Regulation of spatial distribution of BMP ligands for pattern formation

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-ss (TGF-ss) family, have been shown to contribute to embryogenesis and organogenesis during animal development. Relevant studies provide support for the following concepts: (a) BMP signals are evolutionarily highly conserved as a genetic toolkit; (b) spatiotemporal distributions of BMP signals are precisely controlled at the post-translational level; and (c) the BMP signaling network has been co-opted to adapt to diversified animal development. These concepts originated from the historical findings of the Spemann-Mangold organizer and the subsequent studies about how this organizer functions at the molecular level. In this Commentary, we focus on two topics. First, we review how the BMP morphogen gradient is formed to sustain larval wing imaginal disc and early embryo growth and patterning in Drosophila. Second, we discuss how BMP signal is tightly controlled in a context-dependent manner, and how the signal and tissue dynamics are coupled to facilitate complex tissue structure formation. Finally, we argue how these concepts might be developed in the future for further understanding the significance of BMP signaling in animal development.Peer reviewe

Research on chemical constituents, anti-bacterial and anti-cancer effects of components isolated from Zingiber officinale Roscoe from Vietnam

Ginger, a commonly used spice and medicinal herb, is an abundant source of bioactive compounds. However, the utilization of ginger in the pharmaceutical industry is still moderate and not commensurate with the potential of the Vietnamese horticulture industry, mainly due to a lack of information about the quality of input materials. In this study, we compared the volatile compounds of gingers collected from 13 provinces of Vietnam using GC/MS and GC-FID analysis to provide a basis for selecting and standardizing input materials. Furthermore, ginger essential oil from Ben Tre province of Vietnam exhibited significant antibacterial activity particularly in inhibiting Gram-positive bacteria, including S. aureus and S. epidermidis, with inhibition zones of 30.00 ± 1.41 and 24.67 ± 3.30 mm, respectively. However, no significant inhibition was observed against Gram-negative bacteria P. aeruginosa and E. coli. We also isolated 5 non-volatile compounds from ginger extract, namely 6-shogaol (1), quercetin (2), rutin (3), beta-sitosterol (4) and beta-sitosterol-3-O-beta-D-glucopyranoside (5). Among them, compounds 1–3 displayed cytotoxicity against Hep3B, SK-LU-1, MCF-7, SK-LU-1, SW480 and HepG2 tumour cell lines, with an IC50 values ranging between 62.7 ± 2.1 and 97.6 ± 1.1 µM, using Ellipticine as a positive control. Compounds 4 and 5 showed cytotoxicity against Hep3B and HepG2 tumor cells, with the IC50 values ranging between 21.5 ± 5.1 and 46.9 ± 3.7 µM but did not exhibit any significant cytotoxicity against SW480 and SK-LU-1 cells. Compound 4 also demonstrated middling cytotoxicity against the MCF7 cell line, with an IC50 value of 43.6 ± 5.1 µM. These findings suggest further applications of Vietnamese ginger for the treatment of infectious and cancer-related diseases

An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis

Background: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anti-cancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential. Methods:Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first two weeks - or standard care plus tamoxifen 300mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031 . Results: 50 patients were enrolled, (median age 34 years, 35 male). Tamoxifen had no effect on EFA (- 0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference - 0.005log10CFU/ml/day, 95%CI: -0.16, 0.15, P=0.95). Tamoxifen caused QTc prolongation. Conclusion: High dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed. Funding:The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA

Mechano-chemical feedback mediated competition for BMP signalling leads to pattern formation

Developmental patterning is thought to be regulated by conserved signalling pathways. Initial patterns are often broad before refining to only those cells that commit to a particular fate. However, the mechanisms by which pattern refinement takes place remain to be addressed. Using the posterior crossvein (PCV) of the Drosophila pupal wing as a model, into which bone morphogenetic protein (BMP) ligand is extracellularly transported to instruct vein patterning, we investigate how pattern refinement is regulated. We found that BMP signalling induces apical enrichment of Myosin II in developing crossvein cells to regulate apical constriction. Live imaging of cellular behaviour indicates that changes in cell shape are dynamic and transient, only being maintained in those cells that retain vein fate competence after refinement. Disrupting cell shape changes throughout the PCV inhibits pattern refinement. In contrast, disrupting cell shape in only a subset of vein cells can result in a loss of BMP signalling. We propose that mechano-chemical feedback leads to competition for the developmental signal which plays a critical role in pattern refinement.Peer reviewe

Polyethylene glycol functionalized graphene oxide and its influences on properties of Poly(lactic acid) biohybrid materials

International audienceA biohybrid material based on poly(lactic acid)(PLA) incorporated with low contents of polyethylene glycol(PEG) functionalized graphene oxide (GO) was prepared via melting process and their structure, morphology,mechanical performance, and thermal properties were studied in detail. SEM and TEM characterizations confirmedthat the functionalization of GO with PEG (PEGmGO) promoted its exfoliation into thin exfoliated nanosheets,thereby improving the interactions between PEGmGO filler and PLA matrix at interface. FT-IR spectrashowed the presence of strong polar and hydrogen bonding interactions between components in the biohybrid.Mechanical and thermal tests indicated that there was the significant improvement of the stiffness, strength, andthermal stability of such biohybrid material with the addition of 0.3 phr PEGmGO, as compared to pure PLA,PEG-plasticized PLA, PEG-plasticized PLA/GO, and other surveyed PEG-plasticized PLA/PEGmGO biohybrids.This behavior was attributed to the homogeneous dispersion of the PEGmGO nanofillers within PLA matrix alongwith their strong interfacial interaction. The as-obtained biohybrids show highly potential to be useful in thebioengineering applications

Accurate measurement of pipe wall reduction: High-precision instrument and minimization of uncertainties

The magnetic flux density method is suited for monitoring the pipe's wall thinning. However, the quantification of gradual reduction is challenging because its small signal is hindered inside the noise floor of magnetic field measurements. In this work, a high-precision instrument for the accurate measurements of small thickness reductions is presented. The size of a magnetizer is optimized with respect to the size range of pipes and minimization of the wobble effect. The flux density is measured by our ultrahigh-sensitivity magnetometer with a resolution of 1.4 nT and dynamic range from 0 to 50 mT. For reliable measurements, we investigate the appropriate strengths of the magnetizing field, appropriate sensor lift-off distances, and minimizing contributions from other uncertainties, such as signals at the pipe's ends and magnetic flux leakages from abrupt defects. Finally, a real-time measurement of the 12.5 % standard wall reduction sample is found to be highly reliable and reproducible. © 2022 Elsevier LtdFALS

Chemical composition, enzyme inhibitory activities, and molecular docking studies of essential oil of <i>Knema globularia</i> leaves from Vietnam

In the present work, chemical composition, enzyme inhibitory activities, and molecular docking studies of essential oil (EO) of Knema globularia leaves collected from Vinh Phuc Province, Vietnam, were investigated. The EO from the leaves of K. globularia was obtained by hydrodistillation and analyzed by gas chromatography-mass spectrometry (GC-MS) analysis. The leaf EO yield was 0.14 ± 0.01% (w/w), comprising 39 identified components, constituting 96.77% of the EO content. Notable constituents included β-caryophyllene (54.11%), α-humulene (12.67%), and (E)-β-ocimene (8.82%). Enzyme inhibitions were assessed via the α-amylase inhibitory assay (IC50 = 282.71 ± 10.06 μg/mL) and tyrosinase inhibitory assay (IC50 = 993.92 ± 37.40 μg/mL). The molecular docking method has been employed to observe valuable binding interactions and binding energy with the main compounds on the target enzymes α-amylase and tyrosinase. Caryophyllene oxide exhibits the strongest affinity with α-amylase among the other major compounds. Meanwhile, viridiflorene shows the best binding energy with the tyrosinase enzyme. This is the first study providing valuable scientific data on the in vitro inhibitory activities of α-amylase and tyrosinase enzymes of the leaf EO of K. globularia and evaluating its main compounds through a molecular docking approach on these enzyme targets.</p

An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis

BACKGROUND: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential. METHODS: Open label randomized controlled trial. Participants received standard care – amphotericin combined with fluconazole for the first 2 weeks – or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) – the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031. RESULTS: Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (−0.48log10 colony-forming units/mL/CSF control arm versus −0.49 tamoxifen arm, difference −0.005log10CFU/ml/day, 95% CI: −0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation. CONCLUSIONS: High-dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed. FUNDING: The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA

Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

Despite their promise, circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection face challenges in test performance, due mostly to the limited abundance of ctDNA and its inherent variability. To address these challenges, published assays to date demanded a very high-depth sequencing, resulting in an elevated price of test. Herein, we developed a multimodal assay called SPOT-MAS (screening for the presence of tumor by methylation and size) to simultaneously profile methylomics, fragmentomics, copy number, and end motifs in a single workflow using targeted and shallow genome-wide sequencing (~0.55×) of cell-free DNA. We applied SPOT-MAS to 738 non-metastatic patients with breast, colorectal, gastric, lung, and liver cancer, and 1550 healthy controls. We then employed machine learning to extract multiple cancer and tissue-specific signatures for detecting and locating cancer. SPOT-MAS successfully detected the five cancer types with a sensitivity of 72.4% at 97.0% specificity. The sensitivities for detecting early-stage cancers were 73.9% and 62.3% for stages I and II, respectively, increasing to 88.3% for non-metastatic stage IIIA. For tumor-of-origin, our assay achieved an accuracy of 0.7. Our study demonstrates comparable performance to other ctDNA-based assays while requiring significantly lower sequencing depth, making it economically feasible for population-wide screening