV-1-specific cytoxicity than CD8(+) T cells secreting solely interferon-gamma following sorting of these subpopulations according to their cytokine profile. These results suggest that HIV-1-specific cytotoxicity of CD8(+) T cells is preferentially mediated by a subset of CD8(+) T cells secreting both interferon-gamma and TNF-alpha.


Localization of H(+)-ATPases in soybean root nodules.
The localization of H(+)-ATPases in soybean (Glycine max L. cv. Stevens) nodules was investigated using antibodies against both P-type and V-type enzymes. Immunoblots of peribacteroid membrane (PBM) proteins using antibodies against tobacco and Arabidopsis H(+)-ATPases detected a single immunoreactive band at approximately 100 kDa. These antibodies recognized a protein of similar relative molecular mass in the crude microsomal fraction from soybean nodules and uninoculated roots. The amount of this protein was greater in PBM from mature nodules than in younger nodules. Immunolocalization of P-type ATPases using silver enhancement of colloidal-gold labelling at the light-microscopy level showed signal distributed around the periphery of non-infected cells in both the nodule cortex and nodule parenchyma. In the central nitrogen-fixing zone of the nodule, staining was present in both the infected and uninfected cells. Examination of nodule sections using confocal microscopy and fluorescence staining showed an immunofluorescent signal clearly visible around the periphery of individual symbiosomes which appeared as vesicles distributed throughout the infected cells of the central zone. Electron-microscopic examination of immunogold-labelled sections shows that P-type ATPase antigens were present on the PBM of both newly formed, single-bacteroid symbiosomes just released from infection threads, and on the PBM of mature symbiosomes containing two to four bacteroids. Immunogold labelling using antibody against the B-subunit of V-type ATPase from oat failed to detect this protein on symbiosome membranes. Only a very faint signal with this antibody was detected on Western blots of purified PBM. During nodule development, fusion of small symbiosomes to form larger ones containing multiple bacteroids was observed. Fusion was preceded by the formation of cone-like extensions of the PBM, allowing the membrane to make contact with the adjoining membrane of another symbiosome. We conclude that the major H(+)-ATPase on the PBM of soybean is a P-type enzyme with homology to other such enzymes in plants. In vivo, this enzyme is likely to play a critical role in the regulation of nutrient exchange between legume and bacteroids.


Reactivity of cat tracheal smooth muscle to histamine under conditions of experimentally induced inflammation.
The reactivity of cat tracheal smooth muscle to histamine in vitro was studied at various degrees of inflammation of the airways induced experimentally by the intratracheal administration of turpentine oil or Staphylococcus aureus, both in aerosol form. Tracheal smooth muscle preparations from the control animals did not respond to histamine in doses of 10(-9)-10(-3) mol X 1(-1). In tracheal preparations from three groups of cats with turpentine oil inflammation induced 24 h, 48 h and 15 days previously, histamine caused contractions in 20, 70 and 24% of the cats, respectively, according to the degree of inflammation. All tracheal preparations from cats with staphylococcal inflammation responded to histamine by contraction. Atropine, acetylosalicylic acid and phentolamine did not abolish histamine contractions in tracheal preparations, but clemastine did.


Early 20th century untrained nursing staff in the Rockhampton district: a necessary evil?
This paper explores the role of untrained nursing staff within the nursing services of the Rockhampton region, Queensland, Australia, throughout the early 20th century. It details who these nurses were, where they worked and how their work was affected by factors such as legislation and social changes. Despite the increasing prevalence of trained nurses from the late 19th century, nurses who had never undergone any formal training continued to gain work in hospitals, institutions and their local communities. This paper is an historical analysis of a wide range of primary source material relating to untrained nursing staff. The primary source material used related specifically to a limited geographical region in Australia. Untrained nursing staff primarily worked as private duty nurses at the beginning of the 20th century. However, as the century progressed, their opportunities to work as untrained nursing staff tended towards institutions dealing with the chronically ill and the aged. As a result of this transition, their profile altered from that of a married/widowed woman living at home with dependents to one who could live on-site at the institution with no dependents. Furthermore, the level of autonomy of the untrained nurse decreased dramatically throughout this period from being relatively independent to being under the control of a trained nurse within the institution. Consideration of the historical evolution of untrained nursing staff challenges some of the assumptions made about this category of nurse, assumptions that can affect current relationships between professional nurses and others who undertake nursing work.


Mortality trends of amyotrophic lateral sclerosis in Norway 1951-2014: an age-period-cohort study.
Recent studies suggest that the incidence and mortality of amyotrophic lateral sclerosis (ALS) are increasing. Changing environmental factors could influence disease risk differently throughout life span, and also between genders, birth cohorts, and seasons of birth. We aimed at describing long-term ALS mortality trends in Norway between 1951 and 2014 using age-period-cohort analysis. The Norwegian Cause of Death Registry provided ALS mortality data that were age- and sex-adjusted through direct standardization. Poisson regression analyses were used for identification of mortality trends and potential month of birth effects. We identified 5345 ALS cases, of which 54.7 % were men. ALS mortality increased throughout the whole period (p < 0.001), with a mean annual increase of 1.14 %. The increase was confined to those older than 60 years, but rates consistently dropped amongst the absolute oldest. The increase was mainly driven by birth cohort effects that increased from 1860 until 1934 (p < 0.001). No month of birth effect or change in sex ratio was found. The continuous increase in ALS mortality since 1951 is best explained by the long-term changes in exposure to risk factors or in case ascertainment, affecting men and women equally in the generations born since 1860 and at least into 1934.


Reoperation for prosthetic heart valve dysfunction: 19 years' experience.
Between September 1968 and October 1987, 152 patients (66 males and 86 females; age range, 15 to 79 years) underwent 1 or more reoperations (total, 179) for prosthetic valve dysfunction at our hospital. In this report, we present material and statistics reflecting our experience with the last reoperation in these 152 patients. The procedures involved the mitral valve in 93 patients, the aortic valve in 38 patients, double valves (aortic and mitral) in 19, and the tricuspid valve in 2. Sixty-five patients were operated on for mechanical valve dysfunction, and 87 for tissue valve dysfunction. The modes of valve dysfunction that indicated surgery were primary valve failure (85 patients), valvular thrombosis and valve-related thromboembolic episodes (27 patients), paravalvular leak (25 patients), prosthetic valve endocarditis (14 patients), and hemolysis (1 patient). Three patients were in New York Heart Association functional Class II, 77 were in Class III, and 61 were in Class IV; the remaining 11 cases were emergencies. The 30-day operative mortality was 14.5%, the 5-year survival was 75%, and the 10-year survival was 63%. The preoperative functional class and the mode of valve dysfunction significantly influenced both early and late mortality.


Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1-null mice.
Myelin-forming oligodendrocytes facilitate saltatory nerve conduction and support neuronal functions in the mammalian CNS. Although the processes of oligodendrogliogenesis and differentiation from neural progenitor cells have come to light in recent years, the molecular mechanisms underlying oligodendrocyte myelinogenesis are poorly defined. Herein, we demonstrate the pivotal role of the basic helix-loop-helix transcription factor, Olig1, in oligodendrocyte myelinogenesis in brain development. Mice lacking a functional Olig1 gene develop severe neurological deficits and die in the third postnatal week. In the brains of these mice, expression of myelin-specific genes is abolished, whereas the formation of oligodendrocyte progenitors is not affected. Furthermore, multilamellar wrapping of myelin membranes around axons does not occur, despite recognition and contact of axons by oligodendrocytes, and Olig1-null mice develop widespread progressive axonal degeneration and gliosis. In contrast, myelin sheaths are formed in the spinal cord, although the extent of myelination is severely reduced. At the molecular level, we find that Olig1 regulates transcription of the major myelin-specific genes, Mbp, Plp1, and Mag, and suppresses expression of a major astrocyte-specific gene, Gfap. Together, our data indicate that Olig1 is a central regulator of oligodendrocyte myelinogenesis in brain and that axonal recognition and myelination by oligodendrocytes are separable processes.


The water exchange method for colonoscopy-effect of coaching.
The growing popularity of water immersion is supported by its long history as an adjunct to air insufflation; after facilitating colonoscope passage, the infused water is conveniently removed during withdrawal. Water exchange, a modification of water immersion to minimize discomfort in scheduled unsedated patients in the U.S. is new. Even though it may be superior in reducing pain and increasing adenoma detection, the paradigm shift to complete exclusion of air during insertion necessitates removal of infused water containing residual feces, a step often perceived as laborious and time-consuming. The nuances are the efficient steps to remove infused water predominantly during insertion to maintain minimal distension and deliver salvage cleansing. Mastery of the novel maneuvers with practice returns insertion time towards baseline. In this observational study the impact of direct verbal coaching on the primary outcome of intention-to-treat cecal intubation was assessed. The results showed that 14 of 19 (74%) experienced colonoscopists achieved 100% intention-to-treat cecal intubation. Initiation of the examination with water exchange did not preclude completion when conversion to the more familiar air insufflation method was deemed necessary to achieve cecal intubation (total 98%). The overall intention-to-treat cecal intubation rate was 88%, 90% in male and 87% in female. Only 2.7% of bowel preparation was rated as poor during withdrawal. The mean volume of water infused and cecal intubation time was 1558 ml and 18 min, respectively. Direct coaching appears to facilitate understanding of the nuances of the water exchange method. Studies of individual learning curves are necessary.


Aichi virus infection in children with acute gastroenteritis in Finland.
Aichi virus has been proposed as a novel causative agent of acute gastroenteritis. In addition to several Asian countries, South America and Africa, Aichi virus has also recently been found in Europe. Our objective was to study the causative role of Aichi virus in children with acute gastroenteritis in Finland. We analysed 595 stool specimens from infants in an efficacy trial of rotavirus vaccine and 468 stool specimens from children in a hospital-based epidemiological and aetiological study of acute gastroenteritis. The screening was done by nested reverse transcription-polymerase chain reaction amplifying a 519-bp segment and a 223-bp segment in the 3CD junction region of non-structural proteins. Aichi virus was detected in five stool samples (0.5%), of which four were co-infections with other gastroenteritis viruses. Two Aichi virus genotypes, A and B, were found. Aichi virus appears to be rare in children with acute gastroenteritis in Finland.


[The use of neoadjuvant intra-arterial polychemotherapy in the treatment of cancer of the genitalia].
Results are submitted of employment of intraarterial superselective polychemotherapy in the treatment of malignant tumors of female genital organs in 106 patients; of these, forty individuals presented with carcinoma of the neck of the womb, 33 with tumours of the trophoblast, 18 had carcinoma of the ovaries, and 15 carcinoma of the body of the womb. A clinical analysis was done of the results obtained as were clinical-morphological correspondences (there has been studied a therapeutic pathomorphosis of the tumours) depending on the disease stage, individual schemes of polychemotherapy. The greatest benefit from the above treatment occurred in proliferative and invasive vascular mole and choriocarcinoma; patients with carcinoma of the neck and body of the womb derived less benefit, those with carcinoma of the ovaries experienced the least therapeutic effect. Intraarterial polychemotherapy permits the generative function to be preserved in trophoblast disease, the percentage of operability to be raised in carcinoma of the neck and body of the womb.


Induction of Cyclooxygenase-2 by Overexpression of the Human NADPH Oxidase 5 (NOX5) Gene in Aortic Endothelial Cells.
Oxidative stress is a main molecular mechanism that underlies cardiovascular diseases. A close relationship between reactive oxygen species (ROS) derived from NADPH oxidase (NOX) activity and the prostaglandin (PG) biosynthesis pathway has been described. However, little information is available about the interaction between NOX5 homolog-derived ROS and the PG pathway in the cardiovascular context. Our main goal was to characterize NOX5-derived ROS effects in PG homeostasis and their potential relevance in cardiovascular pathologies. For that purpose, two experimental systems were employed: an adenoviral NOX5-β overexpression model in immortalized human aortic endothelial cells (TeloHAEC) and a chronic infarction in vivo model developed from a conditional endothelial NOX5 knock-in mouse. NOX5 increased cyclooxygenase-2 isoform (COX-2) expression and prostaglandin E2 (PGE2) production through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in TeloHAEC. Protein kinase C (PKC) activation and intracellular calcium level (Ca++) mobilization increased ROS production and NOX5 overexpression, which promoted a COX-2/PGE2 response in vitro. In the chronic infarction model, mice encoding endothelial NOX5 enhanced the cardiac mRNA expression of COX-2 and PGES, suggesting a COX-2/PGE2 response to NOX5 presence in an ischemic situation. Our data support that NOX5-derived ROS may modulate the COX-2/PGE2 axis in endothelial cells, which might play a relevant role in the pathophysiology of heart infarction.


A single centre intercomparison between commercial treatment planning systems for 90Y radioembolization using virtual and experimental phantoms.
Dedicated Treatment Planning Systems (TPSs) were developed to personalize 90Y-transarterial radioembolization. This study evaluated the agreement among four commercial TPSs assessing volumes of interest (VOIs) volumes and dose metrics. A homogeneous (EH) and an anthropomorphic phantom with hot and cold inserts (EA) filled with 99mTc-pertechnetate were acquired with a SPECT/CT scanner. Their virtual versions (VH and VA, respectively) and a phantom with activity inside a single voxel (VK) were generated by an in-house MATLAB script. Images and delineated VOIs were imported into the TPSs to compute voxel-based absorbed dose distributions with various dose deposition approaches: local deposition method (LDM) and dose kernel convolution (DKC) with/without local density correction (LDC). VOI volumes and mean absorbed doses were assessed against their median value across TPSs. Dose-volume histograms (DVHs) and VK-derived dose profiles were evaluated. Small (<2.1 %) and large (up to 42.4 %) relative volume differences were observed on large (>500 ml) and small VOIs, respectively. Mean absorbed doses relative differences were < 3 % except for small VOIs with steep dose gradients (up to 89.1 % in the VA Cold Sphere VOI). Within the same TPS, LDC negligibly affected the mean absorbed dose, while DKC and LDM showed differences up to 63 %. DHVs were mostly overlapped in experimental phantoms, with some differences in the virtual versions. Dose profiles agreed within 1 %. TPSs showed an overall good agreement except for small VOI volumes and mean absorbed doses of VOIs with steep dose gradients. These discrepancies should be considered in the dosimetry uncertainty assessment, thus requiring an appropriate harmonization.


Kidney and liver transplantation in HIV-infected patients: case presentations and review.
Until recently, HIV-infected patients have been excluded from consideration for solid organ transplantation. The relatively high mortality rates among HIV-infected transplant recipients observed in the era prior to the use of highly active antiretroviral therapy (HAART), coupled with long waiting times for cadaveric organs, made it difficult to support organ transplantation in this patient group. However, in response to the marked reductions in morbidity and mortality associated with HIV infection, several transplant centers have developed pilot studies or revised their clinical criteria to allow transplantation in this group of patients. We describe two cases, one kidney and one liver transplant recipient, and review the major clinical and research issues related to this topic. Reports of transplantations in the pre-HAART era highlight two important findings. First, some HIV-infected transplant recipients did very well with long survival periods. However, overall progression to AIDS and death appeared accelerated. We recently reported on our preliminary experience with 45 selected transplant recipients in the HAART era. One-year patient survival rates were similar to unmatched survival data from the United Network for Organ Sharing (UNOS) database. Median CD4+ T-cell counts remained stable in the follow-up period compared to pretransplant. HIV-1 RNA nearly uniformly continued to be suppressed below the limits of detection. Preliminary data are promising and support the current efforts to evaluate patient and graft survival among HIV-infected transplant recipients and to explore the mechanisms underlying the many potential complications of transplantation in this population.


Psychosis and academic performance.
It has been suggested that psychosis genes might be associated with beneficial effects, explaining their high frequency in all human populations. To test the relationship between academic success and the incidence of psychotic disorders. The unusually complete demographic and scholastic records available in Iceland were used to locate academically accomplished individuals and assess the probability of previously identified patients with mental disorders and their relatives being among such groups. Close relatives of successful students showed increased risks of psychosis. Individuals who subsequently developed psychosis and relatives of people with psychosis excelled in school performance, particularly in mathematics. The study supports the hypothesis that stimulation associated with psychotic tendencies enhances performance in academic settings.


Octocoral Species Assembly and Coexistence in Caribbean Coral Reefs.
What are the determinant factors of community assemblies in the most diverse ecosystem in the ocean? Coral reefs can be divided in continental (i.e., reefs that develop on the continental shelf, including siliciclastic reefs) and oceanic (i.e., far off the continental shelf, usually on volcanic substratum); whether or not these habitat differences impose community-wide ecological divergence or species exclusion/coexistence with evolutionary consequences, is unknown. Studying Caribbean octocorals as model system, we determined the phylogenetic community structure in a coral reef community, making emphasis on species coexistence evidenced on trait evolution and environmental feedbacks. Forty-nine species represented in five families constituted the species pool from which a phylogenetic tree was reconstructed using mtDNA. We included data from 11 localities in the Western Caribbean (Colombia) including most reef types. To test diversity-environment and phenotype-environment relationships, phylogenetic community structure and trait evolution we carried out comparative analyses implementing ecological and evolutionary approaches. Phylogenetic inferences suggest clustering of oceanic reefs (e.g., atolls) contrasting with phylogenetic overdispersion of continental reefs (e.g., reefs banks). Additionally, atolls and barrier reefs had the highest species diversity (Shannon index) whereas phylogenetic diversity was higher in reef banks. The discriminant component analysis supported this differentiation between oceanic and continental reefs, where continental octocoral species tend to have greater calyx apertures, thicker branches, prominent calyces and azooxanthellate species. This analysis also indicated a clear separation between the slope and the remaining habitats, caused by the presence or absence of Symbiodinium. K statistic analysis showed that this trait is conserved as well as the branch shape. There was strong octocoral community structure with opposite diversity and composition patterns between oceanic and continental reefs. Even habitats with similar depths and overall environmental conditions did not share similar communities between oceanic and continental reefs. This indicates a strong regional influence over the local communities, probably due to water transparency differences between major reef types, i.e., oceanic vs. continental shelf-neritic. This was supported by contrasting patterns found in morphology, composition and evolutionary history of the species between atolls and reef banks.


Investigation of serotonin type 4 receptor expression in human and non-human primate gastrointestinal samples.
The serotonin type 4 (5-HT4) receptor has been associated with functions of the gastrointestinal tract such as modulation of the peristaltic reflex, smooth muscle tone, intestinal secretion and visceral sensitivity. The activation of peripheral 5-HT4 receptors with agonists such as tegaserod has been shown to accelerate gastric emptying and improve symptoms of constipation in animals and humans. However, detailed data on the expression profile and on the localization of this receptor subtype are lacking so far. To study the pattern and expression levels of 5-HT4 receptor messenger RNA expression in the gut. Normal tissue samples were collected from the whole gastrointestinal tract of patients undergoing abdominal surgery and, in addition, of monkeys. We performed a comprehensive analysis of 5-HT4 receptor expression by quantitative reverse transcription-polymerase chain reaction, using human and non-human primate tissues from the oesophagus to the rectum. In addition, the brain and heart of non-human primates were analysed. Significantly higher levels of 5-HT4 receptor mRNA were measured in the human stomach, duodenum, jejunum, ileum and caecum and also in the corresponding non-human primate gut segments, ranging from 2- to 12-fold compared with the liver. No differences were found between females and males of both human and non-human primates. These results show 5-HT4 receptor mRNA expression throughout the gastrointestinal tract in humans and primates, and also support the preclinical and clinical findings of 5-HT4 receptors ligands exhibiting multiple effects throughout the gastrointestinal tract.


TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury.
As one of the most prevalent neurotrophic factors in the central nervous system (CNS), brain-derived neurotrophic factor (BDNF) plays a significant role in CNS injury by binding to its specific receptor Tropomyosin-related kinase receptor B (TrkB). The BDNF/TrkB signaling pathway is crucial for neuronal survival, structural changes, and plasticity. BDNF acts as an axonal growth and extension factor, a pro-survival factor, and a synaptic modulator in the CNS. BDNF also plays an important role in the maintenance and plasticity of neuronal circuits. Several studies have demonstrated the importance of BDNF in the treatment and recovery of neurodegenerative and neurotraumatic disorders. By undertaking in-depth study on the mechanism of BDNF/TrkB function, important novel therapeutic strategies for treating neuropsychiatric disorders have been discovered. In this review, we discuss the expression patterns and mechanisms of the TrkB/BDNF signaling pathway in CNS damage and introduce several intriguing small molecule TrkB receptor agonists produced over the previous several decades.


Differences in voluntary ethanol consumption in Wistar rats from five different suppliers.
Understanding the mechanism of action of ethanol and the neurobiological substrates for alcohol use disorders is challenging. In search of this knowledge, it is imperative to use valid animal experimental models. The Wistar rat is one example of a commonly used strain that also exert foundation stock for several rat lines selectively bred for high and low voluntary ethanol intake. Different studies report varying ethanol intake in Wistar rats posing the question of whether this is because of the methodological differences or the rat strain. The purpose of this study was therefore to compare voluntary ethanol intake in Wistar rats from five different suppliers. Rats from B&K Universal, UK (BK); Charles River, Germany; Harlan Laboratories, IN (Hsd); Harlan Laboratories, The Netherlands (RccHan™); and Taconic, Denmark were exposed to a three-bottle free-choice paradigm with intermittent 24 h access to 5 and 20% ethanol and water three times per week for 6 weeks. A general finding was that the RccHan™ rats differed significantly from the other groups. At the end of the experiment, the RccHan™ group had the highest median ethanol intake of 3.85 g/kg/24 h, whereas the BK rats had the lowest intake of 1.84 g/kg/24 h. The preference for ethanol was also different throughout the experiment. At the end of the experiment, the RccHan™ rats had the highest preference of approximately 80%, whereas the BK rats had the lowest preference around 25%. During the 6-week drinking period, only the Hsd rats increased their ethanol intake, as evidenced by a significant increase of 5% ethanol intake. Although all rats are of Wistar origin, they display profound differences in voluntary ethanol consumption depending on the supplier. The choice of Wistar can therefore have implications for the outcome and make comparisons between studies difficult. The present findings highlight the supplier as an important parameter to consider when planning and performing preclinical animal studies in the field of alcohol research.


[The results of resuscitations in an emergency service].
In a prospective study 166 consecutive cases of prehospital resuscitation by emergency doctors were analysed to ascertain those factors which affect the ultimate outcome. Cardiac causes were most frequent (69%): primary ventricular fibrillation was the most common ECG diagnosis (47%). Average time from definite cardiorespiratory arrest until onset of resuscitation procedures by an emergency doctor was 8.2 minutes, to first measures by other resuscitation personnel it was 6.6 minutes. In all cases in which resuscitation procedures were undertaken (in 33 within 10 minutes) this was done by medical personnel who were nearby by chance. 47 patients (28.3%) could be resuscitated and taken to hospital; 16 of them (9.6%) were discharged after "finally successful resuscitation", 13 without any neurological deficit. Favourable factors were: primary ventricular fibrillation and start of resuscitation manoeuvres within 10 minutes. These results highlight the need for training first-aid personnel so that the number of successful resuscitations can be increased.


Dengue hemorrhagic fever knowledge, perception, and preventive behavior among secondary school students in Bangkok.
To explore dengue hemorrhagic fever (DHF) knowledge, perception, and preventive behavior among secondary school students in Nong-Kheam, Bangkok, Thailand. A cross-sectional descriptive study was conducted with 300 students between 12 and 16 years old currently attending secondary schools in the Bangkok metropolitan areas using self-administered questionnaires. Data were subsequently summarized using descriptive statistics. Only 18.0% of students had a good level of overall knowledge of DHF but more than half had a good level of perception of DHF The results also revealed that only 4.7% of students had a good level of preventive behavior and 75.6% required improvement. The levels of knowledge, perception, and preventive behavior were low. Health education programs should be continued and intensified with emphasis on improving the knowledge of students on prevention and control practices.


[Bioelectrical activity of limb muscles during shivering while stimulating the vestibular apparatus].
The effects of caloric and electric stimulation of the vestibular receptors on the EMG activity of limb muscles in anesthetized cats during cold-induced shivering involved flexor muscles alone. Both types of stimulation suppressed bioelectrical activity, more effectivey in the ipsilateral muscles. The suppression of shivering activity seems to be due to the increased inhibitory effect of descending labyrinth pathways on the function of flexor motoneurons.


Dietary environmental factors shape the immune defense against Cryptosporidium infection.
Cryptosporidium is a leading cause of diarrheal-related deaths in children, especially in resource-poor settings. It also targets the immunocompromised, chronically infecting people living with HIV and primary immunodeficiencies. There is no vaccine or effective treatment. Although it is known from human cases and animal models that CD4+ T cells play a role in curbing Cryptosporidium, the role of CD8+ T cells remains to be defined. Using a Cryptosporidium tyzzeri mouse model, we show that gut-resident CD8+ intraepithelial lymphocytes (IELs) confer resistance to parasite growth. CD8+ IELs express and depend on the ligand-dependent transcription factor aryl hydrocarbon receptor (AHR). AHR deficiency reduces CD8+ IELs, decreases their cytotoxicity, and worsens infection. Transfer of CD8+ IELs rescues severely immunodeficient mice from death following Cryptosporidium challenge. Finally, dietary supplementation of the AHR pro-ligand indole-3-carbinol in newborn mice promotes resistance to infection. Therefore, common dietary metabolites augment the host immune response to cryptosporidiosis, protecting against disease.


Doctors' knowledge, attitudes, and compliance with 2013 ACC/AHA guidelines for prevention of atherosclerotic cardiovascular disease in Singapore.
There is an unmet need for strategies to prevent atherosclerotic cardiovascular disease in Singapore. The main objective of this study was to investigate Singapore physicians' response to the 2013 American College of Cardiology and American Heart Association (ACC/AHA) guidelines for treatment of cholesterol and their impact on clinical practice. This survey was conducted in two stages, qualitative and quantitative. Physicians were initially screened on the basis of an initial screener questionnaire, and eligible physicians were then included in the study. Qualitative (n=19) and quantitative (n=66) surveys were completed by eligible physicians from Singapore. Physicians were less familiar with the 2013 ACC/AHA guidelines (35%) as compared with the Singapore Ministry of Health (MoH) lipid guidelines 2006 (49%). Of the physicians whose opinion was sought on the ACC/AHA guidelines, more than 50% disagreed with the definition of high-, moderate-, and low-intensity statin therapy; recommendation of atorvastatin 40-80 mg and rosuvastatin 20-40 mg as medications for high-intensity statin therapy; and classification of individuals who would benefit from moderate- to high-intensity statin therapy. Most physicians assumed that Asians may be intolerant to high-intensity statin therapy. Although embracing the 2013 ACC/AHA guidelines in clinical practice is expected to provide better clinical care to patients, our study revealed high reluctance by physicians, especially in the use of high-dose statins. However, ACC/AHA guidelines can be easily adopted in Asia as there is a wealth of data available for atorvastatin in primary and secondary prevention of atherosclerotic cardiovascular disease with similar efficacy and safety profiles in the white and Asian populations.


Semi-volatile organic compounds in heating, ventilation, and air-conditioning filter dust in retail stores.
Retail stores contain a wide range of products that can emit a variety of indoor pollutants. Among these chemicals, phthalate esters and polybrominated diphenyl ethers (PBDEs) are two important categories of semi-volatile organic compounds (SVOCs). Filters in heating, ventilation, and air-conditioning (HVAC) system collect particles from large volumes of air and thus potentially provide spatially and temporally integrated SVOC concentrations. This study measured six phthalate and 14 PBDE compounds in HVAC filter dust in 14 retail stores in Texas and Pennsylvania, United States. Phthalates and PBDEs were widely found in the HVAC filter dust in retail environment, indicating that they are ubiquitous indoor pollutants. The potential co-occurrence of phthalates and PBDEs was not strong, suggesting that their indoor sources are diverse. The levels of phthalates and PBDEs measured in HVAC filter dust are comparable to concentrations found in previous investigations of settled dust in residential buildings. Significant correlations between indoor air and filter dust concentrations were found for diethyl phthalate, di-n-butyl phthalate, and benzyl butyl phthalate. Reasonable agreement between measurements and an equilibrium model to describe SVOC partitioning between dust and gas-phase is achieved.


Leveraging genomic sequencing data to evaluate disease surveillance strategies.
In the face of scarce public health resources, it is critical to understand which disease surveillance strategies are effective, yet such validation has historically been difficult. From May 1 to December 31, 2021, a cohort study was carried out in Santa Clara County, California, in which 10,131 high-quality genomic sequences from COVID-19 polymerase chain reaction tests were merged with disease surveillance data. We measured the informational value, the fraction of sequenced links surfaced that are biologically plausible according to genomic sequence data, of different disease surveillance strategies. Contact tracing appeared more effective than spatiotemporal methods at uncovering nonresidential spread settings, school reporting appeared more fruitful than workplace reporting, and passively retrieved links through survey information presented some promise. Given the rapidly dwindling cost of sequencing, the informational value metric may enable near real-time, readily available evaluation of strategies by public health authorities to fight viral diseases beyond COVID-19.


Automated Quantification of Diseased Thoracic Aortic Longitudinal Centerline and Surface Curvatures.
Precise description of vascular morphometry is crucial to support medical device manufacturers and clinicians for improving device development and interventional outcomes. A compact and intuitive method is presented to automatically characterize the surface geometry of tubular anatomic structures and quantify surface curvatures starting from generic stereolithographic (STL) surfaces. The method was validated with software phantoms and used to quantify the longitudinal surface curvatures of 37 human thoracic aortas with aneurysm or dissection. The quantification of surface curvatures showed good agreement with analytic solutions from the software phantoms, and demonstrated better agreement as compared to estimation methods using only centerline geometry and cross-sectional radii. For the human thoracic aortas, longitudinal inner surface curvature was significantly higher than centerline curvature (0.33 ± 0.06 versus 0.16 ± 0.02 cm-1 for mean; 1.38 ± 0.48 versus 0.45 ± 0.11 cm-1 for peak; both p < 0.001). These findings show the importance of quantifying surface curvatures in order to better describe the geometry and biomechanical behavior of the thoracic aorta, which can assist in treatment planning and supplying device manufactures with more precise boundary conditions for mechanical evaluation.


Inducing Homochirality Through Intermediary Catalytic Species: A Stochastic Approach.
A new chiral amplification mechanism based on a stochastic approach is proposed. The mechanism includes five different chemical species, an achiral substrate (A), two chiral forms (L, D), and two intermediary species (LA, DA). The process occurs within a small, semipermeable compartment that can be diffusively coupled with the outside environment. The study considers two alternative primary sources for chiral species within the compartment, one chemical and the other diffusive. As a remarkable fact, the chiral amplification process occurs due to stochastic fluctuations of an intermediary catalytic species (LA, DA) produced in situ, given the interaction of the chiral species with the achiral substrate. The net process includes two different steps: the synthesis of the catalyst (LA and DA) and the catalytic production of new chiral species from the substrate. Stochastic simulations show that proper parameterization can induce a robust chiral state within the compartment regardless of whether the system is open or closed. We also show how an increase in the non-catalytic production of chiral species tends to negatively impact the homochirality degree of the system. By its conception, the proposed mechanism suggests a deeper connection with how most biochemical processes occur in living beings, a fact that could open new avenues for studying this fascinating phenomenon.


Itching at night: A review on reducing nocturnal pruritus in children.
The most common causes of chronic nocturnal itching in children are atopic dermatitis and psoriasis, with lichen simplex chronicus and prurigo nodularis contributing to lesser degrees. Despite the prevalence of nocturnal itching, its pathophysiology remains poorly understood. The most troubling consequence of itching at night is poor quality of sleep. Poor sleep quality in children with nocturnal itching has been linked to adverse neurocognitive, behavioral, and physiologic outcomes, including poor performance in school, attention deficit hyperactivity disorder, short stature, hypertension, obesity, and impaired immune function. There is no consensus on the best management of nocturnal itching in children. We conducted a review of the literature evaluating the efficacy of various treatment options for children with chronic nocturnal pruritus. Our review found three recently conducted randomized controlled trials and one case report demonstrating the efficacy of topical corticosteroids, oral melatonin, and clonidine in reducing nocturnal itching or improving sleep quality in children with nocturnal pruritus. Future research is needed to elucidate the pathophysiology of nocturnal itching to best develop targeted, effective treatment strategies.


Common RyR2 variants associate with ventricular arrhythmias and sudden cardiac death in chronic heart failure.
Ca2+ cycling plays a critical role in heart failure and lethal arrhythmias. As susceptibility to sudden cardiac death is considered to be a heritable trait in general population, we have therefore investigated whether potentially functional variants of genes encoding RyR2 (ryanodine receptor 2) and the L-type Ca2+ channel are related to the risk of ventricular arrhythmias and sudden cardiac death in CHF (chronic heart failure) in a case-control study. We found that the A allele of rs3766871 in RYR2 was associated with an increased risk of ventricular arrhythmias in patients with CHF {odds ratio, 1.66 [95% CI (confidence interval), 1.21-2.26]; P=0.002}. During a median follow-up period of 32 months in 1058 (85.0%) patients, 296 (28.0%) patients died from heart failure, of whom 141 (47.6%) had sudden cardiac death. After adjustment for age, gender and suspected risk factors, patients carrying the A allele of rs3766871 had an increased risk of cardiac death {HR (hazard ratio), 1.53 [95% CI, 1.11-2.12]; P=0.010} and sudden cardiac death [HR, 1.92 (95% CI, 1.25-2.94); P=0.003]. Patients carrying the A allele of rs790896 in RYR2 had a reduced risk of sudden cardiac death [HR, 0.65 (95% CI, 0.45-0.92); P=0.015]. In conclusion, the A allele of rs3766871 in RYR2 not only associates with ventricular arrhythmias, but also serves as an independent predictor of sudden cardiac death, and the A allele of rs790896 in RYR2 is a protective factor against sudden cardiac death in patients with CHF.


Mortality among atomic bomb survivors.
The Atomic Bomb Casualty Commission and its successor, the Radiation Effects Research Foundation, have conducted a long-term follow-up study of a cohort of 120,000 atomic bomb survivors and non-exposed controls since 1950. The most recent findings regarding cancer mortality during the period 1950-85 in this cohort, based on the DS86 doses are as follows: 1) The dosimetry change does not alter the list of radiation-related cancers. Some city differences in dose-response previously thought to be real are no longer significant with the DS86 doses. Assuming a linear dose-response, and using estimated organ-absorbed doses, the risk coefficients derived from the two dosimetries are very similar. If larger RBE values are assumed, the disparity between the two dosimetries increases because the neutron dose is much greater in the T65 dosimetry. 2) Besides the well-known increase of leukemia, there also have been demonstrated increases in cancers of the lung, breast, esophagus, stomach, colon, ovary, urinary bladder, and of multiple myeloma, but no increase has yet been observed in mortality from cancer of the rectum, gallbladder, pancreas, prostate and uterus, and of malignant lymphoma. In general, radiation-induced solid cancer begins to appear after attaining the age at which the cancer is normally prone to develop (the so-called "cancer age"), and continues to increase proportionately with the increase in mortality in the control group as it ages. Sensitivity to radiation, in terms of cancer induction, is higher generally for persons who were young at the time of the bomb (ATB) than for those who were older ATB. Non-cancer mortality in the period 1950-78, based on the T65 doses, which is the most recent published report, did not show an increase with dose, but now, with the accumulation of seven more years of follow-up, there seems to be an excess in the very high dose range, particularly for the younger age ATB cohort. Further follow-up is called for to confirm this suggestion.


The Interplay Between Bone and Glucose Metabolism.
The multiple endocrine functions of bone other than those related to mineral metabolism, such as regulation of insulin sensitivity, glucose homeostasis, and energy metabolism, have recently been discovered. In vitro and murine studies investigated the impact of several molecules derived from osteoblasts and osteocytes on glucose metabolism. In addition, the effect of glucose on bone cells suggested a mutual cross-talk between bone and glucose homeostasis. In humans, these mechanisms are the pivotal determinant of the skeletal fragility associated with both type 1 and type 2 diabetes. Metabolic abnormalities associated with diabetes, such as increase in adipose tissue, reduction of lean mass, effects of hyperglycemia per se, production of the advanced glycation end products, diabetes-associated chronic kidney disease, and perturbation of the calcium-PTH-vitamin D metabolism, are the main mechanisms involved. Finally, there have been multiple reports of antidiabetic drugs affecting the skeleton, with differences among basic and clinical research data, as well as of anti-osteoporosis medication influencing glucose metabolism. This review focuses on the aspects linking glucose and bone metabolism by offering insight into the most recent evidence in humans.


Comparison of IMRT versus 3D-CRT in the treatment of esophagus cancer: A systematic review and meta-analysis.
Esophageal cancer (EC) is a common cancer with high mortality because of its rapid progression and poor prognosis. Radiotherapy is one of the most effective treatments for EC. Three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) are 2 recently developed radiotherapy techniques. IMRT is believed to be more effective than 3D-CRT in target coverage, dose homogeneity, and reducing toxicity to normal organs. However, these advantages have not been demonstrated in the treatment of EC. This meta-analysis was performed to compare IMRT and 3D-CRT in the treatment of EC in terms of dose-volume histograms and outcomes including survival and toxicity. A literature search was performed in PubMed, Embase, and the Cochrane library databases from their inceptions to Dec 30, 2016. Two authors independently assessed the included studies and extracted data. The average percent irradiated volumes of adjacent noncancerous organs were calculated and compared between IMRT and 3D-CRT. The odds ratio of overall survival (OS), and radiation pneumonitis and radiation esophagitis was also evaluated. Totally 7 studies were included. Of them, 5 studies (80 patients) were included in the dosimetric comparison, 3 studies (871 patients) were included in the OS analysis, and 2 studies (205 patients) were included in the irradiation toxicity analysis. For lung in patients receiving doses ≥20 Gy and heart in patients receiving dose = 50 Gy, the average irradiated volumes of IMRT were less than those from 3D-CRT. IMRT resulted in a higher OS than 3D-CRT. However, no significant difference was observed in the incidence of radiation pneumonitis and radiation esophagitis between 2 radiotherapy techniques. Our data suggest that IMRT-delivered high radiation dose produces significantly less average percent volumes of irradiated lung and heart than 3D-CRT. IMRT is superior to 3D-CRT in the OS of EC while shows no benefit on radiation toxicity.


Management of Severe Facial Nerve Cross Stimulation by Cochlear Implant Replacement to Change Pulse Shape and Grounding Configuration: A Case-series.
To investigate the combined effect of changing pulse shape and grounding configuration to manage facial nerve stimulation (FNS) in cochlear implant (CI) recipients. Three adult CI recipients with severe FNS were offered a replacement implant when standard stimulation strategies and programming adjustments did not resolve symptoms. Our hypothesis was that the facial nerve was less likely to be activated when using anodic pulses with "mixed-mode" intra-cochlear and extra-cochlear current return. All patients were reimplanted with an implant that uses a pseudo-monophasic anodic pulse shape, with mixed-mode grounding (stimulus mixed-mode anodic)-the Neuro Zti CI (Oticon Medical). This device also allows measurements of neural function and loudness with monopolar, symmetric biphasic pulses (stimulus MB), the clinical standard used by most CIs as a comparison. The combined effect of pulse shape and grounding configuration on FNS was monitored during surgery. Following CI activation, FNS symptoms and performance with the Neuro Zti implant were compared with outcomes before reimplantation. FNS could only be recorded using stimulus MB for all patients. In clinical use, all patients reported reduced FNS and showed an improvement in Bamford-Kowal-Bench sentences recognition compared with immediately before reimplantation. Bamford-Kowal-Bench scores with a male speaker were lower compared with measurements taken before the onset of severe FNS for patients 1 and 2. In patients where CI auditory performance was severely limited by FNS, charge-balanced pseudo-monophasic stimulation mode with a mixed-mode grounding configuration limited FNS and improved loudness percept compared with standard biphasic stimulation with monopolar grounding.


Effect of boron toxicity on pollen tube cell wall architecture and the relationship of cell wall components of Castanea mollissima Blume.
Boron (B) is essential to plant development. However, excessive B is toxic to plants. This research was performed to evaluate the effects of B toxicity on cell wall architecture of Chinese chestnut (Castanea mollissima Blume) pollen tubes with emphasis on the relationship among pectins, cellulose, and callose. Results showed that 0.8 mM H3BO3 inhibited pollen germination and led to abnormal morphology of the pollen tubes. B toxicity also affected the distribution of cell wall components of the pollen tube. In control pollen tube, esterified and acid pectins were distributed unevenly, with the former mainly at the tip and the latter on the distal region. Cellulose was distributed uniformly on the surface with less at the tip; callose reduced gradually from base to sub-tip of the pollen tubes and no callose at the tip of the tube was detected. B toxicity led to the deposition of esterified and acid pectins, cellulose, and callose at the tip of the pollen tube. Results from scanning electron microscopy and transmission electron microscopy showed that B toxicity also altered pollen tube wall ultrastructure. The results from enzymatic treatment illustrated that there existed a close relationship among pectins, cellulose, and callose. B toxicity also altered the relationship. In a word, B toxicity altered deposition and relationship of pectins, cellulose, and callose of pollen tube wall.


Prediction of vertebral body compressive fracture using quantitative computed tomography.
We performed quantitative computed tomography in vitro on the first and third lumbar vertebrae in human cadavera using a dibasic potassium phosphate phantom for calibration. The quantitative computed-tomography numbers exhibited a significant positive correlation (R2 = 0.89, p less than 0.0001) with direct measurements of the apparent density of the vertebral trabecular bone. We also conducted uniaxial compression tests to failure of the vertebral bodies after removal of the posterior elements, and found that vertebral compressive strength was also correlated at a high level of significance (R2 = 0.82, p less than 0.0001) with direct measurement of the trabecular apparent density. These findings suggested the possibility that the quantitative computed-tomography values might be directly predictive of vertebral compressive strength. However, when we correlated the quantitative computed-tomography values directly with vertebral compressive strength, the results (R2 = 0.46, p less than 0.061) were suggestive but not quite significant. All vertebral bodies failed by compression of the end-plate, suggesting only a modest structural role for the cortical shell under these loading conditions. This was confirmed by comparing the compressive load to failure of twenty additional pairs of vertebrae that were tested with and without an intact vertebral cortex. Removal of the cortex was associated with approximately 10 per cent reduction in vertebral load to failure.


Discrete-time semi-Markov modeling of human papillomavirus persistence.
Multi-state modeling is often employed to describe the progression of a disease process. In epidemiological studies of certain diseases, the disease state is typically only observed at periodic clinical visits, producing incomplete longitudinal data. In this paper we consider fitting semi-Markov models to estimate the persistence of human papillomavirus (HPV) type-specific infection in studies where the status of HPV type(s) is assessed periodically. Simulation study results are presented indicating that the semi-Markov estimator is more accurate than an estimator currently used in the HPV literature. The methods are illustrated using data from the HIV Epidemiology Research Study.


Determination of the effective hydrodynamic radii of small molecules by viscometry.
The effective hydrodynamic radii of small uncharged molecules in dilute aqueous solution were determined using Einstein's classical theory of viscosity. The radii thus obtained are those of a hypothetical sphere whose hydrodynamic behavior is the same as that of the solute molecule plus that water of hydration which is too firmly bound to partake in the viscous shearing process. The results obtained compare favorably with radii determined from molecular models constructed in accordance with atomic dimensions compiled by Pauling. Although the application of the Einstein theory to molecules whose size is comparable to that of water represents a considerable extrapolation, the results suggest that this deviation from the assumptions of the theory, in the case of the molecules studied, is of second order importance. Employing the viscometric radii, we have formulated an empirical correction of the Stokes-Einstein diffusion equation. This correction is similar in form to those previously proposed by Cunningham (22) and Millikan (21) and is of particular significance when the solute molecule is comparable in size to the discontinuities of the surrounding medium. The molecular radii of a number of small organic molecules obtained by means of the corrected Stokes-Einstein equation do not differ significantly from the radii obtained from molecular models of these compounds.


Wastewater Based Epidemiology Perspective as a Faster Protocol for Detecting Coronavirus RNA in Human Populations: A Review with Specific Reference to SARS-CoV-2 Virus.
Wastewater-based epidemiology (WBE) has a long history of identifying a variety of viruses from poliovirus to coronaviruses, including novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The presence and detection of SARS-CoV-2 in human feces and its passage into the water bodies are significant public health challenges. Hence, the hot issue of WBE of SARS-CoV-2 in the coronavirus respiratory disease (COVID-19) pandemic is a matter of utmost importance (e.g., SARS-CoV-1). The present review discusses the background, state of the art, actual status, and prospects of WBE, as well as the detection and quantification protocols of SARS-CoV-2 in wastewater. The SARS-CoV-2 detection studies have been performed in different water matrixes such as influent and effluent of wastewater treatment plants, suburban pumping stations, hospital wastewater, and sewer networks around the globe except for Antarctica. The findings revealed that all WBE studies were in accordance with clinical and epidemiological data, which correlates the presence of SARS-CoV-2 ribonucleic acid (RNA) with the number of new daily positive cases officially reported. This last was confirmed via Reverse Transcriptase-quantitative Polymerase Chain Reaction (RT-qPCR) testing which unfortunately is not suitable for real-time surveillance. In addition, WBE concept may act as a faster protocol to alert the public health authorities to take administrative orders (possible re-emerging infections) due to the impracticality of testing all citizens in a short time with limited diagnostic facilities. A comprehensive and integrated review covering all steps starting from sampling to molecular detection of SARS-CoV-2 in wastewater has been made to guide for the development well-defined and reliable protocols.


From sequence to enzyme mechanism using multi-label machine learning.
In this work we predict enzyme function at the level of chemical mechanism, providing a finer granularity of annotation than traditional Enzyme Commission (EC) classes. Hence we can predict not only whether a putative enzyme in a newly sequenced organism has the potential to perform a certain reaction, but how the reaction is performed, using which cofactors and with susceptibility to which drugs or inhibitors, details with important consequences for drug and enzyme design. Work that predicts enzyme catalytic activity based on 3D protein structure features limits the prediction of mechanism to proteins already having either a solved structure or a close relative suitable for homology modelling. In this study, we evaluate whether sequence identity, InterPro or Catalytic Site Atlas sequence signatures provide enough information for bulk prediction of enzyme mechanism. By splitting MACiE (Mechanism, Annotation and Classification in Enzymes database) mechanism labels to a finer granularity, which includes the role of the protein chain in the overall enzyme complex, the method can predict at 96% accuracy (and 96% micro-averaged precision, 99.9% macro-averaged recall) the MACiE mechanism definitions of 248 proteins available in the MACiE, EzCatDb (Database of Enzyme Catalytic Mechanisms) and SFLD (Structure Function Linkage Database) databases using an off-the-shelf K-Nearest Neighbours multi-label algorithm. We find that InterPro signatures are critical for accurate prediction of enzyme mechanism. We also find that incorporating Catalytic Site Atlas attributes does not seem to provide additional accuracy. The software code (ml2db), data and results are available online at http://sourceforge.net/projects/ml2db/ and as supplementary files.


Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels.
Patients with nonalcoholic fatty liver disease (NAFLD) and normal aminotransferase levels may have advanced liver histology. We conducted a study to characterize the prevalence of and factors associated with advanced liver histology in patients with histologically characterized NAFLD and normal aminotransferase levels. We evaluated 534 adults with biopsy-proven NAFLD and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <40U/L within 3 months of their liver biopsy. Histological phenotypes of primary interest were nonalcoholic steatohepatitis (NASH) with stage 2-3 fibrosis (NASH F2-3) and cirrhosis. Using multiple logistic regression models with Akaike's Information Criteria (AIC), we identified variables associated with these histological phenotypes. We developed and internally validated their clinical prediction models. The prevalence of NASH F2-F3 and cirrhosis was 19% and 7%, respectively. The best multiple regression AIC model for NASH F2-3 consisted of type 2 diabetes, white race, lower low-density lipoprotein, lower platelet count, higher AST/ALT ratio, higher serum triglycerides, and hypertension. The best AIC model for cirrhosis consisted of lower platelet count, lower AST/ALT ratio, higher body mass index, and female sex. The area under the receiver operator curves of the prediction models were 0.70 (95% confidence interval: 0.65-0.76) for detecting NASH-F2-3 and 0.85 (95% confidence interval: 0.77-0.92) for detecting cirrhosis. When models were fixed at maximum Youden's index, their positive and negative predictive values were 35% and 88% for NASH F2-F3 and 30% and 98% for cirrhosis, respectively. Clinically significant histological phenotypes are observed in patients with NAFLD and normal aminotransferase levels. Our models can assist the clinicians in excluding advanced liver histology in NAFLD patients with normal aminotransferase levels.


The history of the case report: a selective review.
The clinical case report is a popular genre in medical writing. While authors and editors have debated the justification for the clinical case report, few have attempted to examine the long history of this genre in medical literature. By reviewing selected literature and presenting and discussing excerpts of clinical case reports from Egyptian antiquity to the 20th century, we illustrate the presence of the genre in medical science and how its form developed. Central features of the clinical case report in different time periods are discussed, including its main components, structure, style and author presence.