bluuebunny/crossref_metadata_2025 huggingface dataset:
Storage duration increases oxidation products in peanut seeds
Authors: Tonnis Brandon , Wang Ming Li , Huang Edward , Bhattarai Uttam , Tallury Shyam
Published: October 2021

Seeds kept in long-term storage are essential for maintaining genetic resources of crops and other plant materials in seed banks and national germplasm systems. But seeds undergo chemical changes over time as part of the ageing process that result in reduced germination rates and seedling normalcy. For example, oilseed crops such as peanuts are particularly vulnerable to oxidation and rancidification due to their high oil content. To test the effect of storage time on seed oil in peanuts, we grew different accessions and harvested fresh seeds to compare the oil composition of new seeds with seeds aged in storage for varying lengths of time. Out of the nine fatty acids detected and measured by gas chromatography, five including oleic, gadoleic, behenic, lignoceric and cerotic acids differed significantly between new and old seeds. Additionally, old seeds accumulated up to four oxidation products together averaging about 1% of the total oil composition. The concentration of these oxidation products was positively correlated with the age of the seeds, increasing linearly up to more than 6% of the total in the oldest seeds. The presence and concentration of oxidation products measured using simple chromatography techniques can be used as an initial indication of quality and viability in older seed inventories stored in germplasm repositories.
Continental Tectonics Inferred From High‐Resolution Imaging of the Mantle Beneath the United States, Through the Combination of USArray Data Types
Authors: Bedle Heather , Lou Xiaoting , van der Lee Suzan
Published: October 2021

A comprehensive North American upper mantle seismic‐tomographic model, NA13, was inferred from a combination of several decades of seismic data from early North American seismic networks and USArray data. This data‐driven modeling inverted a combination of regional waveform fits, teleseismic S delay times, and point constraints on Moho depths. The joint inversion model combines the contrasting and overlapping resolving power of the different data sets, and demonstrates enhanced resolution over regional models created with a single geophysical data set. Resolution in the upper mantle is achieved on the scale of ∼100 km, although travel time delay studies suggest that anomalies in parts of the western United States are smaller. In NA13, velocities beneath the Yellowstone plume are low enough to require the presence of partial melt. NA13 also models a variety of smaller scale velocity variations beneath the Central and Eastern United States that reveal remnant velocity anomalies related to lithospheric variations in the upper mantle between Proterozoic units.
Direct Radiative Effects in Haboobs
Authors: Bukowski J. , van den Heever S. C.
Published: October 2021

Convective dust storms, or haboobs, form when strong surface winds loft loose soils in convective storm outflow boundaries. Haboobs are a public safety hazard and can cause a near instantaneous loss of visibility, inimical air quality, and contribute significantly to regional dust and radiation budgets. Nevertheless, reliable predictions of convective dust events are inhibited by a lack of understanding regarding the complex and non‐linear interactions between density currents, or convective cold pools, and dust radiative effects. In this study, the Weather Research and Forecasting model coupled with Chemistry (WRF‐Chem) is utilized to simulate the effect dust radiation interactions have on a long‐lived haboob case study that spans three distinct radiative regimes: day (high shortwave), evening (low shortwave), and night [longwave (LW) only]. A sophisticated algorithm is used to track and identify the numerous convective old pool boundaries in the simulations and assemble statistics that represent the impact of dust radiative effects. To first order, dust scattering of shortwave radiation in the day leads to a colder, dustier, and faster moving convective cold pool. In the transition period of early evening, the shortwave effects diminish while LW dust absorption leads to warmer, slower density currents that loft less dust as they propagate. At night, the haboob is again warmer due to dust absorption, but gustier in the more stable nocturnal surface layer, leading to enhanced dust emissions.
Cardiovascular mortality risk in young adults with isolated systolic hypertension: findings from population-based MONICA/KORA cohort study
Authors: Atasoy Seryan , Middeke Martin , Johar Hamimatunnisa , Peters Annette , Heier Margit , Ladwig Karl-Heinz
Published: October 2021

The clinical significance of isolated systolic hypertension in young adults (ISHY) remains a topic of debate due to evidence ISHY could be a spurious condition resulting from exageratted pulse pressure amplification in “young tall men with elastic arteries”. Hence, we aimed to investigate whether ISHY is associated with an increased risk of cardivascular (CVD) mortality in a sample of 5597 young adults (49.8% men, 50.2% women) between 25 and 45 years old from the prospective population-based MONICA/KORA cohort. ISHY was prevalent in 5.2% of the population, affecting mostly men (73.1%), and associated with increased smoking, obesity, and hypercholesterolemia in comparison to participants with normal blood pressure (BP). Within a follow-up period of 25.3 years (SD ± 5.2; 141,768 person–years), 133(2.4%) CVD mortality cases were observed. Participants with ISHY had a hazard ratio (HR) of 1.89(1.01–3.53, p < 0.05) times higher risk of CVD mortality than participants with normal BP, even following adjustment for CVD risk factors. However, adjustment for antihypertensive medication (HR 0.46; 0.26–0.81, p < 0.001) and increasing height (HR 0.96; 0.93–0.99, p < 0.05) revealed independently protective effects against CVD mortality, suggesting that although ISHY is associated with an increased risk of CVD mortality, the protective effects of increasing height or antihypertensive medication should be considered in treatment rationale.
A triple-network organization for the mouse brain
Authors: Mandino Francesca , Vrooman Roël M. , Foo Heidi E. , Yeow Ling Yun , Bolton Thomas A. W. , Salvan Piergiorgio , Teoh Chai Lean , Lee Chun Yao , Beauchamp Antoine , Luo Sarah , Bi Renzhe , Zhang Jiayi , Lim Guan Hui Tricia , Low Nathaniel , Sallet Jerome , Gigg John , Lerch Jason P. , Mars Rogier B. , Olivo Malini , Fu Yu , Grandjean Joanes
Published: October 2021

The triple-network model of psychopathology is a framework to explain the functional and structural neuroimaging phenotypes of psychiatric and neurological disorders. It describes the interactions within and between three distributed networks: the salience, default-mode, and central executive networks. These have been associated with brain disorder traits in patients. Homologous networks have been proposed in animal models, but their integration into a triple-network organization has not yet been determined. Using resting-state datasets, we demonstrate conserved spatio-temporal properties between triple-network elements in human, macaque, and mouse. The model predictions were also shown to apply in a mouse model for depression. To validate spatial homologies, we developed a data-driven approach to convert mouse brain maps into human standard coordinates. Finally, using high-resolution viral tracers in the mouse, we refined an anatomical model for these networks and validated this using optogenetics in mice and tractography in humans. Unexpectedly, we find serotonin involvement within the salience rather than the default-mode network. Our results support the existence of a triple-network system in the mouse that shares properties with that of humans along several dimensions, including a disease condition. Finally, we demonstrate a method to humanize mouse brain networks that opens doors to fully data-driven trans-species comparisons.
O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis
Authors: Liu Rui , Gou Dongmei , Xiang Jin , Pan Xuanming , Gao Qingzhu , Zhou Peng , Liu Yi , Hu Jie , Wang Kai , Tang Ni
Published: October 2021

Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation.
Metformin alleviates inflammation through suppressing FASN-dependent palmitoylation of Akt
Authors: Xiong Wenfang , Sun Kuo-Yang , Zhu Yan , Zhang Xiaoqi , Zhou Yi-Hua , Zou Xiaoping
Published: October 2021

Metformin, traditionally regarded as a hypoglycemic drug, has been studied in other various fields including inflammation. The specific mechanism of metformin’s effect on immune cells remains unclear. Herein, it is verified that LPS-induced macrophages are characterized by enhanced endogenous fatty acid synthesis and the inhibition of fatty acid synthase (FASN) downregulates proinflammatory responses. We further show that metformin could suppress such elevation of FASN as well as proinflammatory activation in macrophages. In vivo, metformin treatment ameliorates dextran sulfate sodium (DSS)-induced colitis through impairing proinflammatory activation of colonic lamina propria mononuclear cells (LPMCs). The reduction of FASN by metformin hinders Akt palmitoylation, which further disturbs Akt membrane attachment and its phosphorylation. Metformin-mediated suppression of FASN/Akt pathway and its downstream MAPK signaling contributes to its anti-inflammatory role in macrophages. From the perspective of immunometabolism, our work points towards metformin utilization as an effective and potential intervention against macrophages-involved inflammatory diseases.
The Hh pathway promotes cell apoptosis through Ci-Rdx-Diap1 axis
Authors: Liu Bin , Ding Yan , Sun Bing , Liu Qingxin , Zhou Zizhang , Zhan Meixiao
Published: October 2021

Apoptosis is a strictly coordinated process to eliminate superfluous or damaged cells, and its deregulation leads to birth defects and various human diseases. The regulatory mechanism underlying apoptosis still remains incompletely understood. To identify novel components in apoptosis, we carry out a modifier screen and find that the Hh pathway aggravates Hid-induced apoptosis. In addition, we reveal that the Hh pathway triggers apoptosis through its transcriptional target gene rdx, which encodes an E3 ubiquitin ligase. Rdx physically binds Diap1 to promote its K63-linked polyubiquitination, culminating in attenuating Diap1−Dronc interaction without affecting Diap1 stability. Taken together, our findings unexpectedly uncover the oncogenic Hh pathway is able to promote apoptosis through Ci-Rdx-Diap1 module, raising a concern to choose Hh pathway inhibitors as anti-tumor drugs.
The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites
Authors: Baeken Marius W. , Schwarz Mario , Kern Andreas , Moosmann Bernd , Hajieva Parvana , Behl Christian
Published: October 2021

The sirtuin (SIRT) protein family has been of major research interest over the last decades because of their involvement in aging, cancer, and cell death. SIRTs have been implicated in gene and metabolic regulation through their capacity to remove acyl groups from lysine residues in proteins in an NAD+-dependent manner, which may alter individual protein properties as well as the histone–DNA interaction. Since SIRTs regulate a wide range of different signaling cascades, a fine-tuned homeostasis of these proteins is imperative to guarantee the function and survival of the cell. So far, however, how exactly this homeostasis is established has remained unknown. Here, we provide evidence that neuronal SIRT degradation in Parkinson’s disease (PD) models is executed by autophagy rather than the proteasome. In neuronal Lund human mesencephalic (LUHMES) cells, all seven SIRTs were substrates for autophagy and showed an accelerated autophagy-dependent degradation upon 1-methyl-4-phenylpyridinium (MPP+) mediated oxidative insults in vitro, whereas the proteasome did not contribute to the removal of oxidized SIRTs. Through blockade of endogenous H2O2 generation and supplementation with the selective radical scavenger phenothiazine (PHT), we could identify H2O2-derived species as the responsible SIRT-oxidizing agents. Analysis of all human SIRTs suggested a conserved regulatory motif based on cysteine oxidation, which may have triggered their degradation via autophagy. High amounts of H2O2, however, rapidly carbonylated selectively SIRT2, SIRT6, and SIRT7, which were found to accumulate carbonylation-prone amino acids. Our data may help in finding new strategies to maintain and modify SIRT bioavailability in neurodegenerative disorders.
Downregulation of phosphoglycerate mutase 5 improves microglial inflammasome activation after traumatic brain injury
Authors: Chen Yuhua , Gong Kai , Guo Limin , Zhang Bingchang , Chen Sifang , Li Zhangyu , Quanhua Xu , Liu Wei , Wang Zhanxiang
Published: October 2021

Traumatic brain injury (TBI) is considered as the most common cause of disability and death, and therefore an effective intervention of cascade pathology of secondary brain injury promptly can be a potential therapeutic direction for TBI prognosis. Further study of the physiological mechanism of TBI is urgent and important. Phosphoglycerate mutase 5 (Pgam5), a mitochondrial protein, mediate mitochondrial homeostasis, cellular senescence, and necroptosis. This study evaluated the effects of Pgam5 on neurological deficits and neuroinflammation of controlled cortical impact-induced TBI mouse model in vivo and LPS + ATP-induced microglia model in vitro. Pgam5 was overexpressed post-TBI. Pgam5 depletion reduced pyroptosis-related molecules and improved microglia activation, neuron damage, tissue lesion, and neurological dysfunctions in TBI mice. RNA-seq analysis and molecular biology experiments demonstrated that Pgam5 might regulate inflammatory responses by affecting the post-translational modification and protein expression of related genes, including Nlrp3, caspase1, Gsdmd, and Il-1β. In microglia, Pgam5-sh abrogated LPS + ATP-induced Il-1β secretion through Asc oligomerization-mediated caspase-1 activation, which was independent of Rip3. The data demonstrate the critical role Pgam5 plays in nerve injury in the progression of TBI, which regulates Asc polymerization and subsequently caspase1 activation, and thus reveals a fundamental mechanism linking microglial inflammasome activation to Asc/caspase1-generated Il-1β-mediated neuroinflammation. Thus, our data indicate Pgam5 worsens physiological and neurological outcomes post-TBI, which may be a potential therapeutic target to improve neuroinflammation after TBI.
Structures of active melanocortin-4 receptor–Gs-protein complexes with NDP-α-MSH and setmelanotide
Authors: Heyder Nicolas A. , Kleinau Gunnar , Speck David , Schmidt Andrea , Paisdzior Sarah , Szczepek Michal , Bauer Brian , Koch Anja , Gallandi Monique , Kwiatkowski Dennis , Bürger Jörg , Mielke Thorsten , Beck-Sickinger Annette G. , Hildebrand Peter W. , Spahn Christian M. T. , Hilger Daniel , Schacherl Magdalena , Biebermann Heike , Hilal Tarek , Kühnen Peter , Kobilka Brian K. , Scheerer Patrick
Published: October 2021

The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R–Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor–Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs.
Robust whole slide image analysis for cervical cancer screening using deep learning
Authors: Cheng Shenghua , Liu Sibo , Yu Jingya , Rao Gong , Xiao Yuwei , Han Wei , Zhu Wenjie , Lv Xiaohua , Li Ning , Cai Jing , Wang Zehua , Feng Xi , Yang Fei , Geng Xiebo , Ma Jiabo , Li Xu , Wei Ziquan , Zhang Xueying , Quan Tingwei , Zeng Shaoqun , Chen Li , Hu Junbo , Liu Xiuli
Published: October 2021

Computer-assisted diagnosis is key for scaling up cervical cancer screening. However, current recognition algorithms perform poorly on whole slide image (WSI) analysis, fail to generalize for diverse staining and imaging, and show sub-optimal clinical-level verification. Here, we develop a progressive lesion cell recognition method combining low- and high-resolution WSIs to recommend lesion cells and a recurrent neural network-based WSI classification model to evaluate the lesion degree of WSIs. We train and validate our WSI analysis system on 3,545 patient-wise WSIs with 79,911 annotations from multiple hospitals and several imaging instruments. On multi-center independent test sets of 1,170 patient-wise WSIs, we achieve 93.5%Specificityand 95.1%Sensitivityfor classifying slides, comparing favourably to the average performance of three independent cytopathologists, and obtain 88.5% true positive rate for highlighting the top 10 lesion cells on 447 positive slides. After deployment, our system recognizes a one giga-pixel WSI in about 1.5 min.
Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis
Authors: Zhang David M. , Navara Rachita , Yin Tiankai , Szymanski Jeffrey , Goldsztejn Uri , Kenkel Camryn , Lang Adam , Mpoy Cedric , Lipovsky Catherine E. , Qiao Yun , Hicks Stephanie , Li Gang , Moore Kaitlin M. S. , Bergom Carmen , Rogers Buck E. , Robinson Clifford G. , Cuculich Phillip S. , Schwarz Julie K. , Rentschler Stacey L.
Published: October 2021

Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT. Clinically, RT was associated with increased NaV1.5 expression in 1 of 1 explanted heart. On electrocardiogram (ECG), post-RT QRS durations were shortened in 13 of 19 patients and lengthened in 5 patients. Collectively, this study provides evidence for radiation-induced reprogramming of cardiac conduction as a potential treatment strategy for arrhythmia management in VT patients.
Significance of the organic aerosol driven climate feedback in the boreal area
Authors: Yli-Juuti Taina , Mielonen Tero , Heikkinen Liine , Arola Antti , Ehn Mikael , Isokääntä Sini , Keskinen Helmi-Marja , Kulmala Markku , Laakso Anton , Lipponen Antti , Luoma Krista , Mikkonen Santtu , Nieminen Tuomo , Paasonen Pauli , Petäjä Tuukka , Romakkaniemi Sami , Tonttila Juha , Kokkola Harri , Virtanen Annele
Published: October 2021

Aerosol particles cool the climate by scattering solar radiation and by acting as cloud condensation nuclei. Higher temperatures resulting from increased greenhouse gas levels have been suggested to lead to increased biogenic secondary organic aerosol and cloud condensation nuclei concentrations creating a negative climate feedback mechanism. Here, we present direct observations on this feedback mechanism utilizing collocated long term aerosol chemical composition measurements and remote sensing observations on aerosol and cloud properties. Summer time organic aerosol loadings showed a clear increase with temperature, with simultaneous increase in cloud condensation nuclei concentration in a boreal forest environment. Remote sensing observations revealed a change in cloud properties with an increase in cloud reflectivity in concert with increasing organic aerosol loadings in the area. The results provide direct observational evidence on the significance of this negative climate feedback mechanism.
Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis
Authors: Brastianos Priscilla K. , Strickland Matthew R. , Lee Eudocia Quant , Wang Nancy , Cohen Justine V. , Chukwueke Ugonma , Forst Deborah Anne , Eichler April , Overmoyer Beth , Lin Nancy U. , Chen Wendy Y. , Bardia Aditya , Juric Dejan , Dagogo-Jack Ibiayi , White Michael D. , Dietrich Jorg , Nayyar Naema , Kim Albert E. , Alvarez-Breckenridge Christopher , Mahar Maura , Mora Joana L. , Nahed Brian V. , Jones Pamela S. , Shih Helen A. , Gerstner Elizabeth R. , Giobbie-Hurder Anita , Carter Scott L. , Oh Kevin , Cahill Daniel P. , Sullivan Ryan J.
Published: October 2021

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.
Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases
Authors: Prakadan Sanjay M. , Alvarez-Breckenridge Christopher A. , Markson Samuel C. , Kim Albert E. , Klein Robert H. , Nayyar Naema , Navia Andrew W. , Kuter Benjamin M. , Kolb Kellie E. , Bihun Ivanna , Mora Joana L. , Bertalan Mia Solana , Shaw Brian , White Michael , Kaplan Alexander , Stocking Jackson H. , Wadsworth Marc H. , Lee Eudocia Q. , Chukwueke Ugonma , Wang Nancy , Subramanian Megha , Rotem Denisse , Cahill Daniel P. , Adalsteinsson Viktor A. , Miller Jeffrey W. , Sullivan Ryan J. , Carter Scott L. , Brastianos Priscilla K. , Shalek Alex K.
Published: October 2021

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.
High-throughput RNA sequencing of paraformaldehyde-fixed single cells
Authors: Phan Hoang Van , van Gent Michiel , Drayman Nir , Basu Anindita , Gack Michaela U. , Tay Savaş
Published: October 2021

Single-cell transcriptomic studies that require intracellular protein staining, rare cell sorting, or inactivation of infectious pathogens are severely limited. This is because current high-throughput single-cell RNA sequencing methods are either incompatible with or necessitate laborious sample preprocessing for paraformaldehyde treatment, a common tissue and cell fixation and preservation technique. Here we present FD-seq (Fixed Droplet RNA sequencing), a high-throughput method for droplet-based RNA sequencing of paraformaldehyde-fixed, permeabilized and sorted single cells. We show that FD-seq preserves the RNA integrity and relative gene expression levels after fixation and permeabilization. Furthermore, FD-seq can detect a higher number of genes and transcripts than methanol fixation. We first apply FD-seq to analyze a rare subpopulation of cells supporting lytic reactivation of the human tumor virus KSHV, and identify TMEM119 as a potential host factor that mediates viral reactivation. Second, we find that infection with the human betacoronavirus OC43 leads to upregulation of pro-inflammatory pathways in cells that are exposed to the virus but fail to express high levels of viral genes. FD-seq thus enables integrating phenotypic with transcriptomic information in rare cell subpopulations, and preserving and inactivating pathogenic samples.
Between synchrony and turbulence: intricate hierarchies of coexistence patterns
Authors: Haugland Sindre W. , Tosolini Anton , Krischer Katharina
Published: October 2021

Coupled oscillators, even identical ones, display a wide range of behaviours, among them synchrony and incoherence. The 2002 discovery of so-called chimera states, states of coexisting synchronized and unsynchronized oscillators, provided a possible link between the two and definitely showed that different parts of the same ensemble can sustain qualitatively different forms of motion. Here, we demonstrate that globally coupled identical oscillators can express a range of coexistence patterns more comprehensive than chimeras. A hierarchy of such states evolves from the fully synchronized solution in a series of cluster-splittings. At the far end of this hierarchy, the states further collide with their own mirror-images in phase space – rendering the motion chaotic, destroying some of the clusters and thereby producing even more intricate coexistence patterns. A sequence of such attractor collisions can ultimately lead to full incoherence of only single asynchronous oscillators. Chimera states, with one large synchronized cluster and else only single oscillators, are found to be just one step in this transition from low- to high-dimensional dynamics.
A PTEN variant uncouples longevity from impaired fitness in Caenorhabditis elegans with reduced insulin/IGF-1 signaling
Authors: Park Hae-Eun H. , Hwang Wooseon , Ham Seokjin , Kim Eunah , Altintas Ozlem , Park Sangsoon , Son Heehwa G. , Lee Yujin , Lee Dongyeop , Heo Won Do , Lee Seung-Jae V.
Published: October 2021

Insulin/IGF-1 signaling (IIS) regulates various physiological aspects in numerous species. In Caenorhabditis elegans, mutations in the daf-2/insulin/IGF-1 receptor dramatically increase lifespan and immunity, but generally impair motility, growth, and reproduction. Whether these pleiotropic effects can be dissociated at a specific step in insulin/IGF-1 signaling pathway remains unknown. Through performing a mutagenesis screen, we identified a missense mutation daf-18(yh1) that alters a cysteine to tyrosine in DAF-18/PTEN phosphatase, which maintained the long lifespan and enhanced immunity, while improving the reduced motility in adult daf-2 mutants. We showed that the daf-18(yh1) mutation decreased the lipid phosphatase activity of DAF-18/PTEN, while retaining a partial protein tyrosine phosphatase activity. We found that daf-18(yh1) maintained the partial activity of DAF-16/FOXO but restricted the detrimental upregulation of SKN-1/NRF2, contributing to beneficial physiological traits in daf-2 mutants. Our work provides important insights into how one evolutionarily conserved component, PTEN, can coordinate animal health and longevity.
Prediction of hyperbolic exciton-polaritons in monolayer black phosphorus
Authors: Wang Fanjie , Wang Chong , Chaves Andrey , Song Chaoyu , Zhang Guowei , Huang Shenyang , Lei Yuchen , Xing Qiaoxia , Mu Lei , Xie Yuangang , Yan Hugen
Published: October 2021

Hyperbolic polaritons exhibit large photonic density of states and can be collimated in certain propagation directions. The majority of hyperbolic polaritons are sustained in man-made metamaterials. However, natural-occurring hyperbolic materials also exist. Particularly, natural in-plane hyperbolic polaritons in layered materials have been demonstrated in MoO3 and WTe2, which are based on phonon and plasmon resonances respectively. Here, by determining the anisotropic optical conductivity (dielectric function) through optical spectroscopy, we predict that monolayer black phosphorus naturally hosts hyperbolic exciton-polaritons due to the pronounced in-plane anisotropy and strong exciton resonances. We simultaneously observe a strong and sharp ground state exciton peak and weaker excited states in high quality monolayer samples in the reflection spectrum, which enables us to determine the exciton binding energy of ~452 meV. Our work provides another appealing platform for the in-plane natural hyperbolic polaritons, which is based on excitons rather than phonons or plasmons.
Artificial intelligence system reduces false-positive findings in the interpretation of breast ultrasound exams
Authors: Shen Yiqiu , Shamout Farah E. , Oliver Jamie R. , Witowski Jan , Kannan Kawshik , Park Jungkyu , Wu Nan , Huddleston Connor , Wolfson Stacey , Millet Alexandra , Ehrenpreis Robin , Awal Divya , Tyma Cathy , Samreen Naziya , Gao Yiming , Chhor Chloe , Gandhi Stacey , Lee Cindy , Kumari-Subaiya Sheila , Leonard Cindy , Mohammed Reyhan , Moczulski Christopher , Altabet Jaime , Babb James , Lewin Alana , Reig Beatriu , Moy Linda , Heacock Laura , Geras Krzysztof J.
Published: October 2021

Though consistently shown to detect mammographically occult cancers, breast ultrasound has been noted to have high false-positive rates. In this work, we present an AI system that achieves radiologist-level accuracy in identifying breast cancer in ultrasound images. Developed on 288,767 exams, consisting of 5,442,907 B-mode and Color Doppler images, the AI achieves an area under the receiver operating characteristic curve (AUROC) of 0.976 on a test set consisting of 44,755 exams. In a retrospective reader study, the AI achieves a higher AUROC than the average of ten board-certified breast radiologists (AUROC: 0.962 AI, 0.924 ± 0.02 radiologists). With the help of the AI, radiologists decrease their false positive rates by 37.3% and reduce requested biopsies by 27.8%, while maintaining the same level of sensitivity. This highlights the potential of AI in improving the accuracy, consistency, and efficiency of breast ultrasound diagnosis.
Realization of active metamaterials with odd micropolar elasticity
Authors: Chen Yangyang , Li Xiaopeng , Scheibner Colin , Vitelli Vincenzo , Huang Guoliang
Published: October 2021

Materials made from active, living, or robotic components can display emergent properties arising from local sensing and computation. Here, we realize a freestanding active metabeam with piezoelectric elements and electronic feed-forward control that gives rise to an odd micropolar elasticity absent in energy-conserving media. The non-reciprocal odd modulus enables bending and shearing cycles that convert electrical energy into mechanical work, and vice versa. The sign of this elastic modulus is linked to a non-Hermitian topological index that determines the localization of vibrational modes to sample boundaries. At finite frequency, we can also tune the phase angle of the active modulus to produce a direction-dependent bending modulus and control non-Hermitian vibrational properties. Our continuum approach, built on symmetries and conservation laws, could be exploited to design others systems such as synthetic biofilaments and membranes with feed-forward control loops.
Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer
Authors: Ferreiro-Iglesias Aida , McKay James D. , Brenner Nicole , Virani Shama , Lesseur Corina , Gaborieau Valerie , Ness Andy R. , Hung Rayjean J. , Liu Geoffrey , Diergaarde Brenda , Olshan Andrew F. , Hayes Neil , Weissler Mark C. , Schroeder Lea , Bender Noemi , Pawlita Michael , Thomas Steve , Pring Miranda , Dudding Tom , Kanterewicz Beatriz , Ferris Robert , Thomas Sera , Brhane Yonathan , Díez-Obrero Virginia , Milojevic Maja , Smith-Byrne Karl , Mariosa Daniela , Johansson Mattias J. , Herrero Rolando , Boccia Stefania , Cadoni Gabriella , Lacko Martin , Holcátová Ivana , Ahrens Wolfgang , Lagiou Pagona , Lagiou Areti , Polesel Jerry , Simonato Lorenzo , Merletti Franco , Healy Claire M. , Hansen Bo T. , Nygård Mari , Conway David I. , Wright Sylvia , Macfarlane Tatiana V. , Robinson Max , Alemany Laia , Agudo Antonio , Znaor Ariana , Amos Christopher I. , Waterboer Tim , Brennan Paul
Published: October 2021

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.
Anti-Markovnikov hydro(amino)alkylation of vinylarenes via photoredox catalysis
Authors: Wu Zhao , Gockel Samuel N. , Hull Kami L.
Published: October 2021

Photoredox catalysis is a powerful means to generate odd-electron species under mild reaction conditions from a wide array of radical precursors. Herein, we present the application of this powerful catalytic manifold to address the hydroalkylation and hydroaminoalkylation of electronically diverse vinylarenes. This reaction allows for generalized alkene hydroalkylation leveraging common alkyl radical precursors, such as organotrifluoroborate salts and carboxylic acids. Furthermore, utilizing easily accessible α-silyl amine reagents or tertiary amines directly, secondary and tertiary amine moieties can be installed onto monoaryl and diaryl alkenes to access valuable products, including γ,γ-diarylamines pharmacophores. Thus, under a unified system, both hydroalkylation and hydroaminoalkylation of alkenes are achieved. The substrate scope is evaluated through 57 examples, the synthetic utility of the method is demonstrated, and preliminary mechanistic insights are presented.
The genomic landscape of Mexican Indigenous populations brings insights into the peopling of the Americas
Authors: García-Ortiz Humberto , Barajas-Olmos Francisco , Contreras-Cubas Cecilia , Cid-Soto Miguel Ángel , Córdova Emilio J. , Centeno-Cruz Federico , Mendoza-Caamal Elvia , Cicerón-Arellano Isabel , Flores-Huacuja Marlen , Baca Paulina , Bolnick Deborah A. , Snow Meradeth , Flores-Martínez Silvia Esperanza , Ortiz-Lopez Rocio , Reynolds Austin W. , Blanchet Antonio , Morales-Marín Mirna , Velázquez-Cruz Rafael , Kostic Aleksandar David , Galaviz-Hernández Carlos , García-Zapién Alejandra Guadalupe , Jiménez-López José Concepción , León-Reyes Guadalupe , Salas-Bautista Eva Gabriela , Lazalde-Ramos Blanca Patricia , Jiménez-Ruíz Juan Luis , Salas-Martínez Guadalupe , Ramos-Madrigal Jazmín , Mirzaeicheshmeh Elaheh , Saldaña-Alvarez Yolanda , del Carmen Abrahantes-Pérez María , Loeza-Becerra Francisco , Mojica-Espinosa Raúl , Sánchez-Quinto Federico , Rangel-Villalobos Héctor , Sosa-Macías Martha , Sánchez-Corona José , Rojas-Martinez Augusto , Martínez-Hernández Angélica , Orozco Lorena
Published: October 2021

The genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15–30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4–9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far.
Structural and functional consequences of NEDD8 phosphorylation
Authors: Stuber Katrin , Schneider Tobias , Werner Jill , Kovermann Michael , Marx Andreas , Scheffner Martin
Published: October 2021

Ubiquitin (Ub) and Ub-like proteins (Ubls) such as NEDD8 are best known for their function as covalent modifiers of other proteins but they are also themselves subject to post-translational modifications including phosphorylation. While functions of phosphorylated Ub (pUb) have been characterized, the consequences of Ubl phosphorylation remain unclear. Here we report that NEDD8 can be phosphorylated at S65 - the same site as Ub - and that S65 phosphorylation affects the structural dynamics of NEDD8 and Ub in a similar manner. While both pUb and phosphorylated NEDD8 (pNEDD8) can allosterically activate the Ub ligase Parkin, they have different protein interactomes that in turn are distinct from those of unmodified Ub and NEDD8. Among the preferential pNEDD8 interactors are HSP70 family members and we show that pNEDD8 stimulates HSP70 ATPase activity more pronouncedly than unmodified NEDD8. Our findings highlight the general importance of Ub/NEDD8 phosphorylation and support the notion that the function of pUb/pNEDD8 does not require their covalent attachment to other proteins.
Fluidic bacterial diodes rectify magnetotactic cell motility in porous environments
Authors: Waisbord Nicolas , Dehkharghani Amin , Guasto Jeffrey S.
Published: October 2021

Directed motility enables swimming microbes to navigate their environment for resources via chemo-, photo-, and magneto-taxis. However, directed motility competes with fluid flow in porous microbial habitats, affecting biofilm formation and disease transmission. Despite this broad importance, a microscopic understanding of how directed motility impacts the transport of microswimmers in flows through constricted pores remains unknown. Through microfluidic experiments, we show that individual magnetotactic bacteria directed upstream through pores display three distinct regimes, whereby cells swim upstream, become trapped within a pore, or are advected downstream. These transport regimes are reminiscent of the electrical conductivity of a diode and are accurately predicted by a comprehensive Langevin model. The diode-like behavior persists at the pore scale in geometries of higher dimension, where disorder impacts conductivity at the sample scale by extending the trapping regime over a broader range of flow speeds. This work has implications for our understanding of the survival strategies of magnetotactic bacteria in sediments and for developing their use in drug delivery applications in vascular networks.
Simulating quantum computations with Tutte polynomials
Authors: Mann Ryan L.
Published: October 2021

We establish a classical heuristic algorithm for exactly computing quantum probability amplitudes. Our algorithm is based on mapping output probability amplitudes of quantum circuits to evaluations of the Tutte polynomial of graphic matroids. The algorithm evaluates the Tutte polynomial recursively using the deletion–contraction property while attempting to exploit structural properties of the matroid. We consider several variations of our algorithm and present experimental results comparing their performance on two classes of random quantum circuits. Further, we obtain an explicit form for Clifford circuit amplitudes in terms of matroid invariants and an alternative efficient classical algorithm for computing the output probability amplitudes of Clifford circuits.
Preclinical development of a Pfs230-Pfs48/45 chimeric malaria transmission-blocking vaccine
Authors: Singh Susheel K. , Plieskatt Jordan , Chourasia Bishwanath K. , Singh Vandana , Bengtsson Karin Lövgren , Reimer Jenny M. , van Daalen Renate C. , Teelen Karina , van de Vegte-Bolmer Marga , van Gemert Geert-Jan , Jore Matthijs M. , Theisen Michael
Published: October 2021

The Plasmodium falciparum Pfs230 and Pfs48/45 proteins are leading candidates for a malaria transmission-blocking vaccine (TBV). Previously, we showed that a Pfs230–Pfs48/45 fusion protein elicits higher levels of functional antibodies than the individual antigens, but low yields hampered progression to clinical evaluation. Here we identified a modified construct (ProC6C) with a circumsporozoite protein (CSP) repeat-linker sequence that enhances expression. A scalable and reproducible process in the Lactococcus lactis expression system was developed and ProC6C was successfully transferred for manufacturing under current Good Manufacturing Practices (cGMP). In addition, a panel of analytical assays for release and stability were developed. Intact mass spectrometry analysis and multiangle light scattering showed that the protein contained correct disulfide bonds and was monomeric. Immunogenicity studies in mice showed that the ProC6C adsorbed to Alhydrogel®, with or without Matrix-MTM, elicited functional antibodies that reduced transmission to mosquitoes and sporozoite invasion of human hepatocytes. Altogether, our data support manufacture and clinical evaluation of ProC6C as a multistage malaria-vaccine candidate.
Effect of Delta variant on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK
Authors: Pouwels Koen B. , Pritchard Emma , Matthews Philippa C. , Stoesser Nicole , Eyre David W. , Vihta Karina-Doris , House Thomas , Hay Jodie , Bell John I. , Newton John N. , Farrar Jeremy , Crook Derrick , Cook Duncan , Rourke Emma , Studley Ruth , Peto Tim E. A. , Diamond Ian , Walker A. Sarah
Published: October 2021

The effectiveness of the BNT162b2 and ChAdOx1 vaccines against new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections requires continuous re-evaluation, given the increasingly dominant B.1.617.2 (Delta) variant. In this study, we investigated the effectiveness of these vaccines in a large, community-based survey of randomly selected households across the United Kingdom. We found that the effectiveness of BNT162b2 and ChAdOx1 against infections (new polymerase chain reaction (PCR)-positive cases) with symptoms or high viral burden is reduced with the B.1.617.2 variant (absolute difference of 10–13% for BNT162b2 and 16% for ChAdOx1) compared to the B.1.1.7 (Alpha) variant. The effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity after second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positive cases but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher in vaccinated individuals after a prior infection and in younger adults. With B.1.617.2, infections occurring after two vaccinations had similar peak viral burden as those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with B.1.617.2.
Fractional order stagnation point flow of the hybrid nanofluid towards a stretching sheet
Authors: Saeed Anwar , Bilal Muhammad , Gul Taza , Kumam Poom , Khan Amir , Sohail Muhammad
Published: October 2021

Fractional calculus characterizes a function at those points, where classical calculus failed. In the current study, we explored the fractional behavior of the stagnation point flow of hybrid nano liquid consisting of TiO2 and Ag nanoparticles across a stretching sheet. Silver Ag and Titanium dioxide TiO2 nanocomposites are one of the most significant and fascinating nanocomposites perform an important role in nanobiotechnology, especially in nanomedicine and for cancer cell therapy since these metal nanoparticles are thought to improve photocatalytic operation. The fluid movement over a stretching layer is subjected to electric and magnetic fields. The problem has been formulated in the form of the system of PDEs, which are reduced to the system of fractional-order ODEs by implementing the fractional similarity framework. The obtained fractional order differential equations are further solved via fractional code FDE-12 based on Caputo derivative. It has been perceived that the drifting velocity generated by the electric field E significantly improves the velocity and heat transition rate of blood. The fractional model is more generalized and applicable than the classical one.