bluuebunny/crossref_metadata_2025 huggingface dataset:
Policy Feedback and the Polarization of Interest Groups
Authors: Finger Leslie K. , Reckhow Sarah
Published: November 2021

We use the case of education interest groups to examine how and when policy changes lead interest groups to polarize in their support for political parties. Using over 145,000 campaign contributions from all 50 states from 2000 to 2017, we test whether the passage of private school choice, charter laws, and labor retrenchment policies led to the polarization of education interest groups over time. In 2000, teachers unions were the dominant group and mostly aligned with Democrats. Meanwhile, Republicans lacked support from any education groups. This pattern was consistent across states. Over time, coalitions in some states became polarized, meaning unions grew even more aligned with Democrats and reform groups with Republicans, while other states did not experience such polarization. We show that private school choice programs, but not labor retrenchment or charter laws, contributed to this changing partisan alignment. Our findings demonstrate that policy feedback can shape both the electoral mobilization and party alignments of interest groups.
Lipid-lowering and anti-thrombotic therapy in patients with	peripheral arterial disease
Authors: Belch Jill J. F. , Brodmann Marianne , Baumgartner Iris , Binder Christoph J. , Casula Manuela , Heiss Christian , Kahan Thomas , Parini Paolo , Poredos Pavel , Catapano Alberico L. , Tokgözoğlu Lale
Published: November 2021

Summary: Patients with peripheral arterial disease (PAD) are at very high risk of cardiovascular events, but risk factor management is usually suboptimal. This Joint Task Force from the European Atherosclerosis Society and the European Society of Vascular Medicine has updated evidence on the management on dyslipidaemia and thrombotic factors in patients with PAD. Guidelines recommend a low-density lipoprotein cholesterol (LDLC) goal of more than 50% reduction from baseline and <1.4 mmol/L (<55 mg/dL) in PAD patients. As demonstrated by randomized controlled trials, lowering LDL-C not only reduces cardiovascular events but also major adverse limb events (MALE), including amputations, of the order of 25%. Addition of ezetimibe or a PCSK9 inhibitor further decreases the risk of cardiovascular events, and PCSK9 inhibition has also been associated with reduction in the risk of MALE by up to 40%. Furthermore, statin- based treatment improved walking performance, including maximum walking distance, and pain-free walking distance and duration. This Task Force recommends strategies for managing statin-associated muscle symptoms to ensure that PAD patients benefit from lipid-lowering therapy. Antiplatelet therapy, either daily clopidogrel 75 mg or the combination of aspirin 100 mg and rivaroxaban (2×2.5 mg) is also indicated to prevent cardiovascular events. Dual pathway inhibition (aspirin and rivaroxaban) may be considered following revascularization, taking into account bleeding risk. This Joint Task Force believes that adherence with these recommendations for lipid-lowering and antithrombotic therapy will improve the morbidity and mortality in patients with PAD.
Raton Basin Induced Seismicity Is Hosted by Networks of Short Basement Faults and Mimics Tectonic Earthquake Statistics
Authors: Glasgow M. , Schmandt B. , Wang R. , Zhang M. , Bilek S. L. , Kiser E.
Published: November 2021

The Raton Basin has been an area of injection induced seismicity for the past two decades. Previously, the reactivated fault zone structures and spatiotemporal response of seismicity to evolving injection have been poorly constrained due to sparse publicly available seismic monitoring. The application of a machine‐learning phase picker to 4 years of continuous seismic data from a local array enables the detection and location of ∼38,000 earthquakes. The events from 2016 to 2020 are ∼2.5–6 km below sea level and range from ML < −1 to 4.2. Most earthquakes occur within previously identified ∼N‐S zones of seismicity, however our new catalog illuminates that these zones are composed of many short faults with variable orientations. The two most active zones, the Vermejo Park and Tercio zones, are potentially linked by small intermediate faults. In total, we find ∼60 short (<3 km long) basement faults with strikes from WNW to NNE. Faulting mechanisms are predominantly normal but some variability, including reverse dip‐slip and oblique‐slip, is observed. The Trinidad fault zone, which previously hosted a Mw 5.3 earthquake in 2011, is quiescent during 2016–2020, likely in response to both slow accumulation of tectonic strain after the 2011 sequence, and the significant decrease (80% reduction) in nearby wastewater injection from 2012 to 2016. Unlike some other regions, where induced seismicity was triggered in response to higher injection rates, the Raton Basin's frequency‐magnitude and spatiotemporal statistics are not distinguishable from tectonic seismicity. The similarity suggests that seismicity in the Raton Basin is predominantly releasing tectonic stress.
Field Investigations of Chemical Partitioning and Aqueous Chemistry of Freezing Closed‐Basin Lakes in Mongolia as Analogs of Subsurface Brines on Icy Bodies
Authors: Yoda Masahiro , Sekine Yasuhito , Fukushi Keisuke , Kitajima Takuma , Gankhurel Baasansuren , Davaasuren Davaadorj , Gerelmaa Tuvshin , Ganbat Shuukhaaz , Shoji Daigo , Zolotov Mikhail Y. , Takahashi Yoshio
Published: November 2021

Several icy bodies (e.g., Europa and Ceres) likely possess near‐surface brine reservoirs, which are considered to be sources of salts on their surfaces. Previous studies have proposed processes whereby an overlying ice layer captures salinity from a freezing, subsurface reservoir. However, few field investigations have been conducted to investigate chemical partitioning and aqueous chemistry in freezing brine reservoirs in terrestrial analogs. Here we report results of winter field surveys to ice‐covered, closed‐basin saline lakes in the Valley of the Gobi Lakes, Mongolia. We found that the surface ice exhibited complex features, including both pressure ridges formed by compressive forces and wet cracks formed by tensile forces. The latter provides salinity to the ice layer and surface. In addition to wet cracks, saline lake bottom‐water, along with suspended matter, was continuously captured within the pores of the ice layer during downward freezing. Using a combined mass balance and low‐temperature aqueous chemistry model, we reproduced the ice salinity due to entrapment of Na+, Cl−, and SO42−, suggesting that chemical partitioning of these species in freezing brine reservoirs on icy bodies can be understood based on our current knowledge. In the lake bottom‐water, the metastable phase of carbonates (i.e., amorphous Mg‐carbonate and monohydrocalcite) play key roles in controlling the concentrations of precipitable Mg2+ and Ca2+ and alkalinity, highlighting the importance of metastable phase of carbonate in the aqueous chemistry of subsurface brine reservoirs on icy bodies. Metastable phases might be indicators of freshly erupted materials from brine reservoirs.
High‐Resolution Nudged Isotope Modeling With ECHAM6‐Wiso: Impacts of Updated Model Physics and ERA5 Reanalysis Data
Authors: Cauquoin Alexandre , Werner Martin
Published: November 2021

We present here results of new isotope‐enabled simulations with an enhanced ECHAM6‐wiso model version nudged to the ERA5 reanalyses, at two different spatial resolutions, for the period 1979–2018. The isotopic content of snow on sea ice is considered, yielding surface water vapor with lower isotope ratios over sea ice covered areas, and the kinetic fractionation factors for oceanic evaporation are assumed as independent of wind speed. Also, the supersaturation equation was slightly re‐tuned for a better agreement with the Antarctic isotope observations. In addition to the spatial resolution, the impacts of the improved ECHAM6 model physics and the chosen updated ERA5 reanalyses data set on our simulation results are investigated. For this purpose, detailed comparisons to simulation results obtained from the predecessor ECHAM5‐wiso model nudged to ERA5 reanalyses and from ECHAM6‐wiso nudged to ERA‐Interim are performed. Compared to the ERA‐Interim reanalyses, the nudging to ERA5 does not result in substantial changes of modeled surface isotope values on a global scale but water transport over the tropics clearly changed, with increased precipitation amounts over the Amazonian area and related changes of isotopic contents in water vapor in the high troposphere. An ECHAM6‐wiso simulation at high spatial resolution (0.9° horizontal resolution and 95 vertical levels) generally further improves the modeling of annual mean isotope values. The modeling of temporal isotopic variations at seasonal and (sub‐)daily time scales is also slightly improved for the high spatial resolution configuration. The latter will be very useful for an improved interpretation of various water isotope records.
Comparison of Denitrification Induced by Various Organic Substances—Reaction Rates, Microbiology, and Temperature Effect
Authors: Ortmeyer F. , Begerow D. , Guerreiro M. A. , Wohnlich S. , Banning A.
Published: November 2021

Widespread groundwater pollution with nitrate (NO3−) and the finite and decreasing geogenic NO3− degradation capacity in aquifers require a better understanding of potential treatment methods. This project aimed at exploring and comparing the efficiency of four organic substances as electron donors for heterotrophic denitrification. Circulation column experiments using sediment without NO3− degradation capacity and high agricultural NO3− groundwater were conducted. Acetate, glucose, ascorbic acid, and ethanol were added to these columns in three concentration steps to induce biological denitrification, whereby also temperature dependence of denitrification rates (room temperature and typical groundwater temperature of 10°C) was taken into account. Results show denitrification with all four carbon (C) sources with intensities varying considerably between electron donors. Comparison of the two temperature approaches shows substantial differences between applied organic substances and indicates T as an important variable for denitrification. Ethanol is clearly the most effective electron donor for biodenitrification in groundwater investigated in this study, with a stronger and more effective NO3− degradation at 10°C than at room temperature. In contrast, much higher reaction rates are achieved with glucose at room temperature, compared to 10°C. Denitrification with ascorbic acid is very low at both temperatures; its addition produces biomass which repeatedly led to column clogging. In the entire test series, nitrite (NO2−) accumulation occurred more frequently and in higher concentrations at 10°C. Analysis of microorganisms shows a strong modification in microbial community in reaction to the addition of different organic C as well as between the two temperature approaches.
A systematic review and meta-analysis of the association between maternal polycystic ovary syndrome and neuropsychiatric disorders in children
Authors: Dubey Pallavi , Thakur Bhaskar , Rodriguez Sheryl , Cox Jessika , Sanchez Sheralyn , Fonseca Anacani , Reddy Sireesha , Clegg Deborah , Dwivedi Alok Kumar
Published: November 2021

There is emerging evidence demonstrating an association between maternal polycystic ovary syndrome (PCOS) and autism spectrum disorder (ASD) in children, however, the cumulative effect of maternal PCOS on the development of ASD or other neuropsychiatry disorders (NPD) in children and separately for males and females has not been examined. We sought to systematically evaluate the influence of maternal PCOS on a wide range of NPD including ASD, attention deficit hyperactivity disorder (ADHD), chronic tic disorder (CDT), other behavior disorders, anxiety, depression, bipolar disorder, schizophrenia in children as well as in women of reproductive age only. We queried electronic databases including PubMed, EMBASE, and Google Scholar, until March 2021. We used DerSimonian and Laird (D-L) random effects method to compute pooled effect size in terms of odds ratio (OR). Nineteen studies (1667851 mothers, 2260622 children) were included in this study. Mothers with PCOS had an increased odds of children diagnosed with ASD (OR = 1.40,p < 0.001), ADHD (OR = 1.42,p < 0.001), CTD (OR = 1.44,p = 0.001), anxiety (OR = 1.33,p < 0.001), as well as other behavioral symptoms (OR = 1.45,p < 0.001) in the adjusted analysis. The association between maternal PCOS and ASD (OR: 1.43 vs. 1.66), ADHD (OR: 1.39 vs. 1.54), and CTD (OR: 1.42 vs. 1.51) was found to be significantly consistent between males and females, respectively. Our data do not suggest increased fetal testosterone exposure is associated with increased autistic traits in children. However, PCOS was significantly associated with increased odds of a wide range of NPD in women themselves. Maternal PCOS is a risk factor for various NPD with a similar extent in their children regardless of their underlying comorbidities. Managing PCOS is essential for women’s health as well as for their children’s health. More research is needed to determine the mechanisms and links between maternal PCOS and NPD in children.
Brain-wide functional connectivity patterns support general cognitive ability and mediate effects of socioeconomic status in youth
Authors: Sripada Chandra , Angstadt Mike , Taxali Aman , Clark D. Angus , Greathouse Tristan , Rutherford Saige , Dickens Joseph R. , Shedden Kerby , Gard Arianna M. , Hyde Luke W. , Weigard Alexander , Heitzeg Mary
Published: November 2021

General cognitive ability (GCA) is an individual difference dimension linked to important academic, occupational, and health-related outcomes and its development is strongly linked to differences in socioeconomic status (SES). Complex abilities of the human brain are realized through interconnections among distributed brain regions, but brain-wide connectivity patterns associated with GCA in youth, and the influence of SES on these connectivity patterns, are poorly understood. The present study examined functional connectomes from 5937 9- and 10-year-olds in the Adolescent Brain Cognitive Development (ABCD) multi-site study. Using multivariate predictive modeling methods, we identified whole-brain functional connectivity patterns linked to GCA. In leave-one-site-out cross-validation, we found these connectivity patterns exhibited strong and statistically reliable generalization at 19 out of 19 held-out sites accounting for 18.0% of the variance in GCA scores (cross-validated partialη2). GCA-related connections were remarkably dispersed across brain networks: across 120 sets of connections linking pairs of large-scale networks, significantly elevated GCA-related connectivity was found in 110 of them, and differences in levels of GCA-related connectivity across brain networks were notably modest. Consistent with prior work, socioeconomic status was a strong predictor of GCA in this sample, and we found that distributed GCA-related brain connectivity patterns significantly statistically mediated this relationship (mean proportion mediated: 15.6%,p < 2 × 10−16). These results demonstrate that socioeconomic status and GCA are related to broad and diffuse differences in functional connectivity architecture during early adolescence, potentially suggesting a mechanism through which socioeconomic status influences cognitive development.
Proteomic analysis of necroptotic extracellular vesicles
Authors: Shlomovitz Inbar , Erlich Ziv , Arad Gali , Edry-Botzer Liat , Zargarian Sefi , Cohen Hadar , Manko Tal , Ofir-Birin Yifat , Cooks Tomer , Regev-Rudzki Neta , Gerlic Motti
Published: November 2021

Necroptosis is a regulated and inflammatory form of cell death. We, and others, have previously reported that necroptotic cells release extracellular vesicles (EVs). We have found that necroptotic EVs are loaded with proteins, including the phosphorylated form of the key necroptosis-executing factor, mixed lineage kinase domain-like kinase (MLKL). However, neither the exact protein composition, nor the impact, of necroptotic EVs have been delineated. To characterize their content, EVs from necroptotic and untreated U937 cells were isolated and analyzed by mass spectrometry-based proteomics. A total of 3337 proteins were identified, sharing a high degree of similarity with exosome proteome databases, and clearly distinguishing necroptotic and control EVs. A total of 352 proteins were significantly upregulated in the necroptotic EVs. Among these were MLKL and caspase-8, as validated by immunoblot. Components of the ESCRTIII machinery and inflammatory signaling were also upregulated in the necroptotic EVs, as well as currently unreported components of vesicle formation and transport, and necroptotic signaling pathways. Moreover, we found that necroptotic EVs can be phagocytosed by macrophages to modulate cytokine and chemokine secretion. Finally, we uncovered that necroptotic EVs contain tumor neoantigens, and are enriched with components of antigen processing and presentation. In summary, our study reveals a new layer of regulation during the early stage of necroptosis, mediated by the secretion of specific EVs that influences the microenvironment and may instigate innate and adaptive immune responses. This study sheds light on new potential players in necroptotic signaling and its related EVs, and uncovers the functional tasks accomplished by the cargo of these necroptotic EVs.
IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy
Authors: Qiu Ao-Wang , Huang Da-Rui , Li Bin , Fang Yuan , Zhang Wei-Wei , Liu Qing-Huai
Published: November 2021

Diabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the role of interleukin (IL)-17A, a proinflammatory cytokine mainly produced by T lymphocytes, in retinal pathophysiology particularly in retinal neuronal death during DR process. Ins2Akita (Akita) diabetic mice 12 weeks after the onset of diabetes were used as a DR model. IL-17A-deficient diabetic mice were obtained by hybridization of IL-17A-knockout (IL-17A-KO) mouse with Akita mouse. Primarily cultured retinal Müller cells (RMCs) and retinal ganglion cells (RGCs) were treated with IL-17A in high-glucose (HG) condition. A transwell coculture of RGCs and RMCs whose IL-17 receptor A (IL-17RA) gene had been silenced with IL-17RA-shRNA was exposed to IL-17A in HG condition and the cocultured RGCs were assessed on their survival. Diabetic mice manifested increased retinal microvascular lesions, RMC activation and dysfunction, as well as RGC apoptosis. IL-17A-KO diabetic mice showed reduced retinal microvascular impairments, RMC abnormalities, and RGC apoptosis compared with diabetic mice. RMCs expressed IL-17RA. IL-17A exacerbated HG-induced RMC activation and dysfunction in vitro and silencing IL-17RA gene in RMCs abolished the IL-17A deleterious effects. In contrast, RGCs did not express IL-17RA and IL-17A did not further alter HG-induced RGC death. Notably, IL-17A aggravated HG-induced RGC death in the presence of intact RMCs but not in the presence of RMCs in which IL-17RA gene had been knocked down. These findings establish that IL-17A is actively involved in DR pathophysiology and particularly by RMC mediation it promotes RGC death. Collectively, we propose that antagonizing IL-17RA on RMCs may prevent retinal neuronal death and thereby slow down DR progression.
Bacterial chromosomal mobility via lateral transduction exceeds that of classical mobile genetic elements
Authors: Humphrey Suzanne , Fillol-Salom Alfred , Quiles-Puchalt Nuria , Ibarra-Chávez Rodrigo , Haag Andreas F. , Chen John , Penadés José R.
Published: November 2021

It is commonly assumed that the horizontal transfer of most bacterial chromosomal genes is limited, in contrast to the frequent transfer observed for typical mobile genetic elements. However, this view has been recently challenged by the discovery of lateral transduction in Staphylococcus aureus, where temperate phages can drive the transfer of large chromosomal regions at extremely high frequencies. Here, we analyse previously published as well as new datasets to compare horizontal gene transfer rates mediated by different mechanisms in S. aureus and Salmonella enterica. We find that the horizontal transfer of core chromosomal genes via lateral transduction can be more efficient than the transfer of classical mobile genetic elements via conjugation or generalized transduction. These results raise questions about our definition of mobile genetic elements, and the potential roles played by lateral transduction in bacterial evolution.
Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein
Authors: Plessa Elena , Chu Lien P. , Chan Sammy H. S. , Thomas Oliver L. , Cassaignau Anaïs M. E. , Waudby Christopher A. , Christodoulou John , Cabrita Lisa D.
Published: November 2021

During biosynthesis, proteins can begin folding co-translationally to acquire their biologically-active structures. Folding, however, is an imperfect process and in many cases misfolding results in disease. Less is understood of how misfolding begins during biosynthesis. The human protein, alpha-1-antitrypsin (AAT) folds under kinetic control via a folding intermediate; its pathological variants readily form self-associated polymers at the site of synthesis, leading to alpha-1-antitrypsin deficiency. We observe that AAT nascent polypeptides stall during their biosynthesis, resulting in full-length nascent chains that remain bound to ribosome, forming a persistent ribosome-nascent chain complex (RNC) prior to release. We analyse the structure of these RNCs, which reveals compacted, partially-folded co-translational folding intermediates possessing molten-globule characteristics. We find that the highly-polymerogenic mutant, Z AAT, forms a distinct co-translational folding intermediate relative to wild-type. Its very modest structural differences suggests that the ribosome uniquely tempers the impact of deleterious mutations during nascent chain emergence. Following nascent chain release however, these co-translational folding intermediates guide post-translational folding outcomes thus suggesting that Z’s misfolding is initiated from co-translational structure. Our findings demonstrate that co-translational folding intermediates drive how some proteins fold under kinetic control, and may thus also serve as tractable therapeutic targets for human disease.
Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia
Authors: El Khawanky Nadia , Hughes Amy , Yu Wenbo , Myburgh Renier , Matschulla Tony , Taromi Sanaz , Aumann Konrad , Clarson Jade , Vinnakota Janaki Manoja , Shoumariyeh Khalid , Miething Cornelius , Lopez Angel F. , Brown Michael P. , Duyster Justus , Hein Lutz , Manz Markus G. , Hughes Timothy P. , White Deborah L. , Yong Agnes S. M. , Zeiser Robert
Published: November 2021

Successful treatment of acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) T cells is hampered by toxicity on normal hematopoietic progenitor cells and low CAR T cell persistence. Here, we develop third-generation anti-CD123 CAR T cells with a humanized CSL362-based ScFv and a CD28-OX40-CD3ζ intracellular signaling domain. This CAR demonstrates anti-AML activity without affecting the healthy hematopoietic system, or causing epithelial tissue damage in a xenograft model. CD123 expression on leukemia cells increases upon 5′-Azacitidine (AZA) treatment. AZA treatment of leukemia-bearing mice causes an increase in CTLA-4negative anti-CD123 CAR T cell numbers following infusion. Functionally, the CTLA-4negative anti-CD123 CAR T cells exhibit superior cytotoxicity against AML cells, accompanied by higher TNFα production and enhanced downstream phosphorylation of key T cell activation molecules. Our findings indicate that AZA increases the immunogenicity of AML cells, enhancing recognition and elimination of malignant cells by highly efficient CTLA-4negative anti-CD123 CAR T cells.
An engram of intentionally forgotten information
Authors: Ten Oever Sanne , Sack Alexander T. , Oehrn Carina R. , Axmacher Nikolai
Published: November 2021

Successful forgetting of unwanted memories is crucial for goal-directed behavior and mental wellbeing. While memory retention strengthens memory traces, it is unclear what happens to memory traces of events that are actively forgotten. Using intracranial EEG recordings from lateral temporal cortex, we find that memory traces for actively forgotten information are partially preserved and exhibit unique neural signatures. Memory traces of successfully remembered items show stronger encoding-retrieval similarity in gamma frequency patterns. By contrast, encoding-retrieval similarity of item-specific memory traces of actively forgotten items depend on activity at alpha/beta frequencies commonly associated with functional inhibition. Additional analyses revealed selective modification of item-specific patterns of connectivity and top-down information flow from dorsolateral prefrontal cortex to lateral temporal cortex in memory traces of intentionally forgotten items. These results suggest that intentional forgetting relies more on inhibitory top-down connections than intentional remembering, resulting in inhibitory memory traces with unique neural signatures and representational formats.
The history and geographic distribution of a KCNQ1 atrial fibrillation risk allele
Authors: Hateley Shannon , Lopez-Izquierdo Angelica , Jou Chuanchau J. , Cho Scott , Schraiber Joshua G. , Song Shiya , Maguire Colin T. , Torres Natalia , Riedel Michael , Bowles Neil E. , Arrington Cammon B. , Kennedy Brett J. , Etheridge Susan P. , Lai Shuping , Pribble Chase , Meyers Lindsay , Lundahl Derek , Byrnes Jake , Granka Julie M. , Kauffman Christopher A. , Lemmon Gordon , Boyden Steven , Scott Watkins W. , Karren Mary Anne , Knight Stacey , Brent Muhlestein J. , Carlquist John F. , Anderson Jeffrey L. , Chahine Kenneth G. , Shah Khushi U. , Ball Catherine A. , Benjamin Ivor J. , Yandell Mark , Tristani-Firouzi Martin
Published: November 2021

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins.
Spatiotemporal prediction of COVID-19 cases using inter- and intra-county proxies of human interactions
Authors: Vahedi Behzad , Karimzadeh Morteza , Zoraghein Hamidreza
Published: November 2021

Measurements of human interaction through proxies such as social connectedness or movement patterns have proved useful for predictive modeling of COVID-19, which is a challenging task, especially at high spatial resolutions. In this study, we develop a Spatiotemporal autoregressive model to predict county-level new cases of COVID-19 in the coterminous US using spatiotemporal lags of infection rates, human interactions, human mobility, and socioeconomic composition of counties as predictive features. We capture human interactions through 1) Facebook- and 2) cell phone-derived measures of connectivity and human mobility, and use them in two separate models for predicting county-level new cases of COVID-19. We evaluate the model on 14 forecast dates between 2020/10/25 and 2021/01/24 over one- to four-week prediction horizons. Comparing our predictions with a Baseline model developed by the COVID-19 Forecast Hub indicates an average 6.46% improvement in prediction Mean Absolute Errors (MAE) over the two-week prediction horizon up to 20.22% improvement in the four-week prediction horizon, pointing to the strong predictive power of our model in the longer prediction horizons.
Genomic signatures define three subtypes of EGFR-mutant stage II–III non-small-cell lung cancer with distinct adjuvant therapy outcomes
Authors: Liu Si-Yang , Bao Hua , Wang Qun , Mao Wei-Min , Chen Yedan , Tong Xiaoling , Xu Song-Tao , Wu Lin , Wei Yu-Cheng , Liu Yong-Yu , Chen Chun , Cheng Ying , Yin Rong , Yang Fan , Ren Sheng-Xiang , Li Xiao-Fei , Li Jian , Huang Cheng , Liu Zhi-Dong , Xu Shun , Chen Ke-Neng , Xu Shi-Dong , Liu Lun-Xu , Yu Ping , Wang Bu-Hai , Ma Hai-Tao , Yan Hong-Hong , Dong Song , Zhang Xu-Chao , Su Jian , Yang Jin-Ji , Yang Xue-Ning , Zhou Qing , Wu Xue , Shao Yang , Zhong Wen-Zhao , Wu Yi-Long
Published: November 2021

The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II–IIIA non-small cell lung cancer (NSCLC). However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy.
Operando magnetic resonance imaging for mapping of temperature and redox species in thermo-electrochemical cells
Authors: Gunathilaka Isuru E. , Pringle Jennifer M. , O’Dell Luke A.
Published: November 2021

Low-grade waste heat is an abundant and underutilised energy source. In this context, thermo-electrochemical cells (i.e., systems able to harvest heat to generate electricity) are being intensively studied to deliver the promises of efficient and cost-effective energy harvesting and electricity generation. However, despite the advances in performance disclosed in recent years, understanding the internal processes occurring within these devices is challenging. In order to shed light on these mechanisms, here we report an operando magnetic resonance imaging approach that can provide quantitative spatial maps of the electrolyte temperature and redox ion concentrations in functioning thermo-electrochemical cells. Time-resolved images are obtained from liquid and gel electrolytes, allowing the observation of the effects of redox reactions and competing mass transfer processes such as thermophoresis and diffusion. We also correlate the physicochemical properties of the system with the device performance via simultaneous electrochemical measurements.
Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction
Authors: Lamarthée Baptiste , Marchal Armance , Charbonnier Soëli , Blein Tifanie , Leon Juliette , Martin Emmanuel , Rabaux Lucas , Vogt Katrin , Titeux Matthias , Delville Marianne , Vinçon Hélène , Six Emmanuelle , Pallet Nicolas , Michonneau David , Anglicheau Dany , Legendre Christophe , Taupin Jean-Luc , Nemazanyy Ivan , Sawitzki Birgit , Latour Sylvain , Cavazzana Marina , André Isabelle , Zuber Julien
Published: November 2021

The use of chimeric antigen receptor (CAR)-engineered regulatory T cells (Tregs) has emerged as a promising strategy to promote immune tolerance. However, in conventional T cells (Tconvs), CAR expression is often associated with tonic signaling, which can induce CAR-T cell dysfunction. The extent and effects of CAR tonic signaling vary greatly according to the expression intensity and intrinsic properties of the CAR. Here, we show that the 4-1BB CSD-associated tonic signal yields a more dramatic effect in CAR-Tregs than in CAR-Tconvs with respect to activation and proliferation. Compared to CD28 CAR-Tregs, 4-1BB CAR-Tregs exhibit decreased lineage stability and reduced in vivo suppressive capacities. Transient exposure of 4-1BB CAR-Tregs to a Treg stabilizing cocktail, including an mTOR inhibitor and vitamin C, during ex vivo expansion sharply improves their in vivo function and expansion after adoptive transfer. This study demonstrates that the negative effects of 4-1BB tonic signaling in Tregs can be mitigated by transient mTOR inhibition.
Cross-reactivity of antibodies from non-hospitalized COVID-19 positive individuals against the native, B.1.351, B.1.617.2, and P.1 SARS-CoV-2 spike proteins
Authors: Hojjat Jodaylami Maryam , Djaïleb Abdelhadi , Ricard Pierre , Lavallée Étienne , Cellier-Goetghebeur Stella , Parker Megan-Faye , Coutu Julien , Stuible Matthew , Gervais Christian , Durocher Yves , Desautels Florence , Cayer Marie-Pierre , de Grandmont Marie Joëlle , Rochette Samuel , Brouard Danny , Trottier Sylvie , Boudreau Denis , Pelletier Joelle N. , Masson Jean-Francois
Published: November 2021

SARS-CoV-2 variants of concern (VOCs) have emerged worldwide, with implications on the spread of the pandemic. Characterizing the cross-reactivity of antibodies against these VOCs is necessary to understand the humoral response of non-hospitalized individuals previously infected with SARS-CoV-2, a population that remains understudied. Thirty-two SARS-CoV-2-positive (PCR-confirmed) and non-hospitalized Canadian adults were enrolled 14–21 days post-diagnosis in 2020, before the emergence of the B.1.351 (also known as Beta), B.1.617.2 (Delta) and P.1 (Gamma) VOCs. Sera were collected 4 and 16 weeks post-diagnosis. Antibody levels and pseudo-neutralization of the ectodomain of SARS-CoV-2 spike protein/human ACE-2 receptor interaction were analyzed with native, B.1.351, B.1.617.2 and P.1 variant spike proteins. Despite a lower response observed for the variant spike proteins, we report evidence of a sustained humoral response against native, B.1.351, B.1.617.2 and P.1 variant spike proteins among non-hospitalized Canadian adults. Furthermore, this response inhibited the interaction between the spike proteins from the different VOCs and ACE-2 receptor for ≥ 16 weeks post-diagnosis, except for individuals aged 18–49 years who showed no inhibition of the interaction between B.1.617.1 or B.1.617.2 spike and ACE-2. Interestingly, the affinity (KD) measured between the spike proteins (native, B.1.351, B.1.617.2 and P.1) and antibodies elicited in sera of infected and vaccinated (BNT162b2 and ChAdOx1 nCoV-19) individuals was invariant. Relative to sera from vaccine-naïve (and previously infected) individuals, sera from vaccinated individuals had higher antibody levels (as measured with label-free SPR) and more efficiently inhibited the spike–ACE-2 interactions, even among individuals aged 18–49 years, showing the effectiveness of vaccination.
Genetic diversity in North American Cercis Canadensis reveals an ancient population bottleneck that originated after the last glacial maximum
Authors: Ony Meher , Klingeman William E. , Zobel John , Trigiano Robert N. , Ginzel Matthew , Nowicki Marcin , Boggess Sarah L. , Everhart Sydney , Hadziabdic Denita
Published: November 2021

Understanding of the present-day genetic diversity, population structure, and evolutionary history of tree species can inform resource management and conservation activities, including response to pressures presented by a changing climate.Cercis canadensis(Eastern Redbud) is an economically valuable understory tree species native to the United States (U.S.) that is also important for forest ecosystem and wildlife health. Here, we document and explain the population genetics and evolutionary history of this deciduous tree species across its distributed range. In this study, we used twelve microsatellite markers to investigate 691 wild-type trees sampled at 74 collection sites from 23 Eastern U.S. states. High genetic diversity and limited gene flow were revealed in wild, natural stands ofC. canadensiswith populations that are explained by two major genetic clusters. These findings indicate that an ancient population bottleneck occurred coinciding with the last glacial maximum (LGM) in North America. The structure in current populations likely originated from an ancient population in the eastern U.S. that survived LGM and then later diverged into two contemporary clusters. Data suggests that populations have expanded since the last glaciation event from one into several post-glacial refugia that now occupy this species’ current geographic range. Our enhanced understanding benchmarks the genetic variation preserved within this species and can direct future efforts in conservation, and resource utilization of adaptively resilient populations that present the greatest genetic and structural diversity.
Forensic significance of intracardiac heme oxygenase-1 expression in acute myocardial ischemia
Authors: Kuninaka Yumi , Ishida Yuko , Nosaka Mizuho , Ishigami Akiko , Taruya Akira , Shimada Emi , Kimura Akihiko , Yamamoto Hiroki , Ozaki Mitsunori , Furukawa Fukumi , Kondo Toshikazu
Published: November 2021

Heme oxygenase-1 (HO-1), an inducible stress-response protein, exerts anti-oxidant and anti-apoptotic effects. However, its significance in forensic diagnosis of acute ischemic heart diseases (AIHD) such as myocardial infarction (MI) is still unknown. We examined the immunohistochemical expression of HO-1 in the heart samples to discuss their forensic significance to determine acute cardiac ischemia. The heart samples were obtained from 23 AIHD cases and 33 non-AIHD cases as controls. HO-1 positive signals in cardiomyocyte nuclear were detected in 78.2% of AIHD cases, however, that were detected in only 24.2% control cases with statistical difference between AIHD and non-AIHD groups. In contrast to HO-1 protein expression, there was no significant difference in the appearance of myoglobin pallor regions and leukocyte infiltration in the hearts between AIHD and non-AIHD groups. From the viewpoints of forensic pathology, intracardiac HO-1 expression would be considered a valuable marker to diagnose AIHD as the cause of death.
Spatiotemporal observation of light propagation in a three-dimensional scattering medium
Authors: Inoue Tomoyoshi , Junpei Yuasa , Itoh Seiya , Okuda Tatsuya , Funahashi Akinori , Takimoto Tetsuya , Kakue Takashi , Nishio Kenzo , Matoba Osamu , Awatsuji Yasuhiro
Published: November 2021

Spatiotemporal information about light pulse propagation obtained with femtosecond temporal resolution plays an important role in understanding transient phenomena and light–matter interactions. Although ultrafast optical imaging techniques have been developed, it is still difficult to capture light pulse propagation spatiotemporally. Furthermore, imaging through a three-dimensional (3-D) scattering medium is a longstanding challenge due to the optical scattering caused by the interaction between light pulse and a 3-D scattering medium. Here, we propose a technique for ultrafast optical imaging of light pulses propagating inside a 3D scattering medium. We record an image of the light pulse propagation using the ultrashort light pulse even when the interaction between light pulse and a 3-D scattering medium causes the optical scattering. We demonstrated our proposed technique by recording converging, refracted, and diffracted propagating light for 59 ps with femtosecond temporal resolution.
Toxicity of stainless and mild steel particles generated from gas–metal arc welding in primary human small airway epithelial cells
Authors: Cediel-Ulloa Andrea , Isaxon Christina , Eriksson Axel , Primetzhofer Daniel , Sortica Mauricio A. , Haag Lars , Derr Remco , Hendriks Giel , Löndahl Jakob , Gudmundsson Anders , Broberg Karin , Gliga Anda R.
Published: November 2021

Welding fumes induce lung toxicity and are carcinogenic to humans but the molecular mechanisms have yet to be clarified. The aim of this study was to evaluate the toxicity of stainless and mild steel particles generated via gas–metal arc welding using primary human small airway epithelial cells (hSAEC) and ToxTracker reporter murine stem cells, which track activation of six cancer-related pathways. Metal content (Fe, Mn, Ni, Cr) of the particles was relatively homogenous across particle size. The particles were not cytotoxic in reporter stem cells but stainless steel particles activated the Nrf2-dependent oxidative stress pathway. In hSAEC, both particle types induced time- and dose-dependent cytotoxicity, and stainless steel particles also increased generation of reactive oxygen species. The cellular metal content was higher for hSAEC compared to the reporter stem cells exposed to the same nominal dose. This was, in part, related to differences in particle agglomeration/sedimentation in the different cell media. Overall, our study showed differences in cytotoxicity and activation of cancer-related pathways between stainless and mild steel welding particles. Moreover, our data emphasizes the need for careful assessment of the cellular dose when comparing studies using different in vitro models.
Morphological and spectroscopic analysis of snow and glacier algae and their parasitic fungi on different glaciers of Svalbard
Authors: Fiołka Marta J. , Takeuchi Nozomu , Sofińska-Chmiel Weronika , Wójcik-Mieszawska Sylwia , Irvine-Fynn Tristram , Edwards Arwyn
Published: November 2021

The results show the morphological analyses and spectroscopic studies of snow and glacier algae and their parasitic fungi in Svalbard (High Arctic). Fixed algal cells of two species, Sanguina nivaloides and Ancylonema nordenskioeldii, were imaged using light microscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM). Fluorescence microscopy using Calcofluor white stain supported the observations of parasitic fungi on the algal cells. Images in brightfield microscopy showed chytrid-like fungi penetrating the cells of both algal species. Parasites were found to colonize the cells of A. nordenskioeldii and hypnozygotes of S. nivaloides, while no fungi infected the cyst stages of S. nivaloides. The autofluorescence analysis revealed the ability of S. nivaloides to glow when excited with different wavelengths, while A. nordenskioeldii did not fluoresce. The hypnozygotes of S. nivaloides emitted brighter fluorescence than the cysts, and the most intense luminosity was observed in the UV range. The Fourier-transform infrared spectroscopy (FTIR) and energy-dispersive X-ray spectroscopy (EDS) spectroscopic analysis showed differences in the chemical composition between samples collected from three different sites. Samples dominated by cyst cells were characterized by the presence of an abundant polysaccharide envelope.
Insulin smart drug delivery nanoparticles of aminophenylboronic acid–POSS molecule at neutral pH
Authors: Kim Won Jung , Kwon Yong-Jin , Cho Chung-Hyun , Ye Sang-Kyu , Kim Kyu Oh
Published: November 2021

Self-regulated “smart” insulin administration system that mimic pancreatic endocrine function would be highly desirable for diabetes management. Here, a glucose-responsive continuous insulin delivery system is developed, where novel polyhedral oligosilsesquioxane (POSS) modified with 3‐aminophenylboronic acid (APBA) were used to encapsulate insulin (insulin entrapment efficiency: 73.2%) to prepare a fast response, high stability, good distribution, and excellent biocompatible system. Due to the strong hydrophobicity of POSS, the POSS moiety is located at the core in aqueous solution and combines with the boronic group of APBA and the diol generated in PEG-insulin to form a nanomicelle structure, that is, nanoparticles naturally. Micelles self‐assembled from these molecules possess glucose‐responsiveness at varying glucose concentrations. The interaction of the PBA and diol containing insulin via boronate ester bond and its interchange with glucose was investigated by FT-IR, 1H NMR and XPS. Furthermore, the successful glucose-triggered release of insulin from the POSS-APBA micelles was investigated at neutral pH. A linear graph was plotted with the measured released insulin vs glucose concentrations, with a linear correlation coefficient (R2) value close to 1. Circular dichroism (CD) spectroscopy analysis was performed to measure insulin activity by comparing secondary structures of insulin, PEG-Insulin, and POSS-APBA@insulin. When confirming intracellular apoptosis signaling, cleaved caspase 3 and caspase 9 were not increased by 640 μg/ml POSS-APBA and POSS-APBA@insulin in HeLa, HDF and HUVE cells. Application in the biomedical field for controlled delivery of insulin appear to be promising.
Adipose MDM2 regulates systemic insulin sensitivity
Authors: Hallenborg Philip , Jensen Benjamin Anderschou Holbech , Fjære Even , Petersen Rasmus Koefoed , Belmaâti Mohammed-Samir , Rasmussen Sarah Søndergård , Gunnarsson Jon Petur , Lauritzen Pernille , Cheng Kenneth King Yip , Hermansson Martin , Sonne Si Brask , Ejsing Christer S. , Xu Aimin , Kratchmarova Irina , Krüger Marcus , Madsen Lise , Kristiansen Karsten , Blagoev Blagoy
Published: November 2021

The intimate association between obesity and type II diabetes urges for a deeper understanding of adipocyte function. We and others have previously delineated a role for the tumor suppressor p53 in adipocyte biology. Here, we show that mice haploinsufficient for MDM2, a key regulator of p53, in their adipose stores suffer from overt obesity, glucose intolerance, and hepatic steatosis. These mice had decreased levels of circulating palmitoleic acid [non-esterified fatty acid (NEFA) 16:1] concomitant with impaired visceral adipose tissue expression of Scd1 and Ffar4. A similar decrease in Scd and Ffar4 expression was found in in vitro differentiated adipocytes with perturbed MDM2 expression. Lowered MDM2 levels led to nuclear exclusion of the transcriptional cofactors, MORC2 and LIPIN1, and thereby possibly hampered adipocyte function by antagonizing LIPIN1-mediated PPARγ coactivation. Collectively, these data argue for a hitherto unknown interplay between MDM2 and MORC2/LIPIN1 involved in balancing adipocyte function.