Polymer-assisted intratumoral delivery of ethanol: Preclinical investigation of safety and efficacy in a murine breast cancer model.
Focal tumor ablation with ethanol could provide benefits in low-resource settings because of its low overall cost, minimal imaging technology requirements, and acceptable clinical outcomes. Unfortunately, ethanol ablation is not commonly utilized because of a lack of predictability of the ablation zone, caused by inefficient retention of ethanol at the injection site. To create a predictable zone of ablation, we have developed a polymer-assisted ablation method using ethyl cellulose (EC) mixed with ethanol. EC is ethanol-soluble and water-insoluble, allowing for EC-ethanol to be injected as a liquid and precipitate into a solid, occluding the leakage of ethanol upon contact with tissue. The aims of this study were to compare the 1) safety, 2) release kinetics, 3) spatial distribution, 4) necrotic volume, and 5) overall survival of EC-ethanol to conventional ethanol ablation in a murine breast tumor model. Non-target tissue damage was monitored through localized adverse events recording, ethanol release kinetics with Raman spectroscopy, injectate distribution with in vivo imaging, target-tissue necrosis with NADH-diaphorase staining, and overall survival by proxy of tumor growth. EC-ethanol exhibited decreased localized adverse events, a slowing of the release rate of ethanol, more compact injection zones, 5-fold increase in target-tissue necrosis, and longer overall survival rates compared to the same volume of pure ethanol. A single 150 μL dose of 6% EC-ethanol achieved a similar survival probability rates to six daily 50 μL doses of pure ethanol used to simulate a slow-release of ethanol over 6 days. Taken together, these results demonstrate that EC-ethanol is safer and more effective than ethanol alone for ablating tumors.


Amylin as a Future Obesity Treatment.
Obesity is defined as abnormal or excessive fat accumulation that contributes to detrimental health impacts. One-third of the population suffers from obesity, and it is important to consider obesity as a chronic disease requiring chronic treatment. Amylin is co-secreted with insulin from β pancreatic cells upon nutrient delivery to the small intestine as a satiety signal, acts upon sub-cortical homeostatic and hedonic brain regions, slows gastric emptying, and suppresses post-prandial glucagon responses to meals. Therefore, new pharmacological amylin analogues can be used as potential anti-obesity medications in individuals who are overweight or obese. In this narrative review, we analyse the efficacy, potency, and safety of amylin analogues. The synthetic amylin analogue pramlintide is an approved treatment for diabetes mellitus which promotes better glycaemic control and small but significant weight loss. AM833 (cagrilintide), an investigational novel long-acting acylated amylin analogue, acts as a non-selective amylin receptor. This calcitonin G protein-coupled receptor agonist can serve as an attractive novel treatment for obesity, resulting in reduction of food intake and significant weight loss in a dose-dependent manner.


Whole-proteome phylogeny of large dsDNA viruses and parvoviruses through a composition vector method related to dynamical language model.
The vast sequence divergence among different virus groups has presented a great challenge to alignment-based analysis of virus phylogeny. Due to the problems caused by the uncertainty in alignment, existing tools for phylogenetic analysis based on multiple alignment could not be directly applied to the whole-genome comparison and phylogenomic studies of viruses. There has been a growing interest in alignment-free methods for phylogenetic analysis using complete genome data. Among the alignment-free methods, a dynamical language (DL) method proposed by our group has successfully been applied to the phylogenetic analysis of bacteria and chloroplast genomes. In this paper, the DL method is used to analyze the whole-proteome phylogeny of 124 large dsDNA viruses and 30 parvoviruses, two data sets with large difference in genome size. The trees from our analyses are in good agreement to the latest classification of large dsDNA viruses and parvoviruses by the International Committee on Taxonomy of Viruses (ICTV). The present method provides a new way for recovering the phylogeny of large dsDNA viruses and parvoviruses, and also some insights on the affiliation of a number of unclassified viruses. In comparison, some alignment-free methods such as the CV Tree method can be used for recovering the phylogeny of large dsDNA viruses, but they are not suitable for resolving the phylogeny of parvoviruses with a much smaller genome size.


White blood cell count to mean platelet volume ratio as a novel non-invasive marker predicting long-term outcomes in patients with non-ST elevation acute coronary syndrome.
Total white blood cell (WBC) count and mean platelet volume have previously been shown to predict outcomes in acute coronary syndrome (ACS) patients. In this prospective study, we sought to determine the prognostic value of baseline WBC count to mean platelet volume ratio (WMR) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS). A total of 490 patients with NSTE-ACS were prospectively enrolled. The relationship between baseline WMR and major adverse cardiovascular events (MACE) incidence was assessed during a mean follow-up of 330.8 ± 38 days. The patients' mean age was 60.4 ± 12.9 year, 59% of them were male. The patients were categorized into two groups based on WMR values, high- and low-WMR groups (< 755 vs. ≥ 755). The incidence of MACE was significantly higher in high-WMR compared with that of low-WMR group (22.4% vs. 10.7%, p < 0.001). Total WBC counts (median 7.9 vs. 6.9 ×103/μL, p = 0.004), neutrophil count (median 4.6 vs. 4.2 ×103/μL, p = 0.021), and WMR (median 863.2 vs. 731.5, p = 0.001) were significantly higher in the MACE-positive than MACE-negative group. The high-WMR was found to be significantly associated with the MACE-free survival rate (p < 0.001). In an adjusted cox regression model, the elevated WMR was independently predicted the incidence of MACE (hazard ratio 2.419, 95% CI 1.515-3.862, p < 0.001). The elevated baseline WMR independently predicted the MACE incidence in patients with NSTE-ACS during long-term follow-up.


The microbial ecology of a Mediterranean chlorinated drinking water distribution systems in the city of Valencia (Spain).
Drinking water distribution systems host extensive microbiomes with diverse biofilm communities regardless of treatment, disinfection, or operational practices. In Mediterranean countries higher temperatures can accelerate reactions and microbial growth that may increase aesthetic water quality issues, particularly where material deposits can develop as a result of net zero flows within looped urban networks. This study investigated the use of flow and turbidity monitoring to hydraulically manage mobilisation of pipe wall biofilms and associated material from the Mediterranean city of Valencia (Spain). Pipe sections of different properties were subjected to controlled incremental flushing with monitoring and sample collection for physico-chemical and DNA analysis with Illumina sequencing of bacterial and fungal communities. A core microbial community was detected throughout the network with microorganisms like Pseudomonas, Aspergillus or Alternaria increasing during flushing, indicating greater abundance in underlying and more consolidated material layers. Bacterial and fungal communities were found to be highly correlated, with bacteria more diverse and dynamic during flushing whilst fungi were more dominant and less variable between sampling sites. Results highlight that water quality management can be achieved through hydraulic strategies yet understanding community dynamics, including the fungal component, will be key to maintaining safe and ultimately beneficial microbiomes in drinking water distribution systems.


A fully automated system for adherent cells microinjection.
This paper proposes an automated robotic system to perform cell microinjections to relieve human operators from this highly difficult and tedious manual procedure. The system, which uses commercial equipment currently found on most biomanipulation laboratories, consists of a multitask software framework combining computer vision and robotic control elements. The vision part features an injection pipette tracker and an automatic cell targeting system that is responsible for defining injection points within the contours of adherent cells in culture. The main challenge is the use of bright-field microscopy only, without the need for chemical markers normally employed to highlight the cells. Here, cells are identified and segmented using a threshold-based image processing technique working on defocused images. Fast and precise microinjection pipette positioning over the automatically defined targets is performed by a two-stage robotic system which achieves an average injection rate of 7.6 cells/min with a pipette positioning precision of 0.23 μm. The consistency of these microinjections and the performance of the visual targeting framework were experimentally evaluated using two cell lines (CHO-K1 and HEK) and over 500 cells. In these trials, the cells were automatically targeted and injected with a fluorescent marker, resulting in a correct cell detection rate of 87% and a successful marker delivery rate of 67.5%. These results demonstrate that the new system is capable of better performances than expert operators, highlighting its benefits and potential for large-scale application.


Partitioning of fluorotelomer alcohols to octanol and different sources of dissolved organic carbon.
Interest in the environmental fate of fluorotelomer alcohols (FTOHs) has spurred efforts to understand their equilibrium partitioning behavior. Experimentally determined partition coefficients for FTOHs between soil/water and air/water have been reported, but direct measurements of partition coefficients for dissolved organic carbon (DOC)/water (K(doc)) and octanol/ water(K(ow)) have been lacking. Here we measured the partitioning of 8:2 and 6:2 FTOH between one or more types of DOC and water using enhanced solubility or dialysis bag techniques, and also quantified K(ow) values for 4:2 to 8:2 FTOH using a batch equilibration method. The range in measured log K(doc) values for 8:2 FTOH using the enhanced solubility technique with DOC derived from two soils, two biosolids, and three reference humic acids is 2.00-3.97 with the lowest values obtained for the biosolids and an average across all other DOC sources (biosolid DOC excluded) of 3.54 +/- 0.29. For 6:2 FTOH and Aldrich humic acid, a log K(doc) value of 1.96 +/- 0.45 was measured using the dialysis technique. These average values are approximately 1 to 2 log units lower than previously indirectly estimated K(doc) values. Overall, the affinity for DOC tends to be slightly lower than that for particulate soil organic carbon. Measured log K(ow) values for 4:2 (3.30 +/- 0.04), 6:2 (4.54 +/- 0.01), and 8:2 FTOH (5.58 +/- 0.06) were in good agreement with previously reported estimates. Using relationships between experimentally measured partition coefficients and C-atom chain length, we estimated K(doc) and K(ow) values for shorter and longer chain FTOHs, respectively, that we were unable to measure experimentally.


Mapping the structure of perceptual and visual-motor abilities in healthy young adults.
The ability to quickly detect and respond to visual stimuli in the environment is critical to many human activities. While such perceptual and visual-motor skills are important in a myriad of contexts, considerable variability exists between individuals in these abilities. To better understand the sources of this variability, we assessed perceptual and visual-motor skills in a large sample of 230 healthy individuals via the Nike SPARQ Sensory Station, and compared variability in their behavioral performance to demographic, state, sleep and consumption characteristics. Dimension reduction and regression analyses indicated three underlying factors: Visual-Motor Control, Visual Sensitivity, and Eye Quickness, which accounted for roughly half of the overall population variance in performance on this battery. Inter-individual variability in Visual-Motor Control was correlated with gender and circadian patters such that performance on this factor was better for males and for those who had been awake for a longer period of time before assessment. The current findings indicate that abilities involving coordinated hand movements in response to stimuli are subject to greater individual variability, while visual sensitivity and occulomotor control are largely stable across individuals.


Native conformations of human complement components C3 and C4 show different dependencies on thioester formation.
The thioester bond in complement components C3 and C4 and the protease inhibitor alpha2-macroglobulin have traditionally been thought of as fulfilling the dual roles of mediating covalent attachment and maintaining the native conformational states of these molecules. We previously reported that several human C3 thioester-region mutants, including variants E1012Q and C1010A, in the latter of which thioester-bond formation is precluded, display an unexpected phenotype. Despite the lack of a thioester bond in these mutants, they appear to adopt a native-like conformation as suggested by the finding that they are cleavable by the classical pathway C3 convertase, C4b2a, whereas the C3b-like C3(H2O) species is not. Subsequently, a species referred to as C3(NH3)* was described which potentially could account for the observations with the above mutants. C3(NH3)* is a transient species formed on aminolysis of native C3 that can spontaneously re-form the thioester bond. Importantly, it has a mobility on cation-exchange HPLC that is distinct from both native C3 and C3(H2O), but like the native molecule, it is cleavable by an alternative-pathway C3 convertase. In this study we showed by using cation-exchange HPLC as an additional conformational probe that C3 C1010A and E1012Q mutant proteins did not resemble C3(NH3)*. Instead they displayed a chromatographic behaviour that was indistinguishable from that of native C3. To assess the general applicability of these observations, we engineered the equivalent mutations into human C4, specifically C4 C1010A and C4 E1012Q. As expected, thioester-bond formation did not occur in either of these C4 mutants, but in contrast with the results with C3 we found no evidence for the formation of a stable native-like conformation in either C4 mutant, as assessed using cleavability by C1s as the conformational probe. A possible interpretation of our data is that the adoption of the native conformational state during biosynthesis of C3 and C4 is an energetically permissible process, even if it is not locked in via thioester-bond formation. Whereas this conformational state is stable in mature C3, it is unstable in mature C4, perhaps reflecting the additional post-translational cleavage of C4 before its secretion.


FOXQ1 regulates senescence-associated inflammation via activation of SIRT1 expression.
Cellular senescence is an initial barrier to tumor development that prevents the proliferation of premalignant cells. However, some of the features of senescent cells seem to promote tumor progression via senescence-associated secretory phenotype (SASP). Here, we demonstrated that the protein level of forkhead box Q1 (FOXQ1), which highly overexpresses in several kinds of tumors, was significantly downregulated during both replicative and oncogene-induced senescence. Moreover, overexpression of FOXQ1 delayed senescence, whereas FOXQ1 silence led to premature senescence in human fibroblasts. Furthermore, we identified that FOXQ1 upregulated SIRT1 expression through transcriptional regulation via directly binding to the SIRT1 promoter. Finally, we showed that FOXQ1 remarkably inhibited the replicative senescence through depressing the expression of the inflammatory cytokines interleukin-6 (IL-6) and IL-8 via modulation of SIRT1-NF-κB pathway. In addition, FOXQ1 overexpressed in human esophageal cancer cells and ablation of FOXQ1 restrained the tumourigenic ability of the esophageal cancer cells (EC109 and EC9706) in a mouse xenograft model in vivo. Taken together, these findings uncover a previously unidentified role of FOXQ1 regulating SASP and tumor development at same time.


Using Gaussian process for velocity reconstruction after coronary stenosis applicable in positron emission particle tracking: An in-silico study.
Accurate velocity reconstruction is essential for assessing coronary artery disease. We propose a Gaussian process method to reconstruct the velocity profile using the sparse data of the positron emission particle tracking (PEPT) in a biological environment, which allows the measurement of tracer particle velocity to infer fluid velocity fields. We investigated the influence of tracer particle quantity and detection time interval on flow reconstruction accuracy. Three models were used to represent different levels of stenosis and anatomical complexity: a narrowed straight tube, an idealized coronary bifurcation with stenosis, and patient-specific coronary arteries with a stenotic left circumflex artery. Computational fluid dynamics (CFD), particle tracking, and the Gaussian process of kriging were employed to simulate and reconstruct the pulsatile flow field. The study examined the error and uncertainty in velocity profile reconstruction after stenosis by comparing particle-derived flow velocity with the CFD solution. Using 600 particles (15 batches of 40 particles) released in the main coronary artery, the time-averaged error in velocity reconstruction ranged from 13.4% (no occlusion) to 161% (70% occlusion) in patient-specific anatomy. The error in maximum cross-sectional velocity at peak flow was consistently below 10% in all cases. PEPT and kriging tended to overestimate area-averaged velocity in higher occlusion cases but accurately predicted maximum cross-sectional velocity, particularly at peak flow. Kriging was shown to be useful to estimate the maximum velocity after the stenosis in the absence of negative near-wall velocity.


Mapping multiple genetic loci associated with Ceratomyxa shasta resistance in Oncorhynchus mykiss.
Ceratomyxa shasta is enzootic to some rivers of the Pacific Northwest and California, and has caused extensive mortalities of salmonids, the only known host of the actinosporean stage of the pathogen. Mortalities from C. shasta are induced by severe inflammation and necrosis of the intestinal tract, and no therapeutants have been discovered for the treatment of ceratomyxosis. Inheritance studies by previous investigators suggested that C. shasta resistance is genetically controlled, but none have revealed the number and locations of gene regions associated with resistance. Here, we characterized differences in resistance among clonal lines, and used line crosses between clonal lines with resistance differences for a genetic analysis of C. shasta resistance in Oncorhynchus mykiss, following a short term in situ exposure to the pathogen. We found that Oregon State University (OSU) x Arlee (ARL) clonal hybrids were highly susceptible, while OSU x Clearwater (CW) hybrids were highly resistant to C. shasta. Doubled haploids, produced by androgenesis from an F1 hybrid between the OSU and CW lines, were evaluated for the co-segregation of molecular markers and resistance phenotype. Amplified fragment length polymorphic (AFLP) markers, used to construct a genetic linkage map in this cross, were tested for associations with resistance expressed as absolute survival (binary trait) and days to death (survival analysis). Segregation of the resistance phenotype suggested that the resistance was inherited as a single Mendelian locus, but the binary trait failed to map to a single genomic location. Markers identified in single-marker analyses were used in multiple-regression model selection, within both the linear regression and Cox proportional-hazards survival analysis frameworks, to determine the number and potential location of loci simultaneously contributing to variation in the survival phenotypes of doubled-haploid progeny. We found multiple genomic loci associated with C. shasta resistance through these models, confirming studies by previous investigators that suggested C. shasta resistance is polygenic.


[Andrological status of adolescents and its connection to anthropometric and hormonal descriptions in the students of technical college group].
The purpose of this investigation was to study the interrelation of andrological status with anthropometric and hormonal descriptions for age-specific features discovery of male sexual system pathological states at technical college students. 147 adolescents aged 15-17 years old were examined. Only 41 of them were found to have no abnormalities in their genital system development; in 35 adolescents sexual development was delayed; and 97 adolescents were found to have various andrological diseases (varicocele, phimosis, gynecomastia, testicular asymmetry, etc.) or clinical signs for development of these diseases. In 26 adolescences delayed sexual development was combined with the andrological pathology. The normal andrological status was usually accompanied with the highest frequency of low values of anthropometric indicators and indices that reflect the influence of various hormonal systems on the bodily constitution, as well as expressed anthropometricheterogeneity. In adolescents with andrological pathology or clinical signs for its development, in all anthropometric parameters the higher values were seen more frequently than low values against the background of highest group anthropometric homogeneity. Summative anthropometric characteristics of the adolescents group with delayed sexual development were between those of the adolescents groups with normal andrological status and andrological pathology The number of correlational relationships of anthropometric and hormonal indicators with the levels of cortisol and dehydroepiandrosteronesulphate was the lowest in the group of adolescents with normal andrological status as compared to their peers with delayed sexual development and andrological pathology. Only in the group of adolescents with normal andrological status the correlation analysis of data showed physiological influence of sexual hormones on anthropometric indicators. Thus, lower influence of sexual system hormones during this ontogenesis stage contributes to slowing down the process of sexual maturation both with the development of andrological pathology in adolescents.


Genetic diversity and population structure of Chinese pony breeds using microsatellite markers.
China is one of the principal origins of ponies in the world. We made a comprehensive analysis of genetic diversity and population structure of Chinese ponies based on 174 animals of five indigenous Chinese pony breeds from five provinces using 13 microsatellite markers. One hundred and forty-four alleles were detected; the mean number of effective alleles among the pony breeds ranged from 5.38 (Guizhou) to 6.78 (Sichuan); the expected heterozygosity ranged from 0.82 (Guizhou) to 0.85 (Debao, Sichuan). Although abundant genetic variation was found, the genetic differentiation was low between the ponies, with 6% total genetic variance among the different breeds. All the pairwise F(ST) values were significant; they varied from 0.0424 for the Sichuan-Yunnan pair to 0.0833 for the Guizhou-Sichuan pair. All five pony breeds deviated from Hardy-Weinberg equilibrium, except the Yunnan pony. Phylogenetic trees of the five pony breeds based on genetic distances were constructed using a neighbor-joining method. The Sichuan and Yunnan ponies were grouped into the same branch, with a high bootstrap support value (97%). Guizhou and Ningqiang ponies were clustered into the same branch with a bootstrap value of 56%, whereas the Debao pony was placed in a separate group, with a bootstrap value of 56%. This grouping pattern was supported by genetic structure analysis.


Identification of An mtDNA Setpoint Associated with Highest Levels of CD44 Positivity and Chemoresistance in HGC-27 and MKN-45 Gastric Cancer Cell Lines.
Cancer stem cells (CSCs) have important roles in survival and chemoresistance. These cells are commonly recognized with CD44 and CD24 markers. In this study, we aimed to analyze the effects of mtDNA content on cell surface positivity for anti-CD24 and anti-CD44 antibodies and chemoresistance level in AGS, HGC-27 and MKN-45 gastric cancer (GC) cell lines and to determine a setpoint for mtDNA copy for each cell line. In this experimental study, we initially decreased mtDNA levels in AGS, HGC-27 and MKN-45 by EtBr treatment. This depletion was confirmed with quantitative polymerase chain reaction (qPCR). Changes in cell surface positivity for anti-CD24 and anti-CD44 antibodies in control and mtDNA-depleted AGS, HGC-27 and MKN-45 were then analyzed with flow cytometry. Changes in chemoresistance (5-FU and cisplatin) were analyzed for all cell lines. The relationship between mtDNA content and cell surface positivity for CD24 and CD44 markers was examined. The highest CD44 positivity was found in HGC-27 and MKN-45 ρlow cells which had 33-40% mtDNA content of control cells, however, CD24 positivity decreased with mtDNA depletion in all cell lines. The highest chemoresistance levels were found in all ρlow cells. mtDNA-recovered (i.e. reverted) HGC-27 and MKN-45 cells partially maintained their increased chemoresistance while reverted AGS cells did not maintain an increased level of chemoresistance. mtDNA depletion triggers chemoresistance in cancer cell lines and is correlated with increase and decrease of CD44 and CD24 positivity respectively in HGC-27 and MKN-45 GC cell lines. A mtDNA content above or below the identified setpoint (33-40% of that in control cells), results in the decrease of CD44 positivity and chemoresistance levels.


[Diagnosis and treatment of recurrent coughing and wheezing in children younger than 4 years old].
Recurrent coughing and wheezing occur in 10-20% of children younger than 4 years. Forty per cent of these children develop allergic asthma, while in 60% the symptoms are transient. It is difficult to distinguish between persistent and transient symptoms; signs of allergy and lack of symptom-free intervals are suggestive of persistent asthma. In acute wheezing and coughing a trial treatment with beta-2 sympathicomimetic agents is indicated, preferably using an inhalation aerosol with feed container; for cases with pronounced symptoms or strong suspicion of allergic asthma, high-dose oral corticosteroid treatment is recommended. Maintenance treatment with inhalation corticosteroids is valuable in moderately severe complaints of allergic asthma and in severe complaints about recurrent wheezing.


Effective cerebrovascular thrombectomy requires well-organized structures : Real world experiences of a regional stroke network between 2012-2015.
The objective of this study was to analyse the Neurothrombectomy Network registry of the Neuromed Campus (NMC) of the Kepler University Hospital in Linz (Austria). The data were compared to the results of recently published thrombectomy trials (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME, REVASCAT and THRACE). We retrospectively studied 246 patients with acute ischemic stroke who underwent thrombectomy between January 2012 and December 2015 at the NMC in Upper Austria. The main outcome measures were modified Rankin scale (mRS) score 0-2 at 90 days, all-cause mortality and stroke or thrombectomy-related mortality at discharge, as well as 90 days postdischarge. The median age was 70.4 years (IQR 59.9-76.9) and the median NIHSS at admission 16 (IQR 13-20). The thrombolysis in cerebral infarction (TICI) scale 2b-3 recanalization was achieved in 87.4%, 11.0% of the patients died in hospital and an additional 6.1% within 90 days after discharge. After 90 days, 56.5% had a mRS score 0-2. These data suggest that the positive results of thrombectomy reported in several randomized controlled studies can be achieved in routine clinical practice; therefore, the setting of an organized, regional stroke network proved an effective and appropriate method for delivering regional thrombectomy stroke treatment.


Blocking tumor escape in hematologic malignancies: the anti-PD-1 strategy.
Immunotherapy remains an important tool for treatment of hematologic malignancies. The Programmed Death-1 (PD-1) immune checkpoint pathway has emerged as a mechanism of tumor evasion from the anti-tumor immune response. The recent development of anti-PD-1 monoclonal antibodies has offered a targeted approach to cancer therapy. Several agents are in various stages of development and have shown clinical responses across a broad spectrum of both solid and hematologic malignancies. The use of anti-PD-1 therapy in hematologic malignancies is limited but has demonstrated clinical responses in relapsed/refractory disease following multiple lines of therapy. PD-1 blockade may reduce relapse rates for patients who fail to obtain a complete remission prior to autologous hematopoietic cell transplant. The role of the PD-1 pathway for tumor escape is reviewed. We explore the use of anti-PD-1 therapy in hematologic malignancies. The proposed mechanism of PD-1 blockade as a modulator of the innate and acquired immune response is considered. Finally, the challenges of anti-PD-1 therapy and the future direction of investigation in this area are reviewed.


Constancy of Preparatory Postural Adjustments for Reaching to Virtual Targets across Different Postural Configurations.
Postural and movement components must be coordinated without significant disturbance to balance when reaching from a standing position. Traditional theories propose that muscle activity prior to movement onset create the mechanics to counteract the internal torques generated by the future limb movement, reducing possible instability via centre of mass (CoM) displacement. However, during goal-directed reach movements executed on a fixed base of support (BoS), preparatory postural adjustments (or pPAs) promote movement of the CoM within the BoS. Considering this dichotomy, the current study investigated if pPAs constitute part of a whole-body strategy that is tied to the efficient execution of movement, rather than the constraints of balance. We reasoned that if pPAs were tied primarily to balance control, they would modulate as a function of perceived instability. Alternatively, if tied to dynamics necessary for movement initiation, they would remain unchanged, with feedback-based changes being sufficient to retain balance following volitional arm movement. Participants executed beyond-arm reaching movements in four different postural configurations that altered the quality of the BoS. Quantification of these changes to stability did not drastically alter the tuning or timing of preparatory muscle activity despite modifications to arm and CoM trajectories necessary to complete the reaching movement. In contrast to traditional views, preparatory postural muscle activity is not always tuned for balance maintenance or even as a calculation of upcoming instability but may reflect a requirement of voluntary movement towards a pre-defined location.


Promotion of liver cancer development by brief exposure to dietary 2-acetylaminofluorene plus partial hepatectomy or carbon tetrachloride.
Adult male Fischer rats were exposed to a necrogenic dose (200 mg/kg) of diethylnitrosamine or to nonnecrogenic doses of N-methyl-N-nitrosourea, 1,2-dimethylhydrazine, or benzo(a)pyrene following partial hepatectomy or sham hepatectomy. This treatment by itself led to no hepatocellular carcinomas by 8 to 18 months, except in animals given N-methyl-N-nitrosourea, which showed a 30% incidence by 12 months. With each treatment regimen, exposure to dietary 2-acetylaminofluorene for 2 weeks coupled with partial hepatectomy or the administration of a necrogenic dose of CCl4, was associated with an incidence of 68 to 94% of cancer at 8, 12, or 18 months, depending upon the initiating carcinogen used. Appropriate controls showed either no hepatocellular carcinoma or a much lower incidence. It is concluded that the 2-week exposure to dietary 2-acetylaminofluorene plus partial hepatectomy or the administration of CCl4 has a strong promoting effect on liver carcinogenesis with four different chemical carcinogens.


The lamin B receptor of Drosophila melanogaster.
The lamin B receptor (LBR) is an integral membrane protein of the inner nuclear membrane that has so far been characterized only in vertebrates. Here, we describe the Drosophila melanogaster protein encoded by the annotated gene CG17952 that is the putative ortholog to the vertebrate LBR. The Drosophila lamin B receptor (dLBR) has the following properties in common with the vertebrate LBR. First, structure predictions indicate that the 741 amino acid dLBR protein possesses a highly charged N-terminal domain of 307 amino acids followed by eight transmembrane segments in the C-terminal domain of the molecule. Second, immunolocalization and cell fractionation reveal that the dLBR is an integral membrane protein of the inner nuclear membrane. Third, dLBR can be shown by co-immunoprecipitations and in vitro binding assays to bind to the Drosophila B-type lamin Dm0. Fourth, the N-terminal domain of dLBR is sufficient for in vitro binding to sperm chromatin and lamin Dm0. In contrast to the human LBR, dLBR does not possess sterol C14 reductase activity when it is expressed in the Saccharomyces cerevisiae erg24 mutant, which lacks sterol C14 reductase activity. Our data raise the possibility that, during evolution, the enzymatic activity of this insect protein had been lost. To determine whether the dLBR is an essential protein, we depleted it by RNA interference in Drosophila embryos and in cultured S2 and Kc167 cells. There is no obvious effect on the nuclear architecture or viability of treated cells and embryos, whereas the depletion of Drosophila lamin Dm0 in cultured cells and embryos caused morphological alterations of nuclei, nuclear fragility and the arrest of embryonic development. We conclude that dLBR is not a limiting component of the nuclear architecture in Drosophila cells during the first 2 days of development.


Interpreting spatial language in image captions.
The map as a tool for accessing data has become very popular in recent years, but a lot of data do not have the necessary spatial meta-data to allow for that. Some data such as photographs however have spatial information in their captions and if this could be extracted, then they could be made available via map-based interfaces. Towards this goal, we introduce a model and spatio-linguistic reasoner for interpreting the spatial information in image captions that is based upon quantitative data about spatial language use acquired directly from people. Spatial language is inherently vague, and both the model and reasoner have been designed to incorporate this vagueness at the quantitative level and not only qualitatively.


Automated electron tomography of large nuclear RNP (InRNP) particles--the naturally assembled complexes of precursor messenger RNA and splicing factors.
Splicing of nuclear pre-mRNA is an important step in the regulation of gene expression as only correctly spliced mRNAs will be exported to the cytoplasm to function in protein synthesis. Nuclear RNA transcripts of split genes and their splicing products, as well as the general population of nuclear polyadenylated RNA, are packaged in multicomponent large nuclear ribonucleoprotein (lnRNP) particles. These lnRNP particles, which sediment at the 200S region in sucrose gradients, contain all U snRNPs required for pre-mRNA splicing and several protein splicing factors, including U2AF and the SR proteins and can thus be viewed as naturally assembled complexes of pre-mRNA and splicing factors. We have previously reconstructed the three-dimensional image of negatively stained individual lnRNP particles by automated electron tomography. The reconstruction revealed a compact structure, 50 nm in diameter, composed of four major subunits. Here we further analyzed the reconstructed models and the apparent connectivity between the subunits using a new rendering technique. The uniformity of the lnRNP particles was substantiated by measurement of the volume engulfed by their surface. This study further supports the model proposed for the packaging of nuclear pre-mRNAs in lnRNP particles, where each substructure represents a functional unit. This model is compatible with the requirements for alternative splicing in multiintronic pre-mRNAs, and with the fact that the splicing of multiintronic pre-mRNAs does not occur in a sequential manner.


Constitutive nitric oxide synthase expression in retinal vascular endothelial cells is suppressed by high glucose and advanced glycation end products.
It has been suggested that increased production of nitric oxide (NO), a potent endothelium-derived vasodilator, may be responsible for increased blood flow in the retinal and renal vascular beds in early diabetes. However, NO-mediated vasodilation has been reported as impaired in diabetes, and there is evidence that the synthesis and release of NO by the vascular endothelium may be flawed in this condition. We examined the effect of high ambient glucose and exposure to exogenous glycated proteins on NO synthesis in cultured retinal microvascular endothelial cells (RMECs), using a polarographic sensor to measure released NO gas. Nitrite (the stable end product of the reaction between NO and molecular oxygen) was measured in tissue culture supernatants. The expression of vascular endothelial constitutive nitric oxide synthase (eNOS), which is responsible for NO synthesis in endothelial cells, was studied by Western blot analysis and Northern hybridization experiments. A dose-dependent reduction of NO synthesis by RMECs occurred 5 days after exposure to 15 and 25 mmol/l glucose, and concomitantly we found that accumulation of nitrite in culture supernatants of high-glucose exposed cells was also reduced. Coincubation of endothelial cells with inhibitors of protein kinase C (PKC) increased the accumulation of nitrite but did not restore it to the levels obtained when cells were cultured in 5 mmol/l glucose. The expression of eNOS by RMECs was markedly reduced by 5 days of exposure to 25 mmol/l glucose and glycated albumin. This study implicates the PKC pathway, which is known to be upregulated on exposure to high ambient glucose concentrations, as a possible factor in the inhibition of eNOS expression in RMECs. This study also suggests that glycated proteins may be involved in the pathogenesis of vascular endothelial dysfunction by modulating the nitric oxide synthase (NOS)/NO pathway in retinal vascular endothelial cells.


3DFaceShop: Explicitly Controllable 3D-Aware Portrait Generation.
In contrast to the traditional avatar creation pipeline which is a costly process, contemporary generative approaches directly learn the data distribution from photographs. While plenty of works extend unconditional generative models and achieve some levels of controllability, it is still challenging to ensure multi-view consistency, especially in large poses. In this work, we propose a network that generates 3D-aware portraits while being controllable according to semantic parameters regarding pose, identity, expression and illumination. Our network uses neural scene representation to model 3D-aware portraits, whose generation is guided by a parametric face model that supports explicit control. While the latent disentanglement can be further enhanced by contrasting images with partially different attributes, there still exists noticeable inconsistency in non-face areas when animating expressions. We solve this by proposing a volume blending strategy in which we form a composite output by blending dynamic and static areas, with two parts segmented from the jointly learned semantic field. Our method outperforms prior arts in extensive experiments, producing realistic portraits with vivid expression in natural lighting when viewed from free viewpoints. It also demonstrates generalization ability to real images as well as out-of-domain data, showing great promise in real applications.


[A case of crossed aphasia with echolalia after the resection of tumor in the right medial frontal lobe].
We report a right-handed woman, who developed a non-fluent aphasia after resection of astrocytoma (grade III) in the right medial frontal lobe. On admission to the rehabilitation department, neurological examination revealed mild left hemiparesis, hyperreflexia on the left side and grasp reflex on the left hand. Neuropsychologically she showed general inattention, non-fluent aphasia, acalculia, constructional disability, and mild buccofacial apraxia. No other apraxia, unilateral spatial neglect or extinction phenomena were observed. An MRI demonstrated resected areas in the right superior frontal gyrus, subcortical region in the right middle frontal gyrus, anterior part of the cingulate gyrus, a part of supplementary motor area. Surrounding area in the right frontal lobe showed diffuse signal change. She demonstrated non-fluent aprosodic speech with word finding difficulty. No phonemic paraphasia, or anarthria was observed. Auditory comprehension was fair with some difficulty in comprehending complex commands. Naming was good, but verbal fluency tests for a category or phonemic cuing was severely impaired. She could repeat words but not sentences. Reading comprehension was disturbed by semantic paralexia and writing words was poor for both Kana (syllabogram) and Kanji(logogram) characters. A significant feature of her speech was mitigated echolalia. In both free conversation and examination setting, she often repeated phrases spoken to her which she used to start her speech. In addition, she repeated words spoken to others which were totally irrelevant to her conversation. She was aware of her echoing, which always embarrassed her. She described her echolalic tendency as a great nuisance. However, once echoing being forbidden, she could not initiate her speech and made incorrect responses after long delay. Thus, her compulsive echolalia helped to start her speech. Only four patients with crossed aphasia demonstrated echolalia in the literature. They showed severe aphasia with markedly decreased speech and severe comprehension deficit. A patient with a similar lesion in the right medial frontal lobe had aspontaneity in general and language function per se could not be examined properly. Echolalia related to the medial frontal lesion in the language dominant hemisphere was described as a compulsive speech response, because some other 'echoing' phenomena or compulsive behavior were also observed in these patients. On the other hand, some patients with a large lesion in the right hemisphere tended to respond to stimuli directed to other patients, so called 'response-to-next-patient-stimulation'. This behavior was explained by disinhibited shift of attention or perseveration of the set. Both compulsive speech responses and 'response-to-next-patient-stimulation' like phenomena may have contributed to the echolalia phenomena of the present case.


Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer.
T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this study, we used ascites fluid supernatants (ASC) from patients with ovarian cancer as an authentic component of the TME to evaluate the effects of ASC on neutrophil function and mechanisms for neutrophil-driven immune suppression. ASC prolonged neutrophil life span, decreased neutrophil density, and induced nuclear hypersegmentation. Mass cytometry analysis showed that ASC induced 15 distinct neutrophil clusters. ASC stimulated complement deposition and signaling in neutrophils, resulting in surface mobilization of granule constituents, including NADPH oxidase. NADPH oxidase activation and phosphatidylserine signaling were required for neutrophil suppressor function, although we did not observe a direct role of extracellular reactive oxygen species in inhibiting T-cell proliferation. Postoperative surgical drainage fluid also induced a complement-dependent neutrophil suppressor phenotype, pointing to this effect as a general response to injury. Like circulating lymphocytes, ASC-activated neutrophils caused complement-dependent suppression of tumor-associated lymphocytes. ASC-activated neutrophils adhered to T cells and caused trogocytosis of T-cell membranes. These injury and signaling cues resulted in T-cell immunoparalysis characterized by impaired NFAT translocation, IL2 production, glucose uptake, mitochondrial function, and mTOR activation. Our results demonstrate that complement-dependent priming of neutrophil effector functions in the TME induces a T-cell nonresponsiveness distinct from established checkpoint pathways and identify targets for immunotherapy.See related Spotlight by Cassatella, p. 725.


Effect of Third Interstitial Fluid on Adverse Outcomes in Patients with Severe Pre-eclampsia and Twin Pregnancy: A 5-year Single-center Retrospective Study.
This study aims to identify the effect of third interstitial fluid on adverse outcomes in twin pregnancies with severe pre-eclampsia, and explore the differences in bad ending between twins and singletons. The present retrospective cohort study was conducted on patients with severe pre-eclampsia, who delivered in Tongji Hospital, Wuhan, China, between 2017 and 2022. The adverse outcomes in singleton and twin pregnancies with severe pre-eclampsia were initially investigated. Then, the diverse maternal and fetal consequences between singleton and twin pregnancies in patients with severe pre-eclampsia were compared after merging with the third interstitial fluid. A total of 709 patients were included for the present study. Among these patients, 68 patients had twin pregnancies, and 641 patients had singleton pregnancies. The rate of postpartum hemorrhage (2.81% vs. 13.24%, P<0.001), and admission rate to the Neonatal Intensive Care Unit (NICU) after birth (30.73% vs. 63.24%, P=0.011) were significantly higher in twin pregnancies. The neonatal weight of twins was statistically lower than singletons (1964.73±510.61 g vs. 2142.92±731.25 g, P=0.008). For the groups with the third interstitial fluid, the delivery week (P=0.001) and rate of admission to the NICU after birth were significantly advanced in twin pregnancy group, when compared to singleton pregnancy group (P=0.032), and the length of hospital stay was shorter (P=0.044). Furthermore, there was no statistically significant difference between the twin pregnancy group and the singletony pregnancy group without the third interstitial fluid. The maternal and fetal adverse outcomes of patients with severe pre-eclampsia increased in twin pregnancies, when compared to singleton pregnancies. Thus, when patients develop the third interstitial fluid, twin pregnancies would more likely lead to adverse fetal outcomes, when compared to singleton pregnancies, and there would be no significant difference in maternal adverse outcomes. More attention should be given to patients who merge with the third interstitial fluid.


Another approach to the case study.
Case studies, both actual and simulated, are valuable teaching aids. When cases are presented in a game format, laboratory data correlation becomes an active process for the player. This approach can be used as a learning exercise, to review course content, and to stimulate student interest and further inquiry.


Effectiveness of Zanthoxylum piperitum-derived essential oil as an alternative repellent under laboratory and field applications.
Recently, there were considerable efforts made to promote the use of environmentally friendly and biodegradable natural insecticides and repellents, particularly from botanical sources. In this study, Zanthoxylum piperitum-derived essential oil isolated by steam distillation was investigated and compared to the standard synthetic repellent, N,N-diethyl-3-methylbenzamide (DEET), for repellency against mosquitoes under laboratory and field conditions. The oil of Z. piperitum alone and also with 5% vanillin added repelled laboratory-reared female Aedes aegypti with the median protection times of 1.5 and 2.5 h, respectively. These repellency times were proven to be significantly lower than those of DEET-based products: 25% DEET and 25% DEET + 5% vanillin demonstrating 3.5 and 5.5 h, respectively. However, when applied under field conditions, Z. piperitum oil + 5% vanillin was found to provide better protection against a wide range of natural mosquito populations than 25% DEET + 5% vanillin. While the product of DEET was effective in reducing bites with 99.7% protection, the protective effect of Z. piperitum oil product appeared complete (100%). It had a protective effect against Aedes gardnerii, Anopheles barbirostris, Armigeres subalbatus, Culex tritaeniorhynchus, Culex gelidus, Culex vishnui group, and Mansonia uniformis. The better repellency against a wide range of field mosquitoes derived from Z. piperitum oil products suggested an advantage of efficacy by providing a broad spectrum of activity. Therefore, Z. piperitum could have potential for use in the development of combined repellents as a natural active ingredient, synergist, or additive to conventional synthetic chemicals, particularly in situations when DEET is ineffective and impractical.


Collaborative emergency preparedness and response to cross-institutional outbreaks of multidrug-resistant organisms: a scenario-based approach in two regions of the Netherlands.
The likelihood of large-scale outbreaks of multidrug-resistant organisms (MDRO) is growing. MDRO outbreaks can affect a wide range of healthcare institutions. Control of such outbreaks requires structured collaboration between professionals from all involved healthcare institutions, but guidelines for cross-institutional procedures are, however, often missing. Literature indicates that such multi-actor collaboration is most promising when effective network brokers are present, and when the collaborative actors have clarity about the different roles and responsibilities in the outbreak response network, including collaborative structures and coordination roles. Studying these factors in an imaginary MDRO outbreak scenario, we gained insights into the expectations that health professionals in the Netherlands have in regard to the procedures required to best respond to any future cross-institutional MDRO outbreaks. For exploration purpose, a focus group discussion with ten healthcare professionals was held. Subsequently, an online-survey was conducted among 56 healthcare professionals in two Dutch regions. The survey data was analysed using social network analyses (clique analysis and centrality analysis), which provided insights into the collaborative structures and potential brokers in the outbreak response networks. Additionally, respondents were asked which healthcare institutions and which professions they would prefer as coordinating actors in the collaborative network. Our results show a relatively high level of perceived clarity about the roles and responsibilities that healthcare professionals have during a joint outbreak response. The regional outbreak response networks which were studied appeared inclusive and integrated, with many overlapping groups of fully-connected healthcare actors. Social network analyses resulted in the identification of several central actors from different healthcare institutions with the potential to take on a brokerage role in the collaboration. Actors in the outbreak response networks also showed to prefer several healthcare professionals to take on the coordination roles. Expected collaborative structures during an imaginary regional MDRO outbreak response are relatively dense and integrated. In regard to the coordination of an MDRO outbreak response, based on both the network analysis results and the preferred coordination roles, our findings support a governance structure with several healthcare institutions involved in responding to future cross-institutional MDRO outbreaks.


Competition between global and local online social networks.
The overwhelming success of online social networks, the key actors in the Web 2.0 cosmos, has reshaped human interactions globally. To help understand the fundamental mechanisms which determine the fate of online social networks at the system level, we describe the digital world as a complex ecosystem of interacting networks. In this paper, we study the impact of heterogeneity in network fitnesses on the competition between an international network, such as Facebook, and local services. The higher fitness of international networks is induced by their ability to attract users from all over the world, which can then establish social interactions without the limitations of local networks. In other words, inter-country social ties lead to increased fitness of the international network. To study the competition between an international network and local ones, we construct a 1:1000 scale model of the digital world, consisting of the 80 countries with the most Internet users. Under certain conditions, this leads to the extinction of local networks; whereas under different conditions, local networks can persist and even dominate completely. In particular, our model suggests that, with the parameters that best reproduce the empirical overtake of Facebook, this overtake could have not taken place with a significant probability.


Misperceptions of ovarian cancer risk in women at increased risk for hereditary ovarian cancer.
This study assessed the sociodemographic, medical and psychological predictors of accuracy of perceived risk in women at increased genetic risk for ovarian cancer. Women participating in a large cohort study who were at increased risk of ovarian and fallopian tube cancer, had no personal history of cancer and had ≥1 ovary in situ at cohort enrollment, were eligible. Women completed self-administered questionnaires and attended an interview at enrollment. Of 2,868 women unaffected with cancer at cohort enrollment, 561 were eligible. 335 women (59.8 %) overestimated their ovarian cancer risk, while 215 women (38.4 %) accurately estimated their risk, and 10 (1.8 %) underestimated it. Women who did not know their mutation status were more likely to overestimate their risk (OR 1.74, 95 % CI 1.10, 2.77, p = 0.018), as were those with higher cancer-specific anxiety (OR 1.05, 95 % CI 1.02, 1.08, p < 0.001) and/or a mother who had been diagnosed with ovarian cancer (OR 1.98, 95 % CI 1.23, 3.18, p = 0.005). Amongst the group of women who did not know their mutation status, 63.3 % overestimated their risk and the mean perceived lifetime risk of developing ovarian cancer was 42.1 %, compared to a mean objective risk of 6.4 %. A large number of women at increased risk for ovarian cancer overestimate their risk. This is of concern especially in women who are at moderately increased risk only; for this sub-group of women, interventions are needed to reduce potentially unnecessary psychological distress and minimise engagement in unnecessary surgery or screening.


[The neurophysiological and biochemical mechanisms of the dose-dependent amphetamine modulation of the sensorimotor cortex neurons in developing animals].
The resulting data give evidences, that after injection of the low doses of amphetamine the decrease of amplitudes both negative (NC-3), and positive components (PC-3) of the thalamo-cortical responses (TCR) of the sensorimotor cortex (SMC) takes place in 2nd-3d-weeks-old rabbits of their postnatal life. At the same time the amplitudes of these phases in 45-50-days-old animals change to greatly less extent, without any system, with low level of statistical significance. After injection of medium doses of amphetamine in 2nd-3d-weeks-old rabbits, the increase in amplitudes of both components of TCR SMC in observed, at the same time in definitive animals the amplitudes of these responses decrease greatly. After injection of the high doses of amphetamine in 2nd-3d-weeks-old rabbits the further increase in amplitude PC-3 and NC-3 is displayed, at the same time the growth of amplitude parameters of TCR SMC appears for elder animals under this concentration of amphetamine only. Neurophysiological and neurochemical analyses of these phenomena are developed. Neuro-ontogenesis hypothesis of causes of high vulnerability of the nervous system in young animals and children during critical period of increased risk under the exposure to both psychotropic drugs and endogenous psychopathogenic factors being proposed, that can simplify search for adequate psychopharmacology protector, etc.


Identifying Space Use at Foraging Arena Scale within the Home Ranges of Large Herbivores.
An intermediate spatiotemporal scale of food procurement by large herbivores is evident within annual or seasonal home ranges. It takes the form of settlement periods spanning several days or weeks during which foraging activity is confined to spatially discrete foraging arenas, separated by roaming interludes. Extended by areas occupied for other activities, these foraging arenas contribute towards generating the home range structure. We delineated and compared the foraging arenas exploited by two African large herbivores, sable antelope (a ruminant) and plains zebra (a non-ruminant), using GPS-derived movement data. We developed a novel approach to specifically delineate foraging arenas based on local change points in distance relative to adjoining clusters of locations, and compared its output with modifications of two published methods developed for home range estimation and residence time estimation respectively. We compared how these herbivore species responded to seasonal variation in food resources and how they differed in their spatial patterns of resource utilization. Sable antelope herds tended to concentrate their space use locally, while zebra herds moved more opportunistically over a wider set of foraging arenas. The amalgamated extent of the foraging arenas exploited by sable herds amounted to 12-30 km2, compared with 22-100 km2 for the zebra herds. Half-day displacement distances differed between settlement periods and roaming interludes, and zebra herds generally shifted further over 12h than sable herds. Foraging arenas of sable herds tended to be smaller than those of zebra, and were occupied for period twice as long, and hence exploited more intensively in days spent per unit area than the foraging arenas of zebra. For sable both the intensity of utilization of foraging arenas and proportion of days spent in foraging arenas relative to roaming interludes declined as food resources diminished seasonally, while zebra showed no seasonal variation in these metrics. Identifying patterns of space use at foraging arena scale helps reveal mechanisms generating the home range extent, and in turn the local population density. Thereby it helps forge links between behavioural ecology, movement ecology and population ecology.


Sociality influences thermoregulation and roost switching in a forest bat using ephemeral roosts.
In summer, many temperate bat species use daytime torpor, but breeding females do so less to avoid interferences with reproduction. In forest-roosting bats, deep tree cavities buffer roost microclimate from abrupt temperature oscillations and facilitate thermoregulation. Forest bats also switch roosts frequently, so thermally suitable cavities may be limiting. We tested how barbastelle bats (Barbastella barbastellus), often roosting beneath flaking bark in snags, may thermoregulate successfully despite the unstable microclimate of their preferred cavities. We assessed thermoregulation patterns of bats roosting in trees in a beech forest of central Italy. Although all bats used torpor, females were more often normothermic. Cavities were poorly insulated, but social thermoregulation probably overcomes this problem. A model incorporating the presence of roost mates and group size explained thermoregulation patterns better than others based, respectively, on the location and structural characteristics of tree roosts and cavities, weather, or sex, reproductive or body condition. Homeothermy was recorded for all subjects, including nonreproductive females: This probably ensures availability of a warm roosting environment for nonvolant juveniles. Homeothermy may also represent a lifesaver for bats roosting beneath loose bark, very exposed to predators, because homeothermic bats may react quickly in case of emergency. We also found that barbastelle bats maintain group cohesion when switching roosts: This may accelerate roost occupation at the end of a night, quickly securing a stable microclimate in the newly occupied cavity. Overall, both thermoregulation and roost-switching patterns were satisfactorily explained as adaptations to a structurally and thermally labile roosting environment.


Risk factors for severe Rift Valley fever infection in Kenya, 2007.
A large Rift Valley fever (RVF) outbreak occurred in Kenya from December 2006 to March 2007. We conducted a study to define risk factors associated with infection and severe disease. A total of 861 individuals from 424 households were enrolled. Two hundred and two participants (23%) had serologic evidence of acute RVF infection. Of these, 52 (26%) had severe RVF disease characterized by hemorrhagic manifestations or death. Independent risk factors for acute RVF infection were consuming or handling products from sick animals (odds ratio [OR] = 2.53, 95% confidence interval [CI] = 1.78-3.61, population attributable risk percentage [PAR%] = 19%) and being a herds person (OR 1.77, 95% CI = 1.20-2.63, PAR% = 11%). Touching an aborted animal fetus was associated with severe RVF disease (OR = 3.83, 95% CI = 1.68-9.07, PAR% = 14%). Consuming or handling products from sick animals was associated with death (OR = 3.67, 95% CI = 1.07-12.64, PAR% = 47%). Exposures related to animal contact were associated with acute RVF infection, whereas exposures to mosquitoes were not independent risk factors.


Synovial chondromatosis of the temporomandibular joint: radiologic and histopathologic findings.
Synovial chondromatosis is a formation of multiple intrasynovial nodules resembling osteochondromas, resulting from proliferative changes in the synovial linings of joints; as the disorder progresses, nodules increasingly withdraw from the intrasynovial areas for the joint cavities. This is a relatively unusual case that can arise at unilateral large joints, such as knee, hip, and elbow, with the temporomandibular joint being the rarest one of them. Early recognition of the signs and symptoms with resultant accurate diagnosis, as well as proper surgical treatment, offers patients the best hope of recovery and improved quality of life. We report a conventional radiologic film, computed tomography, magnetic resonance imaging, and histopathologic findings of the synovial chondromatosis presenting as a large right preauricular mass arising from the temporomandibular joint without bone destruction.


Minor physical anomalies in adults with autism spectrum disorder and healthy controls.
Minor Physical Anomalies (MPAs) are subtle abnormalities of the head, face, and limbs, without significant cosmetic or functional impact to the individual. They are assumed to represent external markers of developmental deviations during foetal life. MPAs have been suggested to indicate severity in mental illness and constitute external markers for atypical brain development. Higher frequencies of MPAs can be found in children with autism. The aims of the present study were to examine the prevalence and patterns of MPAs in adults with autism spectrum disorder (ASD) and to investigate whether MPAs are associated with symptom severity and overall functioning. Fifty adults with ASD and intelligence within the normal range and 53 healthy controls were examined with the Waldrop scale, an instrument for assessing MPAs. Face and feet were photographed enabling blinded assessment. Significant differences between the ASD and the control group were found on the MPA total scores, and also in the craniofacial region scores. Moreover, the shape of the ears was associated with autistic traits, in the ASD group. High MPA total scores were associated with poorer functioning. The findings suggest a link between MPAs, autistic traits, and level of functioning. Assessment of MPAs may assist in the diagnostic procedure of psychiatric disorders.


Atypical hemolytic uremic syndrome recurrence after kidney transplantation.
Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a high recurrence rate after kidney transplantation. In most cases, aHUS are caused by genetic mutations of components of the complement alternative pathway. In this single-center series, we present our data of 12 consecutive patients with aHUS and the outcome after kidney transplantation. In this 10-year retrospective study, we identified 12 patients with aHUS who were managed in our center since 2003. We reviewed clinical data, including genetic testing, posttransplant course and response to therapy including the prophylactic use of eculizumab. Overall, eight patients are women. Six of our patients have at least one genetic mutation causing aHUS, including 4 with complement factor H mutations. Nine patients had at least one previous kidney transplant that failed secondary to recurrent aHUS (75% of our patients). Three patients were treated with eculizumab and plasmapheresis for recurrent aHUS after kidney transplantation; two of them responded to the therapy. Four patients received prophylactic eculizumab; three of them received 6 months and one has been on life long therapy. No signs of recurrence have been observed in these 4 patients so far. Genetic mutations of the complement alternative pathway were confirmed in half of our patients, most of those mutations are in CHF. We demonstrate that treatment or prophylaxis with eculizumab was effective in reversing or preventing aHUS whether or not genetic complement mutations were identified.


Staphylococcal cassette chromosome mec containing a novel mec gene complex, B4.
To describe a new subclass of mec class B complex identified in Staphylococcus epidermidis. Four S. epidermidis isolates obtained from bloodstream infections in patients at University Medical Center Groningen (UMCG) were analysed by phenotypic antibiotic susceptibility testing and WGS. Sequence analysis revealed a new staphylococcal cassette chromosome mec (SCCmec) structure in isolate UMCG335. In this structure, plasmid pUB110 was found to be integrated into SCCmec IVc, creating a new SCCmec subtype, IVUMCG335. SCCmec IVc and a copy of plasmid pUB110 were found in other isolates, UMCG364 and UMCG341, respectively, indicating a probability that SCCmec IVUMCG335 could have evolved at the UMCG. SCCmec of UMCG337 contained a new genetic organization of the mec complex (IS431-ΔmecR1-mecA-IS431-pUB110-IS431-ψIS1272) that we have named B4. This new subclass of mec class B complex originated by IS431-mediated inversion of the DNA segment encompassing the plasmid and most of the genes of the mec complex with the exception of IS1272. As the SCCmec organization in UMCG337 differed by the inversion of an ∼10 kb sequence compared with SCCmec IVUMCG335, we have named it SCCmec subtype IVUMCG337. Isolates UMCG335 and UMCG337 carrying SCCmec IVUMCG335 and IVUMCG337, respectively, were associated with a restriction-modification system and a CRISPR-Cas system, creating a composite island of almost 70 kb. Our findings highlight the importance of IS431 in the evolution of the SCCmec region. The increasing genetic diversity identified in the SCCmec elements imposes a great challenge for SCCmec typing methods and highlights possible difficulties with the SCCmec nomenclature.


An experimental study of clearance of inhaled particles from the human nose.
Retention in the extrathoracic airways, and clearance by nose blowing, of monodisperse indium-111-labeled polystyrene particles were followed for at least 2 days after inhalation by healthy volunteers. Nine volunteers inhaled 3-μm aerodynamic diameter particles while sitting at rest, whereas subgroups of 3 or 4 inhaled 1.5-μm or 6-μm particles at rest, and 3-μm or 6-μm particles while performing light exercise. Retention of the initial extrathoracic deposit (IETD) in the extrathoracic airways was described by 4 components: on average 19% IETD cleared by nose blowing; 15% was swallowed before the first measurement, a few minutes after inhalation; 21% cleared by mucociliary action between the first measurement and about an hour later; and 45% subsequently cleared by mucociliary action. Geometric mean times in which 50% and 90% of IETD cleared were 2.5 and 22 hours. The geometric mean retention fractions at 24 and 48 hours were 7% and 2.4% IETD, respectively. No clear trends were found between parameters describing retention and any related to deposition (e.g., particle size). However, the fraction cleared by nose blowing was related to the frequency of nose blowing and therefore appears to be a characteristic of the individual.


[Serotoninergic and catecholaminergic indices in patients with neurotic and depressive disorders and changes in them as a result of reflexotherapy].
The status of the serotoninergic and catecholaminergic systems was studied in patients with neurotic depressive disorders before and after acupuncture (AP). The parameters studied included blood serotonin levels, monoamine oxidase (MAO) activity in the blood serum, as well as urinary excretion of adrenaline, noradrenaline, dopamine, DOPA and 5-HOIAA. Prior to AP patients with anxiety-depressive, depressive-hypochondriac or asthenodepressive manifestations showed different changes in the parameters studied. Following a course of AP they presented a compensatory increase in MAO activity, normalization of blood serotonin levels and of the urinary excretion of noradrenaline, dopamine and DOPA. Improvement in biochemical parameters indicates that this type of therapy is an effective means of the treatment of patients with neuroses with the predominance of depressive disorders.


Measles virus phosphoprotein retains the nucleocapsid protein in the cytoplasm.
Measles virus (MV) proteins were efficiently expressed in COS and Vero cells from vectors based on the strong cytomegalovirus enhancer-promoter and the simian virus 40 origin of replication. When expressed alone, nucleocapsid protein (N) migrates predominantly into the nucleus whereas phosphoprotein (P) is located in the cytoplasm. Coexpression of N and P proteins results in retention of the N protein in the cytoplasm, as seen also in infected cells. The retention of N protein is due to specific interactions with the P protein since coexpression of N with either the matrix or the hemagglutinin protein had no effect. Mapping of the regions of N-P interactions on P protein revealed that the carboxy-terminal 40% of P was sufficient for specific binding to N; however, the carboxy-terminal 60% of P was required for retention of N in the cytoplasm. Thus, the V and C proteins encoded within the first half of the P gene are not involved in the cytoplasmic retention of N protein. N protein might be fortuitously targeted to the nucleus as a result of its many basic amino acids, presumably destined to interact with the MV genome. However, this set of experiments has allowed to analyze in vivo the interactions between the N and P proteins.


The surprising costs of silence: Asymmetric preferences for prosocial lies of commission and omission.
Across 7 experiments (N = 3883), we demonstrate that communicators and targets make egocentric moral judgments of deception. Specifically, communicators focus more on the costs of deception to them-for example, the guilt they feel when they break a moral rule-whereas targets focus more on whether deception helps or harms them. As a result, communicators and targets make asymmetric judgments of prosocial lies of commission and omission: Communicators often believe that omitting information is more ethical than telling a prosocial lie, whereas targets often believe the opposite. We document these effects within the context of health care discussions, employee layoffs, and economic games, among both clinical populations (i.e., oncologists and cancer patients) and lay people. We identify moderators and downstream consequences of this asymmetry. We conclude by discussing psychological and practical implications for medicine, management, behavioral ethics, and human communication. (PsycINFO Database Record


Role of CD18-ICAM-1 in the entrapment of stimulated leukocytes in alveolar capillaries of perfused rat lungs.
This study aimed to examine the behavior of stimulated leukocytes in the pulmonary microcirculation. The leukocyte-endothelium interaction was visualized under physiological shear rates in perfused rat lungs using high-speed confocal laser video microscopy. Leukocytes labeled with carboxyfluorescein were stimulated with cytokine-induced neutrophil chemoattractant (CINC/gro), which caused L-selectin shedding and inverse upregulation of CD18. Neither unstimulated nor stimulated leukocytes exhibited rolling in either pulmonary arterioles or venules, whereas both were sequestered in capillaries. Approximately 50% of stimulated leukocytes showed a transient cessation of movement in pulmonary capillaries. The CINC/ gro stimulation, which inhibited leukocyte rolling and adhesion to mesenteric venules, reduced leukocyte velocity and increased leukocytes in pulmonary capillaries. Pretreatment with monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1) or CD18 attenuated these changes. Confocal microfluorography revealed constitutive expression of ICAM-1 not only in venules but also abundantly in capillary networks. These results suggest that selectin-independent, CD18-ICAM-1-dependent capillary sequestration is one of the major mechanisms by which activated leukocytes accumulate in the lungs.


Clinical and economic comparative effectiveness of robotic-assisted, video-assisted thoracoscopic, and open lobectomy.
We sought to evaluate trends and clinical and economic outcomes between robotic-assisted lobectomy (RL), video-assisted thoracoscopic lobectomy (VL), and open pulmonary lobectomy (OL). Patients who underwent a lobectomy for malignancy from January 1, 2008, to September 30, 2015, were identified in the Premier Healthcare Database. Propensity score matched (PSM) comparisons were performed between RL versus VL and RL versus OL. Patient characteristics were applied to generate propensity scores. In-hospital and perioperative 30-day outcomes and costs were compared within matched cohorts. From 2008 to 2015, there was a marked decline for OL (71% to 43%, P<0.0001) with a significant increase in RL (1% to 17%, P<0.0001) and VL (28% to 41%, P<0.0001). In the early period (January 2008 to December 2012), total operating room time was longer (P<0.0001) and admission to ICU was more common for RL compared to VL or OL (P<0.0001) although the total length of ICU stay was shorter for RL compared to VL or OL (P<0.0001). In the late period (January 2013 to September 2015), RL was associated with significantly lower rates of complications (P<0.05), conversions, and shorter length of stay than VL and OL. When hospital volume was not considered, costs were higher for RL than VL and OL. In hospitals where >25 lobectomies were performed annually, the total cost of RL was comparable to VL (P=0.09) and OL (P=0.11). During the study period, the utilization of RL increased substantially and was associated with improved perioperative outcomes compared with VL and OL. When annual hospital volume was >25 cases, these clinical advantages persisted and there was no significant cost difference between RL, VL, or OL. RL is an effective and cost-comparable approach for lobectomy in patients with lung malignancy.


Effects of bile acids on colon carcinogenesis in rats treated with carcinogens.
Primary bile acids were studied as possible colon tumor promoters or inhibitors in a rat model of chemically induced colon cancer. Cholic acid feeding increased the number of animals with tumors, the number of tumors per animal, and the number of tumors per tumor-bearing animal. Tumor enhancement was attributed to deoxycholic acid, the bacterial metabolite of cholic acid. When chenodeoxycholic acid was fed to the rats in our model, tumor incidence was increased, but the number of tumors per animal and the number of tumors per tumor-bearing animal were similar to controls. The different fecal bile acid pattern obtained with chenodeoxycholic acid may be responsible for the differences in tumor incidence. The methodology to characterize and identify all steroidal components of the feces requires extraction, thin-layer chromatography, gas-liquid chromatography, and gas-liquid chromatography-mass spectrometry. Newer techniques include LH-20 chromatography (for sulfated steroids) and high-pressure liquid chromatography.


[Optimized quality of care for affective disorders by health insurance-based case-management: a controlled cost-study].
Improvement of depression treatment by health insurance based case-management. Criteria of improvement were a higher treatment rate of patients suffering from affective disorders or depression by psychiatrists or psychotherapists than by general practitioners or family doctors and sickness fund payments. Training of health insurance account managers (characteristics of depression, counselling and, case management techniques). Evaluation of outcomes during 12-months against a control group of account managers without training. Intervention group: 87.8 % patients with in average 13.5 contacts to psychiatrists or psychotherapists; control group: 82.6 % patients with 11.8 contacts. The difference was statistically significant. Health insurance payments did not differ. A higher treatment rate by psychiatrists and psychotherapists can be achieved by health insurance-based case-management without a cost-increase.


Reduced isotope dose and imaging time with a high-efficiency CZT SPECT camera.
In light of recent focus on diagnostic imaging, cardiac SPECT imaging needs to become a shorter test with lower radiation exposure to patients. Recently introduced Cadmium Zinc Telluride (CZT) cameras have the potential to achieve both goals. During a 2-month period patients presenting for a Tc-99m sestamibi SPECT MPI study were imaged using a CZT camera using a low-dose rest-stress protocol (5 mCi rest and 15 mCi stress doses). Patients ≥250 lbs or a BMI ≥35 kg/m(2) were excluded. Rest images were processed at 5- and 8-minute acquisition times and stress images at 3- and 5-minute acquisition times. A subset of patients had stress imaging performed using both conventional and CZT SPECT cameras. Image acquisition times and SPECT camera images were compared based on total counts, count rate, image quality, and summed rest and stress scores. Twelve month clinical follow-up was also obtained. 131 patients underwent the study protocol (age 64.9 ± 9.8 years, 54.2% male). There was no significant difference in image quality and mean summed scores between 5- and 8-minute rest images and between 3- and 5-minute stress images. When compared to a conventional SPECT camera in 27 patients, total rest and stress perfusion deficits and calculated LVEF were similar (r = 0.94 and 0.96, respectively). At 12 months there was a benign prognosis in patients with normal perfusion. The effective dose was 5.8 mSv for this protocol which is 49.2% less than conventional Tc-99m studies and 75.7% less than conventional Tl-201/Tc-99m dual isotope studies. New SPECT camera technology with low isotope dose significantly reduces ionizing radiation exposure and imaging times compared to traditional protocols while maintaining image quality and diagnostic accuracy.


Intranasal HIV-1-gp160-DNA/gp41 peptide prime-boost immunization regimen in mice results in long-term HIV-1 neutralizing humoral mucosal and systemic immunity.
An intranasal DNA vaccine prime followed by a gp41 peptide booster immunization was compared with gp41 peptide and control immunizations. Serum HIV-1-specific IgG and IgA as well as IgA in feces and vaginal and lung secretions were detected after immunizations. Long-term humoral immunity was studied for up to 12 mo after the booster immunization by testing the presence of HIV-1 gp41- and CCR5-specific Abs and IgG/IgA-secreting B lymphocytes in spleen and regional lymph nodes in immunized mice. A long-term IgA-specific response in the intestines, vagina, and lungs was obtained in addition to a systemic immune response. Mice immunized only with gp41 peptides and L3 adjuvant developed a long-term gp41-specific serum IgG response systemically, although over a shorter period (1-9 mo), and long-term mucosal gp41-specific IgA immunity. HIV-1-neutralizing serum Abs were induced that were still present 12 mo after booster immunization. HIV-1 SF2-neutralizing fecal and lung IgA was detectable only in the DNA-primed mouse groups. Intranasal DNA prime followed by one peptide/L3 adjuvant booster immunization, but not a peptide prime followed by a DNA booster, was able to induce B cell memory and HIV-1-neutralizing Abs for at least half of a mouse's life span.


Soil amendment as a strategy for the growth of young vines when replanting vineyards in soils with high copper content.
Soil contamination with copper (Cu)-based agrochemicals used in vineyards for pest control is a growing problem. In this context, the application of soil amendment to limit Cu toxicity, especially for young plants after the replanting of vineyards, has been a concern for winemakers. Therefore, the aim of this study was to evaluate how different amendments can contribute to the decrease in Cu availability in areas vocated to viticulture. Furthermore, the aim was to evaluate to the effect of Cu on the biochemical and physiological changes in the development of the young vine plants, both at the shoot and the root level. Vine plants were grown in a greenhouse using a Typic Hapludalf soil characterized by 87.5 mg of Cu kg-1 (control). Three different amendments were applied to the soil: limestone (3 Mg ha-1), calcium silicate (3 Mg ha-1) and vermicompost (30 g of C kg-1). The amendment with vermicompost and calcium silicate caused a significant alkalization of the soil solution. Moreover, specifically for the treatment with vermicompost, the levels of Cu2+ in the soil solution were consistently diminished with a clear benefit for plants (+89% biomass accumulation at the shoot level). In addition, this soil amendment led to a higher photosynthetic rate, lower superoxide dismutase (SOD, EC 126.96.36.199) and guaiacol peroxidase (POD, EC 220.127.116.11) activity and a higher percentage of fine roots with diameter between 0 < L ≥ 0.2 mm (particularly active in water and nutrient acquisition). In conclusion, results showed that vermicompost effectively reduced Cu phytotoxicityin young vines grown in soils with high Cu contents. Furthermore, this amendment might be an asset in enhancing the availability of other important micronutrients such as iron.


Revascularization for bilateral renal artery occlusion after umbilical artery catheterization.
The case of a newborn infant who became hypertensive and oliguric because of bilateral renal artery occlusion following umbilical artery catheterization is presented. Eventual treatment was by microsurgical placement of an aortorenal graft, with subsequent marked improvement in the patient's course. A scan and arteriogram at 1 year showed that the revascularized kidney was responsible for the patient's normal blood urea nitrogen and creatinine concentrations, but the renal artery had recanalized and the graft occluded. The role of umbilical artery catheterization in such catastrophes and the possible future role such microsurgical reconstruction could play in neonatal hypertension are discussed.


Intelligent Monitoring? Assessing the ability of the Care Quality Commission's statistical surveillance tool to predict quality and prioritise NHS hospital inspections.
The Care Quality Commission (CQC) is responsible for ensuring the quality of the health and social care delivered by more than 30 000 registered providers in England. With only limited resources for conducting on-site inspections, the CQC has used statistical surveillance tools to help it identify which providers it should prioritise for inspection. In the face of planned funding cuts, the CQC plans to put more reliance on statistical surveillance tools to assess risks to quality and prioritise inspections accordingly. To evaluate the ability of the CQC's latest surveillance tool, Intelligent Monitoring (IM), to predict the quality of care provided by National Health Service (NHS) hospital trusts so that those at greatest risk of providing poor-quality care can be identified and targeted for inspection. The predictive ability of the IM tool is evaluated through regression analyses and χ2 testing of the relationship between the quantitative risk score generated by the IM tool and the subsequent quality rating awarded following detailed on-site inspection by large expert teams of inspectors. First, the continuous risk scores generated by the CQC's IM statistical surveillance tool cannot predict inspection-based quality ratings of NHS hospital trusts (OR 0.38 (0.14 to 1.05) for Outstanding/Good, OR 0.94 (0.80 to -1.10) for Good/Requires improvement, and OR 0.90 (0.76 to 1.07) for Requires improvement/Inadequate). Second, the risk scores cannot be used more simply to distinguish the trusts performing poorly-those subsequently rated either 'Requires improvement' or 'Inadequate'-from the trusts performing well-those subsequently rated either 'Good' or 'Outstanding' (OR 1.07 (0.91 to 1.26)). Classifying CQC's risk bandings 1-3 as high risk and 4-6 as low risk, 11 of the high risk trusts were performing well and 43 of the low risk trusts were performing poorly, resulting in an overall accuracy rate of 47.6%. Third, the risk scores cannot be used even more simply to distinguish the worst performing trusts-those subsequently rated 'Inadequate'-from the remaining, better performing trusts (OR 1.11 (0.94 to 1.32)). Classifying CQC's risk banding 1 as high risk and 2-6 as low risk, the highest overall accuracy rate of 72.8% was achieved, but still only 6 of the 13 Inadequate trusts were correctly classified as being high risk. Since the IM statistical surveillance tool cannot predict the outcome of NHS hospital trust inspections, it cannot be used for prioritisation. A new approach to inspection planning is therefore required.


Crystal structures of rubidium and cesium anthranilates and salicylates.
In an attempt to probe a potential template role of the large alkali-metal cations rubidium and cesium in the organization of biorelevant ligands, salicylate and anthranilate complexes of the two elements were prepared and structurally investigated. The studies were also expected to show the marked structural differences compared to the corresponding thallium(I) compounds. Rubidium anthranilate and cesium salicylate could be crystallized as the monohydrates Rb(Anth)(H(2)O) and Cs(Sal)(H(2)O). Both have layer structures containing the cations and the polar groups of the ligands in core domains sandwiched by the aromatic rings above and below. The metal atoms have coordination numbers 7 and 8, respectively, with an irregular coordination sphere made up exclusively of oxygen atoms. Crystalline material with a 1:2 stoichiometry, Cs[H(Anth)(2)], is obtained from aqueous solutions of Cs(Anth) upon absorption of carbon dioxide with concomitant formation of cesium bicarbonate, Cs(HCO(3)). The crystal structure of Cs(HCO(3)) was redetermined to obtain precise benchmark data for cesium carbonates and carboxylates. The cesium hydrogen bisanthranilate also has a layer structure with eight-coordinate cesium atoms. The coordination sphere includes one nitrogen donor atom. The organization of all layer structures appears to be governed mainly by steric effects and electrostatic forces with very little directional influence of the cations. This result suggests that the large alkali metals have no efficient template effect for the organization of biological substrates and can explain the low toxicity of rubidium and cesium salts.


Near-field scanning optical microscopy imaging of multimode interference.
By use of a near-field scanning optical microscope (NSOM) in collection mode, the intensity distribution along a 2 x 2 multimode interference coupler was directly imaged as a function of wavelength. Although calculations can predict the general trend of wavelength dependence and the approximate positions of multiple images in the coupler, the accuracy is poor because of uncertainties in the waveguide width. We show that direct imaging using a NSOM bypasses calculational uncertainties and proves to be a powerful technique for studying these waveguide devices.


Transcriptomic analysis reveals the early body wall regeneration mechanism of the sea cucumber Holothuria leucospilota after artificially induced transverse fission.
Sea cucumbers exhibit a remarkable ability to regenerate damaged or lost tissues and organs, making them an outstanding model system for investigating processes and mechanisms of regeneration. They can also reproduce asexually by transverse fission, whereby the anterior and posterior bodies can regenerate independently. Despite the recent focus on intestinal regeneration, the molecular mechanisms underlying body wall regeneration in sea cucumbers still remain unclear. In this study, transverse fission was induced in the tropical sea cucumber, Holothuria leucospilota, through constrainment using rubber bands. Histological examination revealed the degradation and loosening of collagen fibers on day-3, followed by increased density but disorganization of the connective tissue on day-7 of regeneration. An Illumina transcriptome analysis was performed on the H. leucospilota at 0-, 3- and 7-days after artificially induced fission. The differential expression genes were classified and enriched by GO terms and KEGG database, respectively. An upregulation of genes associated with extracellular matrix remodeling was observed, while a downregulation of pluripotency factors Myc, Klf2 and Oct1 was detected, although Sox2 showed an upregulation in expression. In addition, this study also identified progressively declining expression of transcription factors in the Wnt, Hippo, TGF-β, and MAPK signaling pathways. Moreover, changes in genes related to development, stress response, apoptosis, and cytoskeleton formation were observed. The localization of the related genes was further confirmed through in situ hybridization. The early regeneration of H. leucospilota body wall is associated with the degradation and subsequent reconstruction of the extracellular matrix. Pluripotency factors participate in the regenerative process. Multiple transcription factors involved in regulating cell proliferation were found to be gradually downregulated, indicating reduced cell proliferation. Moreover, genes related to development, stress response, apoptosis, and cell cytoskeleton formation were also involved in this process. Overall, this study provides new insights into the mechanisms of whole-body regeneration and uncover potential cross-species regenerative-related genes.


BiTE secretion by adoptively transferred stem-like T cells improves FRα+ ovarian cancer control.
Cancer immunotherapies can produce complete therapeutic responses, however, outcomes in ovarian cancer (OC) are modest. While adoptive T-cell transfer (ACT) has been evaluated in OC, durable effects are rare. Poor therapeutic efficacy is likely multifactorial, stemming from limited antigen recognition, insufficient tumor targeting due to a suppressive tumor microenvironment (TME), and limited intratumoral accumulation/persistence of infused T cells. Importantly, host T cells infiltrate tumors, and ACT approaches that leverage endogenous tumor-infiltrating T cells for antitumor immunity could effectively magnify therapeutic responses. Using retroviral transduction, we have generated T cells that secrete a folate receptor alpha (FRα)-directed bispecific T-cell engager (FR-B T cells), a tumor antigen commonly overexpressed in OC and other tumor types. The antitumor activity and therapeutic efficacy of FR-B T cells was assessed using FRα+ cancer cell lines, OC patient samples, and preclinical tumor models with accompanying mechanistic studies. Different cytokine stimulation of T cells (interleukin (IL)-2+IL-7 vs IL-2+IL-15) during FR-B T cell production and the resulting impact on therapeutic outcome following ACT was also assessed. FR-B T cells efficiently lysed FRα+ cell lines, targeted FRα+ OC patient tumor cells, and were found to engage and activate patient T cells present in the TME through secretion of T cell engagers. Additionally, FR-B T cell therapy was effective in an immunocompetent in vivo OC model, with response duration dependent on both endogenous T cells and FR-B T cell persistence. IL-2/IL-15 preconditioning prior to ACT produced less differentiated FR-B T cells and enhanced therapeutic efficacy, with mechanistic studies revealing preferential accumulation of TCF-1+CD39-CD69- stem-like CD8+ FR B T cells in the peritoneal cavity over solid tumors. These findings highlight the therapeutic potential of FR-B T cells in OC and suggest FR-B T cells can persist in extratumoral spaces while actively directing antitumor immunity. As the therapeutic activity of infused T cell therapies in solid tumor indications is often limited by poor intratumoral accumulation of transferred T cells, engager-secreting T cells that can effectively leverage endogenous immunity may have distinct mechanistic advantages for enhancing therapeutic responses rates.


[Age changes of structural state of synaptic membranes of brain].
In the brain synaptic membranes from old rats (24-26 months) in comparison with the mature ones (6-7 months) an increase was shown in disintegration rate with DDS Na, mobility of 5-, 16-doxyl-stearate spin probes and in thermosensitivity of acetylcholinesterase. The total number of SH-groups decreased. While protein composition remained constant lysophosphatidylcholine and saturated fatty acid content in old animals increased. The age-dependent structural rearrangement of synaptic membranes is suggested.


Poly-L-arginine and an N-formylated chemotactic peptide act synergistically with lectins and calcium ionophore to induce intense chemiluminescence and superoxide production in human blood leukocytes. Modulation by metabolic inhibitors, sugars, and polyelectrolytes.
Various cationic polyelectrolytes (poly-alpha-amino acids and histones), lectins, the chemotactic peptide, f-methionyl-leucyl-phenylalanine (fMLP), the calcium ionophore A23187, and phorbol myristate acetate (PMA) were investigated regarding their capacity to induce luminol-dependent chemiluminescence (LDCL) and superoxide production by human blood leukocytes. Although when tested individually, poly-L-arginine (PARG), phytohemagglutinin (PHA), concanavalin A (Con A), or fMLP induced only a low to moderate LDCL response, very intense synergistic CL reactions were obtained by mixtures of PARG + PHA, PARG + Con A, PARG + PHA + fMLP, Ca2 + ionophore + PARG + PHA + fMLP, and PARG + PMA. The sequence of addition of the various agents to WBC in the presence of luminol absolutely determined the intensity of the LDCL signals obtained, the highest reactions being achieved when the WBC were preincubated for 2-3 min with A23187 followed by the sequential addition of fMLP, PARG, and PHA. These "multiple hits" induced CL reactions which were many times higher than those obtained by each factor alone. On the other hand, neither poly-L-lysine, poly-L-ornithine, poly-L-histidine, nor poly-L-asparagine, when employed at equimolar concentrations, cooperated efficiently with PHA and fMLP to trigger synergistic LDCL responses in leukocytes. Concomitantly with the induction of LDCL, certain ligand mixtures also triggered the production of superoxide. The LDCL which was induced by the "cocktail" of agents was markedly inhibited by sodium azide (93% inhibition), but to a lesser extent by catalase (10% inhibition) or by superoxide dismutase (20%-60% inhibition). On the other hand, scavengers of singlet oxygen and OH (sodium benzoate, histidine) did not affect the synergistic LDCL responses induced by these multiple ligands. Cytochalasin B also markedly inhibited the LDCL responses induced either by soluble stimuli or by streptococci preopsonized either with histone or with polyanethole sulfonate. The LDCL responses which were induced by mixtures of PARG and concanavalin A were also strongly inhibited by mannose, alpha-methyl mannoside, and poly-L-glutamic acid. The data suggest that the LDCL responses induced by the soluble ligands involved a myeloperoxidase-catalyzed reaction. The possible employment of "cocktails" of ligands to enhance the bactericidal effects of PMNs, macrophages, and natural killer cells on microbial cells and mammalian targets is discussed.