Monkeypox, a zoonotic disease caused by an orthopoxvirus, results in a smallpox-like disease in humans. Since monkeypox in humans was initially diagnosed in 1970 in the Democratic Republic of the ...Congo (DRC), it has spread to other regions of Africa (primarily West and Central), and cases outside Africa have emerged in recent years. We conducted a systematic review of peer-reviewed and grey literature on how monkeypox epidemiology has evolved, with particular emphasis on the number of confirmed, probable, and/or possible cases, age at presentation, mortality, and geographical spread. The review is registered with PROSPERO (CRD42020208269). We identified 48 peer-reviewed articles and 18 grey literature sources for data extraction. The number of human monkeypox cases has been on the rise since the 1970s, with the most dramatic increases occurring in the DRC. The median age at presentation has increased from 4 (1970s) to 21 years (2010-2019). There was an overall case fatality rate of 8.7%, with a significant difference between clades-Central African 10.6% (95% CI: 8.4%- 13.3%) vs. West African 3.6% (95% CI: 1.7%- 6.8%). Since 2003, import- and travel-related spread outside of Africa has occasionally resulted in outbreaks. Interactions/activities with infected animals or individuals are risk behaviors associated with acquiring monkeypox. Our review shows an escalation of monkeypox cases, especially in the highly endemic DRC, a spread to other countries, and a growing median age from young children to young adults. These findings may be related to the cessation of smallpox vaccination, which provided some cross-protection against monkeypox, leading to increased human-to-human transmission. The appearance of outbreaks beyond Africa highlights the global relevance of the disease. Increased surveillance and detection of monkeypox cases are essential tools for understanding the continuously changing epidemiology of this resurging disease.
The receptor tyrosine kinase
-like tyrosine kinase 3 (FLT3), involved in regulating survival, proliferation, and differentiation of hematopoietic stem/progenitor cells, is expressed on acute myeloid ...leukemia (AML) cells in most patients. Mutations of FLT3 resulting in constitutive signaling are common in AML, including internal tandem duplication (ITD) in the juxtamembrane domain in 25% of patients and point mutations in the tyrosine kinase domain in 5%. Patients with AML with FLT3-ITD have a high relapse rate and short relapse-free and overall survival after chemotherapy and after transplant. A number of inhibitors of FLT3 signaling have been identified and are in clinical trials, both alone and with chemotherapy, with the goal of improving clinical outcomes in patients with AML with FLT3 mutations. While inhibitor monotherapy produces clinical responses, they are usually incomplete and transient, and resistance develops rapidly. Diverse combination therapies have been suggested to potentiate the efficacy of FLT3 inhibitors and to prevent development of resistance or overcome resistance. Combinations with epigenetic therapies, proteasome inhibitors, downstream kinase inhibitors, phosphatase activators, and other drugs that alter signaling are being explored. This review summarizes the current status of translational and clinical research on FLT3 inhibitors in AML, and discusses novel combination approaches.
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The important role that surface chemical analysis methods can and should play in the characterization of nanoparticles is described. The types of information that can be obtained from analysis of ...nanoparticles using Auger electron spectroscopy (AES), X-ray photoelectron spectroscopy (XPS), time-of-flight secondary-ion mass spectrometry (TOF-SIMS), low-energy ion scattering (LEIS), and scanning-probe microscopy (SPM), including scanning tunneling microscopy (STM) and atomic force microscopy (AFM), are briefly summarized. Examples describing the characterization of engineered nanoparticles are provided. Specific analysis considerations and issues associated with using surface-analysis methods for the characterization of nanoparticles are discussed and summarized, with the impact that shape instability, environmentally induced changes, deliberate and accidental coating, etc., have on nanoparticle properties. graphic removed
Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has ...been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed “side population cells,” which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the “side population” phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured.
With continuous outcomes, the average causal effect is typically defined using a contrast of expected potential outcomes. However, in the presence of skewed outcome data, the expectation (population ...mean) may no longer be meaningful. In practice the typical approach is to continue defining the estimand this way or transform the outcome to obtain a more symmetric distribution, although neither approach may be entirely satisfactory. Alternatively the causal effect can be redefined as a contrast of median potential outcomes, yet discussion of confounding-adjustment methods to estimate the causal difference in medians is limited. In this study we described and compared confounding-adjustment methods to address this gap.
The methods considered were multivariable quantile regression, an inverse probability weighted (IPW) estimator, weighted quantile regression (another form of IPW) and two little-known implementations of g-computation for this problem. Methods were evaluated within a simulation study under varying degrees of skewness in the outcome and applied to an empirical study using data from the Longitudinal Study of Australian Children.
Simulation results indicated the IPW estimator, weighted quantile regression and g-computation implementations minimised bias across all settings when the relevant models were correctly specified, with g-computation additionally minimising the variance. Multivariable quantile regression, which relies on a constant-effect assumption, consistently yielded biased results. Application to the empirical study illustrated the practical value of these methods.
The presented methods provide appealing avenues for estimating the causal difference in medians.
Bacteria are an enormous and largely untapped reservoir of biosensing proteins. We describe an approach to identify and isolate bacterial allosteric transcription factors (aTFs) that recognize a ...target analyte and to develop these TFs into biosensor devices. Our approach utilizes a combination of genomic screens and functional assays to identify and isolate biosensing TFs, and a quantum-dot Förster Resonance Energy Transfer (FRET) strategy for transducing analyte recognition into real-time quantitative measurements. We use this approach to identify a progesterone-sensing bacterial aTF and to develop this TF into an optical sensor for progesterone. The sensor detects progesterone in artificial urine with sufficient sensitivity and specificity for clinical use, while being compatible with an inexpensive and portable electronic reader for point-of-care applications. Our results provide proof-of-concept for a paradigm of microbially-derived biosensors adaptable to inexpensive, real-time sensor devices.
Nanoparticles in a variety of forms are increasing important in fundamental research, technological and medical applications, and environmental or toxicology studies. Physical and chemical drivers ...that lead to multiple types of particle instabilities complicate both the ability to produce, appropriately characterize, and consistently deliver well-defined particles, frequently leading to inconsistencies, and conflicts in the published literature. This perspective suggests that provenance information, beyond that often recorded or reported, and application of a set of core characterization methods, including a surface sensitive technique, consistently applied at critical times can serve as tools in the effort minimize reproducibility issues.
Pristine Li-rich layered cathodes, such as Li1.2Ni0.2Mn0.6O2 and Li1.2Ni0.1Mn0.525Co0.175O2, were identified to exist in two different structures: LiMO2 R3̅m and Li2MO3 C2/m phases. Upon 300 cycles ...of charge/discharge, both phases gradually transform to the spinel structure. The transition from LiMO2 R3̅m to spinel is accomplished through the migration of transition metal ions to the Li site without breaking down the lattice, leading to the formation of mosaic structured spinel grains within the parent particle. In contrast, transition from Li2MO3 C2/m to spinel involves removal of Li+ and O2‑, which produces large lattice strain and leads to the breakdown of the parent lattice. The newly formed spinel grains show random orientation within the same particle. Cracks and pores were also noticed within some layered nanoparticles after cycling, which is believed to be the consequence of the lattice breakdown and vacancy condensation upon removal of lithium ions. The AlF3-coating can partially relieve the spinel formation in the layered structure during cycling, resulting in a slower capacity decay. However, the AlF3-coating on the layered structure cannot ultimately stop the spinel formation. The observation of structure transition characteristics discussed in this paper provides direct explanation for the observed gradual capacity loss and poor rate performance of the layered composite. It also provides clues about how to improve the materials structure in order to improve electrochemical performance.
Recently, allosteric transcription factors (TFs) were identified as a novel class of biorecognition elements for in vitro sensing, whereby an indicator of the differential binding affinity between a ...TF and its cognate DNA exhibits dose‐dependent responsivity to an analyte. Described is a modular bead‐based biosensor design that can be applied to such TF‐DNA‐analyte systems. DNA‐functionalized beads enable efficient mixing and spatial separation, while TF‐labeled semiconductor quantum dots serve as bright fluorescent indicators of the TF‐DNA bound (on bead) and unbound states. The prototype sensor for derivatives of the antibiotic tetracycline exhibits nanomolar sensitivity with visual detection of bead fluorescence. Facile changes to the sensor enable sensor response tuning without necessitating changes to the biomolecular affinities. Assay components self‐assemble, and readout by eye or digital camera is possible within 5 minutes of analyte addition, making sensor use facile, rapid, and instrument‐free.
The allosteric transcription factor TetR acts as a sensor and actuator in this quantum dot enabled fluorescent bead assay for the small molecule anhydrotetracycline. This rapid, antibody‐free biosensor produces a visible change in fluorescent color, which can be detected by eye or with an inexpensive digital camera, based on dose‐dependent analyte‐responsive protein‐DNA binding. The adaptable sensor uses easily accessible biomolecular components.
A recent description of an antibody‐free assay is significantly extended for small molecule analytes using allosteric transcription factors (aTFs) and Förster resonance energy transfer (FRET). The ...FRET signal indicates the differential binding of an aTF–DNA pair with a dose‐dependent response to its effector molecule, i.e., the analyte. The new sensors described here, based on the well‐characterized aTF TetR, demonstrate several new features of the assay approach: 1) the generalizability of the sensors to additional aTF–DNA–analyte systems, 2) sensitivity modulation through the choice of donor fluorophore (quantum dots or fluorescent proteins, FPs), and 3) sensor tuning using aTF variants with differing aTF–DNA binding affinities. While all of these modular sensors self‐assemble, the design reported here based on a recombinant aTF–FP chimera with commercially available dye‐labeled DNA uses readily accessible sensor components to facilitate easy adoption of the sensing approach by the broader community.
Allosteric transcription factor TetR acts as a sensor and an actuator in two Förster resonance energy transfer (FRET) sensor designs to quantify the small molecule anhydrotetracycline. The homogeneous assays use minimal components to produce ratiometric fluorescent readouts based on dose‐dependent analyte‐responsive protein–DNA binding. Component accessibility and ease of assembly facilitate adoption of this generalizable sensor design.
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