Misspellings or "miscellings"-Non-verifiable and unknown cell lines in cancer research publications.

Reproducible laboratory research relies on correctly identified reagents. We have previously described gene research papers with wrongly identified nucleotide sequence(s), including papers studying miR-145. Manually verifying reagent identities in 36 recent miR-145 papers found that 56% and 17% of papers described misidentified nucleotide sequences and cell lines, respectively. We also found 5 cell line identifiers in miR-145 papers with misidentified nucleotide sequences and cell lines, and 18 cell line identifiers published elsewhere, that did not represent indexed human cell lines. These 23 identifiers were described as non-verifiable (NV), as their identities were unclear. Studying 420 papers that mentioned 8 NV identifier(s) found 235 papers (56%) that referred to 7 identifiers (BGC-803, BSG-803, BSG-823, GSE-1, HGC-7901, HGC-803, and MGC-823) as independent cell lines. We could not find any publications describing how these cell lines were established. Six cell lines were sourced from cell line repositories with externally accessible online catalogs, but these cell lines were not indexed as claimed. Some papers also stated that short tandem repeat (STR) profiles had been generated for three cell lines, yet no STR profiles could be identified. In summary, as NV cell lines represent new challenges to research integrity and reproducibility, further investigations are required to clarify their status and identities.

A Comprehensive Enumeration of the Human Proteostasis Network. 2. Components of the Autophagy-Lysosome Pathway.

The condition of having a healthy, functional proteome is known as protein homeostasis, or proteostasis. Establishing and maintaining proteostasis is the province of the proteostasis network, approximately 2,700 components that regulate protein synthesis, folding, localization, and degradation. The proteostasis network is a fundamental entity in biology that is essential for cellular health and has direct relevance to many diseases of protein conformation. However, it is not well defined or annotated, which hinders its functional characterization in health and disease. In this series of manuscripts, we aim to operationally define the human proteostasis network by providing a comprehensive, annotated list of its components. We provided in a previous manuscript a list of chaperones and folding enzymes as well as the components that make up the machineries for protein synthesis, protein trafficking into and out of organelles, and organelle-specific degradation pathways. Here, we provide a curated list of 838 unique high-confidence components of the autophagy-lysosome pathway, one of the two major protein degradation systems in human cells.

Protection of the human gene research literature from contract cheating organizations known as research paper mills.

Human gene research generates new biology insights with translational potential, yet few studies have considered the health of the human gene literature. The accessibility of human genes for targeted research, combined with unreasonable publication pressures and recent developments in scholarly publishing, may have created a market for low-quality or fraudulent human gene research articles, including articles produced by contract cheating organizations known as paper mills. This review summarises the evidence that paper mills contribute to the human gene research literature at scale and outlines why targeted gene research may be particularly vulnerable to systematic research fraud. To raise awareness of targeted gene research from paper mills, we highlight features of problematic manuscripts and publications that can be detected by gene researchers and/or journal staff. As improved awareness and detection could drive the further evolution of paper mill-supported publications, we also propose changes to academic publishing to more effectively deter and correct problematic publications at scale. In summary, the threat of paper mill-supported gene research highlights the need for all researchers to approach the literature with a more critical mindset, and demand publications that are underpinned by plausible research justifications, rigorous experiments and fully transparent reporting.

Mathematical models to study the biology of pathogens and the infectious diseases they cause.

Mathematical models have many applications in infectious diseases: epidemiologists use them to forecast outbreaks and design containment strategies; systems biologists use them to study complex processes sustaining pathogens, from the metabolic networks empowering microbial cells to ecological networks in the microbiome that protects its host. Here, we (1) review important models relevant to infectious diseases, (2) draw parallels among models ranging widely in scale. We end by discussing a minimal set of information for a model to promote its use by others and to enable predictions that help us better fight pathogens and the diseases they cause.

Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability.

Standard oral rapamycin (that is, Rapamune) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mammalian target of rapamycin (mTOR) inhibitor has a narrow therapeutic window and numerous side effects and provides inadequate protection to transplanted cells and tissues. Furthermore, the hydrophobicity of rapamycin limits its use in parenteral formulations. Here, we demonstrate that subcutaneous delivery via poly(ethylene glycol)-b-poly(propylene sulfide) polymersome nanocarriers significantly alters rapamycin's cellular biodistribution to repurpose its mechanism of action for tolerance, instead of immunosuppression, and minimize side effects. While oral rapamycin inhibits T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes modulate antigen presenting cells in lieu of T cells, significantly improving maintenance of normoglycemia in a clinically relevant, major histocompatibility complex-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug by controlling cellular biodistribution.

Modeling robust COVID-19 intensive care unit occupancy thresholds for imposing mitigation to prevent exceeding capacities.

In non-pharmaceutical management of COVID-19, occupancy of intensive care units (ICU) is often used as an indicator to inform when to intensify mitigation and thus reduce SARS-CoV-2 transmission, strain on ICUs, and deaths. However, ICU occupancy thresholds at which action should be taken are often selected arbitrarily. We propose a quantitative approach using mathematical modeling to identify ICU occupancy thresholds at which mitigation should be triggered to avoid exceeding the ICU capacity available for COVID-19 patients and demonstrate this approach for the United States city of Chicago. We used a stochastic compartmental model to simulate SARS-CoV-2 transmission and disease progression, including critical cases that would require intensive care. We calibrated the model using daily COVID-19 ICU and hospital census data between March and August 2020. We projected various possible ICU occupancy trajectories from September 2020 to May 2021 with two possible levels of transmission increase and uncertainty in core model parameters. The effect of combined mitigation measures was modeled as a decrease in the transmission rate that took effect when projected ICU occupancy reached a specified threshold. We found that mitigation did not immediately eliminate the risk of exceeding ICU capacity. Delaying action by 7 days increased the probability of exceeding ICU capacity by 10-60% and this increase could not be counteracted by stronger mitigation. Even under modest transmission increase, a threshold occupancy no higher than 60% was required when mitigation reduced the reproductive number Rt to just below 1. At higher transmission increase, a threshold of at most 40% was required with mitigation that reduced Rt below 0.75 within the first two weeks after mitigation. Our analysis demonstrates a quantitative approach for the selection of ICU occupancy thresholds that considers parameter uncertainty and compares relevant mitigation and transmission scenarios. An appropriate threshold will depend on the location, number of ICU beds available for COVID-19, available mitigation options, feasible mitigation strengths, and tolerated durations of intensified mitigation.

Geographic and demographic heterogeneity of SARS-CoV-2 diagnostic testing in Illinois, USA, March to December 2020.

BACKGROUND: Availability of SARS-CoV-2 testing in the United States (U.S.) has fluctuated through the course of the COVID-19 pandemic, including in the U.S. state of Illinois. Despite substantial ramp-up in test volume, access to SARS-CoV-2 testing remains limited, heterogeneous, and insufficient to control spread. METHODS: We compared SARS-CoV-2 testing rates across geographic regions, over time, and by demographic characteristics (i.e., age and racial/ethnic groups) in Illinois during March through December 2020. We compared age-matched case fatality ratios and infection fatality ratios through time to estimate the fraction of SARS-CoV-2 infections that have been detected through diagnostic testing. RESULTS: By the end of 2020, initial geographic differences in testing rates had closed substantially. Case fatality ratios were higher in non-Hispanic Black and Hispanic/Latino populations in Illinois relative to non-Hispanic White populations, suggesting that tests were insufficient to accurately capture the true burden of COVID-19 disease in the minority populations during the initial epidemic wave. While testing disparities decreased during 2020, Hispanic/Latino populations consistently remained the least tested at 1.87 tests per 1000 population per day compared with 2.58 and 2.87 for non-Hispanic Black and non-Hispanic White populations, respectively, at the end of 2020. Despite a large expansion in testing since the beginning of the first wave of the epidemic, we estimated that over half (50-80%) of all SARS-CoV-2 infections were not detected by diagnostic testing and continued to evade surveillance. CONCLUSIONS: Systematic methods for identifying relatively under-tested geographic regions and demographic groups may enable policymakers to regularly monitor and evaluate the shifting landscape of diagnostic testing, allowing officials to prioritize allocation of testing resources to reduce disparities in COVID-19 burden and eventually reduce SARS-CoV-2 transmission.

Geographic and demographic heterogeneity of SARS-CoV-2 diagnostic testing in Illinois, USA, March to December 2020.

Background: Availability of SARS-CoV-2 testing in the United States (U.S.) has fluctuated through the course of the COVID-19 pandemic, including in the U.S. state of Illinois. Despite substantial ramp-up in test volume, access to SARS-CoV-2 testing remains limited, heterogeneous, and insufficient to control spread. Methods: We compared SARS-CoV-2 testing rates across geographic regions, over time, and by demographic characteristics (i.e., age and racial/ethnic groups) in Illinois during March through December 2020. We compared age-matched case fatality ratios and infection fatality ratios through time to estimate the fraction of SARS-CoV-2 infections that have been detected through diagnostic testing. Results: By the end of 2020, initial geographic differences in testing rates had closed substantially. Case fatality ratios were higher in non-Hispanic Black and Hispanic/Latino populations in Illinois relative to non-Hispanic White populations, suggesting that tests were insufficient to accurately capture the true burden of COVID-19 disease in the minority populations during the initial epidemic wave. While testing disparities decreased during 2020, Hispanic/Latino populations consistently remained the least tested at 1.87 tests per 1000 population per day compared with 2.58 and 2.87 for non-Hispanic Black and non-Hispanic White populations, respectively, at the end of 2020. Despite a large expansion in testing since the beginning of the first wave of the epidemic, we estimated that over half (50-80%) of all SARS-CoV-2 infections were not detected by diagnostic testing and continued to evade surveillance. Conclusions: Systematic methods for identifying relatively under-tested geographic regions and demographic groups may enable policymakers to regularly monitor and evaluate the shifting landscape of diagnostic testing, allowing officials to prioritize allocation of testing resources to reduce disparities in COVID-19 burden and eventually reduce SARS-CoV-2 transmission.