bluuebunny/crossref_metadata_2025 huggingface dataset:
SUBSHIFTS OF FINITE TYPE WITH A HOLE
Authors: CHERIYATH HARITHA , AGARWAL NIKITA
Published: March 2022

We consider a subshift of finite type on q symbols with a union of t cylinders based at words of identical length p as the hole. We explore the relationship between the escape rate into the hole and a rational function,
$r(z)$
, of correlations between forbidden words in the subshift with the hole. In particular, we prove that there exists a constant
$D(t,p)$
such that if
$q>D(t,p)$
, then the escape rate is faster into the hole when the value of the corresponding rational function
$r(z)$
evaluated at
$D(t,p)$
is larger. Further, we consider holes which are unions of cylinders based at words of identical length, having zero cross-correlations, and prove that the escape rate is faster into the hole with larger Poincaré recurrence time. Our results are more general than the existing ones known for maps conjugate to a full shift with a single cylinder as the hole.
Achieving the potential of mHealth in medicine requires challenging the ethos of care delivery
Authors: Ratanawong John P. , Naslund John A. , Mikal Jude P. , Grande Stuart W.
Published: March 2022

Mobile Health (mHealth) interventions have received a mix of praise and excitement, as well as caution and even opposition over recent decades. While the rapid adoption of mHealth solutions due to the COVID-19 pandemic has weakened resistance to integrating these digital approaches into practice and generated renewed interest, the increased reliance on mHealth signals a need for optimizing development and implementation. Despite an historically innovation-resistant medical ethos, mHealth is becoming a normalized supplement to clinical practice, highlighting increased demand. Reaching the full potential of mHealth requires new thinking and investment. The current challenge to broaden mHealth adoption and to ensure equity in access may be overcoming a “design purgatory,” where innovation fails to connect to practice. We recommend leveraging the opportunity presented by the COVID-19 pandemic to disrupt routine practice and with a new focus on theory-driven replicability of mHealth tools and strategies aimed at medical education and professional organizations.
Party Types in the Age of Personalized Politics
Authors: Rahat Gideon
Published: March 2022

Democracies in general and political parties in particular have undergone political personalization in recent decades. The power balance between politicians (one or many) and the team (the party as a collegial entity) has changed, and existing party typologies are no longer suited to the analysis of today’s democratic politics. Although some new personalized party types have been added, what is missing is a systematic attempt to contrast them with the collegial option. This article proposes a new classification of political parties to fill the lacuna. It includes five ideal types of parties: two personalized-decentralized types, referring to collections of separated autonomous activists or to separated autonomous individual politicians (plural); a collegial type, which is about the centrality of the team and is based mainly on collective authorities and collective decision making; and two personalized-centralized types, referring to the centrality of an individual politician in her capacity as the party leader or that of a specific individual who “owns” the party.
SilencingRebelliousPriests: Rodolfo Escamilla García and the Repression of Progressive Catholicism in Cold-War Mexico
Authors: Pensado Jaime M.
Published: March 2022

This article examines the silencing and repression of rebellious priests in Mexico from the 1940s to the mid 1970s and places the divergent actors that composed the Catholic Church during this period as key players in the Cold War. It examines the web of personal and organizational connections of a single emblematic individual whose transnational history has been mostly absent from the accounts of the era: the Jesuit priest Rodolfo Escamilla García. Founder of the Catholic Workers’ Youth (JOC) in the late 1950s, he championed the radical “See, Judge, Act” method that politicized thousands of people across Latin America during the 1960s, when liberation theology emerged throughout the continent and competing conservative authorities came together to repress it. In 1977 Escamilla García was brutally killed in Mexico City, likely with the approval of government security agencies. Yet, his brutal killing, and the murders and torture of other priests examined in this article, were never investigated by police authorities. Further, their silencing points to a moment in Mexican history when government leaders and iconic leftist intellectuals erroneously championed the idea that the nation was exceptional in the Latin American region, meaning less authoritarian and more democratic. The most influential ecclesiastical authorities overwhelmingly agreed. For them, maintaining a productive relationship with the state took precedence over the need to publicly condemn the assassination of rebellious priests. Instead, the loudest voices of condemnation came from progressive Catholics representing the Mexican Social Secretariat (SSM) and the National Center of Social Communications (CENCOS).
Selecting CMIP6 GCMs for CORDEX Dynamical Downscaling: Model Performance, Independence, and Climate Change Signals
Authors: Di Virgilio Giovanni , Ji Fei , Tam Eugene , Nishant Nidhi , Evans Jason P. , Thomas Chris , Riley Matthew L. , Beyer Kathleen , Grose Michael R. , Narsey Sugata , Delage Francois
Published: March 2022

Global climate models (GCMs) are essential for investigating climate change, but their coarse scale limits their efficacy for climate adaptation planning at the regional scales where climate impacts manifest. Dynamical downscaling of GCM outputs better resolves regional climate and thus provides improved guidance for climate policy at regional scales. Being expensive to run, downscaling uses a subset of GCMs, necessitating careful GCM selection. This evaluation identifies a suitable subset of CMIP6 GCMs for downscaling over Australia by assessing individual GCMs against three criteria: (a) performance simulating daily climate variable distributions, climate means, extremes, and modes; (b) model independence; and (c) climate change signal diversity. Over Australia, GCMs are generally biased cold (warm) for maximum (minimum) temperature, with larger biases for minimum temperature. GCMs are generally wet biased, especially over the monsoonal north, but dry biased over eastern regions. Most GCMs show larger biases for temperature and precipitation over geographically complex, heavily populated eastern regions, relative to other regions. Evaluations identify a distinct group of 11 GCMs that perform consistently poorly across climate variables, statistics, and timescales with widespread, statistically significant biases, versus 13 GCMs that show consistent adequate‐to‐good performance with substantially reduced errors. Assessment of model independence highlights the lack of independence between several high‐performing GCMs, particularly from allied modeling groups, demonstrating the importance of careful ensemble selection when making selective samples of climate space. Once GCM climate signal diversity is considered, 6–8 mid‐to‐high‐performing, independent GCMs occupy the full range of the future climate space and, thus, are suitable for dynamical downscaling over CORDEX‐Australasia.
Relationships Between Air‐Sea CO2 Flux and New Production in the Equatorial Pacific
Authors: Pittman Nicholas A. , Strutton Peter G. , Johnson Robert , Matear Richard J. , Sutton Adrienne J.
Published: March 2022

The equatorial Pacific is the largest oceanic source of carbon dioxide to the atmosphere. This outgassing varies depending on the El Niño‐Southern Oscillation (ENSO) and decadal climate variability. New production, the amount of phytoplankton net primary production driven by upwelled nitrate, plays a significant role in modulating air‐sea CO2 fluxes as the biological carbon pump removes carbon from the surface ocean. We aim to understand how the physical drivers of sea surface temperature and wind speed influence interannual and decadal variability of the equatorial Pacific carbon cycle. In the equatorial Pacific, there are three biogeochemical regimes: the upwelling cold tongue east of 140°W and south of the equator (3°N–15°S); the eastern Pacific warm pool north of the equator (3°–15°N); and the 28.5°C western Pacific warm pool, west of 140°W. We find that between 2000 and 2020, air‐sea CO2 flux and ΔpCO2 increased in the cold tongue (45 mmolC m−2 yr−2, 1.5 μatm yr−1, respectively) but decreased elsewhere, while new production decreased everywhere. The western Pacific occasionally became a weak carbon sink, depending on ENSO and this sink was strongest at 165°E during central Pacific “Modoki” El Niño events. We find that changes in wind speed, temperature and ENSO frequency have altered the surface carbon budget. The mean basin‐wide (150°E−90°W and 15°N–15°S) new production for 2000–2020 was 1.2 ± 0.1 PgC yr−1 and air‐sea CO2 flux was 0.5 ± 0.1 PgC yr−1. New production decreased at −7.7 ± 1.6 TgC yr−2, compared to the CO2 flux trend of −1.7 ± 1.4 TgC yr−2.
Does Increasing Horizontal Resolution Improve Seasonal Prediction of Indian Summer Monsoon?: A Climate Forecast System Model Perspective
Authors: Kumar Siddharth , Phani R. , Mukhopadhyay P. , Balaji C.
Published: March 2022

The seasonal prediction skill of climate forecast system model with two different resolutions, namely T126 and T382, is studied using hindcast data. Using novel diagnostic tools such as total variation distance and two‐state Markov Chain analysis, it is shown that increasing the horizontal resolution of the model has minimal impact on the quality of seasonal prediction. The underlying rain distribution and associated transition probabilities are very similar in both model versions. The Markov chain analysis also provides critical clues about the issues associated with convective processes in the model. Both the models produce longer (shorter) wet (dry) spells compared to the observations. Models are trying to bring the atmosphere closer to convective quasi‐equilibrium, leading to a substantial departure from observed features. Although the conventional error metrics are helpful to assess the prediction skills, the new metrics used in the study provide further insights on possible pathways to improve model moist physics.
Ocean Mixed Layer Depth From Dissipation
Authors: Giunta Valentina , Ward Brian
Published: March 2022

The mixed layer depth (MLD) is a widely used parameter for physical, chemical, and biological oceanography. The MLD delimits that region of the ocean, which is directly influenced by the atmosphere. There is a similar length scale referred to as the mixing layer depth, which is determined from profiles of dissipation rate of turbulent kinetic energy, but is less prevalent due to the requirement for specialized instrumentation. Here, we suggest that the MLD can be estimated using density/temperature (henceforth hD) or using dissipation (henceforth hϵ). Utilizing two data sets in the North Atlantic collected with the autonomous Air‐Sea Interaction Profiler, hD and hϵ in the upper 100 m are compared. A new method based on the shape of the dissipation profile for estimating hϵ is presented. The main sources of turbulence in the upper ocean (i.e., wind, waves, and buoyancy fluxes), which tend to deepen the MLD, are more strongly correlated with hϵ variability for both data sets, confirming that the MLD derived from dissipation measurements represents more accurately the variability in the mixed layer. Given that dissipation measurements have become more operational due to the development of ocean microstructure technology, then it is appropriate that hϵ be adopted in the future for estimation of the MLD. This is additionally supported by the fact that hD typically overestimates the MLD when compared to hϵ, thus having consequences for studies where hD is used to represent the extent of mixing in the upper ocean.
Predictable Changes in Extreme Sea Levels and Coastal Flood Risk Due To Long‐Term Tidal Cycles
Authors: Enríquez Alejandra R. , Wahl Thomas , Baranes Hannah E. , Talke Stefan A. , Orton Philip M. , Booth James F. , Haigh Ivan D.
Published: March 2022

We demonstrate that long‐term tidally induced changes in extreme sea levels affect estimates of major flood hazard in a predictable way. Long‐term variations in tides due to the 4.4 and 18.6‐year cycles influence extreme sea levels at 380 global tide gauges out of a total of 581 analyzed. Results show coherent regions where the amplitudes of the modulations are particularly relevant in the 100‐year return sea level, reaching more than 20 cm in some regions (western Europe, north Australia, and Singapore). We identify locations that are currently in a positive phase of the modulation and therefore at a higher risk of flooding, as well as when (year) the next peak of the long‐term tidal modulations is expected to occur. The timing of the peak of the modulation is spatially coherent and influenced by the relative importance of each cycle (4.4 or 18.6‐year) over the total amplitude. An evaluation of four locations suggests that the potentially flooded area in a 100‐year event can vary up to ∼45% (in Boston) as a result of the long‐term tidal cycles; however, the flooded area varies due to local topography and tidal characteristics (6%–13%). We conclude that tidally modulated changes in extreme sea levels can alter the potentially inundated area in a 100‐year event and that the traditional, fixed 100‐year floodplain is inadequate for describing coastal flood risk, even without considering sea‐level rise.
Source Properties and Resonance Characteristics of the Tsunami Generated by the 2021 M 8.2 Alaska Earthquake
Authors: Wang Yuchen , Su Heng‐Yi , Ren Zhiyuan , Ma Yanxue
Published: March 2022

A tsunami was triggered in the North Pacific Ocean by the 2021 Alaska earthquake (M 8.2) on July 29. We studied the source properties and resonance characteristics of the tsunami event using observed records from offshore tsunameters and coastal tide gauges as well as numerical simulation. Spectral analyses were conducted on records at tsunameters and tide gauges. We reconstructed the tsunami source spectrum by calculating the ratio of tsunami spectra to the background spectra of these stations. Based on the source spectrum, we estimated the source size of the 2021 Alaska earthquake to be 332 km (length) 256 km (width), which was generally consistent with the source model proposed by the United States Geological Survey using seismological approaches. In addition, we also performed spectral analyses of the tsunami wavefield in a region of interest, including the Aleutian Islands and the Alaska Peninsula. Standing wave systems were found south of the Alaska Peninsula and the Aleutian Islands. The Aleutian Islands prevent the propagation of tsunami oscillations. Only a small portion of energy propagates through the archipelago from the main part of the Pacific Ocean to the Bering Sea.
Temporal Variations of NDVI and LAI and Interactions With Hydroclimatic Variables in a Large and Agro‐Ecologically Diverse Region
Authors: Ukasha Muhammad , Ramirez Jorge A. , Niemann Jeffrey D.
Published: March 2022

Satellite based vegetation indices are increasingly used to characterize vegetation's response to climate variability and change over large spatial extents. The use of a given index assumes that the index adequately describes the vegetation's response to hydroclimatic forcing. The objective of this study is to compare the temporal behaviors of normalized difference vegetation index (NDVI) and leaf area index (LAI) and their associations with hydroclimatic variables. Observations of monthly precipitation, streamflow, temperature, vapor pressure deficit, evapotranspiration, and total water storage anomalies (TWSA) are processed for the combined Sacramento River and San Joaquin River basins in California for 13 water years (October 2002 to September 2015). Estimates of NDVI and LAI are obtained for the same period from MODerate resolution Imaging Spectroradiometer (MODIS). The seasonal cycle of NDVI peaks 2–3 months earlier than LAI. The seasonal variation in NDVI follows the seasonality of TWSA (i.e., water availability) whereas the seasonal cycle of LAI follows the seasonality in mean temperature and vapor pressure deficit (i.e., atmospheric water demand). Cross‐correlation analyses of NDVI and LAI with the hydroclimatic variables show that LAI is more strongly correlated with most of the hydroclimatic variables considered.
Impact of Low‐Latitude Ionospheric Effects on Precise Position Determination
Authors: Biswas T. , Banerjee P. , Paul A.
Published: March 2022

Precise Point Positioning (PPP) techniques serve as a very important tool, to provide high precision position information, using data from a grid of networked receivers. However, satellite signals are frequently perturbed by inhomogeneities present in the medium of propagation, introducing errors in the measured position, the dominant contribution of which could be attributed to the ionosphere. Low‐latitude stations, like Calcutta (22.58°N, 88.38°E geographic; magnetic dip 34.54°), being situated near the northern crest of Equatorial Ionization Anomaly (EIA), experience some of the worst cases of ionospheric effects on position determination. However, such effects are usually minimal during early morning hours (typically 03–05 local time [LT]). In this study, PPP of the station Calcutta has been obtained under different solar activity conditions to assess and validate the applicability of sub‐centimeter level position accuracy. The PPP values have also been compared with early morning stand‐alone dual‐frequency GPS receiver‐derived position to assess and validate the diurnal ionospheric quiet time. Efforts have also been made to observe the effects of EIA on PPP solution. Data are recorded during a high (March 2014) and low (March 2019) solar activity period. Results of this study reveal agreement with the centimeter‐level accuracy of PPP; however, effect of solar activity is prominent when inspected in millimeter order. Additionally, the diurnal ionospheric quiet time is observed to lie within 04–06 and 02–04 LT for a high and a low solar activity period, respectively. Irrespective of the solar activity conditions, receiver noise contribution in position deviation is measured to be within 150 cm.
Wave Breaking Induced by Opposing Currents in Submerged Vegetation Canopies
Authors: Hu Z. , Lian S. , Zitman T. , Wang H. , He Z. , Wei H. , Ren L. , Uijttewaal W. , Suzuki T.
Published: March 2022

Wave height attenuation in vegetation canopies is often all attributed to the drag force exerted by vegetation, whereas other potential dissipation process is often neglected. Previous studies without vegetation have found that opposing currents can induce wave breaking and greatly increase dissipation. It is not clear if similar process may also occur in vegetation canopies. We conducted systematic flume experiments to show that wave breaking in opposing currents can occur in vegetated flows, but only in submerged canopies with shear currents above vegetation top. Subsequently, we developed a new analytical model to understand and assess the contribution of both drag‐induced dissipation in the lower vegetation layer and current‐induced breaking in the upper free layer. A new generic drag coefficient relation was applied in the model to quantify drag‐induced dissipation with various current‐wave combinations. It shows that breaking induced by opposing currents constitutes an essential part (up to 87%) of the total dissipation, which leads to considerably higher dissipation than the cases with following currents. Breaking can occur with various submergence ratios and with small opposing currents in the submerged vegetation field. It indicates that similar breaking process is likely to occur in real vegetation fields. The present study reveals and quantifies the current‐induced wave breaking process that has not been reported before, which can improve our understanding of vegetation wave dissipation capacity in field conditions.
Empirically Determined Auroral Electron Events at Mars—MAVEN Observations
Authors: Xu Shaosui , Mitchell David L. , McFadden James P. , Schneider Nicholas M. , Milby Zachariah , Jain Sonal , Weber Tristan , Brain David A. , DiBraccio Gina A. , Halekas Jasper , Ruhunusiri Suranga , Mazelle Christian , Lillis Robert J. , Johnston Ben
Published: March 2022

Discrete aurorae have been observed at magnetized planets such as Earth and Jupiter, triggered by accelerated electrons. Similar aurorae have also been observed at Mars with only localized strong crustal magnetisms. However, our understanding of this phenomenon at Mars is still limited. In particular, direct and quantitative comparisons of the auroral and its source electron events are lacking as these two types of observations are usually made at different times and/or locations. In this study, we establish empirical criteria to select electron events (“auroral electrons”) that could trigger detectable auroral emissions with Mars Atmosphere and Volatile EvolutioN measurements, thereby enabling a direct statistical comparison. We find auroral electrons share similar statistical characteristics to those previously reported for discrete auroral events. This study bridges the gap between electron observations and auroral detections and enables collaborations across different Mars missions, as well as comparative planetary studies of discrete aurora.
Transient Precipitation Increase During Winter in the Eastern North America
Authors: Liang Wengui , Zhang Minghua
Published: March 2022

Previous studies have reported that enhanced eddy moisture convergence causes future increase of winter precipitation in the eastern North America in a warmer climate. This study investigates the mechanisms of the change in moisture convergence. Using ensemble simulations from climate models and composite analysis of moisture budget, we show that in the southeast United States, two thirds of the enhanced moisture convergence is caused by local thermodynamics due to increase of moisture, while one third is caused by stronger eddy wind convergence. In the north, it is primarily caused by the increase of moisture gradient associated with the spatial distribution of both the climatological temperature and the large amplitudes of the eddy temperature in the region of the storm tracks. Results help to better understand the physical mechanism of more winter precipitation in the eastern North America in a warmer climate.
Identification of active gaseous-alkane degraders at natural gas seeps
Authors: Farhan Ul Haque Muhammad , Hernández Marcela , Crombie Andrew T , Murrell J Colin
Published: March 2022

Natural gas seeps release significant amounts of methane and other gases including ethane and propane contributing to global climate change. In this study, bacterial actively consuming short-chain alkanes were identified by cultivation, whole-genome sequencing, and stable-isotope probing (SIP)-metagenomics using 13C-propane and 13C-ethane from two different natural gas seeps, Pipe Creek and Andreiasu Everlasting Fire. Nearly 100 metagenome-assembled genomes (MAGs) (completeness 70–99%) were recovered from both sites. Among these, 16 MAGs had genes encoding the soluble di-iron monooxygenase (SDIMO). The MAGs were affiliated to Actinobacteria (two MAGs), Alphaproteobacteria (ten MAGs), and Gammaproteobacteria (four MAGs). Additionally, three gaseous-alkane degraders were isolated in pure culture, all of which could grow on ethane, propane, and butane and possessed SDIMO-related genes. Two Rhodoblastus strains (PC2 and PC3) were from Pipe Creek and a Mycolicibacterium strain (ANDR5) from Andreiasu. Strains PC2 and PC3 encoded putative butane monooxygenases (MOs) and strain ANDR5 contained a propane MO. Mycolicibacterium strain ANDR5 and MAG19a, highly abundant in incubations with 13C-ethane, share an amino acid identity (AAI) of 99.3%. We show using a combination of enrichment and isolation, and cultivation-independent techniques, that these natural gas seeps contain a diverse community of active bacteria oxidising gaseous-alkanes, which play an important role in biogeochemical cycling of natural gas.
Novel indole-mediated potassium ion import system confers a survival advantage to the Xanthomonadaceae family
Authors: Zhu Yuxiang , Han Yong , Liu Guanglei , Bian Zeran , Yan Xiayi , Li Yaoyao , Long Hongan , Yu Guanshuo , Wang Yan
Published: March 2022

Interspecific and intraspecific communication systems of microorganisms are involved in the regulation of various stress responses in microbial communities. Although the significance of signaling molecules in the ubiquitous family Xanthomonadaceae has been reported, the role bacterial communications play and their internal mechanisms are largely unknown. Here, we use Lysobacter enzymogenes, a member of Xanthomonadaceae, to identify a novel potassium ion import system, LeKdpXFABC. This import system participates in the indole-mediated interspecies signaling pathway and matters in environmental adaptation. Compared with the previously reported kdpFABC of Escherichia coli, LekdpXFABC contains a novel indispensable gene LekdpX and is directly regulated by the indole-related two-component system QseC/B. QseC autophosphorylation is involved in this process. The operon LekdpXFABC widely exists in Xanthomonadaceae. Moreover, indole promotes antimicrobial product production at the early exponential phase. Further analyses show that indole enhances potassium ion adsorption on the cell surface by upregulating the production of O-antigenic polysaccharides. Finally, we confirm that LeKdpXFABC mediation by indole is subject to the intraspecific signaling molecules DSFs, of which the biosynthesis genes always exist together with LekdpXFABC. Therefore, as a new idea, the signal collaborative strategy of indole and DSFs might ensure the persistent fitness advantage of Xanthomonadaceae in variable environments.
Validation of a new instrument to guide and support insanity evaluations: the defendant’s insanity assessment support scale (DIASS)
Authors: Parmigiani Giovanna , Mandarelli Gabriele , Roma Paolo , Ferracuti Stefano
Published: March 2022

The insanity defense represents one of the most controversial and debated evaluations performed by forensic psychiatrists and psychologists. Despite the variation among different jurisdictions, in Western countries, the legal standards for insanity often rely on the presence of cognitive and/or volitional impairment of the defendant at the time of the crime. We developed the defendant’s insanity assessment support scale (DIASS) based on a wide view of competent decision-making, which reflects core issues relevant to legal insanity in many jurisdictions. To assess the characteristics of the DIASS we asked 40 forensic experts (16% women; years of experience = 20.6 ± 12.9) to evaluate 10 real-life derived forensic cases with the DIASS; cases included defendants’ psychiatric symptom severity, evaluated through the 24-itemBrief Psychiatric Rating Scale (BPRS). Exploratory factor analysis by principal axis factoring was conducted, which disclosed a two-factor solution explaining 57.6% of the total variance. The DIASS showed a good internal consistency (Cronbach’s alpha = 0.86), and substantial inter-rater reliability (Cohen’s kappa = 0.72). The capacities analyzed through the DIASS were mainly affected by mania/excitement and psychotic dimensions in nonresponsible and with substantially diminished responsibility defendants, while by hostility and negative symptoms in responsible defendants. The DIASS proved to be an effective psychometric tool to guide and structure insanity defense evaluations, in order to improve their consistency and reliability.
Progranulin improves neural development via the PI3K/Akt/GSK-3β pathway in the cerebellum of a VPA-induced rat model of ASD
Authors: Wang Lili , Chen Jianhui , Hu Yuling , Liao Ailing , Zheng Wenxia , Wang Xiaoqing , Lan Junying , Shen Jingjing , Wang Shali , Yang Feng , Wang Yan , Li Yingbo , Chen Di
Published: March 2022

Autism spectrum disorder (ASD) is a neurodevelopmental disease featuring social interaction deficits and repetitive/stereotyped behaviours; the prevalence of this disorder has continuously increased. Progranulin (PGRN) is a neurotrophic factor that promotes neuronal survival and differentiation. However, there have not been sufficient studies investigating its effect in animal models of autism. This study investigated the effects of PGRN on autistic phenotypes in rats treated with valproic acid (VPA) and assessed the underlying molecular mechanisms. PGRN was significantly downregulated in the cerebellum at postnatal day 14 (PND14) and PND35 in VPA-exposed rats, which simultaneously showed defective social preference, increased repetitive behaviours, and uncoordinated movements. When human recombinant PGRN (r-PGRN) was injected into the cerebellum of newborn ASD model rats (PND10 and PND17), some of the behavioural defects were alleviated. r-PGRN supplementation also reduced cerebellar neuronal apoptosis and rescued synapse formation in ASD rats. Mechanistically, we confirmed that PGRN protects neurodevelopment via the PI3K/Akt/GSK-3β pathway in the cerebellum of a rat ASD model. Moreover, we found that prosaposin (PSAP) promoted the internalisation and neurotrophic activity of PGRN. These results experimentally demonstrate the therapeutic effects of PGRN on a rat model of ASD for the first time and provide a novel therapeutic strategy for autism.
m6A demethylase ALKBH5 promotes tumor cell proliferation by destabilizing IGF2BPs target genes and worsens the prognosis of patients with non-small-cell lung cancer
Authors: Tsuchiya Kazuo , Yoshimura Katsuhiro , Iwashita Yuji , Inoue Yusuke , Ohta Tsutomu , Watanabe Hirofumi , Yamada Hidetaka , Kawase Akikazu , Tanahashi Masayuki , Ogawa Hiroshi , Funai Kazuhito , Shinmura Kazuya , Suda Takafumi , Sugimura Haruhiko
Published: March 2022

The modification of N6-methyladenosine (m6A) in RNA and its eraser ALKBH5, an m6A demethylase, play an important role across various steps of human carcinogenesis. However, the involvement of ALKBH5 in non-small-cell lung cancer (NSCLC) development remains to be completely elucidated. The current study revealed that the expression of ALKBH5 was increased in NSCLC and increased expression of ALKBH5 worsened the prognosis of patients with NSCLC. In vitro study revealed that ALKBH5 knockdown suppressed cell proliferation ability of PC9 and A549 cells and promoted G1 arrest and increased the number of apoptotic cells. Furthermore, ALKBH5 overexpression increased the cell proliferation ability of the immortalized cell lines. Microarray analysis and western blotting revealed that the expression of CDKN1A (p21) or TIMP3 was increased by ALKBH5 knockdown. These alterations were offset by a double knockdown of both ALKBH5 and one of the IGF2BPs. The decline of mRNAs was, at least partly, owing to the destabilization of these mRNAs by one of the IGF2BPs. In conclusions, the ALKBH5–IGF2BPs axis promotes cell proliferation and tumorigenicity, which in turn causes the unfavorable prognosis of NSCLC.
MiR-323a regulates ErbB3/EGFR and blocks gefitinib resistance acquisition in colorectal cancer
Authors: Zhang Yuanzhou , Liang Shunshun , Xiao Bowen , Hu Jingying , Pang Yechun , Liu Yuling , Yang Juan , Ao Junpin , Wei Lin , Luo Xiaoying
Published: March 2022

The rapid onset of resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) limits its clinical utility in colorectal cancer (CRC) patients, and pan-erb-b2 receptor tyrosine kinase (ErbB) treatment strategy may be the alternative solution. The aim of this study was to develop a possible microRNA multi-ErbB treatment strategy to overcome EGFR-TKI resistance. We detect the receptor tyrosine kinase activity in gefitinib-resistant colorectal cancer cells, ErbB3/EGFR is significantly activated and provides a potential multi-ErbB treatment target. MiR-323a-3p, a tumor suppressor, could target both ErbB3 and EGFR directly. Apoptosis is the miR-323a-3p inducing main biological process by functional enrichment analysis, and The EGFR and ErbB signaling are the miR-323a-3p inducing main pathway by KEGG analysis. MiR-323a-3p promotes CRC cells apoptosis by targeting ErbB3-phosphoinositide 3‐kinases (PI3K)/PKB protein kinase (Akt)/glycogen synthase kinase 3 beta (GSK3β)/EGFR-extracellular regulated MAP kinase (Erk1/2) signaling directly. And miR-323a-3p, as a multi-ErbBs inhibitor, increase gefitinib sensitivity of the primary cell culture from combination miR-323a-3p and gefitinib treated subcutaneous tumors. MiR-323a-3p reverses ErbB3/EGFR signaling activation in gefitinib-resistant CRC cell lines and blocks acquired gefitinib resistance.
Ferroptosis, a new target for treatment of renal injury and fibrosis in a 5/6 nephrectomy-induced CKD rat model
Authors: Wang Jingyu , Wang Yaqing , Liu Yi , Cai Xintian , Huang Xin , Fu Wenjing , Wang Lei , Qiu Lihua , Li Junying , Sun Li
Published: March 2022

Ferroptosis is a non-traditional form of regulated cell death, characterized by iron overload and lipid peroxidation. Exploration of ferroptosis in chronic kidney disease (CKD) has been extremely limited to date. In this study, we established a rat model of CKD by 5/6 nephrectomy, treated CKD rats with the ferroptosis inducer, cisplatin (CDDP), and the ferroptosis inhibitor, deferoxamine mesylate (DFO), and observed the resulting pathologic changes (injury markers and fibrosis) and ferroptotic biochemical indices. Kidney iron deposition, lipid peroxidation, mitochondrial defects, ferroptosis marker induction, and TUNEL staining positivity were detected in CKD group rats. Further, treatment with CDDP or DFO influenced renal injury and fibrosis by affecting ferroptosis, rather than apoptosis, and ferroptosis occurs in the remnant kidney due to disordered iron metabolism. In conclusion, our study shows for the first time that 5/6 nephrectomy induces ferroptosis in the remnant kidney and clarifies the underlying pathogenesis. Moreover, we demonstrate that ferroptosis is involved in CKD progression and represents a therapeutic target in chronic kidney injury and renal fibrosis.
Gene-lifestyle interactions in the genomics of human complex traits
Authors: Laville Vincent , Majarian Timothy , Sung Yun J. , Schwander Karen , Feitosa Mary F. , Chasman Daniel I. , Bentley Amy R. , Rotimi Charles N. , Cupples L. Adrienne , de Vries Paul S. , Brown Michael R. , Morrison Alanna C. , Kraja Aldi T. , Province Mike , Gu C. Charles , Gauderman W. James ,   the CHARGE Gene-Lifestyle Interactions Working Group, Laville Vincent , Majarian Timothy , Sung Yun J. , Schwander Karen , Feitosa Mary F. , Chasman Daniel I. , Bentley Amy R. , Rotimi Charles N. , Cupples L. Adrienne , de Vries Paul S. , Brown Michael R. , Morrison Alanna C. , Kraja Aldi T. , Province Mike , Gu C. Charles , Gauderman W. James , Rao D. C. , Manning Alisa K. , Aschard Hugues , Rao D. C. , Manning Alisa K. , Aschard Hugues
Published: March 2022

The role and biological significance of gene-environment interactions in human traits and diseases remain poorly understood. To address these questions, the CHARGE Gene-Lifestyle Interactions Working Group conducted series of genome-wide interaction studies (GWIS) involving up to 610,475 individuals across four ancestries for three lipids and four blood pressure traits, while accounting for interaction effects with drinking and smoking exposures. Here we used GWIS summary statistics from these studies to decipher potential differences in genetic associations and G×E interactions across phenotype-exposure-ancestry combinations, and to derive insights on the potential mechanistic underlying G×E through in-silico functional analyses. Our analyses show first that interaction effects likely contribute to the commonly reported ancestry-specific genetic effect in complex traits, and second, that some phenotype-exposures pairs are more likely to benefit from a greater detection power when accounting for interactions. It also highlighted modest correlation between marginal and interaction effects, providing material for future methodological development and biological discussions. We also estimated contributions to phenotypic variance, including in particular the genetic heritability conditional on the exposure, and heritability partitioned across a range of functional annotations and cell types. In these analyses, we found multiple instances of potential heterogeneity of functional partitions between exposed and unexposed individuals, providing new evidence for likely exposure-specific genetic pathways. Finally, along this work, we identified potential biases in methods used to jointly meta-analyze genetic and interaction effects. We performed simulations to characterize these limitations and to provide the community with guidelines for future G×E studies.
Machine learning–based observation-constrained projections reveal elevated global socioeconomic risks from wildfire
Authors: Yu Yan , Mao Jiafu , Wullschleger Stan D. , Chen Anping , Shi Xiaoying , Wang Yaoping , Hoffman Forrest M. , Zhang Yulong , Pierce Eric
Published: March 2022

Reliable projections of wildfire and associated socioeconomic risks are crucial for the development of efficient and effective adaptation and mitigation strategies. The lack of or limited observational constraints for modeling outputs impairs the credibility of wildfire projections. Here, we present a machine learning framework to constrain the future fire carbon emissions simulated by 13 Earth system models from the Coupled Model Intercomparison Project phase 6 (CMIP6), using historical, observed joint states of fire-relevant variables. During the twenty-first century, the observation-constrained ensemble indicates a weaker increase in global fire carbon emissions but higher increase in global wildfire exposure in population, gross domestic production, and agricultural area, compared with the default ensemble. Such elevated socioeconomic risks are primarily caused by the compound regional enhancement of future wildfire activity and socioeconomic development in the western and central African countries, necessitating an emergent strategic preparedness to wildfires in these countries.
Spelling interface using intracortical signals in a completely locked-in patient enabled via auditory neurofeedback training
Authors: Chaudhary Ujwal , Vlachos Ioannis , Zimmermann Jonas B. , Espinosa Arnau , Tonin Alessandro , Jaramillo-Gonzalez Andres , Khalili-Ardali Majid , Topka Helge , Lehmberg Jens , Friehs Gerhard M. , Woodtli Alain , Donoghue John P. , Birbaumer Niels
Published: March 2022

Patients with amyotrophic lateral sclerosis (ALS) can lose all muscle-based routes of communication as motor neuron degeneration progresses, and ultimately, they may be left without any means of communication. While others have evaluated communication in people with remaining muscle control, to the best of our knowledge, it is not known whether neural-based communication remains possible in a completely locked-in state. Here, we implanted two 64 microelectrode arrays in the supplementary and primary motor cortex of a patient in a completely locked-in state with ALS. The patient modulated neural firing rates based on auditory feedback and he used this strategy to select letters one at a time to form words and phrases to communicate his needs and experiences. This case study provides evidence that brain-based volitional communication is possible even in a completely locked-in state.
Decoding internally generated transitions of conscious contents in the prefrontal cortex without subjective reports
Authors: Kapoor Vishal , Dwarakanath Abhilash , Safavi Shervin , Werner Joachim , Besserve Michel , Panagiotaropoulos Theofanis I. , Logothetis Nikos K.
Published: March 2022

A major debate about the neural correlates of conscious perception concerns its cortical organization, namely, whether it includes the prefrontal cortex (PFC), which mediates executive functions, or it is constrained within posterior cortices. It has been suggested that PFC activity during paradigms investigating conscious perception is conflated with post-perceptual processes associated with reporting the contents of consciousness or feedforward signals originating from exogenous stimulus manipulations and relayed via posterior cortical areas. We addressed this debate by simultaneously probing neuronal populations in the rhesus macaque (Macaca mulatta) PFC during a no-report paradigm, capable of instigating internally generated transitions in conscious perception, without changes in visual stimulation. We find that feature-selective prefrontal neurons are modulated concomitantly with subjective perception and perceptual suppression of their preferred stimulus during both externally induced and internally generated changes in conscious perception. Importantly, this enables reliable single-trial, population decoding of conscious contents. Control experiments confirm significant decoding of stimulus contents, even when oculomotor responses, used for inferring perception, are suppressed. These findings suggest that internally generated changes in the contents of conscious visual perception are reliably reflected within the activity of prefrontal populations in the absence of volitional reports or changes in sensory input.
S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions
Authors: Jiang Qiwei , Zhang Xiaomei , Dai Xiaoming , Han Shiyao , Wu Xueji , Wang Lei , Wei Wenyi , Zhang Ning , Xie Wei , Guo Jianping
Published: March 2022

Functioning as a master kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1) plays a fundamental role in phosphorylating and activating protein kinases A, B and C (AGC) family kinases, including AKT. However, upstream regulation of PDK1 remains largely elusive. Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT. Mechanistically, S6K1-mediated phosphorylation of PDK1 augments its interaction with 14-3-3 adaptor protein and homo-dimerization, subsequently dissociating PDK1 from phosphatidylinositol 3,4,5 triphosphate (PIP3) and retarding its interaction with AKT. Pathologically, tumor patient-associated PDK1 mutations, either attenuating S6K1-mediated PDK1 phosphorylation or impairing PDK1 interaction with 14-3-3, result in elevated AKT kinase activity and oncogenic functions. Taken together, our findings not only unravel a delicate feedback regulation of AKT signaling via S6K1-mediated PDK1 phosphorylation, but also highlight the potential strategy to combat mutant PDK1-driven cancers.
Multiplexed action-outcome representation by striatal striosome-matrix compartments detected with a mouse cost-benefit foraging task
Authors: Bloem Bernard , Huda Rafiq , Amemori Ken-ichi , Abate Alex S. , Krishna Gayathri , Wilson Anna L. , Carter Cody W. , Sur Mriganka , Graybiel Ann M.
Published: March 2022

Learning about positive and negative outcomes of actions is crucial for survival and underpinned by conserved circuits including the striatum. How associations between actions and outcomes are formed is not fully understood, particularly when the outcomes have mixed positive and negative features. We developed a novel foraging (‘bandit’) task requiring mice to maximize rewards while minimizing punishments. By 2-photon Ca++imaging, we monitored activity of visually identified anterodorsal striatal striosomal and matrix neurons. We found that action-outcome associations for reward and punishment were encoded in parallel in partially overlapping populations. Single neurons could, for one action, encode outcomes of opposing valence. Striosome compartments consistently exhibited stronger representations of reinforcement outcomes than matrix, especially for high reward or punishment prediction errors. These findings demonstrate multiplexing of action-outcome contingencies by single identified striatal neurons and suggest that striosomal neurons are particularly important in action-outcome learning.
Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors
Authors: Graf Monika , Interlandi Marta , Moreno Natalia , Holdhof Dörthe , Göbel Carolin , Melcher Viktoria , Mertins Julius , Albert Thomas K. , Kastrati Dennis , Alfert Amelie , Holsten Till , de Faria Flavia , Meisterernst Michael , Rossig Claudia , Warmuth-Metz Monika , Nowak Johannes , Meyer zu Hörste Gerd , Mayère Chloe , Nef Serge , Johann Pascal , Frühwald Michael C. , Dugas Martin , Schüller Ulrich , Kerl Kornelius
Published: March 2022

Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease.
A deep-learning approach for online cell identification and trace extraction in functional two-photon calcium imaging
Authors: Sità Luca , Brondi Marco , Lagomarsino de Leon Roig Pedro , Curreli Sebastiano , Panniello Mariangela , Vecchia Dania , Fellin Tommaso
Published: March 2022

In vivo two-photon calcium imaging is a powerful approach in neuroscience. However, processing two-photon calcium imaging data is computationally intensive and time-consuming, making online frame-by-frame analysis challenging. This is especially true for large field-of-view (FOV) imaging. Here, we present CITE-On (Cell Identification and Trace Extraction Online), a convolutional neural network-based algorithm for fast automatic cell identification, segmentation, identity tracking, and trace extraction in two-photon calcium imaging data. CITE-On processes thousands of cells online, including during mesoscopic two-photon imaging, and extracts functional measurements from most neurons in the FOV. Applied to publicly available datasets, the offline version of CITE-On achieves performance similar to that of state-of-the-art methods for offline analysis. Moreover, CITE-On generalizes across calcium indicators, brain regions, and acquisition parameters in anesthetized and awake head-fixed mice. CITE-On represents a powerful tool to speed up image analysis and facilitate closed-loop approaches, for example in combined all-optical imaging and manipulation experiments.