bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network state dynamics underpin craving in a transdiagnostic population
Authors: Ye Jean , Garrison Kathleen A. , Lacadie Cheryl , Potenza Marc N. , Sinha Rajita , Goldfarb Elizabeth V. , Scheinost Dustin 
Published: October 2023

AbstractEmerging fMRI brain dynamic methods present a unique opportunity to capture how brain region interactions across time give rise to evolving affective and motivational states. As the unfolding experience and regulation of affective states affect psychopathology and well-being, it is important to elucidate their underlying time-varying brain responses. Here, we developed a novel framework to identify network states specific to an affective state of interest and examine how their instantaneous engagement contributed to its experience. This framework investigated network state dynamics underlying craving, a clinically meaningful and changeable state. In a transdiagnostic sample of healthy controls and individuals diagnosed with or at risk for craving-related disorders (N=252), we utilized connectome-based predictive modeling (CPM) to identify craving-predictive edges. An edge-centric timeseries approach was leveraged to quantify the instantaneous engagement of the craving-positive and craving-negative networks during independent scan runs. Individuals with higher craving persisted longer in a craving-positive network state while dwelling less in a craving-negative network state. We replicated the latter results externally in an independent group of healthy controls and individuals with alcohol use disorder exposed to different stimuli during the scan (N=173). The associations between craving and network state dynamics can still be consistently observed even when craving-predictive edges were instead identified in the replication dataset. These robust findings suggest that variations in craving-specific network state recruitment underpin individual differences in craving. Our framework additionally presents a new avenue to explore how the moment-to-moment engagement of behaviorally meaningful network states supports our changing affective experiences.
Prevalence and factors associated with fear of COVID-19 in military personnel during the second epidemic wave in Peru
Authors: Valladares-Garrido Danai , Dominguez-Troncos Helena , Picón-Reátegui Cinthia Karina , Valdiviezo-Morales Christopher , Vera-Ponce Víctor J. , Failoc-Rojas Virgilio E. , Pereira-Victorio César Johan , León-Figueroa Darwin A. , Valladares-Garrido Mario J. 
Published: October 2023

AbstractThere is few research in military members that provided protection and security during the COVID-19 crisis. We aimed to determine the prevalence and factors associated with fear of COVID-19 in military members. A cross-sectional study was conducted between November 02 and 09, 2021, during the second wave of the COVID-19 pandemic in the region of Lambayeque, Peru. The outcome was fear of COVID-19, measured with the Fear of COVID-19 Scale. The association with resilience (abbreviated CD-RISC), food insecurity (HFIAS), physical activity (IPAQ-S), eating disorder (EAT-26), and other socio-labor variables were assessed. Of 525 participants, the median age was 22, 95.8% were male, and 19.2% experienced fear of COVID-19. A higher prevalence of fear of COVID-19 was associated with age (PR=1.03; 95% CI: 1.01-1.06), religion (PP=2.05; 95% CI: 1.04-4.05), eating disorder (PR=2.95; 95% CI: 1.99-4.36), and having a relative with mental disorder (PR=2.13; 95% CI: 1.09-4.17). Overweight (PR=0.58; 95% IC: 0.37-0.90) and a high level of resilience (PR=0.63; 95% IC: 0.43-0.93) were associated with a lower prevalence of fear of COVID-19. Two out of ten military personnel were afraid of COVID-19. We recommend special attention to the factors associated with the development of suicide risk in military personnel.
Different pathways toward net-zero emissions imply diverging health impacts: a health impact assessment study for France
Authors: Moutet Léo , Bigo Aurélien , Quirion Philippe , Temime Laura , Jean Kévin 
Published: October 2023

AbstractBackgroundIn the transport sector, efforts to achieve carbon neutrality may generate public health cobenefits by promoting physical activity.ObjectiveThis study aims to quantify the health impacts related to active transportation based on four different scenarios leading France toward carbon neutrality in 2050.MethodsThe French Agency for Ecological Transition developed four consistent and contrasting scenarios (S1 to S4) achieving carbon neutrality by 2050 as well as a business-as-usual (BAU) scenario that extends our current lifestyles until 2050, without reaching net-zero. For each of theseTransitions2050scenarios, we distributed the mobility demand for walking, cycling and e-cycling across age groups. Relying on the health impact assessment framework, we quantified the impacts of the corresponding physical activity on all-cause mortality. The impact of each of the carbon neutrality scenarios was determined by comparison with estimates from the BAU scenario.ResultsIn S1 and S2 scenarios, volumes of active transportation are projected to increase to fulfil the World Health Organisations recommendations by 2050, while they increase slightly in S3 and decrease in S4. S2 scenario reaches the highest levels of health cobenefits, with 494,000 deaths prevented between 2021 and 2050. This would translate into a life expectancy gain of 3.0 months for the general population in 2050, mainly driven by e-bikes. S1 would provide smaller but important health benefits, while these benefits would be modest for S3. On the contrary, S4 implies 52,000 additional deaths as compared to the BAU scenario, and a loss of 0.2 month in life expectancy.DiscussionDifferent ways to decarbonize mobility in a net-zero perspective may achieve very contrasting public health cobenefits. This study illustrates how the public health dimension may provide a relevant insight in choices of collective transformation toward net-zero societies.
A spatiotemporal model of multi-marker antimalarial resistance
Authors: Foo Yong See , Flegg Jennifer A. 
Published: October 2023

AbstractThe emergence and spread of drug-resistantPlasmodium falciparumparasites has hindered efforts to eliminate malaria. Monitoring the spread of drug resistance is vital, as drug resistance can lead to widespread treatment failure. We develop a Bayesian model to produce spatiotemporal maps that depict the spread of drug resistance, and apply our methods for the antimalarial sulfadoxine-pyrimethamine. We infer from genetic count data the prevalences over space and time of various malaria parasite haplotypes associated with drug resistance. Previous work has focused on inferring the prevalence of individual molecular markers. In reality, combinations of mutations at multiple markers confer varying degrees of drug resistance to the parasite, indicating that multiple markers should be modelled together. However, the reporting of genetic count data is often inconsistent as some studies report haplotype counts, whereas some studies report mutation counts of individual markers separately. In response, we introduce a latent multinomial Gaussian process model to handle partially-reported spatiotemporal count data. As drug-resistant mutations are often used as a proxy for treatment efficacy, point estimates from our spatiotemporal maps can help inform antimalarial drug policies, whereas the uncertainties from our maps can help with optimising sampling strategies for future monitoring of drug resistance.
Base Excision Repair Pathway Regulates Transcription-Replication Conflicts in Pancreatic Ductal Adenocarcinoma
Authors: Meng Fan , Singh Anup K. , Li Tiane , Attiyeh Marc , Kohram Fatemeh , Williams Terence , Liu Yilun , Raoof Mustafa 
Published: October 2023

ABSTRACTOncogenic mutations (such as in KRAS) can dysregulate transcription and replication leading to transcription conflicts (TRCs). Unresolved TRCs can cause lethal DNA damage. Here, we sought to investigate the oncogene dependency of TRCs and TRC regulatory pathways in pancreatic ductal adenocarcinoma (PDAC). Human PDAC demonstrated 30-120-fold higher levels of TRC genomic signatures compared to breast, colon and lung cancer (p<0.001). TRCs were significantly enriched in human PDAC cells (Panc-1, BxPC3, MiaPaca2) compared to immortalized human pancreatic ductal epithelial (HPNE). Ectopic oncogenic KRAS(G12D) in HPNE cells enhanced TRCs, and TRC-related DNA:RNA hybrids (R-loops). Inhibition of KRAS or downstream effectors abrogated TRCs in Panc1 and MiaPaca2 cells. An siRNA screen identified several factors in the base-excision repair pathway as regulators of TRCs. In pharmacologic validation, inhibitors of APE1 endonuclease in BER pathway (Methoxyamine and CRT) enhanced TRCs. Mechanistic studies revealed that BER pathway inhibition severely altered RNA polymerase II dynamics at nascent DNA; causing RNAPII trapping and contributing to enhanced TRCs. The ensuing DNA damage activated Chk2-ATR pathway but not Chk1-ATM pathway. Co-treatment with ATR inhibitor (VX970) and BER inhibitor (methoxyamine) at clinically relevant doses, synergistically enhanced DNA damage and reduced cell proliferation in PDAC cells. The study uncovers a novel role of BER pathway defects and oxidative DNA damage in promoting TRCs. Our studies provide mechanistic insights into the regulation of TRCs in PDAC which has implications for genome instability and therapy in PDAC.
Retrosplenial inputs drive diverse visual representations in the medial entorhinal cortex
Authors: Dubanet Olivier , Higley Michael J. 
Published: October 2023

AbstractThe ability of rodents to use visual cues for successful navigation and goal-directed behavior has been long appreciated, although the neural mechanisms supporting sensory representations in navigational circuits are largely unknown. Navigation is fundamentally dependent on the hippocampus and closely connected entorhinal cortex, whose neurons exhibit characteristic firing patterns corresponding to the animal’s location. The medial entorhinal cortex (MEC) receives direct projections from sensory areas in the neocortex, suggesting the ability to encode sensory information. To examine this possibility, we performed high-density recordings of MEC neurons in awake, head-fixed mice presented with simple visual stimuli and assessed the dynamics of sensory-evoked activity. We found a large fraction of neurons exhibited robust responses to visual input that shaped activity relative to ongoing network dynamics. Visually responsive cells could be separated into subgroups based on functional and molecular properties within deep layers of the dorsal MEC, suggesting diverse populations within the MEC contribute to sensory encoding. We then showed that optogenetic suppression of retrosplenial cortex afferents within the MEC strongly reduced visual responses. Overall, our results demonstrate the the MEC can encode simple visual cues in the environment that can contribute to neural representations of location necessary for accurate navigation.
Inhibition of miR-199b-5p reduces pathological alterations in Osteoarthritis by potentially targetingFzd6andGcnt2
Authors: Feng Tong , Zhang Qi , Li Si-Hui , Ping Yan-ling , Tian Mu-qiu , Zhou Shuan-hu , Wang Xin , Wang Jun-Meng , Liang Fan-Rong , Yu Shu-Guang , Wu Qiao-Feng 
Published: October 2023

AbstractOsteoarthritis (OA) is a degenerative disease with a high prevalence in the elderly population, but our understanding of its mechanisms remains incomplete. Analysis of serum exosomal small RNA sequencing data from clinical patients and gene expression data from OA patient serum and cartilage obtained from the GEO database revealed a common dysregulated miRNA, miRNA-199b-5p. In vitro cell experiments demonstrated that miRNA-199b-5p inhibits chondrocyte vitality and promotes extracellular matrix degradation. Conversely, inhibition of miRNA-199b-5p under inflammatory conditions exhibited protective effects against damage. Local viral injection of miRNA-199b-5p into mice induced a decrease in pain threshold and OA-like changes. In an OA model, inhibition of miRNA-199b-5p alleviated the pathological progression of OA. Furthermore, bioinformatics analysis and experimental validation identifiedGcnt2andFzd6as potential target genes of miRNA-199b-5p. Thus, these results indicated that miRNA-199b-5p/Gcnt2andFzd6axis might be a novel therapeutic target for the treatment of OA.
Post-ischemic inactivation of HIF prolyl hydroxylases in endothelium promotes maladaptive kidney repair by inducing glycolysis
Authors: Tiwari Ratnakar , Sharma Rajni , Rajendran Ganeshkumar , Borkowski Gabriella S. , An Si Young , Schonfeld Michael , O’Sullivan James , Schipma Matthew J. , Zhou Yalu , Courbon Guillaume , David Valentin , Quaggin Susan E. , Thorp Edward , Chandel Navdeep S. , Kapitsinou Pinelopi P. 
Published: October 2023

ABSTRACTIschemic acute kidney injury (AKI) is common in hospitalized patients and increases the risk for chronic kidney disease (CKD). Impaired endothelial cell (EC) functions are thought to contribute in AKI to CKD transition, but the underlying mechanisms remain unclear. Here, we identify a critical role for endothelial oxygen sensing prolyl hydroxylase domain (PHD) enzymes 1-3 in regulating post-ischemic kidney repair. In renal endothelium, we observed compartment-specific differences in the expression of the three PHD isoforms in both mice and humans. We found that post-ischemic concurrent inactivation of endothelial PHD1, PHD2, and PHD3 but not PHD2 alone promoted maladaptive kidney repair characterized by exacerbated tissue injury, fibrosis, and inflammation. Single-cell RNA-seq analysis of the post-ischemic endothelial PHD1, PHD2 and PHD3 deficient (PHDTiEC) kidney revealed an endothelial glycolytic transcriptional signature, also observed in human kidneys with severe AKI. This metabolic program was coupled to upregulation of theSLC16A3gene encoding the lactate exporter monocarboxylate transporter 4 (MCT4). Strikingly, treatment with the MCT4 inhibitor syrosingopine restored adaptive kidney repair inPHDTiECmice. Mechanistically, MCT4 inhibition suppressed pro-inflammatory EC activation reducing monocyte-endothelial cell interaction. Our findings suggest avenues for halting AKI to CKD transition based on selectively targeting the endothelial hypoxia-driven glycolysis/MCT4 axis.
Improving protein expression, stability, and function with ProteinMPNN
Authors: Sumida Kiera H. , Núñez-Franco Reyes , Kalvet Indrek , Pellock Samuel J. , Wicky Basile I. M. , Milles Lukas F. , Dauparas Justas , Wang Jue , Kipnis Yakov , Jameson Noel , Kang Alex , De La Cruz Joshmyn , Sankaran Banumathi , Bera Asim K. , Jiménez-Osés Gonzalo , Baker David 
Published: October 2023

AbstractNatural proteins are highly optimized for function, but are often difficult to produce at a scale suitable for biotechnological applications due to poor expression in heterologous systems, limited solubility, and sensitivity to temperature. Thus, a general method that improves the physical properties of native proteins while maintaining function could have wide utility for protein-based technologies. Here we show that the deep neural network ProteinMPNN together with evolutionary and structural information provides a route to increasing protein expression, stability, and function. For both myoglobin and tobacco etch virus (TEV) protease, we generated designs with improved expression, elevated melting temperatures, and improved function. For TEV protease, we identified multiple designs with improved catalytic activity as compared to the parent sequence and previously reported TEV variants. Our approach should be broadly useful for improving the expression, stability, and function of biotechnologically important proteins.
Distinct functions of EHMT1 and EHMT2 in cancer chemotherapy and immunotherapy
Authors: Kang Zhihua , Fu Pan , Ma Hui , Li Tao , Lu Kevin , Liu Juan , Ginjala Vasudeva , Romanienko Peter , Feng Zhaohui , Guan Ming , Ganesan Shridar , Xia Bing 
Published: October 2023

AbstractEHTM1 (GLP) and EHMT2 (G9a) are closely related protein lysine methyltransferases often thought to function together as a heterodimer to methylate histone H3 and non-histone substrates in diverse cellular processes including transcriptional regulation, genome methylation, and DNA repair. Here we show that EHMT1/2 inhibitors cause ATM-mediated slowdown of replication fork progression, accumulation of single-stranded replication gaps, emergence of cytosolic DNA, and increased expression of STING. EHMT1/2 inhibition strongly potentiates the efficacy of alkylating chemotherapy and anti-PD-1 immunotherapy in mouse models of tripe negative breast cancer. The effects on DNA replication and alkylating agent sensitivity are largely caused by the loss of EHMT1-mediated methylation of LIG1, whereas the elevated STING expression and remarkable response to immunotherapy appear mainly elicited by the loss of EHMT2 activity. Depletion of UHRF1, a protein known to be associated with EHMT1/2 and LIG1, also induces STING expression, and depletion of either EHMT2 or UHRF1 leads to demethylation of specific CpG sites in theSTING1promoter, suggestive of a distinct EHMT2-UHRF1 axis that regulates DNA methylation and gene transcription. These results highlight distinct functions of the two EHMT paralogs and provide enlightening paradigms and corresponding molecular basis for combination therapies involving alkylating agents and immune checkpoint inhibitors.
Intrinsic Mechanics of Human Stem Cell Derived Aortic Smooth Muscle Cells Support a Developmental Basis for Aneurysm Localization in Marfan Syndrome
Authors: Wiener Robert J. , Orins Helen , Costa Kevin D. 
Published: October 2023

AbstractMarfan Syndrome (MFS), a connective tissue disorder caused by a mutation in the fibrillin-1 gene, occurs in approximately 1 in 5,000 people worldwide. As an important constituent of the extracellular matrix, mutated fibrillin-1 in Marfan Syndrome leads to aortic medial degeneration, aneurysm, and dissection. TGFβ in the matrix, which is controlled by fibrillin-1, is known to cause pathological effects in smooth muscle cells (SMCs) within the aortic wall during MFS. TGFβ as well as other cytokines have been shown to impact neural crest derived SMCs differently than mesodermal derived SMCs. Furthermore, outcomes of variable cytokine responsiveness of neural crest SMCs are compounded by genetically imposed changes to neural crest SMC integrin distributions in MFS. Thus, it has been hypothesized that neural crest derived SMCs, which give rise to ascending aortic SMCs, are intrinsically mechanically susceptible to aneurysm formation in MFS. This hypothesis has been linked to the clinical observation of aneurysm formation preferentially occurring in the ascending versus descending aorta in MFS. We aim to test the hypothesis that aortic smooth muscle cells (ASMCs) have intrinsic mechanobiological properties which cause cell weakening in Marfan Syndrome. Human induced pluripotent stem cells (hiPSC) from Marfan patients and healthy volunteers were differentiated into either ascending- or descending-ASMCs via their respective developmental lineages, and cultured to either an early (6 days) or late (30 days) stage of post-differentiation maturation. Mass spectrometry-based proteomics of early-stage iPSC-ASMCs revealed an array of depleted proteins unique to MFS ascending-SMCs that were associated with cell mechanics and aortic aneurysm. Targeted examination of the proteomics dataset revealed intracellular proteins (ACTA2, CNN1, TAGLN) were significantly depleted in MFS ascending-ASMCs. The intrinsic, matrix-independent, hiPSC-ASMC stiffness quantified by atomic force microscopy (AFM) revealed that MFS ascending-ASMCs, but not descending-ASMCs, were significantly less stiff than healthy, at the late cell-maturation stage (p<0.0005). Late-stage ascending- and descending-ASMCs also showed clear functional impairments via calcium flux in MFS. AFM revealed a similar mechanical phenotype in early-stage ASMCs, with MFS ascending-ASMCs, but not descending-ASMCs, being significantly less stiff than healthy (p<0.005). In summary, this study supports an emerging hypothesis of ontogenetic predisposition for aneurysm susceptibility in Marfan Syndrome based on locally altered mechanobiology of developmental origin-specific ASMC subtypes. This may lead to new cell-targeted approaches for treating aortic aneurysm in patients with MFS.
The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5
Authors: Zhang Shuyuan , Valenzuela Lucas Fuentes , Zatulovskiy Evgeny , Mangiante Lise , Curtis Christina , Skotheim Jan M. 
Published: October 2023

SummaryMammalian cells make the decision to divide at the G1/S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Rb is inhibited by two parallel pathways. In the canonical pathway, Cyclin D-Cdk4/6 kinase complexes phosphorylate and inactivate Rb. In the second, recently discovered pathway, Rb’s concentration decreases during G1 to promote cells progressing through the G1/S transition. However, the mechanisms underlying this second pathway are unknown. Here, we found that Rb’s concentration drop in G1 and recovery in S/G2 is controlled by phosphorylation-dependent protein degradation. In early G1 phase, un- and hypo-phosphorylated Rb is targeted by the E3 ligase UBR5.UBR5knockout cells have higher Rb concentrations in early G1, exhibit a lower G1/S transition rate, and are more sensitive to Cdk4/6 inhibition. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.
Energy hedging and annual report readability
Authors: Kim Thomas , Sun Li 
Published: October 2023

PurposeUsing a sample of oil and gas firms in the USA, the study examines the relation between the presence of hedging and annual report readability.Design/methodology/approachThe authors use regression analysis to examine the relation between the presence of hedging and annual report readability.FindingsThe authors find that annual reports of firms with the use of hedging are less readable (i.e. difficult to read and understand). The authors also find that the primary results are more pronounced for firms with a higher level of business volatility.Originality/valueThe study contributes to the finance literature on the use and value of hedging and to the accounting literature on the determinants of annual report readability. The Securities and Exchange Commission (SEC) has persistently asked companies to improve the readability of their disclosures to stakeholders (SEC, 1998; 2013, 2014). Hence, the study not only identifies a potential determinant (i.e. hedging) that may influence the level of readability but also supports the current regulatory policy by the SEC, which is encouraging companies to improve readability.