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01/14/2025


Recent developments in fluorescence in situ hybridization (FISH) methods allow the detection and visualization of the genes/genomic regions of bacteria, archaea and infecting viruses at the single cell level. These methods use mixtures of polynucleotides as probes to specifically detect the target of interest. Gene-PROBER enables the design of polynucleotide mixtures for targeting genes or genomic regions in microorganisms. It has four workflows, depending on the availability of non-target sequences and the choice of probe synthesis, either by chemical synthesis or by PCR. It outputs polynucleotides that are spread along the target sequence and have similar melting properties. Therefore, such a polynucleotide mixture can be used as a single probe, in a single hybridization reaction. Gene-PROBER is a freely available web service that can be accessed at http//gene-prober.icbm.de/, and is implemented in the R language using the Shiny package.Coronaviruses are known to infect respiratory tract and intestine. These viruses possess highly conserved viral macro domain A1pp having adenosine diphosphate (ADP)-ribose binding and phosphatase activity sites. A1pp inhibits adenosine diphosphate (ADP)-ribosylation in the host and promotes viral infection and pathogenesis. We performed in silico screening of FDA approved drugs and nucleoside analogue library against the recently reported crystal structure of SARS-CoV-2 A1pp domain. Docking scores and interaction profile analyses exhibited strong binding affinity of eleven FDA approved drugs and five nucleoside analogues NA1 (-13.84), nadide (-13.65), citicholine (-13.54), NA2 (-12.42), and NA3 (-12.27). The lead compound NA1 exhibited significant hydrogen bonding and hydrophobic interaction at the natural substrate binding site. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface (SASA), hydrogen bond formation, principle component analysis, and free energy landscape calculations for NA1 bound protein displayed stable complex formation in 100 ns molecular dynamics simulation, compared to unbound macro domain and natural substrate adenosine-5-diphosphoribose bound macro domain that served as a positive control. The molecular mechanics Poisson-Boltzmann surface area analysis of NA1 demonstrated binding free energy of -175.978 ± 0.401 kJ/mol in comparison to natural substrate which had binding free energy of -133.403 ± 14.103 kJ/mol. In silico analysis by modelling tool ADMET and prediction of biological activity of these compounds further validated them as putative therapeutic molecules against SARS-CoV-2. Taken together, this study offers NA1 as a lead SARS-CoV-2 A1pp domain inhibitor for future testing and development as therapeutics against human coronavirus.
This study reviewed systematically the effects of sleep extension on sports performance.

Systematic review.

The systematic review was conducted in November 2020. Articles published in English were searched in PubMed, Virtual Health Library, SPORTDiscus, and Web of Science and Scopus databases. The search terms used were "sleep extension" AND athlete. The measures of interest were sports performance. Studies were included if they were a) original articles, b) published in English and peer-reviewed article, c) had only athletes as participants, d) experimental protocol whose objective was to investigate the effects of sleep extension on sports performance, including randomized (RCT) and non-randomized controlled trial (nRCT), and e) at least a sports performance measure as a dependent variable.

The primary search revealed that a total of 5 out of 74 articles were considered eligible and 2 studies were subsequently included. The studies used different strategies to extend time in bed or total sleep time (extending 26-106min). From fifteen sports measures, six presented a large effect size, and the others ranged from trivial to medium. Overall, the risk of bias was high to RCT and low to nRCT and the quality of evidence ranged from very low quality to moderate quality in ten outcomes.

The limited evidence suggests that sleep extension interventions may be beneficial to improve sports performance in athletes where the magnitude is dependent on the variable assessed, although such conclusions are tentative because of the quality of the evidence and risk of bias.
The limited evidence suggests that sleep extension interventions may be beneficial to improve sports performance in athletes where the magnitude is dependent on the variable assessed, although such conclusions are tentative because of the quality of the evidence and risk of bias.This prospective, observational study investigated changes in sleep and the effect on energy intake, gestational weight gain, and cardiometabolic health across pregnancy in 52 healthy pregnant women with obesity. Habitual sleep was assessed by wrist-worn actigraphy (time spent in bed; TIB, total sleep time; TST, and sleep efficiency) in early (130-156 weeks) and late (350-366) pregnancy. A change to habitual sleep was defined as change of one-half of the standard deviation of TIB and TST across six consecutive nights from early pregnancy. Energy intake and changes in weight, fasting glucose, insulin, and lipids across pregnancy were compared between women who changed sleep. During early pregnancy, TIB was 924 ± 008 h and varied by 137 ± 007 h across the six nights. TST and sleep efficiency significantly declined from early to late pregnancy (703 ± 008 h to 628 ± 009 h, p less then 0.001) and (76 ± 0.1% to 71 ± 0.2%, p less then 0.001), respectively. For women who increased TIB (n = 11), fasting glucose decreased (-11.6 ± 4.3%, p less then 0.01) across pregnancy and they had a trend towards decreased insulin (-57.8 ± 33.5%; p = 0.09) and HOMA-IR (-72.4 ± 37.3%; p = 0.06) compared to women who decreased TIB (n = 13). https://www.selleckchem.com/products/milademetan.html Women who increased TIB had a significantly lower daily energy intake across pregnancy (-540 ± 163 kcal; p less then 0.01) and tended to have less gestational weight gain (-147 ± 88 g/week; p = 0.10). Changes in TST did not affect plasma markers, energy intake or weight gain. The positive relationship between sleep and cardiometabolic health during pregnancy is explained in part by lower energy intake. We hypothesize lower energy intake is due to a prolonged overnight fast and a decrease in the time available for eating.

01/07/2025


Additionally, VIRIDIC can group viruses into clusters, based on user-defined intergenomic similarity thresholds. The sensitivity of VIRIDIC is given by the BLASTN. Thus, it is able to capture relationships between viruses having in common even short genomic regions, with as low as 65% similarity. Below this similarity level, protein-based analyses should be used, as they are the best suited to capture distant relationships. VIRIDIC is available at viridic.icbm.de, both as a web-service and a stand-alone tool. It allows fast analysis of large phage genome datasets, especially in the stand-alone version, which can be run on the user's own servers and can be integrated in bioinformatics pipelines. VIRIDIC was developed having viruses of Bacteria and Archaea in mind; however, it could potentially be used for eukaryotic viruses as well, as long as they are monopartite.Preventive chemotherapy (PC) is a WHO-recommended strategy to control and eliminate schistosomiasis and soil-transmitted helminths (STHs). We assessed the prevalence, intensity, and correlates of schistosomiasis and STH infection after five rounds of PC in southern Ethiopia. A total of 3162 school children from four schools in Wondo Gennet and Hawella Tula districts were screened for Schistosoma mansoni and STHs infection. The overall prevalence of S. mansoni infection was 25.8% (range between schools 11.6% to 54.1%), with light (19.1%), moderate (5.3%), and heavy (1.4%) infection intensities. A total of 61.6% S. mansoni-infected children were STH co-infected. The overall prevalence of STHs infection was 54.7% (range between schools 30.6-71.0%), with moderate-to-heavy intensity infections being 16.3%. Ascaris lumbricoides was the most prevalent 45% (95% CI, 43.5-47) followed by Trichuris trichiura 25.3% (95% CI, 23.8-26.9) and hookworm 6.1% (95% CI, 5.3-7). A total of 33.7% of STHs-infected children had A. lumbricoides and T. trichiura co-infections. S. mansoni infection was significantly associated with school and STHs co-infection (p less then 0.001). STH infection was correlated with school and younger age (p less then 0.001). Despite repeated PC, S. mansoni and STH infection remain significant health problems, and the WHO target to control schistosomiasis and eliminate STH by 2020 may not be achieved. Intensified control and prevention measures, including drug efficacy surveillance, is recommended.The treatment of patients affected by non-small cell lung cancer (NSCLC) has been revolutionised by the discovery of druggable mutations. ROS1 (c-ros oncogene) is one gene with druggable mutations in NSCLC. ROS1 is currently targeted by several specific tyrosine kinase inhibitors (TKIs), but only two of these, crizotinib and entrectinib, have received Food and Drug Administration (FDA) approval. https://www.selleckchem.com/products/SB-203580.html Crizotinib is a low molecular weight, orally available TKI that inhibits ROS1, MET and ALK and is considered the gold standard first-line treatment with demonstrated significant activity for lung cancers harbouring ROS1 gene rearrangements. However, crizotinib resistance often occurs, making the treatment of ROS1-positive lung cancers more challenging. A great effort has been undertaken to identify a new generation or ROS1 inhibitors. In this review, we briefly introduce the biology and role of ROS1 in lung cancer and discuss the underlying acquired mechanisms of resistance to crizotinib and the promising new agents able to overcome resistance mechanisms and offer alternative efficient therapies.Lung cancer is the major cause of cancer-associated death worldwide, and development of new therapeutic drugs is needed to improve treatment outcomes. Three-dimensional (3D) tumorspheroids offer many advantages over conventional two-dimensional cell cultures due to the similarities to in vivo tumors. We found that isoharringtonine, a natural product purified from Cephalotaxus koreana Nakai, significantly inhibited the growth of tumorspheroids with NCI-H460 cells in a dose-dependent manner and induced apoptotic cell death in our 3D cell culture system. On the other hand, A549 tumorspheroids displayed low sensitivity to isoharringtonine-induced apoptosis. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor known to regulate proliferation and apoptosis of cancer cells. We observed that knockdown of NR4A1 dramatically increased isoharringtonine-induced cancer cell death in A549 tumorspheroids by activating the intrinsic apoptosis pathway. Furthermore, treatment with combined isoharringtonine and iNR4A1 significantly inhibited multivulva formation in a Caenorhabditis elegans model and tumor development in a xenograft mouse model. Taken together, our data suggest that isoharringtonine is a potential natural product for treatment of non-small cell lung cancers, and inhibition of NR4A1 sensitizes cancer cells to anti-cancer treatment.Diabetic patients are at increased risk of developing foot ulcers which may cause bone infections associated with a high probability of both amputation and mortality. Therefore, prompt diagnosis and adequate treatment are of key importance. In our Diabetic Foot Unit, effective multidisciplinary treatment of osteomyelitis secondary to diabetes involves the application of a gentamicin-eluting calcium sulphate/hydroxyapatite bone graft substitute to fill residual bone voids after debridement. The data of all patients treated with the gentamicin-eluting calcium sulphate/hydroxyapatite bone graft substitute for diabetic foot infections with ulcer formation and osteomyelitis at metatarsals, calcaneus and hindfoot at our institute from July 2013 to September 2016 were retrospectively collected and evaluated. A total of 35 patients were included in this retrospective single-arm case series and were either continuously followed up for at least one year or until healing was confirmed. Nineteen lesions affected the distal row of tarsus/talus, ten the calcaneus and a further six were located at the metatarsals. While all of the metatarsal lesions had healed at 1-year follow-up, the healing rate in the hindfoot region was lower with 62.5% at the calcaneus and 72.2% at the distal tarsus and talus at 12 months, respectively. The overall cure rate for ulcerous bone infection was 81.3%. In two calcaneal lesions (25%) and two lesions of distal tarsus/talus (11.1%) amputation was considered clinically necessary. Promising results were achieved in the treatment of diabetic foot infections with soft tissue ulcers by a multidisciplinary approach involving extensive debridement followed by adequate dead space management with a resorbable gentamicin-eluting bone graft substitute.

12/09/2024


Historically, environmental research and monitoring in the Alberta oil sands region (OSR) located in northeastern Alberta, Canada, have largely neglected, meaningful Indigenous participation. Through years of experience on the land, Indigenous knowledge (IK) holders recognize change on the landscape, drawing on inextricable links between environmental health and practicing traditional rights. The cumulative impacts of crude oil production are of great concern to Indigenous communities, and monitoring initiatives in the OSR provide unique opportunities to develop Indigenous community-based monitoring (ICBM). A review of ICBM literature on the OSR from 2009 to 2020 was completed. Based on this review, we identify best practices in ICBM and propose governance structures and a framework to support meaningful integration of ICBM into regulatory environmental monitoring. Because it involves multimedia monitoring and produces data and insights that integrate many aspects of the environment, ICBM is important for naton behalf of Society of Environmental Toxicology & Chemistry (SETAC).IκBs exert principal functions as cytoplasmic inhibitors of NF-kB transcription factors. Additional roles for IκB homologues have been described, including chromatin association and transcriptional regulation. Phosphorylated and SUMOylated IκBα (pS-IκBα) binds to histones H2A and H4 in the stem cell and progenitor cell compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unknown. Here, we show that serine 32-36 phosphorylation of IκBα favors its binding to nucleosomes and demonstrate that p-IκBα association with H4 depends on the acetylation of specific H4 lysine residues. The N-terminal tail of H4 is removed during intestinal cell differentiation by proteolytic cleavage by trypsin or chymotrypsin at residues 17-19, which reduces p-IκBα binding. Inhibition of trypsin and chymotrypsin activity in HT29 cells increases p-IκBα chromatin binding but, paradoxically, impaired goblet cell differentiation, comparable to IκBα deletion. Taken together, our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular basis for the understanding of the restricted nuclear distribution of p-IκBα in specific stem cell compartments.
Accurate and precise platelet (PLT) count is critical for the appropriate management of patients with thrombocytopenia. This study evaluated the performance of PLT counting with the Abbott Alinity hq hematology analyzer, which utilizes multi-dimensional optical technology.

Imprecision, linearity, and accuracy were assessed per CLSI guidelines. Alinity hq PLT results were compared to the international flow cytometry reference method (IRM) in the concentration range of 6.3 to 103.0×10
/L. Additional comparisons were made with Sysmex XN-3000 PLT counts impedance (PLT-I), optical (PLT-O), and optical fluorescent (PLT-F) methods.

The average within-run %CV was 4.7% on patient samples with PLT concentrations ranging from 13.1 to 41.7×10
/L, and the within-laboratory %CV was 3.6% at the level of 68.2×10
/L. Linearity evaluation indicated a maximum deviation of 3.1% from the linear fit in the range of 0.1 to 316.8×10
/L. Comparison between Alinity hq and the IRM PLT counts yielded a correlation coefficient of 0.99 and predicted bias of 0.0 and -0.5×10
/L at 10.0 and 20.0×10
/L transfusion thresholds, respectively. Alinity hq PLT counts also correlated well with Sysmex PLT counts, with strongest correlation obtained with PLT-F and PLT-O (r=.99) methods.

This study demonstrated excellent analytical performance of Alinity hq PLT counting in thrombocytopenic samples, equivalency with the IRM and strong agreement with Sysmex PLT-F and PLT-O methods. The Alinity hq multi-dimensional optical PLT count is available with every CBC without additional reagents and may help promote efficiency in clinical laboratories.
This study demonstrated excellent analytical performance of Alinity hq PLT counting in thrombocytopenic samples, equivalency with the IRM and strong agreement with Sysmex PLT-F and PLT-O methods. The Alinity hq multi-dimensional optical PLT count is available with every CBC without additional reagents and may help promote efficiency in clinical laboratories.
Primary sclerosing cholangitis (PSC) is an idiopathic, cholestatic liver disease with a diverse range of clinical manifestations. Inter-regional data on PSC are variable, but its global geoepidemiology has not been well-studied. We aimed to examine the worldwide incidence, prevalence and features of PSC and PSC-inflammatory bowel disease (PSC-IBD).

A systematic search of multiple databases was conducted to identify all original, full-text studies until December 2020 with data regarding the incidence rate (IR) and/or prevalence of PSC. Outcomes were PSC IR, prevalence, features and IBD concurrence. Additionally, a meta-analysis of PSC IR was performed. The study was registered in PROSPERO (CRD42021224550).

Of the 1003 studies identified, 17 studies spanning three continents were included. PSC IR was 0.60 per 100000 person-years (PY) (95% confidence interval 0.37-0.88 per 100000 PY). In pooled subgroup analysis for studies conducted in Europe and North America, PSC IR was 0.62 and 0.53 per 100000 PY, respectively. PSC prevalence ranged 0-31.7 per 100000 persons, with notable inter-regional differences. Mean age at PSC diagnosis was bimodally distributed, with relative peaks at 15 and 35years. Mean concurrence of IBD with PSC was 50%, with 76% having ulcerative colitis, 17% Crohn's disease and 8% indeterminate/unspecified IBD.

While considerable heterogeneity exists in the geoepidemiology of PSC, overall, the classical dogmata of male predilection, bimodal distribution of mean age and high PSC-IBD concurrence appear to hold true. https://www.selleckchem.com/products/bso-l-buthionine-s-r-sulfoximine.html Despite a seemingly stable IR over time, further studies are needed to better understand the geoepidemiology of PSC.
While considerable heterogeneity exists in the geoepidemiology of PSC, overall, the classical dogmata of male predilection, bimodal distribution of mean age and high PSC-IBD concurrence appear to hold true. Despite a seemingly stable IR over time, further studies are needed to better understand the geoepidemiology of PSC.

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01/14/2025


Recent developments in fluorescence in situ hybridization (FISH) methods allow the detection and visualization of the genes/genomic regions of bacteria, archaea and infecting viruses at the single cell level. These methods use mixtures of polynucleotides as probes to specifically detect the target of interest. Gene-PROBER enables the design of polynucleotide mixtures for targeting genes or genomic regions in microorganisms. It has four workflows, depending on the availability of non-target sequences and the choice of probe synthesis, either by chemical synthesis or by PCR. It outputs polynucleotides that are spread along the target sequence and have similar melting properties. Therefore, such a polynucleotide mixture can be used as a single probe, in a single hybridization reaction. Gene-PROBER is a freely available web service that can be accessed at http//gene-prober.icbm.de/, and is implemented in the R language using the Shiny package.Coronaviruses are known to infect respiratory tract and intestine. These viruses possess highly conserved viral macro domain A1pp having adenosine diphosphate (ADP)-ribose binding and phosphatase activity sites. A1pp inhibits adenosine diphosphate (ADP)-ribosylation in the host and promotes viral infection and pathogenesis. We performed in silico screening of FDA approved drugs and nucleoside analogue library against the recently reported crystal structure of SARS-CoV-2 A1pp domain. Docking scores and interaction profile analyses exhibited strong binding affinity of eleven FDA approved drugs and five nucleoside analogues NA1 (-13.84), nadide (-13.65), citicholine (-13.54), NA2 (-12.42), and NA3 (-12.27). The lead compound NA1 exhibited significant hydrogen bonding and hydrophobic interaction at the natural substrate binding site. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface (SASA), hydrogen bond formation, principle component analysis, and free energy landscape calculations for NA1 bound protein displayed stable complex formation in 100 ns molecular dynamics simulation, compared to unbound macro domain and natural substrate adenosine-5-diphosphoribose bound macro domain that served as a positive control. The molecular mechanics Poisson-Boltzmann surface area analysis of NA1 demonstrated binding free energy of -175.978 ± 0.401 kJ/mol in comparison to natural substrate which had binding free energy of -133.403 ± 14.103 kJ/mol. In silico analysis by modelling tool ADMET and prediction of biological activity of these compounds further validated them as putative therapeutic molecules against SARS-CoV-2. Taken together, this study offers NA1 as a lead SARS-CoV-2 A1pp domain inhibitor for future testing and development as therapeutics against human coronavirus.
This study reviewed systematically the effects of sleep extension on sports performance.

Systematic review.

The systematic review was conducted in November 2020. Articles published in English were searched in PubMed, Virtual Health Library, SPORTDiscus, and Web of Science and Scopus databases. The search terms used were "sleep extension" AND athlete. The measures of interest were sports performance. Studies were included if they were a) original articles, b) published in English and peer-reviewed article, c) had only athletes as participants, d) experimental protocol whose objective was to investigate the effects of sleep extension on sports performance, including randomized (RCT) and non-randomized controlled trial (nRCT), and e) at least a sports performance measure as a dependent variable.

The primary search revealed that a total of 5 out of 74 articles were considered eligible and 2 studies were subsequently included. The studies used different strategies to extend time in bed or total sleep time (extending 26-106min). From fifteen sports measures, six presented a large effect size, and the others ranged from trivial to medium. Overall, the risk of bias was high to RCT and low to nRCT and the quality of evidence ranged from very low quality to moderate quality in ten outcomes.

The limited evidence suggests that sleep extension interventions may be beneficial to improve sports performance in athletes where the magnitude is dependent on the variable assessed, although such conclusions are tentative because of the quality of the evidence and risk of bias.
The limited evidence suggests that sleep extension interventions may be beneficial to improve sports performance in athletes where the magnitude is dependent on the variable assessed, although such conclusions are tentative because of the quality of the evidence and risk of bias.This prospective, observational study investigated changes in sleep and the effect on energy intake, gestational weight gain, and cardiometabolic health across pregnancy in 52 healthy pregnant women with obesity. Habitual sleep was assessed by wrist-worn actigraphy (time spent in bed; TIB, total sleep time; TST, and sleep efficiency) in early (130-156 weeks) and late (350-366) pregnancy. A change to habitual sleep was defined as change of one-half of the standard deviation of TIB and TST across six consecutive nights from early pregnancy. Energy intake and changes in weight, fasting glucose, insulin, and lipids across pregnancy were compared between women who changed sleep. During early pregnancy, TIB was 924 ± 008 h and varied by 137 ± 007 h across the six nights. TST and sleep efficiency significantly declined from early to late pregnancy (703 ± 008 h to 628 ± 009 h, p less then 0.001) and (76 ± 0.1% to 71 ± 0.2%, p less then 0.001), respectively. For women who increased TIB (n = 11), fasting glucose decreased (-11.6 ± 4.3%, p less then 0.01) across pregnancy and they had a trend towards decreased insulin (-57.8 ± 33.5%; p = 0.09) and HOMA-IR (-72.4 ± 37.3%; p = 0.06) compared to women who decreased TIB (n = 13). https://www.selleckchem.com/products/milademetan.html Women who increased TIB had a significantly lower daily energy intake across pregnancy (-540 ± 163 kcal; p less then 0.01) and tended to have less gestational weight gain (-147 ± 88 g/week; p = 0.10). Changes in TST did not affect plasma markers, energy intake or weight gain. The positive relationship between sleep and cardiometabolic health during pregnancy is explained in part by lower energy intake. We hypothesize lower energy intake is due to a prolonged overnight fast and a decrease in the time available for eating.

01/07/2025


Additionally, VIRIDIC can group viruses into clusters, based on user-defined intergenomic similarity thresholds. The sensitivity of VIRIDIC is given by the BLASTN. Thus, it is able to capture relationships between viruses having in common even short genomic regions, with as low as 65% similarity. Below this similarity level, protein-based analyses should be used, as they are the best suited to capture distant relationships. VIRIDIC is available at viridic.icbm.de, both as a web-service and a stand-alone tool. It allows fast analysis of large phage genome datasets, especially in the stand-alone version, which can be run on the user's own servers and can be integrated in bioinformatics pipelines. VIRIDIC was developed having viruses of Bacteria and Archaea in mind; however, it could potentially be used for eukaryotic viruses as well, as long as they are monopartite.Preventive chemotherapy (PC) is a WHO-recommended strategy to control and eliminate schistosomiasis and soil-transmitted helminths (STHs). We assessed the prevalence, intensity, and correlates of schistosomiasis and STH infection after five rounds of PC in southern Ethiopia. A total of 3162 school children from four schools in Wondo Gennet and Hawella Tula districts were screened for Schistosoma mansoni and STHs infection. The overall prevalence of S. mansoni infection was 25.8% (range between schools 11.6% to 54.1%), with light (19.1%), moderate (5.3%), and heavy (1.4%) infection intensities. A total of 61.6% S. mansoni-infected children were STH co-infected. The overall prevalence of STHs infection was 54.7% (range between schools 30.6-71.0%), with moderate-to-heavy intensity infections being 16.3%. Ascaris lumbricoides was the most prevalent 45% (95% CI, 43.5-47) followed by Trichuris trichiura 25.3% (95% CI, 23.8-26.9) and hookworm 6.1% (95% CI, 5.3-7). A total of 33.7% of STHs-infected children had A. lumbricoides and T. trichiura co-infections. S. mansoni infection was significantly associated with school and STHs co-infection (p less then 0.001). STH infection was correlated with school and younger age (p less then 0.001). Despite repeated PC, S. mansoni and STH infection remain significant health problems, and the WHO target to control schistosomiasis and eliminate STH by 2020 may not be achieved. Intensified control and prevention measures, including drug efficacy surveillance, is recommended.The treatment of patients affected by non-small cell lung cancer (NSCLC) has been revolutionised by the discovery of druggable mutations. ROS1 (c-ros oncogene) is one gene with druggable mutations in NSCLC. ROS1 is currently targeted by several specific tyrosine kinase inhibitors (TKIs), but only two of these, crizotinib and entrectinib, have received Food and Drug Administration (FDA) approval. https://www.selleckchem.com/products/SB-203580.html Crizotinib is a low molecular weight, orally available TKI that inhibits ROS1, MET and ALK and is considered the gold standard first-line treatment with demonstrated significant activity for lung cancers harbouring ROS1 gene rearrangements. However, crizotinib resistance often occurs, making the treatment of ROS1-positive lung cancers more challenging. A great effort has been undertaken to identify a new generation or ROS1 inhibitors. In this review, we briefly introduce the biology and role of ROS1 in lung cancer and discuss the underlying acquired mechanisms of resistance to crizotinib and the promising new agents able to overcome resistance mechanisms and offer alternative efficient therapies.Lung cancer is the major cause of cancer-associated death worldwide, and development of new therapeutic drugs is needed to improve treatment outcomes. Three-dimensional (3D) tumorspheroids offer many advantages over conventional two-dimensional cell cultures due to the similarities to in vivo tumors. We found that isoharringtonine, a natural product purified from Cephalotaxus koreana Nakai, significantly inhibited the growth of tumorspheroids with NCI-H460 cells in a dose-dependent manner and induced apoptotic cell death in our 3D cell culture system. On the other hand, A549 tumorspheroids displayed low sensitivity to isoharringtonine-induced apoptosis. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor known to regulate proliferation and apoptosis of cancer cells. We observed that knockdown of NR4A1 dramatically increased isoharringtonine-induced cancer cell death in A549 tumorspheroids by activating the intrinsic apoptosis pathway. Furthermore, treatment with combined isoharringtonine and iNR4A1 significantly inhibited multivulva formation in a Caenorhabditis elegans model and tumor development in a xenograft mouse model. Taken together, our data suggest that isoharringtonine is a potential natural product for treatment of non-small cell lung cancers, and inhibition of NR4A1 sensitizes cancer cells to anti-cancer treatment.Diabetic patients are at increased risk of developing foot ulcers which may cause bone infections associated with a high probability of both amputation and mortality. Therefore, prompt diagnosis and adequate treatment are of key importance. In our Diabetic Foot Unit, effective multidisciplinary treatment of osteomyelitis secondary to diabetes involves the application of a gentamicin-eluting calcium sulphate/hydroxyapatite bone graft substitute to fill residual bone voids after debridement. The data of all patients treated with the gentamicin-eluting calcium sulphate/hydroxyapatite bone graft substitute for diabetic foot infections with ulcer formation and osteomyelitis at metatarsals, calcaneus and hindfoot at our institute from July 2013 to September 2016 were retrospectively collected and evaluated. A total of 35 patients were included in this retrospective single-arm case series and were either continuously followed up for at least one year or until healing was confirmed. Nineteen lesions affected the distal row of tarsus/talus, ten the calcaneus and a further six were located at the metatarsals. While all of the metatarsal lesions had healed at 1-year follow-up, the healing rate in the hindfoot region was lower with 62.5% at the calcaneus and 72.2% at the distal tarsus and talus at 12 months, respectively. The overall cure rate for ulcerous bone infection was 81.3%. In two calcaneal lesions (25%) and two lesions of distal tarsus/talus (11.1%) amputation was considered clinically necessary. Promising results were achieved in the treatment of diabetic foot infections with soft tissue ulcers by a multidisciplinary approach involving extensive debridement followed by adequate dead space management with a resorbable gentamicin-eluting bone graft substitute.

12/09/2024


Historically, environmental research and monitoring in the Alberta oil sands region (OSR) located in northeastern Alberta, Canada, have largely neglected, meaningful Indigenous participation. Through years of experience on the land, Indigenous knowledge (IK) holders recognize change on the landscape, drawing on inextricable links between environmental health and practicing traditional rights. The cumulative impacts of crude oil production are of great concern to Indigenous communities, and monitoring initiatives in the OSR provide unique opportunities to develop Indigenous community-based monitoring (ICBM). A review of ICBM literature on the OSR from 2009 to 2020 was completed. Based on this review, we identify best practices in ICBM and propose governance structures and a framework to support meaningful integration of ICBM into regulatory environmental monitoring. Because it involves multimedia monitoring and produces data and insights that integrate many aspects of the environment, ICBM is important for naton behalf of Society of Environmental Toxicology & Chemistry (SETAC).IκBs exert principal functions as cytoplasmic inhibitors of NF-kB transcription factors. Additional roles for IκB homologues have been described, including chromatin association and transcriptional regulation. Phosphorylated and SUMOylated IκBα (pS-IκBα) binds to histones H2A and H4 in the stem cell and progenitor cell compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unknown. Here, we show that serine 32-36 phosphorylation of IκBα favors its binding to nucleosomes and demonstrate that p-IκBα association with H4 depends on the acetylation of specific H4 lysine residues. The N-terminal tail of H4 is removed during intestinal cell differentiation by proteolytic cleavage by trypsin or chymotrypsin at residues 17-19, which reduces p-IκBα binding. Inhibition of trypsin and chymotrypsin activity in HT29 cells increases p-IκBα chromatin binding but, paradoxically, impaired goblet cell differentiation, comparable to IκBα deletion. Taken together, our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular basis for the understanding of the restricted nuclear distribution of p-IκBα in specific stem cell compartments.
Accurate and precise platelet (PLT) count is critical for the appropriate management of patients with thrombocytopenia. This study evaluated the performance of PLT counting with the Abbott Alinity hq hematology analyzer, which utilizes multi-dimensional optical technology.

Imprecision, linearity, and accuracy were assessed per CLSI guidelines. Alinity hq PLT results were compared to the international flow cytometry reference method (IRM) in the concentration range of 6.3 to 103.0×10
/L. Additional comparisons were made with Sysmex XN-3000 PLT counts impedance (PLT-I), optical (PLT-O), and optical fluorescent (PLT-F) methods.

The average within-run %CV was 4.7% on patient samples with PLT concentrations ranging from 13.1 to 41.7×10
/L, and the within-laboratory %CV was 3.6% at the level of 68.2×10
/L. Linearity evaluation indicated a maximum deviation of 3.1% from the linear fit in the range of 0.1 to 316.8×10
/L. Comparison between Alinity hq and the IRM PLT counts yielded a correlation coefficient of 0.99 and predicted bias of 0.0 and -0.5×10
/L at 10.0 and 20.0×10
/L transfusion thresholds, respectively. Alinity hq PLT counts also correlated well with Sysmex PLT counts, with strongest correlation obtained with PLT-F and PLT-O (r=.99) methods.

This study demonstrated excellent analytical performance of Alinity hq PLT counting in thrombocytopenic samples, equivalency with the IRM and strong agreement with Sysmex PLT-F and PLT-O methods. The Alinity hq multi-dimensional optical PLT count is available with every CBC without additional reagents and may help promote efficiency in clinical laboratories.
This study demonstrated excellent analytical performance of Alinity hq PLT counting in thrombocytopenic samples, equivalency with the IRM and strong agreement with Sysmex PLT-F and PLT-O methods. The Alinity hq multi-dimensional optical PLT count is available with every CBC without additional reagents and may help promote efficiency in clinical laboratories.
Primary sclerosing cholangitis (PSC) is an idiopathic, cholestatic liver disease with a diverse range of clinical manifestations. Inter-regional data on PSC are variable, but its global geoepidemiology has not been well-studied. We aimed to examine the worldwide incidence, prevalence and features of PSC and PSC-inflammatory bowel disease (PSC-IBD).

A systematic search of multiple databases was conducted to identify all original, full-text studies until December 2020 with data regarding the incidence rate (IR) and/or prevalence of PSC. Outcomes were PSC IR, prevalence, features and IBD concurrence. Additionally, a meta-analysis of PSC IR was performed. The study was registered in PROSPERO (CRD42021224550).

Of the 1003 studies identified, 17 studies spanning three continents were included. PSC IR was 0.60 per 100000 person-years (PY) (95% confidence interval 0.37-0.88 per 100000 PY). In pooled subgroup analysis for studies conducted in Europe and North America, PSC IR was 0.62 and 0.53 per 100000 PY, respectively. PSC prevalence ranged 0-31.7 per 100000 persons, with notable inter-regional differences. Mean age at PSC diagnosis was bimodally distributed, with relative peaks at 15 and 35years. Mean concurrence of IBD with PSC was 50%, with 76% having ulcerative colitis, 17% Crohn's disease and 8% indeterminate/unspecified IBD.

While considerable heterogeneity exists in the geoepidemiology of PSC, overall, the classical dogmata of male predilection, bimodal distribution of mean age and high PSC-IBD concurrence appear to hold true. https://www.selleckchem.com/products/bso-l-buthionine-s-r-sulfoximine.html Despite a seemingly stable IR over time, further studies are needed to better understand the geoepidemiology of PSC.
While considerable heterogeneity exists in the geoepidemiology of PSC, overall, the classical dogmata of male predilection, bimodal distribution of mean age and high PSC-IBD concurrence appear to hold true. Despite a seemingly stable IR over time, further studies are needed to better understand the geoepidemiology of PSC.

12/03/2024


As MUTYH is intimately associated with targetable molecular partners, therapeutic options for MUTYH driven ovarian cancers include programed-death 1/programed-death ligand-1 inhibitors and poly-adenosine diphosphate ribose polymerase inhibitors. Understanding the function of MUTYH and its associated partners is critical for determining screening, risk reduction, and therapeutic approaches for MUTYH-driven ovarian cancers.Glioblastoma (GBM) is the most common malignant brain tumor and its malignant phenotypic characteristics are classified as grade IV tumors. Molecular interactions, such as protein-protein, protein-ncRNA, and protein-peptide interactions are crucial to transfer the signaling communications in cellular signaling pathways. Evidences suggest that signaling pathways of stem cells are also activated, which helps the propagation of GBM. Hence, it is important to identify a common signaling pathway that could be visible from multiple GBM gene expression data. microRNA signaling is considered important in GBM signaling, which needs further validation. We performed a high-throughput analysis using micro array expression profiles from 574 samples to explore the role of non-coding RNAs in the disease progression and unique signaling communication in GBM. A series of computational methods involving miRNA expression, gene ontology (GO) based gene enrichment, pathway mapping, and annotation from metabolic pathways databases, and network analysis were used for the analysis. Our study revealed the physiological roles of many known and novel miRNAs in cancer signaling, especially concerning signaling in cancer progression and proliferation. Overall, the results revealed a strong connection with stress induced senescence, significant miRNA targets for cell cycle arrest, and many common signaling pathways to GBM in the network.All-trans retinoic acid (ATRA) is known to induce complete remission of acute promyelocytic leukemia (APL) and its use has significantly improved the cure rate of APL. However, ATRA also causes side effects such as differentiation syndrome or intracranial hypertension. In our case, the patient was diagnosed with APL and developed hearing loss thrice while being treated with ATRA. Therefore, we reduced the dose of ATRA instead of stopping it altogether and administered dexamethasone to the patient. A hearing test performed thereafter revealed recovery of hearing. No recurrence of hearing loss occurred after prednisolone and ATRA were combined in the maintenance phase. In conclusion, ATRA-associated hearing loss is reversible, and it is not necessary to stop ATRA. We recommend completion of a randomized clinical trial using dexamethasone in combination with ATRA to prevent hearing loss caused by ATRA.There is a significant body of research that has identified specific, high-end cognitive demand activities and lifestyles that may play a role in building cognitive brain reserve, including volume changes in gray matter and white matter, increased structural connectivity, and enhanced categorical perception. While normal aging produces trends of decreasing white matter (WM) integrity, research on cognitive brain reserve suggests that complex sensory-motor activities across the life span may slow down or reverse these trends. Previous research has focused on structural and functional changes to the human brain caused by training and experience in both linguistic (especially bilingualism) and musical domains. The current research uses diffusion tensor imaging to examine the integrity of subcortical white matter fiber tracts in lifelong musicians. Our analysis, using Tortoise and ICBM-81, reveals higher fractional anisotropy, an indicator of greater WM integrity, in aging musicians in bilateral superior longitudinal fasciculi and bilateral uncinate fasciculi. Statistical methods used include Fisher's method and linear regression analysis. Another unique aspect of this study is the accompanying behavioral performance data for each participant. This is one of the first studies to look specifically at musicianship across the life span and its impact on bilateral WM integrity in aging.N-linked glycosylation is a crucial post-translational modification involved in protein folding, function, and clearance. N-linked glycosylation is also used therapeutically to enhance the half-lives of many proteins. Antithrombin, a serpin with four potential N-glycosylation sites, plays a pivotal role in hemostasis, wherein its deficiency significantly increases thrombotic risk. https://www.selleckchem.com/products/ferrostatin-1.html In this study, we used the introduction of N-glycosylation sites as a tool to explore what effect this glycosylation has on the protein folding, secretion, and function of this key anticoagulant. To accomplish this task, we introduced an additional N-glycosylation sequence in each strand. Interestingly, all regions that likely fold rapidly or were surrounded by lysines were not glycosylated even though an N-glycosylation sequon was present. The new sequon in the strands of the A- and B-sheets reduced secretion, and the B-sheet was more sensitive to these changes. However, the mutations in the strands of the C-sheet allowed correct folding and secretion, which resulted in functional variants. Therefore, our study revealed crucial regions for antithrombin secretion and could potentially apply to all serpins. These results could also help us understand the functional effects of natural variants causing type-I deficiencies.The development of nanotechnology based on graphene and its derivatives has aroused great scientific interest because of their unusual properties. Graphene (GN) and its derivatives, such as reduced graphene oxide (rGO), exhibit antitumor effects on glioblastoma multiforme (GBM) cells in vitro. The antitumor activity of rGO with different contents of oxygen-containing functional groups and GN was compared. Using FTIR (fourier transform infrared) analysis, the content of individual functional groups (GN/exfoliation (ExF), rGO/thermal (Term), rGO/ammonium thiosulphate (ATS), and rGO/ thiourea dioxide (TUD)) was determined. Cell membrane damage, as well as changes in the cell membrane potential, was analyzed. Additionally, the gene expression of voltage-dependent ion channels (clcn3, clcn6, cacna1b, cacna1d, nalcn, kcne4, kcnj10, and kcnb1) and extracellular receptors was determined. A reduction in the potential of the U87 glioma cell membrane was observed after treatment with rGO/ATS and rGO/TUD flakes. Moreover, it was also demonstrated that major changes in the expression of voltage-dependent ion channel genes were observed in clcn3, nalcn, and kcne4 after treatment with rGO/ATS and rGO/TUD flakes.

11/26/2024


 putida S12 strains for FDCA production.The stoichiometric Cu2O2(CO)n+ (n = 3-7) clusters are generated via a laser vaporization supersonic cluster source in gas phase and identified by infrared photodissociation spectroscopy in the C-O stretching region. The infrared spectra are interpreted and the cluster structures are determined by density functional calculations. The ground state of Cu2O2(CO)n+ are intrinsically a dicopper superoxide carbonyl with [(OC)xCuOOCu(CO)y]+ ( x + y = n) structures in which CO ligands coordinate a zigzag Cu(OO)Cu+ core. The structure characterization for Cu(OO)Cu+ core-based clusters is crucial to correctively understand the associated catalytic reactions by metal clusters.A one-pot synthesis of 1,3-diyne-tethered trifluoromethylcyclopropanes starting from 2-CF3-3,5-diyne-1-enes and sulfur ylides via a sulfur ylide mediated cyclopropanation and a DBU-mediated epimerization sequence is described in this work. This process is highly diastereoselective with broad substrate scope. Moreover, a series of synthetic transformations based on the diyne moieties were conducted smoothly, affording cyclopropanes featuring trifluoromethyl-substituted all-carbon quaternary centers.The combination of the many-body Green's function GW approximation and the Bethe-Salpeter equation (BSE) formalism has shown to be a promising alternative to time-dependent density functional theory (TD-DFT) for computing vertical transition energies and oscillator strengths in molecular systems. The BSE formalism can also be employed to compute ground-state correlation energies thanks to the adiabatic-connection fluctuation-dissipation theorem (ACFDT). Here, we study the topology of the ground-state potential energy surfaces (PESs) of several diatomic molecules near their equilibrium bond length. https://www.selleckchem.com/products/Mubritinib-TAK-165.html Using comparisons with state-of-art computational approaches (CC3), we show that ACFDT@BSE is surprisingly accurate and can even compete with lower-order coupled cluster methods (CC2 and CCSD) in terms of total energies and equilibrium bond distances for the considered systems. However, we sometimes observe unphysical irregularities on the ground-state PES in relation with difficulties in the identification of a few GW quasiparticle energies.Quantification of the rate of direct repeat deletion (DRD) is an important aspect in the research of DNA rearrangement. The widely used tetracycline selection method usually introduces antibiotic pressure to the tested organism, which may interfere with the DRD process. Also the length of repeat arm (LRA) is limited by the length of the TetR coding sequence. On the basis of the fluorescent microscopy and high-throughput imaging processing, here we developed a two-module genetic circuit, termed TFDEC (which stands for three-color fluorescence-based deletion event counter), to quantify the DRD rate under neutral conditions. DRD events were determined from the state of a three-state fluorescent logic gate constructed through coupling of an OR gate and an AND gate. TFDEC was applied in Pseudomonas aeruginosa, and we found that the DRD rate was RecA-dependent for long repeat arms (>500 bp) and RecA-independent for short repeat arms ( less then 500 bp), which was consistent with the case in Escherichia coli. In addition, the increase of DRD rate followed an S-shaped curve with the increase of LRA, while treating cells with ciprofloxacin did not change the LRA-dependence of DRD. We also detected a significant increased DRD rate for long repeat arms in the uvrD (8-fold) and radA (4-fold) mutants. Our results show that the TFDEC method could be used as a complement tool for quantification of the DRD rate in the future.Untargeted molecular analyses of complex mixtures are relevant for many fields of research, including geochemistry, pharmacology, and medicine. Ultrahigh-resolution mass spectrometry is one of the most powerful tools in this context. The availability of open scripts and online tools for specific data processing steps such as noise removal or molecular formula assignment is growing, but an integrative tool where all crucial steps are reproducibly evaluated and documented is lacking. We developed a novel, server-based tool (ICBM-OCEAN, "Institute for Chemistry and Biology of the Marine Environment, Oldenburg - complex molecular mixtures, evaluation and analysis") that integrates published and novel approaches for standardized processing of ultrahigh-resolution mass spectrometry data of complex molecular mixtures. Different from published approaches, we offer diagnostic and validation tools for all relevant steps. Among other features, we included objective and reproducible reduction of noise and systematic errors, spectra recalibration and alignment, and identification of likeliest molecular formulae. With 15 chemical elements, the tool offers high flexibility in formula attribution. Alignment of mass spectra among different samples prior to molecular formula assignment improves mass error and facilitates molecular formula confirmation with help of isotopologues. The online tool and the detailed instruction manual can be freely accessed at www.icbm.de/icbm-ocean.Artificial color pixels based on dielectric Mie resonators are appealing for scientific research as well as practical design. Vivid colors are imperative for displays and imaging. Dielectric metasurface-based artificial pixels are promising candidates for developing flat, flexible, and/or wearable displays. Considering the application feasibility of artificial color pixels, wide color gamuts are crucial for contemporary display technology. To achieve a wide color gamut, ensuring the purity and efficiency of nanostructure resonance peaks in the visible spectrum is necessary for structural color design. Low-loss dielectric materials are suitable for achieving vivid colors with structural color pixels. However, high-order Mie resonances prevent color pixels based on dielectric metasurfaces from efficiently generating highly saturated colors. In particular, fundamental Mie resonances (electric/magnetic dipole) for red can result in not only a strong resonance peak at 650 nm but also high-order Mie resonances at shorter wavelengths, which reduces the saturation of the target color.