bluuebunny/crossref_metadata_2025 huggingface dataset:
Parental mental health and risk of poor mental health and death by suicide in offspring: a population-wide data-linkage study
Authors: Maguire A. , Ross E. , O'Reilly D.
Published: April 2022

Aims

Suicide is a major public health concern. Identifying those most at risk is vital to ensure the implementation of effective interventions. Mental health (MH) is known to have a genetic component and parental MH is associated with offspring MH. However, little is known about the effect of parental psychopathology on offspring suicide risk. The aim of this study is to determine if children living with parents with poor MH are at an increased risk of poor MH, or death by suicide.

Methods

This population-wide cohort study linked data from the 2011 Northern Ireland Census to 6 years' death records (2011–2016). Information on MH status, in addition to other individual and household-level attributes, was derived from the 2011 Census. Logistic regression was utilised to examine the association between parental poor MH and offspring MH and suicide risk, with adjustment for socio-demographic characteristics.

Results

Overall, 11.6% of the cohort of 618 970 individuals were residing with parents who reported poor MH; 1.6% reported poor MH themselves, and 0.04% (n = 260) died by suicide. Living with a parent with poor MH increased the odds of offspring poor MH (OR = 2.80, 95% CI 2.59–3.03). After adjustment for age, gender, physical illness, socio-economic status and own MH, children living with 1 parent with poor MH were 76% more likely to die by suicide compared to children of parents who did not report poor MH (OR = 1.76, 95% CI 1.31–2.36). The effect size increased for children living with 2 parents with poor MH, and was higher in children aged under 24 years.

Conclusions

Living with a parent with poor MH is a significant risk factor for offspring poor MH and suicide, even after adjustment for personal MH status. When treating mental ill-health in parents, potential interventions for their children should also be considered.
Mapping the selection, availability, price and affordability of essential medicines for mental health conditions at a global level
Authors: Todesco B. , Ostuzzi G. , Barbui C.
Published: April 2022

Aims

To provide a cross-country analysis of selection, availability, prices and affordability of essential medicines for mental health conditions, aiming to identify areas for improvement.

Methods

We used the World Health Organization (WHO) online repository of national essential medicines lists (EMLs) to extract information on the inclusion of essential psychotropic medicines within each country's EML. Data on psychotropic medicine availability, price and affordability were obtained from the Health Action International global database. Additional information on country availability, prices and affordability of essential medicines for mental disorders was identified by searching, up to January 2021, PubMed/Medline, CINAHIL, Scopus and the WHO Regional Databases. We summarised and compared the indicators across lowest-price generic and originator brand medicines in the public and private sectors, and by country income groups.

Results

A total of 112 national EMLs were analysed, and data on psychotropic medicine availability, price and affordability were obtained from 87 surveys. While some WHO essential psychotropic medicines, such as chlorpromazine, haloperidol, amitriptyline, carbamazepine and diazepam, were selected by most national lists, irrespective of the country income level, other essential medicines, such as risperidone or clozapine, were included by most national lists in high-income countries, but only by a minority of lists in low-income countries. Up to 40% of low-income countries did not include medicines that have been in the WHO list for decades, such as long-acting fluphenazine, lithium carbonate and clomipramine. The availability of generic and originator psychotropic medicines in the public sector was below 50% for all medicines, with low-income countries showing rates lower than the overall average. Analysis of price data revealed that procurement prices were lower than patient prices in the public sector, and medicines in the private sector were associated with the highest prices. In low-income countries, the average patient price for amitriptyline and fluoxetine was three times the international unit reference price, while the average patient price for diazepam was ten times the international unit reference price. Affordability was higher in the public than the private sector, and in high-income than low-income countries.

Conclusion

Access to medicines for mental health conditions is an ongoing challenge for health systems worldwide, and no countries can claim to be fully aligned with the general principle of providing full access to essential psychotropic medicines. Low availability and high costs are major barriers to the use of and adherence to essential psychotropic medicines, particularly in low-and middle-income countries.
DeepSpot: A deep neural network for RNA spot enhancement in single-molecule fluorescence in-situ hybridization microscopy images
Authors: Bouilhol Emmanuel , Savulescu Anca F. , Lefevre Edgar , Dartigues Benjamin , Brackin Robyn , Nikolski Macha
Published: April 2022

Detection of RNA spots in single-molecule fluorescence in-situ hybridization microscopy images remains a difficult task, especially when applied to large volumes of data. The variable intensity of RNA spots combined with the high noise level of the images often requires manual adjustment of the spot detection thresholds for each image. In this work, we introduce DeepSpot, a Deep Learning-based tool specifically designed for RNA spot enhancement that enables spot detection without the need to resort to image per image parameter tuning. We show how our method can enable downstream accurate spot detection. DeepSpot’s architecture is inspired by small object detection approaches. It incorporates dilated convolutions into a module specifically designed for context aggregation for small object and uses Residual Convolutions to propagate this information along the network. This enables DeepSpot to enhance all RNA spots to the same intensity, and thus circumvents the need for parameter tuning. We evaluated how easily spots can be detected in images enhanced with our method by testing DeepSpot on 20 simulated and 3 experimental datasets, and showed that accuracy of more than 97% is achieved. Moreover, comparison with alternative deep learning approaches for mRNA spot detection (deepBlink) indicated that DeepSpot provides more precise mRNA detection. In addition, we generated single-molecule fluorescence in-situ hybridization images of mouse fibroblasts in a wound healing assay to evaluate whether DeepSpot enhancement can enable seamless mRNA spot detection and thus streamline studies of localized mRNA expression in cells.
Exploring the influence of weeds on cranberry yield and quality
Authors: Colquhoun Jed , Besançon Thierry , Ghantous Katherine , Sandler Hilary
Published: April 2022

The influence of weeds on cranberry yield and quality is not well known and cannot be extrapolated from other cropping systems given the unique nature of both cranberry production and the weed species spectrum. The work presented here addresses this need with four common weed species across multiple production seasons and systems in Wisconsin, Massachusetts, and New Jersey: Carolina redroot, earth loosestrife, bristly dewberry, and polytrichum moss. The objectives were to use these representative species to quantify the impact of weed density, groundcover, and biomass on several cranberry yield components and related interactions with other cranberry pests, and to determine whether these relationships were consistent enough across seasons to be reliably used in weed management decision-making. The relationships between Carolina redroot and bristly dewberry growth measures and marketable cranberry yield were highly significant (P ≤ 0.001 in 12 of 13 regressions) and consistent across growing seasons, but not significant for similar regressions with earth loosestrife. In particular, the strong relationship between Carolina redroot and bristly dewberry visual groundcover observations and cranberry yield suggests a simple way for growers and crop scouts to reliably estimate yield loss. The relationship between polytrichum moss biomass and cranberry yield was also significant in both years, but not consistent between years. Weed competition also affected cranberry quality, in that Carolina redroot density was strongly related to the percentage of insect-damaged fruit and bristly dewberry growth reduced cranberry color development. On a practical level, this information can be used to educate growers, consultants, agrichemical registrants, and regulators about the impacts of weeds on cranberry yield and quality, and to economically prioritize management efforts based on the weed species and extent of infestation.
Efficacy of halosulfuron-methyl in the management of Navua sedge (Cyperus aromaticus): differential responses of plants with and without established rhizomes
Authors: Chadha Aakansha , Florentine Singarayer K. , Dhileepan Kunjithapatham , Turville Christopher , Dowling Kim
Published: April 2022

Navua sedge is a creeping perennial sedge commonly found in tropical environments and is currently threatening many agroecosystems and ecosystems in Pacific Island countries and northern Queensland, Australia. Pasture and crop productions have been significantly impacted by this weed. The efficacy of halosulfuron-methyl on Navua sedge plants with and without well-established rhizomes was evaluated under glasshouse conditions. Halosulfuron-methyl was applied to plants with established rhizomes at three stages; mowed, pre-flowering, and flowering growth stages, whereas plants without established rhizomes were treated at seedling, pre-flowering and flowering growth stages. At each application time, halosulfuron-methyl was applied at four dose rates of 0, 38, 75, and 150 g ai ha−1. Mortality of 27.5%, 0%, and 5% was recorded in rhizomatous Navua sedge when treated with 75 g ai ha−1 of halosulfuron-methyl at the mowed, pre-flowering stage and flowering stages, respectively. At 10 wk after treatment (WAT), there were no tillers in surviving plants treated at any of the application times. By 16 WAT, the number of tillers increased to 15, 24, and 26 in mowed, pre-flowering, and flowering stages, respectively. Although halosulfuron-methyl is effective in controlling aboveground growth, subsequent emergence of new growth from the rhizome confirms the failure of the herbicide to kill the rhizome. Application of 75 g ai ha−1 of halosulfuron-methyl provided 100% mortality in plants treated at seedling and pre-flowering stages, and 98% mortality when treated at flowering stage in non-rhizomatous plants. A single application of halosulfuron-methyl is highly effective at controlling Navua sedge seedlings but not effective at controlling plants with established rhizomes.
Kohortentrends in schulfachbezogenen Selbstkonzepten und Interessen bei Mädchen und Jungen
Authors: Schneider Rebecca , Gentrup Sarah , Jansen Malte , Stanat Petra
Published: April 2022

Zusammenfassung. Schulfachbezogene Selbstkonzepte und Interessen gehören zu den wichtigsten motivationalen Konstrukten in der Pädagogischen Psychologie und zeigen typischerweise stereotype Geschlechtsunterschiede: Während Jungen in Mathematik und den Naturwissenschaften im Mittel ein höheres Selbstkonzept und Interesse aufweisen, berichten Mädchen höhere Werte in sprachlichen Fächern. Erste empirische Ergebnisse von wiederholt durchgeführten Studien des Bildungsmonitorings weisen auf einen leichten Rückgang im Selbstkonzept und Interesse in Deutschland über den Verlauf der untersuchten Kohorten hin. Jüngste Befunde zeigen diesen Rückgang insbesondere für Jungen im MINT-Bereich. Trotz substantieller Zusammenhänge zwischen motivationalen Merkmalen und schulischen Leistungen wurde bisher nicht untersucht, inwiefern diese Motivationsrückgänge auf Veränderungen in schulischen Leistungen zurückgeführt werden können. Der vorliegende Beitrag untersucht deshalb, (a) ob die Kohortentrends in den fachbezogenen Selbstkonzepten und Interessen für Jungen und Mädchen je nach Fach unterschiedlich ausfallen und insbesondere, (b) ob sich etwaige (geschlechtsspezifische) Trends in der fachbezogenen Motivation auf Unterschiede in Testleistungen und Noten zwischen den Erhebungszeitpunkten zurückführen lassen. Auf Basis der IQB-Bildungstrendstudien wurden Daten von je etwa 25000 Neuntklässlerinnen und Neuntklässlern in den Jahren 2012 und 2018 (Fächer Mathematik, Physik, Chemie und Biologie) bzw. von je etwa 35000 Neuntklässlerinnen und Neuntklässlern in den Jahren 2009 und 2015 (Fach Deutsch) ausgewertet. Während sich für Mädchen in Mathematik und den naturwissenschaftlichen Fächern keine oder geringfügig positive Veränderungen zwischen den Kohorten zeigten (–0.05 >≤ d >≤ 0.07), fanden sich für Jungen zumeist (leichte) Rückgänge in den Selbstkonzepten und Interessen (–0.31 >≤ d >≤ –0.08). Insbesondere die Veränderung im Mathematikinteresse bei Jungen war bedeutsam ( d = –0.31). Im Fach Deutsch zeigte sich ein gegensätzliches Bild: Bei beiden Geschlechtern stiegen die Selbstkonzeptwerte im Kohortentrend geringfügig an (Mädchen/Jungen: d = 0.07/0.06). Diese geschlechtsspezifischen Trends in der Motivation ließen sich nicht bedeutsam auf Testleistungs- und Notenunterschiede zwischen den Kohorten zurückführen. Die Ergebnisse werden im Hinblick auf verschiedene Erklärungsansätze für (geschlechtsspezifische) Kohortentrends in schulischer Motivation diskutiert.
Comparison of Nitrate Isotopes Between the South China Sea and Western North Pacific Ocean: Insights Into Biogeochemical Signals and Water Exchange
Authors: Yang Jin‐Yu Terence , Tang Jin‐Ming , Kang Sijing , Dai Minhan , Kao Shuh‐Ji , Yan Xiuli , Xu Min Nina , Du Chuanjun
Published: April 2022

Reconstructing past changes in the oceanic nitrate inventory with sedimentary N records in the South China Sea (SCS), which is the terminal of North Pacific Intermediate Water (NPIW), has regional and global implications. However, water‐column nitrate cycling that affects N isotope preservation remains poorly understood in the SCS. We present a new data set of nitrate isotopes ( and ) to elucidate nitrate dynamics in the SCS and the adjoining western North Pacific Ocean (wNPO). Greater increases in than in are observed in the SCS euphotic zone, suggesting a combined effect of partial nitrate assimilation and nitrification. In the subsurface and thermocline waters of both regions, upward disproportional decreases in and accompanied by elevated nitrate anomalies (N*) indicate an accumulation of external N. Such changes are less significant in the SCS due to higher nitrate concentrations therein, although external N influxes are comparable in both regions. High and values in the wNPO intermediate water result from the lateral transport of NPIW with isotopically more enriched nitrate from the remote denitrification zones followed by mixing with overlying water containing isotopically depleted nitrate. As NPIW flows into the SCS, its isotopically enriched signal is further diluted by strong vertical mixing with overlying and underlying waters in the interior. Compared to its source water from the wNPO, the SCS deep water has consistent nitrate isotopic compositions but significantly lower N*, indicating increased benthic denitrification at the wNPO margins with an estimated rate of 0.26–0.41 mmol N m−2 day−1.
Parameterization of Stochastically Entraining Convection Using Machine Learning Technique
Authors: Shin Jihoon , Baik Jong‐Jin
Published: April 2022

A stochastic mixing model with a machine learning technique is proposed for mass flux convection schemes. The model consists of the stochastic differential equations (SDEs) for the fractional entrainment rate, fractional detrainment rate, fractional dilution rate, and vertical acceleration. Unknowns in SDEs are parameterized using a deep neural network with the inputs of cloud and environment properties. The deep neural network is found to predict entrainment and detrainment rates better than previously proposed parameterizations. The new mixing model is implemented in a unified convection scheme (UNICON) and tested in a single‐column mode for two marine shallow convection cases. It is shown that the simulations with the new mixing model produce realistic mean and variance of various convective updraft properties and that the appropriate amount of stochasticity is generated. Consistently accurate simulations of updraft mass fluxes and moist conserved variables reduce model errors in the original UNICON. Additional sensitivity simulations enabling or disabling the stochasticity in mixing and initialization suggest that most of the cloud variabilities are generated from the mixing process.
Comparison of Seven Weibull Distribution Models for Predicting Relative Hydraulic Conductivity
Authors: Shan Jipeng , Yang Zhenlei , Kuang Xingxing , Li Ling , Liu Junguo
Published: April 2022

Modeling water flow in unsaturated soils requires accurate characterization of relative hydraulic conductivity (RHC) and water retention curve (WRC). The overall objective of this study is to investigate the performances of seven Weibull distribution models for predicting RHC using the Assouline et al. (1998), https://doi.org/10.1029/97WR03039 WRC. Specifically, a new RHC model was proposed via the approach of Assouline (2001), https://doi.org/10.1029/2000WR900254 with the assumptions of Burdine (1953), https://doi.org/10.2118/225-G and Kosugi (1999), https://doi.org/10.2136/sssaj1999.03615995006300020003x. The proposed model, together with the other six models, was then compared with data from 40 soils to explore their predictive performances for RHC. The results showed that the proposed model provides the best agreement with measured data and yields a 16.1% improvement in RHC prediction compared to the widely used Assouline et al. (1998), https://doi.org/10.1029/97WR03039‐Mualem (1976), https://doi.org/10.1029/WR012i003p00513 model. The proposed model can be used as RHC parameterization for water flow modeling in the unsaturated zone.
Experimental Support for a Simplified Approach to CTRW Transport Models and Exploration of Parameter Interpretation
Authors: Hansen Scott K.
Published: April 2022

We empirically test our earlier theoretical arguments about simplification of continuous‐time random walk (CTRW) solute transport models, namely that without loss of generality the velocity‐like term, vψ, may be set to mean groundwater velocity, the dispersion‐like term, Dψ, defined by a classical, velocity‐independent dispersivity, and the so‐called time constant, τ, to unity. We also argue that for small‐scale heterogeneous advection (HA) and mobile‐immobile mass transfer (MIMT) CTRW transition time distributions, ψ(t), are unaffected by mean flow velocity. To experimentally test these claims, we re‐analyze two bench‐scale transport experiments—one for HA, one for MIMT—each performed at multiple flow rates in otherwise identical conditions, and show it is possible to simultaneously explain all breakthrough curves in each, subject to the above constraints. We compare our calibrations with earlier efforts for the same data sets. In the HA calibration we identify a ψ(t) of the same functional form as previous authors, and which yielded breakthrough predictions essentially identical to theirs, but with greatly differing parameters. This illustrates how values of individual CTRW parameters may not map one‐to‐one onto underlying physics. We recommend reporting complete model descriptions, discuss how the simplified approach assists in this and other theoretical considerations.
Improved Understanding of How Catchment Properties Control Hydrological Partitioning Through Machine Learning
Authors: Cheng Shujie , Cheng Lei , Qin Shujing , Zhang Lu , Liu Pan , Liu Liu , Xu Zhicheng , Wang Qilin
Published: April 2022

Long‐term hydrological partitioning of catchments can be well described by the Budyko framework with a parameter (e.g., Fu's equations with parameter ω). The Budyko framework considers aridity index as the dominant control on hydrological partitioning, while the parameter represents integrated influences of catchment properties. Our understanding regarding the controls of catchment properties on the parameter is still limited. In this study, two machine learning methods, that is, boosted regression tree (BRT) and CUBIST, were used to model ω. Interpretable machine learning methods were adopted for better physical understanding including feature importance, accumulated local effects (ALE), and local interpretable model‐agnostic explanations. Among the 15 properties of 443 Australian catchments, analysis of feature importance showed that root zone storage capacity (SR), vapor pressure, vegetation coverage (M), precipitation depth, climate seasonality and asynchrony index (SAI), and water use efficiency (WUE) were the six primary control factors on ω. ALE showed that ω varied nonlinearly with all factors, and varied non‐monotonically with M, SAI, and WUE. LIME showed that the importance of the six dominant factors on ω varied between regions. CUBIST was further used to build regionally varying relationships between ω and the primary factors. Continental scale ω and evapotranspiration were further mapped across Australia based on the most robust BRT‐trained parameterization scheme with a resolution of 0.05°. Instead of using the machine learning method as a black box, we employed interpretability approaches to identify the controls. Our findings not only improved the capability of the Budyko method for hydrological partitioning across Australia, but also demonstrated that the controls of catchment properties on hydrological partitioning vary in different regions.
Glaciers of the Olympic Mountains, Washington—The Past and Future 100 Years
Authors: Fountain Andrew G. , Gray Christina , Glenn Bryce , Menounos Brian , Pflug Justin , Riedel Jon L.
Published: April 2022

In 2015, the Olympic Mountains contained 255 glaciers and perennial snowfields totaling 25.34 ± 0.27 km2, half of the area in 1900, and about 0.75 ± 0.19 km3 of ice. Since 1980, glaciers shrank at a rate of −0.59 km2 yr−1 during which time 35 glaciers and 16 perennial snowfields disappeared. Area changes of Blue Glacier, the largest glacier in the study region, was a good proxy for glacier change of the entire region. Modeled glacier mass balance, based on monthly air temperature and precipitation, correlates with glacier area change. The mass balance is highly sensitive to changes in air temperature rather than precipitation, typical of maritime glaciers. In addition to increasing summer melt, warmer winter temperatures changed the phase of precipitation from snow to rain, reducing snow accumulation. Changes in glacier mass balance are highly correlated with the Pacific North American index, a proxy for atmospheric circulation patterns and controls air temperatures along the Pacific Coast of North America. Regime shifts of sea surface temperatures in the North Pacific, reflected in the Pacific Decadal Oscillation (PDO), trigger shifts in the trend of glacier mass balance. Negative (“cool”) phases of the PDO are associated with glacier stability or slight mass gain whereas positive (“warm”) phases are associated with mass loss and glacier retreat. Over the past century the overall retreat is due to warming air temperatures, +0.7°C in winter and +0.3°C in summer. The glaciers in the Olympic Mountains are expected to largely disappear by 2070.
Grem1 accelerates nucleus pulposus cell apoptosis and intervertebral disc degeneration by inhibiting TGF-β-mediated Smad2/3 phosphorylation
Authors: Chen Shunlun , Lei Linchuan , Li Zemin , Chen Fan , Huang Yuming , Jiang Guowei , Guo Xingyu , Zhao Zhuoyang , Liu Hui , Wang Hua , Liu Caijun , Zheng Zhaomin , Wang Jianru
Published: April 2022

Intervertebral disc degeneration (IVDD) is a main cause of low back pain, and inflammatory factors play key roles in its pathogenesis. Gremlin-1 (Grem1) was reported to induce an inflammatory response in other fields. This study aimed to investigate the mechanisms of Grem1 in the degenerative process of intervertebral discs. Dysregulated genes were determined by analyzing microarray profiles. The expression of Grem1 in 17 human disc samples (male:female = 9:8) and rat models (n = 5 each group) was measured by western blotting (WB), real-time quantitative PCR (RT-qPCR), and immunohistochemistry (IHC). The regulatory effects of Grem1 on apoptosis were examined using siRNAs, flow cytometry, immunofluorescence (IF), and WB. The therapeutic effect was evaluated by locally injecting specific Grem1 siRNA into IVDD rats. The expression of Grem1 was significantly increased in human degenerative intervertebral discs; furthermore, the expression of Grem1 positively correlated with the level of intervertebral disc degeneration. Grem1 was significantly overexpressed in tumor necrosis factor (TNF)-α-induced degenerative NP cells. Apoptosis in degenerative NP cells transfected with siRNA targeting Grem1 was significantly lower than that in the control group. Specific Grem1 siRNA markedly repressed the development of IVDD in surgery-induced IVDD rats. These results indicated that the expression of Grem1 was positively correlated with the severity of intervertebral disc degeneration, and Grem1 siRNA could inhibit Grem1-induced apoptosis and extracellular matrix alterations by mediating the TGF-β/Smad signaling pathway. This study may provide a therapeutic strategy for alleviating inflammation-induced apoptosis associated with intervertebral disc degeneration.
Lanthanide doped lead-free double perovskites as the promising next generation ultra-broadband light sources
Authors: Zhang Li , Yuan Mingjian
Published: April 2022

Efficient ultra-broadband emitter is realized by using lanthanide ion doping coupled with “DPs-in-glass composite” (DiG) structure. The synergy of self-trapped exciton together with the energy transition induce this ultra-broadband emission emerge.
Towards a modular and scalable holographic display
Authors: Blanche Pierre-Alexandre
Published: April 2022

Holographic three-dimensional (3D) display can be made very large using a modular system that allows seamless spatial tiling of multiple coarse integral holographic images.
Body mass index associated with monoclonal gammopathy of undetermined significance (MGUS) progression in Olmsted County, Minnesota
Authors: Kleinstern Geffen , Larson Dirk R. , Allmer Cristine , Norman Aaron D. , Muntifering Grace , Sinnwell Jason , Visram Alissa , Rajkumar Vincent , Dispenzieri Angela , Kyle Robert A. , Slager Susan L. , Kumar Shaji , Vachon Celine M.
Published: April 2022

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder that progresses to multiple myeloma (MM), or other plasma-cell or lymphoid disorders at a rate of 1%/year. We evaluate the contribution of body mass index (BMI) to MGUS progression beyond established clinical factors in a population-based study. We identified 594 MGUS through a population-based screening study in Olmsted County, Minnesota, between 1995 and 2003. Follow-up time was calculated from the date of MGUS to last follow-up, death, or progression to MM/another plasma-cell/lymphoid disorder. BMI (kg/m2 < 25/≥25) was measured close to screening date. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of BMI ≥ 25 versus BMI < 25 with MGUS progression and also evaluated the corresponding c-statistic and 95% CI to describe discrimination of the model for MGUS progression. Median follow-up was 10.5 years (range:0–25), while 465 patients died and 57 progressed and developed MM (N = 39), AL amyloidosis (N = 8), lymphoma (N = 5), or Waldenstrom-macroglobulinemia (N = 5). In univariate analyses, BMI ≥ 25 (HR = 2.14,CI:1.05–4.36, P = 0.04), non-IgG (HR = 2.84, CI:1.68–4.80, P = 0.0001), high monoclonal (M) protein (HR = 2.57, CI:1.50–4.42, P = 0.001), and abnormal free light chain ratio (FLCr) (HR = 3.39, CI:1.98–5.82, P < 0.0001) were associated with increased risk of MGUS progression, and were independently associated in a multivariable model (c-statistic = 0.75, CI:0.68–0.82). The BMI association was stronger among females (HR = 3.55, CI:1.06–11.9, P = 0.04) vs. males (HR = 1.39, CI:0.57–3.36, P = 0.47), although the interaction between BMI and sex was not significant (P = 0.15). In conclusion, high BMI is a prognostic factor for MGUS progression, independent of isotype, M protein, and FLCr. This association may be stronger among females.
Flubendazole induces mitochondrial dysfunction and DRP1-mediated mitophagy by targeting EVA1A in breast cancer
Authors: Zhen Yongqi , Yuan Zhaoxin , Zhang Jiahui , Chen Yao , Fu Yuning , Liu Yi , Fu Leilei , Zhang Lan , Zhou Xian-Li
Published: April 2022

Breast cancer is still one of the most common malignancies worldwide and remains a major clinical challenge. We previously reported that the anthelmintic drug flubendazole induced autophagy and apoptosis via upregulation of eva-1 homolog A (EVA1A) in triple-negative breast cancer (TNBC) and was repurposed as a novel anti-tumor agent. However, the detailed underlying mechanisms remain unclear and need further investigation. Here, we found that flubendazole impairs the permeability of the mitochondrial outer membrane and mitochondrial function in breast cancer. Meanwhile, flubendazole increased dynamin-related protein (DRP1) expression, leading to the accumulation of PTEN induced putative kinase 1 (PINK1) and subsequent mitochondrial translocation of Parkin, thereby promoting excessive mitophagy. The resultant excessive mitophagy contributed to mitochondrial damage and dysfunction induced by flubendazole, thus inhibiting breast cancer cells proliferation and migration. Moreover, we demonstrated that excessive DRP1-mediated mitophagy played a critical role in response to the anti-tumor effects of EVA1A in breast cancer. Taken together, our results provide new insights into the molecular mechanisms in relation to the anti-tumor activities of flubendazole, and may be conducive to its rational use in potential clinical applications.
NOX activation in reactive astrocytes regulates astrocytic LCN2 expression and neurodegeneration
Authors: Liu Ruijia , Wang Jun , Chen Yang , Collier Jenelle M. , Capuk Okan , Jin Shijie , Sun Ming , Mondal Sujan K. , Whiteside Theresa L. , Stolz Donna B. , Yang Yongjie , Begum Gulnaz
Published: April 2022

Reactive astrocytes (RA) secrete lipocalin-2 (LCN2) glycoprotein that regulates diverse cellular processes including cell death/survival, inflammation, iron delivery and cell differentiation. Elevated levels of LCN2 are considered as a biomarker of brain injury, however, the underlying regulatory mechanisms of its expression and release are not well understood. In this study, we investigated the role of astrocytic Na+/H+ exchanger 1 (NHE1) in regulating reactive astrocyte LCN2 secretion and neurodegeneration after stroke. Astrocyte specific deletion of Nhe1 in Gfap-CreER+/−;Nhe1f/f mice reduced astrogliosis and astrocytic LCN2 and GFAP expression, which was associated with reduced loss of NeuN+ and GRP78+ neurons in stroke brains. In vitro ischemia in astrocyte cultures triggered a significant increase of secreted LCN2 in astrocytic exosomes, which caused neuronal cell death and neurodegeneration. Inhibition of NHE1 activity during in vitro ischemia with its potent inhibitor HOE642 significantly reduced astrocytic LCN2+ exosome secretion. In elucidating the cellular mechanisms, we found that stroke triggered activation of NADPH oxidase (NOX)-NF-κB signaling and ROS-mediated LCN2 expression. Inhibition of astrocytic NHE1 activity attenuated NOX signaling and LCN2-mediated neuronal apoptosis and neurite degeneration. Our findings demonstrate for the first time that RA use NOX signaling to stimulate LCN2 expression and secretion. Blocking astrocytic NHE1 activity is beneficial to reduce LCN2-mediated neurotoxicity after stroke.
ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation
Authors: Li Zheqi , McGinn Olivia , Wu Yang , Bahreini Amir , Priedigkeit Nolan M. , Ding Kai , Onkar Sayali , Lampenfeld Caleb , Sartorius Carol A. , Miller Lori , Rosenzweig Margaret , Cohen Ofir , Wagle Nikhil , Richer Jennifer K. , Muller William J. , Buluwela Laki , Ali Simak , Bruno Tullia C. , Vignali Dario A. A. , Fang Yusi , Zhu Li , Tseng George C. , Gertz Jason , Atkinson Jennifer M. , Lee Adrian V. , Oesterreich Steffi
Published: April 2022

Estrogen receptor alpha (ER/ESR1) is frequently mutated in endocrine resistant ER-positive (ER+) breast cancer and linked to ligand-independent growth and metastasis. Despite the distinct clinical features of ESR1 mutations, their role in intrinsic subtype switching remains largely unknown. Here we find that ESR1 mutant cells and clinical samples show a significant enrichment of basal subtype markers, and six basal cytokeratins (BCKs) are the most enriched genes. Induction of BCKs is independent of ER binding and instead associated with chromatin reprogramming centered around a progesterone receptor-orchestrated insulated neighborhood. BCK-high ER+ primary breast tumors exhibit a number of enriched immune pathways, shared with ESR1 mutant tumors. S100A8 and S100A9 are among the most induced immune mediators and involve in tumor-stroma paracrine crosstalk inferred by single-cell RNA-seq from metastatic tumors. Collectively, these observations demonstrate that ESR1 mutant tumors gain basal features associated with increased immune activation, encouraging additional studies of immune therapeutic vulnerabilities.
Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models
Authors: Lissa Delphine , Takahashi Nobuyuki , Desai Parth , Manukyan Irena , Schultz Christopher W. , Rajapakse Vinodh , Velez Moises J. , Mulford Deborah , Roper Nitin , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Chen Yuanbin , Guha Udayan , Rajan Arun , Atkinson Devon , El Meskini Rajaa , Weaver Ohler Zoe , Thomas Anish
Published: April 2022

Molecular subtypes of small cell lung cancer (SCLC) defined by the expression of key transcription regulators have recently been proposed in cell lines and limited number of primary tumors. The clinical and biological implications of neuroendocrine (NE) subtypes in metastatic SCLC, and the extent to which they vary within and between patient tumors and in patient-derived models is not known. We integrate histology, transcriptome, exome, and treatment outcomes of SCLC from a range of metastatic sites, revealing complex intra- and intertumoral heterogeneity of NE differentiation. Transcriptomic analysis confirms previously described subtypes based on ASCL1, NEUROD1, POU2F3, YAP1, and ATOH1 expression, and reveal a clinical subtype with hybrid NE and non-NE phenotypes, marked by chemotherapy-resistance and exceedingly poor outcomes. NE tumors are more likely to have RB1, NOTCH, and chromatin modifier gene mutations, upregulation of DNA damage response genes, and are more likely to respond to replication stress targeted therapies. In contrast, patients preferentially benefited from immunotherapy if their tumors were non-NE. Transcriptional phenotypes strongly skew towards the NE state in patient-derived model systems, an observation that was confirmed in paired patient-matched tumors and xenografts. We provide a framework that unifies transcriptomic and genomic dimensions of metastatic SCLC. The marked differences in transcriptional diversity between patient tumors and model systems are likely to have implications in development of novel therapeutic agents.
CO2 signaling mediates neurovascular coupling in the cerebral cortex
Authors: Hosford Patrick S. , Wells Jack A. , Nizari Shereen , Christie Isabel N. , Theparambil Shefeeq M. , Castro Pablo A. , Hadjihambi Anna , Barros L. Felipe , Ruminot Iván , Lythgoe Mark F. , Gourine Alexander V.
Published: April 2022

Neurovascular coupling is a fundamental brain mechanism that regulates local cerebral blood flow (CBF) in response to changes in neuronal activity. Functional imaging techniques are commonly used to record these changes in CBF as a proxy of neuronal activity to study the human brain. However, the mechanisms of neurovascular coupling remain incompletely understood. Here we show in experimental animal models (laboratory rats and mice) that the neuronal activity-dependent increases in local CBF in the somatosensory cortex are prevented by saturation of the CO2-sensitive vasodilatory brain mechanism with surplus of exogenous CO2 or disruption of brain CO2/HCO3− transport by genetic knockdown of electrogenic sodium-bicarbonate cotransporter 1 (NBCe1) expression in astrocytes. A systematic review of the literature data shows that CO2 and increased neuronal activity recruit the same vasodilatory signaling pathways. These results and analysis suggest that CO2 mediates signaling between neurons and the cerebral vasculature to regulate brain blood flow in accord with changes in the neuronal activity.
Bird populations most exposed to climate change are less sensitive to climatic variation
Authors: Bailey Liam D. , van de Pol Martijn , Adriaensen Frank , Arct Aneta , Barba Emilio , Bellamy Paul E. , Bonamour Suzanne , Bouvier Jean-Charles , Burgess Malcolm D. , Charmantier Anne , Cusimano Camillo , Doligez Blandine , Drobniak Szymon M. , Dubiec Anna , Eens Marcel , Eeva Tapio , Ferns Peter N. , Goodenough Anne E. , Hartley Ian R. , Hinsley Shelley A. , Ivankina Elena , Juškaitis Rimvydas , Kempenaers Bart , Kerimov Anvar B. , Lavigne Claire , Leivits Agu , Mainwaring Mark C. , Matthysen Erik , Nilsson Jan-Åke , Orell Markku , Rytkönen Seppo , Senar Juan Carlos , Sheldon Ben C. , Sorace Alberto , Stenning Martyn J. , Török János , van Oers Kees , Vatka Emma , Vriend Stefan J. G. , Visser Marcel E.
Published: April 2022

The phenology of many species shows strong sensitivity to climate change; however, with few large scale intra-specific studies it is unclear how such sensitivity varies over a species’ range. We document large intra-specific variation in phenological sensitivity to temperature using laying date information from 67 populations of two co-familial European songbirds, the great tit (Parus major) and blue tit (Cyanistes caeruleus), covering a large part of their breeding range. Populations inhabiting deciduous habitats showed stronger phenological sensitivity than those in evergreen and mixed habitats. However, populations with higher sensitivity tended to have experienced less rapid change in climate over the past decades, such that populations with high phenological sensitivity will not necessarily exhibit the strongest phenological advancement. Our results show that to effectively assess the impact of climate change on phenology across a species’ range it will be necessary to account for intra-specific variation in phenological sensitivity, climate change exposure, and the ecological characteristics of a population.
Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors
Authors: Savill Kristin M. Zimmerman , Lee Brian B. , Oeh Jason , Lin Jie , Lin Eva , Chung Wei-Jen , Young Amy , Chen Wennie , Miś Monika , Mesh Kathryn , Eastham Jeffrey , Gnad Florian , Jiang Zhaoshi , Stawiski Eric W. , Haley Benjamin , Daemen Anneleen , Wang Xiaojing , Koeppen Hartmut , Modrusan Zora , Martin Scott E. , Sampath Deepak , Lin Kui
Published: April 2022

The AKT kinases have emerged as promising therapeutic targets in oncology and both allosteric and ATP-competitive AKT inhibitors have entered clinical investigation. However, long-term efficacy of such inhibitors will likely be challenged by the development of resistance. We have established prostate cancer models of acquired resistance to the allosteric inhibitor MK-2206 or the ATP-competitive inhibitor ipatasertib following prolonged exposure. While alterations in AKT are associated with acquired resistance to MK-2206, ipatasertib resistance is driven by rewired compensatory activity of parallel signaling pathways. Importantly, MK-2206 resistance can be overcome by treatment with ipatasertib, while ipatasertib resistance can be reversed by co-treatment with inhibitors of pathways including PIM signaling. These findings demonstrate that distinct resistance mechanisms arise to the two classes of AKT inhibitors and that combination approaches may reverse resistance to ATP-competitive inhibition.
Widespread and increased drilling of wells into fossil aquifers in the USA
Authors: GebreEgziabher Merhawi , Jasechko Scott , Perrone Debra
Published: April 2022

Most stored groundwater is ‘fossil’ in its age, having been under the ground for more than ~12 thousand years. Mapping where wells tap fossil aquifers is relevant for water quality and quantity management. Nevertheless, the prevalence of wells that tap fossil aquifers is not known. Here we show that wells that are sufficiently deep to tap fossil aquifers are widespread, though they remain outnumbered by shallower wells in most areas. Moreover, the proportion of newly drilled wells that are deep enough to tap fossil aquifers has increased over recent decades. However, this widespread and increased drilling of wells into fossil aquifers is not necessarily associated with groundwater depletion, emphasizing that the presence of fossil groundwater does not necessarily indicate a non-renewable water supply. Our results highlight the importance of safeguarding fossil groundwater quality and quantity to meet present and future water demands.
An anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA
Authors: Zhao Jianyuan , Wang Jing , Pang Xu , Liu Zhenlong , Li Quanjie , Yi Dongrong , Zhang Yongxin , Fang Xiaomei , Zhang Tao , Zhou Rui , Zhang Tao , Guo Zhe , Liu Wancang , Li Xiaoyu , Liang Chen , Deng Tao , Guo Fei , Yu Liyan , Cen Shan
Published: April 2022

The emergence of new highly pathogenic and drug-resistant influenza strains urges the development of novel therapeutics for influenza A virus (IAV). Here, we report the discovery of an anti-IAV microbial metabolite called APL-16-5 that was originally isolated from the plant endophytic fungus Aspergillus sp. CPCC 400735. APL-16-5 binds to both the E3 ligase TRIM25 and IAV polymerase subunit PA, leading to TRIM25 ubiquitination of PA and subsequent degradation of PA in the proteasome. This mode of action conforms to that of a proteolysis targeting chimera which employs the cellular ubiquitin-proteasome machinery to chemically induce the degradation of target proteins. Importantly, APL-16-5 potently inhibits IAV and protects mice from lethal IAV infection. Therefore, we have identified a natural microbial metabolite with potent in vivo anti-IAV activity and the potential of becoming a new IAV therapeutic. The antiviral mechanism of APL-16-5 opens the possibility of improving its anti-IAV potency and specificity by adjusting its affinity for TRIM25 and viral PA protein through medicinal chemistry.
Connecting high-resolution 3D chromatin organization with epigenomics
Authors: Feng Fan , Yao Yuan , Wang Xue Qing David , Zhang Xiaotian , Liu Jie
Published: April 2022

The resolution of chromatin conformation capture technologies keeps increasing, and the recent nucleosome resolution chromatin contact maps allow us to explore how fine-scale 3D chromatin organization is related to epigenomic states in human cells. Using publicly available Micro-C datasets, we develop a deep learning model, CAESAR, to learn a mapping function from epigenomic features to 3D chromatin organization. The model accurately predicts fine-scale structures, such as short-range chromatin loops and stripes, that Hi-C fails to detect. With existing epigenomic datasets from ENCODE and Roadmap Epigenomics Project, we successfully impute high-resolution 3D chromatin contact maps for 91 human tissues and cell lines. In the imputed high-resolution contact maps, we identify the spatial interactions between genes and their experimentally validated regulatory elements, demonstrating CAESAR’s potential in coupling transcriptional regulation with 3D chromatin organization at high resolution.
Methane emissions from US low production oil and natural gas well sites
Authors: Omara Mark , Zavala-Araiza Daniel , Lyon David R. , Hmiel Benjamin , Roberts Katherine A. , Hamburg Steven P.
Published: April 2022

Eighty percent of US oil and natural gas (O&G) production sites are low production well sites, with average site-level production ≤15 barrels of oil equivalent per day and producing only 6% of the nation’s O&G output in 2019. Here, we integrate national site-level O&G production data and previously reported site-level CH4measurement data (n = 240) and find that low production well sites are a disproportionately large source of US O&G well site CH4emissions, emitting more than 4 (95% confidence interval: 3—6) teragrams, 50% more than the total CH4emissions from the Permian Basin, one of the world’s largest O&G producing regions. We estimate low production well sites represent roughly half (37—75%) of all O&G well site CH4emissions, and a production-normalized CH4loss rate of more than 10%—a factor of 6—12 times higher than the mean CH4loss rate of 1.5% for all O&G well sites in the US. Our work suggests that achieving significant reductions in O&G CH4emissions will require mitigation of emissions from low production well sites.
Memristor-based analogue computing for brain-inspired sound localization with in situ training
Authors: Gao Bin , Zhou Ying , Zhang Qingtian , Zhang Shuanglin , Yao Peng , Xi Yue , Liu Qi , Zhao Meiran , Zhang Wenqiang , Liu Zhengwu , Li Xinyi , Tang Jianshi , Qian He , Wu Huaqiang
Published: April 2022

The human nervous system senses the physical world in an analogue but efficient way. As a crucial ability of the human brain, sound localization is a representative analogue computing task and often employed in virtual auditory systems. Different from well-demonstrated classification applications, all output neurons in localization tasks contribute to the predicted direction, introducing much higher challenges for hardware demonstration with memristor arrays. In this work, with the proposed multi-threshold-update scheme, we experimentally demonstrate the in-situ learning ability of the sound localization function in a 1K analogue memristor array. The experimental and evaluation results reveal that the scheme improves the training accuracy by ∼45.7% compared to the existing method and reduces the energy consumption by ∼184× relative to the previous work. This work represents a significant advance towards memristor-based auditory localization system with low energy consumption and high performance.