bluuebunny/crossref_metadata_2025 huggingface dataset:
Cheating in online gaming spreads through observation and victimization
Authors: Kim Ji Eun , Tsvetkova Milena
Published: January 2022

Antisocial behavior can be contagious, spreading from individual to individual and rippling through social networks. Moreover, it can spread not only through third-party influence from observation, just like innovations or individual behavior do, but also through direct experience, via “pay-it-forward” retaliation. Here, we distinguish between the effects of observation and victimization for the contagion of antisocial behavior by analyzing large-scale digital trace data. We study the spread of cheating in more than a million matches of an online multiplayer first-person shooter game, in which up to 100 players compete individually or in teams against strangers. We identify event sequences in which a player who observes or is killed by a certain number of cheaters starts cheating and evaluate the extent to which these sequences would appear if we preserve the team and interaction structure but assume alternative gameplay scenarios. The results reveal that social contagion is only likely to exist for those who both observe and experience cheating, suggesting that third-party influence and “pay-it-forward” reciprocity interact positively. In addition, the effect is present only for those who both observe and experience more than once, suggesting that cheating is more likely to spread after repeated or multi-source exposure. Approaching online games as models of social systems, we use the findings to discuss strategies for targeted interventions to stem the spread of cheating and antisocial behavior more generally in online communities, schools, organizations, and sports.
Natural Selection of Independently Originated Life Clades
Authors: Hermida Margarida
Published: January 2022

Life on Earth descends from a common ancestor. However, it is likely that there are other instances of life in the universe. If so, each abiogenesis event will have given rise to an independently originated life clade (IOLC), of which Earth-life is an example. In this paper, I argue that the set of all IOLCs in the universe forms a Darwinian population subject to natural selection, with more widely dispersed IOLCs being less likely to face extinction. As a result, we should expect that, over time, more planets will become inhabited by fewer, more successful IOLCs.
RADIOCARBON DATING ROZHOK I, A MIDDLE PALEOLITHIC OPEN-AIR SITE IN SOUTHERN RUSSIA
Authors: Otcherednoy A K , Nehoroshev P E , Vishnyatsky L B , Voskresenskaya E V , Southon J R , Hoffecker J F
Published: January 2022

Samples of bone and teeth from the Middle Paleolithic open-air site of Rozhok I, located on the Gulf of Taganrog, were dated by radiocarbon (14C). We obtained 26 accelerator mass spectrometry (AMS) dates on a large sample of nonhuman bone and teeth recovered by N. D. Praslov during 1961–1962 from 5 of the 6 occupation horizons at Rozhok I. Two rigorous pretreatment methods were applied to the samples: ultra-filtration and XAD resin. The 14C ages from the uppermost two layers (Horizons 1 and 2) are infinite with the exception of one age near the limit of the 14C method. By contrast, the dates from Horizon 3 and the two lowermost layers (Horizons 5 and 6) are all finite ages and some are less than 45,000 BP (uncalibrated). While there is evidence of some post-depositional disturbance, there is no evidence of a stratigraphic reversal of the cultural layers. The simplest explanation for the pattern is that bones and teeth in the lower layers have been contaminated by groundwater containing young carbon. We conclude that Rozhok I probably antedates 50,000 cal BP and is beyond the range of 14C dating.
Duke Leopold of Lorraine, Small State Diplomacy, and the Stuart Court in Exile, 1716–1729
Authors: Griffin Stephen
Published: January 2022

This article examines how rulers of early modern small states attempted to survive and increase their status in the ever-shifting political world of early eighteenth-century Europe. To do so it takes the example of Duke Leopold of Lorraine and his connections with the exiled James Francis Edward Stuart and his court. Like many other small state princes, Leopold was politically dependent upon the decisions of his larger neighbours and his policies were designed to ensure his continued survival and to increase his own prestige. Historians have long acknowledged the relationship between Leopold and James in 1713–15 but they have done little to explore their interactions between 1716 and 1729. In drawing attention to this neglected sequence of encounters, the article highlights their connection to broader and more well-known political affairs in the 1710s and 1720s. It demonstrates how Leopold utilized his connection with the Stuarts as he reacted to a changing political situation in Europe in the years following the Peace of Utrecht. In return, the Stuarts, seeking to achieve their political goals, could rely upon ducal advice and aid. This dynamic suggests that these small but well-connected princes and their diplomatic activities require further consideration when examining international relations.
Ambiguities in the Search for Christian Unity: The General Council of Protestant Evangelical Missions in Korea, 1905–1912
Authors: SEO DONGJUN
Published: January 2022

The formation of the General Council of Protestant Evangelical Missions in Korea in 1905 with the ultimate objective of achieving church union beyond denominational boundaries is a significant but neglected episode in the twentieth-century ecumenical movement. The council was reorganised in 1912 as the Federal Council of Protestant Evangelical Missions in Korea, which marked a significant shift of ecumenical objectives from institutional union to missionary cooperation. This article examines why and how this change happened and its implications for interpretations of the wider ecumenical movement in the twentieth century.
Evaluating the interactive effects of dietary habits and human gut microbiome on the risks of depression and anxiety
Authors: Yao Yao , Qi Xin , Jia Yumeng , Ye Jing , Chu Xiaomeng , Wen Yan , Cheng Bolun , Cheng Shiqiang , Liu Li , Liang Chujun , Wu Cuiyan , Wang Xi , Ning Yujie , Wang Sen , Zhang Feng
Published: January 2022

Background

Gut microbiome and dietary patterns have been suggested to be associated with depression/anxiety. However, limited effort has been made to explore the effects of possible interactions between diet and microbiome on the risks of depression and anxiety.

Methods

Using the latest genome-wide association studies findings in gut microbiome and dietary habits, polygenic risk scores (PRSs) analysis of gut microbiome and dietary habits was conducted in the UK Biobank cohort. Logistic/linear regression models were applied for evaluating the associations for gut microbiome-PRS, dietary habits-PRS, and their interactions with depression/anxiety status and Patient Health Questionnaire (PHQ-9)/Generalized Anxiety Disorder-7 (GAD-7) score by R software.

Results

We observed 51 common diet–gut microbiome interactions shared by both PHQ score and depression status, such as overall beef intake × genus Sporobacter [hurdle binary (HB)] (PPHQ = 7.88 × 10−4, Pdepression status = 5.86 × 10−4); carbohydrate × genus Lactococcus (HB) (PPHQ = 0.0295, Pdepression status = 0.0150). We detected 41 common diet–gut microbiome interactions shared by GAD score and anxiety status, such as sugar × genus Parasutterella (rank normal transformed) (PGAD = 5.15 × 10−3, Panxiety status = 0.0347); tablespoons of raw vegetables per day × family Coriobacteriaceae (HB) (PGAD = 6.02 × 10−4, Panxiety status = 0.0345). Some common significant interactions shared by depression and anxiety were identified, such as overall beef intake × genus Sporobacter (HB).

Conclusions

Our study results expanded our understanding of how to comprehensively consider the relationships for dietary habits–gut microbiome interactions with depression and anxiety.
Algebras of UTxO blockchains
Authors: Gabbay Murdoch J.
Published: January 2022

We condense the theory of UTxO blockchains down to a simple and compact set of four type equations (Idealised EUTxO), and to an algebraic characterisation (abstract chunk systems), and exhibit an adjoint pair of functors between them. This gives a novel account of the essential mathematical structures underlying blockchain technology, such as Bitcoin.
Gestational diabetes: changed health beliefs in migrant women from five Asian countries living in Sweden: a prospective qualitative study
Authors: Hjelm Katarina , Bard Karin , Apelqvist Jan
Published: January 2022

Aim:

The aim of this study was to explore the temporal development of beliefs about health, illness and health care in migrant women with gestational diabetes (GD) born in Asia residing in Sweden, and the influence on health-related behaviour in terms of self-care and seeking care.

Background:

Migrant Asian women are a high-risk group for developing GD. Adapting to the culture in the new society and the healthcare system, being diagnosed with GD and becoming a mother is demanding. The question is whether Asian migrants’ patterns of beliefs and behaviour change over time, as no previous study has been revealed on this topic.

Method:

Qualitative prospective exploratory study. Semi-structured interviews were held on three occasions: during pregnancy and three and fourteen months after delivery, with women born in Asia, diagnosed with GD. Data were analysed with qualitative content analysis.

Findings:

There was a temporal change of beliefs influencing health-related behaviour, showing a rising curve in risk awareness. An increasing number of persons described developing a healthy diet/lifestyle based on initial advice and shifted focus from the child to worries about the woman’s health and risk of developing type 2 diabetes and being unable to care for the child/family. Also, the number of women perceiving GD as a transient condition decreased and more believed it would last forever. Beliefs about health care were unchanged, the healthcare model was perceived working well but information about GD and follow-ups was requested even after delivery, and competent staff was expected. Health professionals’ beliefs about the seriousness of GD influence patients’ beliefs and need to be considered. Migrant women need support with adequate information, based on their individual beliefs, to continue develop a sustainable healthy lifestyle even after giving birth, to promote health and prevent type 2 diabetes.
North Atlantic Cooling is Slowing Down Mass Loss of Icelandic Glaciers
Authors: Noël Brice , Aðalgeirsdóttir Guðfinna , Pálsson Finnur , Wouters Bert , Lhermitte Stef , Haacker Jan M. , van den Broeke Michiel R.
Published: January 2022

Icelandic glaciers have been losing mass since the Little Ice Age in the mid‐to‐late 1800s, with higher mass loss rates in the early 21st century, followed by a slowdown since 2011. As of yet, it remains unclear whether this mass loss slowdown will persist in the future. By reconstructing the contemporary (1958–2019) surface mass balance of Icelandic glaciers, we show that the post‐2011 mass loss slowdown coincides with the development of the Blue Blob, an area of regional cooling in the North Atlantic Ocean to the south of Greenland. This regional cooling signal mitigates atmospheric warming in Iceland since 2011, in turn decreasing glacier mass loss through reduced meltwater runoff. In a future high‐end warming scenario, North Atlantic cooling is projected to mitigate mass loss of Icelandic glaciers until the mid‐2050s. High mass loss rates resume thereafter as the regional cooling signal weakens.
Orbital Forcing Strongly Influences the Poleward Shift of the Spring Himalayan Jet During the Past Millennium
Authors: Thapa U. K. , Stevenson S. , Midhun M.
Published: January 2022

The latitudinal position of the subtropical jet over the Himalayas (Himalayan jet latitude or HJL) controls the region's climate during winter and spring by guiding moisture‐delivering storms. Here we use the Community Earth System Model‐Last Millennium Ensemble to diagnose forced trends in HJL during the past millennium. During 850–1849, there is a weak equatorward trend in winter HJL. In contrast, the spring HJL has a relatively larger poleward trend, and increases in both variance and frequency of poleward/equatorward excursions. We demonstrate changes in orbital precession reduced the thermal gradient between tropical and subtropical Asia, shifting the spring HJL poleward. During 1850–2005, the spring HJL exhibits no trend due to compensating influences from orbital and anthropogenic greenhouse gas forcings. These findings suggest it is essential climate models properly simulate the effects of and potential interactions between orbital forcing and anthropogenic factors to accurately project Himalayan jet variability and associated storm tracks.
Dynamics of ENSO Phase–Locking and Its Biases in Climate Models
Authors: Chen Han‐Ching , Jin Fei‐Fei
Published: January 2022

The contributions of different oceanic feedbacks to the El Niño–Southern Oscillation (ENSO) phase‐locking are examined by deriving ENSO dynamics based on the recharge‐discharge framework. In observations, the significant winter preference of the ENSO peak is determined by a strong seasonal modulation of SST growth rate, which is controlled by the zonal advective and thermodynamic feedbacks. However, the majority of climate models fail to simulate ENSO phase‐locking because the contribution of zonal advective feedback to the seasonal modulation of the SST growth rate is much smaller compared to observations. The weak annual cycle of the SST‐current coupling coefficient and small annual mean of the negative climatological zonal SST gradient are two factors contributing to the weak‐biased seasonality of zonal advective feedback. Further analysis shows that the Niño3.4 SSTA has better phase‐locking performance than Niño3 SSTA in the climate models due to the better simulation of zonal advection feedback in the Niño3.4 region.
Analysis of E × B Drifts in Earth's Magnetosphere During Geomagnetic Reversals: Potential Consequences for Plasmasphere Behavior and Stability
Authors: Caggiano J. A. , Paty C. S.
Published: January 2022

Geomagnetic pole reversals occur frequently throughout geologic history, although one has not yet occurred in recorded time. Magnetohydrodynamic models of Earth's core have revealed that during a reversal, the magnetic dipole moment disappears, leaving higher‐order moments. Previous research examined quadrupole magnetic field topologies and quantitatively specified the magnetic equators of those topologies but did not fully examine charged particle drift motion and stability in the inner magnetosphere. Earth's closed magnetosphere is primarily dominated by two electric fields, the corotational and convection generated electric fields. drifts from these fields ultimately drives the behavior of the cold plasma of the plasmasphere. In a quadrupole‐dominated magnetic field, the plasma motion generated by the drifts would be dramatically different from the classical dipole field plasma convection. Three quadrupole topologies were evaluated, and the drift was analyzed along the magnetic equators of these topologies to characterize and quantify the resultant plasma motion and evaluate the behavior, structure and stability of the plasmasphere. We also tested for plasmaspause and magnetopause boundary sensitivity to magnetic field strength. The direction of the convection flow is hemispherically dependent for the η = 0 and 0.5 quadrupole topologies, that is, the plasma in the Northern Hemisphere convects tailward, and the Southern Hemisphere convects sunward. The η = 1 topology demonstrates evidence of strong plasmasphere erosion due to the intersection of the magnetic equators, and the magnetopause and plasmapause of the η = 1 topology are particularly sensitive to reductions in magnetic field strength.
Understanding the Paths of Surface Ozone Abatement in the Los Angeles Basin
Authors: Kim Si‐Wan , McDonald Brian C. , Seo Seunghwan , Kim Kyoung‐Min , Trainer Michael
Published: January 2022

Ozone in the urban atmosphere can accumulate from photochemistry involving nitrogen oxides, carbon monoxide, and volatile organic compounds mainly emitted from fossil fuel combustions and volatile chemical products. Concentrated ozone near the earth's surface has a detrimental impact on the ecosystem and our health. The Los Angeles Basin is a classic example of an urban region with long‐standing ozone pollution, frequently in violation of its standard, designated by the US Environmental Protection Agency (EPA). Studies have reported substantial declines of ozone and their precursor concentrations over the past half century in this area due to extensive pollution controls. Since 2000, however, the ozone design value has remained the same and has not been able to fully reach the air quality standard set by the EPA despite decreases in its precursor concentrations. To understand this phenomenon, we utilize a chemical transport modeling approach to reproduce historical ozone trends and to conduct sensitivity runs relative to a 2010 baseline. Based on our analysis of the model simulations comparing the weekends and weekdays, rather than focusing only on the weekly averages, we diagnose that the Los Angeles Basin is actually going under a significant transition in photochemistry toward a lower ozone concentration. This reveals how air quality management strategies are slowly moving towards a pathway of reducing ozone concentrations in the future. Our study, however, suggests that further reductions of NOx emissions can lead to continued improvement of ozone pollution in this area.
Studies on the Competition Between Homogeneous and Heterogeneous Ice Nucleation in Cirrus Formation
Authors: Kärcher B. , DeMott P. J. , Jensen E. J. , Harrington J. Y.
Published: January 2022

Cirrus ice crystals are produced heterogeneously on ice‐nucleating particles (INPs) and homogeneously in supercooled liquid solution droplets. They grow by uptake of water molecules from the ice‐supersaturated vapor. The precursor particles, characterized by disparate ice nucleation abilities and number concentrations, compete for available vapor during ice formation events. We investigate cirrus formation events systematically in different temperature and updraft regimes, and for different INP number concentrations and time‐independent nucleation efficiencies. We consider vertical air motion variability due to mesoscale gravity waves and effects of supersaturation‐dependent deposition coefficients for water molecules on ice surfaces. We analyze ice crystal properties to better understand the dynamics of competing nucleation processes. We study the reduction of ice crystal numbers produced by homogeneous freezing due to INPs in both, individual simulations assuming constant updraft speeds and in ensemble simulations based on a stochastic representation of vertical wind speed fluctuations. We simulate and interpret probability distributions of total nucleated ice crystal number concentrations, showing signatures of homogeneous and heterogeneous nucleation. At typically observed, mean updraft speeds (≈15 cm s−1) competing nucleation should occur frequently, even at rather low INP number concentrations (<10 L−1). INPs increase cirrus occurrence and may alter cirrus microphysical properties without entirely suppressing homogeneous freezing events. We suggest to improve ice growth models, especially for low cirrus temperatures (<220 K) and low ice supersaturation (<0.3).
Estimating Soil Surface Roughness With Models Based on the Information About Tillage Practises and Soil Parameters
Authors: Herodowicz‐Mleczak Karolina , Piekarczyk Jan , Kaźmierowski Cezary , Nowosad Jakub , Mleczak Mateusz
Published: January 2022

The quantitative description of the soil surface roughness is necessary for effective monitoring of wind, water and tillage erosion, hydrological processes or greenhouse gas emissions. The aim of this work was to build soil roughness predictive models based on the type of tillage tool, the roughness indices and soil properties. The roughness formed by five tillage tools was determined. Two surface roughness indices: Height Standard Deviation (HSD) and T3D (Tortuosity index) were calculated from Digital Elevation Model. The both roughness indices demonstrated a significant correlation, however, they provided different information about soil roughness. The HSD describes roughness on the “macro,” while T3D refers to the “micro” scale. Hence, our findings show that a single index is not sufficient to describe the roughness of post‐treatment surface. The linear and random forest models were built to describe the relationships between the roughness indices, type of tillage tool and soil properties. The HSD analysis indicated that the type of tillage tools had the greatest impact on post‐treatment roughness. In contrast, T3D analysis found soil texture to have a significant effect, together with tillage tools. In all modeling scenarios, T3D was more accurately predicted than HSD by both the linear (R2 = 0.62 vs. R2 = 0.60) and random forest models (R2 = 0.58 vs. R2 = 0.55). Predictive soil surface roughness models can be applied effectively for estimating water retention in soil, the intensity and speed of surface water flow, soil erosion, the level of reflected shortwave solar radiation or soil properties by remote sensing techniques.
Rare and localized events stabilize microbial community composition and patterns of spatial self-organization in a fluctuating environment
Authors: Ciccarese Davide , Micali Gabriele , Borer Benedict , Ruan Chujin , Or Dani , Johnson David R
Published: January 2022

Spatial self-organization is a hallmark of surface-associated microbial communities that is governed by local environmental conditions and further modified by interspecific interactions. Here, we hypothesize that spatial patterns of microbial cell-types can stabilize the composition of cross-feeding microbial communities under fluctuating environmental conditions. We tested this hypothesis by studying the growth and spatial self-organization of microbial co-cultures consisting of two metabolically interacting strains of the bacterium Pseudomonas stutzeri. We inoculated the co-cultures onto agar surfaces and allowed them to expand (i.e. range expansion) while fluctuating environmental conditions that alter the dependency between the two strains. We alternated between anoxic conditions that induce a mutualistic interaction and oxic conditions that induce a competitive interaction. We observed co-occurrence of both strains in rare and highly localized clusters (referred to as “spatial jackpot events”) that persist during environmental fluctuations. To resolve the underlying mechanisms for the emergence of spatial jackpot events, we used a mechanistic agent-based mathematical model that resolves growth and dispersal at the scale relevant to individual cells. While co-culture composition varied with the strength of the mutualistic interaction and across environmental fluctuations, the model provides insights into the formation of spatially resolved substrate landscapes with localized niches that support the co-occurrence of the two strains and secure co-culture function. This study highlights that in addition to spatial patterns that emerge in response to environmental fluctuations, localized spatial jackpot events ensure persistence of strains across dynamic conditions.
Efficacy and safety of enasidenib and azacitidine combination in patients with IDH2 mutated acute myeloid leukemia and not eligible for intensive chemotherapy
Authors: Venugopal Sangeetha , Takahashi Koichi , Daver Naval , Maiti Abhishek , Borthakur Gautam , Loghavi Sanam , Short Nicholas. J. , Ohanian Maro , Masarova Lucia , Issa Ghayas , Wang Xuemei , Carlos Bueso-Ramos , Yilmaz Musa , Kadia Tapan , Andreeff Michael , Ravandi Farhad , Konopleva Marina , Kantarjian Hagop M. , DiNardo Courtney D.
Published: January 2022

Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2mutAML). This open label phase II trial enrolled patients (pts) with documented IDH2mutAML. All patients received AZA 75 mg/m2/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed (NCT03683433).Twenty-six pts received ENA + AZA (median 68 years, range, 24–88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The composite complete remission rate (CRc) [complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)] was 100% in ND AML, and 58% in R/R AML. Median OS was not reached in ND AML with median follow-up of 13.1 months (mo); Pts treated in first relapse had improved OS than those with ≥2 relapse (median OS not reached vs 5.2 mo; HR 0.24, 95% CI 0.07–0.79, p = 0.04). Two patients received ENA + AZA with a concomitant FLT3i, one responding ND AML patient and one nonresponding R/R AML patient. Seven R/R AML pts received ENA + AZA + VEN triplet, and with median follow up of 11.2 mo, median OS was not reached and 6-mo OS was 70%. The most frequent treatment-emergent adverse events include febrile neutropenia (23%). Adverse events of special interest included all-grade IDH differentiation syndrome (8%) and indirect hyperbilirubinemia (35%). ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2mutAML.

Clinical trial registration information: https://clinicaltrials.gov/.NCT03683433
Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia
Authors: Martin Ludovic , Kaci Nabil , Benoist-Lasselin Catherine , Mondoloni Marine , Decaudaveine Suzanne , Estibals Valentin , Cornille Maxence , Loisay Léa , Flipo Justine , Demuynck Benoît , de la Luz Cádiz-Gurrea Maria , Barbault Florent , Fernández-Arroyo Salvador , Schibler Laurent , Segura-Carretero Antonio , Dambroise Emilie , Legeai-Mallet Laurence
Published: January 2022

A gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3) results in achondroplasia (ACH), the most frequent form of dwarfism. Constitutive activation of FGFR3 impairs bone formation and elongation and many signal transduction pathways. Identification of new and relevant compounds targeting the FGFR3 signaling pathway is of broad importance for the treatment of ACH, and natural plant compounds are prime drug candidate sources. Here, we found that the phenolic compound (-)-epicatechin, isolated from Theobroma cacao, effectively inhibited FGFR3’s downstream signaling pathways. Transcriptomic analysis in an Fgfr3 mouse model showed that ciliary mRNA expression was modified and influenced significantly by the Indian hedgehog and PKA pathways. (-)-Epicatechin is able to rescue mRNA expression impairments that control both the structural organization of the primary cilium and ciliogenesis-related genes. In femurs isolated from a mouse model (Fgfr3Y367C/+) of ACH, we showed that (-)-epicatechin eliminated bone growth impairment during 6 days of ex vivo culture. In vivo, we confirmed that daily subcutaneous injections of (-)-epicatechin to Fgfr3Y367C/+ mice increased bone elongation and rescued the primary cilium defects observed in chondrocytes. This modification to the primary cilia promoted the typical columnar arrangement of flat proliferative chondrocytes and thus enhanced bone elongation. The results of the present proof-of-principle study support (-)-epicatechin as a potential drug for the treatment of ACH.
KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge
Authors: Mao Zhongwei , Xiao Hongying , Shen Panpan , Yang Yu , Xue Jing , Yang Yunyun , Shang Yanguo , Zhang Lilan , Li Xin , Zhang Yuying , Du Yanan , Chen Chun-Chi , Guo Rey-Ting , Zhang Yonghui
Published: January 2022

KRAS mutation occurs in nearly 30% of human cancers, yet the most prevalent and oncogenic KRAS(G12D) variant still lacks inhibitors. Herein, we designed a series of potent inhibitors that can form a salt bridge with KRAS’s Asp12 residue. Our ITC results show that these inhibitors have similar binding affinity with both GDP-bound and GTP-bound KRAS(G12D), and our crystallographic studies reveal the structural basis of inhibitor binding-induced switch-II pocket in KRAS(G12D), experimentally confirming the formation of a salt bridge between the piperazine moiety of the inhibitors and the Asp12 residue of the mutant protein. Among KRAS family proteins and mutants, both ITC and enzymatic assays demonstrate the selectivity of the inhibitors for KRAS(G12D); and the inhibitors disrupt the KRAS–CRAF interaction. We also observed the inhibition of cancer cell proliferation as well as MAPK signaling by a representative inhibitor (TH-Z835). However, since the inhibition was not fully dependent on KRAS mutation status, it is possible that our inhibitors may have off-target effects via targeting non-KRAS small GTPases. Experiments with mouse xenograft models of pancreatic cancer showed that TH-Z835 significantly reduced tumor volume and synergized with an anti-PD-1 antibody. Collectively, our study demonstrates proof-of-concept for a strategy based on salt-bridge and induced-fit pocket formation for KRAS(G12D) targeting, which warrants future medicinal chemistry efforts for optimal efficacy and minimized off-target effects.
Systematic decomposition of sequence determinants governing CRISPR/Cas9 specificity
Authors: Fu Rongjie , He Wei , Dou Jinzhuang , Villarreal Oscar D. , Bedford Ella , Wang Helen , Hou Connie , Zhang Liang , Wang Yalong , Ma Dacheng , Chen Yiwen , Gao Xue , Depken Martin , Xu Han
Published: January 2022

The specificity of CRISPR/Cas9 genome editing is largely determined by the sequences of guide RNA (gRNA) and the targeted DNA, yet the sequence-dependent rules underlying off-target effects are not fully understood. To systematically explore the sequence determinants governing CRISPR/Cas9 specificity, here we describe a dual-target system to measure the relative cleavage rate between off- and on-target sequences (off-on ratios) of 1902 gRNAs on 13,314 synthetic target sequences, and reveal a set of sequence rules involving 2 factors in off-targeting: 1) a guide-intrinsic mismatch tolerance (GMT) independent of the mismatch context; 2) an “epistasis-like” combinatorial effect of multiple mismatches, which are associated with the free-energy landscape in R-loop formation and are explainable by a multi-state kinetic model. These sequence rules lead to the development of MOFF, a model-based predictor of Cas9-mediated off-target effects. Moreover, the “epistasis-like” combinatorial effect suggests a strategy of allele-specific genome editing using mismatched guides. With the aid of MOFF prediction, this strategy significantly improves the selectivity and expands the application domain of Cas9-based allele-specific editing, as tested in a high-throughput allele-editing screen on 18 cancer hotspot mutations.
Characterization of the COPD alveolar niche using single-cell RNA sequencing
Authors: Sauler Maor , McDonough John E. , Adams Taylor S. , Kothapalli Neeharika , Barnthaler Thomas , Werder Rhiannon B. , Schupp Jonas C. , Nouws Jessica , Robertson Matthew J. , Coarfa Cristian , Yang Tao , Chioccioli Maurizio , Omote Norihito , Cosme Carlos , Poli Sergio , Ayaub Ehab A. , Chu Sarah G. , Jensen Klaus H. , Gomez Jose L. , Britto Clemente J. , Raredon Micha Sam B. , Niklason Laura E. , Wilson Andrew A. , Timshel Pascal N. , Kaminski Naftali , Rosas Ivan O.
Published: January 2022

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance in COPD. Using transcriptomic network analyses, we predict capillary endothelial cells are inflamed in COPD, particularly through increased CXCL-motif chemokine signaling. Finally, we detect a high-metallothionein expressing macrophage subpopulation enriched in advanced COPD. Collectively, these findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD.
Modular assembly of the principal microtubule nucleator γ-TuRC
Authors: Würtz Martin , Zupa Erik , Atorino Enrico S. , Neuner Annett , Böhler Anna , Rahadian Ariani S. , Vermeulen Bram J. A. , Tonon Giulia , Eustermann Sebastian , Schiebel Elmar , Pfeffer Stefan
Published: January 2022

The gamma-tubulin ring complex (γ-TuRC) is the principal microtubule nucleation template in vertebrates. Recent cryo-EM reconstructions visualized the intricate quaternary structure of the γ-TuRC, containing more than thirty subunits, raising fundamental questions about γ-TuRC assembly and the role of actin as an integral part of the complex. Here, we reveal the structural mechanism underlying modular γ-TuRC assembly and identify a functional role of actin in microtubule nucleation. During γ-TuRC assembly, a GCP6-stabilized core comprising GCP2-3-4-5-4-6 is expanded by stepwise recruitment, selective stabilization and conformational locking of four pre-formed GCP2-GCP3 units. Formation of the lumenal bridge specifies incorporation of the terminal GCP2-GCP3 unit and thereby leads to closure of the γ-TuRC ring in a left-handed spiral configuration. Actin incorporation into the complex is not relevant for γ-TuRC assembly and structural integrity, but determines γ-TuRC geometry and is required for efficient microtubule nucleation and mitotic chromosome alignment in vivo.
Magnetic Moment Tensor Potentials for collinear spin-polarized materials reproduce different magnetic states of bcc Fe
Authors: Novikov Ivan , Grabowski Blazej , Körmann Fritz , Shapeev Alexander
Published: January 2022

We present the magnetic Moment Tensor Potentials (mMTPs), a class of machine-learning interatomic potentials, accurately reproducing both vibrational and magnetic degrees of freedom as provided, e.g., from first-principles calculations. The accuracy is achieved by a two-step minimization scheme that coarse-grains the atomic and the spin space. The performance of the mMTPs is demonstrated for the prototype magnetic system bcc iron, with applications to phonon calculations for different magnetic states, and molecular-dynamics simulations with fluctuating magnetic moments.
A review of plant extracts as green corrosion inhibitors for CO2 corrosion of carbon steel
Authors: Fazal Basit Raza , Becker Thomas , Kinsella Brian , Lepkova Katerina
Published: January 2022

The use of corrosion inhibitors is a cost-effective corrosion mitigation strategy for carbon steel. There is an increased focus on developing and using low-cost, biodegradable and environmentally friendly inhibitor formulations. Plant-based extracts have been evaluated in many studies using a multitude of electrochemical methods and characterisation techniques. Although plant extracts appear as promising alternatives for commercially synthesised inhibitor formulations, a significant amount of optimisation is required. The majority of the research on plant extracts does not elucidate the effect of other synergistic combinations in commercial inhibitor formulations. Therefore, further development of plant extracts as corrosion inhibitors is of significant interest.
Recognition of NiCrAlY coating based on convolutional neural network
Authors: Liu Rui , Wang Minghao , Wang Huan , Chi Jianning , Meng Fandi , Liu Li , Wang Fuhui
Published: January 2022

This paper established an eight-layer convolu-tional neural network to automatically recognize the characteristic phases of the NiCrAlY coating, the coating/substrate interface, and the oxide layer. Using this neural network, the Cr-rich phase, the coating/substrate interface, and the oxide layer, as the features of the NiCrAlY coating, were successfully identified and retrieved at different constant oxidation temperatures. Based on this achievement, the variations of the Cr-rich phase distribution and the changes of the oxide layer thickness calculated by the network were obtained, which are all consistent with the trend of the oxidation kinetic curves at different temperatures; the preliminary intelligent calculation of oxidation kinetics of the coating was carried out through the thickness of the oxide layer from the SEM images.
GWAS identifies candidate susceptibility loci and microRNA biomarkers for acute encephalopathy with biphasic seizures and late reduced diffusion
Authors: Kasai Mariko , Omae Yosuke , Kawai Yosuke , Shibata Akiko , Hoshino Ai , Mizuguchi Masashi , Tokunaga Katsushi
Published: January 2022

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a severe encephalopathy preceded by viral infections with high fever. AESD is a multifactorial disease, however, few disease susceptibility genes have previously been identified. Here, we conducted a genome-wide association study (GWAS) and assessed functional variants in non-coding regions to study genetic susceptibility in AESD using 254 Japanese children with AESD and 799 adult healthy controls. We also performed a microRNA enrichment analysis using GWAS statistics to search for candidate biomarkers in AESD. The variant with the lowest p-value, rs1850440, was located in the intron of serine/threonine kinase 39 gene (STK39) on chromosome 2q24.3 (p = 2.44 × 10−7, odds ratio = 1.71). The minor allele T of rs1850440 correlated with the stronger expression of STK39 in peripheral blood. This variant possessed enhancer histone modification marks in STK39, the encoded protein of which activates the p38 mitogen-activated protein kinase (MAPK) pathway. In the replication study, the odds ratios of three SNPs, including rs1850440, showed the same direction of association with that in the discovery stage GWAS. One of the candidate microRNAs identified by the microRNA enrichment analysis was associated with inflammatory responses regulated by the MAPK pathway. This study identified STK39 as a novel susceptibility locus of AESD, found microRNAs as potential biomarkers, and implicated immune responses and the MAPK cascade in its pathogenesis.
NLRP3 inflammasome in rosmarinic acid-afforded attenuation of acute kidney injury in mice
Authors: Akhter Juheb , Khan Jasim , Baghel Madhu , Beg Mirza Masroor Ali , Goswami Poonam , Afjal Mohd Amir , Ahmad Shahzad , Habib Haroon , Najmi Abul Kalam , Raisuddin Sheikh
Published: January 2022

Cisplatin (CP) is a well-known anticancer drug used to effectively treat various kinds of solid tumors. CP causes acute kidney injury (AKI) and unfortunately, there is no therapeutic approach in hand to prevent AKI. Several signaling pathways are responsible for inducing AKI which leads to inflammation in proximal convoluted tubule cells in the kidney. Furthermore, the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome is involved in the CP-induced AKI. In this study, we investigated therapeutic effects of rosmarinic acid (RA) against inflammation-induced AKI. RA was orally administered at the dose of 100 mg/kg for two consecutive days after 24 h of a single injection of CP at the dose of 20 mg/kg administered intraperitoneally in Swiss albino male mice. Treatment of RA inhibited the activation of NLRP3 signaling pathway by blocking the activated caspase-1 and downstream signal molecules such as IL-1β and IL18. CP activated HMGB1-TLR4/MyD88 axis was also found to be downregulated with the RA treatment. Activation of nuclear factor-κB and elevated protein expression of cyclooxygenase-2 (COX-2) were also found to be downregulated in RA-treated animals. Alteration of early tubular injury biomarker, kidney injury molecule-1 (KIM-1), was found to be subsided in RA-treated mice. RA has been earlier reported for antioxidant and anti-inflammatory properties. Our findings show that blocking a critical step of inflammasome signaling pathway by RA treatment can be a novel and beneficial approach to prevent the CP-induced AKI.
Parvalbumin expressing interneurons control spike-phase coupling of hippocampal cells to theta oscillations
Authors: Strüber Michael , Sauer Jonas-Frederic , Bartos Marlene
Published: January 2022

Encoding of information by hippocampal neurons is defined by the number and the timing of action potentials generated relative to ongoing network oscillations in the theta (5–14 Hz), gamma (30–80 Hz) and ripple frequency range (150–200 Hz). The exact mechanisms underlying the temporal coupling of action potentials of hippocampal cells to the phase of rhythmic network activity are not fully understood. One critical determinant of action potential timing is synaptic inhibition provided by a complex network of Gamma-amino-hydroxy-butyric acid releasing (GABAergic) interneurons. Among the various GABAergic cell types, particularly Parvalbumin-expressing cells are powerful regulators of neuronal activity. Here we silenced Parvalbumin-expressing interneurons in hippocampal areas CA1 and the dentate gyrus in freely moving mice using the optogenetic silencing tool eNpHR to determine their influence on spike timing in principal cells. During optogenetic inhibition of Parvalbumin-expressing cells, local field potential recordings revealed no change in power or frequency of CA1 or dentate gyrus network oscillations. However, CA1 pyramidal neurons exhibited significantly reduced spike-phase coupling to CA1 theta, but not gamma or ripple oscillations. These data suggest that hippocampal Parvalbumin-expressing interneurons are particularly important for an intact theta-based temporal coding scheme of hippocampal principal cell populations.
Sensitive asprosin detection in clinical samples reveals serum/saliva correlation and indicates cartilage as source for serum asprosin
Authors: Morcos Yousef A. T. , Lütke Steffen , Tenbieg Antje , Hanisch Franz-Georg , Pryymachuk Galyna , Piekarek Nadin , Hoffmann Thorben , Keller Titus , Janoschek Ruth , Niehoff Anja , Zaucke Frank , Dötsch Jörg , Hucklenbruch-Rother Eva , Sengle Gerhard
Published: January 2022

The C-terminal pro-fibrillin-1 propeptide asprosin is described as white adipose tissue derived hormone that stimulates rapid hepatic glucose release and activates hunger-promoting hypothalamic neurons. Numerous studies proposed correlations of asprosin levels with clinical parameters. However, the enormous variability of reported serum and plasma asprosin levels illustrates the need for sensitive and reliable detection methods in clinical samples. Here we report on newly developed biochemical methods for asprosin concentration and detection in several body fluids including serum, plasma, saliva, breast milk, and urine. Since we found that glycosylation impacts human asprosin detection we analyzed its glycosylation profile. Employing a new sandwich ELISA revealed that serum and saliva asprosin correlate strongly, depend on biological sex, and feeding status. To investigate the contribution of connective tissue-derived asprosin to serum levels we screened two cohorts with described cartilage turnover. Serum asprosin correlated with COMP, a marker for cartilage degradation upon running exercise and after total hip replacement surgery. This together with our finding that asprosin is produced by primary human chondrocytes and expressed in human cartilage suggests a contribution of cartilage to serum asprosin. Furthermore, we determined asprosin levels in breast milk, and urine, for the first time, and propose saliva asprosin as an accessible clinical marker for future studies.
Effect of delayed entry of blood culture bottles in BACTEC automated blood culture system in the context of laboratory consolidation
Authors: Deslandes Vincent , Rafipour Darya , Gorn Ivan , Sabri Elham , Sant Nadia , Desjardins Marc
Published: January 2022

Delayed entry of blood culture bottles is frequent in consolidated laboratories. A retrospective study evaluated time from insertion to detection and total detection time as a function of preincubation time, and we prospectively looked for false negative results. 69,604 blood culture bottles were reviewed for preincubation time, incubation time and total detection time. Positive cultures for specific bacterial subtypes were reviewed to assess the effect of preincubation time on likelihood of detection. 492 negative blood cultures were prospectively tested by 16S RNA PCR and Staphylococcus-specific PCR for the presence of bacterial DNA. Mean preincubation time for samples collected within the city-limits was 3.94 h versus 9.49–18.89 h for other client sites. Higher preincubation times were partially mitigated by a lower incubation time, with an overall increase in total detection time. A lower odds ratio of recovery of Staphylococcus spp was identified, but not confirmed by terminal subcultures and molecular assays. Prolonged preincubation of blood cultures affects total detection time despite a reduction in incubation time. Successful centralization of microbiological services may depend upon optimization of courier routes for inoculated blood culture bottles. Our data supports consideration for an increase in suggested maximum preincubation times.
Population transcriptomics reveals the effect of gene flow on the evolution of range limits
Authors: Tamagawa Katsunori , Yoshida Kotone , Ohrui Shiori , Takahashi Yuma
Published: January 2022

One of the most important questions in evolutionary biology is how the spatial distribution of species is limited. Asymmetric gene flow from core populations is suggested to increase the number of poorly adapted immigrants in the populations at the range edge. Genetic load due to migration, i.e., migration load, should prevent adaptation to the local habitat, leading to decreases in distribution range via local extinction or the limiting range expansion. However, few experimental studies have examined the effects of immigration on fitness and natural selection within recipient populations. To investigate the influence of migration load on the evolution of distribution range, we performed field and laboratory observations as well as population transcriptomics for the common river snail, Semisulcospira reiniana. This species meets the conditions that migration from source populations can prevent local adaptation in a sink population because they inhabit the broader range of environments, including middle/upper reaches of a river and estuaries within a single river and they may be more vulnerable to being swept away by water currents due to lowered spontaneous (upward) locomotion activity. We found that river steepness was related to the lower distribution limit of S. reiniana, with a narrower distribution range in the steeper river. Population transcriptomic analysis showed that gene flow was heavily asymmetric from the upstream populations to downstream ones in the steep river, suggesting a greater migration load in the steep river. The number of genes putatively involved in adaptation to the local habitat was lower in the steep river than in the gentle river. Gene expression profiles suggested that individuals achieve better local adaptation in the gentle river. Laboratory experiments suggested that evolutionary differences in salinity tolerance among local populations were only found in the gentle river. Our results consistent with the hypothesis that migration load owing to asymmetric gene flow disturbs local adaptation and restricts the distribution range of river snails.