bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell RNA-seq data analysis reveals functionally relevant biomarkers of early brain development and their regulatory footprints in human embryonic stem cells (hESCs)
Authors: Alamin Md , Humaira Sultana Most , Babarinde Isaac Adeyemi , Azad A K M , Moni Mohammad Ali , Xu Haiming 
Published: May 2024

Abstract
The complicated process of neuronal development is initiated early in life, with the genetic mechanisms governing this process yet to be fully elucidated. Single-cell RNA sequencing (scRNA-seq) is a potent instrument for pinpointing biomarkers that exhibit differential expression across various cell types and developmental stages. By employing scRNA-seq on human embryonic stem cells, we aim to identify differentially expressed genes (DEGs) crucial for early-stage neuronal development. Our focus extends beyond simply identifying DEGs. We strive to investigate the functional roles of these genes through enrichment analysis and construct gene regulatory networks to understand their interactions. Ultimately, this comprehensive approach aspires to illuminate the molecular mechanisms and transcriptional dynamics governing early human brain development. By uncovering potential links between these DEGs and intelligence, mental disorders, and neurodevelopmental disorders, we hope to shed light on human neurological health and disease. In this study, we have used scRNA-seq to identify DEGs involved in early-stage neuronal development in hESCs. The scRNA-seq data, collected on days 26 (D26) and 54 (D54), of the in vitro differentiation of hESCs to neurons were analyzed. Our analysis identified 539 DEGs between D26 and D54. Functional enrichment of those DEG biomarkers indicated that the up-regulated DEGs participated in neurogenesis, while the down-regulated DEGs were linked to synapse regulation. The Reactome pathway analysis revealed that down-regulated DEGs were involved in the interactions between proteins located in synapse pathways. We also discovered interactions between DEGs and miRNA, transcriptional factors (TFs) and DEGs, and between TF and miRNA. Our study identified 20 significant transcription factors, shedding light on early brain development genetics. The identified DEGs and gene regulatory networks are valuable resources for future research into human brain development and neurodevelopmental disorders.
Secukinumab in adult patients with lichen planus: efficacy and safety results from the randomized placebo-controlled proof-of-concept PRELUDE study
Authors: Passeron Thierry , Reinhardt Maximilian , Ehst Benjamin , Weiss Jonathan , Sluzevich Jason , Sticherling Michael , Reygagne Pascal , Wohlrab Johannes , Hertl Michael , Fazel Nasim , Muscianisi Elisa , Fan Heng , Hampele Isabelle , Compagno Nicolò 
Published: May 2024

Abstract

Background
Patients with lichen planus (LP) refractory to available therapies often experience a high disease burden, representing a population with a clear unmet need for new treatments.

Objectives
To evaluate the efficacy and safety of secukinumab 300 mg over 32 weeks in adult patients with biopsy-proven cutaneous LP (CLP), mucosal LP (MLP) or lichen planopilaris (LPP) that is inadequately controlled by topical corticosteroids.

Methods
PRELUDE was a randomized double-blind placebo-controlled phase II proof-of-concept study that enrolled patients with CLP, MLP or LPP. Eligible patients were randomized to either secukinumab 300 mg every 4 weeks for 32 weeks (SECQ4W) or placebo for 16 weeks followed by secukinumab 300 mg every 2 weeks (SECQ2W) for 16 weeks. The primary endpoint was achievement of the newly designed Investigator’s Global Assessment (IGA) score ≤ 2 at week 16.

Results
Overall, 111 patients were randomized (n = 37 each) to CLP, MLP and LPP cohorts. As the proof-of-concept criteria were not met for any of the three cohorts, the primary objective was not met. A numerically higher proportion of patients achieved IGA ≤ 2 response at week 16 with SECQ4W vs. placebo in the MLP {37.5% [95% credibility interval (Crl) 20.3–57.2] vs. 23.1% (95% Crl 6.5–49.2)} and LPP cohorts [37.5% (95% Crl 20.2–57.3) vs. 30.8% (95% Crl 10.8–57.6)]. In the LPP cohort, a sustained response for IGA ≤ 2 from week 16 to week 32 was achieved with SECQ4W (week 16, 37.5%; week 32, 45.8%), and a substantial improvement was observed in IGA ≤ 2 response in patients from this cohort who switched from placebo (week 16, 30.8%) to SECQ2W after week 16 (week 32, 63.6%). The safety profile was consistent with the known profile of secukinumab and showed no new or unexpected signals.

Conclusions
PRELUDE is the first randomized controlled basket trial evaluating interleukin (IL)-17A inhibition with secukinumab across three subtypes of LP. Secukinumab was well tolerated and safe, showing different response rates across the three subtypes, with numerical IGA improvements in MLP and LPP, and no response in CLP. The study raises the question of a differential role of IL-17A across LP subtypes. The novel IGA score showed significant correlation with both patient- and physician-reported outcome measurements.
Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders
Authors: Liu James , He Yi , Lwin Cara , Han Marina , Guan Bin , Naik Amelia , Bender Chelsea , Moore Nia , Huryn Laryssa A , Sergeev Yuri V , Qian Haohua , Zeng Yong , Dong Lijin , Liu Pinghu , Lei Jingqi , Haugen Carl J , Prasov Lev , Shi Ruifang , Dollfus Hélène , Aristodemou Petros , Laich Yannik , Németh Andrea H , Taylor John , Downes Susan , Krawczynski Maciej R , Meunier Isabelle , Strassberg Melissa , Tenney Jessica , Gao Josephine , Shear Matthew A , Moore Anthony T , Duncan Jacque L , Menendez Beatriz , Hull Sarah , Vincent Andrea L , Siskind Carly E , Traboulsi Elias I , Blackstone Craig , Sisk Robert A , Miraldi Utz Virginia , Webster Andrew R , Michaelides Michel , Arno Gavin , Synofzik Matthis , Hufnagel Robert B 
Published: May 2024

Abstract
Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear.
We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists.
Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.
In Pursuit of Equanimity: Managing Change and Adversity in Early Modern English Households, c.1570–c.1670
Authors: Greenall Abigail 
Published: May 2024

Abstract
This article establishes equanimity as an important emotional ideal in the late sixteenth and seventeenth centuries. In showing how equanimity served to strengthen positive emotions and temper disruptive states, it promotes a more positive view of the era’s emotional landscape. The article employs the pursuit of equanimity as an intimate analytical device for uncovering the agency of ordinary people, and thus offers historians a new perspective on momentous change and adversity in the early modern period. It charts personal experiences of adversity—from physical and spiritual threats to familial disputes, uncertain patriarchal power and economic precarity—alongside individual management of religious, social and political change following the English Reformations and during the Civil War. Where other scholars have examined how different social groups reactively negotiated new realities, this microhistorical study of one gentry family in the North West of England urges historians to refocus their attention on the proactive courses that people took. Through a detailed examination of 541 manuscript letters, domestic decorative schemes, and archaeological evidence of ritual practices of protection, the article uncovers how the Moretons of Little Moreton Hall in Cheshire managed change and mitigated disaster. It discusses instances where equanimity played a persistent role in motivating the family’s actions and behaviours in daily life, and argues that practices designed to promote emotional harmony were crucial for preserving kinship networks and managing personal well-being, as well as gender relations within households, in early modern England.
Early survival in Atlantic salmon is associated with parental genotypes at loci linked to timing of maturation
Authors: Aykanat Tutku , McLennan Darryl , Metcalfe Neil B , Prokkola Jenni M 
Published: May 2024

Abstract
Large effect loci often contain genes with critical developmental functions and potentially broad effects across life stages. However, their life stage-specific fitness consequences are rarely explored. In Atlantic salmon, variation in two large-effect loci, six6 and vgll3, is linked to age at maturity and several physiological and behavioral traits in early life. By genotyping the progeny of wild Atlantic salmon that were planted into natural streams with nutrient manipulations, we tested if genetic variation in these loci is associated with survival in early life. We found that higher early-life survival was linked to the genotype associated with late maturation in the vgll3, but with early maturation in the six6 locus. These effects were significant in high nutrients but not in low-nutrient streams. The differences in early survival were not explained by additive genetic effects in the offspring generation but by maternal genotypes in the six6 locus and by both parents’ genotypes in the vgll3 locus. Our results suggest that indirect genetic effects of large-effect loci can be significant determinants of offspring fitness. This study demonstrates an intriguing case of how large-effect loci can exhibit complex fitness associations across life stages in the wild and indicates that predicting evolutionary dynamics is difficult.
Effect of abdominal tissue thickness on trabecular bone score and fracture risk in adults with diabetes: the Manitoba BMD registry
Authors: Leslie William D , Binkley Neil , Schousboe John T , Silva Barbara C , Hans Didier 
Published: May 2024

Abstract
Individuals with type 2 diabetes have lower trabecular bone score (TBS) and increased fracture risk despite higher bone mineral density. However, measures of trabecular microarchitecture from high-resolution peripheral computed tomography are not lower in type 2 diabetes. We hypothesized that confounding effects of abdominal tissue thickness may explain this discrepancy, since central obesity is a risk factor for diabetes and also artifactually lowers TBS. This hypothesis was tested in individuals aged 40 years and older from a large DXA registry, stratified by sex and diabetes status. When DXA-measured abdominal tissue thickness was not included as a covariate, men without diabetes had lower TBS than women without diabetes (mean difference −0.074, P &lt; .001). TBS was lower in women with versus without diabetes (mean difference −0.037, P &lt; .001), and men with versus without diabetes (mean difference −0.007, P = .042). When adjusted for tissue thickness these findings reversed, TBS became greater in men versus women without diabetes (mean difference +0.053, P &lt; .001), in women with versus without diabetes (mean difference +0.008, P &lt; .001), and in men with versus without diabetes (mean difference +0.014, P &lt; .001). During mean 8.7 years observation, incident major osteoporotic fractures were seen in 7048 (9.6%). Adjusted for multiple covariates except tissue thickness, TBS predicted fracture in all subgroups with no significant diabetes interaction. When further adjusted for tissue thickness, HR per SD lower TBS remained significant and even increased slightly. In conclusion, TBS predicts fractures independent of other clinical risk factors in both women and men, with and without diabetes. Excess abdominal tissue thickness in men and individuals with type 2 diabetes may artifactually lower TBS using the current algorithm, which reverses after accounting for tissue thickness. This supports ongoing efforts to update the TBS algorithm to directly account for the effects of abdominal tissue thickness for improved fracture risk prediction.
Effective timing of hyaluronate gel injection in image-guided adaptive brachytherapy for uterine cervical cancer: a proposal of the ‘adjusted dose score’
Authors: Miyata Yusaku , Ogo Etsuyo , Murotani Kenta , Tsuda Naotake , Suzuki Gen , Tsuji Chiyoko , Akeda Ryosuke , Muraki Koichiro , Hattori Chikayuki , Abe Toshi 
Published: May 2024

Abstract
Hyaluronate gel injection (HGI) in the rectovaginal septum and vesicovaginal septum is effective in the setting of high-dose-rate image-guided adaptive brachytherapy (IGABT) for cervical cancer. We aimed to retrospectively investigate optimal conditions for HGI to achieve optimal dose distribution with a minimum number of HGI. We classified 50 IGABT plans of 13 patients with cervical cancer who received IGABT both with and without HGI in the rectovaginal septum and vesicovaginal septum into the following two groups: plan with (number of plans = 32) and plan without (number of plans = 18) HGI. The irradiation dose parameters of high-risk clinical target volume (CTVHR) and organs at risk per fraction were compared between these groups. We also developed the adjusted dose score (ADS), reflecting the overall irradiation dose status for four organs at risk and CTVHR in one IGABT plan and investigated its utility in determining the application of HGI. HGI reduced the maximum dose to the most exposed 2.0 cm3 (D2.0 cm3) of the bladder while increasing the minimum dose covering 90% of CTVHR and the percentage of CTVHR receiving 100% of the prescription dose in one IGABT plan without causing any associated complications. An ADS of ≥2.60 was the optimum cut-off value to decide whether to perform HGI. In conclusion, HGI is a useful procedure for improving target dose distribution while reducing D2.0 cm3 in the bladder in a single IGABT plan. The ADS can serve as a useful indicator for the implementation of HGI.
Impact of DNA ligase inhibition on the nick sealing of polβ nucleotide insertion products at the downstream steps of base excision repair pathway
Authors: Almohdar Danah , Kamble Pradnya , Basavannacharya Chandrakala , Gulkis Mitchell , Calbay Ozlem , Huang Shuang , Narayan Satya , Çağlayan Melike 
Published: May 2024

Abstract
DNA ligase (LIG) I and IIIα finalize base excision repair (BER) by sealing a nick product after nucleotide insertion by DNA polymerase (pol) β at the downstream steps. We previously demonstrated that a functional interplay between polβ and BER ligases is critical for efficient repair, and polβ mismatch or oxidized nucleotide insertions confound the final ligation step. Yet, how targeting downstream enzymes with small molecule inhibitors could affect this coordination remains unknown. Here, we report that DNA ligase inhibitors, L67 and L82-G17, slightly enhance hypersensitivity to oxidative stress-inducing agent, KBrO3, in polβ+/+ cells more than polβ-/- null cells. We showed less efficient ligation after polβ nucleotide insertions in the presence of the DNA ligase inhibitors. Furthermore, the mutations at the ligase inhibitor binding sites (G448, R451, A455) of LIG1 significantly affect nick DNA binding affinity and nick sealing efficiency. Finally, our results demonstrated that the BER ligases seal a gap repair intermediate by the effect of polβ inhibitor that diminishes gap filling activity. Overall, our results contribute to understand how the BER inhibitors against downstream enzymes, polβ, LIG1, and LIGIIIα, could impact the efficiency of gap filling and subsequent nick sealing at the final steps leading to the formation of deleterious repair intermediates.
Kinetic pathway of HIV-1 TAR cotranscriptional folding
Authors: Jin Lei , Zhang Sicheng , Song Zhenwei , Heng Xiao , Chen Shi-Jie 
Published: May 2024

Abstract
The Trans-Activator Receptor (TAR) RNA, located at the 5′-end untranslated region (5′ UTR) of the human immunodeficiency virus type 1 (HIV-1), is pivotal in the virus’s life cycle. As the initial functional domain, it folds during the transcription of viral mRNA. Although TAR’s role in recruiting the Tat protein for trans-activation is established, the detailed kinetic mechanisms at play during early transcription, especially at points of temporary transcriptional pausing, remain elusive. Moreover, the precise physical processes of transcriptional pause and subsequent escape are not fully elucidated. This study focuses on the folding kinetics of TAR and the biological implications by integrating computer simulations of RNA folding during transcription with nuclear magnetic resonance (NMR) spectroscopy data. The findings reveal insights into the folding mechanism of a non-native intermediate that triggers transcriptional pause, along with different folding pathways leading to transcriptional pause and readthrough. The profiling of the cotranscriptional folding pathway and identification of kinetic structural intermediates reveal a novel mechanism for viral transcriptional regulation, which could pave the way for new antiviral drug designs targeting kinetic cotranscriptional folding pathways in viral RNAs.
Antisense RNA C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms a triplex-like structure and binds small synthetic ligand
Authors: Błaszczyk Leszek , Ryczek Marcin , Das Bimolendu , Mateja-Pluta Martyna , Bejger Magdalena , Śliwiak Joanna , Nakatani Kazuhiko , Kiliszek Agnieszka 
Published: May 2024

Abstract
The abnormal expansion of GGGGCC/GGCCCC hexanucleotide repeats (HR) in C9orf72 is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Structural polymorphisms of HR result in the multifactorial pathomechanism of ALS/FTD. Consequently, many ongoing studies are focused at developing therapies targeting pathogenic HR RNA. One of them involves small molecules blocking sequestration of important proteins, preventing formation of toxic nuclear foci. However, rational design of potential therapeutics is hindered by limited number of structural studies of RNA-ligand complexes. We determined the crystal structure of antisense HR RNA in complex with ANP77 ligand (1.1 Å resolution) and in the free form (0.92 and 1.5 Å resolution). HR RNA folds into a triplex structure composed of four RNA chains. ANP77 interacted with two neighboring single-stranded cytosines to form pseudo-canonical base pairs by adopting sandwich-like conformation and adjusting the position of its naphthyridine units to the helical twist of the RNA. In the unliganded structure, the cytosines formed a peculiar triplex i-motif, assembled by trans C•C+ pair and a third cytosine located at the Hoogsteen edge of the C•C+ pair. These results extend our knowledge of the structural polymorphisms of HR and can be used for rational design of small molecules targeting disease-related RNAs.
Global economic order and global economic governance
Authors: Susskind Daniel , Vines David 
Published: May 2024

AbstractThis issue of the Oxford Review of Economic Policy explores the origins of the US-led liberal multilateral economic order in the post-war world and the threats which that order now faces, drawing on contributions from two different groups of people—academic international relations (IR) scholars and international economists. This introductory essay attempts to weave the various strands of this intellectual collaboration together. First, it provides a narrative history of how economic collaboration emerged in the aftermath of the Second World War. Second, it describes the nature of the global economic governance that emerged and provides a new formal framework for analysing it, making use of the idea of ‘concerted unilateralism’. Third, it explores how contemporary challenges—a broadening of policy requirements, the rise of economic nationalism, and the rise of China as a new hegemon—mean that the global economic order is now in flux. And finally, it concludes with a general observation that runs through the paper: that IR scholars are inclined to analyse international economic regimes, economists to study particular policy proposals, and that these two perspectives can—and should—complement one another.
Alternative electron pathways of photosynthesis power green algal CO2 capture
Authors: Peltier Gilles , Stoffel Carolyne , Findinier Justin , Madireddi Sai Kiran , Dao Ousmane , Epting Virginie , Morin Amélie , Grossman Arthur , Li-Beisson Yonghua , Burlacot Adrien 
Published: May 2024

Abstract
Microalgae contribute to about half of global net photosynthesis, which converts sunlight into the chemical energy (ATP and NADPH) used to transform CO2 into biomass. Alternative electron pathways of photosynthesis have been proposed to generate additional ATP that is required to sustain CO2 fixation. However, the relative importance of each alternative pathway remains elusive. Here, we dissect and quantify the contribution of cyclic, pseudo-cyclic, and chloroplast-to-mitochondrion electron flows for their ability to sustain net photosynthesis in the microalga Chlamydomonas reinhardtii. We show that (i) each alternative pathway can provide sufficient additional energy to sustain high CO2 fixation rates, (ii) the alternative pathways exhibit cross-compensation, and (iii) the activity of at least one of the three alternative pathways is necessary to sustain photosynthesis. We further show that all pathways have very different efficiencies at energizing CO2 fixation, with the chloroplast–mitochondrion interaction being the most efficient. Overall, our data lay bioenergetic foundations for biotechnological strategies to improve CO2 capture and fixation.
A transthyretin-like protein acts downstream of miR397 and LACCASE to regulate grain yield in rice
Authors: Yu Yang , He Rui-Rui , Yang Lu , Feng Yan-Zhao , Xue Jiao , Liu Qing , Zhou Yan-Fei , Lei Meng-Qi , Zhang Yu-Chan , Lian Jian-Ping , Chen Yue-Qin 
Published: May 2024

Abstract
Increasing grain yield is a major goal of breeders due to the rising global demand for food. We previously reported that the miR397–LACCASE (OsLAC) module regulates brassinosteroid (BR) signaling and grain yield in rice (Oryza sativa). However, the precise roles of laccase enzymes in the BR pathway remain unclear. Here, we report that OsLAC controls grain yield by preventing the turnover of TRANSTHYRETIN-LIKE (OsTTL), a negative regulator of BR signaling. Overexpressing OsTTL decreased BR sensitivity in rice, while loss-of-function of OsTTL led to enhanced BR signaling and increased grain yield. OsLAC directly binds to OsTTL and regulates its phosphorylation-mediated turnover. The phosphorylation site Ser226 of OsTTL is essential for its ubiquitination and degradation. Overexpressing the dephosphorylation-mimic form of OsTTL (OsTTLS226A) resulted in more severe defects than did overexpressing OsTTL. These findings provide insight into the role of an ancient laccase in BR signaling and suggest that the OsLAC–OsTTL module could serve as a target for improving grain yield.