bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple herbicide resistance in waterhemp (Amaranthus tuberculatus) accessions from Wisconsin
Authors: Faleco Felipe A. , Oliveira Maxwel C. , Arneson Nicholas J. , Renz Mark , Stoltenberg David E. , Werle Rodrigo
Published: November 2022

A comprehensive, Wisconsin state-wide assessment of waterhemp response to a diverse group of herbicide sites of action has not been conducted. Our objective was to characterize the response of a state-wide collection of waterhemp accessions to postemergence (POST) and preemergence (PRE) herbicides commonly used in corn and soybean in Wisconsin. Greenhouse experiments were conducted with more than 80 accessions from 27 counties. POST treatments included 2,4-D, atrazine, dicamba, fomesafen, glufosinate, glyphosate, imazethapyr, and mesotrione at 1× and 3× label rates. PRE treatments included atrazine, fomesafen, mesotrione, metribuzin, and S-metolachlor at 0.5×, 1×, and 3× label rates. Ninety-eight percent and 88% of the accessions exhibited ≥50% plant survival after exposure to imazethapyr and glyphosate POST 3× rate, respectively. Seventeen percent, 16%, and 3% of the accessions exhibited ≥50% plant survival after exposure to 2,4-D, atrazine, and dicamba, respectively, applied POST at the 1× rate. Survival of all accessions was ≤25% after exposure to 2,4-D or dicamba applied POST at the 3× rate, or glufosinate, fomesafen, and mesotrione applied POST at either rate evaluated. No plant of any accession survived exposure to glufosinate at either rate. Forty-five percent and 3% of the accessions exhibited <90% plant density reduction after exposure to atrazine applied PRE at the 3× rate and fomesafen PRE at the 1× rate, respectively. Plant density reduction of all accessions was ≥96% after exposure to fomesafen applied PRE at the 3× rate, or metribuzin, S-metolachlor, and mesotrione applied PRE at the 1× rate. Our results suggest that waterhemp resistance to imazethapyr and glyphosate applied POST is widespread in Wisconsin, whereas resistance to 2,4-D, atrazine, and dicamba applied POST is present to a lower extent. One accession (A75, Fond du Lac County) exhibited multiple resistance to imazethapyr, atrazine, glyphosate, and 2,4-D when applied POST. Overall, atrazine applied PRE was ineffective for waterhemp control in Wisconsin. Proactive resistance management and the use of effective PRE and POST herbicides are fundamental for waterhemp management in Wisconsin.
Geospatial Database for the Prince Edward Islands
Authors: Makoni Munyaradzi
Published: November 2022

South African scientists map uninhabited islands in the Southern Ocean.
Assessment and Constraint of Mesozooplankton in CMIP6 Earth System Models
Authors: Petrik C. M. , Luo J. Y. , Heneghan R. F. , Everett J. D. , Harrison C. S. , Richardson A. J.
Published: November 2022

Although zooplankton play a substantial role in the biological carbon pump and serve as a crucial link between primary producers and higher trophic level consumers, the skillful representation of zooplankton is not often a focus of ocean biogeochemical models. Systematic evaluations of zooplankton in models could improve their representation, but so far, ocean biogeochemical skill assessment of Earth system model (ESM) ensembles have not included zooplankton. Here we use a recently developed global, observationally based map of mesozooplankton biomass to assess the skill of mesozooplankton in six CMIP6 ESMs. We also employ a biome‐based assessment of the ability of these models to reproduce the observed relationship between mesozooplankton biomass and surface chlorophyll. The combined analysis found that most models were able to reasonably simulate the large regional variations in mesozooplankton biomass at the global scale. Additionally, three of the ESMs simulated a mesozooplankton‐chlorophyll relationship within the observational bounds, which we used as an emergent constraint on future mesozooplankton projections. We highlight where differences in model structure and parameters may give rise to varied mesozooplankton distributions under historic and future conditions, and the resultant wide ensemble spread in projected changes in mesozooplankton biomass. Despite differences, the strength of the mesozooplankton‐chlorophyll relationships across all models was related to the projected changes in mesozooplankton biomass globally and in regional biomes. These results suggest that improved observations of mesozooplankton and their relationship to chlorophyll will better constrain projections of climate change impacts on these important animals.
Evidence for Turbulent Magnetic Diffusion in Earth's Core
Authors: Holdenried‐Chernoff D. , Buffett B. A.
Published: November 2022

Fluctuations in the paleomagnetic field suggest that the dipole decay time is shorter than expected, based on current estimates for the molecular magnetic diffusivity in the outer core. Similar behavior is observed in turbulent dynamo simulations, where the short magnetic field decay time cannot be attributed to higher‐order decay modes. We interpret the short decay time as a signature of turbulent diffusion and show that mean‐field theory can quantitatively account for the dynamo results. The predictions depend on the amplitude and length scale of the flow that interacts with the magnetic field. We rely on the pairwise balance between Lorentz/Coriolis and buoyancy/Coriolis forces to identify the relevant part of the flow, and use the resulting flow properties to reproduce results from numerical dynamo simulations within their uncertainties. Upon extending these predictions to the paleomagnetic field, we find that the inferred decay time requires a bulk root‐mean‐square velocity less than 0.8–1.2 mm s−1. Somewhat lower velocities have been estimated at the top of the core from observations of secular variation. These results show that velocities in the interior of the core are constrained by paleomagnetic observations, and that the amplitude of this flow cannot substantially exceed estimates at the core surface.
The 2020 Westmorland, California Earthquake Swarm as Aftershocks of a Slow Slip Event Sustained by Fluid Flow
Authors: Sirorattanakul Krittanon , Ross Zachary E. , Khoshmanesh Mostafa , Cochran Elizabeth S. , Acosta Mateo , Avouac Jean‐Philippe
Published: November 2022

Swarms are bursts of earthquakes without an obvious mainshock. Some have been observed to be associated with transient aseismic fault slip, while others are thought to be related to fluids. However, the association is rarely quantitative due to insufficient data quality. We use high‐quality GPS/GNSS, InSAR, and relocated seismicity to study a swarm of >2,000 earthquakes which occurred between 30 September and 6 October 2020, near Westmorland, California. Using 5 min sampled Global Positioning System (GPS) supplemented with InSAR, we document a spontaneous shallow Mw 5.2 slow slip event that preceded the swarm by 2–15 hr. The earthquakes in the early phase were predominantly non‐interacting and driven primarily by the slow slip event resulting in a nonlinear expansion. A stress‐driven model based on the rate‐and‐state friction successfully explains the overall spatial and temporal evolution of earthquakes, including the time lag between the onset of the slow slip event and the swarm. Later, a distinct back front and a square root of time expansion of clustered seismicity on en‐echelon fault structures suggest that fluids helped sustain the swarm. Static stress triggering analysis using Coulomb stress and statistics of interevent times suggest that 45%–65% of seismicity was driven by the slow slip event, 10%–35% by inter‐earthquake interactions, and 10%–30% by fluids. Our model also provides constraints on the friction parameter and the pore pressure and suggests that this swarm behaved like an aftershock sequence but with the mainshock replaced by the slow slip event.
Temperature Variability and Eddy‐Flow Interaction in the South of Oyashio Extension
Authors: Yang Haiyuan , Zhu Ruichen , Chen Zhaohui , Li Jianchao , Wu Lixin
Published: November 2022

Based on observations and eddy‐resolving model products, this study investigates the temperature variability south of the Oyashio Extension (OE). During 2016–2021, six dramatic cold events, which significantly impact the local ecosystems, are captured by in situ and satellite observations. It reveals that interaction between the OE front (OEF) and anticyclonic mesoscale eddies originating from the Kuroshio Extension is responsible for these cold events. Accompanied by intense eddy‐flow baroclinic energy exchange, the OEF meanders to the south and favors a southward cold‐water intrusion. Further analysis illustrates that the cold events tend to occur during spring and autumn, which is associated with the seasonal evolutions of OEF and anticyclonic eddies.
WNK3 inhibition elicits antitumor immunity by suppressing PD-L1 expression on tumor cells and activating T-cell function
Authors: Yoon Hyun Ju , Kim Gi-Cheon , Oh Sejin , Kim Hakhyun , Kim Yong Keon , Lee Yunji , Kim Min Seo , Kwon Gino , Ok Yeon-Su , Kwon Ho-Keun , Kim Hyun Seok
Published: November 2022

Immune checkpoint therapies, such as programmed cell death ligand 1 (PD-L1) blockade, have shown remarkable clinical benefit in many cancers by restoring the function of exhausted T cells. Hence, the identification of novel PD-L1 regulators and the development of their inhibition strategies have significant therapeutic advantages. Here, we conducted pooled shRNA screening to identify regulators of membrane PD-L1 levels in lung cancer cells targeting druggable genes and cancer drivers. We identified WNK lysine deficient protein kinase 3 (WNK3) as a novel positive regulator of PD-L1 expression. The kinase-dead WNK3 mutant failed to elevate PD-L1 levels, indicating the involvement of its kinase domain in this function. WNK3 perturbation increased cancer cell death in cancer cell–immune cell coculture conditions and boosted the secretion of cytokines and cytolytic enzymes, promoting antitumor activities in CD4+ and CD8+ T cells. WNK463, a pan-WNK inhibitor, enhanced CD8+ T-cell-mediated antitumor activity and suppressed tumor growth as a monotherapy as well as in combination with a low-dose anti-PD-1 antibody in the MC38 syngeneic mouse model. Furthermore, we demonstrated that the c-JUN N-terminal kinase (JNK)/c-JUN pathway underlies WNK3-mediated transcriptional regulation of PD-L1. Our findings highlight that WNK3 inhibition might serve as a potential therapeutic strategy for cancer immunotherapy through its concurrent impact on cancer cells and immune cells.
The natural product salicin alleviates osteoarthritis progression by binding to IRE1α and inhibiting endoplasmic reticulum stress through the IRE1α-IκBα-p65 signaling pathway
Authors: Zhu Zhenglin , Gao Shengqiang , Chen Cheng , Xu Wei , Xiao Pengcheng , Chen Zhiyu , Du Chengcheng , Chen Bowen , Gao Yan , Wang Chunli , Liao Junyi , Huang Wei
Published: November 2022

Despite the high prevalence of osteoarthritis (OA) in older populations, disease-modifying OA drugs (DMOADs) are still lacking. This study was performed to investigate the effects and mechanisms of the small molecular drug salicin (SA) on OA progression. Primary rat chondrocytes were stimulated with TNF-α and treated with or without SA. Inflammatory factors, cartilage matrix degeneration markers, and cell proliferation and apoptosis markers were detected at the mRNA and protein levels. Cell proliferation and apoptosis were evaluated by EdU assays or flow cytometric analysis. RNA sequencing, molecular docking and drug affinity-responsive target stability analyses were used to clarify the mechanisms. The rat OA model was used to evaluate the effect of intra-articular injection of SA on OA progression. We found that SA rescued TNF-α-induced degeneration of the cartilage matrix, inhibition of chondrocyte proliferation, and promotion of chondrocyte apoptosis. Mechanistically, SA directly binds to IRE1α and occupies the IRE1α phosphorylation site, preventing IRE1α phosphorylation and regulating IRE1α-mediated endoplasmic reticulum (ER) stress by IRE1α-IκBα-p65 signaling. Finally, intra-articular injection of SA-loaded lactic-co-glycolic acid (PLGA) ameliorated OA progression by inhibiting IRE1α-mediated ER stress in the OA model. In conclusion, SA alleviates OA by directly binding to the ER stress regulator IRE1α and inhibits IRE1α-mediated ER stress via IRE1α-IκBα-p65 signaling. Topical use of the small molecular drug SA shows potential to modify OA progression.
Plant-associated Bacillus mobilizes its secondary metabolites upon perception of the siderophore pyochelin produced by a Pseudomonas competitor
Authors: Andrić Sofija , Rigolet Augustin , Argüelles Arias Anthony , Steels Sébastien , Hoff Grégory , Balleux Guillaume , Ongena Loïc , Höfte Monica , Meyer Thibault , Ongena Marc
Published: November 2022

Bacillus velezensis is considered as model species for plant-associated bacilli providing benefits to its host such as protection against phytopathogens. This is mainly due to the potential to secrete a wide range of secondary metabolites with specific and complementary bioactivities. This metabolite arsenal has been quite well defined genetically and chemically but much remains to be explored regarding how it is expressed under natural conditions and notably how it can be modulated upon interspecies interactions in the competitive rhizosphere niche. Here, we show that B. velezensis can mobilize a substantial part of its metabolome upon the perception of Pseudomonas, as a soil-dwelling competitor. This metabolite response reflects a multimodal defensive strategy as it includes polyketides and the bacteriocin amylocyclicin, with broad antibiotic activity, as well as surfactin lipopeptides, contributing to biofilm formation and enhanced motility. Furthermore, we identified the secondary Pseudomonas siderophore pyochelin as an info-chemical, which triggers this response via a mechanism independent of iron stress. We hypothesize that B. velezensis relies on such chelator sensing to accurately identify competitors, illustrating a new facet of siderophore-mediated interactions beyond the concept of competition for iron and siderophore piracy. This phenomenon may thus represent a new component of the microbial conversations driving the behavior of members of the rhizosphere community.
Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC
Authors: Wang Longhao , Hu Tao , Shen Zhibo , Zheng Yuanyuan , Geng Qishun , Li Lifeng , Sha Beibei , Li Miaomiao , Sun Yaxin , Guo Yongjun , Xue Wenhua , Xuan Dan , Chen Ping , Zhao Jie
Published: November 2022

The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, apoptosis, and autophagy in ML-323-treated HCC cells. In addition, blocking autophagy using the AMPK inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.
SR9009 inhibits lethal prostate cancer subtype 1 by regulating the LXRα/FOXM1 pathway independently of REV-ERBs
Authors: Xu Hang , Zhang Jiapeng , Zheng Xiaonan , Tan Ping , Xiong Xingyu , Yi Xianyanling , Yang Yang , Wang Yan , Liao Dazhou , Li Hong , Wei Qiang , Ai Jianzhong , Yang Lu
Published: November 2022

Perturbations of the circadian clock are linked to multiple diseases, including cancers. Pharmacological activation of REV-ERB nuclear receptors, the core components of the circadian clock, has antitumor effects on various malignancies, while the impact of SR9009 on prostate cancer (PCa) remains unknown. Here, we found that SR9009 was specifically lethal to PCa cell lines but had no cytotoxic effect on prostate cells. SR9009 significantly inhibited colony formation, the cell cycle, and cell migration and promoted apoptosis in PCa cells. SR9009 treatment markedly inhibited prostate cancer subtype 1 (PCS1), the most lethal and aggressive PCa subtype, through FOXM1 pathway blockade, while it had no impacts on PCS2 and PCS3. Seven representative genes, including FOXM1, CENPA, CENPF, CDK1, CCNB1, CCNB2, and BIRC5, were identified as the shared genes involved in the FOXM1 pathway and PCS1. All of these genes were upregulated in PCa tissues, associated with worse clinicopathological outcomes and downregulated after SR9009 treatment. Nevertheless, knockdown or knockout of REV-ERB could not rescue the anticancer effect of SR9009 in PCa. Further analysis confirmed that it was LXRα rather than REV-ERBs which has been activated by SR9009. The expression levels of these seven genes were changed correspondingly after LXRα knockdown and SR9009 treatment. An in vivo study validated that SR9009 restrained tumor growth in 22RV1 xenograft models and inhibited FOXM1 and its targeted gene expression. In summary, SR9009 can serve as an effective treatment option for highly aggressive and lethal PCS1 tumors through mediating the LXRα/FOXM1 pathway independently of REV-ERBs.
MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis
Authors: Zou Xiaodong , Ouyang Hongsheng , Lin Feng , Zhang Huanyu , Yang Yang , Pang Daxin , Han Renzhi , Tang Xiaochun
Published: November 2022

Genetic mutations in the MYBPC3 gene encoding cardiac myosin binding protein C (cMyBP-C) are the most common cause of hypertrophic cardiomyopathy (HCM). Myocardial fibrosis (MF) plays a critical role in the development of HCM. However, the mechanism for mutant MYBPC3-induced MF is not well defined. In this study, we developed a R495Q mutant pig model using cytosine base editing and observed an early-onset MF in these mutant pigs shortly after birth. Unexpectedly, we found that the “cardiac-specific” MYBPC3 gene was actually expressed in cardiac fibroblasts from different species as well as NIH3T3 fibroblasts at the transcription and protein levels. CRISPR-mediated disruption of Mybpc3 in NIH3T3 fibroblasts activated nuclear factor κB (NF-κB) signaling pathway, which increased the expression of transforming growth factor beta (TGF-β1) and other pro-inflammatory genes. The upregulation of TGF-β1 promoted the expression of hypoxia-inducible factor-1 subunit α (HIF-1α) and its downstream targets involved in glycolysis such as GLUT1, PFK, and LDHA. Consequently, the enhanced aerobic glycolysis with higher rate of ATP biosynthesis accelerated the activation of cardiac fibroblasts, contributing to the development of HCM. This work reveals an intrinsic role of MYBPC3 in maintaining cardiac fibroblast homeostasis and disruption of MYBPC3 in these cells contributes to the disease pathogenesis of HCM.
Is there a “pandemic effect” on individuals’ willingness to take genetic tests?
Authors: Deruelle Thibaud , Kalouguina Veronika , Trein Philipp , Wagner Joël
Published: November 2022

In this cross-sectional, semi-longitudinal and quasi-experimental study, our goal was to determine the effect of data storage conditions on willingness to take a genetic test. We compared individuals’ preferences regarding how they want to store health data collected from genetic tests through two survey experiments fielded in Switzerland in March 2020 and January 2022. We tested for differences whether genetic data are presented as private goods or public goods. Results confirm our initial research expectation: more control over storage increases willingness, so does framing genetic data as private good. However, they also show that the willingness to take a genetic test has noticeably increased between 2020 and 2022. Our results point toward a “pandemic effect” which would have increased willingness take a genetic test, nevertheless, more data are needed to understand this putative effect.
Magic-angle-spinning NMR structure of the kinesin-1 motor domain assembled with microtubules reveals the elusive neck linker orientation
Authors: Zhang Chunting , Guo Changmiao , Russell Ryan W. , Quinn Caitlin M. , Li Mingyue , Williams John C. , Gronenborn Angela M. , Polenova Tatyana
Published: November 2022

Microtubules (MTs) and their associated proteins play essential roles in maintaining cell structure, organelle transport, cell motility, and cell division. Two motors, kinesin and cytoplasmic dynein link the MT network to transported cargos using ATP for force generation. Here, we report an all-atom NMR structure of nucleotide-free kinesin-1 motor domain (apo-KIF5B) in complex with paclitaxel-stabilized microtubules using magic-angle-spinning (MAS) NMR spectroscopy. The structure reveals the position and orientation of the functionally important neck linker and how ADP induces structural and dynamic changes that ensue in the neck linker. These results demonstrate that the neck linker is in the undocked conformation and oriented in the direction opposite to the KIF5B movement. Chemical shift perturbations and intensity changes indicate that a significant portion of ADP-KIF5B is in the neck linker docked state. This study also highlights the unique capability of MAS NMR to provide atomic-level information on dynamic regions of biological assemblies.
Helicity dependent photoresistance measurement vs. beam-shift thermal gradient
Authors: Yang Haozhe , Schmoranzerová Eva , Jang Pyunghwa , Nath Jayshankar , Guillet Thomas , Joumard Isabelle , Auffret Stéphane , Jamet Matthieu , Němec Petr , Gaudin Gilles , Miron Ioan-Mihai
Published: November 2022

Optical detection techniques are among the most powerful methods used to characterize spintronic phenomena. The spin orientation can affect the light polarization, which, by the reciprocal mechanism, can modify the spin density. Numerous recent experiments, report local changes in the spin density induced by a circularly polarized focused laser beam. These effects are typically probed electrically, by detecting the variations of the photoresistance or photocurrent associated to the reversal of the light helicity. Here we show that in general, when the light helicity is modified, the beam profile is slightly altered, and the barycenter of the laser spot is displaced. Consequently, the temperature gradients produced by the laser heating will be modulated, producing thermo-electric signals that alternate in phase with the light polarization. These unintended signals, having no connection with the electron spin, appear under the same experimental conditions and can be easily misinterpreted. We show how this contribution can be experimentally assessed and removed from the measured data. We find that even when the beam profile is optimized, this effect is large, and completely overshadows the spin related signals in all the materials and experimental conditions that we have tested.
Low cost and massively parallel force spectroscopy with fluid loading on a chip
Authors: Akbari Ehsan , Shahhosseini Melika , Robbins Ariel , Poirier Michael G. , Song Jonathan W. , Castro Carlos E.
Published: November 2022

Current approaches for single molecule force spectroscopy are typically constrained by low throughput and high instrumentation cost. Herein, a low-cost, high throughput technique is demonstrated using microfluidics for multiplexed mechanical manipulation of up to ~4000 individual molecules via molecular fluid loading on-a-chip (FLO-Chip). The FLO-Chip consists of serially connected microchannels with varying width, allowing for simultaneous testing at multiple loading rates. Molecular force measurements are demonstrated by dissociating Biotin-Streptavidin and Digoxigenin-AntiDigoxigenin interactions along with unzipping of double stranded DNA of varying sequence under different dynamic loading rates and solution conditions. Rupture force results under varying loading rates and solution conditions are in good agreement with prior studies, verifying a versatile approach for single molecule biophysics and molecular mechanobiology. FLO-Chip enables straightforward, rapid, low-cost, and portable mechanical testing of single molecules that can be implemented on a wide range of microscopes to broaden access and may enable new applications of molecular force spectroscopy.
Statistical inference links data and theory in network science
Authors: Peel Leto , Peixoto Tiago P. , De Domenico Manlio
Published: November 2022

The number of network science applications across many different fields has been rapidly increasing. Surprisingly, the development of theory and domain-specific applications often occur in isolation, risking an effective disconnect between theoretical and methodological advances and the way network science is employed in practice. Here we address this risk constructively, discussing good practices to guarantee more successful applications and reproducible results. We endorse designing statistically grounded methodologies to address challenges in network science. This approach allows one to explain observational data in terms of generative models, naturally deal with intrinsic uncertainties, and strengthen the link between theory and applications.
Integrase-mediated differentiation circuits improve evolutionary stability of burdensome and toxic functions in E. coli
Authors: Williams Rory L. , Murray Richard M.
Published: November 2022

Advances in synthetic biology, bioengineering, and computation allow us to rapidly and reliably program cells with increasingly complex and useful functions. However, because the functions we engineer cells to perform are typically burdensome to cell growth, they can be rapidly lost due to the processes of mutation and natural selection. Here, we show that a strategy of terminal differentiation improves the evolutionary stability of burdensome functions in a general manner by realizing a reproductive and metabolic division of labor. To implement this strategy, we develop a genetic differentiation circuit in Escherichia coli using unidirectional integrase-recombination. With terminal differentiation, differentiated cells uniquely express burdensome functions driven by the orthogonal T7 RNA polymerase, but their capacity to proliferate is limited to prevent the propagation of advantageous loss-of-function mutations that inevitably occur. We demonstrate computationally and experimentally that terminal differentiation increases duration and yield of high-burden expression and that its evolutionary stability can be improved with strategic redundancy. Further, we show this strategy can even be applied to toxic functions. Overall, this study provides an effective, generalizable approach for protecting burdensome engineered functions from evolutionary degradation.
The Neo-PLANET phase II trial of neoadjuvant camrelizumab plus concurrent chemoradiotherapy in locally advanced adenocarcinoma of stomach or gastroesophageal junction
Authors: Tang Zhaoqing , Wang Yan , Liu Dan , Wang Xuefei , Xu Chen , Yu Yiyi , Cui Yuehong , Tang Cheng , Li Qian , Sun Jing , Zhang Qian , Ji Yuan , Ma Guifen , Li Haojie , Shen Zhenbin , Shen Kuntang , Zheng Rongrong , Hou Zhiguo , Liu Tianshu , Wang Jiping , Sun Yihong
Published: November 2022

The synergistic effect of neoadjuvant immunotherapy and chemoradiotherapy in gastric adenocarcinoma is unclear. This phase II trial (NCT03631615) investigated this neoadjuvant combination in locally advanced adenocarcinoma of stomach or gastroesophageal junction. Thirty-six patients received capecitabine 850 mg/m2 twice daily and simultaneous radiotherapy for 5 weeks, sandwiched by a 21-day cycle of oxaliplatin 130 mg/m2 (day 1) plus capecitabine 1000 mg/m2 twice daily (days 1–14), respectively, followed by surgery. Camrelizumab 200 mg (day 1) was given for 5 cycles since initiating chemotherapy. Primary endpoint was pathological complete response (pCR, ypT0) rate. Secondary endpoints included total pCR (tpCR, ypT0N0) rate, major pathological response (MPR, < 10% residual tumor cells) rate, margin-free (R0) resection rate, downstaging, progression-free survival (PFS), overall survival (OS), and safety. The pCR rate was 33.3% (95% CI, 18.6–51.0), meeting pre-specified endpoint. TpCR, MPR, and R0 resection rates were 33.3%, 44.4%, and 91.7%, respectively. Twenty-eight (77.8%) patients reached ypN0. Two-year PFS and OS rates were 66.9% and 76.1%, respectively. The most common grade 3–4 adverse event was decreased lymphocyte count (27 [75.0%]). Neoadjuvant camrelizumab plus concurrent chemoradiotherapy exhibits promising pathological response in patients with locally advanced gastric adenocarcinoma, with an acceptable safety profile.
De novo identification of microbial contaminants in low microbial biomass microbiomes with Squeegee
Authors: Liu Yunxi , Elworth R. A. Leo , Jochum Michael D. , Aagaard Kjersti M. , Treangen Todd J.
Published: November 2022

Computational analysis of host-associated microbiomes has opened the door to numerous discoveries relevant to human health and disease. However, contaminant sequences in metagenomic samples can potentially impact the interpretation of findings reported in microbiome studies, especially in low-biomass environments. Contamination from DNA extraction kits or sampling lab environments leaves taxonomic "bread crumbs" across multiple distinct sample types. Here we describe Squeegee, a de novo contamination detection tool that is based upon this principle, allowing the detection of microbial contaminants when negative controls are unavailable. On the low-biomass samples, we compare Squeegee predictions to experimental negative control data and show that Squeegee accurately recovers putative contaminants. We analyze samples of varying biomass from the Human Microbiome Project and identify likely, previously unreported kit contamination. Collectively, our results highlight that Squeegee can identify microbial contaminants with high precision and thus represents a computational approach for contaminant detection when negative controls are unavailable.
Lipidomic signatures align with inflammatory patterns and outcomes in critical illness
Authors: Wu Junru , Cyr Anthony , Gruen Danielle S. , Lovelace Tyler C. , Benos Panayiotis V. , Das Jishnu , Kar Upendra K. , Chen Tianmeng , Guyette Francis X. , Yazer Mark H. , Daley Brian J. , Miller Richard S. , Harbrecht Brian G. , Claridge Jeffrey A. , Phelan Herb A. , Zuckerbraun Brian S. , Neal Matthew D. , Johansson Pär I. , Stensballe Jakob , Namas Rami A. , Vodovotz Yoram , Sperry Jason L. , Billiar Timothy R. ,   PAMPer study group, Zenati Mazen S. , Brown Joshua B. , Triulzi Darrell J. , Young Barbara J. Early , Adams Peter W. , Alarcon Louis H. , Callaway Clifton W. , Forsythe Raquel M. , Yealy Donald M. , Peitzman Andrew B. , Buck Meghan L. , Ryman Ashley M. , Gimbel Elizabeth A. , Gilchrist Erin G. , Buhay Meghan , Chang Chung-Chou H. , Talisa Victor B. , Xu Tianyuan , Kalloway Kyle , Yates Andrew , Rawn Susan , Jenkins Judith M. , Trachtenberg Laura S. , Eden Randi K. , Fraifogl Joanne , Bates Craig , Howard Christina , Stebbins Cari , Witham William R. , McNeill Cathy , Putnam A. Tyler. , Snyder Amy , Ropp Jason , Duane Therese M. , Caliman Celeste , Beamon Mieshia
Published: November 2022

Alterations in lipid metabolism have the potential to be markers as well as drivers of pathobiology of acute critical illness. Here, we took advantage of the temporal precision offered by trauma as a common cause of critical illness to identify the dynamic patterns in the circulating lipidome in critically ill humans. The major findings include an early loss of all classes of circulating lipids followed by a delayed and selective lipogenesis in patients destined to remain critically ill. The previously reported survival benefit of early thawed plasma administration was associated with preserved lipid levels that related to favorable changes in coagulation and inflammation biomarkers in causal modelling. Phosphatidylethanolamines (PE) were elevated in patients with persistent critical illness and PE levels were prognostic for worse outcomes not only in trauma but also severe COVID-19 patients. Here we show selective rise in systemic PE as a common prognostic feature of critical illness.
Ferritin triggers neutrophil extracellular trap-mediated cytokine storm through Msr1 contributing to adult-onset Still’s disease pathogenesis
Authors: Jia Jinchao , Wang Mengyan , Meng Jianfen , Ma Yuning , Wang Yang , Miao Naijun , Teng Jialin , Zhu Dehao , Shi Hui , Sun Yue , Liu Honglei , Cheng Xiaobing , Su Yutong , Ye Junna , Chi Huihui , Liu Tingting , Zhou Zhuochao , Wan Liyan , Chen Xia , Wang Fan , Zhang Hao , Ben Jingjing , Wang Jing , Yang Chengde , Hu Qiongyi
Published: November 2022

Hyperferritinemic syndrome, an overwhelming inflammatory condition, is characterized by high ferritin levels, systemic inflammation and multi-organ dysfunction, but the pathogenic role of ferritin remains largely unknown. Here we show in an animal model that ferritin administration leads to systemic and hepatic inflammation characterized by excessive neutrophil leukocyte infiltration and neutrophil extracellular trap (NET) formation in the liver tissue. Ferritin-induced NET formation depends on the expression of peptidylarginine deiminase 4 and neutrophil elastase and on reactive oxygen species production. Mechanistically, ferritin exposure increases both overall and cell surface expression of Msr1 on neutrophil leukocytes, and also acts as ligand to Msr1 to trigger the NET formation pathway. Depletion of neutrophil leukocytes or ablation of Msr1 protect mice from tissue damage and the hyperinflammatory response, which further confirms the role of Msr1 as ferritin receptor. The relevance of the animal model is underscored by the observation that enhanced NET formation, increased Msr1 expression and signalling on neutrophil leukocytes are also characteristic to adult-onset Still’s disease (AOSD), a typical hyperferritinemic syndrome. Collectively, our findings demonstrate an essential role of ferritin in NET-mediated cytokine storm, and suggest that targeting NETs or Msr1 may benefit AOSD patients.
Systematic characterization of cancer transcriptome at transcript resolution
Authors: Hu Wei , Wu Yangjun , Shi Qili , Wu Jingni , Kong Deping , Wu Xiaohua , He Xianghuo , Liu Teng , Li Shengli
Published: November 2022

Transcribed RNAs undergo various regulation and modification to become functional transcripts. Notably, cancer transcriptome has not been fully characterized at transcript resolution. Herein, we carry out a reference-based transcript assembly across >1000 cancer cell lines. We identify 498,255 transcripts, approximately half of which are unannotated. Unannotated transcripts are closely associated with cancer-related hallmarks and show clinical significance. We build a high-confidence RNA binding protein (RBP)-transcript regulatory network, wherein most RBPs tend to regulate transcripts involved in cell proliferation. We identify numerous transcripts that are highly associated with anti-cancer drug sensitivity. Furthermore, we establish RBP-transcript-drug axes, wherein PTBP1 is experimentally validated to affect the sensitivity to decitabine by regulating KIAA1522-a6 transcript. Finally, we establish a user-friendly data portal to serve as a valuable resource for understanding cancer transcriptome diversity and its potential clinical utility at transcript level. Our study substantially extends cancer RNA repository and will facilitate anti-cancer drug discovery.
An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss
Authors: Asrani Kaushal , Woo Juhyung , Mendes Adrianna A. , Schaffer Ethan , Vidotto Thiago , Villanueva Clarence Rachel , Feng Kewen , Oliveira Lia , Murali Sanjana , Liu Hans B. , Salles Daniela C. , Lam Brandon , Argani Pedram , Lotan Tamara L.
Published: November 2022

The mechanistic target of rapamycin complex 1 (mTORC1) integrates inputs from growth factors and nutrients, but how mTORC1 autoregulates its activity remains unclear. The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1 following lysosomal recruitment by RagC/D GTPases in response to amino acid stimulation. We find that starvation-induced lysosomal localization of the RagC/D GAP complex, FLCN:FNIP2, is markedly impaired in a mTORC1-sensitive manner in renal cells with TSC2 loss, resulting in unexpected TFEB hypophosphorylation and activation upon feeding. TFEB phosphorylation in TSC2-null renal cells is partially restored by destabilization of the lysosomal folliculin complex (LFC) induced by FLCN mutants and is fully rescued by forced lysosomal localization of the FLCN:FNIP2 dimer. Our data indicate that a negative feedback loop constrains amino acid-induced, FLCN:FNIP2-mediated RagC activity in renal cells with constitutive mTORC1 signaling, and the resulting MiT/TFE hyperactivation may drive oncogenesis with loss of the TSC2 tumor suppressor.
Development and validation of self-monitoring auto-updating prognostic models of survival for hospitalized COVID-19 patients
Authors: Levy Todd J. , Coppa Kevin , Cang Jinxuan , Barnaby Douglas P. , Paradis Marc D. , Cohen Stuart L. , Makhnevich Alex , van Klaveren David , Kent David M. , Davidson Karina W. , Hirsch Jamie S. , Zanos Theodoros P.
Published: November 2022

Clinical prognostic models can assist patient care decisions. However, their performance can drift over time and location, necessitating model monitoring and updating. Despite rapid and significant changes during the pandemic, prognostic models for COVID-19 patients do not currently account for these drifts. We develop a framework for continuously monitoring and updating prognostic models and apply it to predict 28-day survival in COVID-19 patients. We use demographic, laboratory, and clinical data from electronic health records of 34912 hospitalized COVID-19 patients from March 2020 until May 2022 and compare three modeling methods. Model calibration performance drift is immediately detected with minor fluctuations in discrimination. The overall calibration on the prospective validation cohort is significantly improved when comparing the dynamically updated models against their static counterparts. Our findings suggest that, using this framework, models remain accurate and well-calibrated across various waves, variants, race and sex and yield positive net-benefits.
Maprotiline restores ER homeostasis and rescues neurodegeneration via Histamine Receptor H1 inhibition in retinal ganglion cells
Authors: Chen Wei , Liu Pingting , Liu Dong , Huang Haoliang , Feng Xue , Fang Fang , Li Liang , Wu Jian , Liu Liang , Solow-Cordero David E. , Hu Yang
Published: November 2022

When the protein or calcium homeostasis of the endoplasmic reticulum (ER) is adversely altered, cells experience ER stress that leads to various diseases including neurodegeneration. Genetic deletion of an ER stress downstream effector, CHOP, significantly protects neuron somata and axons. Here we report that three tricyclic compounds identified through a small-scale high throughput screening using a CHOP promoter-driven luciferase cell-based assay, effectively inhibit ER stress by antagonizing their common target, histamine receptor H1 (HRH1). We further demonstrated that systemic administration of one of these compounds, maprotiline, or CRISPR-mediated retinal ganglion cell (RGC)-specific HRH1 inhibition, delivers considerable neuroprotection of both RGC somata and axons and preservation of visual function in two mouse optic neuropathy models. Finally, we determine that maprotiline restores ER homeostasis by inhibiting HRH1-mediated Ca2+ release from ER. In this work we establish maprotiline as a candidate neuroprotectant and HRH1 as a potential therapeutic target for glaucoma.
Rare and common genetic determinants of metabolic individuality and their effects on human health
Authors: Surendran Praveen , Stewart Isobel D. , Au Yeung Victoria P. W. , Pietzner Maik , Raffler Johannes , Wörheide Maria A. , Li Chen , Smith Rebecca F. , Wittemans Laura B. L. , Bomba Lorenzo , Menni Cristina , Zierer Jonas , Rossi Niccolò , Sheridan Patricia A. , Watkins Nicholas A. , Mangino Massimo , Hysi Pirro G. , Di Angelantonio Emanuele , Falchi Mario , Spector Tim D. , Soranzo Nicole , Michelotti Gregory A. , Arlt Wiebke , Lotta Luca A. , Denaxas Spiros , Hemingway Harry , Gamazon Eric R. , Howson Joanna M. M. , Wood Angela M. , Danesh John , Wareham Nicholas J. , Kastenmüller Gabi , Fauman Eric B. , Suhre Karsten , Butterworth Adam S. , Langenberg Claudia
Published: November 2022

Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant–metabolite associations (P < 1.25 × 10−11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant–metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
Acute and postacute sequelae associated with SARS-CoV-2 reinfection
Authors: Bowe Benjamin , Xie Yan , Al-Aly Ziyad
Published: November 2022

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs’ national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93–2.45), hospitalization (HR = 3.32, 95% CI 3.13–3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.
Soft ordered double quantitative approximations based three-way decisions and their applications
Authors: Santos-García Gustavo , Ali Abbas , Rehman Noor
Published: November 2022

The classical theory of rough set was established by Pawlak, which mainly focusses on the approximation of sets characterized by a single equivalence relation over the universe. However, most of the current single granulation structure models cannot meet the user demand or the target of solving problems. Multigranulation rough sets approach can better deal with the problems, where data might be spread over various locations. In this article, we present the idea of soft preference and soft dominance relation for the development of soft dominance rough set in an incomplete information system. Subsequently, several important structural properties and results of the proposed model are carefully analyzed. After employing soft dominance based rough set approach to it for any times, we can only get six different sets at most in an incomplete information system. That is to say, every rough set in a universe can be approximated by only six sets, where the lower and upper approximations of each set in the six sets are still lying among these six sets. The relationships among these six sets are established. Based on soft dominance relation, we introduce logical disjunction/conjunction soft dominance optimistic/pessimistic multigranulation decision theoretic rough approximations in an incomplete information. Meanwhile, to measure the uncertainty of soft dominance optimistic/pessimistic multigranulation decision theoretic rough approximation and some of their interesting properties are examined. Thereafter, a novel multi attribute with multi decision making problem approach based on logical disjunction/conjunction soft dominance optimistic/pessimistic multigranulation decision theoretic rough sets approach are developed to solve the selection of medicine to treat the coronavirus disease (COVID-19). The basic principle and the detailed steps of the decision making model (algorithms) are presented in detail. To demonstrate the applicability and potentiality of the proposed model, we present a practical example of a medical diagnosis is given to validate the practicality of the technique.