The transcription factor CREB (cAMP Response-Element Binding Protein) is overexpressed in the majority of acute myeloid leukemia (AML) patients, and this is associated with a worse prognosis. ...Previous work revealed that CREB overexpression augmented AML cell growth, while CREB knockdown disrupted key AML cell functions in vitro. In contrast, CREB knockdown had no effect on long-term hematopoietic stem cell activity in mouse transduction/transplantation assays. Together, these studies position CREB as a promising drug target for AML. To test this concept, a small molecule inhibitor of CREB, XX-650-23, was developed. This molecule blocks a critical interaction between CREB and its required co-activator CBP (CREB Binding Protein), leading to disruption of CREB-driven gene expression. Inhibition of CBP-CREB interaction induced apoptosis and cell-cycle arrest in AML cells, and prolonged survival in vivo in mice injected with human AML cells. XX-650-23 had little toxicity on normal human hematopoietic cells and tissues in mice. To understand the mechanism of XX-650-23, we performed RNA-seq, ChIP-seq and Cytometry Time of Flight with human AML cells. Our results demonstrate that small molecule inhibition of CBP-CREB interaction mostly affects apoptotic, cell-cycle and survival pathways, which may represent a novel approach for AML therapy.
Microtubule dynamics is essential for many vital cellular processes such as morphogenesis and motility. Protein kinase CK2 is a ubiquitous protein kinase that is involved in diverse cellular ...functions. CK2 holoenzyme is composed of two catalytic α or α′ subunits and two regulatory β subunits. We show that the α subunit of CK2 binds directly to both microtubules and tubulin heterodimers. CK2 holoenzyme but neither of its individual subunits exhibited a potent effect of inducing microtubule assembly and bundling. Moreover, the polymerized microtubules were strongly stabilized by CK2 against cold-induced depolymerization. Interestingly, the kinase activity of CK2 is not required for its microtubule-assembling and stabilizing function because a kinase-inactive mutant of CK2 displayed the same microtubule-assembling activity as the wild-type protein. Knockdown of CK2α/α′ in cultured cells by RNA interference dramatically destabilized their microtubule networks, and the destabilized microtubules were readily destructed by colchicine at a very low concentration. Further, over-expression of chicken CK2α or its kinaseinactive mutant in the endogenous CK2α/α′-depleted cells fully restored the microtubule resistance to the low dose of colchicine. Taken together, CK2 is a microtubule-associated protein that confers microtubule stability in a phosphorylation-independent manner.
This work provides an overview of the most common polymeric corrosion inhibitors for the oil and gas industry. Exploration, production and transportation of petroleum and natural gas products ...constantly deal with highly corrosive environments due to oxygen, acid stimulation, CO2 and H2S contamination. Therefore, versatile materials are required in order to keep corrosion rates in control. Unlike small molecule corrosion inhibitors, polymers possess multi-functionality and better film-forming capabilities, which could significantly improve protective barrier properties. In this article, polymeric architectures tested in relevant oil and gas media are compiled in order to highlight certain moieties capable of complex formation with the metal surface or chelation on corrosive agents resulting to improved corrosion inhibition.
Introduction
In March 2020, the coronavirus disease 2019 (COVID-19) pandemic forced medical schools in the Philippines to stop face-to-face learning activities and abruptly shift to an online ...curriculum. This study aimed to identify barriers to online learning from the perspective of medical students in a developing country.
Methods
The authors sent out an electronic survey to medical students in the Philippines from 11 to 24 May 2020. Using a combination of multiple-choice, Likert scale, and open-ended questions, the following data were obtained: demographics, medical school information, access to technological resources, study habits, living conditions, self-assessment of capacity for and perceived barriers to online learning, and proposed interventions. Descriptive statistics were calculated. Responses were compared between student subgroups using nonparametric tests.
Results
Among 3670 medical students, 93% owned a smartphone and 83% had a laptop or desktop computer. To access online resources, 79% had a postpaid internet subscription while 19% used prepaid mobile data. Under prevailing conditions, only 1505 students (41%) considered themselves physically and mentally capable of engaging in online learning. Barriers were classified under five categories: technological, individual, domestic, institutional, and community barriers.
Discussion
Medical students in the Philippines confronted several interrelated barriers as they tried to adapt to online learning. Most frequently encountered were difficulty adjusting learning styles, having to perform responsibilities at home, and poor communication between educators and learners. By implementing student-centered interventions, medical schools and educators play a significant role in addressing these challenges during the COVID-19 pandemic and beyond.
Nanostructured mesoscale materials find wide-ranging applications in medicine and energy. Top-down manufacturing schemes are limited by the smallest dimension accessible; therefore, we set out to ...study a bottom-up approach mimicking biological systems, which self-assemble into systems that orchestrate complex energy conversion functionalities. Inspired by nature, we turned toward protein-based nanoparticle structures formed by plant viruses, specifically the cowpea mosaic virus (CPMV). We report the formation of hierarchical CPMV nanoparticle assemblies on colloidal-patterned, conducting polymer arrays using a protocol combining colloidal lithography, electrochemical polymerization, and electrostatic adsorption. In this approach, a hexagonally close-packed array of polystyrene microspheres was assembled on a conductive electrode to function as the sacrificial colloidal template. A thin layer of conducting polypyrrole material was electrodeposited within the interstices of the colloidal microspheres and monitored in situ using electrochemical quartz crystal microbalance with dissipation (EC-QCM-D). Etching the template revealed an inverse opaline conducting polymer pattern capable of forming strong electrostatic interactions with CPMV and therefore enabling immobilization of CPMV on the surface. The CPMV–polymer films were characterized by atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS). Furthermore, molecular probe diffusion experiments revealed selective ion transport properties as a function of the presence of the CPMV nanoparticles on the surface. Lastly, by utilizing its electromechanical behavior, the polymer/protein membrane was electrochemically released as a free-standing film, which can potentially be used for developing high surface area cargo delivery systems, stimuli-responsive plasmonic devices, and chemical and biological sensors.
The MAVEN SupraThermal And Thermal Ion Compostion (STATIC) instrument is designed to measure the ion composition and distribution function of the cold Martian ionosphere, the heated suprathermal tail ...of this plasma in the upper ionosphere, and the pickup ions accelerated by solar wind electric fields. STATIC operates over an energy range of 0.1 eV up to 30 keV, with a base time resolution of 4 seconds. The instrument consists of a toroidal “top hat” electrostatic analyzer with a
360
∘
×
90
∘
field-of-view, combined with a time-of-flight (TOF) velocity analyzer with
22.5
∘
resolution in the detection plane. The TOF combines a
−
15
kV
acceleration voltage with ultra-thin carbon foils to resolve
H
+
,
He
+
+
,
He
+
,
O
+
,
O
2
+
, and
CO
2
+
ions. Secondary electrons from carbon foils are detected by microchannel plate detectors and binned into a variety of data products with varying energy, mass, angle, and time resolution. To prevent detector saturation when measuring cold ram ions at periapsis (
∼
10
1
1
eV/cm
2
s
sr
eV
), while maintaining adequate sensitivity to resolve tenuous pickup ions at apoapsis (
∼
10
3
eV/cm
2
s
sr
eV
), the sensor includes both mechanical and electrostatic attenuators that increase the dynamic range by a factor of
10
3
. This paper describes the instrument hardware, including several innovative improvements over previous TOF sensors, the ground calibrations of the sensor, the data products generated by the experiment, and some early measurements during cruise phase to Mars.
Summary
objective Acromegalic patients have been shown to have an increase in the concentrations of small dense low‐density lipoprotein (LDL) and remnant‐like lipoprotein particles (RLP). These ...lipoproteins are atherogenic and may contribute to the cardiovascular risk of these patients. The aim of this study was to determine whether treatment of acromegaly using Sandostatin® LAR® could lower these atherogenic lipoproteins.
methods Fourteen patients with active acromegaly were recruited and Sandostatin® LAR®, a long‐acting somatostatin analogue, was given every 4 weeks by intramuscular injection for 6 months. Fasting lipids, lipoproteins, lipolytic enzymes were determined at baseline, 12 and 24 weeks after treatment. Small dense LDL was measured using density gradient ultracentrifugation and RLP‐cholesterol (RLP‐C) by an immunoseparation assay.
results There was already a marked reduction in GH and IGF‐1 by week 8 and, in all subjects, IGF‐1 levels within their respective age‐specific normal range were achieved. At week 12, plasma triglyceride significantly decreased (P < 0·01) and both HDL2 (P < 0·01) and HDL3 (P < 0·01) subfractions increased. A reduction was seen in small dense LDL concentration (P < 0·05) and RLP‐C (P < 0·05). Lipoprotein lipase (LPL) activity increased (P < 0·01) and the magnitude of the increase in LPL activity correlated with the increase in HDL at 3 months (r = 0·55, P < 0·05) but not with the changes in plasma triglyceride, small dense LDL or RLP‐C. The improvement in plasma lipids and lipoproteins persisted until the end of the study.
conclusion Sandostatin® LAR® is effective in the treatment of acromegaly and is associated with favourable changes in plasma lipids and a reduction in small dense LDL and RLP‐C.
Summary
objective Multiple endocrine neoplasia type 1 (MEN1) is characterized by a triad of neoplasia affecting the parathyroid glands, enteropancreatic endocrine tissue and the anterior pituitary ...gland.
design In order to define the prevalence of MEN1 germ‐line mutations in Southern Chinese patients with MEN1 syndrome, we performed direct sequencing of the entire open reading frame of the MEN1 gene for 12 index patients and their first‐degree relatives.
results Six patients had familial MEN1 syndrome and six had apparently sporadic disease. Nine different germ‐line mutations at the MEN1 gene were identified, including three novel mutations 248–249delTT in exon 2, K559X(AAG → TAG) in exon 10 and IVS 2nt + 2(G → T) in intron 2. All patients with familial MEN1 syndrome were heterozygous carriers of a germ‐line mutation and MEN1‐related disorders were only evident in their first‐degree relatives who also carried the mutation. All patients with an enteropancreatic lesion were mutation carriers and the absence of mutation in three apparently sporadic MEN1 patients with only hyperparathyroidism and pituitary microadenoma might represent the presence of MEN1 phenocopy.
conclusions The finding of MEN1 germ‐line mutation in all patients with familial MEN1 syndrome suggests that genetic screening should be useful in our population to identify affected individuals within a kindred and allow early detection of MEN1‐related tumours.
Summary
Guidelines for doctors managing osteoporosis in the Asia-Pacific region vary widely. We compared 18 guidelines for similarities and differences in five key areas. We then used a structured ...consensus process to develop clinical standards of care for the diagnosis and management of osteoporosis and for improving the quality of care.
Purpose
Minimum clinical standards for assessment and management of osteoporosis are needed in the Asia-Pacific (AP) region to inform clinical practice guidelines (CPGs) and to improve osteoporosis care. We present the framework of these clinical standards and describe its development.
Methods
We conducted a structured comparative analysis of existing CPGs in the AP region using a “5IQ” model (identification, investigation, information, intervention, integration, and quality). One-hundred data elements were extracted from each guideline. We then employed a four-round Delphi consensus process to structure the framework, identify key components of guidance, and develop clinical care standards.
Results
Eighteen guidelines were included. The 5IQ analysis demonstrated marked heterogeneity, notably in guidance on risk factors, the use of biochemical markers, self-care information for patients, indications for osteoporosis treatment, use of fracture risk assessment tools, and protocols for monitoring treatment. There was minimal guidance on long-term management plans or on strategies and systems for clinical quality improvement. Twenty-nine APCO members participated in the Delphi process, resulting in consensus on 16 clinical standards, with levels of attainment defined for those on identification and investigation of fragility fractures, vertebral fracture assessment, and inclusion of quality metrics in guidelines.
Conclusion
The 5IQ analysis confirmed previous anecdotal observations of marked heterogeneity of osteoporosis clinical guidelines in the AP region. The Framework provides practical, clear, and feasible recommendations for osteoporosis care and can be adapted for use in other such vastly diverse regions. Implementation of the standards is expected to significantly lessen the global burden of osteoporosis.
A straightforward in situ detection method for dengue infection was demonstrated through the molecular imprinting of a dengue nonstructural protein 1 (NS1) epitope into an electropolymerized ...molecularly imprinted polyterthiophene (E-MIP) film sensor. The key enabling step in the sensor fabrication is based on an epitope imprinting strategy, in which short peptide sequences derived from the original target molecules were employed as the main template for detection and analysis. The formation of the E-MIP sensor films was facilitated using cyclic voltammetry (CV) and monitored in situ by electrochemical quartz crystal microbalance (EC-QCM). Surface properties were analyzed using different techniques including atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and polarization modulation-infrared reflection-adsorption (PM-IRRAS). The standard calibration curve (
R
= 0.9830) was generated for the detection of the epitope, Ac-VHTWTEQYKFQ-NH
2
, with a linear range of 0.2 to 30 μg/mL and detection limit of 0.073 μg/mL. A separate calibration curve (
R
= 0.9786) was obtained using spiked buffered solutions of dengue NS1 protein, which resulted in a linear range of 0.2 to 10 μg/mL and a detection limit of 0.056 μg/mL. The fabricated E-MIP sensor exhibited long-term stability, high sensitivity, and good selectivity towards the targeted molecules. These results indicated that the formation of the exact and stable cavity imprints in terms of size, shape, and functionalities was successful. In our future work, we aim to use our E-MIP sensors for NS1 detection in real-life samples such as serum and blood.
Graphical abstract
PDF
