bluuebunny/crossref_metadata_2025_split huggingface dataset:
The wake- and sleep-modulating neurons of the lateral hypothalamic area demonstrate a differential pattern of degeneration in Alzheimer’s disease
Authors: Satpati Abhijit , Pereira Felipe L. , Soloviev Alexander V. , Mladinov Mihovil , Larsen Eva , Li Song Hua , Tu Chia-Ling , Leite Renata E. P. , Suemoto Claudia K. , Rodriguez Roberta D. , Paes Vitor R. , Walsh Christine , Spina Salvatore , Seeley William W. , Pasqualucci Carlos A. , Filho Wilson Jacob , Chang Wenhan , Neylan Thomas C. , Grinberg Lea T. 
Published: March 2024

BackgroundSleep-wake dysfunction is an early and common event in Alzheimer’s disease (AD). The lateral hypothalamic area (LHA) regulates the sleep and wake cycle through wake-promoting orexinergic neurons (OrxN) and sleep-promoting melanin-concentrating hormone or MCHergic neurons (MCHN). These neurons share close anatomical proximity with functional reciprocity. This study investigated LHA OrxNand MCHNloss patterns in AD individuals. Understanding the degeneration pattern of these neurons will be instrumental in designing potential therapeutics to slow down the disease progression and remediate the sleep-wake dysfunction in AD.MethodsPostmortem human brain tissue from donors with AD (across progressive stages) and controls were examined using unbiased stereology. Formalin-fixed, celloidin-embedded hypothalamic sections were stained with Orx-A/MCH, p-tau (CP13), and counterstained with gallocyanin. Orx or MCH-positive neurons with or without CP13 inclusions and gallocyanin-stained neurons were considered for stereology counting. Additionally, we extracted RNA from the LHA using conventional techniques. We used customized Neuropathology and Glia nCounter®(Nanostring) panels to study gene expression. Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when the p-value was <.05.ResultsWe observed a progressive decline in OrxNalongside a relative preservation of MCHN. OrxNdecreased by 58% (p=.03) by Braak stages (BB) 1-2 and further declined to 81% (p=.03) by BB 5-6. Conversely, MCHNdemonstrated a non-statistical significant decline (27%, p=.1088) by BB 6. We observed a progressive increase in differentially expressed genes (DEGs), starting with glial profile changes in BB2. While OrxNloss was observed, Orx-related genes showed upregulation in BB 3-4 compared to BB 0-1. GO and KEGG terms related to neuroinflammatory pathways were mainly enriched.ConclusionsTo date, OrxNloss in the LHA represents the first neuronal population to die preceding the loss of LC neurons. Conversely, MCHN shows resilience to AD p-tau accumulation across Braak stages. The initial loss of OrxNcorrelates with specific neuroinflammation, glial profile changes, and overexpression of HCRT, possibly due to hyperexcitation following compensation mechanisms. Interventions preventing OrxNloss and inhibiting p-tau accumulation in the LHA could prevent neuronal loss in AD and, perhaps, the progression of the disease.
Sendai virus persistence questions the transient naive reprogramming method for iPSC generation
Authors: De Los Angeles Alejandro , Hug Clemens B. , Gladyshev Vadim N. , Church George M. , Velychko Sergiy 
Published: March 2024

AbstractSince the revolutionary discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka, the comparison between iPSCs and embryonic stem cells (ESCs) has revealed significant differences in their epigenetic states and developmental potential. A recent compelling study published inNatureby Buckberry et al.1demonstrated that a transient-naive-treatment (TNT) could facilitate epigenetic reprogramming and improve the developmental potential of human iPSCs (hiPSCs). However, the study characterized bulk hiPSCs instead of isolating clonal lines and overlooked the persistent expression of Sendai virus carrying exogenous Yamanaka factors. Our analyses revealed that Sendai genes were expressed in most control PSC samples, including hESCs, which were not intentionally infected. The highest levels of Sendai expression were detected in samples continuously treated with naive media, where it led to overexpression of exogenous MYC, SOX2, and KLF4, altering both the expression levels and ratios of reprogramming factors. Our findings call for further research to verify the effectiveness of the TNT method in the context of delivery methods that ensure prompt elimination of exogenous factors, leading to the generation of bona fide transgene-independent iPSCs.
Molecular mechanism of parental H3/H4 recycling at a replication fork
Authors: Nagae Fritz , Murayama Yasuto , Terakawa Tsuyoshi 
Published: March 2024

ABSTRACTIn eukaryotic chromatin replication, faithful recycling of histones from parental DNA to replicated leading and lagging strands is essential for maintaining epigenetic information across generations. A recent experimental study has revealed that disrupting interactions between the N-terminal disordered tail of Mcm2, a subunit in DNA replication machinery, and a histone H3/H4 tetramer, a carrier of epigenetic modifications, perturbs their faithful recycling. However, the molecular pathways via which the H3/H4 tetramer attached to Mcm2 is recycled to the replicated strands have yet to be deciphered. Furthermore, the factors that regulate the ratio recycled to each strand and the destination location still need to be discovered. The elucidation requires visualization of a structural trajectory from H3/H4 bound to Mcm2 until recycled to the replicated strands. In this study, we performed molecular dynamics simulations of yeast DNA replication machinery (Mcm2-7, Cdc45, GINS, Pol ε, and RPA), an H3/H4 tetramer, and replicated DNA strands. The simulations demonstrated that histones are recycled via Cdc45-mediated and unmediated pathways even without histone chaperones, as ourin vitrobiochemical assays supported. Also, RPA binding to the ssDNA portion of the lagging strand regulated the ratio recycled to each strand, whereas DNA bending by Pol ε modulated the destination location. Together, the simulations in this study provided testable hypotheses, which are vital for clarifying intracellular histone recycling controlled by the cooperation of many histone chaperones.
The unexplored diversity of wild lupins provides rich genomic resources and insights into lupin evolution
Authors: Susek Karolina , Franco Edoardo , Tomaszewska Magdalena , Kroc Magdalena , Jamil Humaira , Tanwar Umesh , Nelson Matthew N. , Papa Roberto , Delledonne Massimo , Jackson Scott A. 
Published: March 2024

AbstractLupin crops provide nutritious seeds as an excellent source of dietary protein. However, extensive genomic resources are needed for the adaptation of lupin crops, particularly to improve their nutritional value and facilitate their adaptation to harsh environments caused by the changing climate. Such resources can be derived from crop wild relatives, which represent a large untapped source of genetic variation for crop improvement. Here we describe the first whole-genome sequences of the cross-compatible speciesLupinus cosentinii(Mediterranean) and its pan-Saharan wild relativeL. digitatus, which are well adapted to drought-prone environments and partially domesticated. We found that both species are tetraploids, with similar genome structures, distributions of gene duplications, and numbers of expanded and contracted gene families. The expansion and contraction of gene families that determine seed size, a paradigmatic domestication trait, indicates that gene duplication may have led to morphological adaptations inL. cosentiniiandL. digitatusdiffering from those inL. albus, a domesticated lupin used as a reference. Seed size may therefore reflect convergent evolution mechanisms that play a key role in lupin domestication.
PGBTR: A powerful and general method for inferring bacterial transcriptional regulatory networks
Authors: Gu Wei-Cheng , Ma Bin-Guang 
Published: March 2024

AbstractPredicting bacterial transcriptional regulatory networks (TRNs) through computational methods is a core challenge in systems biology, and there is still a long way to go. Here we propose a powerful, general, and stable computational framework called PGBTR, which employs Convolutional Neural Networks (CNN) to predict bacterial transcriptional regulatory relationships from gene expression data and genomic information. PGBTR consists of two main components: the input generation step PDGD and the deep learning model CNNBTR. On the realEscherichia coliandBacillus subtilisdatasets, PGBTR outperforms other advanced supervised and unsupervised learning methods in terms of AUROC, AUPR, and F1-score. Moreover, PGBTR exhibits greater stability in identifying real transcriptional regulatory interactions compared to existing methods. PGBTR provides a new software tool for bacterial TRNs inference, and its core ideas can be further extended to other molecular network inference tasks and other biological problems using gene expression data.
Development of alcoholic liver disease model for drug evaluation from human induced pluripotent stem cell derived liver organoids
Authors: Feng Zhiwei , Zhou Bingrui , Shuai Qizhi , Wei Yunliang , Jin Ning , Wang Xiaoling , Zhao Hong , Liu Zhizhen , Xu Jun , Mu Jianbing , Xie Jun 
Published: March 2024

AbstractAlcoholic liver disease (ALD) poses a significant health challenge, demanding comprehensive research efforts to enhance our comprehension and treatment strategies. However, the development of effective treatments is hindered by the limitations of existing liver disease models. Liver organoids, characterized by their cellular complexity and three-dimensional (3D) tissue structure closely resembling the human liver, hold promise as ideal models for liver disease research. In this study, we employ a meticulously designed protocol involving the differentiation of human induced pluripotent stem cells (hiPSCs) into liver organoids. This process incorporates a precise combination of cytokines and small molecule compounds within a 3D culture system to guide the differentiation process. Subsequently, these differentiated liver organoids are subjected to ethanol treatment to induce ALD, thus establishing a disease model. Rigorous assessment through a series of experiments reveals that this model partially replicates key pathological features observed in clinical ALD, including cellular mitochondrial damage, elevated cellular reactive oxygen species (ROS) levels, fatty liver, and hepatocyte necrosis. In addition, this model offers potential utility in screening drugs for ALD treatment. Taken together, the liver organoids model of ALD, derived from hiPSCs differentiation, emerges as an invaluable platform for advancing our understanding and management of ALD in clinical settings.
Small molecule modulation of insulin receptor-insulin like growth factor-1 receptor heterodimers in human endothelial cells
Authors: Myers Chloe G , Viswambharan Hema , Haywood Natalie J , Bridge Katherine , Turvey Samuel , Armstrong Tom , Lunn Lydia , Meakin Paul J , Clavane Eva M , Beech David J , Cubbon Richard M , Wheatcroft Stephen B , McPhillie Martin J , Issad Tarik , Fishwick Colin WG , Kearney Mark T , Simmons Katie J 
Published: March 2024

AbstractObjectivesThe insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are heterodimers consisting of two extracellular α-subunits and two transmembrane β -subunits. Insulin αβ and insulin like growth factor-1 αβ hemi-receptors can heterodimerize to form hybrids composed of one IR αβ and one IGF-1R αβ. The function of hybrids in the endothelium is unclear. We sought insight by developing a small molecule capable of reducing hybrid formation in endothelial cells.MethodsWe performed a high-throughput small molecule screening, based on a homology model of hybrid structure. Endothelial cells were studied using western blotting and qPCR to determine the effects of small molecules that reduced hybrid formation.ResultsOur studies unveil a first-in-class quinoline-containing heterocyclic small molecule that reduces hybrids by >50% in human umbilical vein endothelial cells (HUVECs) with no effects on insulin or insulin like growth factor-1 receptors. This small molecule reduced expression of the negative regulatory p85α subunit of phosphatidylinositol 3-kinase, increased basal phosphorylation of the downstream target Akt and enhanced insulin/insulin-like growth factor-1 and shear stress-induced serine phosphorylation of Akt. In primary saphenous vein endothelial cells (SVEC) from patients with type 2 diabetes mellitus undergoing coronary artery bypass (CABG) surgery, hybrid receptor expression was greater than in patients without type 2 diabetes mellitus. The small molecule significantly reduced hybrid expression in SVEC from patients with type 2 diabetes mellitus.ConclusionsWe identified a small molecule that decreases the formation of IR: IGF-1R hybrid receptors in human endothelial cells, without significant impact on the overall expression of IR or IGF-1R. In HUVECs, reduction of IR: IGF-1R hybrid receptors leads to an increase in insulin-induced serine phosphorylation of the critical downstream signalling kinase, Akt. The underpinning mechanism appears, at least in part to involve the attenuation of the adverse effect of IR: IGF-1R hybrid receptors on PI3-kinase signalling.HighlightsWe have discovered a small molecule (HI) that inhibits insulin receptor/IGF-1 receptor hybrid formation.HI reveals previously unrecognised actions of insulin receptor/IGF-1 receptor hybrids distinct to insulin and IGF-1 receptors in endothelial cells.Treatment of endothelial cells with HI enhances activity of the downstream signalling kinase Akt due to inhibitory regulation via PI3-K.
A Microphysiological HHT-on-a-Chip Platform Recapitulates Patient Vascular Lesions
Authors: Fang Jennifer S. , Hatch Christopher J. , Andrejecsk Jillian , Trigt William Van , Juat Damie J. , Chen Yu-Hsi , Matsumoto Satomi , Lee Abe P. , Hughes Christopher C.W. 
Published: March 2024

AbstractHereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations focally develop in multiple organs. These can be small (telangiectasias) or large (arteriovenous malformations, AVMs) and may rupture leading to frequent, uncontrolled bleeding. There are few treatment options and no cure for HHT. Most HHT patients are heterozygous for loss-of-function mutations for Endoglin (ENG) or Alk1 (ACVRL1), however, why loss of these genes manifests as vascular malformations remains poorly understood. To complement ongoing work in animal models, we have developed a microphysiological system model of HHT. Based on our existing vessel-on-a-chip (VMO) platform, our fully human cell-based HHT-VMO recapitulates HHT patient vascular lesions. Using inducibleACVRL1(Alk1)-knockdown, we control timing and extent of endogenous Alk1 expression in primary human endothelial cells (EC) in the HHT-VMO. HHT-VMO vascular lesions develop over several days, and are dependent upon timing of Alk1 knockdown. Interestingly, in chimera experiments AVM-like lesions can be comprised of both Alk1-intact and Alk1-deficient EC, suggesting possible cell non-autonomous effects. Single cell RNA sequencing data are consistent with microvessel pruning/regression as contributing to AVM formation, while loss of PDGFB expression implicates mural cell recruitment. Finally, lesion formation is blocked by the VEGFR inhibitor pazopanib, mirroring the positive effects of this drug in patients. In summary, we have developed a novel HHT-on-a-chip model that faithfully reproduces HHT patient lesions and that is sensitive to a treatment effective in patients. The VMO-HHT can be used to better understand HHT disease biology and identify potential new HHT drugs.SignificanceThis manuscript describes development of an organ-on-a-chip model of Hereditary Hemorrhagic Telangiectasia (HHT), a rare genetic disease involving development of vascular malformations. Our VMO-HHT model produces vascular malformations similar to those seen in human HHT patients, including small (telangiectasias) and large (arteriovenous malformations) lesions. We show that VMO-HHT lesions are sensitive to a drug, pazopanib, that appears to be effective in HHT human patients. We further use the VMO-HHT platform to demonstrate that there is a critical window during vessel formation in which the HHT gene, Alk1, is required to prevent vascular malformation. Lastly, we show that lesions in the VMO-HHT model are comprised of both Alk1-deficient and Alk1-intact endothelial cells.
Bootstrapping Deconfined Quantum Tricriticality
Authors: Chester Shai M. , Su Ning 
Published: March 2024

The paradigmatic example of deconfined quantum criticality is the Neel to valence bond solid phase transition. The continuum description of this transition is the N=2 case of the CPN−1 model, which is a field theory of N complex scalars in 3D coupled to an Abelian gauge field with SU(N)×U(1) global symmetry. Lattice studies and duality arguments suggest the global symmetry of the CP1 model is enhanced to SO(5). We perform a conformal bootstrap study of SO(5) invariant fixed points with one relevant SO(5) singlet operator, which would correspond to two relevant SU(2)×U(1) singlets, i.e., a tricritical point. We find that the bootstrap bounds are saturated by four different predictions from the large N computation of monopole operator scaling dimensions, which were recently shown to be very accurate even for small N. This suggests that the Neel to valence bond solid phase transition is described by this bootstrap bound, which predicts that the second relevant singlet has dimension ≈2.36.

Published by the American Physical Society
2024
Dynamic Nanoindentation and Short-Range Order in Equiatomic NiCoCr Medium-Entropy Alloy Lead to Novel Density Wave Ordering
Authors: Naghdi A. , Domínguez-Gutiérrez F. J. , Huo W. Y. , Karimi K. , Papanikolaou S. 
Published: March 2024

Chemical short-range order is believed to be a key contributor to the exceptional properties of multicomponent alloys. However, its direct validation and confirmation has been highly elusive in most compounds. Recent studies for equiatomic NiCoCr alloys have shown that thermal treatments (i.e., annealing and aging) may facilitate and manipulate such ordering. In this work, by using molecular simulations, we show that nanomechanical probes, such as nanoindentation, may be utilized toward further manipulation of chemical short-range order, providing explicit validation pathways. By using well established interatomic potentials, we perform hybrid molecular-dynamics–Monte Carlo at room temperature to demonstrate that particular dwell nanoindentation protocols can lead, through thermal Monte Carlo equilibration, to local reorganization under the indenter tip, toward a density-wave stripe pattern. We characterize the novel density-wave structures, which are highly anisotropic and dependent on local, nanoindentation-induced stress concentrations, and we show how they deeply originate from intrinsic features of interelemental interactions. Furthermore, we show that these novel patterns consistently scale with the incipient plastic zone, under the indenter tip, justifying their observation at experimentally feasible nanoindentation depths.

Published by the American Physical Society
2024
Confronting a leadership vacuum: the principal’s leadership role in peace education in South African schools
Authors: Ndwandwe Ntokozo Dennis 
Published: March 2024

PurposeThis research aimed to assess the leadership role of principals in the implementation of peace education in selected secondary schools in the Western Cape, South Africa.Design/methodology/approachThis study employed qualitative research approach to assess the leadership role of principals in the implementation of peace education in selected secondary schools in the Western Cape, South Africa. Data were gathered from a small sample of six principals from six selected secondary schools which were engaged in the implementation of a peace education programme, and data were analysed using thematic content analyses.FindingsFindings of the study suggest that principals possess a low level of understanding or awareness of their leadership role in the implementation of peace education. The study pointed out the constraints such as time constraints and learners' negative attitudes and social influences hinder the effective implementation of peace education in selected secondary schools.Research limitations/implicationsFirst, the data were self-reported and therefore subject to social desirability bias; participants may have provided socially desirable responses rather than their true belief or experiences. Thus, participants may have overstated their role in and commitment to the peace education programme.Originality/valueStudies that aim to explore alternative approaches to combat violence, such as peace education, are still limited in South Africa. Hence, this paper served to close that gap by contributing to the growing body of research on the leadership role of the principal in the implementation of peace education in the school and exploring barriers hampering its effective implementation.
Study on dynamic characteristics of acceleration process of spherical hybrid sliding bearings rotor system
Authors: Xue Weiqiang , Shen Jingfeng , Fan Yawen 
Published: March 2024

Purpose
The transient loads on the spherical hybrid sliding bearings (SHSBs) rotor system during the process of accelerating to stable speed are related to time, which exhibits a complex transient response of the rotor dynamics. The current study of the shaft center trajectory of the SHSBs rotor system is based on the assumption that the rotational speed is constant, which cannot truly reflect the trajectory of the rotor during operation. The purpose of this paper truly reflects the trajectory of the rotor and further investigates the stability of the rotor system during acceleration of SHSBs.

Design/methodology/approach
The model for accelerated rotor dynamics of SHSBs is established. The model is efficiently solved based on the fourth-order Runge–Kutta method and then to obtain the shaft center trajectory of the rotor during acceleration.

Findings
Results show that the bearing should choose larger angular acceleration in the acceleration process from startup to the working speed; rotor system is more stable. With the target rotational speed increasing, the changes in the shaft trajectory of the acceleration process are becoming more complex, resulting in more time required for the bearing stability. When considering the stability of the rotor system during acceleration, the rotor equations of motion provide a feasible solution for the simulation of bearing rotor system.

Originality/value
The study can simulate the running stability of the shaft system from startup to the working speed in this process, which provides theoretical guidance for the stability of the rotor system of the SHSBs in the acceleration process.