Transcription and decay of the lac messenger: role of an intergenic terminator.
Prior work has indicated that the polycistronic lacZYA mRNA of Escherichia coli is cleaved during decay at approximately intergenic sites (L. W. Lim and D. Kennell, J. Mol. Biol. 135: 369-390, 1979). In this work, we characterized the products by using probes specific for the different cistrons. This analysis indicated that six lac mRNA species are present in the following order of decreasing abundance: lacZ, -A, -ZYA, -ZY, -YA, and -Y. Very little lacYA and lacY mRNAs were present, whereas in cells induced to steady state, there was 10 times more lacZ than lacZYA mRNA. The lacZ mRNA appeared as a discrete species extending to a site in the lacZ-Y intergenic space (ca. residue 3150). This site is just distal to a potential rho-independent termination sequence. We examined the function of this sequence to determine whether it contributes to the distribution of the mRNAs. Although the termination sequence was shown to function in vitro, when it was recloned into an expression vector, no termination was seen in vivo. Moreover, direct examination of the kinetics of lac messenger synthesis revealed that after initiation, most transcription continued to the end of the operon. We conclude that during normal growth, the operon is transcribed in its entirety and that the individual lac mRNAs are formed by cleavage. These results confirm earlier work implying that the lac operon is transcribed in its entirety but are in conflict with several recent reports suggesting that internal termination occurs. Our findings indicate that the natural polarity of the operon (lacZ is expressed sixfold more strongly than lacA) is based on posttranslational effects and not on polarity of transcription.


Methacholine provocation of Prinzmetal's variant angina pectoris: a revised perspective.
We report 13 patient with unequivocal Prinzmetal's variant angina pectoris as the entire experience with this syndrome during a 7-year period in a single institution. The clinical diagnosis of this relatively uncommon disorder is emphasized. Five patients were given 10 mg of methacholine subcutaneously. Three demonstrated subsequent delayed appearance of chest pain, ECG change, and coronary vasospasm following early appearance of muscarinic effects. Two Prinzmetal patients had no provocation of variant angina following methacholine, though they did experience significantly less blood pressure fall in response to muscarinic provocation. Another 23 subjects with incompletely explained chest pain given methacholine had neither ECG change nor spasm. Methacholine provocation of variant angina need not necessarily implicated a parasympathomimetic mechanism for otherwise spontaneous episodes. Rather, provocation would appear to occur via the customary reflex adrenergic response to drug-induced hypotension. Methacholine is probably safe though unreliable as an agent to be used for spasm provocation.


Viral aetiology of acute lower respiratory tract illness in hospitalised paediatric patients of a tertiary hospital: one year prospective study.
Acute lower respiratory tract infections (ALRI), ranked as the second leading cause of death are the primary cause of hospitalisation in children. Viruses are the most important causative agents of ALRI. To study the viral aetiology of ALRI in children at a tertiary care hospital. One year prospective observational study in a tertiary care hospital of King George's Medical University, Lucknow. Nasopharyngeal aspirate (NPA) was collected from children admitted with signs and symptoms of ALRI who were aged 0-14 years. Samples were transported to the laboratory at 4°C in viral transport media and processed for detection of respiratory syncytial virus (RSV) A and B, influenza virus A and B, adenovirus (ADV), human Boca virus (HBoV), human metapneumo virus (hMPV) and parainfluenzavirus 1, 2, 3 and 4 using mono/multiplex real-time polymerase chain reaction (RT-PCR). STATA was used for statistical analysis. In one year, 188 NPAs were screened for respiratory viruses, of which 45.7% tested positive. RSV was most commonly detected with 21.3% positivity followed by measles virus (8.5%), influenza A virus (7.4%), ADV (5.3%), influenza B virus (1.6%), hMPV (1.1%) and HBoV (0.5%). Month wise maximum positivity was seen in December and January. Positivity rate of RSV was highest in children aged < 1 year, which decreased with increase in age, while positive rate of influenza virus increased with increasing age. The occurrence of viral predominance in ALRI is highlighted.


Primary pyomyositis: an unusual presentation in an older patient with no recognised risk factors.
Primary pyomyositis is a subacute deep bacterial infection of skeletal muscle. It is typically seen in tropical countries with Staphylococcus aureus being the commonest pathogen. Immunocompromised states and trauma are associated with cases in temperate climates where there is an increasing incidence, typically in children and young adults. However, the authors present a case of primary pyomyositis in a previously healthy 80-year-old female. The authors highlight the potential difficulties in early diagnosis of this rare condition in the UK indicating the need for early MRI imaging and the low sensitivity of blood cultures and serum creatine kinase measurements. Treatment, including early surgical drainage and appropriate antibiotic therapy, is discussed.


Detection in a murine T lymphoma of a lipid-like factor that inhibits cell growth.
In this paper we show that MCG3 cells, a murine T lymphoma, contain a factor(s) that inhibits the proliferation of cells of different histological origin. The lack of sensitivity of this cell proliferation-inhibiting factor (CPIF) to the treatment with proteolytic enzymes and its solubility in organic solvent demonstrated that it is a lipid-like substance. Separation by thin-layer chromatography showed it migrates before the prostaglandins with activity on cell proliferation. CPIF activity was reversible and more intense on bone marrow cells than on tumor cells, suggesting that it can play a role in cell growth regulation.


Magnetic and 57Fe Mössbauer study of magneto-electric GaFeO3 prepared by the sol-gel route.
This work reports the preparation of magneto-electric GaFeO(3) by the sol-gel route and its characterization by x-ray diffraction, dc-magnetization, ac-susceptibility, low temperature and high field (57)Fe Mössbauer spectroscopy and dielectric constant measurements. The prepared samples are found to be single phase from x-ray diffraction studies. The crystallite sizes are found to be in the nano-regime for the samples sintered at low temperatures. From the temperature dependent dc-magnetization (M-T) measurements, bifurcation of the zero-field cooled (ZFC)-field cooled data and a cusp in the ZFC data are observed. With the help of low-field ac-susceptibility, (57)Fe Mössbauer and detailed dc-magnetic measurements these features are explained in terms of the magnetic anisotropy of the sample ruling out phenomena like spin-glass and super-paramagnetism as quoted in the literature for this compound. Apart from this, very interesting and different M-H behavior mimicking composite two-phase magnets is observed for the samples sintered at different temperatures. A symmetric M-H loop is observed for samples sintered at low temperatures and a pinched M-H loop is observed for samples sintered at high temperatures. The observed magnetic properties are explained by estimating the Fe cation distribution using high field (57)Fe Mössbauer spectroscopy measurements. An anomaly in the dielectric constant data at the Curie temperature indicates the ME coupling of the samples.


Cumulative effects of suspended sediments, organic nutrients and temperature stress on early life history stages of the coral Acropora tenuis.
Coral reproduction is vulnerable to both declining water quality and warming temperatures, with simultaneous exposures likely compounding the negative impact of each stressor. We investigated how early life processes of the coral Acropora tenuis respond to increasing levels of suspended sediments in combination with temperature or organic nutrients. Fertilization success and embryo development were more sensitive to suspended sediments than to high temperatures or nutrient enrichment, while larval development (after acquisition of cilia) and settlement success were predominantly affected by thermal stress. Fertilization success was reduced 80% by suspended sediments, and up to 24% by temperature, while the addition of nutrients to suspended sediments had no further impact. Larval survivorship was unaffected by any of these treatments. However, settlement success of larvae developing from treatment-exposed embryos was negatively affected by all three stressors (e.g. up to 55% by suspended sediments), while exposure only during later larval stages predominantly responded to temperature stress. Environmentally relevant levels of suspended sediments and temperature had the greatest impacts, affecting more processes than the combined impacts of sediments and nutrients. These results suggest that management strategies to maintain suspended sediments at low concentrations during coral spawning events will benefit coral recruitment, especially with warming climate.


Antimicrobial resistance of Shigella spp isolated from diarrheal patients between 1989 and 1998 in Vietnam.
Shigellosis is an important cause of infectious diarrhea in Vietnam, caused mainly by Shigella flexneri. This study provides for the first time in the international literature, data on the development of antimicrobial resistance in Shigella between 1988 to 1998, including data reported to the National Program for Surveillance of Antimicrobial Resistance (NPSAR). Our studies show that about 80% of the Shigella strains tested were resistant to ampicillin, chloramphenicol, oxytetracycline, trimethoprim and sulfonamides. This combination of drugs was also the most common antibiogram among multiple-resistant S. flexneri (57%). Resistance to tetracyclines, sulfonamides and, in particular trimethoprim (p<0.001), increased during the study period. Our findings indicate that tetracyclines and co-trimoxazole (a combination of a sulfonamide and trimethoprim), which are recommended and commonly used drugs for the treatment of shigellosis in Vietnam, may have limited therapeutic effect. In contrast to neighboring countries, low percentages of resistance were found to nalidixic acid and norfloxacin (3-5%) and no resistance was found to ciprofloxacin, indicating that nalidixic acid with its low cost and safety in children could be recommended for the treatment of shigellosis. The NPSAR provides a useful picture of the levels and development of antimicrobial resistance in Vietnam and should receive continued support for further improvement by increasing the number of provinces covered, the numbers of isolates tested from rural areas, and the communication of results to medical practitioners and others prescribing and/or selling antimicrobials.


First multicentric real-life experience with the combination of CCNU and temozolomide in newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma.
The randomized phase 3 CeTeG/NOA-09 trial assessed whether CCNU plus temozolomide was superior to temozolomide alone in newly diagnosed MGMT promoter methylated glioblastoma patients. Survival was significantly improved from 31.4 months (temozolomide) to 48.1 months (CCNU plus temozolomide). In view of this encouraging data, we assessed safety and efficacy of this regimen under real-life conditions. We retrospectively collected clinical and radiographic data from adult newly diagnosed MGMT promoter methylated IDH wildtype glioblastoma patients from five neuro-oncology centers in Germany. For inclusion in our analysis, treatment with CCNU and temozolomide had to be performed for at least six weeks (one course). Seventy patients were included. Median progression-free survival was 14.4 months and median overall survival 33.8 months. Patients with TTFields treatment for at least 8 weeks and CCNU plus temozolomide (n = 22, 31%) had a prolonged progression-free survival compared to those with TTFields treatment for less than eight weeks (n = 48, 69%) (21.5 versus 11.2 months; P = .0105). In a multivariable Cox regression analysis, TTFields treatment for eight weeks or longer together with CCNU plus temozolomide and a Karnofsky performance score ≥ 90% were independent prognostic factors for progression-free and overall survival. Pseudoprogression occurred in n = 16 (33%) of investigated n = 49 (70%) patients. In n = 31 (44%) patients high-grade hematotoxicity was observed. The results from this multicentric trial indicate that-under real-life conditions-toxicity and survival estimates are comparable to the CeTeG/NOA-09 trial. TTFields therapy for at least eight weeks in combination with this regimen was independently associated with prolonged survival.


Enhancing individual and collaborative eyewitness memory with category clustering recall.
Most crimes have multiple eyewitnesses. The police typically interview co-witnesses separately. In time-sensitive investigations, this could slow down evidence accumulation. Having co-witnesses collaboratively recall a crime could potentially expedite evidence accumulation. However, past research shows that collaborative group members often have conflicting retrieval strategies that disrupt each other, degrading overall recall. This cost could potentially be overcome by aligning group members' retrieval strategies with category clustering recall (CCR), which is a retrieval strategy where information is recalled from a series of forensically relevant categories (e.g., recalling the protagonists' appearance, then actions). This study examined the costs and benefits of collaborative eyewitness memory by having collaborative pairs of strangers, nominal pairs (i.e., two individuals whose recall is pooled) and lone individuals watch a crime and recall it using free recall or CCR. The collaborative pairs recalled the crime faster than the nominal pairs. They also recalled more correct information than individuals but less than nominal pairs, irrespective of the retrieval method. There is therefore a speed-recall completeness trade-off when collaborative groups recall crimes. Importantly, all participants recalled more correct information when using CCR. This provides initial evidence suggesting that CCR is superior to free recall. Further research examining CCR's benefits is recommended.


Qualitative and quantitative determination of a humic model compound in microbial cultures by cyclic voltammetry.
The humic model compound, anthraquinone-2,6-disulfonate (AQDS), was characterized and measured in microbial cultures by cyclic voltammetry (CV). Under the experimental conditions, the formal reduction potential (E(o')) of the couple AQDS/AHQDS was found to be of -0.520 V vs. SCE (standard calomel electrode) at pH value of 7.0. Control experiments showed that there were no interferences of the culture medium or the microbial consortium on the quantitative determination of the quinone. The linear equation E(o') = -0.294 - 0.032 pH was found, showing that the pH used (7.0-7.8) did not affect significantly the AQDS determination by CV and AHQDS was the predominant hydroquinone formed. A calibration curve was obtained by plotting current response versus AQDS concentration with a linear correlation (r = 0.999) from 0.2 to 10 mM of AQDS. This technique was applied in a denitrifying culture to establish kinetic profiles for AHQDS formation coupled to acetate and p-cresol oxidation. CV results showed that organic matter oxidation by the denitrifying sludge was stoichiometrically associated to AQDS reduction into AHQDS-. CV was shown to be a useful tool for monitoring oxidation/reduction processes of quinones occurring in complex microbial media.


Developmental stages and germ cell lineage of the loach (Misgurnus anguillicaudatus).
The staging of embryonic and larval development, and the germ cell lineage of the loach, Misgurnus anguillicaudatus, are described. Fertilized eggs were obtained by artificial insemination. For the convenience of detailed observation and photography of the external appearance, we use dechorionated embryos. Through a series of operations, these embryos were cultured at 20 degrees C in an incubator. Embryonic and larval development of the loach was divided into five periods: cleavage, blastula, gastrula, segmentation, and hatching. Stages were assigned within each of these periods. Developmental stages were determined and named by morphological features and somite number. The staging series were photographed and tabulated. The germ cell lineage was then elucidated by whole mount in situ hybridization of mRNA expression of the germ-cell-specific marker vasa and histological analysis. Primordial germ cells (PGCs) of the loach derived from the cleavage furrows of 8-cell stage embryos began proliferation in the late blastula period and migrated to the gonadal anlagen through a migration pathway similar to that of the zebrafish. However, it is characteristic of the loach that PGCs migrate a long distance and stay in the posterior part of the yolk-extension region.


Widespread subcutaneous haematoma after thrombolytic therapy in stroke patients. Mild falls at stroke onset may be dangerous.
Recombinant tissue Plasminogen Activator (rtPA) is one of the more and more often used therapies in ischemic stroke. Main adverse effect of rtPA could be bleeding in different anatomical sites. Onset of the stroke is often associated with falls due to sudden limb weakness. Mild trauma can be not reported by patients and their families and can leave no visible signs on the skin. Thrombolytic therapy given in such cases can cause potentially dangerous complication such as subcutaneous or subfascial hematoma. The article presents two cases of patients with ischemic stroke who received thrombolytic therapy with subsequent complication of wide-spread subcutaneous hematomas.


Treatment of Femoral Shaft Fractures in Patients with Klippel-Trénaunay Syndrome: A Report of 2 Cases.
Long-bone fractures in patients with Klippel-Trénaunay syndrome (KTS), a rare disorder of the venous, lymphatic, and capillary system, are difficult to treat with many complications. Two patients diagnosed with KTS presented with closed femoral shaft fractures after low-energy falls. Conservative treatment, open reduction internal fixation, and intramedullary nailing resulted in painful nonunions. Ultimately, both patients achieved pain relief and the ability to ambulate after en bloc resection and reconstruction. These cases demonstrate the challenges in achieving bony union when treating long-bone fractures in KTS. The feasibility of undergoing extensive resection and reconstruction to regain function is best approached with a multidisciplinary team.


Up-regulation of SNHG6 activates SERPINH1 expression by competitive binding to miR-139-5p to promote hepatocellular carcinoma progression.
We aimed to assess the roles of small nucleolar RNA host gene 6 (SNHG6) in hepatocellular carcinoma (HCC) progression, and establish the lncRNA-miRNA-mRNA regulation mechanism for HCC therapy. SNHG6 is one of the host genes in small nucleolar RNAs (snoRNAs), which make a difference in the development of human cancers. SERPINH1 is a gene encoding a member of the serpin superfamily of serine proteinase inhibitors with miRNA predicted by TargetScan and DIANA Tools. SNHG6, serpin family H member 1 (SERPINH1) and miR-139-5p expression levels in HCC tissues and cells were determined by quantitative real-time PCR (qRT-PCR). Migration and invasion of HCC cells were measured by transwell assay. Cell cycle analysis was determined by using flow cytometry. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and colony formation assay were performed for cell viability analysis. The expression of SERPINH1 was detected by qRT-PCR and western blot. Dual-luciferase reporter gene assay was conducted to identify the targeted relationship between miR-139-5p and SNHG6, as well as SERPINH1 and miR-139-5p. The positive regulation between SNHG6 and SERPINH1 was demonstrated in this study. In contrast, miR-139-5p was significantly down-regulated in HCC cells, the inhibition of miR-139-5p promotes the proliferation of HCC cells, and accelerated the cell cycle of HCC cells. Our study demonstrated the co-expression of SNHG6 and SERPINH1 in HCC cells for the first time, which revealed that SNHG6 could serve as a novel oncogene for the HCC therapy by its regulation.


Photochromic Semiconductors: Bottom-Up Strategy to Construct Type II-Stacking Viologen π-Aggregates.
Semiconductor conductivities depend largely on the crystal structures and the associated electronic structures. If the electronic structures can be switched reversibly in the same crystal structure, then a drastic conductivity change may be controllable. The effect of electron transfer (ET) on semiconductor conductivity remained elusive so far. In this work, a series of two pillared inorganicorganic hybrid photochromic semiconductors (PSCs), [(CQ)Pb3X6(H2O)]·2H2O [X = Cl (1) and Br (2), CQ = N-4,4'-bipyridiniopropionate (viologen)], with II-stacking viologen π-aggregates, are constructed by a bottom-up self-assembly strategy through inorganic skeleton-directed intercalation and intermolecular noncovalent interaction. The conductivities are abnormally "invariant" after photoinduced ET, breaking the convention that the generation of radicals favors conductivity. The abnormally "invariant" conductivities are mainly derived from approximate electronic couplings before and after ET between II-stacking viologen π-aggregates.


Monte carlo method-based QSAR modeling of penicillins binding to human serum proteins.
The binding of penicillins to human serum proteins was modeled with optimal descriptors based on the Simplified Molecular Input-Line Entry System (SMILES). The concentrations of protein-bound drug for 87 penicillins expressed as percentage of the total plasma concentration were used as experimental data. The Monte Carlo method was used as a computational tool to build up the quantitative structure-activity relationship (QSAR) model for penicillins binding to plasma proteins. One random data split into training, test and validation set was examined. The calculated QSAR model had the following statistical parameters: r(2) = 0.8760, q(2) = 0.8665, s = 8.94 for the training set and r(2) = 0.9812, q(2) = 0.9753, s = 7.31 for the test set. For the validation set, the statistical parameters were r(2) = 0.727 and s = 12.52, but after removing the three worst outliers, the statistical parameters improved to r(2) = 0.921 and s = 7.18. SMILES-based molecular fragments (structural indicators) responsible for the increase and decrease of penicillins binding to plasma proteins were identified. The possibility of using these results for the computer-aided design of new penicillins with desired binding properties is presented.


Bedside ultrasound and the assessment of renal colic: a review.
Renal colic is a common emergency department (ED) presentation. The use of CT in the diagnosis of renal colic has increased over the past two decades and is now the most common imaging modality used in many institutions. However, with growing concerns about cumulative radiation exposure, increasing healthcare costs and patient flow in EDs, alternative approaches may need to be considered. Point-of-care ultrasound may offer a radiation-free, rapid and cost-effective alternative. The authors reviewed the literature and synthesised some of the data comparing point-of-care ultrasound with CT scanning as well as some of the evidence for how it might be incorporated into a renal colic management strategy. It is concluded that there is enough evidence to define a rational algorithm for renal colic management. A prospectively validated algorithm would greatly assist primary care and emergency practitioners while reducing costs and radiation dose.


In vivo cardiotonic activity of aryl- and pyridyl-substituted fused imidazoles.
Two new imidazo[2,1-b]thiazoles related to sulmazole were synthesized and subjected to an in vivo cardiotonic assay with 14 analog compounds which gave the best results in previously reported in vitro tests. The data obtained show that three substituents (3-pyridyl, 4-pyridyl and 2,5-dimethoxyphenyl group) are useful pharmacophoric groups in modulating the in vivo cardiotonic activity of the fused imidazoles considered.


Countywide school-based influenza immunization: direct and indirect impact on student absenteeism.
Live attenuated influenza vaccine was given to 5319 (44%) of the 12090 students enrolled in public elementary schools in Carroll County, Maryland, during the fall of 2005. We examined the impact of this community-based intervention on countywide student absenteeism during the subsequent influenza outbreak. This study used existing, anonymous information: census data, community influenza tests, and public school absenteeism data. The intervention group was Carroll County, years 2005-2006. The control group included Carroll County, years 2001-2005, and adjacent Frederick County, years 2001-2006. Weekly student absenteeism was determined during baseline influenza-free periods and influenza outbreak periods for all of the public schools. The absolute change in absenteeism during the influenza outbreak periods over baseline in elementary schools was 0.61% for the intervention group and 1.79% for the control group. Similarly, the change in absenteeism during the influenza outbreak period over baseline for high schools was 0.32% for the intervention group and 1.80% for the control group. Although not statistically significant, trends in middle schools were similar. Countywide school-based influenza vaccination was associated with reduced absenteeism during an influenza outbreak. The data suggest not only a direct impact on elementary schools but also an indirect impact on high schools. School-based programs provide an efficient method of providing influenza vaccination to children, and protection may extend to unvaccinated community members. Additional research is needed to determine whether school-based vaccination of children reduces morbidity and mortality associated with influenza outbreaks.


Enhancing performances of a resistivity-type hydrogen sensor based on Pd/SnO2/RGO nanocomposites.
Palladium/tin oxide/reduced graphene oxide (Pd/SnO2/RGO) nanocomposites with Pd and SnO2 crystalline nanoparticles of high density and uniformity coated on RGO have been synthesized by a two-step reduction process. A novel hydrogen (H2) sensor based on Pd/SnO2/RGO nanocomposites was fabricated by placing Pd/SnO2/RGO nanocomposites onto a pair of gold electrodes. The Pd/SnO2/RGO nanocomposite-based sensor exhibited higher responses than Pd/RGO to H2 because the introduction of SnO2 nanoparticles enhances H2 adsorption and forms a P-N junction with RGO. The sensor shows a high response of 55% to 10 000 ppm H2, and a low detection limit, fast response, good selectivity and repeatability due to a combination effect of the Pd and SnO2 nanoparticles. The studies provide a novel strategy for great potential applications of graphene-based gas sensors.


Staffs' physiological responses to irrelevant background speech and mental workload in open-plan bank office workspaces.
Acoustic comfort is one of the most critical challenges in the open-plan workspace. This study was aimed to assess the effect of irrelevant background speech (IBS) and mental workload (MWL) on staffs' physiological parameters in open-plan bank office workspaces. In this study, 109 male cashier staff of the banks were randomly selected. The 30-minute equivalent noise level (LAeq) of the participants was measured in three intervals at the beginning (section A), middle (section B), and end of working hours (section C). The heart rate (HR) and heart rate variability (HRV): low frequency (LF), high frequency (HF), and LF/HF of the staff were also recorded in sections A, B, and C. Moreover, staff was asked to rate the MWL using the NASA-Task load. The dominant frequency of the LAeq was 500 Hz, and the LAeq in the frequency range of 250 to 2000 was higher than other frequencies. The LAeq (500 Hz) was 55.82, 69.35, and 69.64 dB(A) in sections A, B, and C, respectively. The results show that the IBS affects staffs' physiological responses so that with increasing in IBS, the HF power decreases. Moreover, with higher MWL, increasing noise exposure, especially IBS, causes more increases in LF power and LF/HF ratio. It seems that the IBS can affect physiological responses and increase staff stress in open-plan bank office workspaces. Moreover, the mental workload can intensify these consequences in these working settings.


Neural correlates of olfactory change detection.
Detecting changes in a stream of sensory information is vital to animals and humans. While there have been several studies of automatic change detection in various sensory modalities, olfactory change detection is largely unstudied. We investigated brain regions responsive to both passive and active detection of olfactory change using fMRI. Nine right-handed healthy, normosmic subjects (five men) were scanned in two conditions while breathing in synchrony with a metronome. In one condition, subjects mentally counted infrequent odors (Attend condition), whereas in the other condition, subjects' attention was directed elsewhere as they counted auditory tones (Ignore condition). Odors were delivered via a nasal cannula using a computer-controlled air-dilution olfactometer. Infrequently occurring olfactory stimuli evoked significant (P < .05, corrected) activity in the subgenual cingulate and in central posterior orbitofrontal cortex, but only in the Ignore condition, as confirmed by direct comparison of the Ignore session with the Attend session (P < .05, corrected). Subgenual cingulate and posterior orbital cortex may therefore play a role in detecting discrepant olfactory events while attention is otherwise engaged in another sensory modality.


Advances in heart failure: a review of biomarkers, emerging pharmacological therapies, durable mechanical support and telemonitoring.
The purpose of this review is to provide an overview of diagnosis, prognosis and management of heart failure (HF) with reduced ejection fraction (HFrEF). Specifically, this review is divided into three sections. The first section will address biomarkers. The discovery of biomarkers has allowed further understanding of the pathophysiology of HF and provides insight into potential therapeutic targets. This review will focus on novel applications of natriuretic peptides (NPs) in clinical trials. Next, emerging biomarkers of HF, such as ST2, galectin-3 and copeptin, will be discussed. The second section aims to highlight HF therapies, including novel drugs and durable devices. The last section will review home haemodynamic monitoring and mobile health. We aim to provide context for the understanding of novel diagnostic and therapeutic advances in HF that are still in phase II or III trials, and have yet to become widely available.


Evolution of Hybridization Probes to DNA Machines and Robots.
Hybridization probes are RNA or DNA oligonucleotides or their analogs that bind to specific nucleotide sequences in targeted nucleic acids (analytes) via Watson-Crick base pairs to form probe-analyte hybrids. Formation of a stable hybrid would indicate the presence of a DNA or RNA fragment complementary to the known probe sequence. Some of the well-known technologies that rely on nucleic acid hybridization are TaqMan and molecular beacon (MB) probes, fluorescent in situ hybridization (FISH), polymerase chain reaction (PCR), antisense, siRNA, and CRISPR/cas9, among others. Although invaluable tools for DNA and RNA recognition, hybridization probes suffer from several common disadvantages including low selectivity under physiological conditions, low affinity to folded single-stranded RNA and double-stranded DNA, and high cost of dye-labeled and chemically modified probes. Hybridization probes are evolving into multifunctional molecular devices (dubbed here "multicomponent probes", "DNA machines", and "DNA robots") to satisfy complex and often contradictory requirements of modern biomedical applications. In the definition used here, "multicomponent probes" are DNA probes that use more than one oligonucleotide complementary to an analyzed sequence. A "DNA machine" is an association of a discrete number of DNA strands that undergoes structural rearrangements in response to the presence of a specific analyte. Unlike multicomponent probes, DNA machines unify several functional components in a single association even in the absence of a target. DNA robots are DNA machines equipped with computational (analytic) capabilities. This Account is devoted to an overview of the ongoing evolution of hybridization probes to DNA machines and robots. The Account starts with a brief excursion to historically significant and currently used instantaneous probes. The majority of the text is devoted to the design of (i) multicomponent probes and (ii) DNA machines for nucleic acid recognition and analysis. The fundamental advantage of both designs is their ability to simultaneously address multiple problems of RNA/DNA analysis. This is achieved by modular design, in which several specialized functional components are used simultaneously for recognition of RNA or DNA analytes. The Account is concluded with the analysis of perspectives for further evolution of DNA machines into DNA robots.


[Current status of laparoscopic sacrocolpopexy in the treatment of pelvic organ prolapse.]
Surgical restoration of pelvic floor anatomy in pelvic organ prolapse (POP) should avoid extensive areas that may injure healthy tissues and lead to scar fibrosis producing dysfunctional rigidity. Laparoscopic sacrocolpopexy corrects POP by lifting pelvic elements with a minimally invasive procedure.Various current strategies and approaches make it a diverse procedure. We performed a bibliographic review on the published experience about abdominal sacrocolpopexy over the last 20 years. We analyze the philosophy of each technique, advantages, disadvantages, and results. Among current theories that explain how is the anatomy and function of the pelvic floor, the comprehensive theory of the pelvic floor announces that anatomical deviation produces pelvic dysfunction (diagnostic algorithm)(1). Surgical invasion with reconstructive purposes may hide results if the true physiopathology of the defects found is not known. Although current diagnostic tools cannot solve the problem as a whole, results of different techniques are much better than those of previous times. Laparoscopic sacrocolpopexy is an adequate strategy that restores anatomy in POP, mainly apical, and function with minimal invasion. Technical development and better knowledge of the female pelvis functional anatomy is enabling today a more precise understanding of its physiopathology, so it facilitates the design of site-specific operations. Various surgical approaches and techniques are offered depending on the defect, where combined procedures give good solutions. It is necessary to have an appropriate surgical training to obtain the better competence, and a safe and correct repair.


Light and electron microscope study of nerve cells in traumatic oedematous human cerebral cortex.
The cerebral cortex of eight patients with complicated head and brain traumatic injuries has been examined with light and transmission electron microscopes. The neuronal and neuroglial cell bodies and their processes have been examined to study the changes induced by the brain injury and the associated vasogenic and cytotoxic, moderate or severe, brain oedema. Light microscopy study showed oedematous and ischaemic neurons and neuroglial cells in both moderate and severe oedema, and breakdown of the blood-brain barrier with perivascular and parenchymatous haemorrhagic foci. Astrocytes and oligodendrocytes exhibited oedematous and reactive changes. At the electron microscope level oedematous changes were found in intraneuronal and glial somatic compartment. Myelinated axons showed clear and dark degenerative features. Beaded dendrites and clear and dense synaptic degeneration were also found. The extracellular space appeared distended, with the presence of clear and electron-dense haematogenous oedema fluid and fibrinous organization. Phagocytosis of degenerated myelinated axons and synaptic endings by neuroglial cells and non-nervous invading cells were observed. The clinical evolution time of traumatic brain injuries was considered in relation to nerve cell degenerative features.


Reunions between adoptees and birth parents: the adoptive parents' view.
This article looks at the reactions of adoptive parents to reunions between their adopted children and the children's birth parents. The focus is on how adoptive parents feel the reunion affects the family's integrity. Three types of family responses are identified: (1) closed, (2) divided, and (3) open. Acceptance of the differences between families created by adoption of children and those created by childbirth was a factor in the families' openness. Closed families saw no difference, and reunion suggested to the adults that they had failed as parents. Parents in open families understood the difference in families, saw the children as separate, and felt no threat to their competence as parents. Families' need for boundaries is examined, and the way the concept of family is constructed is discussed. Implications for the practice of adoption are considered.


EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.
The EML4-ALK fusion gene has been detected in approximately 7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLC and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK-containing cell lines in vitro and in vivo. We screened 305 primary NSCLC [both U.S. (n = 138) and Korean (n = 167) patients] and 83 NSCLC cell lines using reverse transcription-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo. We detected four different variants, including two novel variants, of EML4-ALK using reverse transcription-PCR in 8 of 305 tumors (3%) and 3 of 83 (3.6%) NSCLC cell lines. All EML4-ALK-containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (<10 pack-years) cigarette smokers compared with current/former smokers (6% versus 1%; P = 0.049). TAE684 inhibited the growth of one of three (H3122) EML4-ALK-containing cell lines in vitro and in vivo, inhibited Akt phosphorylation, and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to coactivation of epidermal growth factor receptor and ERBB2. The combination of TAE684 and CL-387,785 (epidermal growth factor receptor/ERBB2 kinase inhibitor) inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line. EML4-ALK is found in the minority of NSCLC. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK.


Adipose tissue lymphocytes: types and roles.
Besides adipocytes, specialized in lipid handling and involved in energy balance regulation, white adipose tissue (WAT) is mainly composed of other cell types among which lymphocytes represent a non-negligible proportion. Different types of lymphocytes (B, alphabetaT, gammadeltaT, NK and NKT) have been detected in WAT of rodents or humans, and vary in their relative proportion according to the fat pad anatomical location. The lymphocytes found in intra-abdominal, visceral fat pads seem representative of innate immunity, while those present in subcutaneous fat depots are part of adaptive immunity, at least in mice. Both the number and the activity of the different lymphocyte classes, except B lymphocytes, are modified in obesity. Several of these modifications in the relative proportions of the lymphocyte classes depend on the degree of obesity, or on leptin concentration, or even fat depot anatomical location. Recent studies suggest that alterations of lymphocyte number and composition precede the macrophage increase and the enhanced inflammatory state of WAT found in obesity. Lymphocytes express receptors to adipokines while several proinflammatory chemokines are produced in WAT, rendering intricate crosstalk between fat and immune cells. However, the evidences and controversies available so far are in favour of an involvement of lymphocytes in the control of the number of other cells in WAT, either adipocytes or immune cells and of their secretory and metabolic activities. Therefore, immunotherapy deserves to be considered as a promising approach to treat the endocrino-metabolic disorders associated to excessive fat mass development.


Multiple rather than specific autoantibodies were identified in irritable bowel syndrome with HuProt™ proteome microarray.
Immune activation and several autoantibodies might be involved in the pathophysiology of irritable bowel syndrome (IBS). We aimed to identify serum biomarkers for IBS by HuProt™ microarray. IBS patients met Rome III criteria were enrolled. Control groups included healthy controls (HCs) and disease controls (DCs). In stage I, we profiled sera from IBS and control groups with HuProt™ microarrays. Based on significant different proteins in stage I, IBS focused microarrays were constructed and validated in a larger cohort in stage II, then decision tree models were generated to establish a combination of biomarkers. In stage III, 4 purified proteins were verified by ELISA. Finally, we analyzed the correlation of autoantibodies with symptoms. In stage I, we identified 47 significant different proteins including 8 autoantibodies of IgG, 2 of IgA between IBS and HCs; 13 autoantibodies of IgG, 13 of IgA between IBS and DCs. In stage II, we found the positive rates of 14 IgG and IgA autoantibodies in IBS were significantly higher than HCs. Five autoantibodies of IgG and 7 IgA were comprehensively involved in differentiating IBS and HCs with the sensitivity and specificity to diagnose IBS as 40%-46.7% and 79.4%-86.3%. The median optical density value of ELAVL4 (IgG) and PIGP (IgA) were significantly higher in IBS than HCs. Parts of autoantibodies above were related to IBS symptoms. We found a combination of autoantibodies to differentiate IBS with HCs, but no specific autoantibodies could serve as serum biomarkers for IBS.


Engineered magnetic hybrid nanoparticles with enhanced relaxivity for tumor imaging.
Clinically used contrast agents for magnetic resonance imaging (MRI) suffer by the lack of specificity; short circulation time; and insufficient relaxivity. Here, a one-step combinatorial approach is described for the synthesis of magnetic lipid-polymer (hybrid) nanoparticles (MHNPs) encapsulating 5 nm ultra-small super-paramagnetic iron oxide particles (USPIOs) and decorated with Gd(3+) ions. The MHNPs comprise a hydrophobic poly(lactic acid-co-glycolic acid) (PLGA) core, containing up to ~5% USPIOs (w/w), stabilized by lipid and polyethylene glycol (PEG). Gd(3+) ions are directly chelated to the external lipid monolayer. Three different nanoparticle configurations are presented including Gd(3+) chelates only (Gd-MHNPs); USPIOs only (Fe-MHNPs); and the combination thereof (MHNPs). All three MHNPs exhibit a hydrodynamic diameter of about 150 nm. The Gd-MHNPs present a longitudinal relaxivity (r1 = 12.95 ± 0.53 (mM s)(-1)) about four times larger than conventional Gd-based contrast agents (r1 = 3.4 (mM s)(-1)); MHNPs have a transversal relaxivity of r2 = 164.07 ± 7.0 (mM s)(-1), which is three to four times larger than most conventional systems (r2 ~ 50 (mM s)(-1)). In melanoma bearing mice, elemental analysis for Gd shows about 3% of the injected MHNPs accumulating in the tumor and 2% still circulating in the blood, at 24 h post-injection. In a clinical 3T MRI scanner, MHNPs provide significant contrast confirming the observed tumor deposition. This approach can also accommodate the co-loading of hydrophobic therapeutic compounds in the MHNP core, paving the way for theranostic systems.


[Phase I clinical trials in oncology: ethical issues].
The scientific goal of phase I clinical trials in oncology is to determine and optimise the drug dose and schedule on the basis of the toxicity profile. These trials also respond to a need: they offer the chance of early access to a new therapy for cancer patients who are characterised by both the lack of a therapeutic option and a desire to fulfil personal ambitions. The therapeutic relationship in this context must reconcile unreasonable hopes and anxiety regarding death and follow the same rules as in other doctor-patient relationships, with the triple requirement being that it should be genuine, therapeutic and empathetic.


Host genetic variation and its microbiome interactions within the Human Microbiome Project.
Despite the increasing recognition that microbial communities within the human body are linked to health, we have an incomplete understanding of the environmental and molecular interactions that shape the composition of these communities. Although host genetic factors play a role in these interactions, these factors have remained relatively unexplored given the requirement for large population-based cohorts in which both genotyping and microbiome characterization have been performed. We performed whole-genome sequencing of 298 donors from the Human Microbiome Project (HMP) healthy cohort study to accompany existing deep characterization of their microbiomes at various body sites. This analysis yielded an average sequencing depth of 32x, with which we identified 27 million (M) single nucleotide variants and 2.3 M insertions-deletions. Taxonomic composition and functional potential of the microbiome covaried significantly with genetic principal components in the gastrointestinal tract and oral communities, but not in the nares or vaginal microbiota. Example associations included validation of known associations between FUT2 secretor status, as well as a variant conferring hypolactasia near the LCT gene, with Bifidobacterium longum abundance in stool. The associations of microbial features with both high-level genetic attributes and single variants were specific to particular body sites, highlighting the opportunity to find unique genetic mechanisms controlling microbiome properties in the microbial communities from multiple body sites. This study adds deep sequencing of host genomes to the body-wide microbiome sequences already extant from the HMP healthy cohort, creating a unique, versatile, and well-controlled reference for future studies seeking to identify host genetic modulators of the microbiome.


Environmental Factors and Ventilation Affect Concentrations of Microorganisms in Hospital Wards of Southern Thailand.
Hospitals tend to have high density of occupancy. Poor indoor environmental quality in hospital buildings can exacerbate the health problems of patients and also harm visitors and staff. This study investigated the environmental characteristics and ventilation affecting the concentration of microorganisms in multiple-bed hospital wards. The measurements were accomplished by using a biosampler and an open plate method at four wards, different positions of electric fans, and different times. Data were analyzed by t-test and MANOVA. The results revealed that the concentrations of airborne bacteria were higher than the concentrations of fungi. There were significant differences in the concentrations of bacteria and fungi between sampling times and between hospital wards (p < 0.05), while no difference was observed by positions of electric fans. Correlations between the concentrations and other environmental parameters indicate that temperature, number of occupants, and humidity were physical factors associated with the concentrations of microorganisms. In addition, mostly, Gram-positive bacteria were observed. This indicates the conditions in buildings in the tropical climate, and regular housekeeping of all room areas is needed to prevent the growth of airborne contaminants and the related risks to patients, visitors, and staff.


Cell cycle related uptake, retention and toxicity of idarubicin, daunorubicin and doxorubicin.
Exponentially growing Molt-4 cells were separated by means of counterflow centrifugation into fractions enriched for cells in early G1, late G1, S, or G2+M phase of the cell cycle. Subsequently, cells were exposed for 2 h to Idarubicin (Ida, 0.02-0.15 microgram/ml). Daunorubicin (Dnr, 0.1-0.75 microgram/ml) or Doxorubicin (Dox, 0.1-0.75 microgram/ml). Drug uptake, measured by flow cytometry, increased progressively with cell cycle traverse from early G1-to M-phase. The relative fraction of drug lost following an extensive wash procedure was 72% in case of Ida and 23% for Dnr and Dox and was independent of the cell cycle phase. Inhibition of DNA synthesis was determined by qualitative flow cytometric analysis of 5-iodo-2'-deoxyuridine (IdUrd) incorporation into DNA. The three drugs showed a similar gradual increase of inhibition of DNA synthesis from G1 to G2+M phase, demonstrating that cell cycle phase dependency of drug toxicity applies to all three anthracyclines studied.


Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome.
Drawing on our experience of 16 cases and a review of the English literature, we propose that CSS is under-diagnosed because of exclusive emphasis upon pathologic recognition of the disorder. The classical histological picture comprises a necrotizing vasculitis, eosinophilic tissue infiltration and extravascular granulomas, but it is only found in a minority of cases, and is not pathognomonic of the condition (69, 108). On the other hand, the clinical pattern of the disorder is most distinctive, and CSS can be readily identified on clinical grounds. Typically, it begins with allergic rhinitis, which is often complicated by nasal polyposis and sinusitis. Asthma and peripheral blood eosinophilia are essential features, often accompanied by pulmonary infiltrates. The systemic vasculitis of CSS resembles that of PAN, but severe renal disease is uncommon (the typical renal lesion is a focal segmental glomerulonephritis), and cardiac involvement accounts for 50% of deaths. Diagnostic difficulties arise from the close relationship of CSS to other granulomatous, vasculitic and eosinophilic disorders. CSS is usefully regarded as a point of overlap between these three disease spectrums (Fig. 5). Individual components of each spectrum can occur in the course of CSS; hence cases may be reported as PAN developing as a complication of Löffler syndrome or eosinophilic gastroenteritis (37, 57, 66). The hypereosinophilia of CSS tends to be less severe and more steroid-responsive than in HES, and evidence of eosinophil degranulation was not found in the patients we studied. Complement abnormalities are not a prominent feature of the disorder, and circulating immune complexes were detected in only two cases; both contained IgM. This may be of pathogenetic significance as IgM deposition was a dominant feature in four of the five cases with positive renal immunofluorescence. IgE levels were elevated in all patients studied during the vasculitic phase, and skin-prick tests were positive in 8 of 10 patients tested. CSS responds well to treatment with steroids, although some patients benefit from the addition of immunosuppressive agents. The vasculitic illness is usually of limited duration, but relapses can occur, and should be detected and treated early. Major problems in the post-vasculitic phase stem from hypertension and persisting peripheral nerve damage. Allergic upper and lower respiratory tract disease is an important cause of morbidity in the pre- and post-vasculitic periods.


Chronic obstructive pulmonary disease. An original model of cognitive decline.
In order to characterize the neuropsychologic profile of patients with hypoxic-hypercapnic chronic obstructive pulmonary disease (COPD), the performance of 36 patients with COPD 69 +/- 10 yr of age (mean +/- SD) on 19 tests exploring eight cognitive domains was compared with those of 29 normal adults (69 +/- 7 yr of age), 20 normal elderly adults (78 +/- 2 yr of age), 26 patients with Alzheimer-type dementia (72 +/- 6 yr of age), and 28 with multi-infarct dementia (MID) (70 +/- 8 yr of age). The discriminant analysis of cognitive test scores showed that 48.5% of patients with COPD had a specific pattern of cognitive deterioration characterized by a dramatic impairment in verbal and verbal memory tasks, well-preserved visual attention, and diffuse worsening of the other functions. The remaining patients with COPD were functionally classified as normal adults (12.1%), normal elderly adults (15.2%), those with MID (12.1%), and those with Alzheimer-type dementia (12.1%) according to discriminant analysis. Cognitive impairment was significantly and positively correlated with age (p < 0.05) and duration of hypoxic-hypercapnic chronic respiratory failure (p < 0.05). Because patients with COPD were receiving oxygen therapy from the beginning of oxyhemoglobin desaturation, results suggest that continuous oxygen therapy does not prevent or only partly prevents cognitive decline in COPD. Although some analogies between age-related and COPD-related cognitive decline are evident, a distinct cognitive profile was found in a large fraction of patients with COPD and it differs in several aspects from those of both normal and demented subjects.


Protective effects of Acanthopanax divaricatus vat. albeofructus and its active compound on ischemia-reperfusion injury of rat liver.
In the present study, the potential antioxidant and anti-inflammatory effects of Acanthopanax divaricatus vat. albeofructus (AE) and acanthoside-D (AD) isolated from AE against hepatic ischemia-reperfusion (I/R) injury were investigated in a rat model. Male Sprague-Dawley rats (200-220 g) were randomized into seven groups: normal controls; sham-operated controls; I/R injury model; I/R injury model with AE pretreatment at 150, 300, and 600 mg/kg body weight; and I/R injury model with AD pretreatment at 600 μg/kg body weight (equivalent to high dose of AE). The AE and AD pretreatments were administered orally for 2 weeks prior to I/R injury surgery. All rats recovered for 1 week with AE and AD treatment after surgery. Compared to the normal control groups, the I/R injury model group without supplemental treatment showed a significantly lower level of serum superoxide dismutase (SOD) and significantly higher levels of tumor necrosis factor-alpha (TNF-α, interleukin (IL)-6, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), as well as lactate dehydrogenase (LDH) activity. The I/R-induced decrease in SOD and increases in TNF-α and IL-6 were resolved, at least partially, by AE and AD treatments, as evidenced by significantly higher antioxidant activities and significantly lower inflammatory cytokine levels in the treatment groups as compared to the I/R injury model group. The AE and AD treatment groups also showed significantly higher levels of serum IL-10 than I/R injury model group. Histological examination revealed that the AE and AD treated groups had less extensive liver necrosis than I/R injury model group. Concomitantly, AE lowered the I/R-induced increases in AST, ALT, ALP levels and LDH activity. In conclusion, AE and AD are capable of alleviating I/R-induced hepatic injury by inhibiting inflammatory cell infiltration, thereby mitigating the release of inflammatory cytokines and balancing the oxidant-antioxidant status mediated by p38 MAPK and JNK/SAPK signaling.


A Smart Shoe Insole to Monitor Frail Older Adults' Walking Speed: Results of Two Evaluation Phases Completed in a Living Lab and Through a 12-Week Pilot Study.
Recent World Health Organization reports propose wearable devices to collect information on activity and walking speed as innovative health indicators. However, mainstream consumer-grade tracking devices and smartphone apps are often inaccurate and require long-term acceptability assessment. Our aim is to assess the user acceptability of an instrumented shoe insole in frail older adults. This device monitors participants' walking speed and differentiates active walking from shuffling after step length calibration. A multiphase evaluation has been designed: 9 older adults were evaluated in a living lab for a day, 3 older adults were evaluated at home for a month, and a prospective randomized trial included 35 older adults at home for 3 months. A qualitative research design using face-to-face and phone semistructured interviews was performed. Our hypothesis was that this shoe insole was acceptable in monitoring long-term outdoor and indoor walking. The primary outcome was participants' acceptability, measured by a qualitative questionnaire and average time of insole wearing per day. The secondary outcome described physical frailty evolution in both groups. Living lab results confirmed the importance of a multiphase design study with participant involvement. Participants proposed insole modifications. Overall acceptability had mixed results: low scores for reliability (2.1 out of 6) and high scores for usability (4.3 out of 6) outcomes. The calibration phase raised no particular concern. During the field test, a majority of participants (mean age 79 years) were very (10/16) or quite satisfied (3/16) with the insole's comfort at the end of the follow-up. Participant insole acceptability evolved as follows: 63% (12/19) at 1 month, 50% (9/18) at 2 months, and 75% (12/16) at 3 months. A total of 9 participants in the intervention group discontinued the intervention because of technical issues. All participants equipped for more than a week reported wearing the insole every day at 1 month, 83% (15/18) at 2 months, and 94% (15/16) at 3 months for 5.8, 6.3, and 5.1 hours per day, respectively. Insole data confirmed that participants effectively wore the insole without significant decline during follow-up for an average of 13.5 days per 4 months and 5.6 hours per day. For secondary end points, the change in frailty parameters or quality of life did not differ for those randomly assigned to the intervention group compared to usual care. Our study reports acceptability data on an instrumented insole in indoor and outdoor walking with remote monitoring in frail older adults under real-life conditions. To date, there is limited data in this population set. This thin instrumentation, including a flexible battery, was a technical challenge and seems to provide an acceptable solution over time that is valued by participants. However, users still raised certain acceptability issues. Given the growing interest in wearable health care devices, these results will be useful for future developments. ClinicalTrials.gov NCT02316600; https://clinicaltrials.gov/ct2/show/NCT02316600.


Assessment of plasma and red cell trace element concentrations, disease severity, and outcome in patients with critical illness.
The purpose of the study is to examine the value of both plasma and red cell trace element measurements when assessing nutritional status in patients with critical illness. A total of 125 patients who were admitted to intensive care unit with evidence of systemic inflammatory response as per Bone's criteria were recruited. Venous blood samples were obtained from all on admission and, in 31 of the 125 patients, on approximately days 4 and 7. Copper, zinc, and selenium concentrations were measured in plasma and erythrocytes and results related to mortality and patient outcome measures. A total of 125 critically ill patients were recruited; 81 (66%) were male, the median age was 60 (range, 18-100), and the medical/surgical proportion was 55/70 (44%/56%). The median (lower and upper 2.5th percentile) Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, and length of stay and mortality were 21 (16-26), 7 (4-9) 3.7 days (1.5-11.1) and 19%, respectively. Plasma zinc and selenium concentrations were significantly lower on admission compared with reference intervals, whereas copper was increased. Normal plasma glutathione peroxidase activity suggested selenium status was adequate on admission; erythrocyte concentrations of glutathione peroxidase and trace elements were normal, suggesting adequate nutritional status 1 to 2 months before admission. Only plasma zinc and selenium were inversely associated with C-reactive protein (rs = -0.266, P = .004, rs = -0.322, P < .001, respectively). Compared with survivors, albumin (P < .001) concentrations were significantly lower in the nonsurvivor group. No significant difference of plasma selenium and zinc between survivors and nonsurvivors was found, although plasma selenium concentrations tended to be lower (P = .04). On multivariate logistic regression analysis of the significant variables, none was independently associated with mortality. The altered plasma concentrations of zinc, selenium, and copper in patients with critical illness were primarily due to the effects of the systemic inflammatory response and do not reliably indicate their status.


Block staining of mammalian tissues with hematoxylin and eosin.
Various mammalian tissues were stained en bloc with hematoxylin and eosin after fixation and prior to embedding in paraffin wax and sectioning. The choice of fixative is important and best results are obtained using Worcester's Fluid, a combination of saturated aqueous mercuric chloride, formaldehyde, and glacial acetic acid. After fixation, blocks of tissue up to 1.5 cm thick are stained for seven days in hematoxylin. Excess stain is removed by washing tissues in running water overnight. Tissue blocks then are dehydrated with graded concentrations of ethyl alcohols to 80% and counterstained, with further dehydration, in 0.5% spirit soluble eosin in 90% ethyl alcohol for five days. The tissue is subsequently transferred to 90% ethyl alcohol overnight to differentiate eosin staining; dehydration is completed in absolute ethyl alcohol. The blocks are cleared in in cedarwood oil and briefly in xylene prior to embedding, sectioning, and mounting. Following removal of wax by xylene, coverslips are applied. General morphological and histological features were particularly well differentiated and very selectively and reliably stained by this method.


Different ventilation modes combined with ambroxol in the treatment of respiratory distress syndrome in premature infants.
The aim of the present study was to compare the effectiveness of different modes of mechanical ventilation in combination with secretolytic therapy with ambroxol in premature infants with respiratory distress syndrome. Seventy-three premature infants with hyaline membrane disease (HMD) (stage III-IV), also known as respiratory distress syndrome, who were supported by mechanical ventilation in the neonatal intensive care unit (NICU) of Xuzhou Central Hospital, were involved in the present study, between January 2013 and February 2015. Forty cases were randomly selected and treated with high frequency oscillatory ventilation (HFOV), forming the HFOV group, whereas 33 cases were selected and treated with conventional mechanical ventilation (CMV), forming the CMV group. Patients in the two groups were administered ambroxol intravenously at a dosage rate of 30 mg/kg body weight at the beginning of the study. The present study involved monitoring the blood gas index as well as changes in the respiratory function index in the two groups. Additionally, the incidence of complications in the premature infants in the two groups was observed prior to and following the ventilation. Pulmonary arterial oxygen tension (PaO2), the PaO2/fraction of inspired oxygen (FiO2) ratio, the oxygenation index [OI = 100 × mean airway pressure (MAP) × FiO2/PaO2], as well as the arterial/alveolar oxygen partial pressure ratio (a/APO2) = PaO2/(713 × FiO2 partial pressure of carbon dioxide (PaCO2)/0.8) of the patients in the HFOV group after 1, 12 and 24 h of treatment were significantly improved as compared to the patients of the CMV group. However, there was no significant difference between patients in the two groups with regard to the number of mortalities, complications such as pneumothorax, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and the time of ventilation. In conclusion, combining HFOV with ambroxol secretolytic therapy is a more viable option, as the combined treatment resulted in significant improvements in arterial blood gas levels, oxygenation and the respiratory function of lungs in preterm infants.


Restructuring hospitals, restructuring nursing.
The global economy is in the depths of recession. Organizations from virtually every industry, including manufacturing and service, have responded by reducing expenses and cutting operational costs. Health care restructuring is one result of the new economy. Hospitals worldwide have been flattening organizational charts and reducing costs. Downsizing, rightsizing, restructuring--whatever term is used, the message is the same: people are a cost to be reduced.


Priorities and challenges for a palliative approach to care for rural indigenous populations: A scoping review.
We carried out a scoping review to identify key priorities and challenges relevant to rural Indigenous palliative care stated in existing literature. Our scoping review activities followed Arskey and O'Malley's principles for conducting a scoping review. We included peer-reviewed literature from MEDLINE, CINAHL and EMBASE that included a discussion of Indigenous populations, palliative care, and rural settings, and did not use date limits. The literature search was conducted in April 2016, and the retrieved literature was screened for relevance and appropriateness April 2016-March of 2017. In addition to the academic literature, a scan of the grey literature was conducted in March 2017. The retrieved grey literature was screened for relevance and reviewed by a team from a provincial health authority serving Indigenous peoples to ensure relevance in a rural BC setting. Once reviewed for relevance and appropriateness, we added four reports to supplement our analysis. Ultimately, 44 peer-reviewed articles and 4 pieces of grey literature met our inclusion criteria and were included in the review. Our analysis revealed several challenges and priorities relevant to rural Indigenous palliative care. Key challenges included: (i) environmental and contextual issues; (ii) institutional barriers; and (iii) interpersonal dynamics challenging client/clinician interactions. Priorities included: (i) family connections throughout the dying process; (ii) building local capacity for palliative care to provide more relevant and culturally appropriate care; and (iii) flexibility and multi-sectoral partnerships to address the complexity of day-to-day needs for patients/families. These findings point to several areas for change and action that can improve the relevance, access and comprehensiveness of palliative care programming for rural Indigenous communities in Canada and elsewhere. Taking into account of the diversity and unique strengths of each Indigenous community will be vital in developing sustainable and meaningful change.


Effects of musical training on speech-induced modulation in corticospinal excitability.
We investigated the effect of previous musical training on lateralization of language as indexed by the effects of reading aloud on the modulation of motor evoked potentials (MEPs) induced in the first dorsal interosseus muscles (FDI) by transcranial magnetic stimulation (TMS) of the primary motor cortex. We studied 13 right-handed subjects, seven musicians who had been playing a musical instrument for >10 years and six controls who had never studied a musical instrument. In all subjects, the amplitude of MEPs in the right FDI was facilitated by reading aloud. However, the musicians also showed significant facilitation in the left FDI, while controls did not. These results illustrate striking effects of musical training on lateralization of motor and language functions.


Mechanical disassembly of human picobirnavirus like particles indicates that cargo retention is tuned by the RNA-coat protein interaction.
Here we investigate the cargo retention of individual human picobirnavirus (hPBV) virus-like particles (VLPs) which differ in the N-terminal of their capsid protein (CP): (i) hPBV CP contains the full-length CP sequence; (ii) hPBV Δ45-CP lacks the first 45 N-terminal residues; and (iii) hPBV Ht-CP is the full-length CP with a N-terminal 36-residue tag that includes a 6-His segment. Consequently, each VLP variant holds a different interaction with the ssRNA cargo. We used atomic force microscopy (AFM) to induce and monitor the mechanical disassembly of individual hPBV particles. First, while Δ45-CP particles that lack ssRNA allowed a fast tip indentation after breakage, CP and Ht-CP particles that pack heterologous ssRNA showed a slower tip penetration after being fractured. Second, mechanical fatigue experiments revealed that the increased length in 8% of the N-terminal (Ht-CP) makes the virus particles to crumble ∼10 times slower than the wild type N-terminal CP, indicating enhanced RNA cargo retention. Our results show that the three differentiated N-terminal topologies of the capsid result in distinct cargo release dynamics during mechanical disassembly experiments because of the different interaction with RNA.


Human host defence peptide LL37 and anti-cyclic citrullinated peptide antibody in early inflammatory arthritis.
Antibodies to citrullinated peptides (anti-CCP) develop in individuals predisposed to rheumatoid arthritis (RA). Neutrophil extracellular traps are a major source of citrullinated antigens and the immunomodulatory host defence peptide LL-37. Vitamin D regulates LL-37 expression. This study assessed the associations of LL-37 and anti-CCP, vitamin D metabolites and vitamin D receptor (VDR) polymorphisms in early inflammatory arthritis (EIA). Serum LL-37, 25-hydroxy-vitamin D (25OHvitD) and anti-CCP were measured by ELISA in treatment naïve EIA (n = 181). VDR single nucleotide polymorphisms (Fok1, Bsm1, Apa1, Taq1, Cdx-2) and HLADRB1 shared epitope (SE) alleles were detected by DNA amplification. Associations were tested in multivariable models. Median (25%, 75%) or percentiles are reported. Participants (70 % female, age 56 [45, 66] years, disease activity score [DAS28ESR3var] 3.7 [2.8, 4.8], 41 % anti-CCP positive, 68 % RA) had low serum 25OHvitD; 20.5 nmol/L (13.9, 29.0). In multivariable models, controlling for age, sex, SE, smoking and vitamin D deficiency, LL37 level (top quartile) associated with anti-CCP seropositivity (OR 22; 95% CI 4 to 104). Levels of circulating LL-37 are associated with anti-CCP seropositivity. LL37 activity may be one mechanism linking infection and toxin exposure to anti-CCP generation.


Palladium/zinc co-catalyzed asymmetric transfer hydrogenation of oxabenzonorbornadienes with alcohols as hydrogen sources.
Asymmetric transfer hydrogenation of oxabenzonorbornadienes was realized by using alcohols as hydrogen sources under a co-catalytic system of palladium and zinc. Both primary and secondary alcohols could serve as reductants and afforded enantiomerically enriched 1,2-dihydronaphth-1-ol products with high optical purities.


Heat-stone massage for patients with chronic musculoskeletal pain: a protocol for multicenter randomized controlled trial.
Chronic musculoskeletal pain bothers the quality of life for approximately 1.71 billion people worldwide. Although pharmacological therapies play an important role in controlling chronic pain, overuse of opioids, persistent or recurrent symptoms, and pain-related disability burden still need to be addressed. Heat-stone massage is using the heated stone to stimulate muscles and ligaments followed by massage for relax, which can potentially treat the chronic musculoskeletal pain. To determine the efficacy and safety of heat-stone massage for patients with chronic musculoskeletal pain is needed. This multicenter, 2-arm, randomized, positive drug-controlled trial will include a total of 120 patients with chronic musculoskeletal pain. The intervention group will receive a 2 week heat-stone massage, 3 times per week, whereas the control group will receive the flurbiprofen plaster twice per day for 2 weeks. The primary end point is the change in Global Pain Scale from baseline to the end of the 2 week intervention. The secondary outcomes include the pain severity (Numerical Rating Scale), pain acceptance (Chronic Pain Acceptance Questionnaire), self-management (Health Education Impact Questionnaire), self-efficacy (Pain Self-Efficacy Questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale), quality of life (Short Form-36). The intention-to-treat dataset will be used for analysis. The pain management remains the research topic that patients always pay close attention to. This will be the first randomized clinical trial to evaluate whether heat-stone massage, a non-pharmacological therapy, is effective in the chronic musculoskeletal pain management. The results will provide evidence for new option of daily practice. World Health Organization Chinese Clinical Trial Registry [ChiCTR2200065654; https://www.chictr.org.cn/showproj.html?proj=185403]; International Traditional Medicine Clinical Trial Registry [ITMCTR2022000104; http://itmctr.ccebtcm.org.cn/en-US/Home/ProjectView?pid=51776b6f-77b8-4811-9b5a-a0fec10f2cee].


Immiscibility in N2-H2O solids up to 140 GPa.
Nitrogen and water are very abundant in nature; however, the way they chemically react at extreme pressure-temperature conditions is unknown. Below 6 GPa, they have been reported to form clathrate compounds. Here, we present Raman spectroscopy and x-ray diffraction studies in the H2O-N2 system at high pressures up to 140 GPa. We find that clathrates, which form locally in our diamond cell experiments above 0.3 GPa, transform into a fine grained state above 6 GPa, while there is no sign of formation of mixed compounds. We point out size effects in fine grained crystallites, which result in peculiar Raman spectra in the molecular regime, but x-ray diffraction shows no additional phase or deviation from the bulk behavior of familiar solid phases. Moreover, we find no sign of ice doping by nitrogen, even in the regimes of stability of nonmolecular nitrogen.


Visualisation of human dental pulp vasculature by immunohistochemical and immunofluorescent detection of CD34: a comparative study.
CD34 is considered a pan-endothelial cell marker for paraffin-embedded sections. In this study, both immunohistochemistry and immunofluorescence were applied in human dental pulp specimens of moderate thickness (10 microm) in order to observe the vasculature of this tissue using CD34. Both techniques revealed a homogenous staining pattern with capillaries and larger vessels showing complete and strong membrane staining reflecting the high capacity of the pulp for regeneration and response to different stimuli. A novel approach in the identification of the pulpal vasculature by Cy5-conjugated anti-CD34 is introduced in this study. By this technique the dense capillary plexus of the sub-odontoblastic region, which is responsible for the reaction of the tissue to any physical or chemical stimuli or pathological condition, can be clearly identified, while immunohistochemistry did not reveal such a detailed staining pattern.


Correction: Vibrational dynamics and solvatochromism of the label SCN in various solvents and hemoglobin by time dependent IR and 2D-IR spectroscopy.
Correction for 'Vibrational dynamics and solvatochromism of the label SCN in various solvents and hemoglobin by time dependent IR and 2D-IR spectroscopy' by Luuk J. G. W. van Wilderen et al., Phys. Chem. Chem. Phys., 2014, 16, 19643-19653.


A CONTACT ZONE WITH NONCOINCIDENT CLINES FOR SEX-SPECIFIC MARKERS IN THE FIELD VOLE (MICROTUS AGRESTIS).
A field vole (Microtus agrestis) population characterized by unique mitochondrial DNA (mtDNA) and Y chromosome markers occurs in southwest Sweden. A contact zone between this Lund (Lu) population and a standard (St) population was examined with two sex-specific genetic markers. The field vole mtDNA and Y chromosome clines display a remarkable lack of coincidence, rarely observed in contact zones. The cline width for both markers is about 50 km, but the two clines are displaced from each other: the mtDNA cline is found in the central part of the study area, whereas the cline for the Y chromosome is located in the eastern part. Thus, the absolute width of the Lu-St zone spans about 95-110 km. As a result of the cline shift, all male hybrids carry the Lu-Y chromosome and St-type mtDNA. The other possible male hybrid class is lacking. The distinct noncoincidence of the mtDNA and Y chromosome clines is most likely explained by selection against male hybrids with the St-Y chromosome and Lu-mtDNA. It is possible that incompatibilities between the maternal genome of Lu-type animals and the paternal genome of St-type individuals exist. However, alternative explanations based on neutrality or selective advantage cannot be totally dismissed.


Toward a national nurse-managed health center data set: findings and lessons learned over 3 years.
Although primary care nurse-managed health centers (NMHCs) have gained increasing recognition, there are limited standardized clinical and financial data on these centers. The purpose of this paper is to present the process, benefits, and challenges in collecting standardized national data based on a consensus process from NMHCs over 3 consecutive years. The Institute for Nursing Centers (INC) NMHC Survey focuses on demographic, clinical, and financial data. A detailed codebook accompanied the INC NMHC Survey. A total of 42 NMHCs responded in at least 1 of the 3 years. Despite the challenges in collecting some of the data, especially for the first survey year, data quality improved remarkably when the INC NMHC Survey was repeated. Financial data seemed to be more easily reported than demographic or clinical data. NMHCs increase access to care, often for vulnerable populations, yet to date there are limited standardized clinical and financial data on these centers. The INC NHMC Survey and data described in this paper begins to address that gap.


The construction of an engineered bacterium to remove cadmium from wastewater.
The removal of cadmium (Cd) from wastewater before it is released from factories is important for protecting human health. Although some researchers have developed engineered bacteria, the resistance of these engineered bacteria to Cd have not been improved. In this study, two key genes involved in glutathione synthesis (gshA and gshB), a serine acetyltransferase gene (cysE), a Thlaspi caerulescens phytochelatin synthase gene (TcPCS1), and a heavy metal ATPase gene (TcHMA3) were transformed into Escherichia coli BL21. The resistance of the engineered bacterium to Cd was significantly greater than that of the initial bacterium and the Cd accumulation in the engineered bacterium was much higher than in the initial bacterium. In addition, the Cd resistance of the bacteria harboring gshB, gshA, cysE, and TcPCS1 was higher than that of the bacteria harboring gshA, cysE, and TcPCS1. This finding demonstrated that gshB played an important role in glutathione synthesis and that the reaction catalyzed by glutathione synthase was the limiting step for producing phytochelatins. Furthermore, TcPCS1 had a greater specificity and a higher capacity for removing Cd than SpPCS1, and TcHMA3 not only played a role in T. caerulescens but also functioned in E. coli.


Gastrointestinal decontamination in the management of the poisoned patient.
Ipecac syrup is the agent of choice to promote emesis in awake, alert, and cooperative patients who have ingested poison. Lavage is a reasonable alternative when ipecac fails or emesis is contraindicated. Activated charcoal is effective in minimizing absorption of ingested toxins, and saline cathartics may be useful to hasten the elimination of activated charcoal and possibly of enteric-coated or sustained release medications.


Ferroelectric Polarization and Oxygen Vacancy Synergistically Induced an Ultrasensitive and Fast Humidity Sensor for Multifunctional Applications.
With the arrival of the Internet of Things and artificial intelligence, humidity sensors monitoring water emissions from human metabolism have attracted great attention in the fields of smart wearable devices and noncontact human-machine interaction. However, their application is seriously limited by the trade-off between the sensitivity and response speed for traditional humidity sensors. Herein, to overcome it, a self-powered high performance humidity sensor is developed on the basis of the electric-poled and oxygen vacancy-rich BiFeO3 (BFO) ferroelectric material. The synergistic effect of ferroelectric polarization and oxygen vacancy provides a strong driving force and active adsorption sites for an abundance of OH/H2O adsorption, resulting in an ultrahigh response (∼104) and ultrafast response/recovery speed (∼84/376 ms). Benefiting from its promising advantages, the wearable humidity sensor can accurately record the respiration rate/depth and recognize different human respiratory behaviors in real-time. Importantly, by utilizing the moisture from mouth-blowing and skin, the sensors are successfully applied to noncontact control of a robotic car, noncontact switch, and noncontact interface for visualization applications. This work provides an effective strategy for developing excellent humidity sensors that meet the requirement of noncontact interaction for next-generation intelligent electronics.


Malaria - an overview.
Malaria is caused by protozoan parasites of the genus Plasmodium and is a major cause of mortality and morbidity worldwide. These parasites have a complex life cycle in their mosquito vector and vertebrate hosts. The primary factors contributing to the resurgence of malaria are the appearance of drug-resistant strains of the parasite, the spread of insecticide-resistant strains of the mosquito and the lack of licensed malaria vaccines of proven efficacy. This minireview includes a summary of the disease, the life cycle of the parasite, information relating to the genome and proteome of the species lethal to humans, Plasmodium falciparum, together with other recent developments in the field.


A Comparison of Ex Vivo Leak Pressures for Four Enterotomy Closures in a Canine Model.
Initial and maximum intraluminal leak pressures of four enterotomy closures were compared. Closure patterns included a modified Gambee, simple interrupted, simple continuous, and skin staple closure. Forty-eight 3-cm enterotomy constructs were created from jejunal segments harvested from 12 dogs. Twelve each were randomly assigned to the four closure methods. Time of closure, as well as initial and maximum leak pressures, were measured and compared. The modified Gambee closure was the slowest closure to perform, with skin staple closure being the fastest. All suture patterns tested had higher mean initial leak pressures than reported physiologic intestinal pressures during peristalsis, although the skin staple closures resulted in leakage below normal physiologic pressure in several samples. The modified Gambee closure was able to sustain a significantly higher initial leak pressure than skin staple closures. The modified Gambee suture pattern had the greatest maximum leak pressure of all enterotomy closure patterns tested. Use of the modified Gambee suture pattern should be considered in enterotomy closure, although in vivo studies are required to determine if these differences are clinically significant.


Can In-Bag Manual Morcellation Represent an Alternative to Uncontained Power Morcellation in Laparoscopic Myomectomy? A Randomized Controlled Trial.
The study aimed to evaluate feasibility and safety of in-bag manual morcellation compared to uncontained power morcellation during laparoscopic myomectomy. A total of 72 women undergoing laparoscopic myomectomy were randomized into 2 treatment groups: 34 patients underwent in-bag manual morcellation (experimental group) and 38 were submitted to uncontained power morcellation (control group). The primary end point was the comparison of morcellation operative time (MOT). Total operative time (TOT), rate of intraoperative complication, and postoperative outcomes in the 2 groups were regarded as secondary outcomes. Mean MOT and TOT were longer in the experimental group than in the control one (MOT: 9.47 ± 5.05 vs. 6.16 ± 7.73 min; p = 0.01; TOT: 113.24 ± 28.12 vs. 96.74 ± 33.51 min; p = 0.01). No intraoperative complications occurred in either group and no cases of bag disruption or laparotomic conversion were recorded. No significant difference in hemoglobin drop, hospital stay, and postoperative outcomes was reported between groups. In-bag manual morcellation appears a safe and feasible procedure and, despite slightly longer operative time, could represent an alternative to uncontained power morcellation.


Effect of different terpene-containing essential oils on percutaneous absorption of trazodone hydrochloride through mouse epidermis.
The aim of our study was to investigate the enhancing effect of several essential oils in the percutaneous absorption of trazodone hydrochloride (TZN). For this purpose, fennel oil, eucalyptus oil, citronella oil, and mentha oil were applied on the skin membrane in three different ways: included in the transdermal device, as a pretreatment, or both. To investigate the effect of penetration enhancers used in this study on the percutaneous absorption of TZN through mouse epidermis, Keshary-Chien diffusion cells were employed. The receptor phase was constantly stirring saline phosphate buffer of pH 7.4 at 37 +/- 1 degrees C. Results showed that pretreatment of skin with essential oils increases the flux values of TZN compared with the values obtained when the same essential oils were included in the transdermal devices. The percutaneous penetration flux for TZN was increased with skin pretreatment by 10% essential oils in the following order: fennel oil > eucalyptus oil > citronella oil > mentha oil. The amount of TZN retained in the skin after pretreatment with essential oils was found to be very similar in all cases and much higher than in the experiments without skin pretreatment.


Multiplex plasmonic sensor for detection of different metal ions based on a single type of gold nanorod.
In this paper, a label-free multiplex plasmonic sensor has been developed to selectively determine different metal ions including Fe(3+), Hg(2+), Cu(2+), and Ag(+) ions based on a single type of gold nanorod (GNR). Under proper conditions, these metal ions can react with GNRs, resulting in changes of nanostructure and composition. The determination of Fe(3+), Hg(2+), Cu(2+), and Ag(+) ions is therefore readily implemented due to changes of longitudinal plasmon wavelength (LPW) of nanorods. Moreover, the GNR-based assay can not only determine all four kinds of metal ions successively but also can detect which of any one or several kinds of metal ions. This assay is sensitive to detect Fe(3+), Hg(2+), Cu(2+), and Ag(+) as low as 10(-6), 10(-8), 10(-10), and 10(-8) M, respectively. Importantly, the special nanostructure and composition of the nanorods are induced by these metal ions, which allow this sensor to maintain high selectivity to determine these metal ions. This nanosensor abrogates the need for complicated chemosensors or sophisticated equipment, providing a simple and highly selective detection platform.


Effect of the applied organic load rate on biodegradable polymer production by mixed microbial cultures in a sequencing batch reactor.
This article studies the operation of a new process for the production of biopolymers (polyhydroxyalkanoates, PHAs) at different applied organic load rates (OLRs). The process is based on the aerobic enrichment of activated sludge to obtain mixed cultures able to store PHAs at high rates and yields. A mixture of acetic, lactic, and propionic acids at different concentrations (in the range 8.5-31.25 gCOD/L) was fed every 2 h in a sequencing batch reactor (SBR). The resulting applied OLR was in the range 8.5-31.25 gCOD/L/day. Even though, as expected, the increase in the OLR caused an increase in biomass concentration (up to about 8.7 g COD/L), it also caused a relevant decrease of maximal polymer production rate. This decrease in polymer production rate was related to the different extent of "feast and famine" conditions, as function of the applied OLR and of the start-up conditions. As a consequence the best performance of the process was obtained at an intermediate OLR (20 gCOD/L/day) where both biomass productivity and PHA storage were high enough. However, at this high OLR the process was unstable and sudden decrease of performance was also observed. The sludge characterized by the highest PHA storage response was investigated by 16S rDNA clone library. The clone library contained sequences mostly from PHA producers (e.g., Alcaligenes and Comamonas genera); however many genera and among them, one of the dominant (Thauera), were never described before in relation to PHA storage response.


CYTONUCLEAR THEORY FOR HAPLODIPLOID SPECIES AND X-LINKED GENES. II. STEPPING-STONE MODELS OF GENE FLOW AND APPLICATION TO A FIRE ANT HYBRID ZONE.
We develop cytonuclear, hybrid zone models for haplodiploid species or X-linked genes in diploid species using a stepping-stone framework of migration, in which migration rates vary with both direction and sex. The equilibrium clines for the allele frequencies, cytonuclear disequilibria, and frequencies of pure parental types are examined for species with diagnostic markers, under four important migration schemes: uniform migration of both sexes in both directions, greater migration of both sexes from one direction, greater migration of females, and greater migration of males. Of the three cytonuclear variables examined, the allele frequency clines are the most informative in differentiating among the various migration patterns. The cytonuclear disequilibria and the frequency of the pure parental types tend to be useful only in revealing directional asymmetries in migration. The extent of hybrid zone subdivision has quantitative but not qualitative effects on the distribution of cytonuclear variables, in that the allele frequency clines become more gradual, the cytonuclear disequilibria decrease in magnitude, and the frequencies of pure parentals decline with increasing subpopulation number. Also, the only major difference between the X-linked and haplodiploid frameworks is that a higher frequency of pure parentals is found when considering haplodiploids, in which male production does not require mating. The final important theoretical result is that censusing after migration yields greater disequilibria and parental frequencies than censusing after mating. We analyzed cytonuclear data from two transects from a naturally occurring hybrid zone between two haplodiploid fire ant species, Solenopsis invicta and S. richteri, using our stepping-stone framework. The frequency of S. invicta mtDNA exceeds the frequency of the S. invicta nuclear markers through much of this hybrid zone, indicating that sex differences in migration or selection may be occurring. Maximum-likelihood estimates for the migration rates are very high, due to an unexpectedly large number of pure parental types in the hybrid zone, and differ substantially between the two transects. Overall, our model does not provide a good fit, in part because the S. invicta-S. richteri hybrid zone has not yet reached equilibrium.


Nuclear expression and gain-of-function β-catenin mutation in glomangiopericytoma (sinonasal-type hemangiopericytoma): insight into pathogenesis and a diagnostic marker.
Glomangiopericytoma (sinonasal-type hemangiopericytoma) is a rare mesenchymal neoplasm with myoid phenotype (smooth muscle actin-positive), which distinguishes this tumor from soft tissue hemangiopericytoma/solitary fibrous tumor. Molecular genetic changes underlying the pathogenesis of glomangiopericytoma are not known. In this study, 13 well-characterized glomangiopericytomas were immunohistochemically evaluated for β-catenin expression. All analyzed tumors showed strong expression and nuclear accumulation of β-catenin. Following this observation, β-catenin glycogen serine kinase-3 beta phosphorylation region, encoded by exon 3, was PCR amplified in all cases and evaluated for mutations using Sanger sequencing. Heterozygous mutations were identified in 12 of 13 tumors. All mutations consisted of single-nucleotide substitutions: three in codon 32 (c.94G>C (n=2) and c.95A>T), four in codon 33 (two each c.98C>G and c.98C>T), two in codon 37 (c.109T>G), one in codon 41 (c.121A>G), and two in codon 45 (c.133T>C). At the protein level, these substitutions would lead to p.D32H, p.D32V, p.S33C, p.S33F, p.S37A, p.T41A, and p.S45L mutations, respectively. Previously, similar mutations have been reported in different types of cancers and shown to trigger activation of β-catenin signaling. All analyzed glomangiopericytomas showed prominent nuclear expression of cyclin D1, as previously shown for tumors with nuclear expression of β-catenin as a sign of oncogenic activation. These results demonstrate that mutational activation of β-catenin and associated cyclin D1 overexpression may be central events in the pathogenesis of glomangiopericytoma. In additon, nuclear accumulation of β-catenin is a diagnostic marker for glomangiopericytoma.


The folding equilibrium of huntingtin exon 1 monomer depends on its polyglutamine tract.
Expansion of the polyglutamine (polyQ) tract in exon 1 of the huntingtin protein (Httex1) leads to Huntington's disease resulting in fatal neurodegeneration. However, it remains poorly understood how polyQ expansions alter protein structure and cause toxicity. Using CD, EPR, and NMR spectroscopy, we found here that monomeric Httex1 consists of two co-existing structural states whose ratio is determined by polyQ tract length. We observed that short Q-lengths favor a largely random-coil state, whereas long Q-lengths increase the proportion of a predominantly α-helical state. We also note that by following a mobility gradient, Httex1 α-helical conformation is restricted to the N-terminal N17 region and to the N-terminal portion of the adjoining polyQ tract. Structuring in both regions was interdependent and likely stabilized by tertiary contacts. Although little helicity was present in N17 alone, each Gln residue in Httex1 enhanced helix stability by 0.03-0.05 kcal/mol, causing a pronounced preference for the α-helical state at pathological Q-lengths. The Q-length-dependent structuring and rigidification could be mimicked in proteins with shorter Q-lengths by a decrease in temperature, indicating that lower temperatures similarly stabilize N17 and polyQ intramolecular contacts. The more rigid α-helical state of Httex1 with an expanded polyQ tract is expected to alter interactions with cellular proteins and modulate the toxic Httex1 misfolding process. We propose that the polyQ-dependent shift in the structural equilibrium may enable future therapeutic strategies that specifically target Httex1 with toxic Q-lengths.


Biological variation database: structure and criteria used for generation and update.
Numerical data on the components of biological variation (BV) have many uses in laboratory medicine, including in the setting of analytical quality specifications, generation of reference change values and assessment of the utility of conventional reference values. Generation of a series of up-to-date comprehensive database of components of BV was initiated in 1997, integrating the more relevant information found in publications concerning BV. A scoring system was designed to evaluate the robustness of the data included. The database has been updated every 2 years, made available on the Internet and derived analytical quality specifications for imprecision, bias and total allowable error included in the tabulation of data. Our aim here is to document, in detail, the methodology we used to evaluate the reliability of the included data compiled from the published literature. To date, our approach has not been explicitly documented, although the principles have been presented at many symposia, courses and conferences.


De novo generation of dual-target ligands for the treatment of SARS-CoV-2 using deep learning, virtual screening, and molecular dynamic simulations.
De novo generation of molecules with the necessary features offers a promising opportunity for artificial intelligence, such as deep generative approaches. However, creating novel compounds having biological activities toward two distinct targets continues to be a very challenging task. In this study, we develop a unique computational framework for the de novo synthesis of bioactive compounds directed at two predetermined therapeutic targets. This framework is referred to as the dual-target ligand generative network. Our approach uses a stochastic policy to explore chemical spaces called a sequence-based simple molecular input line entry system (SMILES) generator. The steps in the high-level workflow would be to gather and prepare the training data for both targets' molecules, build a neural network model and train it to make molecules, create new molecules using generative AI, and then virtually screen the newly validated molecules against the SARS-CoV-2 PLpro and 3CLpro drug targets. Results shows that novel molecules generated have higher binding affinity with both targets than the conventional drug i.e. Remdesivir being used for the treatment of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.