bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of chronic fluoxetine treatment on anxiety- and depressive-like behaviors in adolescent rodents – systematic review and meta-analysis
Authors: Kryst Joanna , Majcher-Maślanka Iwona , Chocyk Agnieszka
Published: September 2022

Background

Drugs prescribed for psychiatric disorders in adolescence should be studied very extensively since they can affect developing and thus highly plastic brain differently than they affect the adult brain. Therefore, we aimed to summarize animal studies reporting the behavioral consequences of chronic exposure to the most widely prescribed antidepressant drug among adolescents i.e., fluoxetine.

Methods

Electronic databases (Medline via Pubmed, Web of Science Core Collection, ScienceDirect) were systematically searched until April 12, 2022, for published, peer-reviewed, controlled trials concerning the effects of chronic fluoxetine administration vs. vehicle on anxiety and depression measures in naïve and stress-exposed adolescent rodents. All of the relevant studies were selected and critically appraised, and a meta-analysis of eligible studies was performed.

Results

A total of 18 studies were included in the meta-analysis. In naïve animals, chronic adolescent fluoxetine administration showed dose-related anxiogenic-like effects, measured as a reduction in time spent in the open arms of the elevated plus maze. No significant effects of chronic adolescent fluoxetine on depression-like behavior were reported in naïve animals, while in stress-exposed rodents chronic adolescent fluoxetine significantly decreased immobility time in the forced swim test compared to vehicle.

Conclusions

These results suggest that although chronic fluoxetine treatment proves positive effects in animal models of depression, it may simultaneously increase anxiety in adolescent animals in a dose-related manner. Although the clinical implications of the data should be interpreted with extreme caution, adolescent patients under fluoxetine treatment should be closely monitored.
Analyzing spatial variations of heart disease and type-2 diabetes: A multi-scale geographically weighted regression approach
Authors: Cui Wencong , Hu Nanzhou , Zhang Shuyang , Li Diya , Martinez Luis , Goldberg Daniel , Güneralp Burak , Zhang Zhe
Published: September 2022

Heart disease is the leading cause of death in the United States. A person who has type-2 diabetes is twice as likely to have heart disease than someone who doesn’t have diabetes. Therefore, analyzing factors associated with both diseases and their interrelationships is essential for cardiovascular disease control and public health. In this article, we propose a Multi-scale Geographically Weighted Regression (MGWR) approach to observe spatial variations of environmental and demographic risk factors such as alcohol consumption behavior, lack of physical activity, obesity rate, urbanization rate, and income from 2005 to 2015 in the United States. The MGWR model has applied to eight census divisions of the United States at the county level: New England, Middle Atlantic, East North Central, West North Central, South Atlantic, East South Central, West South Central, and Mountain. Results illustrate that there are notable differences in the spatial variation of the risk factors behind these two diseases. In particular, obesity has been a leading factor that associate with diabetes in the east, south-central, and south Atlantic regions of the U.S. On the other hand, smoking and alcohol consumption was the primary concern in the northern part of the U.S., in 2005. In 2015, alcohol consumption levels decreased, but the smoking level remained the same in those regions, which showed a significant impact on diabetes in the neighboring regions. Between 2005 and 2015, lack of physical exercise has become a significant risk factor associated with diabetes in the Northeast and West parts of the U.S. The proposed MGWR produced high goodness to fit (R2) for most of the areas in the United States.
Science for implementation: the roles, experiences, and perceptions of practitioners involved in the Intergovernmental Panel on Climate Change
Authors: North M. A. , Hunter N. B. , Roberts D. C. , Slotow R.
Published: September 2022

In the climate change arena, the assessments of the Intergovernmental Panel on Climate Change (IPCC), while not policy prescriptive, are important for informing international negotiations and the decisions of policy and practice communities. Since 2015, when the Paris Agreement was adopted, there has been an increasing demand for climate action and calls for the inclusion of a broader base of stakeholders in global assessments. We use publicly available information on IPCC authors, and the results of a survey (n = 29) and interviews (n = 17) with authors who apply science in practice (practitioners), to examine their roles, experiences, and challenges in the IPCC’s Fifth Assessment. The results show that while practitioners form only a very small proportion of authors, they contribute real-world experience, including the translation of academic language into meaningful messages for decision-makers. Although familiar with working at the interface of science and practice, study participants described barriers to their participation and shared several recommendations for improving the relevance, uptake, and timeliness of IPCC assessments, and practitioner participation. Our findings indicate that IPCC assessments provide an evidence base to support action on climate change, and due to their skill set, practitioners are often able to make contributions that allow for greater accessibility by decision-makers.

Graphical Abstract
A Survey on Methods for Predicting Polyadenylation Sites from DNA Sequences, Bulk RNA-Seq, and Single-Cell RNA-Seq
Authors: Ye Wenbin , Lian Qiwei , Ye Congting , Wu Xiaohui
Published: September 2022

Alternative polyadenylation (APA) plays important roles in modulating mRNA stability, translation, and subcellular localization, and contributes extensively to shaping eukaryotic transcriptome complexity and proteome diversity. Identification of poly(A) sites (pAs) on a genome-wide scale is a critical step toward understanding the underlying mechanism of APA-mediated gene regulation. A number of established computational tools have been proposed to predict pAs from diverse genomic data. Here we provided an exhaustive overview of computational approaches for predicting pAs from DNA sequences, bulk RNA sequencing (RNA-seq) data, and single-cell RNA sequencing (scRNA-seq) data. Particularly, we examined several representative tools using bulk RNA-seq and scRNA-seq data from peripheral blood mononuclear cells and put forward operable suggestions on how to assess the reliability of pAs predicted by different tools. We also proposed practical guidelines on choosing appropriate methods applicable to diverse scenarios. Moreover, we discussed in depth the challenges in improving the performance of pA prediction and benchmarking different methods. Additionally, we highlighted outstanding challenges and opportunities using new machine learning and integrative multi-omics techniques, and provided our perspective on how computational methodologies might evolve in the future for non-3′ untranslated region, tissue-specific, cross-species, and single-cell pA prediction.
Narrow, Fast, and “Cool” Mantle Plumes Caused by Strain‐Weakening Rheology in Earth's Lower Mantle
Authors: Gülcher A. J. P. , Golabek G. J. , Thielmann M. , Ballmer M. D. , Tackley P. J.
Published: September 2022

The rheological properties of Earth's lower mantle are key for mantle dynamics and planetary evolution. The main rock‐forming minerals in the lower mantle are bridgmanite (Br) and smaller amounts of ferropericlase (Fp). Previous work has suggested that the large differences in viscosity between these minerals greatly affect the bulk rock rheology. The resulting effective rheology becomes highly strain‐dependent as weaker Fp minerals become elongated and eventually interconnected. This implies that strain localization may occur in Earth's lower mantle. So far, there have been no studies on global‐scale mantle convection in the presence of such strain‐weakening (SW) rheology. Here, we present 2D numerical models of thermo‐chemical convection in spherical annulus geometry including a new strain‐dependent rheology formulation for lower mantle materials, combining rheological weakening and healing terms. We find that SW rheology has several direct and indirect effects on mantle convection. The most notable direct effect is the changing dynamics of weakened plume channels as well as the formation of larger thermochemical piles at the base of the mantle. The weakened plume conduits act as lubrication channels in the mantle and exhibit a lower thermal anomaly. SW rheology also reduces the overall viscosity, notable in terms of increasing convective vigor and core‐mantle boundary heat flux. Finally, we put our results into context with existing hypotheses on the style of mantle convection and mixing. Most importantly, we suggest that the new kind of plume dynamics may explain the discrepancy between expected and observed thermal anomalies of deep‐seated mantle plumes on Earth.
Explicit Physical Knowledge in Machine Learning for Ocean Carbon Flux Reconstruction: The pCO2‐Residual Method
Authors: Bennington Val , Galjanic Tomislav , McKinley Galen A.
Published: September 2022

The ocean reduces human impacts on global climate by absorbing and sequestering CO2 from the atmosphere. To quantify global, time‐resolved air‐sea CO2 fluxes, surface ocean pCO2 is needed. A common approach for estimating full‐coverage pCO2 is to train a machine learning algorithm on sparse in situ pCO2 data and associated physical and biogeochemical observations. Though these associated variables have understood relationships to pCO2, it is often unclear how they drive pCO2 outputs. Here, we make two advances that enhance connections between physical understanding and reconstructed pCO2. First, we apply pre‐processing to the pCO2 data to remove the direct effect of temperature. This enhances the biogeochemical/physical component of pCO2 in the target variable and reduces the complexity that the machine learning must disentangle. Second, we demonstrate that the resulting algorithm has physically understandable connections between input data and the output biogeochemical/physical component of pCO2. The final pCO2 reconstruction agrees modestly better with independent data than most other approaches. Uncertainties in the reconstructed pCO2 and impacts on the estimated CO2 fluxes are quantified. Uncertainty in piston velocity drives substantial flux uncertainties in some regions, but does not increase globally integrated estimates of uncertainty in CO2 fluxes from observation‐based products. Our reconstructed CO2 fluxes show larger interannual variability than smoother neural network approaches, but a lesser trend since 2005. We estimate an air‐sea flux of −1.8 PgC/yr (anthropogenic flux of −2.3 ± 0.5 PgC/yr) for 1990–2019, agreeing with other data products and the Global Carbon Budget 2020 (−2.3 ± 0.4 PgC/yr).
Source‐Labeled Anthropogenic Carbon Reveals a Large Shift of Preindustrial Carbon From the Ocean to the Atmosphere
Authors: Holzer Mark , DeVries Tim
Published: September 2022

Two centuries of anthropogenic CO2 emissions have increased the CO2 concentration of the atmosphere and the dissolved inorganic carbon (DIC) concentration of the ocean compared to preindustrial times. These anthropogenic carbon perturbations are often equated to the amount of anthropogenically emitted carbon in the atmosphere or ocean, which ignores the possibility of a shift of natural carbon between the oceanic and atmospheric carbon reservoirs. Here we use a data‐assimilated ocean circulation model and numerical tracers akin to ideal isotopes to label carbon when it is emitted by anthropogenic sources. We find that emitted carbon accounts for only about 45% of the atmospheric CO2 increase since preindustrial times, the remaining 55% being natural CO2 that outgassed from the ocean in response to anthropogenically emitted carbon invading the ocean. This outgassing is driven by the order‐10 seawater carbonate buffer factor which causes increased leakage of natural CO2 as DIC concentrations increase. By 2020, the ocean had outgassed ∼159 Pg of natural carbon, which is counteracted by the ocean absorbing ∼347 Pg of emitted carbon, about 1.8 times more than the net increase in oceanic carbon storage of ∼188 PgC. These results do not challenge existing estimates of anthropogenically driven changes in atmospheric or oceanic carbon inventories, but they shed new light on the composition of these changes and the fate of anthropogenically emitted carbon in the Earth system.
Causes for Asymmetric Warming of Sub‐Diurnal Temperature Responding to Global Warming
Authors: Doan Quang‐Van , Chen Fei , Asano Yuki , Gu Ying , Nishi Akifumi , Kusaka Hiroyuki , Niyogi Dev
Published: September 2022

Defined as the difference between the daily maximum (Tmax) and minimum surface air temperature (Tmin), the diurnal temperature range (DTR) is critical to local climate, ecosystem, and socio‐economic functioning. This study investigates how DTR responds to the future global warming, using a novel, fine‐resolution convection‐permitting regional climate model. Results demonstrate the asymmetrical impact of global warming, that is, the more substantial warming in Tmin, and the lower in Tmax. This asymmetry results in the DTR reduction of 0.5°K in the mid‐latitude and 0.25°K in the low‐altitude area (under 2°K warming scenario). The increase in daytime cloudiness under warmer climates is likely responsible for the reduction of incoming short‐wave radiation reduction, consequently causing Tmax “underwarming.” Study results also suggest that atmospheric instability could play a vital role in the difference in DTR response between the tropical and mid‐latitude areas.
A North Atlantic Warming Hole Without Ocean Circulation
Authors: He Chengfei , Clement Amy C. , Cane Mark A. , Murphy Lisa N. , Klavans Jeremy M. , Fenske Tyler M.
Published: September 2022

The sea surface temperature (SST) in the subpolar North Atlantic decreased during the past century, a remarkable feature known as the “warming hole (WH).” It is commonly claimed that the WH results from the slowdown of the Atlantic meridional overturning circulation. However, using an ensemble of the Community Earth System Model coupled to a slab ocean model simulation, we show the atmosphere alone can account for ∼50% of the observed cooling trend in the subpolar North Atlantic and ∼90% of the cooling relative to the temperature change of the global ocean. We find this cooling is caused by increased local westerlies in response to external forcing that enhance heat loss from the ocean through turbulent heat fluxes. This cooling is partly compensated by the damping in SST and the warming due to the rise of greenhouse gases. We further suggest that wind‐driven ocean processes can enhance the cooling in the real world, but that nonetheless the ultimate driver resides in the atmosphere.
A Realistic Projection of Climate Change in the Upper Atmosphere Into the 21st Century
Authors: Cnossen I.
Published: September 2022

Climate change in the upper atmosphere (∼90–500 km altitude) has important impacts on practical applications. To prepare for these, realistic projections of future climate change are needed. The first climate projection up to 500 km altitude is presented here based on a long transient simulation with the whole atmosphere community climate model extension, following Shared Socio‐economic Pathway 2–4.5, a moderate emission scenario. Effects of predicted main magnetic field changes and reasonable solar radiative and particle forcings are also included. The predicted global mean cooling in the thermosphere and associated decline in thermosphere density for 2015–2070 are significantly stronger than for the historical period, which is ascribed to the more rapid increase in CO2 concentration. Trends in global mean ionospheric parameters also increase in magnitude, but there are considerable spatial variations, caused by changes in the Earth's magnetic field. The largest ionospheric changes are expected in the region of ∼50°S–20°N and ∼90–0°W.
Phytoplankton Light Absorption Impacted by Photoprotective Carotenoids in a Global Ocean Spectrally‐Resolved Biogeochemistry Model
Authors: Álvarez Eva , Losa Svetlana N. , Bracher Astrid , Thoms Silke , Völker Christoph
Published: September 2022

The chlorophyll‐specific absorption spectrum of phytoplankton multiplied with phytoplankton chlorophyll provides the total absorption coefficient of phytoplankton [], a fundamental quantity with significance in many marine biogeochemical (BGC) and environmental processes. Representing accurately the sources of variability of in BGC ocean models is a crucial task. The two main sources of variability in are changes in the pigment composition of the phytoplankton community and the size‐dependent constraints to pigment packaging. Therefore, changes in community structure and physiological state impact and consequently . The objective of this work is to improve estimates of in a BGC model of the global ocean by portraying the variability of driven by the variable content in photoprotective carotenoids (PPCs) in the phytoplankton community. We used a three‐dimensional spectrally‐resolved BGC model to simulate the inherent and apparent optical properties of the global ocean based on its content on optically active constituents. The for each phytoplankton type represented in the model were made variable as a function of the type‐specific content in PPCs. By comparing model‐derived to satellite retrievals and an extensive field data set of optical and BGC observations, we concluded that photoprotective pigments content impacted significantly the contribution of the to the total non‐water absorption in the ocean. Pigment‐impacted contributed to reproduce the global variability of as well as the observed bio‐optical relationship between and chlorophyll. The improved representation of the of the phytoplankton community influenced model simulations in terms of water‐leaving radiances.
Evaluation and Optimization of Snow Albedo Scheme in Noah‐MP Land Surface Model Using In Situ Spectral Observations in the Colorado Rockies
Authors: Abolafia‐Rosenzweig Ronnie , He Cenlin , McKenzie Skiles S. , Chen Fei , Gochis David
Published: September 2022

The Biosphere‐Atmosphere Transfer Scheme (BATS) ground snow albedo algorithm is commonly used in land‐surface models (LSM), weather forecasting and research applications. This study addresses key uncertainties in BATS simulated ground snow albedo within the Noah‐MP LSM framework through evaluation and optimization of the Noah‐MP BATS ground snow albedo formulation using 2‐band (visible and near‐infrared (NIR)) in situ albedo observations at Rocky Mountain field stations. The Noah‐MP BATS ground snow albedo scheme is extremely sensitive to its input parameters. Namely, an ensemble generated by varying BATS input parameters within potentially plausible ranges provides an average daily range (maximum ensemble member minus minimum ensemble member) of ground snow albedo exceeding 0.45 in visible and NIR bands. Parameter optimization improves agreement between simulated and in situ observed ground snow albedo in visible, NIR and broadband spectrums. Importantly, optimized parameters result in reduced biases relative to observed fresh‐snow albedo and better agreement with observed albedo decay. Our analysis across different sites supports that the optimized BATS ground snow albedo parameters are appropriate to transfer in space and time, at least within the region studied (the central‐southern Rocky Mountains). The primary error source remaining after parameter optimization is that observed fresh‐snow albedo is highly variable, particularly in the NIR spectrum, whereas BATS fresh‐snow albedo is constant, an issue which requires further investigation. This study shows significant correlations between observed fresh‐snow albedo and surface meteorological conditions (e.g., downward shortwave radiation and temperature) which can support future model development that attempts to include a time‐varying formulation for fresh‐snow albedo.
Metabolism and memory: α-synuclein level in children with obesity and children with type 1 diabetes; relation to glucotoxicity, lipotoxicity and executive functions
Authors: Salah Nouran Yousef , Taha Sara Ibrahim , Hassan Safeya , Abdeen Mai Seif ElDin , Hashim Mostafa Ahmad , Mahmoud Rana
Published: September 2022

Background/Objectives

Children with obesity and those with type 1diabetes (T1D) exhibit subtle neurocognitive deficits, the mechanism of which remains unknown. α-synuclein plays a fundamental role in neurodegeneration. Moreover, its role in glucose and lipids metabolism is emerging. This study aims to assess whether α-synuclein is correlated with the degree of neurodegeneration in children with obesity and those with T1D in comparison to healthy controls and correlate it to various neurocognitive and metabolic parameters.

Subjects/Methods

Forty children with obesity, 40 children with T1D and 40 matched-healthy controls were assessed for anthropometric measurements and blood-pressure. Cognitive evaluation was performed using Stanford–Binet scale and Barkley Deficits in Executive Functioning (EF) Scale-Children and Adolescents. α-synuclein, fasting lipids and glucose were measured with calculation of the homeostatic model of insulin-resistance and estimated-glucose disposal rate.

Results

Children with obesity and those with T1D had significantly higher α-synuclein (p < 0.001) and total EF percentile (p = 0.001) than controls. α-synuclein was negatively correlated to total IQ (p < 0.001 and p = 0.001), and positively correlated with total EF percentile (p = 0.009 and p = 0.001) and EF symptom count percentile (p = 0.005 and p < 0.001) in children with T1D and obesity, respectively. Multivariate-regression revealed that α-synuclein was independently related to age (p = 0.028), diabetes-duration (p = 0.006), HbA1C% (p = 0.034), total IQ (p = 0.013) and EF symptom count percentile (p = 0.003) among children with T1D, and to diastolic blood-pressure percentile (p = 0.013), waist/hip ratio SDS (p = 0.007), total EF percentile (P = 0.033) and EF symptom count percentile (p < 0.001) in children with obesity.

Conclusion

α-synuclein could have a mechanistic role in neurocognitive deficit among children with obesity and T1D.
Adult and children’s use of hand sanitizer during a pandemic – an observational study
Authors: Lopez Theresa K. , Jones Kelly , Roseberry-Lincoln Ann , Zidek Angelika , MacKinnon Leona , Marro Leonora
Published: September 2022

Background

The use of hand sanitizers has been one of the key public health measures recommended to reduce the transmission of SARS-CoV-2 during the pandemic. As such, its daily use among the general population has reportedly increased dramatically since the onset of the COVID-19 pandemic.

Objective

To better understand the impact of this recommendation, hand sanitizer use, including the frequency and amount handled, was examined among adults in a non-occupational setting and children in both the home and school/childcare settings.

Methods

An online survey of Canadians (conducted from September to October 2021) was employed to estimate use frequency, amount, and pattern of hand sanitizer use.

Results

Responses were received from 655 adults in the general population and 298 teachers of children up to the age of 18 years. The frequency of hand sanitizer use during the pandemic was found to be as high as 25 times per day in children and over 9 times per day in adults. Notable differences were found when comparing the frequency of hand sanitizer use by children in the home to children in a school or childcare setting.

Significance

This is the first study, known to the authors, examining hand sanitizer use among children during the pandemic, including use in a childcare or school setting. This study illustrates the importance of examining the change in consumer behaviors during a pandemic and the need to look beyond the home when attempting to understand product use patterns in children.

Impact statement

This research explores uses of hand sanitizer, before and during pandemic conditions, in the general population of Canada with a particular focus on use among children. The results can be used to estimate exposure to chemicals in hand sanitizer from non-occupational use in Canada and among similar populations and signal the importance of examining changing consumer behaviors and use of consumer products in school settings, especially among children.
Extracorporeal photopheresis in acute and chronic steroid‑refractory graft-versus-host disease: an evolving treatment landscape
Authors: Greinix Hildegard T. , Ayuk Francis , Zeiser Robert
Published: September 2022

Patients with steroid-refractory graft-versus-host disease (GvHD) are known to have a poor prognosis and for decades no approved drug has been available to treat this serious condition. Although ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor demonstrated significantly higher response rates in randomized trials compared to the best available therapy, and thus, is of benefit in both acute as well as chronic GvHD, there is an urgent medical need to improve results, such as durability of responses, response in eye, liver and lung manifestations and reduction of infectious complications. In this “Review” article we would like to offer strategies for improving treatment results in patients with steroid-refractory GvHD by combining ruxolitinib with extracorporeal photopheresis (ECP), a leukapheresis-based immunomodulatory treatment frequently applied in T-cell mediated immune disease including GvHD. Our article explores key published evidence supporting the clinical efficacy of both ruxolitinib and ECP in the treatment of GvHD and highlights their potentially complementary mechanisms of action.
The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells
Authors: Tang Weimei , Pei Miaomiao , Li Jiaying , Xu Nanzhu , Xiao Wushuang , Yu Zhen , Zhang Jieming , Hong Linjie , Guo Zheng , Lin Jianjiao , Dai Weiyu , Xiao Yizhi , Wu Xiaosheng , Liu Guangnan , Zhi Fachao , Li Guoxin , Xiong Jing , Chen Ye , Zhang Hui , Xiang Li , Li Aimin , Liu Side , Wang Jide
Published: September 2022

Although the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the molecular mechanisms underlying miR-3648 progression and metastasis in gastric cancer (GC) remain unclear. miR-3648 expression is downregulated and its ectopic expression in GC cells significantly suppressed cell proliferation and metastasis. Mechanistic analyses indicated that miR-3648 directly targets FRAT1 or FRAT2 and inhibits FRAT1- or FRAT2-mediated invasion and motility in vitro and in vivo. Moreover, FRAT1 physically interacted with FRAT2. Furthermore, FRAT1 overexpression promoted GC cell invasion, whereas siRNA-mediated repression of FRAT2 in FRAT1-overexpressing GC cells reversed its invasive potential. Besides, miR-3648 inactivated the Wnt/β-catenin signalling pathway by downregulating FRAT1 and FRAT2 in GC. Interestingly, c-Myc, a downstream effector of Wnt/β-catenin signalling, was also downregulated by miR-3648 overexpression. In turn, c-Myc negatively regulated miR-3648 expression by binding to the miR-3648 promoter. In addition, miR-3648 expression levels were negatively correlated with c-Myc, FRAT1, and FRAT2 expression in fresh gastric samples. Our studies suggest that miR-3648 acts as a tumour-suppressive miRNA and that the miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop could be a critical regulator of GC progression.
Gastric acid and escape to systemic circulation represent major bottlenecks to host infection by Citrobacter rodentium
Authors: Woodward Sarah E , Vogt Stefanie L , Peña-Díaz Jorge , Melnyk Ryan A , Cirstea Mihai , Serapio-Palacios Antonio , Neufeld Laurel M P , Huus Kelsey E , Wang Madeline A , Haney Cara H , Finlay B Brett
Published: September 2022

The gastrointestinal (GI) environment plays a critical role in shaping enteric infections. Host environmental factors create bottlenecks, restrictive events that reduce the genetic diversity of invading bacterial populations. However, the identity and impact of bottleneck events on bacterial infection are largely unknown. We used Citrobacter rodentium infection of mice, a model of human pathogenic Escherichia coli infections, to examine bacterial population dynamics and quantify bottlenecks to host colonization. Using Sequence Tag-based Analysis of Microbial Populations (STAMP) we characterized the founding population size (Nb′) and relatedness of C. rodentium populations at relevant tissue sites during early- and peak-infection. We demonstrate that the GI environment severely restricts the colonizing population, with an average Nb′ of only 12–43 lineages (of 2,000+ inoculated) identified regardless of time or biogeographic location. Passage through gastric acid and escape to the systemic circulation were identified as major bottlenecks during C. rodentium colonization. Manipulating such events by increasing gastric pH dramatically increased intestinal Nb′. Importantly, removal of the stomach acid barrier had downstream consequences on host systemic colonization, morbidity, and mortality. These findings highlight the capability of the host GI environment to limit early pathogen colonization, controlling the population of initial founders with consequences for downstream infection outcomes.
Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers
Authors: Dijkstra Francis , O’Donnell Patricio , Klaassen Erica , Buhl Derek , Asgharnejad Mahnaz , Rosen Laura , Zuiker Rob , van Gerven Joop , Jacobs Gabriël
Published: September 2022

TAK-653 is a novel AMPA receptor positive allosteric modulator in clinical development for the treatment of major depressive disorder (MDD). This study aimed to measure the functional pharmacodynamic central nervous system (CNS) effects of TAK-653. A randomised, double-blind, placebo-controlled, three-way crossover (placebo, TAK-653 0.5 mg and 6 mg) study with 24 healthy volunteers was performed. NeuroCart tests consisting of body sway (BS), saccadic peak velocity (SPV), smooth pursuit eye movements (SP), adaptive tracking (AT), Bowdle and Bond and Lader Visual Analogue Scales (B-VAS and BL-VAS) and Stroop test were performed pre-dose and 3.5 and 4 h post-dose. Data were analysed using a mixed model analysis of covariance with baseline as covariate. It was found that TAK-653 did not affect BS and subjective drug effects as measured by B-VAS and BL-VAS at either dose level. TAK-653 0.5 mg increased SPV (degrees/second) (19.49 [5.98, 32.99],P = 0.02) and affected Stroop difference in reaction time between correct congruent and correct incongruent answers and number of correct responses in incongruent trials (22.0 [4.0, 40.0],P = 0.05 and −0.3 [−0.5, −0.1],P = 0.02, respectively). TAK-653 6 mg improved AT (%) (1.68 [0.51, 2.84],P = 0.02) and increased SPV (degrees/s) (15.40 [1.91, 28.90],P = 0.06) and SP (%) (2.32 [0.37, 4.27],P = 0.05). Based on these findings it can be concluded that TAK-653 demonstrated a psychostimulant-like pharmacodynamic profile on the NeuroCart consistent with previously reported increase of cortical excitability following Transcranial Magnetic Stimulation (TMS) of the human motor cortex.
Quantitative trait locus analysis for endophenotypes reveals genetic substrates of core symptom domains and neurocognitive function in autism spectrum disorder
Authors: Lee In-Hee , Koelliker Ekaterina , Kong Sek Won
Published: September 2022

Autism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders and is largely attributable to genetic risk factors. Phenotypic and genetic heterogeneity of ASD have been well-recognized; however, genetic substrates for endophenotypes that constitute phenotypic heterogeneity are not yet known. In the present study, we compiled data from the Autism Genetic Resource Exchange, which contains the demographic and detailed phenotype information of 11,961 individuals. Notably, the whole-genome sequencing data available from MSSNG and iHART for 3833 individuals in this dataset was used to perform an endophenotype-wide association study. Using a linear mixed model, genome-wide association analyses were performed for 29 endophenotype scores and 0.58 million common variants with variant allele frequency ≥ 5%. We discovered significant associations between 9 genetic variants and 6 endophenotype scores comprising neurocognitive development and severity scores for core symptoms of ASD at a significance threshold of p < 5 × 10–7. Of note, the Stereotyped Behaviors and Restricted Interests total score in Autism Diagnostic Observation Schedule Module 3 was significantly associated with multiple variants in the VPS13B gene, a causal gene for Cohen syndrome and a candidate gene for syndromic ASD. Our findings yielded loci with small effect sizes due to the moderate sample size and, thus, require validation in another cohort. Nonetheless, our endophenotype-wide association analysis extends previous candidate gene discovery in the context of genotype and endophenotype association. As a result, these candidate genes may be responsible for specific traits that constitute core symptoms and neurocognitive function of ASD rather than the disorder itself.
A calpain-6/YAP axis in sarcoma stem cells that drives the outgrowth of tumors and metastases
Authors: Tchicaya-Bouanga Joëlle , Hung Yu-Jen , Schwartz Jean-Marc , Yoon Diane Ji Yun , Chotard Emilie , Marty Clarice , Odri Guillaume Anthony , de Pinieux Gonzague , Cohen-Solal Martine , Modrowski Dominique
Published: September 2022

Sarcomas include cancer stem cells, but how these cells contribute to local and metastatic relapse is largely unknown. We previously showed the pro-tumor functions of calpain-6 in sarcoma stem cells. Here, we use an osteosarcoma cell model, osteosarcoma tissues and transcriptomic data from human tumors to study gene patterns associated with calpain-6 expression or suppression. Calpain-6 modulates the expression of Hippo pathway genes and stabilizes the hippo effector YAP. It also modulates the vesicular trafficking of β-catenin degradation complexes. Calpain-6 expression is associated with genes of the G2M phase of the cell cycle, supports G2M-related YAP activities and up-regulated genes controlling mitosis in sarcoma stem cells and tissues. In mouse models of bone sarcoma, most tumor cells expressed calpain-6 during the early steps of tumor out-growth. YAP inhibition prevented the neoformation of primary tumors and metastases but had no effect on already developed tumors. It could even accelerate lung metastasis associated with large bone tumors by affecting tumor-associated inflammation in the host tissues. Our results highlight a specific mechanism involving YAP transcriptional activity in cancer stem cells that is crucial during the early steps of tumor and metastasis outgrowth and that could be targeted to prevent sarcoma relapse.
Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFβ/SMAD signalling during gliomagenesis
Authors: Zhou Xuexia , Li Xuebing , Wang Run , Hua Dan , Sun Cuiyun , Yu Lin , Shi Cuijuan , Luo Wenjun , Jiang Zhendong , An Wenzhe , Wang Qian , Yu Shizhu
Published: September 2022

Synergies of transcription factors, chromatin modifiers and their target genes are vital for cell fate determination in human cancer. Although the importance of numerous epigenetic machinery for regulating gliomagenesis has been previously recognized, how chromatin modifiers collaborate with specific transcription factors remains largely elusive. Herein we report that Pontin chromatin remodelling factor acts as a coactivator for LEF1 to activate TGFβ/SMAD signalling, thereby contributing to gliomagenesis. Pontin is highly expressed in gliomas, and its overexpression paralleled the grade elevation and poor prognosis of patients. Functional studies verified its oncogenic roles in GBM cells by facilitating cell proliferation, survival and invasion both in vitro and in vivo. RNA sequencing results revealed that Pontin regulated multiple target genes involved in TGFβ/SMAD signalling. Intriguingly, we found that Pontin amplified TGFβR2 gene transcription by recruiting LEF1, thereby activating TGFβ/SMAD signalling and facilitating gliomagenesis. Furthermore, higher TGFβR2 expression conferred worse patient outcomes in glioma. To conclude, our study revealed that the Pontin-LEF1 module plays a crucial role in driving TGFβR2 gene transcription, which could be exploited to target TGFβ/SMAD signalling for anti-glioma therapy.
Inhibition of USP1 enhances anticancer drugs-induced cancer cell death through downregulation of survivin and miR-216a-5p-mediated upregulation of DR5
Authors: Woo Seon Min , Kim Seok , Seo Seung Un , Kim Shin , Park Jong-Wook , Kim Gyeonghwa , Choi Yu-Ra , Hur Keun , Kwon Taeg Kyu
Published: September 2022

Ubiquitin-specific protease 1 (USP1) is a deubiquitinase involved in DNA damage repair by modulating the ubiquitination of major regulators, such as PCNA and FANCD2. Because USP1 is highly expressed in many cancers, dysregulation of USP1 contributes to cancer therapy. However, the role of USP1 and the mechanisms underlying chemotherapy remain unclear. In this study, we found high USP1 expression in tumor tissues and that it correlated with poor prognosis in RCC. Mechanistically, USP1 enhanced survivin stabilization by removing ubiquitin. Pharmacological inhibitors (ML23 and pimozide) and siRNA targeting USP1 induced downregulation of survivin expression. In addition, ML323 upregulated DR5 expression by decreasing miR-216a-5p expression at the post-transcriptional level, and miR-216a-5p mimics suppressed the upregulation of DR5 by ML323. Inhibition of USP1 sensitized cancer cells. Overexpression of survivin or knockdown of DR5 markedly prevented the co-treatment with ML323 and TRAIL-induced apoptosis. These results of in vitro were proved in a mouse xenograft model, in which combined treatment significantly reduced tumor size and induced survivin downregulation and DR5 upregulation. Furthermore, USP1 and survivin protein expression showed a positive correlation, whereas miR-216a-5p and DR5 were inversely correlated in RCC tumor tissues. Taken together, our results suggest two target substrates of USP1 and demonstrate the involvement of survivin and DR5 in USP1-targeted chemotherapy.
Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity
Authors: Bradley David , Smith Alan J. , Blaszczak Alecia , Shantaram Dharti , Bergin Stephen M. , Jalilvand Anahita , Wright Valerie , Wyne Kathleen L. , Dewal Revati S. , Baer Lisa A. , Wright Katherine R. , Stanford Kristin I. , Needleman Bradley , Brethauer Stacy , Noria Sabrena , Renton David , Joseph Joshua J. , Lovett-Racke Amy , Liu Joey , Hsueh Willa A.
Published: September 2022

Decreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in humans. Here we obtain adipose tissue from obese and lean volunteers. Regulatory T cell abundance is lower in obese vs. lean visceral and subcutaneous adipose tissue and associates with reduced insulin sensitivity and altered adipocyte metabolic gene expression. Regulatory T cells numbers decline following high-fat diet induction in lean volunteers. We see alteration in major histocompatibility complex II pathway in adipocytes from obese patients and after high fat ingestion, which increases T helper 1 cell numbers and decreases regulatory T cell differentiation. We also observe increased expression of inhibitory co-receptors including programmed cell death protein 1 and OX40 in visceral adipose tissue regulatory T cells from patients with obesity. In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance.
Synthetic neuromorphic computing in living cells
Authors: Rizik Luna , Danial Loai , Habib Mouna , Weiss Ron , Daniel Ramez
Published: September 2022

Computational properties of neuronal networks have been applied to computing systems using simplified models comprising repeated connected nodes, e.g., perceptrons, with decision-making capabilities and flexible weighted links. Analogously to their revolutionary impact on computing, neuro-inspired models can transform synthetic gene circuit design in a manner that is reliable, efficient in resource utilization, and readily reconfigurable for different tasks. To this end, we introduce the perceptgene, a perceptron that computes in the logarithmic domain, which enables efficient implementation of artificial neural networks in Escherichia coli cells. We successfully modify perceptgene parameters to create devices that encode a minimum, maximum, and average of analog inputs. With these devices, we create multi-layer perceptgene circuits that compute a soft majority function, perform an analog-to-digital conversion, and implement a ternary switch. We also create a programmable perceptgene circuit whose computation can be modified from OR to AND logic using small molecule induction. Finally, we show that our approach enables circuit optimization via artificial intelligence algorithms.
Tail proteins of phage SU10 reorganize into the nozzle for genome delivery
Authors: Šiborová Marta , Füzik Tibor , Procházková Michaela , Nováček Jiří , Benešík Martin , Nilsson Anders S. , Plevka Pavel
Published: September 2022

Escherichia coliphage SU10 belongs to the genusKuravirusfrom the classCaudoviricetesof phages with short non-contractile tails. In contrast to other short-tailed phages, the tails of Kuraviruses elongate upon cell attachment. Here we show that the virion of SU10 has a prolate head, containing genome and ejection proteins, and a tail, which is formed of portal, adaptor, nozzle, and tail needle proteins and decorated with long and short fibers. The binding of the long tail fibers to the receptors in the outer bacterial membrane induces the straightening of nozzle proteins and rotation of short tail fibers. After the re-arrangement, the nozzle proteins and short tail fibers alternate to form a nozzle that extends the tail by 28 nm. Subsequently, the tail needle detaches from the nozzle proteins and five types of ejection proteins are released from the SU10 head. The nozzle with the putative extension formed by the ejection proteins enables the delivery of the SU10 genome into the bacterial cytoplasm. It is likely that this mechanism of genome delivery, involving the formation of the tail nozzle, is employed by all Kuraviruses.
Lactobacillus supports Clostridiales to restrict gut colonization by multidrug-resistant Enterobacteriaceae
Authors: Djukovic Ana , Garzón María José , Canlet Cécile , Cabral Vitor , Lalaoui Rym , García-Garcerá Marc , Rechenberger Julia , Tremblay-Franco Marie , Peñaranda Iván , Puchades-Carrasco Leonor , Pineda-Lucena Antonio , González-Barberá Eva María , Salavert Miguel , López-Hontangas José Luis , Sanz Miguel Á. , Sanz Jaime , Kuster Bernhard , Rolain Jean-Marc , Debrauwer Laurent , Xavier Karina B. , Xavier Joao B. , Ubeda Carles
Published: September 2022

Infections by multidrug-resistantEnterobacteriaceae(MRE) are life-threatening to patients. The intestinal microbiome protects against MRE colonization, but antibiotics cause collateral damage to commensals and open the way to colonization and subsequent infection. Despite the significance of this problem, the specific commensals and mechanisms that restrict MRE colonization remain largely unknown. Here, by performing a multi-omic prospective study of hospitalized patients combined with mice experiments, we find thatLactobacillusis key, though not sufficient, to restrict MRE gut colonization.Lactobacillus rhamnosusandmurinusincrease the levels of Clostridiales bacteria, which induces a hostile environment for MRE growth through increased butyrate levels and reduced nutrient sources. This mechanism of colonization resistance, an interaction betweenLactobacillusspp. and Clostridiales involving cooperation between microbiota members, is conserved in mice and patients. These results stress the importance of exploiting microbiome interactions for developing effective probiotics that prevent infections in hospitalized patients.
Bond engineering of molecular ferroelectrics renders soft and high-performance piezoelectric energy harvesting materials
Authors: Hu Yuzhong , Parida Kaushik , Zhang Hao , Wang Xin , Li Yongxin , Zhou Xinran , Morris Samuel Alexander , Liew Weng Heng , Wang Haomin , Li Tao , Jiang Feng , Yang Mingmin , Alexe Marin , Du Zehui , Gan Chee Lip , Yao Kui , Xu Bin , Lee Pooi See , Fan Hong Jin
Published: September 2022

Piezoelectric materials convert mechanical stress to electrical energy and thus are widely used in energy harvesting and wearable devices. However, in the piezoelectric family, there are two pairs of properties that improving one of them will generally compromises the other, which limits their applications. The first pair is piezoelectric strain and voltage constant, and the second is piezoelectric performance and mechanical softness. Here, we report a molecular bond weakening strategy to mitigate these issues in organic-inorganic hybrid piezoelectrics. By introduction of large-size halide elements, the metal-halide bonds can be effectively weakened, leading to a softening effect on bond strength and reduction in polarization switching barrier. The obtained solid solution C6H5N(CH3)3CdBr2Cl0.75I0.25exhibits excellent piezoelectric constants (d33 = 367 pm/V,g33 = 3595 × 10−3 Vm/N), energy harvesting property (power density is 11 W/m2), and superior mechanical softness (0.8 GPa), promising this hybrid as high-performance soft piezoelectrics.
Tunable quantum gaps to decouple carrier and phonon transport leading to high-performance thermoelectrics
Authors: Yu Yong , Xu Xiao , Wang Yan , Jia Baohai , Huang Shan , Qiang Xiaobin , Zhu Bin , Lin Peijian , Jiang Binbin , Liu Shixuan , Qi Xia , Pan Kefan , Wu Di , Lu Haizhou , Bosman Michel , Pennycook Stephen J. , Xie Lin , He Jiaqing
Published: September 2022

Thermoelectrics enable direct heat-to-electricity transformation, but their performance has so far been restricted by the closely coupled carrier and phonon transport. Here, we demonstrate that the quantum gaps, a class of planar defects characterized by nano-sized potential wells, can decouple carrier and phonon transport by selectively scattering phonons while allowing carriers to pass effectively. We choose the van der Waals gap in GeTe-based materials as a representative example of the quantum gap to illustrate the decoupling mechanism. The nano-sized potential well of the quantum gap in GeTe-based materials is directly visualized by in situ electron holography. Moreover, a more diffused distribution of quantum gaps results in further reduction of lattice thermal conductivity, which leads to a peak ZT of 2.6 at 673 K and an average ZT of 1.6 (323–723 K) in a GeTe system. The quantum gap can also be engineered into other thermoelectrics, which provides a general method for boosting their thermoelectric performance.