An evolutionarily stable strategy to colonize spatially extended habitats.
The ability of a species to colonize newly available habitats is crucial to its overall fitness1-3. In general, motility and fast expansion are expected to be beneficial for colonization and hence for the fitness of an organism4-7. Here we apply an evolution protocol to investigate phenotypical requirements for colonizing habitats of different sizes during range expansion by chemotaxing bacteria8. Contrary to the intuitive expectation that faster is better, we show that there is an optimal expansion speed for a given habitat size. Our analysis showed that this effect arises from interactions among pioneering cells at the front of the expanding population, and revealed a simple, evolutionarily stable strategy for colonizing a habitat of a specific size: to expand at a speed given by the product of the growth rate and the habitat size. These results illustrate stability-to-invasion as a powerful principle for the selection of phenotypes in complex ecological processes.


Direct evidence that the kinase activity of protein kinase C is involved in transcriptional activation through a TPA-responsive element.
In order to examine the involvement of protein kinase C (PKC) in the transcriptional activation of genes by TPA (12-0-tetradecanoyl phorbol 13-acetate) we have constructed a series of PKC expression plasmids. Transient expression of an active fragment of PKC in rat fibroblasts resulted in the transcriptional activation of a TRE (TPA-responsive element)-CAT chimeric gene which contains various repetitions of collagenase TREs. These provide the first direct evidence that kinase activity of PKC is involved in TPA-induced transcriptional activation through TRE.


Pyrolysis of end-of-life polystyrene in a pilot-scale reactor: Maximizing styrene production.
Chemical recycling of polystyrene (PS) via pyrolysis is of great industrial, and academic interest, with styrene being the primary product of interest. To identify the optimal process conditions, the pyrolysis of end-of-life PS was studied in a pilot-scale unit consisting of an extruder, and a continuous stirred tank reactor (CSTR). The PS was pyrolyzed with continuous feeding at a pressure range from 0.02 to 1.0bara, and a temperature range from 450 to 600 °C, giving primarily styrene, other mono-aromatics, and oligomers. The comprehensive two-dimensional gas chromatography (GC × GC) coupled with flame ionization detector (FID), and time-of-flight mass spectrometer (ToF-MS) as well as GC with thermal conductivity detector (TCD) were used to characterize the liquid, and gaseous products exhaustively. The styrene yield increased from 36 wt% at 1.0bara, and 450 °C to 56 wt% at 0.02bara, and 550 °C. Working under a vacuum enhanced the styrene recovery at all corresponding temperature levels. The yield of benzene, toluene, ethylbenzene, and xylene (BTEX) increased from 4 wt% at 450 °C, and 0.02 bara to 17 wt% at 450 °C, and 1.0 bara. The experimental results have been used in a mathematical model that can explain the combined effect of temperature, and pressure on the yield of the primary products. The present work illustrates the potential of a continuous pyrolysis process for end-of-life PS, and paves the way for this technology to be rapidly transferred from mere laboratory use to industrial processes in the circular (petro-) chemical industry.


High frequency stimulation of the subthalamic nucleus improves treadmill locomotion in unilateral 6-hydroxydopamine lesioned rats.
This study investigated the influence of electrical stimulation of the subthalamic nucleus (STN) on motor impairment induced by unilateral 6-hydroxydopamine (6-OHDA) lesions in the medial forebrain bundle. Rats were trained to walk on a treadmill and then implanted with microelectrode arrays in and near the STN. The neurotoxin 6-OHDA was injected into the medial forebrain bundle (MFB) unilaterally to produce a targeted lesion of the dopaminergic system. Successful lesions produced impaired treadmill walking behavior. High frequency stimulation (HFS) of the STN improved treadmill walking immediately and restored normal walking patterns. The same HFS failed to evoke visible side effects such as stepping, turning, raising of the head or facial muscle contraction in the absence of treadmill movement, or to change rotational behaviors elicited by the dopamine (DA) agonist apomorphine in unilateral lesioned rats. This suggests that the stimulation did not cause movement by an activation of brainstem locomotor regions or an increase attention leading to movement. Apomorphine-induced rotation may represent an imbalance of dopaminergic activation which remains during HFS. This work may provide a rodent model for deep brain stimulation (DBS) in patients with Parkinson's disease, and be suitable for further investigation of the neural mechanisms underlying the therapeutic effects of DBS.


Relationships between third-molar juxta-apical radiolucencies and mandibular canals in panoramic and cone beam computed tomography images.
This study aimed to determine the relationship between third-molar juxta-apical radiolucencies and mandibular canals on panoramic and cone beam computed tomography (CBCT) images. Forty-two patients were included in this retrospective study. The root apices and the relationships of the juxta-apical radiolucencies to the mandibular canals were evaluated on both panoramic and CBCT images. The McNemar test (P < .05) was used to compare panoramic with CBCT findings. Root apices were visualized clearly with CBCT in most cases for which the apices were not seen clearly on panoramic images. Similarly, juxta-apical radiolucencies were separate from the mandibular canals with CBCT in most cases. The present study found that there is no consistent intimate relationship between juxta-apical radiolucencies and the mandibular canals. Similar studies with larger sample sizes are required to further confirm these findings.


Increased expression of S100A6 is associated with decreased metastasis and inhibition of cell migration and anchorage independent growth in human osteosarcoma.
While most osteosarcoma patients have metastatic or micrometastatic lesions, less than 15% of them have clinically detectable metastatic diseases at presentation. To identify potential markers that may predict osteosarcoma metastasis, we analyzed the expression of S100A6 in 50 osteosarcoma cases and found that 84% of the analyzed specimens stained positive for S100A6. There is a trend towards decreased clinically evident metastasis with increased S100A6 staining. Overexpression of S100A6 in osteosarcoma cells decreases cell motility and anchorage independent growth on collagen gels. Our findings provide evidence that, while S100A6 is commonly overexpressed in human osteosarcoma, loss of its expression correlates with a metastatic phenotype.


The effect of alloying elements on the properties of pressed and non-pressed biodegradable Fe-Mn-Ag powder metallurgy alloys.
Current trends in the biodegradable scaffold industry call for powder metallurgy methods in which compression cannot be applied due to the nature of the scaffold template itself and the need to retain the shape of an underlying template throughout the fabrication process. Iron alloys have been shown to be good candidates for biomedical applications where load support is required. Fe-Mn alloys were researched extensively for this purpose. Current research shows that all metallurgical characterisation and corrosion test on Fe-Mn and Fe-Mn-Ag non pre-alloyed powder alloys are performed on alloys which are initially pressed into greens and subsequently sintered. In order to combine the cutting-edge field of biodegradable metallic alloys with scaffold production, metallurgical characterisation of pressed and non-pressed Fe, Fe-Mn and Fe-Mn-Ag sintered elemental powder compacts was carried out in this study. This was performed along with determination of the corrosion rate of the same alloys in in vitro mimicking solutions. These solutions were synthesised to mimic the osteo environment in which the final scaffolds are to be used. Both pressed and non-pressed alloys formed an austenite phase under the right sintering conditions. The corrosion rate of the non-pressed alloy was greater than that of its pressed counterpart. In a potentiodynamic testing scenario, addition of silver to the alloy formed a separate silver phase which galvanically increased the corrosion rate of the pressed alloy. This result wasn't replicated in the non-pressed alloys in which the corrosion rate was seen to remain similar to the non-silver-bearing alloy counterparts.


Deoxynivalenol and nivalenol in wheat and by-products in Argentina.
The deoxynivalenol and nivalenol contamination in wheat and by-products obtained through milling was analized by Trucksess method slightly modified in the proportion of acetonitrile-water (3:1).Only one sample of wheat showed deoxynivalenol contamination, 1,200μg/kg.No samples obtained in different stages of the milling were contaminated with deoxynivalenol or nivalenol.In the commercial wheat flours the levels found ranged between 400 and 800μg/kg, as follows: 400μ/kg, 5 samples; 800jug/kg, 1 sample.


Racial and Ethnic Disparities in Survival Among People With Second Primary Cancer in the US.
Comprehensive data for racial and ethnic disparities after second primary cancers (SPCs) are lacking despite the growing burden of SPCs. To quantify racial and ethnic disparities in survival among persons with SPCs. This population-based, retrospective cohort study used data from 18 Surveillance, Epidemiology, and End Results registries in the US for persons diagnosed with the most common SPCs at age 20 years or older from January 1, 2000, to December 31, 2013 (with follow-up through December 31, 2018). Data were analyzed between January and April 2023. Race and ethnicity (Hispanic, non-Hispanic Asian or Pacific Islander, non-Hispanic Black, and non-Hispanic White). The main outcomes were 5-year relative survival and cause-specific survival. Cause-specific hazard ratios (HRs) were calculated for death from cancer or cardiovascular disease (CVD) in each racial and ethnic minority population compared with the White population overall and stratified by SPC type, with adjustment for sex, year and age at SPC diagnosis, and prior cancer type and stage (baseline model) and additionally for county attributes (household income, urbanicity), SPC characteristics (stage, subtype), and treatment. Among 230 370 persons with SPCs (58.4% male), 4.5% were Asian or Pacific Islander, 9.6% were Black, 6.4% were Hispanic, and 79.5% were White. A total of 109 757 cancer-related deaths (47.6%) and 18 283 CVD-related deaths (7.9%) occurred during a median follow-up of 54 months (IQR, 12-93 months). In baseline models, compared with the White population, the risk of cancer-related death overall was higher in the Black (HR, 1.21; 95% CI, 1.18-1.23) and Hispanic (HR, 1.10; 95% CI, 1.07-1.13) populations but lower in the Asian or Pacific Islander population (HR, 0.93; 95% CI, 0.90-0.96). When stratified by 13 SPC types, the risk of cancer-related death was higher for 10 SPCs in the Black population, with the highest HR for uterine cancer (HR, 1.87; 95% CI, 1.63-2.15), and for 7 SPCs in the Hispanic population, most notably for melanoma (HR, 1.46; 95% CI, 1.21-1.76). For CVD-related death, the overall HR was higher in the Black population (HR, 1.41; 95% CI, 1.34-1.49), with elevated risks evident for 11 SPCs, but lower in the Asian or Pacific Islander (HR, 0.75; 95% CI, 0.69-0.81) and Hispanic (HR, 0.90; 95% CI, 0.84-0.96) populations than in the White population. After further adjustments for county attributes and SPC characteristics and treatment, HRs were reduced for cancer-related death and for CVD-related death and associations in the same direction remained. In this cohort study of SPC survivors, the Black population had the highest risk of both death from cancer and death from CVD, and the Hispanic population had a higher risk of death from cancer than the White population. Attenuations in HRs after adjustment for potentially modifiable factors highlight opportunities to reduce survival disparities among persons with multiple primary cancers.


Pharmacokinetic study of netilmicin.
Netilmicin at a dose of 2 mg/kg was infused intravenously into 10 healthy volunteers. A peak serum concentration of 16.56 mug/ml was obtained at the end of the infusion. Thirty-nine percent of the infused dose was excreted in the urine during the first 8 h after infusion. The pharmacokinetic parameters of netilmicin were derived by analyzing the elimination data according to a two-compartment model.


Hospital activity analysis: a source of information about serial hospital admissions.
This paper describes a method for linking serial hospital admissions for the same patient on the basis of existing Hospital Activity Analysis data. Details are given of a linkage procedure suitable for use with a computer, which takes account of possible errors in the recording of items of personal information. Applications of the procedure to give the clinician better access to information about previous hospital admissions and as a basis for monitoring the effectiveness of particular hospital-based procedures are described.


Plasmalemmal pH-gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P magnetic resonance spectroscopy.
31p Magnetic resonance spectroscopy (MRS) was employed to investigate tumor pH in xenografts of drug-sensitive and drug-resistant MCF-7 human breast carcinoma cells. Measured extracellular pH values were found to be lower than the intracellular pH in all three tumor types investigated. The magnitude of this acid-outside plasmalemmal pH gradient increased with increasing tumor size in tumors of two drug-resistant variants of MCF-7 cells, but not in tumors of the parent (drug-sensitive) cells. The partitioning of weak-base or weak-acid drug molecules across the plasma membrane of a tumor cell is dependent upon the acid-dissociation constant (pKa) of the drug as well as the plasmalemmal pH gradient. A large acid-outside pH gradient, such as those seen in MCF-7 xenografts, can exert a protective effect on the cell from weak-base drugs such as anthracyclines and Vinca alkaloids, which have pKa values of 7.5 to 9.5. The possibility of enhancing the therapeutic efficacy of weak-base drugs by dietary or metabolic manipulation of the extracellular pH, in order to reduce or reverse the plasmalemmal pH gradient, deserves investigation.


Improvement in Post-Autologous Stem Cell Transplant Survival of Multiple Myeloma Patients: A Long-Term Institutional Experience.
Multiple myeloma (MM) represents 1.8% of all new cancer cases in the U.S. While not curable, advances in treatment, including autologous stem cell transplant (ASCT) and maintenance therapy, have dramatically improved progression-free survival (PFS) and overall survival (OS). We performed a retrospective survival analysis on newly diagnosed MM (NDMM) patients receiving ASCT from 1992−2016 at the Ohio State University. A total of 1001 consecutive NDMM patients were eligible. Patients were split into five groups based on historic changes in novel agents for the treatment of MM. Across the years (1992−2016), there was a statistically significant improvement in both PFS (p < 0.01) and OS (p < 0.01). Significant improvements in both PFS and OS were seen in patients ≤65 years (p < 0.001 and p = 0.002) and >65 years old (p < 0.001 and p = 0.001), respectively. Improved PFS and OS were seen in both standard-risk (p < 0.001 and p < 0.001) and high-risk patients (p < 0.001 and p = 0.019). The post-transplant response showed statistically significant improvement across the years (p < 0.01). Survival rates for NDMM patients have significantly improved primarily due to the inclusion of novel therapies and post-ASCT maintenance.


Individualized Fall Prevention Program in an Acute Care Setting: An Evidence-Based Practice Improvement.
A 245-bed community hospital established patient fall prevention as its patient safety priority. The hospital's fall prevention program was not consistently effective. The baseline fall rate was 3.21, higher than the National Database of Nursing Quality Indicators' median of 2.91. An interprofessional fall prevention team evaluated the hospital's fall program using the evidence-based practice improvement model. A clinical practice guideline with 7 key practices guided the development of an individualized fall prevention program with interventions to address 4 fall risk categories and an algorithm to identify interventions. Interventions included nurse-driven mobility assessment, purposeful hourly rounding, and video monitoring for confused and impulsive fall-risk patients. The fall rate decreased to 1.14, with a 72% expense reduction based on decreased sitter usage. An interprofessional team successfully reduced falls with an evidence-based fall prevention program.


Molecular mechanisms underlying endometriosis pathogenesis revealed by bioinformatics analysis of microarray data.
To identify differentially expressed genes (DEGs) in endometriosis and further analyze molecular mechanisms implicated in disease pathogenesis. Gene expression data (ID: GSE7846) of human endometrial endothelial cells (HEECs) collected from eutopic endometria tissue of patients with and without endometriosis were downloaded from Gene Expression Omnibus. DEGs were screened using Limma package, followed by enrichment analysis using clusterProfiler package in R. Thereafter, protein-protein interactions (PPIs) were analyzed using STRING (Search Tool for the Retrieval of Interacting Genes) database and visualized by Cytoscape software. Meanwhile, transcription factors were screened from the DEGs based on TRANSFA database, followed by construction of regulatory network using Cytoscape. A total of 2255 up- and 408 down-regulated genes were identified in endometriosis patients as compared with control patients. Those DEGs were predominantly enriched in focal adhesion (e.g., FN1, EGF, FYN, EGFR, RAC1, CCND1 and JUN), regulation of actin cytoskeleton (e.g., FN1, EGF, EGFR, RAC1 and JUN) and MAPK signaling pathway (e.g., EGF, EGFR, RAC1, JUN, TGFB1 and MYC). Importantly, EGF, EGFR, JUN, FN1, RAC1, TGFB1, CCND1 and FYN were hub nodes in the PPI network. Additionally, TGFB1, SMAD1 and SMAD4 showed up-regulation in TGFB signaling pathway. Transcription factor MYC had a regulatory effect on the most DEGs, including TGFB1, RAC1 and CCND1. Focal adhesion, regulation of actin cytoskeleton, MAPK and TGFB/SMAD signaling pathway may be important molecular mechanism underlying the pathogenesis of endometriosis.


A preliminary consideration of cue-exposure, response-prevention treatment for pathological gambling behaviour: two case studies.
Cue-exposure, response-prevention, a promising treatment for cigarette-smoking, substance abuse, obsessive-compulsive disorder, etc. has not been fully utilized as a treatment for pathological gambling. Two case-studies, modelled on work by R. Self (1989), with cigarette smoking behaviour, report on an active and thorough application of this treatment to pathological gambling. In both cases, self-report of gambling behaviour and urges to gamble in any situation were found to decrease substantially. Outcome differences between participants were discussed with reference to different levels of pathological gambling as measured by the South Oaks Gambling Screen. It was concluded that cue-exposure, response-prevention should be given more serious consideration as a treatment approach for pathological gambling.


Comparison of collapsing methods for the statistical analysis of rare variants.
Novel technologies allow sequencing of whole genomes and are considered as an emerging approach for the identification of rare disease-associated variants. Recent studies have shown that multiple rare variants can explain a particular proportion of the genetic basis for disease. Following this assumption, we compare five collapsing approaches to test for groupwise association with disease status, using simulated data provided by Genetic Analysis Workshop 17 (GAW17). Variants are collapsed in different scenarios per gene according to different minor allele frequency (MAF) thresholds and their functionality. For comparing the different approaches, we consider the family-wise error rate and the power. Most of the methods could maintain the nominal type I error levels well for small MAF thresholds, but the power was generally low. Although the methods considered in this report are common approaches for analyzing rare variants, they performed poorly with respect to the simulated disease phenotype in the GAW17 data set.


Molar absorption coefficients and stability constants of metal complexes of 4-(2-pyridylazo)resorcinol (PAR): Revisiting common chelating probe for the study of metalloproteins.
4-(2-Pyridylazo)resorcinol (PAR) is one of the most popular chromogenic chelator used in the determination of the concentrations of various metal ions from the d, p and f blocks and their affinities for metal ion-binding biomolecules. The most important characteristics of such a sensor are the molar absorption coefficient and the metal-ligand complex dissociation constant. However, it must be remembered that these values are dependent on the specific experimental conditions (e.g. pH, solvent components, and reactant ratios). If one uses these values to process data obtained in different conditions, the final result can be under- or overestimated. We aimed to establish the spectral properties and the stability of PAR and its complexes accurately with Zn(2+), Cd(2+), Hg(2+), Co(2+), Ni(2+), Cu(2+), Mn(2+) and Pb(2+) at a multiple pH values. The obtained results account for the presence of different species of metal-PAR complexes in the physiological pH range of 5 to 8 and have been frequently neglected in previous studies. The effective molar absorption coefficient at 492 nm for the ZnHx(PAR)2 complex at pH7.4 in buffered water solution is 71,500 M(-1) cm(-1), and the dissociation constant of the complex in these conditions is 7.08×10(-13) M(2). To confirm these values and estimate the range of the dissociation constants of zinc-binding biomolecules that can be measured using PAR, we performed several titrations of zinc finger peptides and zinc chelators. Taken together, our results provide the updated parameters that are applicable to any experiment conducted using inexpensive and commercially available PAR.


Codon expansion and systematic transcriptional deletions produce tetra-, pentacoded mitochondrial peptides.
Genes include occasionally isolated codons with a fourth (and fifth) silent nucleotide(s). Assuming tetracodons, translated hypothetical peptides align with regular GenBank proteins; predicted tetracodons coevolve with predicted tRNAs with expanded anticodons in each mammal, Drosophila and Lepidosauria mitogenomes, GC contents and with lepidosaurian body temperatures, suggesting that expanded codons are an adaptation of translation to high temperature. Hypothetically, continuous stretches of tetra- and pentacodons code for peptides. Both systematic nucleotide deletions during transcription, and translation by tRNAs with expanded anticodons could produce these peptides. Reanalyses of human nanoLc mass spectrometry peptidome data detect numerous tetra- and pentapeptides translated from the human mitogenome. These map preferentially on (BLAST-detected) human RNAs matching the human mitogenome, assuming systematic mono- and dinucleotide deletions after each third nucleotide (delRNAs). Translation by expanded anticodons is incompatible with silent nucleotides in the midst rather than at codon 3' extremity. More than 1/3 of detected tetra- and pentapeptides assume silent positions at codon extremity, suggesting that both mechanisms, regular translation of delRNAs and translation of regular RNAs by expanded anticodons, produce this peptide subgroup. Results show that systematically deleting polymerization occurs, and confirm serial translation of expanded codons. Non-canonical transcriptions and translations considerably expand the coding potential of DNA and RNA sequences.


Skin resurfacing for the burned patient.
It has been estimated that 2 million people per year have burns requiring medical attention in the United States. The available and expert clinicians in dedicated burn centers around the country have cared successfully for these patients and given them a second chance at a functional life. It still behooves current-day plastic surgeons to be knowledgeable and adept in their care, not only because they may be called upon at times to manage some of the smaller acute burns, but also because many of the general principles of burn reconstruction and wound management are relevant to other areas of general plastic surgery. Acute burns should be dealt with like any other major trauma with the ABCs of aggressive resuscitation and airway management. Like any other wound, debridement and nutrition are important (i.e., early escharectomy of the burn wound and enteral nutrition during the hypermetabolic state). Early coverage of the open wound is essential to limit bacterial colonization and prevent infection and to reduce fluid and electrolyte and heat loss. If autografts are not available immediately, temporary coverage with one of the above-mentioned barrier materials should be used. Still, autografts, when available, should be the burn surgeon's first choice. Donor sites may be reharvested to provide more autograft than was anticipated with large-percentage TBSA burns. Physicians should keep in mind the advantages (and disadvantages) of using the scalp and back. As far as research and technological advances in the area of plastic surgery, burn surgery may be the most progressive, with the evolution of biologic tissue-engineered skin substitutes and the research of growth factors in healing. Further improvements in tissue engineering and technology should result in even more effective skin substitutes and hence better functional and aesthetic outcomes with economic efficiency in large burns.


Using quality improvement methodology and tools to reduce patient wait time in a paediatric subspecialty rheumatology clinic.
Our paediatric rheumatology clinic has experienced inefficient patient flow. Our aim was to reduce mean wait time and minimise variation for patients. Baseline data showed that most waiting occurs after a patient has been roomed, while waiting for the physician. Wait time was not associated with a patient's age, time of day, day of the week or individual physician. We implemented a checkout sheet and staggered start times. After a series of plan-do-study-act cycles, we observed an initial 26% reduction in the variation of wait time and a final 17% reduction in the mean wait time. There was no impact on patient-physician contact time. Overall, we demonstrate how process improvement methodology and tools were used to reduce patient wait time in our clinic, adding to the body of literature on process improvement in an ambulatory setting.


Thiopurine methyltransferase and 6-thioguanine nucleotide measurement: early experience of use in clinical practice.
Azathioprine and 6-mercaptopurine (6-MP) are well established for the treatment of inflammatory bowel disease (IBD). Assessing thiopurine methyltransferase (TPMT) status has been recommended to reduce the risk of serious toxicity. Measuring red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) concentrations has been recommended for dose adjustment. To describe the results of measuring TPMT activity and genotype, and 6-TGN concentration in New Zealand. Canterbury Health Laboratories provided these analyses for New Zealand. Those with low TPMT activity also underwent genotyping. All results were collated and analysed descriptively. 6-TGN concentrations were correlated with the dose of thiopurine when known. TPMT enzyme activity (range 1-22 U/mL) from 574 patients showed a trimodal distribution. Genotyping results matched this distribution with only mild overlap between (*1/*1) homozygote and (*1/*3) heterozygote groups. One patient without TPMT measurement before therapy had life-threatening neutropenia and was later found to have (*3/*3) genotype. TPMT analysis probably prevented two further such cases. Of 884 6-TGN concentrations (range 0-1434 pmol/10(8) RBC), 41, 39 and 20% were within, below, and above the therapeutic range of 235-450 pmol/10(8) RBC, respectively. Leucopenia was seen in some patients with high 6-TGN. 6-MMP concentrations in 177 patients with low 6-TGN suggested non-compliance in 31, underdosing in 130, and preferential metabolism of 6-MP to 6-methylmercaptopurine in 16. There was poor correlation between azathioprine dose and 6-TGN concentration (r(2) = 0.002), supporting 6-TGN monitoring. Measurement of TPMT enzyme activity and 6-TGN concentration has been well-integrated into clinical practice. These tests should reduce the risk of toxicity and improve efficacy with thiopurines in patients with IBD.


Langya virus outbreak: current challenges and lesson learned from previous henipavirus outbreaks in China, Australia, and Southeast Asia.
A new novel virus, Langya virus (LayV), was detected in China in August 2022, 3 years after the COVID-19 pandemic. LayV is similar to the previously discovered Mojiang henipavirus. Other zoonotic henipaviruses include the Hendra and Nipah viruses. The emergence of the zoonotic Langya virus is attributed to climate change and wildlife encroachment, as LayV is detected in shrews. Those who are infected in China showed various symptoms, but no deaths have been recorded yet. This review aims to shed light on the current state of Langya virus outbreak, its infection control efforts, and the remaining challenges that need to be addressed to curb the outbreak. We utilized online publication databases such as PubMed, Google Scholar, and Scopus in writing this review article. A surveillance study on thirty-five febrile patients in Eastern China identified the Langya virus outbreak. The current efforts from the Chinese government and health authorities to reduce the transmission and spread of Langya virus such as isolation and characterization of LayV, challenges associated with the increase in cases of LayV, and trackable recommendations such as strengthening the healthcare system in China, sensitization of people about risks associated with Langya virus outbreaks, creating an intensive surveillance system network, etc. were discussed. It is germane and pertinent that the Chinese government and health authorities continue to intensify efforts against Langya virus and address the challenges to effectively reduce transmission.


Soluble low-density lipoprotein receptor-related protein.
Soluble forms of receptors can influence the activity of their membrane-bound counterparts by affecting their interactions with ligands. Low density lipoprotein (LDL) receptor-related protein (LRP), a member of the LDL receptor family, binds multiple classes of ligands and has been implicated in a broad range of normal and disease processes involving lipid metabolism, protease clearance, and cell migration. We recently identified a soluble form of LRP (sLRP) in human plasma and showed that it retains LRP-ligand binding ability. These findings open potentially important additional aspects in the biology of this multifunctional receptor. This review summarizes characteristics of soluble LRP and relates these to the membrane-bound form of the receptor.


Sesquiterpenes and acetogenins from the marine red alga Laurencia okamurai.
Three new halogenated sesquiterpenes, 10-bromo-7α,8α-expoxychamigr-1-en-3-ol (1), 10-bromo-β-chamigren-8-ol (2), and 10-bromo-3-chlorocupar-5-en-2-ol (3), one new C₁₂-acetogenin, desepilaurallene (7), one new naturally occurring sesquiterpene, 7-hydroxylaurene acetate (4), two known sesquiterpenes, allolaurinterol acetate (5) and laurene (6), and one known C₁₅-acetogenin, epilaurallene (8), were isolated from the marine red alga Laurencia okamurai collected from the coast of Rongcheng, China. The structures of these compounds were unambiguously established by 1D, 2D NMR and mass spectroscopic techniques. The bioassay results showed that 4, 5 exhibited potent antibacterial activity, and 1, 4, 5 were toxic to brine shrimp.


Prostacyclin (PGI2) in pregnant human uterus.
Prostacyclin lowers the tonus and reduces the spontaneous motility of isolated pregnant human myometrium. This effect seems to be related to coclic-AMP accumulation, since PGI2 increases the formation of this cyclic nucleotide in incubated minces of pregnant and non-pregnant uterus. The ability of this tissue to generate a labile substance which inhibits platelets aggregation, has been demonstrated and discussed.


Systematic variation of the benzoylhydrazine moiety of the GluN2A selective NMDA receptor antagonist TCN-201.
GluN2A containing N-methyl-D-aspartate receptors (NMDARs) are important ion channels in the central nervous system and highly involved in several different neurophysiological but also neuropathophysiological processes. However, current understanding of the contribution of GluN2A containing NMDARs in these processes is incomplete. Therefore, highly selective compounds are required to further investigate these ion channels. In 2010, TCN-201 (2), one of the first selective negative allosteric modulators was reported. While the binding site of 2 and the influence of the substitution pattern of the benzenesulfonamide part has been reported recently, detailed structure-activity-relationships of the diacylhydrazine part and the linked phenyl moiety are still missing. In order to examine the critical interactions between these moieties and the binding site, several TCN-201 analogs with modified diacylhydrazine part were synthesized. The negative allosteric effect was recorded by two-electrode voltage clamp (TEVC) experiments using GluN1a/GluN2A expressing Xenopus laevis oocytes. Our data led to the conclusion, that the terminal phenyl moiety is involved in a cation-π-interaction with the guanidinium moiety of Arg755 of the GluN1a subunit, which plays a crucial role for high activity. Additionally, structure optimization by replacing the phenyl moiety with a thiophen-2-yl (10c), indol-2-yl (10g) or indol-3-yl (10h) moiety significantly increased the activity of 2 by the factor 2.5. At a test compound concentration of 200 nM, the negative allosteric effect of the most potent ligands 10c, 10h and 17 was significantly influenced by the glycine concentration. Although glycine dependency is higher than those of the lead compound 4, 10c and 17 showed significantly higher negative allosteric effects than 4 at glycine concentrations from 1 μM up to 10 μM. The potent GluN2A-NMDA receptor inhibitors 10c, 10h and 17 did not influence the ion current of GluN2B-NMDA receptors.


CO2/CH4 separation performance of SiO2/PES composite membrane prepared by gas phase hydrolysis and grafting coating in gas-liquid membrane contactor: A comparative study.
The gas-liquid membrane contactor (GLMC) is a new and promising kind of gas separation technique, but still exhibits limitations, especially in membrane performance. In order to solve the above problems, we fabricated and characterized novel OH/SiO2/PES composite membranes using gas phase hydrolysis and graft coating methods, respectively. In the preparation process, whether to use alkali to pretreat the membrane was used as an evaluation index. The CO2/CH4 separation performance was tested using the modified OH/SiO2/PES hollow fiber membrane as the membrane contactor in GLMC. In the experiment, we conducted a single factor experiment with diethanolamine (DEA) as the adsorbent to analyze the effect of the flow rate and concentration of DEA on the separation of CO2/CH4. The collected gas had a CH4 content of 99.92% and a CO2 flux of 10.1059 × 10-3 mol m-2 s-1 while DEA at a concentration of 1 mol/L was flowing at a rate of 16 L/h. The highest separation factor occurred at this moment, which was 833.67. Overall, the CO2/CH4 separation performance in GLMC was enhanced with the use of the fluorinated OH/SiO2/PES composite membrane.


Functional Implications of Domain Organization Within Prokaryotic Rhomboid Proteases.
Intramembrane proteases are membrane embedded enzymes that cleave transmembrane substrates. This interesting class of enzyme and its water mediated substrate cleavage mechanism occurring within the hydrophobic lipid bilayer has drawn the attention of researchers. Rhomboids are a family of ubiquitous serine intramembrane proteases. Bacterial forms of rhomboid proteases are mainly composed of six transmembrane helices that are preceded by a soluble N-terminal domain. Several crystal structures of the membrane domain of the E. coli rhomboid protease ecGlpG have been solved. Independently, the ecGlpG N-terminal cytoplasmic domain structure was solved using both NMR and protein crystallography. Despite these structures, we still do not know the structure of the full-length protein, nor do we know the functional role of these domains in the cell. This chapter will review the structural and functional roles of the different domains associated with prokaryotic rhomboid proteases. Lastly, we will address questions remaining in the field.


Autoradiographic observations on the innervation of the carotid body of the domestic fowl.
Tritiated leucine was injected into the distal vagal ganglion of 11 domestic fowl, which survived for 12-24 h under general anaesthesia. The cells of this ganglion are known to be exclusively afferent. EM autoradiography showed that in all 11 birds the vast majority of the silver grains fell upon the nervous tissues of the carotid body. In 5 of these birds a quantitative analysis was made, using point-counting morphometry. The incidence of silver grain per unit area was found to be 26 times greater in axonal endings than in the non-nervous components, and 15 times greater in axons in transit than in non-nervous components. The difference in incidence per unit area between these nervous and non-nervous components was highly significant (P less than 0.001). Of all the observed axonal endings 77% were labelled, but there is evidence that this is a substantial underestimate of the total population of afferent endings; in one bird 88% of the endings were labelled. Of the axons in transit, 18% were labelled. This low value is believed to be related to transfer of the label to the axonal endings by the fast component of axonal transport. Afferent and reciprocal synapses occurred in labelled axonal endings, which were therefore considered to have an afferent function. 'Efferent' type synapses also occurred in labelled endings, and therefore belonged to axons which in fact were afferent in function. It is concluded that the innervation of the carotid body of the domestic fowl is almost entirely afferent, the nerve cell bodies being in the distal vagal ganglion. Only very few efferent axonal endings are present. Ultrastructural features, including synaptic morphology, appear to constitute unreliable criteria for distinguishing between afferent and efferent axonal endings in the carotid body.


The main bioactive compounds of Scutellaria baicalensis Georgi. for alleviation of inflammatory cytokines: A comprehensive review.
Scutellaria baicalensis Georgi., a plant used in traditional Chinese medicine, has multiple biological activities, including anti-inflammatory, antiviral, antitumor, antioxidant, and antibacterial effects, and can be used to treat respiratory tract infections, pneumonia, colitis, hepatitis, and allergic diseases. The main active substances of S. baicalensis, baicalein, baicalin, wogonin, wogonoside, and oroxylin A, can act directly on immune cells such as lymphocytes, macrophages, mast cells, dendritic cells, monocytes, and neutrophils, and inhibit the production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, and other inflammatory mediators such as nitric oxide, prostaglandins, leukotrienes, and reactive oxygen species. The molecular mechanisms underlying the immunomodulatory and anti-inflammatory effects of the active compounds of S. baicalensis include downregulation of toll-like receptors, activation of the Nrf2 and PPAR signaling pathways, and inhibition of the nuclear thioredoxin system and inflammation-associated pathways such as those of MAPK, Akt, NFκB, and JAK-STAT. Given that in addition to the downregulation of cytokine production, the active constituents of S. baicalensis also have antiviral and antibacterial effects, they may be more promising candidate therapeutics for the prevention of infection-related cytokine storms than are drugs having only antimicrobial or anti-inflammatory activities.


Development of an evaluation framework for publicly funded R&D projects: The case of Korea's Next Generation Network.
For decades, efforts have been made globally to measure the performance of large-scale public projects and to develop a framework to perform such measurements due to the complexity and dynamics of R&D and stakeholder interests. Still, limitations such as the use of a simply modified model and the lack of a comprehensive viewpoint are prevalent in existing approaches. In light of these research gaps, this study suggests a practical model to evaluate the performance of large-scale and publicly funded projects. The proposed model suggests a standard matrix framework of indices that evaluates the performance of particular elements in an industrial ecosystem in vertical categories and the economic and technological outcomes of those elements in horizontal categories. Based on the application of a balanced scorecard, this study uses mixed methodologies such as social network analysis, inter-industry analysis, and the analytic hierarchy process. Finally, the model evaluates the performance of Korea's Next Generation Network project as a case study.


High-Density Electromyography Provides New Insights into the Flexion Relaxation Phenomenon in Individuals with Low Back Pain.
Recent research using high-density electromyography (HDEMG) has provided a more precise understanding of the behaviour of the paraspinal muscles in people with low back pain (LBP); but so far, HDEMG has not been used to investigate the flexion relaxation phenomenon (FRP). To evaluate this, HDEMG signals were detected with grids of electrodes (13 × 5) placed bilaterally over the lumbar paraspinal muscles in individuals with and without LBP as they performed repetitions of full trunk flexion. The root mean square of the HDEMG signals was computed to generate the average normalized amplitude; and the spatial FRP onset was determined and expressed as percentage of trunk flexion. Smoothing spline analysis of variance models and the contrast cycle difference approach using the Bayesian interpretation were used to determine statistical inference. All pain-free controls and 64.3% of the individuals with LBP exhibited the FRP. Individuals with LBP and the FRP exhibited a delay of its onset compared to pain-free controls (significant mean difference of 13.3% of trunk flexion). They also showed reduced normalized amplitude compared to those without the FRP, but still greater than pain-free controls (significant mean difference of 27.4% and 11.6% respectively). This study provides novel insights into changes in lumbar muscle behavior in individuals with LBP.


Racemization, optical resolution and crystallization-induced asymmetric transformation of amino acids and pharmaceutical intermediates.
Tanabe Seiyaku has been investigating an efficient optical resolution method for the productionof optically active amino acids since the 1950s. As one of the practical applications of the resolutionmethods, we focused on crystallization-induced asymmetric transformation, with which it is possibleto obtain more than 50% of one enantiomer of a racemate. In order to achieve the asymmetrictransformation, an elegant method for racemization of optically active amino acids and their saltswas developed. This successful racemization procedure led to efficient and economical preparationpaths for various optically active amino acids by the two crystallization-induced asymmetric transformations,one of which is a combination of enantiomeric resolution and simultaneous racemization and theother is a combination of diastereomeric resolution and simultaneous epimerization. Here, manyexamples of our studies and recent reports of pharmaceutical intermediates are presented.


Oral supplementation with carbohydrate- and branched-chain amino acid-enriched nutrients improves postoperative quality of life in patients undergoing hepatic resection.
The long-term outcomes of branched-chain amino acid (BCAA) administration in patients undergoing hepatic resection remain unclear. The aim of this study is to assess the impact of oral supplementation with BCAA-enriched nutrients on postoperative quality of life (QOL) in patients undergoing liver resection. A prospective randomized clinical trial was conducted in 96 patients undergoing hepatic resection. Patients were randomly assigned to receive BCAA supplementation (AEN group, n = 48) or a conventional diet (control group, n = 48). Postoperative QOL and short-term outcomes were regularly and continuously evaluated in all patients using a short-form 36 (SF-36) health questionnaire and by measuring various clinical parameters. This study demonstrated a significant improvement in QOL after hepatectomy for liver neoplasm in the AEN group based on the same patients' preoperative SF-36 scores (P < 0.05). Perioperative BCAA supplementation preserved liver function and general patient health in the short term for AEN group patients compared to those not receiving the nutritional supplement. BCAA supplementation improved postoperative QOL after hepatic resection over the long term by restoring and maintaining nutritional status and whole-body kinetics. This study was registered at http://www.clinicaltrials.gov (registration number: NCT00945568).


Medical academic libraries in Romania - breaking with the past and turning towards the future.
This article is part of a series in this regular feature which looks at new directions in health science libraries. This article provides an updated overview of medical libraries in Romania, with a focus on the academic libraries which function under the patronage of medical schools. Information was collected through a survey questionnaire sent out to Romanian academic medical libraries in March 2017. The responses provide an overall picture of the state of Romanian medical libraries, highlighting the main trends and areas in which progress is evident, as well as the problems confronting these libraries. J.M.


Severe headache as the only symptom of long-standing shunt dysfunction in hydrocephalic children with normal or slit ventricles revealed by computed tomography.
Four patients aged 11, 11, 8 and 18 years, shunted in early childhood for hydrocephalus, were followed in the outpatient clinic for severe headache from 3 months to 2 years. The headache lasted for days and up to a week, was usually severe, and was often followed by screaming attacks or aggressive behavior. In all patients repeated computed tomography disclosed a normal ventricular system or slit ventricles. The intracranial pressure (ICP) was measured in all four patients and showed an increased intracranial steady-state pressure between 20-50 mmHg, plateau waves and, in two of the patients, a very high intracranial pulse-pressure amplitude. At operation all patients had dysfunction of the shunt (most often of the distal end). In three patients ICP monitoring post-operatively showed normal intracranial pressure without any abnormal increments from the normal steady-state pressure. Thus, severe headache can be the only symptom of long-standing shunt dysfunction, even without ventricular dilation. In shunted hydrocephalic children complaining of headaches, ICP measurement is highly recommended.


Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling.
Cellular signaling proteins such as metabotropic glutamate receptors, Shank, and different types of ion channels are physically linked by Vesl (VASP/Ena-related gene up-regulated during seizure and LTP)/Homer proteins [Curr. Opin. Neurobiol. 10 (2000) 370; Trends Neurosci. 23 (2000) 80; J. Cell Sci. 113 (2000) 1851]. Vesl/Homer proteins have also been implicated in differentiation and physiological adaptation processes [Nat. Neurosci. 4 (2001) 499; Nature 411 (2001) 962; Biochem. Biophys. Res. Commun. 279 (2000) 348]. Here we provide evidence that a Vesl/Homer subtype, Vesl-1L/Homer-1c (V-1L), reduces the function of the intracellular calcium channel ryanodine receptor type 2 (RyR2). In contrast, Vesl-1S/Homer-1a (V-1S) had no effect on RyR2 function but reversed the effects of V-1L. In live cells, in calcium release studies and in single-channel electrophysiological recordings of RyR2, V-1L reduced RyR2 activity. Important physiological functions and pharmacological properties of RyR2 are preserved in the presence of V-1L. Our findings demonstrate that a protein-protein interaction between V-1L and RyR2 is not only necessary for organizing the structure of intracellular calcium signaling proteins [Curr. Opin. Neurobiol. 10 (2000) 370; Trends Neurosci. 23(2000)80; J. Cell Sci. 113 (2000) 1851; Nat Neurosci. 4 (2001) 499; Nature 411 (2001) 962; Biochem. Biophys. Res. Commun. 279 (2000) 348; Nature 386 (1997) 284], but that V-1L also directly regulates RyR2 channel activity by changing its biophysical properties. Thereby it may control cellular calcium homeostasis. These observations suggest a novel mechanism for the regulation of RyR2 and calcium-dependent cellular functions.


Fabrication of a Mandibular Advancement Device Using a Fully Digital Workflow: A Clinical Report.
Obstructive sleep apnea (OSA) is a common disorder among adults with a potential to be life-threatening. Continuous positive airway pressure is the gold-standard for the treatment of OSA, but patient compliance may be reduced due to various reasons. Mild to moderate cases of OSA can be treated reliably and successfully using oral appliances, and the mandibular advancement device (MAD) is the most frequently used appliance. The aim of this clinical report is to present a fully digital workflow for fabrication of a custom non-adjustable MAD using computer aided design/computer aided manufacturing and additive manufacturing for the treatment of a patient with moderate OSA.


On the evolution of dominance modifiers I. A nonlinear analysis.
A well known mathematical model of evolution of dominance is subjected to a nonlinear analysis. For the case where the primary locus and the modifying locus are completely linked (r = 0) a global Ljapunov function is given. This proves that selection of dominance modifiers entirely due to their modifying effect is possible. This result is also extended to small recombination fractions r by using the method of Ljapunov functions in a more sophisticated way. For r = 0 and mu = 0 a lower bound for the success of selection of the modifier is given. Furthermore, the influence of the dominance relations between the alleles (measured by the parameters h and k) is investigated. Finally it is shown that differential and difference equations lead to the same results (which need not be the case in general). As a by-product we obtain a new equilibrium point in the classical one locus selection-mutation model.


5-Azido neuraminic acid thioglycoside as sialylation donor.
5-Azido neuraminic acid thioglycoside with O-benzyl protecting groups was synthesized. The sialylations of this new donor type showed good alpha-selectivities for certain primary hydroxyls.


Effects of mood induction on eating behavior and cigarette craving in dietary restrainers.
Women high in dietary restraint ("restrainers") increase food intake more than nonrestrainers following emotional arousal. When restrained smokers are deprived of cigarettes during elevated mood states, nicotine craving should increase with food craving. The present study investigated the interaction of smoking and affect on food intake in 60 women, 18-25 years old, who were identified as restrainers. The study consisted of smokers and nonsmokers who viewed a domestic violence or comedy film segment, followed by exposure to snacks. Emotional arousal, regardless of valence, did not result in a difference in food consumption between smokers and nonsmokers. Furthermore, smokers showed similar levels of nicotine craving after both films. Self-report of mood changed only in the domestic violence condition, indicating the difficulty of positive mood induction. Limitations to the study and suggestions for further research are discussed.


Assessment of dose rate to terrestrial biota in the area around coal fired power plant applying ERICA tool and RESRAD BIOTA code.
This paper presents the environmental radiation risk assessment based on two software program approaches ERICA Tool (version 1.2) and RESRAD BIOTA (version 1.5) to estimate dose rates to terrestrial biota in the area around the largest coal fired power plant in Serbia. For dose rate assessment software's default reference animals and plants and the best estimated values of activity concentrations of 238U, 234U, 234Th, 232Th, 230Th, 226Ra, 210Pb, 210Po, 137Cs in soil were used. Both approaches revealed the highest contribution to the internal dose rate due to 226Ra and 210Po, while 137Cs contributed the most to the external dose rate. In the investigated area total dose rate to biota derived using ERICA Tool ranged from 0.3 to 14.4 μGy h-1. The natural radionuclides exhibited significantly higher contribution to the total dose rate than the artificial one. In the investigated area, only dose rate for lichens and bryophytes exceeded ERICA Tool screening value of total dose rate of 10 μGy h-1 suggested as confident that environmental risks are negligible. The assessed total dose rates for reference animals and plants using RESRAD BIOTA were found to be 7 and 3 μGy h-1, respectively. In RESRAD BIOTA - Level 3, 10 species (Lumbricus terrestris, Rana lessonae, Sciurus vulgaris, Anas platyrhynchos, Lepus europaeus, Vulpes vulpes, Capreolus capreolus, Suss crofa, Quercu srobur, Tilia spp.) representative for the study area were modeled. Among them the highest total dose rate (4.5 μGy h-1) was obtained for large mammals. Differences in the predicted dose rates to biota using the two software programs are the consequence of the difference in the values of transfer parameters used to calculate activity concentrations in biota. Doses of ionizing radiation estimated in this study will not exhibit deterministic effects at the population level. Thus, the obtained results indicate no significant radiation impact of coal fired power plant operation on terrestrial biota. This paper confirms the use ERICA Tool and RESRAD BIOTA softwares as flexible and effective means of radiation impact assessment.


HER2 G776S mutation promotes oncogenic potential in colorectal cancer cells when accompanied by loss of APC function.
Clinical cancer genome sequencing detects oncogenic variants that are potential targets for cancer treatment, but it also detects variants of unknown significance. These variants may interact with each other to influence tumor pathophysiology, however, such interactions have not been fully elucidated. Additionally, the effect of target therapy for those variants also unclarified. In this study, we investigated the biological functions of a HER2 mutation (G776S mutation) of unknown pathological significance, which was detected together with APC mutation by cancer genome sequencing of samples from a colorectal cancer (CRC) patient. Transfection of the HER2 G776S mutation alone slightly increased the kinase activity and phosphorylation of HER2 protein, but did not activate HER2 downstream signaling or alter the cell phenotype. On the other hand, the HER2 G776S mutation was shown to have strong oncogenic potential when loss of APC function was accompanied. We revealed that loss of APC function increased Wnt pathway activity but also increased RAS-GTP, which increased ERK phosphorylation triggered by HER2 G776S transfection. In addition, afatinib, a pan-HER tyrosine kinase inhibitor, suppressed tumor growth in xenografts derived from HER2 G776S-transfected CRC cells. These findings suggest that this HER2 mutation in CRC may be a potential therapeutic target.


COVID-19 in Italy: Considerations on official data.
COVID-19 represents a major public health issue in Italy; estimating the size of the outbreak could direct public health policies and inform us of the extent of the reorganization needed in the healthcare system, the efficacy of quarantine measures, and eventually on the achievement of herd immunity. To chart the real extent of COVID-19 infection in Italy official data need to be interpreted, considering various aspects such as the "suspected-case" definition that changed during recent months, the management of asymptomatic and untested symptomatic cases, the system for reporting deaths, and short-term fluctuations. All these aspects should be considered when reflecting on the meaning of the official COVID-19 figures in Italy. Regionalization of the healthcare system and fragmentation of data represent real challenges in the management of the COVID-19 outbreak in Italy. The authors' opinion is that transparent and accurate reporting could guide policy-making and help reorganize health services.


Synthesis of Diverse o-Arylthio-Substituted Diaryl Ethers by Direct Oxythiolation of Arynes with Diaryl Sulfoxides Involving Migratory O-Arylation.
A diverse range of o-arylthio-substituted diaryl ethers has been synthesized by direct oxythiolation of arynes with diaryl sulfoxides that involves the formation of the C-O and C-S bonds followed by migratory O-arylation.


Sonographic diagnosis of subarachnoid hemorrhage in premature newborn infants: a retrospective study with histopathologic and CT correlation.
The role of ultrasound in the diagnosis of neonatal subarachnoid hemorrhage was assessed by retrospective analysis. The findings were correlated with either computed tomography or autopsy. An overall true-positive rate of 88 per cent was obtained.


Recently reported biological activities of pyrazole compounds.
The pyrazole nucleus is an aromatic azole heterocycle with two adjacent nitrogen atoms. Pyrazole derivatives have exhibited a broad spectrum of biological activities, and approved pyrazole-containing drugs include celecoxib, antipyrine, phenylbutazone, rimonabant, and dipyrone. Many research groups have synthesized and evaluated pyrazoles against several biological agents. This review examines recent publications relating the structures of pyrazoles with their corresponding biological activities.


Puberty timing and adiposity change across childhood and adolescence: disentangling cause and consequence.
Is earlier puberty more likely a result of adiposity gain in childhood than a cause of adiposity gain in adulthood? Pre-pubertal fat mass is associated with earlier puberty timing but puberty timing is not associated with post-pubertal fat mass change. Age at puberty onset has decreased substantially in the last several decades. Whether reducing childhood adiposity prevents earlier puberty and if early puberty prevention itself also has additional independent benefits for prevention of adult adiposity is not well understood. Prospective birth cohort study of 4176 participants born in 1991/1992 with 18 232 repeated measures of fat mass from age 9 to 18 years. We used repeated measures of height from 5 to 20 years to identify puberty timing (age at peak height velocity, aPHV) and repeated measures of directly measured fat mass from age 9 to 18 years, from a contemporary UK birth cohort study to model fat mass trajectories by chronological age and by time before and after puberty onset. We then examined associations of these trajectories with puberty timing separately in females and males. In models by chronological age, a 1-year later aPHV was associated with 20.5% (95% confidence interval (CI): 18.6-22.4%) and 23.4% (95% (CI): 21.3-25.5%) lower fat mass in females and males, respectively, at 9 years. These differences were smaller at age 18 years: 7.8% (95% (CI): 5.9-9.6%) and 12.4% (95% (CI): 9.6-15.2%) lower fat mass in females and males per year later aPHV. Trajectories of fat mass by time before and after puberty provided strong evidence for an association of pre-pubertal fat mass with puberty timing, and little evidence of an association of puberty timing with post-pubertal fat mass change. The role of chance is likely to be small in this study given the large sample sizes available. Participants included in our analyses were more socially advantaged than those excluded. The findings of this work may not apply to non-White populations and further work examining associations of puberty timing and fat mass in other ethnicities is required. Previous research has relied on self-reported measures of puberty timing such as age of voice breaking in males, has lacked data on pre-and post-pubertal adiposity together and relied predominantly on indirect measures of adiposity such as BMI. This has led to conflicting results on the nature and direction of the association between puberty timing and adiposity in females and males. Our work provides important clarity on this, suggesting that prevention of adiposity in childhood is key for prevention of early puberty, adult adiposity and associated cardiovascular risk. In contrast, our findings suggest that prevention of early puberty without prevention of childhood adiposity would have little impact on prevention of adult adiposity. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for Avon Longitudinal Study of Parents and Children (ALSPAC). L.M.O.K. is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1) and a Health Research Board (HRB) of Ireland Emerging Investigator Award (EIA-FA-2019-007 SCaRLeT). J.A.B. is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). L.D.H. and A.F. are supported by Career Development Awards from the UK Medical Research Council (grants MR/M020894/1 and MR/M009351/1, respectively). All authors work in a unit that receives funds from the UK Medical Research Council (grant MC_UU_00011/3, MC_UU_00011/6). No competing interests to declare. N/A.


[Vein reconstruction in lower limb injuries (author's transl)].
Reconstructive venous surgery is essential in lower limb injuries to avoid circulatory insufficiency when the main vein is severed. The repair requires a vein graft with adequate lumen--two segments of the saphenous vein are slit open and sutured together. A technique for atraumatic preparation of this composite graft is described. A peripheral temporary A-V fistula is advocated to prevent thrombosis of the graft.


Atomic force microscopy of bacteria reveals the mechanobiology of pore forming peptide action.
Time-resolved AFM images revealed that the antimicrobial peptide (AMP) caerin 1.1 caused localised defects in the cell walls of lysed Klebsiella pneumoniae cells, corroborating a pore-forming mechanism of action. The defects continued to grow during the AFM experiment, in corroboration with large holes that were visualised by scanning electron microscopy. Defects in cytoplasmic membranes were visualised by cryo-EM using the same peptide concentration as in the AFM experiments. At three times the minimum inhibitory concentration of caerin, 'pores' were apparent in the outer membrane. The capsule of K. pneumoniae AJ218 was unchanged by exposure to caerin, indicating that the ionic interaction of the positively charged peptide with the negatively charged capsular polysaccharide is not a critical component of AMP interaction with K. pneumoniae AJ218 cells. Further, the presence of a capsule confers no advantage to wild-type over capsule-deficient cells when exposed to the AMP caerin.


A review on MXene and its nanocomposites for the detection of toxic inorganic gases.
In the search of the viable candidate for the sensing of pollutant gases, two-dimensional (2D) material transition metal carbides (MXenes) have attracted immense attention due to their outstanding physical and chemical properties for sensing purposes. The formation of unique 2D layered structure with high conductivity, large mechanical strength, and high adsorption properties furnish their strong interactions with gaseous molecules, which holds a promising place for developing ideal gas sensing devices. This review looks at recent achievements in diversified MXenes, with a focus gaining on in-depth understanding of MXene-based materials in room temperature inorganic gas sensors through both theoretical and experimental studies. In the first part of the review, the properties and advantages of sensing material (MXene) in comparison with other 2D materials are discussed. In the second part, the unique advantages of chemiresistive based sensors and the demerits of other detection methods are summarized in detail. This section is followed by the unique structural design of MXene bases materials for improving the sensing performance towards detection of inorganic gases. The interaction between MXene and the adsorbed gases on its surface is discussed, with a possible sensing mechanism. Finally, an overview of the current progress and opportunities for the demand of MXene is emphasized and perspectives for future improvement of the design of MXene in gas sensors are highlighted. Therefore, this review highlights the opportunities and the advancement in 2D material-based gas sensors which could provide a new avenue for rapid detection of toxic gases in the environment.


Ribosomal scanning on the highly structured insulin-like growth factor II-leader 1.
The complex architecture of human insulin-like growth factor (IGF) II-leader 1 of 592 nucleotides (nt), with one open reading frame (ORF), and the potential to fold into stable structures makes efficient linear ribosomal scanning difficult to comprehend. Indeed, leader 1-driven reporter expression is low in rabbit reticulocyte lysate. Contrarily, leader 1 is very efficient in cells. Therefore, we tested whether this 5'UTR uses an alternative mechanism for translation initiation in vivo, internal entry or ribosomal shunting. Internal initiation was tested by introducing leader 1 into the intercistronic region of a bicistronic vector. Second cistron expression, driven by leader 1, was lower than by the intercistronic beta-globin 5'UTR, indicating that leader 1 does not contain an internal ribosomal entry site (IRES). Shunting was tested by inserting hairpin (HP) structures, capable of blocking ribosomal scanning, at eight positions in leader 1. After transfection, these mutant 5'UTRs were incapable of directing reporter expression. Less stable HPs at the same positions increased the activity to 50% of wild-type activity, indicating that insertions at these positions are not disastrous for initiation. These data indicate that the translational machinery encounters major parts of leader 1. As scanning seems unlikely, and internal entry and shunting were shown not to occur, we discuss a modified scanning mechanism for architecturally complex 5'UTRs.


Free vascularized nail grafts.
A considerable amount of literature has been written on microneurovascular surgery for the reconstruction of partial defects in fingers, but little has been published on reconstruction to replace lost fingernails. We report on two clinical cases in which a free vascularized nail graft and a "double onychocutaneous flap" were used successfully. We suggest that the free vascularized nail graft is a superior method in reconstruction to treat fingernail loss or deformity.


Single-shot spinal block for labour analgesia in multiparous parturients*.
Intrathecal analgesia (ITA) is effective in late, rapidly progressing labour. In 1998, our hospital implemented the use of single-shot spinal block for pain relief in multiparous parturients. As part of a quality assurance programme, we assessed the analgesic efficacy, obstetric and neonatal outcomes and maternal satisfaction after this form of analgesia now in routine use in our labour ward. Two hundred and twenty-nine consecutive multiparous parturients presenting for vaginal delivery and requesting analgesia were asked to participate in this prospective study. All parturients received our standard ITA: 2.5 mg bupivacaine (1 ml) + 25 microg fentanyl (0.5 ml) inserted via the L2-3 or L3-4 interspace. Routine monitoring included maternal vital signs, uterine contraction and fetal heart rate tracing. Pain scores (visual analogue scale (VAS) 0-10), sensory levels, motor block, side-effects and maternal satisfaction were recorded. Satisfactory analgesia was defined as a decrease in pain scores to three or less within 20 min after injection. The number of parturients requesting additional analgesia and the duration of spinal block (time from injection until request for additional medication after satisfactory analgesia had worn off) were recorded. Two hundred and nine parturients were included in the study. Satisfactory analgesia was achieved in 153 (73%) parturients. Fifty-five (26%) women requested additional analgesia: 38 (18%) because of unsatisfactory analgesia and 17 (8%) because analgesia ended before delivery. The duration of spinal block was 101 +/- 34 min. Pruritus occurred in 64%, fetal bradycardia in 7% and hypotension in 2% of deliveries. Pain relief was rated excellent by 65%, moderate by 20% and inadequate by 14% of the parturients. One hundred and sixty-nine (81%) women stated that they would like to have spinal analgesia again for pain relief during delivery. The majority of multiparous parturients found ITA adequate for pain relief during delivery. However, modifications are required in terms of improved timing, reliability and duration of analgesia.


A simple method for the collection of Necator americanus larvae.
A simple method for the collection of third-stage larvae of Necator americanus has been described. This technique provides repeated recovery of very clean larvae from cultures in moderate numbers.


Disruption of CREB function in brain leads to neurodegeneration.
Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem(-/-) background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.


Biochemical and pharmacokinetic evaluation of a novel pyrimidine nucleoside nitric oxide donor as a potential anticancer/antiviral agent.
The objective of this study was to determine the physiochemical, biochemical and pharmacokinetic properties of 5-iodo-3'-O-nitro-2'-deoxyuridine (INUdR), a novel prodrug releasing both nitric oxide (NO) and 5-iodo-2'-deoxyuridine. The INUdR partition coefficient (log P=1.12) was determined by both the shake-flask method and by calculation using Interactive Analysis Log P Program. In vitro binding of INUdR to bovine serum albumin (BSA) was estimated using an ultrafiltration method to be 65 to 77%, depending on the INUdR concentration. INUdR was stable in phosphate buffer (pH 7.4) and in water, at both ambient temperature and at 37 degrees C. INUdR was resistant to phosphorolysis when incubated with thymidine phosphorylase. Plasma, L-cysteine and glutathione catalyzed release of NO from INUdR, as determined using the Griess reaction. In all three systems, the release of NO by INUdR was equal to or greater than that of the reference drug isosorbide dinitrate. The pharmacokinetics of INUdR following single intravenous bolus and oral doses of INUdR (40 mg/kg) to male Sprague-Dawley rats were characterized by a short elimination half-life (T(1/2) 0.27 h), a large steady-state volume of distribution (V(ss) 0.89 l/kg) and high oral bioavailability (F=0.95). In conclusion, INUdR lipophilicity, shelf-stability, and resistance towards catabolic breakdown by thymidine phosphorylase, together with its non-spontaneous, yet considerable NO release, constitute favorable characteristics of a potential anticancer/antiviral agent.


Comparison of the three-dimensional protein and nucleotide structure of the FAD-binding domain of p-hydroxybenzoate hydroxylase with the FAD- as well as NADPH-binding domains of glutathione reductase.
The chain fold of the FAD-binding domain of p-hydroxybenzoate hydroxylase resembles the chain folds of the two nucleotide-binding domains of glutathione reductase. This fold consists of a four-stranded parallel beta-sheet sandwiched between a three-stranded antiparallel beta-sheet and alpha-helices. The nucleotides bind in similar positions relative to this chain fold. The best superposition of the folds has been established and geometrically quantified, giving rise to an equivalencing scheme for 110 residue positions, of which only four residues are identical in all three domains. It is discussed whether this chain fold is also present in a number of other FAD-binding proteins with known sequence. After the second strand of the parallel beta-sheet both FAD-binding domains contain long chain excursions, which make intimate contacts to rather distant parts of the respective molecules. In the environment of the isoalloxazine rings we observe interesting similarities. In both enzymes the si-face of this ring is covered by polypeptide, and only the re-face is accessible for the cofactor NADPH. Furthermore, there is a long alpha-helix in each enzyme, which points with its N-terminal start to the O-2 alpha region of isoalloxazine. These helices are spatially in the same position with respect to the isoalloxazine ring but are at quite different positions along the polypeptide chain. Since they can stabilize a negative charge around O-2 alpha, they may be important for the catalytic processes.


A spectrophotometric assay for strictosidine synthase.
A spectrophotometric assay for strictosidine synthase is described. Strictosidine is extracted with ethyl acetate and, where high substrate concentrations are used, the organic extract is washed with dilute ammonia to remove coextracted secologanin; after evaporation of the solvent, the residue is heated with 5 M H2SO4 for 45 min and the A348 value is measured. Strictosidine production is calculated from the response of similarly treated standards. A minimum production of 10-25 nmol of strictosidine may be determined. The assay is demonstrated using extracts of cultured Cinchona ledgeriana cells.


Inherited coagulation disorders.
Inherited coagulation disorders have been diagnosed in many breeds of dogs as well as in mongrels and cats. This article presents the different coagulation factor deficiencies that are known to exist in small animals. A description is given of each coagulation factor along with the relevant clinical signs, inheritance, and the breeds affected. Suggestions are also given for the diagnosis and therapy of these deficiencies.


Murine mammary tumour cells in vitro. II. Recruitment of quiescent cells.
The development of a pure quiescent (Q) tumour cell population can be induced in three mouse mammary tumour lines (66, 67 and 68H) by nutrient deprivation. When these Q cells were removed from nutrient-deprived cultures and replated in fresh medium at a lower cell concentration within 72 hr of entering quiescence virtually all of the Q cells could re-enter the proliferating (P) state. This recruitment was characterized by an increase in cell volume, an increase in total cellular RNA, and a resumption of cell division. The length of the Q to P transition varied among the three cell lines and the depth of the quiescent state depended on the amount of time the cells had been quiescent. Once re-entry into the P compartment was completed, cell-cycle times, as estimated by the culture doubling time, were the same as the cells that had not entered the Q state, however, after 72 hr in quiescence, not all of the 66 cells could reattach after trypsinization and of those that could reattach approximately equal to 50% were incapable of either increasing their RNA levels to that of proliferating G1 cells or entering S. Clonogenicity of the nutrient-deprived Q cells in these lines decreases exponentially from time the cells enter quiescence with approximate half-times of 32, 34, and 96 hr for the 66, 68H and 67 cells, respectively. Since clonogenicity was already declining at a time when all the Q cells could re-enter the P compartment, the ability of a Q cell to form a colony is not determined solely by its capacity to re-enter the proliferating compartment.


Mild core hypothermia and anesthetic requirement for loss of responsiveness during propofol anesthesia for craniotomy.
Mild hypothermia may be induced during neurosurgery for brain protection. However, its effect on propofol requirement has not been defined. Accordingly, we tested the hypothesis that 3 degrees C of core hypothermia decreases the propofol blood concentration at which patients respond to command (CP50-awake) in neurosurgical patients. Forty patients were anesthetized with alfentanil 50 microg/kg i.v., nitrous oxide, propofol target-controlled infusion, and rocuronium. The bispectral index (version 3.12) was monitored continuously. Patients were randomized to a core temperature of 34 degrees C or 37 degrees C. At the end of surgery, neuromuscular blockade was reversed, nitrous oxide was ceased, and propofol was infused to achieve a blood target determined by the previous patient's response. Responsiveness to command was assessed 15 min later. Results were analyzed with logistic regression models; P < 0.05 was considered statistically significant. The CP50-awake of propofol was 3.05 microg/mL (95% confidence interval, 2.34-3.66). Propofol concentration, but not core temperature, predicted loss of response to command (odds ratio, 11.76; 95% confidence interval, 2.40-57.63; P < 0.01). Core temperature did not alter the relationship between bispectral index and response to command. Propofol infusion regimens may not require adjustment during mild hypothermia. Neurosurgical patients may be allowed to become mildly hypothermic during anesthesia in an effort to provide brain protection. Propofol maintenance infusion doses may not require adjustment in these patients.


Polyomavirus BK Induces Inflammation via Up-regulation of CXCL10 at Translation Levels in Renal Transplant Patients with Nephropathy.
Polyomavirus BK-associated nephropathy (BKAN) is an important mechanism for renal losing after kidney transplantation. It seems that Polyomavirus BK can induce nephropathy by direct cell lysis and stimulation of the immune system and induction of inflammation. CXCL10 is a pro-inflammatory cytokine which stimulates the migration and activation of immune cells to the infected sites. Therefore, the aim of the current study was to evaluate the messenger RNA (mRNA) and protein levels of CXCL10 in the Polyomavirus BK-infected and Polyomavirus BK-non-infected post renal transplanted nephropathic patients in comparison to healthy controls. In this cross-sectional study, Polyomavirus BK-infected post renal transplanted nephropathic patients, Polyomavirus BK-non-infected post renal transplanted nephropathic patients, and healthy controls were enrolled to evaluate mRNA and protein levels of CXCL10 by real-time PCR and ELISA techniques, respectively. mRNA levels of CXCL10 were not significantly different among participants, while serum levels of CXCL10 were significantly elevated in the Polyomavirus BK-infected patients when compared to non-infected patients as well as controls and in non-infected patients when compared to healthy controls. Due to the results, it seems that Polyomavirus BK may potentially induce renal losing through stimulation of inflammation via increasing translation of CXCL10, as a pro-inflammatory chemokine.


Exercise left ventricular ejection fraction predicts events in right bundle branch block.
Interpretation of the electrocardiogram (ECG) during exercise is not easy in patients with right bundle branch block (RBBB). Also, the value of exercise echocardiography (ExE) for predicting outcome in them has not been addressed. We sought to assess its prognostic value in patients with RBBB and known/suspected coronary disease. Retrospective analysis of data on 703 patients with RBBB who were submitted to a clinically-indicated ExE. The end points were overall mortality and combined myocardial infarction and cardiovascular mortality. During follow-up (4.1 ± 4.5 years) there were 130 deaths and 108 combined events. Independent predictors of combined events were history of coronary artery disease (hazard ratio [HR] = 2.37, 95% Confidence Interval [CI] = 1.24-4.52, p = 0.009) resting wall motion score index (HR = 2.14, 95% CI = 1.12-4.10, p = 0.02), metabolic equivalents (HR = 0.89, 95% CI = 0.93-0.97, p = 0.007), Δ in double product with exercise (HR = 0.96, 95% CI = 0.92-1.00, p = 0.036) and Δ in left ventricular ejection fraction (LVEF) with exercise (HR = 0.97, 95% CI = 0.94-0.99, p = 0.01). Neither positive clinical nor ECG exercise testing was predictive. Combined event rates were 3.3% in patients with ΔLVEF > 5%, 4.7% in those with ΔLVEF between 1-5% and 8.2% in those with no increase (Δ < 1%). A decrease in LVEF during exercise is predictive of serious events in patients with RBBB.


A proposal for enhancing the general surgical workforce and access to surgical care.
The goals of this focused meeting were to verify and clarify the causes and extent of the general surgery (GS) workforce shortfalls. We also sought to define workable solutions within the existing framework of medical accreditation and certification. Numerous peer-reviewed and lay reports describe a current and worsening availability of GS services, affecting rural areas as well as large cities, academia, and the military. Primary recommendations were broadly agreed upon by attendee surgeons who were selected from numerous different professional scenarios and included 2 nonmedical observers. (1) enhance the number of GS trainees and the breadth of training, (2) incorporate more flexibility and breadth in residency, (3) minimally invasive surgery should largely return to GS, (4) broader use of community hospitals in these efforts, (5) publicize loan forgiveness and improved visa status for international medical graduates going into GS, and (6) select candidates with a bias toward a general surgical career. These methods are promising approaches to this serious deficiency but will require regular reporting and publicity for the recording of actual increases in GS output.


The splicing factor YBX1 promotes the progression of osteosarcoma by upregulating VEGF165 and downregulating VEGF165b.
VEGF165 and its isoform VEGF165b have the same length but opposite functions in cancer. Some studies have indicated the important role of VEGF165 in osteosarcoma (OS); however, VEGF165b has not been taken into consideration. This study aims to clarify the roles of the two isoforms in OS and the mechanism controlling their formation from an alternative splicing perspective. By in vivo and in vitro experiments, we assessed the expression and function of VEGF165 and VEGF165b, screened the underlying splicing factors, and verified the regulatory function of splicing factor YBX1 on the two isoforms and its role in OS. The results showed that in OS, VEGF165 was upregulated but VEGF165b was downregulated. VEGF165 promoted the proliferation, migration and invasion of OS cells and induced angiogenesis in OS tumours; however, VEGF165b showed the opposite function. Of the four screened splicing factors, YBX1 was upregulated in OS tissues. It was positively correlated with VEGF165 but negatively correlated with VEGF165b. Further study indicated that YBX1 could upregulate VEGF165 but downregulate VEGF165b. Moreover, YBX1 promoted the proliferation, migration and invasion of OS cells and induced angiogenesis in OS tumours. OS patients with higher YBX1 had a poor prognosis within five years, but this difference disappeared in a longer follow-up. In conclusion, VEGF165b was antineoplastic and downregulated in OS, in contrast to VEGF165. YBX1 was found to be an important splicing factor that increased VEGF165 but decreased VEGF165b. Targeting YBX1 could endogenously alter the levels of VEGF165 and VEGF165b simultaneously.


Medullary thyrotropin-releasing hormone mediates vagal-dependent adaptive gastric protection induced by mild acid in rats.
Adaptive gastric protection is dependent on vagal pathways in rats. It is hypothesized that medullary thyrotropin-releasing hormone (TRH), known to regulate vagal function, is part of the brain mechanisms mediating adaptive gastric protection. Urethane-anesthetized rats were pretreated with either acute bilateral subdiaphragmatic vagotomy, sham operation, or intracisternal injection of purified control, TRH, or peptide YY antibody. Gastric lesions were assessed 75 minutes after orogastric administration of 1 mL of either vehicle or 0.35N HCl followed 15 minutes later by 0.6N or 1.0N HCl. Injection of 0.6N and 1.0N HCl induced gastric lesions covering 23.1% +/- 2.7% and 37.8% +/- 3.3% of the corpus mucosa, respectively. Pretreatment with 0.35N HCl resulted in 67.3% and 50.5% reductions in gastric lesions induced by 0.6N and 1.0N HCl, respectively. Subdiaphragmatic vagotomy or intracisternal injection of TRH antibody increased gastric lesions induced by 0.6N HCl to 32.2% +/- 2.2% and 42.9% +/- 5.6%, respectively, and completely abolished the protective effect of 0.35N HCl pretreatment. Control or peptide YY antibody injected intracisternally did not alter the gastric protection induced by mild acid. These results indicate that medullary TRH plays a role in the vagally mediated adaptive gastric protection induced by mild acid.


Difference in renal alpha-galactosidase levels in male and female Chinese hamsters (Cricetulus griseus).
1. The activity of alpha-galactosidase was found to be significantly higher in the kidney of female than that of male Chinese hamsters in a highly inbred colony but its activity in liver, heart and spleen remained similar between female and male animals. 2. Partially purified renal alpha-galactosidase by sequential column chromatography on Sepharose 6B and DEAE-Sepharose CL-6B showed identical elution profiles, pH optima (4.5), KmS (4.4 mM) and heat-inactivation curves between enzymes of male and female animals. 3. Thus, the observed higher activity of renal alpha-galactosidase in the females was due to elevated enzyme concentration, not a result of enzyme polymorphism.


Natural mineral fibers: conducting inhalation toxicology studies-part B: development of a nose-only exposure system for repeat-exposure in vivo study of Libby amphibole aerosol.
Exposure to asbestos is associated with malignant and nonmalignant respiratory disease. To strengthen the scientific basis for risk assessment on fibers, the National Institute of Environmental Health Sciences (NIEHS) has initiated a series of studies to address fundamental questions on the toxicology of naturally occurring asbestos and related mineral fibers after inhalation exposure. A prototype nose-only exposure system was previously developed and validated. The prototype system was expanded to a large-scale exposure system in this study for conducting subsequent in vivo rodent inhalation studies of Libby amphibole (LA) 2007, selected as a model fiber. The exposure system consisting of six exposure carousels was able to independently deliver stable LA 2007 aerosol to individual carousels at target concentrations of 0 (control group), 0.1, 0.3, 1, 3, or 10 mg/m3. A single aerosol generator was used to provide aerosol to all carousels to ensure that exposure atmospheres were chemically and physically similar, with aerosol concentration as the only major variable among the carousels. Transmission electron microscopy (TEM) coupled with energy dispersive spectrometry (EDS) and selected area electron diffraction (SAED) analysis of aerosol samples collected at the exposure ports indicated the fiber dimensions, chemical composition, and mineralogy were equivalent across exposure carousels and were comparable to the bulk LA 2007 material. The exposure system developed is ready for use in conducting nose-only inhalation toxicity studies of LA 2007 in rats. The exposure system is anticipated to have applicability for the inhalation toxicity evaluation of other natural mineral fibers of concern.


Human secondary somatosensory cortex is involved in the processing of somatosensory rare stimuli: an fMRI study.
In the human somatosensory system, the contralateral primary somatosensory cortex (SI) is presumed to process and encode type and intensity of the sensory inputs, whereas the bilateral secondary somatosensory cortex (SII) is believed to perform higher order functions including sensorimotor integration, integration of information from the two body halves, attention, learning and memory. In this fMRI study we investigated the effect of attention on the activation of SI and SII, as induced by nonpainful and painful rare deviant electric stimuli during somatosensory oddball tasks. The working hypothesis is of stronger effects of attention on SII with respect to SI. Four runs were acquired according to an oddball scheme. Frequent nonpainful electrical stimuli were delivered to the ulnar nerve at motor threshold, whereas rare/deviant stimuli were delivered to median nerve in four conditions (one condition per run): nonpainful, painful, counting nonpainful, and counting painful. Results showed a statistically significant fMRI activation in bilateral SII but not in contralateral SI when the rare/deviant median nerve stimuli were delivered at nonpainful and painful levels as well as at the two levels of attention considered (i.e., associated with counting and non-counting tasks). Furthermore, fMRI activation in SII did not differ across the different levels of stimulus intensity (nonpainful, painful) and attention (non-counting, counting). These results corroborate the notion that SII is the target of independent pathways for the processing and integration of nonpainful and painful somatosensory stimuli salient for further high-order elaborations.


Cell-biological effects of zinc oxide spheres and rods from the nano- to the microscale at sub-toxic levels.
Zinc oxide particles were synthesized in various sizes and shapes, i.e., spheres of 40-nm, 200-nm, and 500-nm diameter and rods of 40∙100 nm2 and 100∙400 nm2 (all PVP-stabilized and well dispersed in water and cell culture medium). Crystallographically, the particles consisted of the hexagonal wurtzite phase with a primary crystallite size of 20 to 100 nm. The particles showed a slow dissolution in water and cell culture medium (both neutral; about 10% after 5 days) but dissolved within about 1 h in two different simulated lysosomal media (pH 4.5 to 4.8). Cells relevant for respiratory exposure (NR8383 rat alveolar macrophages) were exposed to these particles in vitro. Viability, apoptosis, and cell activation (generation of reactive oxygen species, ROS, release of cytokines) were investigated in an in vitro lung cell model with respect to the migration of inflammatory cells. All particle types were rapidly taken up by the cells, leading to an increased intracellular zinc ion concentration. The nanoparticles were more cytotoxic than the microparticles and comparable with dissolved zinc acetate. All particles induced cell apoptosis, unlike dissolved zinc acetate, indicating a particle-related mechanism. Microparticles induced a stronger formation of reactive oxygen species than smaller particles probably due to higher sedimentation (cell-to-particle contact) of microparticles in contrast to nanoparticles. The effect of particle types on the cytokine release was weak and mainly resulted in a decrease as shown by a protein microarray. In the particle-induced cell migration assay (PICMA), all particles had a lower effect than dissolved zinc acetate. In conclusion, the biological effects of zinc oxide particles in the sub-toxic range are caused by zinc ions after intracellular dissolution, by cell-to-particle contacts, and by the uptake of zinc oxide particles into cells. Graphical headlights • The cytotoxicity of zinc oxide particles is mainly due to the intracellular release of zinc ions. • The size and shape of zinc oxide micro- and nanoparticles has only small effects on lung cells in the sub-toxic range. • Zinc oxide particles are rapidly taken up by cells, regardless of their size and shape. • Zinc oxide particles rapidly dissolve after cellular uptake in endolysosomes.


High-average-power, carrier-envelope phase-stable, few-cycle pulses at 2.1 μm from a collinear BiB3O6 optical parametric amplifier.
We generate self-carrier-to-envelope phase-stable, 630 μJ pulses, centered at 2.1 μm, with 42 fs (6 cycle) duration based on collinear optical parametric amplification in BiB(3)O(6) at 3 kHz. These pulses are generated through a traveling wave amplifier scheme, and the bandwidth supports 28 fs (4 cycle) pulse duration. Carrier-to-envelope phase stability was measured to be 410 mrad over 10 min or 260 mrad over 35 s.


HPV infection and the genital cytokine milieu in women at high risk of HIV acquisition.
Human papillomavirus (HPV) infection correlates with higher rates of HIV acquisition, but the underlying biological mechanisms are unclear. Here we study associations between HPV and HIV acquisition and relate these to vaginal cytokine profiles in an observational cohort of women at high risk of HIV infection (CAPRISA 004, n = 779) and with 74% HPV prevalence. We report here that HPV infection associates with a 2.5-fold increase in HIV acquisition risk in this population (95% CI: 1.2-5.3). Among 48 vaginal cytokines profiled, cytokines associated with HPV infection overlap substantially with cytokines associated with HIV risk, but are distinct from those observed in HPV negative women. Although our data do not establish a causative link between HPV status and the risk of HIV, we suggest that increasing HPV vaccination coverage may carry an additional benefit of reducing the risk of contracting HIV infection, particularly in regions with high HPV prevalence.


Knock-down of glutaminase 2 expression decreases glutathione, NADH, and sensitizes cervical cancer to ionizing radiation.
Phosphate-activated mitochondrial glutaminase (GLS2) is suggested to be linked with elevated glutamine metabolism. It plays an important role in catalyzing the hydrolysis of glutamine to glutamate. The present study was to investigate the potent effect of GLS2 on radioresistance of cervical carcinoma. GLS2 was examined in 144 cases of human cervical cancer specimens (58 radioresistant specimens, 86 radiosensitive specimens) and 15 adjacent normal cervical specimens with immunohistochemistry. HeLa cells were treated with a cumulative dose of 50Gy X-rays, over 6months, yielding the resistant sub-line HeLaR. The expressions of GLS2 were measured by Western blot. Radioresistance was tested by colony survival assay. Apoptosis was determined by flow cytometry. The levels of glutathione (GSH), reactive oxygen species (ROS), NAD(+)/NADH ratio and NADP(+)/NADPH ratio were detected by quantization assay kit. Xenografts were used to confirm the effect of GLS2 on radioresistance in vivo. The expressions of GLS2 were significantly enhanced in tumor tissues of radioresistant patients compared with that in radiosensitive patients. In vitro, the radioresistant cell line HeLaR exhibited significantly increased GLS2 levels than its parental cell line HeLa. GLS2 silenced radioresistant cell HeLaR shows substantially enhanced radiosensitivity with lower colony survival and higher apoptosis in response to radiation. In vivo, xenografts with GLS2 silenced HeLaR were more sensitive to radiation. At the molecular level, knock-down of GLS2 increased the intracellular ROS levels of HeLaR exposed to irradiation by decreasing the productions of antioxidant GSH, NADH and NADPH. GLS2 may have an important role in radioresistance in cervical cancer patients.


Magnitudes and mutual orientations of dipolar and shielding interaction tensors determined from the orientation dependence of spinning sidebands of slowly rotating powder samples.
It is shown that the orientation dependence of spinning sidebands of slowly rotating solids can be exploited to determine with good precision the heteronuclear bond distances and mutual orientation of dipolar and shielding tensors from a single dipolar modulated chemical shift anisotropy spectrum. The method is based on the dynamics of polarization transfer in the initial period of tens of microseconds, and may be useful in solids with relatively isolated groups of spins.