The rising prevalence of multidrug-resistant bacteria is an urgent health crisis that can only be countered through renewed investment in the discovery and development of antibiotics. There is no ...panacea for the antibacterial resistance crisis; instead, a multifaceted approach is called for. In this Perspective we make the case that, in the face of evolving clinical needs and enabling technologies, numerous validated antibacterial targets and associated lead molecules deserve a second look. At the same time, many worthy targets lack good leads despite harboring druggable active sites. Creative and inspired techniques buoy discovery efforts; while soil screening efforts frequently lead to antibiotic rediscovery, researchers have found success searching for new antibiotic leads by studying underexplored ecological niches or by leveraging the abundance of available data from genome mining efforts. The judicious use of “polypharmacology” (i.e., the ability of a drug to alter the activities of multiple targets) can also provide new opportunities, as can the continued search for inhibitors of resistance enzymes with the capacity to breathe new life into old antibiotics. We conclude by highlighting available pharmacoeconomic models for antibacterial discovery and development while making the case for new ones.
Developing uniformly formatted, densified feedstock from lignocellulosic biomass is of interest to achieve consistent physical properties such as size and shape, bulk and unit density, and ...durability, which significantly influence storage, transportation and handling characteristics, and, by extension, feedstock cost and quality. A variety of densification systems are considered for producing a uniform format feedstock commodity for bioenergy applications, including (i) pellet mill, (ii) cuber, (iii) screw extruder, (iv) briquette press, (v) roller press, (vi) tablet press, and (vii) agglomerator. Each of these systems has varying impacts on feedstock chemical and physical properties, and energy consumption. This review discusses the suitability of these densification systems for biomass feedstocks and the impact these systems have on specific energy consumption and end‐product quality. For example, a briquette press is more flexible in terms of feedstock variables where higher moisture content and larger particles are acceptable for making good quality briquettes; or among different densification systems, a screw press consumes the most energy because it not only compresses but also shears and mixes the material. Pre‐treatment options like pre‐heating, grinding, steam explosion, torrefaction, and ammonia fiber explosion (AFEX) can also help to reduce specific energy consumption during densification and improve binding characteristics. Binding behavior can also be improved by adding natural binders, such as proteins, or commercial binders, such as lignosulfonates. The quality of the densified biomass for both domestic and international markets is evaluated using PFI (United States standard) or CEN (European standard). Published in 2011 by John Wiley & Sons, Ltd
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PCR of upper respiratory specimens is the diagnostic standard for severe acute respiratory syndrome coronavirus 2 infection. However, saliva sampling is an easy alternative to nasal and throat ...swabbing. We found similar viral loads in saliva samples and in nasal and throat swab samples from 110 patients with coronavirus disease.
BackgroundAlthough recent epidemiological data suggest that pneumococci may contribute to the risk of SARS-CoV-2 disease, cases of coinfection with Streptococcus pneumoniae in patients with ...coronavirus disease 2019 (COVID-19) during hospitalization have been reported infrequently. This apparent contradiction may be explained by interactions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and pneumococci in the upper airway, resulting in the escape of SARS-CoV-2 from protective host immune responses.MethodsHere, we investigated the relationship of these 2 respiratory pathogens in 2 distinct cohorts of health care workers with asymptomatic or mildly symptomatic SARS-CoV-2 infection identified by systematic screening and patients with moderate to severe disease who presented to the hospital. We assessed the effect of coinfection on host antibody, cellular, and inflammatory responses to the virus.ResultsIn both cohorts, pneumococcal colonization was associated with diminished antiviral immune responses, which primarily affected mucosal IgA levels among individuals with mild or asymptomatic infection and cellular memory responses in infected patients.ConclusionOur findings suggest that S. pneumoniae impair host immunity to SARS-CoV-2 and raise the question of whether pneumococcal carriage also enables immune escape of other respiratory viruses and facilitates reinfection.Trial registrationISRCTN89159899 (FASTER study) and ClinicalTrials.gov NCT03502291 (LAIV study).
Monitoring and measuring the behaviour and movement of aquatic animals in the wild is typically challenging, though micro-accelerometer (archival or telemetry) tags now provide the means to remotely ...identify and quantify behavioural states and rates such as resting, swimming and migrating, and to estimate activity and energy budgets. Most studies use low-frequency (≤32 Hz) accelerometer sampling because of battery and data-archiving constraints. In this study we assessed the effect of sampling frequency (aliasing) on activity detection probability using the great sculpin (Myoxocephalus polyacanthoceaphalus) as a model species. Feeding strikes and escape responses (fast-start activities) and spontaneous movements among seven different great sculpin were triggered, observed and recorded using video records and a tri-axial accelerometer sampling at 100 Hz. We demonstrate that multiple parameters in the time and probability domains can statistically differentiate between activities with high detection (90%) and identification (80%) probabilities. Detection probability for feeding and escape activities decreased by 50% when sampling at <10 Hz. Our analyses illustrate additional problems associated with aliasing and how activity and energy-budget estimates can be compromised and misinterpreted. We recommend that high-frequency (>30 Hz) accelerometer sampling be used in similar laboratory and field studies. If battery and/or data storage is limited, we also recommend archiving the events via an on-board algorithm that determines the highest likelihood and subsequent archiving of the various event classes of interest.
The economic competitiveness of cellulosic ethanol production is highly dependent on feedstock cost, which constitutes 35–50% of the total ethanol production cost, depending on various geographical ...factors and the types of systems used for harvesting, collecting, preprocessing, transporting, and handling the material. Consequently, as the deployment of cellulosic ethanol biorefineries approaches, feedstock cost and availability are the driving factors that influence pioneer biorefinery locations and will largely control the rate at which this industry grows. Initial scenarios were postulated to develop a pioneer dry feedstock supply system design case as a demonstration of the current state of technology. Based on this pioneer design, advanced scenarios were developed to determine key cost barriers, needed supply system improvements, and technology advancements to achieve government and private sector cost targets. Analysis of the pioneer supply system resulted in a delivered feedstock cost to the throat of the pretreatment reactor of $37.00 per dry tonne (2002 $). Pioneer supply systems will start by using current infrastructure and technologies and be individually designed for biorefineries using specific feedstock types and varieties based on local geographic conditions. As the industry develops and cost barriers are addressed, the supply systems will incorporate advanced technologies that will eliminate downstream diversity and provide a uniform, tailored feedstock for multiple biorefineries located in different regions. Published in 2007 by John Wiley & Sons, Ltd.
Despite its relatively low incidence, pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths because of the aggressive growth/metastasis of the tumor, the lack of early symptoms, ...and the poor treatment options. Basic research to identify potential therapeutic targets for PDAC is greatly needed.
We used a negative-selection genome-wide CRISPR screen to identify essential genes in the PANC-1 human pancreatic carcinoma cell line. We validated the top hits with follow-up siRNA screens, using the HPNE, HPAF-II, AsPC-1, and Mia PaCa-2 cell lines.
The PSMA6 gene was an identified candidate hit after the CRISPR screen, siRNA validation screen, and siRNA deconvolution screen. Spheroid formation assays and flow cytometry analysis showed that PSMA6 is critical for survival in many pancreatic ductal carcinoma cell models. Lastly, as PSMA6 protein is a proteosomal subunit of the 20S core complex, we showed that bortezomib, a proteasome inhibitor, was especially toxic in PANC-1 cells.
Further study of PSMA6 and the proteasome subunit that it encodes, along with other hits identified in our CRISPR screens, may provide valuable insights into potential therapeutic targets for PDAC.
2D hybrid organic–inorganic halide perovskites emerge as a new class of 2D semiconductors with the potential to combine excellent optoelectronic properties with symmetry‐enabled properties such as ...ferroelectricity. Although many lead‐based ferroelectric 2D halide perovskites are reported, there is yet to be a conclusive report of ferroelectricity in tin‐based 2D perovskites. Here, the structures and properties of a new series of 2D Dion–Jacobson (DJ) Sn perovskites: (4AMP)SnI4, (4AMP)(MA)Sn2I7, and (4AMP)(FA)Sn2I7 (4AMP = 4‐(aminomethyl)piperidinium, MA = methylammonium, and FA = formamidinium), are reported. Structural characterization reveals that (4AMP)SnI4 is polar with in‐plane spontaneous polarization whereas (4AMP)(MA)Sn2I7 and (4AMP)(FA)Sn2I7 are centrosymmetric. Further, (4AMP)SnI4 displays second harmonic generation (SHG) and polarization‐electric field hysteresis measurements confirm it is ferroelectric with a spontaneous polarization of 10.0 µC cm−2 at room temperature. (4AMP)SnI4 transitions into a centrosymmetric structure above 367 K. As the first direct experimental observation of the spontaneous ferroelectric polarization of a Sn‐based 2D hybrid perovskite, this work opens up environmentally friendly 2D tin halide perovskites for ferroelectricity and other physical property studies.
New lead‐free 2D Dion–Jacobson tin perovskites containing the 4‐(aminomethyl)piperidinium (4AMP) spacer cation are studied: (4AMP)SnI4, (4AMP)(MA)Sn2I7, and (4AMP)(FA)Sn2I7 (MA = methylammonium, FA = formamidinium). Structural analysis reveals that only (4AMP)SnI4 is noncentrosymmetric, confirmed by second harmonic generation. Ferroelectric hysteresis measurements provide clear evidence of ferroelectricity of (4AMP)SnI4 at room temperature with spontaneous polarization of 10.0 µC cm−2.
The affordability of next-generation genomic sequencing and the improvement of medical data management have contributed largely to the evolution of biological analysis from both a clinical and ...research perspective. Precision medicine is a response to these advancements that places individuals into better-defined subsets based on shared clinical and genetic features. The identification of personalized diagnosis and treatment options is dependent on the ability to draw insights from large-scale, multi-modal analysis of biomedical datasets. Driven by a real use case, we premise that platforms that support precision medicine analysis should maintain data in their optimal data stores, should support distributed storage and query mechanisms, and should scale as more samples are added to the system. We extended a genomics-based columnar data store, GenomicsDB, for ease of use within a distributed analytics platform for clinical and genomic data integration, known as the ODA framework. The framework supports interaction from an i2b2 plugin as well as a notebook environment. We show that the ODA framework exhibits worst-case linear scaling for array size (storage), import time (data construction), and query time for an increasing number of samples. We go on to show worst-case linear time for both import of clinical data and aggregate query execution time within a distributed environment. This work highlights the integration of a distributed genomic database with a distributed compute environment to support scalable and efficient precision medicine queries from a HIPAA-compliant, cohort system in a real-world setting. The ODA framework is currently deployed in production to support precision medicine exploration and analysis from clinicians and researchers at UCLA David Geffen School of Medicine.
Background Peripheral artery disease (PAD) increases the risk of cardiovascular events and limb events including amputations. PAD is twice as prevalent in Black compared with non‐Hispanic White ...individuals, especially among men. Screening for PAD using the ankle–brachial index in community settings, such as the barbershop, could lead to earlier diagnosis and treatment. Methods and Results A pilot study was conducted at 2 barbershops in Cleveland, OH from June to December 2020 to assess the feasibility of screening for PAD in the barbershop setting and the effect of an educational intervention on PAD awareness. After screening with both automated and Doppler ankle–brachial index, PAD was identified in 5/31 (16.1%) of participants. Baseline systolic blood pressure, low‐density lipoprotein cholesterol, and random blood glucose were higher in participants who screened positive for PAD ( P <0.001). PAD awareness was low overall. There was a significant improvement in PAD awareness assessment scores obtained at the initial and exit visits (9.93±4.23 to 12.50±4.41, P =0.004). An association was found between PAD awareness at baseline and highest education level achieved: compared with those with some college/associate's degree or higher, non–high school graduates scored lower on PAD awareness ( P =0.022), as did those who only had a high school diploma or tests of General Educational Development ( P =0.049). Conclusions In a pilot study, barbershop‐based screening for PAD among Black men revealed a higher than expected PAD prevalence and low PAD awareness. An educational video was effective at increasing PAD awareness. Ankle–brachial index screening and educational outreach in the barbershop may be a feasible and effective tool to diagnose PAD and reduce PAD disparities among Black men at highest risk.
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