Neuronal activity of human caudate nucleus and prefrontal cortex in cognitive tasks.
Lesions of the caudate nucleus and prefrontal cortex may display similar cognitive deficits. Recent advances in cognitive neuroscience have clarified the functional role of prefrontal cortical areas in certain cognitive operations involved in simple language tasks. We have addressed the role of the caudate nucleus in tasks of lexical decision, semantic categorization, recognition memory, reading aloud and object naming by recording neuronal activity in patients with depth electrodes. During visual processing of words, caudate cells exhibited excitatory responses related to both semantic and phonological-articulatory encoding with non-overlapping time courses. The firing rate of the cells was increased when the semantic processing was required. This occurred within 400-600 ms after the stimulus onset, or within the first 200-300 ms of the delay period. The increased firing within 1000-1200 ms after the stimulus onset was related to the phonological processing. These responses turned out to be strikingly similar to those in Broca's area. Both reading aloud and explicit memory retrieval tasks elicited a sustained inhibition of firing of the same cells with a greater onset latency. Chronometric comparison of prefrontal, temporo-parietal and caudate activities in similar tasks relates the time course of these activations to the fronto-caudate anatomical loops and helps further understanding of the anatomy and circuitry involved in human cognition.


Densitometric properties of rapid manual processing solutions: abbreviated versus complete rapid processing.
Rapid manual processing solutions produce wet, readable radiographs in 1 to 2 min. However, some manufacturers permit time reductions for various processing steps to obtain images even more quickly. Differences in densitometric characteristics and spatial resolution between abbreviated rapid processing (ARP) and complete rapid processing were examined in four rapid manual processing systems on D- and E-speed film. When compared with films processed conventionally in an automatic processor, films processed in rapid manual processing chemistries had more fog and generally lower levels of speed and contrast. ARP radiographs were excessively stained unless they were washed for at least 60 s after fixing. The most severe depreciation in ARP film quality occurred when developing time was reduced by 50%; the complete rapid processing developing time should always be used. E-speed films produced radiographs with comparable densitometric and resolution characteristics to D-speed films for ARP and complete rapid processing techniques while requiring 40% less radiation.


Caspase-dependent and -independent apoptosis of mast cells induced by withdrawal of IL-3 is prevented by Toll-like receptor 4-mediated lipopolysaccharide stimulation.
IL-3-dependent mucosal-like mast cells undergo apoptosis upon withdrawal of IL-3. Generally, the apoptosis is mediated by the activation of caspases and inhibited by addition of the pan-caspase inhibitors z-VAD-FMK or BOC-D-FMK. However, DNA fragmentation, a typical characteristic of apoptosis, is not inhibited by z-VAD-FMK or BOC-D-FMK in mast cell apoptosis. In this study, we demonstrate that the apoptosis of mast cells is mediated by both caspase-dependent and -independent mechanisms. The caspase-independent apoptosis is mediated by the translocation of endonuclease G from mitochondria into nuclei. Withdrawal of IL-3 caused down-regulation of Bcl-xL, resulting in a drop in mitochondrial membrane transition potential followed by the release of cytochrome c and endonuclease G from mitochondria. However, stimulation of mast cells through Toll-like receptor 4 (TLR4) by lipopolysaccharide prevented mast cell apoptosis by inducing expression of Bcl-xL. Moreover, the activation of mast cells by LPS is enhanced in the presence of IFN-gamma, which up-regulates the expression of cell surface TLR4. Taken together, these observations provide evidence that mast cells play important roles not only in allergic reactions but also in innate immunity recognizing enterobacteria through TLR4, and are regulated differently from allergic inflammation by Th1 cytokines.


Establishment and verification of prognostic model and ceRNA network analysis for colorectal cancer liver metastasis.
Colorectal cancer (CRC) is one of the most common cancers in the world. Approximately two-thirds of patients with CRC will develop colorectal cancer liver metastases (CRLM) at some point in time. In this study, we aimed to construct a prognostic model of CRLM and its competing endogenous RNA (ceRNA) network. RNA-seq of CRC, CRLM and normal samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database. Limma was used to obtain differential expression genes (DEGs) between CRLM and CRC from sequencing data and GSE22834, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses were performed, respectively. Univariate Cox regression analysis and lasso Cox regression models were performed to screen prognostic gene features and construct prognostic models. Functional enrichment, estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm, single-sample gene set enrichment analysis, and ceRNA network construction were applied to explore potential mechanisms. An 8-gene prognostic model was constructed by screening 112 DEGs from TCGA and GSE22834. CRC patients in the TCGA and GSE29621 cohorts were stratified into either a high-risk group or a low-risk group. Patients with CRC in the high-risk group had a significantly poorer prognosis compared to in the low-risk group. The risk score was identified as an independent predictor of prognosis. Functional analysis revealed that the risk score was closly correlated with various immune cells and immune-related signaling pathways. And a prognostic gene-associated ceRNA network was constructed that obtained 3 prognosis gene, 14 microRNAs (miRNAs) and 7 long noncoding RNAs (lncRNAs). In conclusion, a prognostic model for CRLM identification was proposed, which could independently identify high-risk patients with low survival, suggesting a relationship between local immune status and prognosis of CRLM. Moreover, the key prognostic genes-related ceRNA network were established for the CRC investigation. Based on the differentially expressed genes between CRLM and CRC, the prognosis model of CRC patients was constructed.


Clinical experience with the Medpor porous polyethylene implant.
The Medpor porous polyethylene implant is a highly stable and somewhat flexible porous alloplast that has been shown to exhibit rapid tissue ingrowth into its pores. A total of 116 Medpor implants were placed in 70 patients over a four-year period. Implants were used for the chin, malar area, nasal reconstruction, ear reconstruction, orbital reconstruction, and the correction of craniofacial contour deformities. Many of these implants were placed in areas long considered problematic such as areas of thin soft tissue coverage, extensive scarring, and severe facial burns. Nine complications occurred including seven exposures, all of which occurred in areas of minimal soft tissue coverage. Because of the rapid vascularization of the implants, only two implants were removed, both from the columella. On the basis of our results, it is felt that the Medpor implant is an excellent alternative to existing implant materials. The implant is easy to shape; it is strong yet somewhat flexible; it is remarkably stable; and it exhibits tissue ingrowth into its pores.


Physiological and biochemical investigations on egg stickiness in common carp.
The properties and behaviour of common carp, Cyprinus carpio, eggs in water and in ovarian fluids were studied at different temperature, pH, and with divalent cation concentrations. The biochemical composition of zona radiata externa (ZRE) was analyzed qualitatively and quantitatively on amino acids, carbohydrates, uronic acid and sialic acids using chemical assays; on proteins using electrophoresis. Comparative biochemical studies were performed on the chub, Leuciscus cephalus, the vimba, Vimba vimba and the bleak, Chalcalburnus chalcoides. Eggs of common carp became sticky within seconds after mixing with water. Egg stickiness was not affected by water pH in a range of 6-9, by water temperatures between 4 and 30 degrees C, by divalent cations in concentrations < or =20 mmol/l, and by sodium chloride concentrations < or =50 mmol/l. Our investigations indicated that specific proteins of the cyprinid ovarian fluid are controlling (inhibiting) the initiation of egg stickiness: egg stickiness did not develop as long as the eggs were incubated in ovarian fluid. When however the ovarian fluid proteins were removed from the ovarian fluid by heat treatment, eggs developed stickiness within seconds, like they do in water. Biochemically, the ZRE consisted of nine types of proteins whereby four of them were glycoproteins. Glucose, fructose, galactose, and uronic acids were the major carbohydrates. Treatment of the egg membrane with invertase or amyloglucosidase did not affect the egg stickiness. Treatment with protease prevented stickiness. From these results and from additional histochemical results, we conclude that glycoproteins are likely to be the molecules responsible for stickiness.


A cross-cultural study of nonprofit self-organized ridesharing.
Nonprofit ridesharing presents an underutilized opportunity for increasing transportation sustainability, as well as users' economic and social benefits, while reducing adverse environmental impacts. However, while app-based ridesharing has achieved only modest uptake, mostly limited to longer trips, in certain contexts, self-organized ridesharing (SORS) has shown significant achievements, even for the challenging short- and mid-range commuting trips. Still, knowledge regarding the key elements and mechanisms behind successful SORS is partial, hindering the ability to effectively leverage SORS diffusion and scaling potential. Following the premise that successful initiatives may provide learning opportunities, this study aims at narrowing this knowledge gap by performing a comparative cross-cultural systematic study of eight diverse SORS cases. The study uses a recently designed conceptual framework and multiple research methods (mainly online data exploration, personal interviews, observations, and documents analysis) to comprehensively examine SORSs' attributes and evolution stages and processes. Study findings highlight repeated patterns as well as the role of context, official actors, and local practices in shaping initiative's dynamics towards success. The study offers general and specific policy recommendations for supporting the early development, growth, and diffusion of SORS, as well as reflections on post pandemic ridesharing.


Association of early suspected acute exacerbations of idiopathic pulmonary fibrosis with subsequent clinical outcomes and healthcare resource utilization.
Idiopathic pulmonary fibrosis (IPF) may be complicated by episodes of acute exacerbation. This study quantified the association between occurrence of suspected acute exacerbations of IPF (AEx-IPF) in the 6 months post-IPF diagnosis with clinical outcomes and IPF-related healthcare resource utilization (HRU). U.S. pulmonologists participated in a retrospective chart review of IPF patients. Patient eligibility criteria included: 1) ≥40 years of age and a confirmed date of first IPF diagnosis with HRCT and/or lung biopsy between January 2011-June 2013; 2) 2 separate FVC results recorded around first diagnosis and 6 months post-diagnosis. Patients with a suspected AEx-IPF within 6 months post-diagnosis were categorized as "early AEx-IPF." Subsequent clinical outcomes and IPF-related HRU were assessed from 6 months post-diagnosis until the latest physician contact date. The sample included 490 IPF patients from 168 pulmonologists; 72 (15%) patients had a suspected early AEx-IPF. At IPF diagnosis, the mean (SD) age was 61 (11) years, 68% were male, and the mean FVC percent predicted was 60% (26%). Compared to patients without a suspected early AEx-IPF, patients with an early AEx-IPF had higher mortality risk (HR = 2.87, p < 0.001) and higher rates of subsequent suspected AEx-IPF (IRR = 3.87, p < 0.001), outpatient visits (IRR = 1.46, p < 0.001), ER visits (IRR = 4.39, p < 0.001), hospitalizations (IRR = 7.96, p < 0.001), and ICU stays (IRR = 9.74, p < 0.001). Using a large sample of IPF patients from varied practice settings, we found a strong relationship between suspected early AEx-IPF and worse subsequent clinical outcomes and increased IPF-related HRU. This relationship was particularly pronounced for acute resource use.


Evidence that three structural genes code for human alkaline phosphatases.
The number of structural gene loci that code for the different molecular forms of human alkaline phosphatase is unknown. Physical properties of the enzymes, immunological data, chemical inhibition and genetic studies suggest that at least three structural genes are involved: one coding for alkaline phosphatase from placenta, another for the enzyme from intestine, and one or more for the enzymes from liver, kidney and bone. Badger and Sussman have shown that alkaline phosphatases from human liver and placenta are products of different structural genes, and Greene and Sussman have shown that alkaline phosphatase from a metastasised bronchogenic carcinoma was nearly identical to the enzyme from placenta. However, other tumour-associated alkaline phosphatases and the enzymes from normal tissue other than placenta and liver have not been identified by conclusive structural criteria, and thus it is not known whether these onco-alkaline phosphatases represent ectopic production or unusual post-translational modification of the enzymes found in normal tissues. We present here, using a sensitive peptide-mapping technique, structural evidence that the enzyme forms from liver, kidney and serum from a patient with Paget's disease of bone (osteitis deformans) are products of the same structural gene and can be easily distinguished from either the intestinal or placental isoenzymes. The technqiue seems to be useful for the classification of tumour-associated alkaline phosphatases on a structural basis.


Response of protein S100B to playing American football, lifting weights, and treadmill running.
To determine if serum S100B increases similarly as a result of playing American football compared to exercise alone. Serum S100B was measured in division III collegiate football players before and after every home game during a single football season. Serum S100B was also measured before and after subjects walked on a treadmill for 30 minutes at a leisurely pace, ran on a treadmill while wearing and not wearing a football helmet at 6 mph for 8 minutes, and performed low-, moderate-, or high-intensity resistance exercise. Serum S100B increased significantly (P < 0.05) when subjects played in a football game, ran on a treadmill, or performed moderate-intensity resistance exercise. Pre-game serum S100B did not accumulate throughout the football season in any of the players (P > 0.05). The increase in serum S100B during football games was moderately and significantly correlated with both the number of hits (R2 = 0.407) and the number of plays (R2 = 0.484) that each player experienced (P < 0.001). Post-game serum S100B was greater in football players who played more than 50 plays compared to those players who played <50 plays, subjects who exercised on a treadmill, or subjects performing resistance exercise (P < 0.05). It is unclear if the higher S100B concentration in football players playing at least 50 plays was caused by exercise or hits. Therefore, if serum S100B is to be used as a biomarker of impacts, and possible brain injury in sport, exercise time and intensity should be taken into account as confounding variables.


Genetic parameters of growth traits and carcass weight of New Zealand white rabbits in a tropical dry forest area.
The objective of this study was to estimate the heritability (h 2), repeatability (r), and correlations (rŷiyi ) in some traits of zootechnical interest in a population of New Zealand white rabbits of a tropical dry forest area. Three mating groups were formed, each one of 1 male and 70 females. The traits evaluated were litter size at birth (LB), born alive (BA), born dead (BD), litter weight born alive (LW), litter weight at weaning (LWW), weaning weight (WW), slaughter weight (SW), and carcass weight (CW). Weaning took place at 42 days, and the fattening phase lasted 60 ± 3 days. A descriptive statistical study was carried out on the study variables. Paternal heritability was estimated ( h f 2 ) and maternal ( h m 2 ), repeatability, rabbit index IC, and Pearson's correlations (rŷiyi ) between traits. The descriptive statistics showed high variation for the BD traits. The values of the productivity found were similar to those presented in studies around the world. h 2 presented magnitudes between low and medium. h f 2 ranged between 0.09 and 0.42 and between 0.11 and 0.45 for h m 2 . In general, the values of h m 2 were higher than the values of h f 2 . The r values for the traits LB, BA, LW, LWW, and SW presented low magnitude, while it was medium for WW and CW. From the values of r, IC was calculated for each of the rabbits, allowing their categorization, which will be used in future selection plans. rŷiyi among the variables ranged from -0.01 to 0.860. They were generally positive and mostly not significant (p > 0.05); they took a magnitude from low to moderate, except for the correlation between LB and BA. The production of rabbits under tropical conditions is similar to other reports. The genetic parameters evaluated were medium-to-low, indicating a robust non-additive gene and/or environmental effect.


An N-terminally fused Xenopus transcription factor IIIA synthesized in Escherichia coli is biologically active.
A 1.5-kilobase DNA fragment containing the Xenopus transcription factor IIIA (TFIIIA) gene was inserted into the prokaryotic expression vector pIN-III(A) containing the lpp/lac promoter. The recombinant DNA was introduced into Escherichia coli K-12 strain SB221. The expression TFIIIA gene was induced by isopropyl-beta-D-thiogalactopyranoside, which resulted in the synthesis of a recombinant TFIIIA with an extra 17 amino acids fused to its N terminus as predicted from the nucleotide sequence. The engineered gene product, purified to at least 90% homogeneity, retained its binding affinity to the intragenic control region of the 5 S RNA gene, as well as its activity to stimulate 5 S RNA gene transcription in vitro.


Cesarean section and perinatal outcome: response from the House of Horne.
A direct comparison between Parkland Memorial Hospital in Dallas, Texas, and the National Maternity Hospital in Dublin, Ireland, on the basis of limited numbers taken from one year only (1983) led to the conclusion that the liberal use of cesarean section in Dallas was associated with a sevenfold decrease in intrapartum fetal deaths and a twofold decrease in neonatal seizures. However, when the scope of the survey is extended to include the year before (1982) and the year after (1984), a different picture emerges. During this extended period there were almost four times as many cesarean sections performed in Dallas with no significant difference in overall perinatal mortality, while for two of three years the incidence of neonatal seizures was twice as high in Dallas when compared with Dublin. The fact that high cesarean rates continue to rely on evidence of such a tenuous nature must remain a matter of concern.


Building-related illness. A review of available scientific data.
The allergist-immunologist is ideally trained to play a critical role in the recognition and evaluation of patients with building-related illness. The practitioners of this subspecialty should also take an active role in critical studies that will expand the knowledge base in this whole area, and collaborate as well with colleagues in toxicology and industrial hygiene to develop accurate and sensitive measures of implicated pollutants, irritants, and allergens. The role of multiple low level pollutants on healthy workers must be assessed in an objective fashion. Methods to evaluate and enforce regulations on building ventilation should be developed and widely applied. It is only in this fashion that an expanding population of office workers can be assured a suitable work environment as we emerge from the age of the industrial blue collar worker to the technical, office-based white collar worker.


HeLa cells contain a 2'-phosphate-specific phosphotransferase similar to a yeast enzyme implicated in tRNA splicing.
We have previously shown that HeLa cells contain activities implicated in tRNA splicing in yeast, a ligase capable of joining tRNA half-molecules and an NAD-dependent activity capable of removing the 2'-phosphate created at the splice junction by the ligase (Zillmann, M., Gorovsky, M.A., and Phizicky, E.M. (1991) Mol. Cell. Biol. 11, 5410-5416). We show here that removal of the splice junction 2'-phosphate is, as in yeast, a 2'-phosphate-specific phosphotransfer reaction that produces the same, as yet unidentified, small molecule. This enzyme is highly specific for oligomeric substrates having internal 2'-phosphates. Oligomers bearing terminal 2'-phosphates are at least 50-fold less reactive and those bearing 5'- or 3'-terminal phosphates are at least 600-fold less reactive. The requirement for an internal 2'-phosphate can be satisfied by a substrate as small as a dimer.


Avoidance and treatment of complications of distal radius fractures.
The treatment of distal radius fractures continues to be fraught with complications. The more widespread use of internal fixation and supple-mental bone grafting with external fixation has decreased the incidence of malunions from closed-cast treatment and percutaneous pinning, but increased the risk of the complications specific to surgical intervention. Careful diagnosis, surgical planning, surgical technique, and postoperative rehabilitation can help optimize outcome in these difficult fractures.


Fetal ascites immediately after rupture of ovarian cysts.
Ruptured fetal ovarian cysts are difficult to diagnose. We report on ultrasonograms recorded before and immediately after spontaneous rupture of fetal ovarian cysts followed by transient ascites. Ultrasound findings of transient ascites accompanied by rapid reduction in cyst size could aid in diagnosing rupture of fetal ovarian cysts.


The antioxidative effect of bread crust in a mouse macrophage reporter cell line.
Free radicals and oxidative stress are important factors in the biology of aging and responsible for the development of age-related diseases. One way to reduce the formation of free radicals is to boost the antioxidative system by nutrition. Heat treatment of food promote the Maillard reaction which is responsible for their characteristic color and taste. During the Maillard reaction reducing sugars react with proteins in a non-enzymatic way leading to the formation of advanced glycation end products (AGEs). As an AGE-rich source our group used bread crust (BCE) to investigate the effect of AGEs on the antioxidant defense. It is well known that the NF-kB pathway is activated by treatment of cells with AGEs. Therefore for stimulation with the BCE we used the macrophage reporter cell line RAW/NF-kB/SEAPorter™. Amino acid analysis and LC-MS/MS by Orbitrap Velo was used to determine the bioactive compounds in the soluble BCE. The radical scavenging effect was conducted by the DPPH-assay. BCE induced the NF-kB pathway in RAW/NF-kB/SEAPorter™ cells and also showed a concentration-dependent antioxidative capacity by the DPPH-assay. With the LC/MS and amino acid analyses, we identified the presence of gliadin in BCE confirmed by using specific gliadin antibodies. By immunoprecipitation (IP) with an antibody against γ-gliadin and western blot probing against the AGE carboxymethyllysine (CML) the presence of AGE-gliadin in BCE was confirmed. Stimulation of the RAW/NF-kB/SEAPorter™ cells with the γ-gliadin depleted fractions did not activate the NF-kB pathway. CML-modified gliadin in the BCE is a bioactive compound of the bread crust which is responsible for the antioxidative capacity and for the induction of the NF-kB pathway in mouse macrophages.


Effects of metalloprotease ADAMTS12 on cervical cancer cell phenotype and its potential mechanism.
ADAMTS12 is a gene widely expressed in human tissues. We studied the expression level of ADAMTS12 in cervical cancer tissue and its relationship with clinicopathological features. We also explored the function of ADAMTS12 in cervical cancer cells and its underlying mechanisms. We found the higher expression level of ADAMTS12 in cancer tissues, which was associated with the worse overall survival rate. The immunofluorescence assay showed that the cytoplasm of cervical cancer cells is the main expression site of ADAMTS12. Overexpression of ADAMTS12 in HeLa and CaSki cells prominently promoted the cell proliferation, migration and invasion. We found that 2032 genes were correlated with ADAMTS12, which was mainly related to extracellular matrix, TGF-β signaling pathway. The phosphorylation levels of mTOR and 4E-BP1 were upregulated in ADAMTS12-overexpressing cells. Co-Immunoprecipitation combined with protein mass spectrometry showed that TGF-β signaling pathway-related proteins interacting with ADAMTS12 were screened from HeLa cells with ADAMTS12 overexpression. Therefore, we concluded that ADAMTS12 may affect the mTOR signaling pathway through the interacting with TGF-β1, and then affect the biological function of cervical cancer cells.


Tea polyphenols alleviates acetochlor-induced apoptosis and necroptosis via ROS/MAPK/NF-κB signaling in Ctenopharyngodon idellus kidney cells.
Overuse of acetochlor pollutes soil and rivers, causing threats to the ecosystem. Studies found that acetochlor exposure could damage multiple organs and tissues in fish and mammal. Tea polyphenols (TP), a natural antioxidant that extracted from tea, has been widely used in food and feed additions. However, the mechanism by which acetochlor causes tissue damage is unclear, and its mitigating agent has yet to be developed. Therefore, we established acetochlor exposure and TP mitigation models by treating Ctenopharyngodon idellus kidney (CIK) cells with 20 μM acetochlor and/or 2.5 μg/mL TP for 24 h, and detected the programmed cell death and its related pathways. The results showed that acetochlor exposure modified antioxidant enzyme activities, induced oxidative stress, resulted in the decline of MMP and ATP levels, enhanced glycolysis and lactate accumulation, and triggered apoptosis and necroptosis in CIK cells. However, TP could inhibit CYP450s expression, activate Nrf2 pathway, enhance antioxidant capacity, further effectively alleviate acetochlor-induced CIK cell death. Overall, the present study proved that acetochlor exposure triggered mitochondrial damage and lactate accumulation-mediated apoptosis and necroptosis through CYP450s/ROS/MAPK/NF-κB pathway. Furthermore, TP could alleviate effectively cell death through relieving oxidative stress and lightening Warburg-like effect.


15-Deoxy-delta12,14-prostaglandin J2, a ligand for peroxisome proliferators-activated receptor-gamma, induces apoptosis in human hepatoma cells.
15-deoxy-delta12,14-prostaglandin J2 (15-d-PGJ2) induces apoptosis in several carcinoma cell lines and is a potent activator of peroxisome proliferators-activated receptor-gamma (PPAR-gamma). In the present study, we examined the effect of 15-d-PGJ2 on human hepatoma cells. HuH-7 and HepG2 cell lines were used in all the experiments. The mRNA expression of PPAR-gamma was studied by reverse transcriptase-polymerase chain reaction. The cell viability was determined by a modified MTT assay. Two methods were used for the determination of apoptosis in hepatoma cells: the TUNEL assay, and detection of fragmented mono- and oligo-nucleosomes by ELISA. The expression of PPAR-gamma mRNA and protein was detected in HuH-7 and HepG2. Treatment with 15-d-PGJ2 decreased cell viability in a time- and dose-dependent manner. 15-d-PGJ2 induced apoptosis and this effect was time-dependent. Exposure of cells to 15-d-PGJ2 induced caspase-3 and -9 activation. Furthermore, co-treatment with the pan-caspase inhibitor Z-VAD-FMK or the caspase-3 inhibitor Z-DEVD-FMK blocked apoptosis of human hepatoma cells that had been treated with 15-d-PGJ2. Our study demonstrates that PPAR-gamma is expressed in human hepatoma cell lines and that treatment with 15-d-PGJ2 inhibits the growth of these cells by inducing apoptosis through caspase activation.


Studies of peptide a- and b-type fragment ions using stable isotope labeling and integrated ion mobility/tandem mass spectrometry.
The structures of peptide a- and b-type fragment ions were studied using synthetic peptides including a set of isomeric peptides, differing in the sequence location of an alanine residue labeled with (15)N and uniformly with (13)C. The pattern of isotope labeling of second-generation fragment ions derived via a(n) and b(n) ions (where n = 4 or 5) suggested that these intermediates existed in part as macrocyclic structures, where alternative sites of ring opening gave rise to different linear forms whose simple cleavage might give rise to the observed final products. Similar conclusions were derived from combined ion mobility/tandem MS analyses where different fragmentation patterns were observed for isomeric a- or b-type ions that display different ion mobilities. These analyses were facilitated by a new approach to the processing of ion mobility/tandem MS data, from which distinct and separate product ion spectra are derived from ions that are incompletely separated by ion mobility. Finally, an example is provided of evidence for a macrocyclic structure for b(n) ions where n = 8 or 9.


Radioimmunoassay for the detection of virus-specific IgA antibodies in saliva.
The use of a sensitive and versatile radioimmunoassay (RIA) for detection of mumps-specific IgA and measles-specific IgA in unconcentrated saliva samples is described. The samples were obtained either by expectoration or by swabbing of the oral cavity, with or without stimulation of secretion, and were inactivated and clarified before testing. Mumps-specific IgA antibodies were detected as early as one day after onset of illness and peaked at 1-2 weeks after onset. Measles-specific salivary IgA antibodies were detected in 15-month old children 2-3 weeks after immunization. These results suggest that the RIA technique may be useful for early diagnosis of viral infections and for confirmation of response to immunization without the need for a blood sample, as well as for the study of the secretory immune response in very young and older subjects.


Deep convolutional neural network applied to the liver imaging reporting and data system (LI-RADS) version 2014 category classification: a pilot study.
To develop a deep convolutional neural network (CNN) model to categorize multiphase CT and MRI liver observations using the liver imaging reporting and data system (LI-RADS) (version 2014). A pre-existing dataset comprising 314 hepatic observations (163 CT, 151 MRI) with corresponding diameters and LI-RADS categories (LR-1-5) assigned in consensus by two LI-RADS steering committee members was used to develop two CNNs: pre-trained network with an input of triple-phase images (training with transfer learning) and custom-made network with an input of quadruple-phase images (training from scratch). The dataset was randomly split into training, validation, and internal test sets (70:15:15 split). The overall accuracy and area under receiver operating characteristic curve (AUROC) were assessed for categorizing LR-1/2, LR-3, LR-4, and LR-5. External validation was performed for the model with the better performance on the internal test set using two external datasets (EXT-CT and EXT-MR: 68 and 44 observations, respectively). The transfer learning model outperformed the custom-made model: overall accuracy of 60.4% and AUROCs of 0.85, 0.90, 0.63, 0.82 for LR-1/2, LR-3, LR-4, LR-5, respectively. On EXT-CT, the model had an overall accuracy of 41.2% and AUROCs of 0.70, 0.66, 0.60, 0.76 for LR-1/2, LR-3, LR-4, LR-5, respectively. On EXT-MR, the model had an overall accuracy of 47.7% and AUROCs of 0.88, 0.74, 0.69, 0.79 for LR-1/2, LR-3, LR-4, LR-5, respectively. Our study shows the feasibility of CNN for assigning LI-RADS categories from a relatively small dataset but highlights the challenges of model development and validation.


Bats of Georgia - an occurrence dataset from 1835 through 2022.
In Georgia, currently, 30 species of bats are recorded from four families and eleven genera. Although the oldest record of bats is from 1835 and continues until today, there are no comprehensive data available for bat diversity and distribution in Georgia. Thus, we aimed to fill that gap and make complete, expertly curated literature and our own published data openly available (through GBIF) for researchers and conservationists. In this publication, out of 1987 records, 1243 (62.4%) are new and unpublished data. Generally, out of all records, 34% are literature and museum data and 66% are data collected by us. Additionally, for the first time in the history of the study of bats in Georgia, we initiated surveys in forested areas of the country.


Apoptosis is induced in leishmanial cells by a novel protein kinase inhibitor withaferin A and is facilitated by apoptotic topoisomerase I-DNA complex.
Protein kinase C (PKC) is an important constituent of the signaling pathways involved in apoptosis. We report here that like staurosporine, withaferin A is a potent inhibitor of PKC. In Leishmania donovani, the inhibition of PKC by withaferin A causes depolarization of DeltaPsim and generates ROS inside cells. Loss of DeltaPsim leads to the release of cytochrome c into the cytosol and subsequently activates caspase-like proteases and oligonucleosomal DNA cleavage. Moreover, in treated cells, oxidative DNA lesions facilitate the stabilization of topoisomerase I-mediated cleavable complexes, which also contribute to DNA fragmentation. However, withaferin A and staurosporine cannot induce cleavable complex formation in vitro with recombinant topoisomerase I nor with nuclear extracts from control cells. Taken together, our results indicate that inhibition of PKC by withaferin A is a central event for the induction of apoptosis and that the stabilization of topoisomerase I-DNA complex is necessary to amplify apoptotic process.


MicroRNA-29a-3p strengthens the effect of dexmedetomidine on improving neurologic damage in newborn rats with hypoxic-ischemic brain damage by inhibiting HDAC4.
Hypoxic-ischemic brain damage (HIBD) is a common brain injury caused by hypoxia or ischemia of the brain. This study aims to investigate the effect of dexmedetomidine (Dex) post-treatment on neurological impairment of newborn rats with HIBD via modulating microRNA-29a-3p (miR-29a-3p) and histone deacetylase 4 (HDAC4). HIBD model of newborn rats was established. Newborn modeled rats were injected with Dex, miR-29a-3p mimic or HDAC4 siRNA to figure their roles in learning and memory abilities, left hemisphere atrophy, brain tissue injury, inflammatory response and apoptosis rate of nerve cells of rats. The expression of miR-29a-3p and HDAC4 in hippocampal tissues of rats were detected, and the potential relationship between miR-29a-3p and HDAC4 was analyzed. Decreased miR-29a-3p and elevated HDAC4 were found in hippocampal tissues of rats with HIBD. In addition, Dex, elevated miR-29a-3p or declined HDAC4 enhanced spatial learning and memory abilities in rats with HIBD. Moreover, Dex, up-regulated miR-29a-3p or declined HDAC4 alleviated brain atrophy, repressed brain tissue injury, retrained the inflammation, repressed the apoptosis of neurons in the hippocampal region of rats with HIBD. HDAC4 was targeted and negatively regulated by miR-29a-3p. The study concludes that miR-29a-3p strengthened the effect of Dex on improving neurologic damage in newborn rats with HIBD by inhibiting HDAC4.


The dynamics of electric powered wheelchair sideways tips and falls: experimental and computational analysis of impact forces and injury.
To reduce the occurrence of wheelchair falls and to develop effective protection systems, we aimed to quantify sideways tip and fall dynamics of electric power wheelchairs (EPWs). We hypothesized that driving speed, curb height and angle of approach would affect impact forces and head injury risk for wheelchair riders. We further expected that fall dynamics and head injury risk would be greater for unrestrained riders compared to restrained riders. Sideways wheelchair tip and fall dynamics were reconstructed using a remotely operated rear wheel drive EPW and a Hybrid III test dummy driving at different approach angles (5 to 63°) over an adjustable height curb (0.30 to 0.41 m) at speeds of 0.6-1.5 m/s. Rigid body dynamics models (Madymo, TASS International, Livonia, MI) were developed in parallel with the experiments to systematically study and quantify the impact forces and the sideways tip or fall of an EPW user in different driving conditions. Shallower approach angles (25°) (p < 0.05) and higher curbs (0.4 m) (p < 0.05) were the most significant predictors of tipping for restrained passengers. Unrestrained passengers were most affected by higher curbs (0.4 m) (p < 0.005) and fell forward from the upright wheelchair when the approach angle was 60°. Head impact forces were greater in unrestrained users (6181 ± 2372 N) than restrained users (1336 ± 827 N) (p = 0.00053). Unrestrained users had significantly greater head impact severities than restrained users (HIC = 610 ± 634 vs HIC = 29 ± 38, p = 0.00013) and several tip events resulted in HICs > 1000 (severe head injury) in unrestrained users. Sideways tips and forward falls from wheelchairs were most sensitive to curb height and approach angle but were not affected by driving speed. Sideways tips and falls resulted in impact forces that could result in concussions or traumatic brain injury and require injury prevention strategies. Seat belts eliminated the risk of falling from an upright chair and reduced head impact forces in sideways wheelchair tips in this study; however, their use must be considered within the ethical and legal definitions of restraints.


Correlates of excessive daytime sleepiness in Parkinson's disease.
Measures of excessive daytime sleepiness, neuropsychologic function, and mood were assessed in twenty-two persons with mid-stage Parkinson's disease (PD) and sixteen age-matched healthy controls. Levodopa dose equivalents (LDE) were computed for the patients. While Epworth sleepiness score (ESS), Mini Mental State Exam, logical memory, Stroop, and the mood scales, reliably distinguished patients from controls, only the mood scales (especially anxiety) were reliably associated with ESS. LDE was not significantly associated with ESS. Excessive daytime sleepiness in patients with mid-stage PD may be more strongly related to anxiety than to other neuropsychologic dysfunction or dopaminergic dosing levels.


Origin of craniopharyngiomas: implication on the growth pattern.
The surgical management of craniopharyngiomas has been among the most challenging neurosurgical procedures because of their complex topographical relationship with surrounding structures and high recurrence rate after subtotal resection. Craniopharyngiomas have been classified only by their location to determine an appropriate surgical approach without due regard to other factors that could affect the surgical results, such as the extent of adhesion to surrounding structures or the nature of the tumor. We describe the role of the diaphragm sellae on the growth patterns of craniopharyngiomas from surgical experiences and pathological evidences, suggesting the classification of craniopharyngiomas into three categories by the level of origin and the competence of the diaphragm sellae: a tumor of subdiaphragmatic origin with competent diaphragm sellae, subdiaphragmatic with incompetent diaphragm sellae, and supradiaphragmatic. Tumors in each category have shown peculiar topographical relationship with the optic chiasm, third ventricle, and also adhesion extents. The nature of the tumor itself, e.g., the composition of cystic and solid parts, may bring additional minor variations to the topographical features of a craniopharyngioma, but will maintain the major characteristics determined by its level of origin and competence of the diaphragm sellae. This classification scheme, which considers the origin level, is clinically relevant and useful because optimal surgical approaches could be designed by considering multiple factors affecting surgical procedure and outcome, including the expected extent of adhesion and preferred sites of recurrence, as well as the topographical location of the tumor. In subdiaphragmatic tumors, which correspond to intrasellar and prechiasmatic tumors, a transsphenoidal approach could be reasonably attempted even with considerable suprasellar extensions because they tend to adhere to the intrasellar structures, and the superior surface of the tumor may be easily separated from the brain structures by pulling. Supradiaphragmatic tumors, however, may need a wider surgical approach that can provide direct vision of the tumor because of possible extensive adhesion.


VAP: just how good a benchmark is it really?
VAP shares symptoms with several conditions common to the ICU. Diagnosis is considered to be more reliable in the outpatient setting. New measures should reflect the totality of complications that can affect ventilated patients in addition to pneumonia.


A Structure-Activity Analysis for Probing the Mechanism of Processive Double-Stranded DNA Digestion by λ Exonuclease Trimers.
λ exonuclease (λexo) is an ATP-independent 5'-to-3' exonuclease that binds to double-stranded DNA (dsDNA) ends and processively digests the 5'-strand into mononucleotides. The crystal structure of λexo revealed that the enzyme forms a ring-shaped homotrimer with a central funnel-shaped channel for tracking along the DNA. On the basis of this structure, it was proposed that dsDNA enters the open end of the channel, the 5'-strand is digested at one of the three active sites, and the 3'-strand passes through the narrow end of the channel to emerge out the back. This model was largely confirmed by the structure of the λexo-DNA complex, which further revealed that the enzyme unwinds the DNA by 2 bp prior to cleavage, to thread the 5'-end of the DNA into the active site. On the basis of this structure, an "electrostatic ratchet" model was proposed, in which the enzyme uses a hydrophobic wedge to insert into the base pairs to unwind the DNA, a two-metal mechanism for nucleotide hydrolysis, a positively charged pocket to bind to the terminal 5'-phosphate generated after each round of cleavage, and an arginine residue (Arg-45) to bind to the minor groove of the downstream end of the DNA. To test this model, in this study we have determined the effects of 11 structure-based mutations in λexo on DNA binding and exonuclease activities in vitro, and on DNA recombination in vivo. The results are largely consistent with the model for the mechanism that was proposed on the basis of the structure and provide new insights into the roles of particular residues of the protein in promoting the reaction. In particular, a key role for Arg-45 in DNA binding is revealed.


Knowledge of nosocomial infections, standard precautions, and source of information among physiotherapy undergraduates in Sri Lanka; an observational study.
Physiotherapists and physiotherapy undergraduates have direct contact with patients which make them transmitters of infections if they do not follow standard precautions. Hence, the purpose of this study was to assess the knowledge of nosocomial infections, standard precautions, and source of information among physiotherapy undergraduates in Sri Lanka. An observational Google based survey study was conducted among 294 physiotherapy undergraduates, of which there were 103 in University of Peradeniya, 103 in University of Colombo, and 88 in General Sir John Kotelawala Defence University. The Infection Control Standardized Questionnaire comprising three domains: knowledge of nosocomial infections, standard precautions and hand hygiene was used for data collection along with a self-constructed data sheet for socio-demographic information and source of information. Participants achieved mean knowledge of 67.1 ± 16.8, 84.4 ± 14.7 and 66.4 ± 15.4 for nosocomial infections, standard precautions, and hand hygiene respectively. Of the total sample, 225 (76.5%) achieved adequate level of total knowledge. Eighty-three of them (28.3%) equally mentioned, formal teaching at faculty and informal sources as the most important source of knowledge. There was no significant impact of university and the duration of clinical exposure on knowledge of nosocomial infections, standard precautions, hand hygiene and total knowledge. The study year has a significant impact on standard precautions (P = 0.004) and total knowledge (P = 0.035) and final years had highest knowledge compared to the other study years. Knowledge of nosocomial infections and infection control measures were satisfactory among the physiotherapy undergraduates in Sri Lanka. Further developments of formal sources of information about nosocomial infections are recommended.


Left ventricular imaging by digital subtraction angiography.
Digital radiography is a rapidly developing new approach to cardiovascular imaging that converts radiographic and fluoroscopic video images into digital format for subsequent image enhancement analysis, and storage. Left ventriculography can be performed by this method using either intravenous or low-dose intraventricular contrast administration. Advantages over standard radiography include reduced radiation and contrast medium burden, visualization of very low contrast medium concentrations, and an image format that can be directly analyzed by quantitative techniques. As these cardiac applications are developed and improved archiving is implemented, it is likely that the digital left ventriculography will replace standard cardiac angiography.


Major depression and immunity: preliminary evidence of decreased natural killer cell populations.
1. Alterations in cellular immunity have been suggested to occur in major depressed patients. 2. To investigate the populations of B-cells, T-cells and T-cell subsets in major depression, the authors utilized monoclonal antibody techniques to enumerate the number of total lymphocytes, B-cells and T-cell subpopulations in recently admitted patients with major depression or non-affective disorders. 3. The authors also studied the relationship between the immune state and hypercortisolism as measured by post-dexamethasone serum cortisol. 4. The preliminary findings from this pilot study suggest that major depressed patients may have altered cellular immunity as demonstrated by lower numbers of natural killer cells. 5. Further study will be necessary to confirm the trend for lower numbers of T-cell lymphocytes and T-cell subpopulations including helper cells, suppressor cells and natural killer cells in patients with non-suppression of serum cortisol following dexamethasone.


Chromosomal Microarray Reinterpretation: Applications to Pediatric Practice.
Chromosomal microarray analysis (CMA) frequently yields inconclusive results. We reexamined inconclusive CMA results from 33 previously tested patients and reached a definitive diagnosis in 3 (9.1%) and identified the need for additional testing in 4 (12.1%). Reinterpretation may resolve inconclusive CMA results.


Severe cyanobacteria accumulation potentially induces methylotrophic methane producing pathway in eutrophic lakes.
Although cyanobacteria blooms lead to an increase in methane (CH4) emissions in eutrophic lakes have been intensively studied, the methane production pathways and driving mechanisms of the associated CH4 emissions are still unclear. In this study, the hypereutrophic Lake Taihu, which has extreme cyanobacteria accumulation, was selected to test hypothesis of a potential methylotrophic CH4 production pathway. Field observation displayed that the CH4 emission flux from the area with cyanobacteria accumulation was 867.01 μg m-2·min-1, much higher than the flux of 3.44 μg m-2·min-1 in the non-cyanobacteria accumulation area. The corresponding abundance of methane-producing archaea (MPA) in the cyanobacteria-concentrated area was 77.33% higher than that in the non-concentrated area via RT-qPCR technologies. Synchronously, sediments from these areas were incubated in anaerobic bottles, and results exhibited the high CH4 emission potential of the cyanobacteria concentrated area versus the non-concentrated area (1199.26 vs. 205.76 μmol/L) and more active biological processes (CO2 emission, 2072.8 vs. -714.62 μmol/L). We also found evidence for the methylotrophic methane producing pathway, which contributed to the high CH4 emission flux from the cyanobacteria accumulation area. Firstly, cyanobacteria decomposition provided the prerequisite of abundant methyl thioether substances, including DMS, DMDS, and DMTS. Results showed that the content of methyl thioethers increased with the biomass of cyanobacteria, and the released DMS, DMDS, and DMTS was up to 96.35, 3.22 and 13.61 μg/L, respectively, in the highly concentrated 25000 g/cm3 cyanobacteria treatment. Then, cyanobacteria decomposition created anaerobic microenvironments (DO 0.06 mg/L and Eh -304.8Mv) for methylotrophic methane production. Lastly, the relative abundance of Methanosarcinales was increased from 7.67% at the initial stage to 36.02% at the final stage within a sediment treatment with 10 mmol/L N(CH3)3. Quantitatively, the proportion of the methylotrophic methane production pathway was as high as 32.58%. This finding is crucial for accurately evaluating the methane emission flux, and evaluating future management strategies of eutrophic lakes.


Silent ovulation in rhesus monkeys (M. mulatta): dissociation of hormonal and behavioral states.
Ovarian hormone levels were monitored in rhesus monkeys during the breeding and non-breeding seasons. Ovulation (as inferred from progesterone levels in blood serum in excess of 1.5 ng/ml) was most frequent in the breeding season but was absent only during the month of August. Summer (non-breeding season) ovulations were more frequently "silent," or without heterosexual behavior, than were winter ovulations. This finding suggested that estradiol stimulation may cause different behavioral responses at different times of the year. To test this hypothesis, ovariectomized females were treated with subcutaneously implanted estradiol capsules at different times within and outside the normal breeding season. In either season, treatment with estradiol resulted in increased female-to-female sexual behavior. Only during the breeding season, however, did the estradiol-treated ovariectomized females interact sexually with males. Although males copulated with both estradiol-treated and gonadally intact, untreated females during the breeding season, their rate of copulation with the intact females was higher. The results suggest that: (1) Some female rhesus monkeys displaying strictly seasonal breeding behavior continue to have luteal activity indicative of ovulation in May, June and July, (2) Summer ovulatory cycles are rarely accompanied by sexual behavior, (3) Estradiol treatment of ovariectomized females induces female-to-female sexual behavior both in the breeding and non-breeding seasons, and (4) Males are less responsive to the presence of estrogen-stimulated females in the non-breeding season than in the breeding season.


Ectopic pregnancy after cesarean hysterectomy.
Ectopic pregnancy after a total abdominal hysterectomy is rare and, for this reason, delay in diagnosis may occur when such a patient presents with abdominal pain. A multiparous patient with a history of cesarean hysterectomy 12 years before presented to the emergency department with abdominal pain and incidental positive urine beta-human chorionic gonadotrophin (hCG). A computed tomography scan revealed a loculated left cystic mass in the pelvis. Laparotomy findings revealed a left adnexal mass; pathology revealed chorionic villi consistent with pregnancy. Ectopic pregnancy may occur after hysterectomy, but typically presents near the time of surgery and is more commonly associated with vaginal hysterectomy. However, because ectopic pregnancy is possible after hysterectomy, it should be considered in the differential diagnosis of adnexal mass in such a patient.


Harnessing transposons for cancer gene discovery.
Recently, it has become possible to mobilize the Tc1/mariner transposon, Sleeping Beauty (SB), in mouse somatic cells at frequencies high enough to induce cancer. Tumours result from SB insertional mutagenesis of cancer genes, thus facilitating the identification of the genes and signalling pathways that drive tumour formation. A conditional SB transposition system has also been developed that makes it possible to limit where SB mutagenesis occurs, providing a means to selectively model many types of human cancer. SB mutagenesis has already identified a large collection of known cancer genes in addition to a plethora of new candidate cancer genes and potential drug targets.


Translational organoid technology - the convergence of chemical, mechanical, and computational biology.
Successful clinical translation of organoid technology requires insights that extend beyond biology and biochemistry, notably from the fields of mechanical and computational biology. This review highlights recent advances in the organoid field that could potentially accelerate translation. We first review organoid fabrication methods, focusing on engineering approaches that increase organoid reproducibility, controllability, and production ability, as well as the physical conditions, culture media, and extracellular materials that regulate cell signaling and mechanotransduction. We then review computation-based organoid evaluation, including both information acquisition and data mining. Finally, we summarize the limitations of current advances and application horizons as well as the perspective of digital organoids.


Does tuftsin alter phagocytosis by human polymorphonuclear neutrophils?
The physiological significance of the putative phagocytosis-promoting peptide, tuftsin, was investigated by measurement of chemiluminescence generated during phagocytosis and by assay of the uptake of radiolabeled bacteria. We found no differences in either assay when we compared serum from splenectomized patients (which purportedly lacks tuftsin) with normal serum. Further, there was no difference when serum from splenectomized patients was employed in the presence of absence of exogenous tuftsin. Similar results were obtained under a variety of conditions, utilizing three different challenge particles with varying particle-cell ratios and serum from 20 different splenectomized patients. These results do not agree with the hypothesis that tuftsin plays a major role in promoting phagocytosis.


Evidence-Based Practice in the social sciences? A scale of causality, interventions, and possibilities for scientific proof.
This article discusses Evidence-Based Practice (EBP) in the social sciences. After a brief outline of the discussion, the work of William Herbert Dray (1921-2009) is examined. Dray, partly following Collingwood, worked on different forms of causality and methodology in historical explanation (in comparison to the social sciences), based on a distinction between causes and reasons. Dray's ladder of rational understanding is also explored here. Taking his argumentation further and sometimes turning it upside-down, a scale of forms of causality is developed with accompanying types of interventions and possibilities for scientific proof of their effectivity. This scale makes it possible to weigh interventions regarding the degree to which "hard" scientific proof is possible for them. The article concludes with a brief discussion of how interventions in psychology and education should be chosen and can be justified, both those that do and those that don't lend themselves to empirical research.


Cigarette smoking as an etiologic factor in cleft lip and palate.
A case-control study has been made on smoking habits in women who, during 1975, gave birth to infants with closure defects of the central nervous system (ASB) or with cleft lip or cleft palate (CLP). For each case, two control subjects with nonmalformed infants were selected and matched for delivery unit, time of delivery, maternal age, and maternal parity. Smoking habits were routinely included in hospital records at first visit to a maternity health clinic during pregnancy. Data were studied for 66 cases of CLP, 66 cases of ASB, and 261 control subjects. Significantly more women who had infants with CLP smoked than did control women, but women with ASB infants showed a normal smoking pattern. Drug use did not explain the findings. It is suggested that maternal smoking is one of many factors of importance in the etiology of cleft lip and cleft palate in humans.


Comparative studies of neoplastic response to a single dose of nitroso compounds. 6. The effect of diethylnitrosamine in Syrian golden hamsters.
The effect of a single subcutaneous injection of different DEN doses was examined in adult Syrian hamsters observed for life. The minimal effective dose (threshold dose) for neoplastic response, reflected by induction of papillary polyps in the larynx and/or trachea, was 1.03 mg DEN/kg body weight. No tumors were found which could be related to treatment in other segments of the respiratory epithelium nor in other tissues.


Chromatin remodeling at DNA double-strand breaks.
DNA double-strand breaks (DSBs) can arise from multiple sources, including exposure to ionizing radiation. The repair of DSBs involves both posttranslational modification of nucleosomes and concentration of DNA-repair proteins at the site of damage. Consequently, nucleosome packing and chromatin architecture surrounding the DSB may limit the ability of the DNA-damage response to access and repair the break. Here, we review early chromatin-based events that promote the formation of open, relaxed chromatin structures at DSBs and that allow the DNA-repair machinery to access the spatially confined region surrounding the DSB, thereby facilitating mammalian DSB repair.


Towards a green future for Sub-Saharan Africa: do electricity access and public debt drive environmental progress?
The combination of rising debt levels, poor electricity access, and environmental deterioration could threaten the attainment of the sustainable development goals (SDGs). Hence, this inquiry examined the implications of public borrowing and access to electricity on environmental sustainability (proxied by ecological footprint (ECOL) and carbon dioxide (CO2) emissions) in Sub-Saharan Africa (SSA), largely overlooked in the literature. In addition to pre-estimation, diagnostic, and robustness checks utilized in the study, the instrumental variable generalized method of moment (IV-GMM) approach is employed to examine annual data from 39 SSA economies between 2005 and 2018. The key findings indicate that public debt negatively influences environmental sustainability in the region at a certain level of threshold, while access to electricity has the potential to trigger environmental sustainability but remain below the expected threshold to mitigate environmental damage in SSA. The study provides recommendations for SSA policymakers to significantly reduce pollution and protect the environment which is vital for sustainable development.


Cr3C2 nanoparticles decorated carbon nanofibers for efficient nitrate reduction to ammonia at ambient conditions.
Electrochemical nitrate (NO3-) reduction is a promising approach to relieve nitrate pollution and produce value-added ammonia (NH3), but efficient and durable catalysts are required due to the large bond dissociation energy of nitrate and low selectivity. Herein, we propose chromium carbide (Cr3C2) nanoparticles loaded carbon nanofibers (Cr3C2@CNFs) as electrocatalysts to convert nitrate to ammonia. In phosphate buffer saline containing 0.1 mol L-1 NaNO3, such catalyst achieves a large NH3 yield of 25.64 mg h-1 mg-1cat. and a high faradaic efficiency of 90.08% at -1.1 V vs the reversible hydrogen electrode, which also shows excellent electrochemical durability and structural stability. Theoretical calculations reveal the adsorption energy for nitrate at Cr3C2 surfaces reaches -1.92 eV and the potential determining step (*NO→*N) for Cr3C2 hits a low energy increase of 0.38 eV.


Diabetes-Related Complications and Mortality in Patients With Atrial Fibrillation Receiving Different Oral Anticoagulants : A Nationwide Analysis.
Evidence about the association between types of oral anticoagulants and hazards of diabetes complications is limited in patients with atrial fibrillation (AF) and diabetes mellitus (DM). To compare the hazards of diabetes complications and mortality between patients with AF and DM receiving non-vitamin K antagonist oral anticoagulants (NOACs) and those receiving warfarin. A retrospective cohort study. Nationwide data obtained from Taiwan's National Health Insurance Research Database. Patients with AF and DM receiving NOACs or warfarin between 2012 and 2017 in Taiwan were enrolled. Treatment groups were determined by patients' first initiation of oral anticoagulants. Hazards of diabetes complications (macrovascular complications, microvascular complications, and glycemic emergency) and mortality in the NOAC and warfarin users were investigated with a target trial design. Cause-specific Cox proportional hazards models were used to estimate hazard ratios (HRs). Propensity score methods with stabilized inverse probability of treatment weighting were applied to balance potential confounders between treatment groups. In total, 19 909 NOAC users and 10 300 warfarin users were included. Patients receiving NOACs had significantly lower hazards of developing macrovascular complications (HR, 0.84 [95% CI, 0.78 to 0.91]; P < 0.001), microvascular complications (HR, 0.79 [CI, 0.73 to 0.85]; P < 0.001), glycemic emergency (HR, 0.91 [CI, 0.83 to 0.99]; P = 0.043), and mortality (HR, 0.78 [CI, 0.75 to 0.82]; P < 0.001) than those receiving warfarin. Analyses with propensity score matching showed similar results. Several sensitivity analyses further supported the robustness of our findings. The claims-based data did not allow for detailed data on patients' lifestyles and laboratory examinations to be obtained. Non-vitamin K antagonist oral anticoagulants were associated with lower hazards of diabetes complications and mortality than warfarin in patients with AF and DM. Hualien Tzu Chi Hospital.


Hooked from the first cigarette.
New research has overturned the dogma that cigarette addiction takes years to develop. Studies of adolescent smokers show that symptoms of addiction, such as withdrawal, craving for cigarettes and failed attempts at quitting, can appear within the first weeks of smoking. To account for these findings, scientists have developed a new theory positing that the brain quickly develops adaptations that counter the effects of nicotine. These adaptations lead to withdrawal symptoms when the effects of nicotine wear off. The results highlight the importance of boosting government funding for antismoking campaigns, particularly those aimed at youngsters.


Associations of cephalad drainage in neonatal veno-venous ECMO - A mixed-effects, propensity score adjusted retrospective analysis of 20 years of ELSO data.
Neurologic complications can occur during neonatal Veno-Venous (VV) ECMO. The addition of a cephalad drainage cannula (i.e., VVDL+V) to dual lumen cannulation (i.e., VVDL) has been advocated to reduce such complications, but previous studies have presented mixed results. Data from the ECMO Registry of the Extracorporeal Life Support Organization was used to extract all neonates (≤28 days old) who underwent VV ECMO for respiratory support between 2000 and 2019. Primary outcomes were mortality, conversion to Veno-Arterial (VA) ECMO, pump flows, and complications. A mixed-effects, propensity score adjusted analysis was performed. 4,275 neonates underwent VV ECMO, 581 (13.6%) via VVDL+V cannulation, and 3,694 (86.4%) via VVDL. On unadjusted analyses, VVDL+V patients had higher rates of mortality (25.5% vs 19.0%, p<0.001), conversion to VA ECMO (14.5% vs 4.1%, p<0.001), and higher pump flows at 4 h from ECMO initiation (112.7 vs 105.5 mL/Kg/min, p<0.001), but lower at 24 h (100.3 vs 104.0 mL/Kg/min, p = 0.004), and a higher proportion of them experienced hemorrhagic (29.3% vs 18.3%, p<0.001), cardiovascular (60.8% vs 45.8%, p<0.001), and mechanical (42.5% vs 32.6%, p<0.001) complications compared to VVDL patients. After adjusting for propensity scores and the multi-level nature of ELSO data, there were no differences in neurologic outcomes, pump flows, or mortality. Rather, VVDL+V cannulation was associated with higher rates of conversion to VA ECMO (adjusted odds ratio [AOR] 43.3, 95% CI 24.3 - 77.4, p<0.001), and increased mechanical (AOR 2.2, 95% CI 1.6 - 3.0, p<0.001) and hemorrhagic (AOR 2.0, 95% CI 1.4 - 3.0, p<0.001) complications. In this analysis, VVDL+V cannulation was not associated with any improvement in neurologic outcomes, pump flows, or mortality, but was rather associated with higher rates of conversion to Veno-Arterial ECMO, mechanical, and hemorrhagic complications.


Plant Sense: The Rise of Calcium Channels.
Although calcium (Ca2+) elevation triggered by abiotic and biotic stimuli has long been a documented phenomenon in plants, the mechanism underlying the control of Ca2+ spikes remains elusive. Recent progress, reported by Tian et al., Wang et al., Yu et al., Jiang et al., and Wu et al., has been made in elucidating how Ca2+ channels are controlled during pathogen attack, cell death, and salt or hydrogen peroxide sensing.


The use of low temperature X-ray diffraction to evaluate freezing methods used in freeze-fracture electron microscopy.
Two methods of freezing samples for freeze-fracture electron microscopy have been compared using X-ray diffraction and freeze-fracture results from lipid-water model systems. Perturbations of the molecular organization of hydrocarbon chains and the extent of ice crystal formation have been evaluated for lamellar phases of egg lecithin containing 16% water and egg lecithin-phosphatidylinositol containing 55% water, both freeze quenched in liquid Freon-22 near its melting temperature (113 K). Very thin samples sandwiched between copper sheets separated by an electron microscope grid show much less freezing induced structural rearrangement than small smaples contained on conventional Balzers-type gold planchettes. These results show that the rate of freezing in the very thin preparations is greater than in the conventional ones, which is probably due in part to the improved dissipation of heat from a poorly conductive sample through highly conductive copper sheets.


Protein and amino acid metabolism and requirements in older persons.
In this short review, some aspects of body protein and amino-acid metabolism during aging in human subjects have been explored. There is a progressive diminution of total body protein with aging, due largely to a decline in the size of the skeletal muscle mass. These changes are accompanied by a shift in the overall pattern of whole body protein synthesis and breakdown, with muscle mass estimated to account for about 30 per cent of whole body protein turnover in the young adult, as compared with a lower value of 20 per cent or less in the elderly subject. Because skeletal muscle mass plays an important role in the response of body protein and amino-acid metabolism to stress, such as infection and trauma, this decline in the contribution of muscle to total body protein metabolism might be a factor responsible for the reduced ability of older people to withstand unfavorable circumstances. The determination of the dietary requirements for individual essential amino acids and for total protein has been discussed, and it is evident that the data are limited and often contradictory. However, elderly individuals are more likely to be affected by various biological, environmental, and social factors, which would generally increase protein needs above those for younger adults. Thus, in practice, the protein needs in the elderly are likely to be higher than those in the young. The decline in energy intake, together with its possible consequences for reducing the efficiency of dietary protein utilization, also will tend to increase the protein need for elderly subjects, relative to that for physically more active young adults. Until more data become available, it is recommended, for food planning purposes, that an appropriate protein allowance would be 12 to 14 per cent of the total energy intake, for mixed protein sources characteristic of the diets of industrialized countries or the more affluent sector of populations in developing countries. Energy intake should be at a level that meets the estimates proposed by FAO/WHO/UNU8 for older persons. Higher levels of protein intake would be required to achieve tissue protein repletion following periods of undernutrition or increased body protein (nitrogen) losses due to stressful stimuli of physical or psychological origin.


Generation of Myocardial Ischemic Wounds and Healing with Stem Cells.
Myocardial ischemia is a common manifestation of cardiovascular diseases (CVD) that affects the health and lives of millions of people worldwide. While numerous treatment options exist that address cardiac damage after ischemic injury, none of these can repair damaged cardiac tissue. Stem cell-mediated therapy is an emerging approach for cardiac tissue regeneration that has shown promise in preclinical models and in clinical studies. However, much more research in this field must be carried out to bring effective stem cell therapies to clinical settings. This protocol discusses the methods for generation of an animal model of myocardial ischemia in a preclinical setting, expansion of viable hematopoietic stem cells on a nanofiber scaffold, and administration of cells into the ischemic animal to verify therapeutic efficacy.


Mesoporous structured estrone imprinted Fe3O4@SiO2@mSiO2 for highly sensitive and selective detection of estrogens from water samples by HPLC.
In the present work, mesoporous structured estrone (E1) imprinted Fe3O4@SiO2@mSiO2 (MM-MIPs) was prepared and applied as extraction sorbent for selective pre-concentration and specific recognition of E1, 17β-estradiol (E2) and estriol (E3) from water samples. MM-MIPs present higher binding capacity, faster mass transfer and higher extraction efficiency for three estrogens than the non-porous structured Fe3O4@SiO2. Application of MM-MIPs to dispersive solid phase extraction of three estrogens from spiked tap, river and lake water samples at 0.5, 1.0, 10 μg L(-1) resulted in good recoveries ranging from 85% to 95% with relative standard deviation values lower than 6.0% in all cases. Limits of detection were in the range of 0.086-0.43 μg L(-1). The extraction method based on MM-MIPs proved to be a highly-effective enrichment method with enrichment factor about 1700, which is much higher than the value nearly 620 obtained by non-mesoporous Fe3O4@SiO2, during the process of simultaneous separation and sensitive determination of estrogens in complicated water samples. Furthermore, the mesoporous silica could be expanded to imprint other compounds.


Assessment of binge drinking of alcohol in highly educated employees.
This study evaluated the usefulness of the Alcohol Use Disorders Identification Test (AUDIT) and CAGE, a standardized screening instrument for detecting alcohol dependence in identifying binge drinking among highly educated employees. Brochures were mailed to an entire workforce inviting employees to learn about their coping strategies, stress levels, and risk for alcohol-related problems, with 228 employees providing complete data. Binge drinking in the previous 3 months was reported by 29% of the employees, with greater binge drinking reported by White employees, of mixed/other ethnic background, or younger. The AUDIT achieved a sensitivity of 35% in identifying respondents who reported binge drinking and a specificity of 98% in accurately identifying respondents who did not report binge drinking. Sensitivity using the cut-off of scoring one or more positive hits on the CAGE was 67%, and specificity was 84%. Therefore, neither the AUDIT nor the CAGE achieved adequate sensitivity, as well as specificity, as screening tools for assessing binge drinking. A more accurate method for assessing binge drinking appears to be by directly asking for the largest number of drinks consumed in a single drinking session.


Occurrence of and exposure to benzothiazoles and benzotriazoles from textiles and infant clothing.
Benzothiazoles (BTHs) and benzotriazoles (BTRs) are used in a wide range of applications, including rubber vulcanization and corrosion inhibition. Limited studies have reported the occurrence of BTHs and BTRs in textiles, including children's clothing. In this study, 79 textile samples (raw as well as tailored) collected in Albany, New York, USA, were analyzed to determine the occurrence of BTH, BTR and their seven common derivatives. BTH, 2-methylthio-benzothiazole (2-Me-S-BTH) and 2-hydroxy-benzothiazole (2-OH-BTH) were found in textiles at a detection rate (DR) of 86%, 54% and 19%, respectively. The DRs of tolyltriazole (TTR), BTR and 5-chloro-benzotriazole (5-Cl-BTR) in textiles were below 20%. Although BTH was the most frequently detected compound, BTR levels were elevated in certain textiles and the overall mean concentrations of BTR in textiles were higher than those of BTH. The concentrations of BTH in textiles ranged from 6.1 to 1120ng/g. The highest concentration of BTR (14,000ng/g) was found in a printed graphic of infant's bodysuit. On the basis of the measured concentrations, we calculated dermal exposure doses to BTHs and BTRs by infants. The dermal exposure doses were high from the use of socks (244 to 395pg/kg·bw/d), and the exposure doses of BTHs and BTRs from textiles were as high as 3740pg/kg·bw/d. Printed graphics on clothes, as well as socks, accounted for a major proportion of the exposure doses to BTHs and BTRs.


Equation for evolution of temporal width of a solute band migrating in chromatographic column.
An alternative differential equation to model the development of the temporal width of a solute band during its migration in a chromatographic column is developed. This model uses the solute residency, the inverse of the solute velocity, as parameter, which has the advantage to be an always finite quantity even at the column outlet in GC-MS where carrier gas velocity approaches infinity. The new differential equation is derived from a known equation describing the evolution of the spatial variance of migrating band. Supplemental material illustrating solutions of the newly developed equation in several special cases is provided.


Regenerative medicine and human models of human disease.
Recent advances in stem-cell technology are now allowing the mechanisms of human disease to be studied in human cells. A new era for regenerative medicine is arising from such disease models, extending beyond early cell-based therapies and towards evaluating genetic variation in humans and identifying the molecular pathways that lead to disease, as well as targets for therapy.


DNA integrity-protecting and survival-promoting activity of serotonergic system in sturgeon juveniles and sazans.
The study concerns evaluation of engagement of serotonergic system in the mechanisms of antimutagenic protection and survival under adverse conditions. It is shown that under long-term exposure to oil and industrial pollution, simultaneous sharp increase of mutations level in the erythrocytes and downregulation of serotonin-modulating anticonsolidation protein (SMAP; Mekhtiev 2000) in the livers of the sturgeon juveniles (Acipenser gueldenstaedtii persicus) is observed. Mutation level was evaluated by the micronucleus analysis and SMAP level-by the indirect ELISA-test utilizing anti-SMAP immunoglobulins. Intramuscular administration of SMAP leads to significant decrease of micronucleus amount in the erythrocytes of the sturgeon juveniles exposed to sediments polluted with PAH and heavy metals. Pre-conditioning of sazans by low dose of insecticide actara (100 mg/l) leads to upregulation of SMAP and to survival of all the animals in the experimental group, kept under high concentration of actara (400 mg/l), while all animals in the control group succumbed under these conditions. I.m. administration of SMAP prior to putting the sazans into the water containing high levels of actara (400 mg/l), in contrast to controls, leads to their total survival. Participation of serotonergic system in the mechanisms of antimutagenic protection and survival promotion under damaging conditions is concluded.


MR imaging of postischemic neuronal death in the substantia nigra and thalamus following middle cerebral artery occlusion in rats.
The goal of this study was to investigate apparent diffusion coefficient (ADC) and T(2) relaxation time (T(2)) in the substantia nigra and thalamus after middle cerebral artery occlusion in rats. In the substantia nigra ipsilateral to infarct, ADC was significantly lower and T(2) was significantly higher on the third and fourth days, but they did not change significantly on the first, second, eighth and 15th days. In the ipsilateral thalamus, ADC and T(2) did not change significantly between the first and fourth days, but were significantly lower on the eighth and 15th days. This combination of MR findings suggested that secondary degeneration in the thalamus was different from that in the substantia nigra.


Leisure time physical activity patterns in Odisha, India.
The World Health Organization has recommended a moderate intensity physical activity of 150min, or 75min vigorous-intensity physical activity per week to achieve optimal health benefits. It is not known if Indian populations who indulge in leisure time physical exercises satisfy these recommendations. This study used a questionnaire to obtain data regarding demographic details, current engagement in leisure time physical activities, and dosages of these exercises from participants between 18 and 64 years of age. Data was collected from a total of 390 participants (231 males and 159 females). 50.76% and 34.35% of the participants reported exercising voluntarily and for health benefits respectively. Most participants (94.61%) indicated exercising without prescription. 55.38% and 12.82% of the participants under and above 38 years of age perform moderate to vigorous intensity exercises respectively. The over-all results of this study indicate that the participants' choices of leisure time physical exercises are based on their personal choices and beliefs. The exercise intensities undertaken do not meet the global recommended intensities, especially in those above 38 years of age. Professionals and facilities to engage the public in the WHO recommended intensities of physical activity needs to be established.


Early stages in the formation of the cerebellum in the frog.
The formation of the cerebellum was studied during the first 6 months of the tadpole stage of the bullfrog by using standard histological methods and reconstructions from serial horizontal sections. Three major developmental phases were noted in the formation of the cerebellum. (1) During the first 5 weeks of development, the neuroepithelium proliferated and the dorsal mesencephalic plates increased in size. (2) Starting in the sixth week, a patch of neuroepithelium began to differentiate and gave rise to a small population of Purkinje cells. In subsequent weeks, the area of differentiation continued to spread and a Purkinje cell layer became established along the dorsal margin of the cerebellar plate. (3) In the 12th week, the ventrolateral part of the cerebellar plate began to increase in size and generate two populations of small cells. The lateralmost part of the neuroepithelium in this area generated a group of cells that formed an external granular layer that was one cell deep. Cells of this external granular layer migrated inward into the primitive molecular layer, and by the 26th week only a remnant of an external granular layer remained in the cerebellum. The more medially situated part of the neuroepithelium gave rise to another population of small cells that formed a column, which appeared to be continuous with the Purkinje cells, but differed from them in size. It should be noted that full maturation of the cerebellum occurs during metamorphosis, which in this species remains some 2 years away.


The prognostic value of epidermal growth factor receptors, determined by both immunohistochemistry and ligand binding assays, in primary epithelial ovarian cancer: a pilot study.
After our previous studies on the incidence of epidermal growth factor receptors (EGF-R) and its relationships with other tumour characteristics in more than 100 ovarian tumours, in the present study we investigated the prognostic value of EGF-R with respect to progression-free survival in 50 patients with primary ovarian cancer and sufficient follow-up (median 26 months, range 10-33 months). EGF-R was measured by both biochemical and two immunohistochemical methods, using two monoclonal antibodies (MAb), in addition to oestrogen receptors (ER) and progesterone receptors (PgR). EGF-R by ligand binding assay and Scatchard analysis were detectable in 63% of the tumours, by immunohistochemistry with MAb 2E9 in 82% and with MAb EGF-R1 in 78% of the tumours. ER-positivity was found in 58% and PgR-positivity in 38% of the patients. The results of the three measurements of EGF-R showed only weak to moderate associations with Spearman rank correlations (Rs) between 0.13 and 0.46. ER and PgR were only weakly correlated (Rs = 0.20) and they showed no significant association with EGF-R status. There was no clear evidence of the existence of correlations between receptor values and FIGO stage and tumour rest. Univariate Cox regression analyses showed that a higher FIGO stage and larger tumour rest were associated with shorter progression-free survival (P = 0.001), while PgR positivity was associated with a longer progression-free survival (P = 0.02). The level of EGF-R (irrespective of the method of determination used) showed a positive correlation with the risk of progression, but this correlation was not statistically significant.


Three-dimensional co-culture of blood-brain barrier-composing cells in a culture insert with a collagen vitrigel membrane.
The blood-brain barrier (BBB) is a structure located in brain capillaries that protects the brain from toxic substances in blood due to its high barrier function. The brain capillaries form a layered structure with pericytes, neurons, glial cells, and extracellular matrix proteins that is called neurovascular unit, and the structure is important to express the high barrier function of BBB. Here, we propose a method to construct a three-dimensional BBB tissue using three human BBB-composing cells, including brain endothelial cells, pericytes, and astrocytes, that mimics the in vivo BBB-like layered structure. Primary human brain endothelial cells were plated on the back side (outside) of the collagen vitrigel membrane of a culture insert, pericytes were plated on the upper side (inside), and astrocytes mixed in Matrigel were plated on the pericyte layer. The layered structure was maintained for at least 2 wk. The BBB tissue-loaded collagen vitrigel membrane can be detached from the insert frame using acetone with the tissue fixed intact and used for vertical cryosectioning to analyze the tissue interior. We also measured transendothelial electrical resistance (TEER) in the three-dimensional BBB co-culture to investigate barrier function of the brain endothelial cells. We believe that our co-culture method is useful to study engineered BBB tissues and develop reliable in vitro human BBB models in the future.


The effects of progressive muscle relaxation and autogenic relaxation on young soccer players' mood states.
This study was designed to compare the effects of two different relaxation techniques, namely progressive muscle relaxation (PMR) and autogenic relaxation (AGR) on moods of young soccer players. sixteen adolescent athletes (mean age: 14.1 ± 1.3) received either PMR or AGR training. Using Profile of Mood States- Adolescents, their mood states were measured one week before relaxation training, before the first relaxation session, and after the twelfth relaxation session. Mixed ANOVA revealed no significant interaction effects and no significant main effects in any of the subscales. However, significant main effects for testing sessions were found for confusion, depression, fatigue, and tension subscales. Post hoc tests revealed post-intervention reductions in the confusion, depression, fatigue, and tension subscale scores. These two relaxation techniques induce equivalent mood responses and may be used to regulate young soccer players' mood states.


Population structure of Borrelia turcica from Greece and Turkey.
Borrelia turcica, a member of the reptile-associated Borrelia clade, is vectored by Hyalomma aegyptium. The only suggested reservoir hosts of B. turcica are tortoises of the genus Testudo. Borrelia turcica has been described to occur in several Southeastern European countries including Turkey, Romania, Bulgaria and Greece but so far nothing is known about the relationship of these populations and whether or how they are structured. Using multilocus sequence typing (MLST) on eight chromosomally located housekeeping loci (clpA, clpX, nifS, pepX, pyrG, recG, rplB and uvrA) we analyzed 43 B. turcica isolates from Serres, Greece (n = 15) collected in 2017 and Izmir, Turkey (n = 28) collected in 2018. To understand their relationship a maximum-likelihood phylogenetic tree and goeBURST analysis were done based on MLST sequence data and allelic profiles, respectively. The data we generated confirmed that the samples of B. turcica investigated here were divergent from Lyme disease (LD) and relapsing fever (RF) species. Within the B. turcica clade, samples of different geographic origin (Greece, Turkey) clustered together in terminal branches; no obvious differences between the Greek and Turkish samples were noticeable. A goeBURST analysis using triple-locus variants revealed very few clonal complexes with the majority of samples appearing as singletons. Minor clonal complexes (consisting of two sequence types) comprised only Greek isolates, only Turkish isolates or both, so no pattern of clustering of isolates from the two geographical regions was observed. Interestingly, very little population structure was discerned in our study. This was surprising in view of the large geographic distance between collection sites of B. turcica and raises questions about the evolution or spatial spread of this species.


Dupilumab Efficacy in Steroid-Dependent Severe Asthma by Baseline Oral Corticosteroid Dose.
Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4/-13, key and central drivers of type 2 inflammation in multiple diseases. In the phase 3 LIBERTY ASTHMA VENTURE (VENTURE) study (NCT02528214), dupilumab versus placebo reduced oral corticosteroid (OCS) dose and improved clinical outcomes in patients with OCS-dependent severe asthma. Dupilumab efficacy in patients with varying disease burden (defined by baseline OCS dose) has not been assessed. This post hoc analysis of VENTURE evaluated dupilumab efficacy across subgroups defined by baseline OCS dose. The OCS dose, proportion no longer needing OCS at week 24, annualized severe exacerbation rate, and least squares mean change from baseline in pre- and post-bronchodilator forced expiratory volume in 1 second at week 24 were evaluated in VENTURE patients with OCS-dependent severe asthma receiving dupilumab 300 mg every 2 weeks versus placebo, categorized by a baseline OCS dose of less than 10 mg/d or 10 or more mg/d. Dupilumab reduced daily OCS dose from baseline at week 24 in both dose groups. In dupilumab-/placebo-treated patients with a baseline OCS dose of less than 10 mg/d and 10 or more mg/d, 72%/42% and 37%/23% stopped OCS by week 24 (P < .01/P < .05), respectively. Dupilumab significantly reduced the annualized severe exacerbation rate by 71% and 48% (P < .01/P < .05). At week 24, dupilumab improved pre- and post-bronchodilator forced expiratory volume in 1 second in patients in both dose groups. In patients with OCS-dependent severe asthma receiving lower or higher baseline OCS doses, dupilumab significantly reduced the OCS dose and improved the likelihood of no longer requiring OCS while also reducing exacerbations and improving lung function.


In silico approach to screen compounds active against parasitic nematodes of major socio-economic importance.
Infections due to parasitic nematodes are common causes of morbidity and fatality around the world especially in developing nations. At present however, there are only three major classes of drugs for treating human nematode infections. Additionally the scientific knowledge on the mechanism of action and the reason for the resistance to these drugs is poorly understood. Commercial incentives to design drugs that are endemic to developing countries are limited therefore, virtual screening in academic settings can play a vital role is discovering novel drugs useful against neglected diseases. In this study we propose to build robust machine learning model to classify and screen compounds active against parasitic nematodes. A set of compounds active against parasitic nematodes were collated from various literature sources including PubChem while the inactive set was derived from DrugBank database. The support vector machine (SVM) algorithm was used for model development, and stratified ten-fold cross validation was used to evaluate the performance of each classifier. The best results were obtained using the radial basis function kernel. The SVM method achieved an accuracy of 81.79% on an independent test set. Using the model developed above, we were able to indentify novel compounds with potential anthelmintic activity. In this study, we successfully present the SVM approach for predicting compounds active against parasitic nematodes which suggests the effectiveness of computational approaches for antiparasitic drug discovery. Although, the accuracy obtained is lower than the previously reported in a similar study but we believe that our model is more robust because we intentionally employed stringent criteria to select inactive dataset thus making it difficult for the model to classify compounds. The method presents an alternative approach to the existing traditional methods and may be useful for predicting hitherto novel anthelmintic compounds.


Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding.
Loss-of-function mutations in glypican-3 (GPC3), one of the six mammalian glypicans, causes the Simpson-Golabi-Behmel overgrowth syndrome (SGBS), and GPC3 null mice display developmental overgrowth. Because the Hedgehog signaling pathway positively regulates body size, we hypothesized that GPC3 acts as an inhibitor of Hedgehog activity during development. Here, we show that GPC3 null embryos display increased Hedgehog signaling and that GPC3 inhibits Hedgehog activity in cultured mouse embryonic fibroblasts. In addition, we report that GPC3 interacts with high affinity with Hedgehog but not with its receptor, Patched, and that GPC3 competes with Patched for Hedgehog binding. Furthermore, GPC3 induces Hedgehog endocytosis and degradation. Surprisingly, the heparan sulfate chains of GPC3 are not required for its interaction with Hedgehog. We conclude that GPC3 acts as a negative regulator of Hedgehog signaling during mammalian development and that the overgrowth observed in SGBS patients is, at least in part, the consequence of hyperactivation of the Hedgehog signaling pathway.


Continuous production of controlled release dosage forms based on hot-melt extruded gum arabic: Formulation development, in vitro characterization and evaluation of potential application fields.
Controlled release matrices based on gum arabic are prepared by applying a continuous hot-melt extrusion technology: the pre-mixture consisting of gum arabic and the incorporated API is plasticized by a co-rotating twin-screw extruder, an intermediate strand is formed by a round nozzle. Single dosed matrices are prepared by cutting the semi elastic strand with a rotary fly cutter. Paracetamol and phenazone are used as model drug substances. High drug loadings up to 70% can be realized. Matrices are characterized concerning their crystalline structure, in vitro dissolution, disintegration time and various physical parameters including glass transition temperature (Tg). Release characteristic behavior is mainly influenced by erosion of the matrices. At higher drug loadings also diffusion based transport gain importance. The solubility of the API shows an influence on the erosion rate of the matrix and should therefore be considered during formulation development. Tg is mainly influenced by the solubility of the API in the surrounding matrix. High soluble phenazone shows a decrease, whereas paracetamol addition has nearly no influence on the Tg of the polymeric system. Activation energy (EA) of the glass transition is determined via dynamic mechanical analysis. The addition of APIs leads to a reduction of EA indicating an increased molecular movement at Tg region compared to placebo extrudates. X-ray diffraction is used to determine the crystalline state of the extruded matrices and interaction between matrix and incorporated APIs. The production of thin layer matrices is an interesting option to provide a fast drug delivery to the oral cavity. High mechanical strength combined with fast disintegration times can be a great advantage for the development of oro-dispersible tablets. A great benefit of the evaluated processing technology is the simple adaption of the final dose by varying either the cutting length or the diameter of the nozzle resulting in a cost-effective production of single dosed matrices without modification of the base formula.


Evaluation of the efficacy of elastic compression stockings in prevention of hypotension during epidural anaesthesia for elective caesarean section.
The ability of graduated compression elastic stockings to prevent hypotension during elective epidural caesarean section was evaluated. Twenty women were randomly assigned to two groups of ten, one group being fitted with the stockings. The incidence and degree of hypotension were the same in both groups. Graduated compression elastic stockings are of no benefit in reducing the incidence of maternal hypotension during caesarean section.


Aluminium-induced impairment of transcellular calcium absorption in the small intestine: calcium uptake and glutathione influence.
Aluminium (Al) has been recognised as a cause of bone tissue disorders. The aims of this work were to investigate: (i) whether Al affects calcium (Ca) entry into enterocyte, and (ii) the possibility that the Al effect upon calbindin-D-related Ca transport would be influenced by intestinal glutathione (GSH) levels. In isolated chicken duodenal enterocytes, 100 microM Al lactate produced a decrease in both, the maximum uptake rate and the affinity constant of 45Ca uptake (CaUPT). This effect of Al on CaUPT was concentration-dependent in the micromolar range, showing an inhibitory saturation type phenomenon which appeared to be higher at pH 6.5 than at pH 7.4, and was not modified by the Ca channel activators A23187 and capsaicin. The simultaneous administration of Al (50 mg elemental Al/kg body weight, as AlCl3) and GSH (10 mmol/kg body weight) to rats during 7 days, prevented the inhibitory effects of Al on Ca transport. The protective effect of GSH was accompanied by an increased duodenal calbindin-D9k expression. Experimental depletion of intestinal GSH by means of D,L-buthionin-[S,R] sulfoximine, a gamma-glutamylcystein-synthase inhibitor, given as a single i.p. dose of 2 mmol/kg body weight, enhanced the degree of reduction of Ca absorption ascribed to Al. Our results suggest that Al might interfere Ca uptake by enterocytes through a general effect on cell membrane, and that an oxidative stress state induced by Al would reduce intestine GSH level affecting calbindin-D function and/or synthesis, thus leading to a reduced transcellular Ca absorption in the small intestine.


Unrelated strain methicillin-resistant Staphylococcus aureus colonization of health care workers in a neonatal intensive care unit: findings of an outbreak investigation.
Three neonates and 5 health care workers were identified as colonized with methicillin-resistant Staphylococcus aureus (MRSA) out of 222 individuals screened during an outbreak investigation in an 18-bed neonatal intensive care unit. Two of 3 MRSA neonatal isolates demonstrated identical pulsed-field gel electrophoresis clonal patterns but no clonal association was found among isolates from the 5 employees or between employees and neonates. Increased MRSA-unrelated strain colonization among health care workers supports increased MRSA community prevalence and probable decreased utility of mass screening.