bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing Single-Cell Transcriptomes of Blood and Cerebrospinal Fluid Leukocytes in Multiple Sclerosis
Authors: Sayad Saed , Hiatt Mark , Mustafa Hazem
Published: May 2024

Background

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system, marked by inflammation, demyelination, and neurodegeneration. Diagnosis is complex due to overlapping symptoms with other neurological conditions, typically relying on clinical evaluation, neurological exams, and tests like magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis. Recent advances in technology, particularly single-cell analysis of blood and CSF leukocytes, hold promise for enhancing MS diagnosis by providing insights into immune cell involvement at a molecular level, potentially enabling more precise diagnostics and personalized treatments.

Method

We acquired single-cell RNA Sequence (RNA-Seq) data (GSE138266) from the website of the National Institutes of Health of the United States (NIH), comprising blood and CSF samples from patients diagnosed with idiopathic intracranial hypertension (IIH) and MS. Our analysis focused on identifying genes, pathways and gene ontology terms with distinct expression patterns in MS compared to IIH.

Results

We identified clear differences in gene expression profiles between blood and CSF samples in MS, contrasting with single-cell leukocyte samples from IIH. The increased expression of genes in MS suggests a boost in immune activity and regulation of cellular proliferation, while decreased expression points to disruptions across various functional categories. Gene ontology analysis identifies upregulated terms associated with cellular differentiation, apoptotic regulation, and immune responses in MS, while downregulated terms suggest disruptions in cellular signaling cascades and myelination processes. Similarly, Reactome pathway analysis unveils upregulated pathways in MS related to cell cycle regulation and immune mechanisms, contrasting with downregulated pathways indicative of disruptions in oxygen transport and cellular metabolism.

Conclusion

Our study offers a thorough examination of single-cell transcriptomic data, unveiling unique gene expression patterns, gene ontology terms, and Reactome pathways linked to MS pathophysiology. Notably, our findings identifyCD69andHNRNPKas potential key genes driving MS progression. By clarifying molecular differences between MS and IIH, our findings enhances our grasp of MS pathogenesis and unveils promising targets for diagnostic and therapeutic interventions.
Health and TB systems resilience and pandemic preparedness: Insights from a cross-country analysis of data from policymakers in India, Indonesia, and Nigeria
Authors: Brubacher Laura Jane , Yellappa Vijayashree , Lestari Bony Wiem , Heitkamp Petra , Vasquez Nathaly Aguilera , Sassi Angelina , Olusola-Faleye Bolanle , Thapa Poshan , Klinton Joel Shyam , Sheokand Surbhi , Pai Madhukar , Oga-Omenka Charity
Published: May 2024

Introduction

The COVID-19 pandemic was an unprecedented challenge to health systems worldwide and had a severe impact on tuberculosis (TB) case notifications and service delivery. India, Indonesia, and Nigeria are high TB-burden countries where the majority of initial care-seeking happens in the private health sector. The objectives of this study were to (1) explore policymakers’ perspectives on the impact of the COVID-19 pandemic on private sector TB service delivery in India, Indonesia, and Nigeria; and (2) identify cross-cutting lessons learned for pandemic preparedness with respect to TB service delivery.

Methods

From May – November 2021, thirty-three interviews were conducted with key policymakers involved in health service administration, TB service delivery, and/or the COVID-19 response in India, Indonesia, and Nigeria (n = 11 in each country). Interviews focused on the impact of COVID-19 on TB services and lessons learned for pandemic preparedness with respect to TB. Data were analyzed thematically using a hybrid inductive-deductive approach, informed by Haldane et al.’s (2021) Determinants of Health Systems Resilience Framework.

Results

Policymakers highlighted the crucial role of intersectoral collaboration, effective governance, innovative financing strategies, health workforce reallocation, and technological advancements such as virtual consultations and mHealth in strengthening TB service delivery amid the COVID-19 pandemic. India relied on patient-provider support agencies to implement a joint strategy for TB care across sectors and states. Indonesia engaged networks of private provider professional associations to facilitate coordination of the COVID-19 response. Nigeria implemented a pandemic policy for public-private referral for the continuity of TB care.

Conclusion

Countries implemented varied measures to support TB service delivery during the COVID-19 pandemic. This study presents lessons learned from three countries (India, Indonesia, and Nigeria) that together offer a ‘menu’ of possibilities for supporting pandemic preparedness with respect to TB care vis-à-vis strengthening health systems resilience.
Investigating the relationship between climatic factors and malaria transmission dynamics in Southwest states of Nigeria
Authors: Yusuf Owolabi , Okoronkwo Chukwu , Ademu Cyril , Silal Sheetal P.
Published: May 2024

Background

In order to combat malaria, numerous strategic initiatives have been deployed over the years, with the goal of eliminating the disease in Nigeria. Despite these efforts, malaria morbidity still persists across the nation, and is presently under control measures. Various factors, encompassing both climatic and non-climatic elements, significantly impact the dynamics of malaria transmission across the country. This study applied time series analysis methods to understand the relationship between climatic factors, particularly temperature and rainfall, and the occurrence of malaria in the Southwest area of Nigeria.

Methods

This study analysed monthly data on documented cases of uncomplicated malaria obtained from the District Health Information System version 2, overseen by the Federal Ministry of Health. Additionally, monthly rainfall and temperature data spanning from 2013 to 2021, acquired from the Nigeria Meteorological Agency, were analysed. The datasets used for analysis were accessed on June 7, 2022, for research purposes. We applied univariate time series models to analyse monthly data on average temperature, rainfall, and malaria cases. Subsequently, cross-correlation analyses were conducted to investigate the relationships between malaria case data and the corresponding rainfall and temperature patterns, following a pre-whitening process.

Results

The patterns of malaria transmission exhibit variability among the various states within the Southwest region of Nigeria from 2013 to 2021. On average, Oyo State consistently recorded relatively higher temperatures compared to its neighbouring states. Conversely, Ondo State receives a higher average monthly rainfall. This state, similar to others in the region, experiences two distinct wet seasons, each characterised by different peak periods.

In terms of temporal relationships, it is predicted that rainfall precedes malaria cases by one month across all the states. However, with regard to temperature, the five other states (excluding Osun state) lead by two months.

Conclusion

The results of this study underscore the varied characteristics of malaria transmission patterns and climate change, even across the individual states within the Southwest region of the country. This recognition of variations in malaria transmission and climatic factors is valuable for policymakers as it enables them to strategically allocate and optimise the implementation of interventions at state-specific level, rather than at zonal level. These interventions might involve distributing and advocating for the use of insecticide-treated bed nets, indoor residual spraying, and seasonal malaria chemoprevention tailored to the unique requirements and circumstances at the state level.
Endoscopic ultrasound-guided biliary rendezvous after failed cannulation, and comparison between benign vs malignant biliopancreatic disorders: outcomes at a single tertiary-care center
Authors: Gornals Joan B , Sumalla-Garcia Albert , Quintana Sergi , Luna-Rodriguez Daniel , Velasquez-Rodriguez Julio G , Puigcerver-Mas Maria , Escuer Julia , Maisterra Sandra , Marin Mar , Munoa Virginia , Laquente Berta , Busquets Juli
Published: May 2024

Background

Endoscopic ultrasound (EUS)-guided biliary rendezvous (RV) is an EUS-assisted technique described as a rescue method in cases of failed biliary cannulation via endoscopic retrograde cholangiography (ERC). Current literature remains unclear regarding its current role. The study aim was to evaluate the effectiveness for biliary EUS-RV, and comparison between benign vs malignant biliopancreatic disorders.

Methods

Retrospective observational study with prospective consecutive inclusion in a specific database from a tertiary-center. All patients with biliopancreatic diseases that underwent a EUS-assisted ERC between October-2010 and November-2022 for failed ERC were included. Main outcomes were technical/overall success. Secondary outcomes were safety, potential factors related to failure/success or safety; and a comparative analysis between EUS-RV and EUS-guided transmural drainage (TMD) in malignant cases.

Results

A total of 69 patients who underwent EUS-RV procedures, with benign and malignant pathologies (n=40 vs n=29), were included. Technical/overall success and related-adverse events (AEs) were 79.7% (95%CI, 68.3-88.4)/74% (95%CI, 61-83.7) and 24% (95%CI, 15.1-36.5), respectively. Failed cases were mainly related with guidewire manipulation. Seven failed RV were successfully rescued by EUS-TMD. On multivariable analysis, EUS-RV and malignant pathology was associated with a greater failure rate (technical success: OR,0.21; 95%CI,0.05-0.72; p=0.017), and higher AEs rate (OR,3.46; 95%CI,1.13-11.5; p=0.034). Also, the EUS-TMD group had greater technical success (OR,16.96; 95%CI,4.69-81.62; p<0.001) and overall success (OR, 3.09; 95%CI,1.18-8-16; p<0.026) with a lower AEs rate (OR,0.30; 95%CI,0.11-0.78; p=0.014) than EUS-RV in malignant disorders.

Conclusions

EUS-RV is a demanding technique with better outcomes in benign than in malignant biliopancreatic diseases. Comparison of the EUS-TMD group on malignant disorders showed worse outcomes with EUS-RV. Given these findings, maybe EUS-RV is not the best option for malignant biliopancreatic disorders.
Intra-Ventricular Diastolic Hemodynamics under Pharmacological Stress in Patients with Ischemic Heart Disease: Analysis of 4D-Flow and Myocardial Flow Reserve using hybrid13N-ammonia Positron Emission Tomography/Magnetic Resonance
Authors: Endo Keiichiro , Fukushima Kenji , Katahira Masataka , Kiko Takatoyo , Yamakuni Ryo , Ukon Naoyuki , Shimizu Takeshi , Ishii Shiro , Yamaki Takayoshi , Nakazato Kazuhiko , Ito Hiroshi , Takeishi Yasuchika
Published: May 2024

Objectives

This study aimed to explore the linkage between intra-left ventricular (LV) diastolic hemodynamics and coronary endothelial function, utilizing four-dimensional (4D) flow magnetic resonance imaging (MR) and myocardial flow reserve (MFR) through simultaneous acquisition using hybrid PETMR system in patients with ischemic heart disease (IHD).

Methods

Sixty-eight patients (mean 66 ± 15 years, male 55) with IHD who underwent rest-pharmacological stress13N-ammonia PET/MR were included. MFR and summed defect score (SSS and SRS for stress and rest) were obtained thorough rest-stress PET images. MR acquisition was performed simultaneously during PET scan to obtain rest-stress 4D flow datasets and followed by cine-MRI for the LV volume measurement. LV diastolic inflow(mL/s), peak velocity(cm/s), and averaged diastolic kinetic energy (KE)(μJ/mL) indexed with endo-diastolic volume were computed.

Results

Diastolic LV inflow parameters and KE significantly increased in stress scan compared to the rest (74.8 ± 17.5 cm/s vs. 64.5 ± 14.4 cm/s, p<0.0001; 10.1 ± 5.2 vs. 13.3 ± 7.8, p=0.0004 for peak velocity and KE, respectively). Stress KE showed a significant and weak correlation to MFR and SSS (r = 0.3, p=0.004; r=-0.4, p=0.002 for MFR and SSS, respectively). In patients with MFR above median value (1.76), stress KE significantly elevated from rest KE, while no significant change was observed for the patients with MFR below median (11.0 ± 4.6 vs. 16.2 ± 8.8, p=0.0002; 9.7 ± 5.4 vs. 10.3 ± 5.1 for rest vs. stress, respectively).

Conclusion

Non-invasive assessment of intra-LV diastolic hemodynamics derived from 4D flow MRI demonstrated significant alterations under stress, and was found to have a notable association with the extent of ischemia and coronary endothelial dysfunction.
Genetically edited human placental organoids cast new light on the role of ACE2 in placental development
Authors: Arthurs Anya L. , Dietrich Bianca , Knöfler Martin , Lushington Caleb J. , Thomas Paul Q. , Adikusuma Fatwa , Jankovic-Karasoulos Tanja , Smith Melanie D. , Pringle Kirsty G. , Roberts Claire T.
Published: May 2024

ACE2 expression is altered in pregnancy disorders andACE2gene variants are associated with several major pregnancy complications including small-for-gestational-age, fetal growth restriction and preeclampsia. This study utilised gene-editing to generate bothACE2knockout andACE2rs2074192 placental organoids, facilitating mechanistic studies into the role ofACE2in placental development, and the effect of fetal carriage ofACE2rs2074192 CC, CT and TT genotypes. Parameters of cell and organoid growth were measured, together with qPCR, Western Blotting, and ELISA assessments, in all groups from both organoid models. Here, we report thatACE2knockout results in delayed placental cell growth and increased cell death.ACE2knockout organoids had lower ACE protein expression, reduced organoid diameters and asymmetrical growth. Placental organoids with the ACE2 rs2074192 TT genotype had significantly higher expression ofACE2mRNA and ACE2 protein with elevated ACE2:ACE expression ratio and no change in ACE protein expression. Despite increased expression of ACE2 protein, ACE2 enzyme activity was significantly decreased in ACE2 rs2074192 TT placental organoids. TT organoids also had reduced diameters and asymmetrical growth. Our research provides new molecular understanding of the role of ACE2 in placental development, with potential implications for pregnancy in carriage of theACE2rs2074192 gene variant.
Fight, Retreat, Repeat: Field observation of male-male agonistic behavior in the wood-feeding cockroach,Panesthia angustipennis spadica(Dictyoptera: Blattodea: Blaberidae)
Authors: Osaki Haruka , Nakazono Tomohiro , Yabe Kiyotaka , Takata Mamoru , Mikaelyan Aram
Published: May 2024

Conflict is one of the most critical factors affecting the behavior of animals related to their reproduction and survival, with aggressive interactions being central to acquiring resources or mating partners. This phenomenon is more common among males than females, impacting reproduction strategy and beginning of biparental care. Investigating such interactions in species closely related to social species can be illuminating, offering valuable insights into the factors that influence the emergence and maintenance of more complex social behaviors. In this context, we present a field study of male-male agonistic behavior in the wood-feeding cockroach,Panesthia angustipennis. Panesthiais the closest genus to the subsocial genusSalganea, which is known for its biparental care. Our field observations reveal a characteristic behavior where one male pushes a rival away from a female. The victorious male repeatedly returns to a specific site near the female, suggesting a strategy to minimize unnecessary conflict or protect the female. This behavior provides insights into the potential evolutionary strategies that may have evolved in the common ancestor shared bySalganeaandPanesthia. Notably, the displaced males persistently reengage, highlighting the high resource value attributed to females and the consequential intensity of male competition. This study not only sheds light on the aggressive and pacifist tendencies inP. angustipennisbut also contributes to understanding the evolutionary development of social structures inSalganea. Further experimental investigations into the aggressive behaviors ofP. angustipenniswill enhance our comprehension of the factors shaping the evolution of sociality in these species.
Neurocomputational Mechanisms Underlying Maladaptive Self-Belief Formation in Depression
Authors: Czekalla Nora , Schröder Alexander , Mayer Annalina V , Stierand Janine , Stolz David S , Kube Tobias , Korn Christoph W. , Wilhelm-Groch Ines , Klein Jan Philipp , Paulus Frieder M , Krach Sören , Müller-Pinzler Laura
Published: May 2024

Maladaptive self-beliefs are a core symptom of major depressive disorder. These are perpetuated by negatively biased feedback processing. Understanding the neurocomputational mechanisms of biased belief updating may help to counteract maladaptive beliefs. The present study uses functional neuroimaging to examine neural activity associated with prediction error-based learning in persons with major depression and healthy controls. We hypothesized that increased symptom burden is associated with negatively biased self-belief formation and altered neural tracking of social feedback. Results showed that a higher symptom burden was associated with forming more negative self-beliefs and more positive beliefs about others. This bias was driven by reduced learning from positive prediction errors in depression. Neural reactivity of the insula showed increased tracking of more negative self-related prediction errors. The interplay of increased neural responsiveness to negative feedback and reduced learning from positive feedback may contribute to the persistence of maladaptive self-beliefs and, thus, the maintenance of depression.
Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain
Authors: Guerra Denise , Radić Laura , Brinkkemper Mitch , Poniman Meliawati , van der Maas Lara , Torres Jonathan L. , Ward Andrew B. , Sliepen Kwinten , Schinkel Janke , Sanders Rogier W. , van Gils Marit J. , Beaumont Tim
Published: May 2024

Monoclonal neutralizing antibodies (mAbs) are considered an important prophylactic against SARS-CoV-2 infection in at-risk populations and a strategy to counteract future sarbecovirus-induced disease. However, most mAbs isolated so far neutralize only a few sarbecovirus strains. Therefore, there is a growing interest in bispecific antibodies (bsAbs) which can simultaneously target different spike epitopes and thereby increase neutralizing breadth and prevent viral escape. Here, we generate and characterize a panel of 30 novel broadly reactive bsAbs using an efficient controlled Fab-arm exchange protocol. We specifically combine some of the broadest mAbs described so far, which target conserved epitopes on the receptor binding domain (RBD). Several bsAbs show superior cross-binding and neutralization compared to the parental mAbs against sarbecoviruses from diverse clades, including recent SARS-CoV-2 variants. BsAbs which include mAb COVA2-02 are among the most potent and broad combinations. As a result, we study the unknown epitope of COVA2-02 and show that this mAb targets a distinct conserved region at the base of the RBD, which could be of interest when designing next-generation bsAb constructs to contribute to a better pandemic preparedness.
The molecular mechanism of on-demand sterol biosynthesis at organelle contact sites
Authors: Zung Naama , Aravindan Nitya , Boshnakovska Angela , Valenti Rosario , Preminger Noga , Jonas Felix , Yaakov Gilad , Willoughby Mathilda M. , Homberg Bettina , Keller Jenny , Kupervaser Meital , Dezorella Nili , Dadosh Tali , Wolf Sharon G. , Itkin Maxim , Malitsky Sergey , Brandis Alexander , Barkai Naama , Fernández-Busnadiego Rubén , Reddi Amit R. , Rehling Peter , Rapaport Doron , Schuldiner Maya
Published: May 2024

Contact-sites are specialized zones of proximity between two organelles, essential for organelle communication and coordination. The formation of contacts between the Endoplasmic Reticulum (ER), and other organelles, relies on a unique membrane environment enriched in sterols. However, how these sterol-rich domains are formed and maintained had not been understood. We found that the yeast membrane protein Yet3, the homolog of human BAP31, is localized to multiple ER contact sites. We show that Yet3 interacts with all the enzymes of the post-squalene ergosterol biosynthesis pathway and recruits them to create sterol-rich domains. Increasing sterol levels at ER contacts causes its depletion from the plasma membrane leading to a compensatory reaction and altered cell metabolism. Our data shows that Yet3 provides on-demand sterols at contacts thus shaping organellar structure and function. A molecular understanding of this protein’s functions gives new insights into the role of BAP31 in development and pathology.
Collagen fibril formation at the plasma membrane occurs independently from collagen secretion
Authors: Pickard Adam , Garva Richa , Adamson Antony , Calverley Ben C. , Hoyle Anna , Hayward Christina E. , Spiller David , Lu Yinhui , Hodson Nigel , Mandolfo Oriana , Kim Kevin K. , Bou-Gharios George , Swift Joe , Bigger Brian , Kadler Karl E.
Published: May 2024

Collagen fibrils are the primary supporting scaffold of vertebrate tissues but how they are assembled is unclear. Here, using CRISPR-tagging of type I collagen and SILAC labelling, we elucidate the cellular mechanism for the spatiotemporal assembly of collagen fibrils, in cultured fibroblasts. Our findings reveal multifaceted trafficking of collagen, including constitutive secretion, intracellular pooling, and plasma membrane-directed fibrillogenesis. Notably, we differentiate the processes of collagen secretion and fibril assembly and identify the crucial involvement of endocytosis in regulating fibril formation. By employing Col1a1 knockout fibroblasts we demonstrate the incorporation of exogenous collagen into nucleation sites at the plasma membrane through these recycling mechanisms. Our study sheds light on the assembly process and its regulation in health and disease. Mass spectrometry data are available via ProteomeXchange with identifier PXD036794.
The LC3-interacting region of NBR1 is a protein interaction hub enabling optimal flux
Authors: North Brian J , Ohnstad Amelia E , Ragusa Michael J , Shoemaker Christopher J
Published: May 2024

During autophagy, potentially toxic cargo is enveloped by a newly formed autophagosome and trafficked to the lysosome for degradation. Ubiquitinated protein aggregates, a key target for autophagy, are identified by multiple autophagy receptors. NBR1 is an archetypal autophagy receptor and an excellent model for deciphering the role of the multivalent, heterotypic interactions made by cargo-bound receptors. Using NBR1 as a model, we find that three critical binding partners – ATG8-family proteins, FIP200, and TAX1BP1 – each bind to a short linear interaction motif (SLiM) within NBR1. Mutational peptide arrays indicate that these binding events are mediated by distinct overlapping determinants, rather than a single, convergent, SLiM. AlphaFold modeling underlines the need for conformational flexibility within the NBR1 SLiM, as distinct conformations mediate each binding event. To test the extent to which overlapping SLiMs exist beyond NBR1, we performed peptide binding arrays on >100 established LC3-interacting regions (LIRs), revealing that FIP200 and/or TAX1BP1 binding to LIRs is a common phenomenon and suggesting LIRs as protein interaction hotspots. Comparative analysis of phosphomimetic peptides highlights that while FIP200 and Atg8-family binding are generally augmented by phosphorylation, TAX1BP1 binding is nonresponsive, suggesting differential regulation of these binding events. In vivo studies confirm that LIR-mediated interactions with TAX1BP1 enhance NBR1 activity, increasing autophagosomal delivery by leveraging an additional LIR from TAX1BP1. In sum, these results reveal a one-to-many binding modality in NBR1, providing key insights into the cooperative mechanisms among autophagy receptors. Furthermore, these findings underscore the pervasive role of multifunctional SLiMs in autophagy, offering substantial avenues for further exploration into their regulatory functions.
A conserved chronobiological complex timesC. elegansdevelopment
Authors: Spangler Rebecca K. , Braun Kathrin , Ashley Guinevere E. , van der Does Marit , Wruck Daniel , Ramos Coronado Andrea , Ragle James Matthew , Iesmantavicius Vytautas , Morales Moya Lucas J. , Jonnalagadda Keya , Partch Carrie L. , Großhans Helge , Ward Jordan D.
Published: May 2024

The mammalian PAS-domain protein PERIOD (PER) and itsC. elegansorthologue LIN-42 have been proposed to constitute an evolutionary link between two distinct, circadian and developmental, timing systems. However, while the function of PER in animal circadian rhythms is well understood molecularly and mechanistically, this is not true for LIN-42’s function in timing rhythmic development. Here, using targeted deletions, we find that the LIN-42 PAS domains are dispensable for the protein’s function in timing molts. Instead, we observe arrhythmic molts upon deletion of a distinct sequence element, conserved with PER. We show that this element, designated CK1δ-binding domain (CK1BD), mediates stable binding to KIN-20, theC. elegansCK1δ/ε orthologue. We demonstrate that CK1δ phosphorylates LIN-42 and define two conserved helical motifs in the CK1BD, CK1BD-A and CK1BD-B, that have distinct roles in controlling CK1δ-binding and kinase activityin vitro. KIN-20 and the LIN-42 CK1BD are required for proper molting timingin vivo, and loss of LIN-42 binding changes KIN-20 subcellular localization. The interactions mirror the central role of a stable circadian PER–CK1 complex in setting a robust ∼24-hour period. Hence, our results establish LIN-42/PER – KIN-20/CK1δ/ε as a functionally conserved signaling module of two distinct chronobiological systems.
Deep learning based reconstruction of embryonic cell-division cycle from label-free microscopy time-series of evolutionarily diverse nematodes
Authors: Khatri Dhruv , Athale Chaitanya A.
Published: May 2024

Microscopy of cellular dynamics during embryogenesis of non-model organisms can be tech- nically challenging due to limitations of molecular labelling methods. Label-free differential interference contrast (DIC) microscopy of the first embryonic cell division of nematodes related toCaenorhabditis eleganshas been successfully employed to examine the constraints and divergence of intra-cellular mechanisms during this asymmetric cell division. However, identifying stages of the cell division cycle were performed interactively, pointing to a need to automate of cell stage identification from DIC microscopy. To this end, we have trained deep convolutional neural networks (CNNs), both pre-existing such as ResNet, VGGNet and EfficientNet, and a customized shallow network, EvoCellNet, to automatically classify first-embryonic division into the stages: (i) pro-nuclear migration and (ii) centration and rotation, (iii) spindle elongation and (iv) cytokinesis, with all networks performing with 91% or greater accuracy. The activations of the networks superimposed on the images result in segmentation-free detection of intracellular features such as pro-nuclei, spindle and spindle- poles in case of the shallow EvoCellNet, while ResNet, VGGNet and and EfficientNet detect large-scale, features that are less biologically meaningful. The UMAP space representation combined with support vector machines (SVM) allows for stage boundary identification and recovers a cyclical map connecting the states (i) to (iv) of the division. This approach could be used to automate quantification of cell division stages and sub-cellular dynamics without explicit labelling in label-free microscopy.

We have trained multiple convolutional neural networks (CNNs) to classify the stages of cell division from the first embryonic division of diverse nematodes, evolutionarily related toCaenorhabditis elegans. We find two classifiers, VggNet and a customized EvoCellNet, can detect intracellular features and a UMAP representation can reconstruct the cyclical progression of first embryonic division from related species.
The structural landscape of Microprocessor mediated pri-let-7miRNA processing
Authors: Garg Ankur , Shang Renfu , Cvetanovic Todor , Lai Eric C. , Joshua-Tor Leemor
Published: May 2024

miRNA biogenesis is initiated upon cleavage of a primary miRNA (pri-miRNA) hairpin by the Microprocessor (MP), composed of the Drosha RNase III enzyme and its partner DGCR8. Multiple pri-miRNA sequence motifs affect MP recognition, fidelity, and efficiency. Here, we performed cryo-EM and biochemical studies of several let-7 family pri-miRNAs in complex with human MP. We show that MP has the structural plasticity to accommodate a range of pri-miRNAs. These structures revealed key features of the 5’ UG sequence motif, more comprehensively represented as the “fUN” motif. Our analysis explains how cleavage of class-II pri-let-7 members harboring a bulged nucleotide generates a noncanonical precursor with a 1-nt 3’ overhang. Finally, the MP-SRSF3-pri-let-7f1 structure reveals how SRSF3 contributes to MP fidelity by interacting with the CNNC-motif and Drosha’s PAZ-like domain. Overall, this study sheds light on the mechanisms for flexible recognition, accurate cleavage, and regulated processing of different pri-miRNAs by MP.
DivIVA controls the dynamics of septum splitting and cell elongation inStreptococcus pneumoniae
Authors: Trouve Jennyfer , Zapun André , Bellard Laure , Juillot Dimitri , Pelletier Anais , Freton Celine , Baudoin Morgane , Carballido-Lopez Rut , Campo Nathalie , Wong Yung-Sing , Grangeasse Christophe , Morlot Cecile
Published: May 2024

Bacterial shape and division rely on the dynamics of cell wall assembly, which involves regulated synthesis and cleavage of the peptidoglycan. In ovococci, these processes are coordinated in an annular mid-cell region with nanometric dimensions. More precisely, the cross-wall that is synthesized by the divisome is split to generate lateral wall, whose expansion is insured by insertion of so-called peripheral peptidoglycan by the elongasome. Septum cleavage and peripheral peptidoglycan synthesis are thus crucial remodeling events for ovococcal cell division and elongation. The structural DivIVA protein has long been known as a major regulator of these processes but its mode of action remains unknown. Here, we integrate click chemistry-based peptidoglycan labeling, direct stochastic optical reconstruction microscopy and in silico modeling, as well as epifluorescence and stimulated emission depletion microscopy to investigate the role of DivIVA inStreptococcus pneumoniaecell morphogenesis. Our work reveals two distinct phases of peptidoglycan remodeling along the cell cycle, that are differentially controlled by DivIVA. In particular, we show that DivIVA ensures homogeneous septum cleavage and peripheral peptidoglycan synthesis around the division site, and their maintenance throughout the cell cycle. Our data additionally suggest that DivIVA impacts the contribution of the elongasome and class A PBPs to cell elongation. We also report the position of DivIVA on either side of the septum, consistent with its known affinity for negatively curved membranes. Finally, we take the opportunity provided by these new observations to propose hypotheses for the mechanism of action of this key morphogenetic protein.

Importance

This study sheds light on fundamental processes governing bacterial cell growth and division, using integrated click chemistry, advanced microscopy and computational modeling approaches. More precisely, it addresses mechanisms involved in the regulation of cell wall synthesis and remodeling inStreptococcus pneumoniae. This bacterium belongs to the morphological group of ovococci, which includes many human pathogens, such as streptococci and enterococci. In this study, we have dissected the function of DivIVA, which is a structural protein involved in cell division, cell morphogenesis and chromosome partitioning in Gram-positive bacteria. This work unveils the role of DivIVA in the orchestration of cell division and elongation along the pneumococcal cell cycle. It not only helps understanding how ovoid bacteria proliferate, but also offers an opportunity to consider how DivIVA might serve as a scaffold and sensor for particular membrane regions, and thus be involved in various processes associated with the cell cycle.
Structure and mechanism of biosynthesis ofStreptococcus mutanscell wall polysaccharide
Authors: Rush Jeffrey S. , Zamakhaeva Svetlana , Murner Nicholas R. , Deng Pan , Morris Andrew J. , Kenner Cameron W. , Black Ian , Heiss Christian , Azadi Parastoo , Korotkov Konstantin V. , Widmalm Göran , Korotkova Natalia
Published: May 2024

Streptococcus mutans,the causative agent of human dental caries, expresses a cell wall attached Serotypec-specific Carbohydrate (SCC) that is critical for cell viability. SCC consists of a repeating →3)α-Rha(1→2)α-Rha(1→ polyrhamnose backbone, with glucose (Glc) side-chains and glycerol phosphate (GroP) decorations. This study reveals that SCC has one major and two minor Glc modifications. The major Glc modification, α-Glc, attached to position 2 of 3-rhamnose, is installed by SccN and SccM glycosyltransferases and is the site of the GroP addition. The minor Glc modifications are β-Glc linked to position 4 of 3-rhamnose installed by SccP and SccQ glycosyltransferases, and α-Glc attached to position 4 of 2-rhamnose installed by SccN working in tandem with an unknown enzyme. Both the major and the minor β-Glc modifications control bacterial morphology, but only the GroP and major Glc modifications are critical for biofilm formation.
Intraplacental injection of human iPSC-derived PDX1+ pancreatic progenitors prolongs Pdx1-deficient mice survival
Authors: Wakimoto Arata , Jeon Hyojung , Shahri Zeynab Javanfekr , Hayashi Takuto , Liao Ching-Wei , Gogoleva Natalia , Suchy Fabian , Noda Atsushi , An Yuri , Nakauchi Hiromitsu , Hayashi Yohei , Hamada Michito , Takahashi Satoru
Published: May 2024

Interspecies chimeras comprising human tissues have potential for use in disease modeling and regenerative medicine. Here, we successfully transplanted human induced pluripotent stem cell (iPSC)-derived PDX1+ pancreatic progenitor cells into Pdx1-deficient mouse embryos via intraplacental injection. The engrafted human cells predominantly localized to the duodenum, produced insulin, and extended the lifespan ofPdx1-/-mice by up to 10 days after birth. Transcriptomic analyses confirmed human pancreatic gene expression in human cells engrafted into the mouse duodenum. Our findings demonstrate the feasibility of generating interspecies chimeras with functional human pancreatic cells throughin uterotransplantation of lineage-committed progenitors. This approach circumvents developmental barriers while minimizing ethical concerns associated with PSCs. However, the incomplete rescue of thePdx1-/-phenotype highlights the need for further research to enhance human cell engraftment and tissue integration. Overall, this study provides a foundation for developing human-animal chimera models for studying human development and regenerative therapies.
Vacuum chambers for Swiss Light Source arcs
Authors: Ganter R. , Braschoss P. , Braun H.-H. , Buchmann J. , Citterio A. , Dehler M. , Gaiffi N. , Kirchgeorg N. , Magjar M. , Rosenberg C. , Stephan D. , Schulz L. , Sieber R. , Wang X. , Zandonella A.
Published: May 2024

The vacuum chambers for diffraction limited storage ring differ from the previous storage rings generation in three main aspects: the cross-section dimension, which is divided by a factor of 2 or more to fit smaller magnet apertures; the material, which includes much more copper for heat dissipation and to limit resistive wakefields; the coating of the inner surface with a nonevaporable getter (NEG) to ensure good pumping level despite low conductance. This paper gives a detailed description of the vacuum chambers’ design used in the arc section of SLS 2.0, starting with conceptual design choices based among others on synchrotron radiation heat and wakefield considerations. The particular case of the main bending magnet vacuum chamber is explained in detail from design to manufacturing, including the development of an appropriate NEG coating procedure. Finally, the overall assembly of a 17 m long arc, its activation to reach pressure in the 10−11  mbar range followed by transport and installation into the magnets is presented. This validates the choice of activation for an arc vessel made out of copper, with wall thicknesses as small as 1 mm and with less than 0.5 mm clearance to magnet poles.

Published by the American Physical Society
2024
Stable many-body localization under random continuous measurements in the no-click limit
Authors: De Tomasi Giuseppe , Khaymovich Ivan M.
Published: May 2024

In this work, we investigate the localization properties of a paradigmatic model, coupled to a monitoring environment and possessing a many-body localized (MBL) phase. We focus on the postselected no-click limit with quench random rates, i.e., random gains and losses. In this limit, the system is modeled by adding an imaginary random potential, rendering non-Hermiticity in the system. Numerically, we provide evidence that the system is localized for any finite amount of disorder. To analytically understand our results, we extend the quantum random energy model (QREM) to the non-Hermitian scenario. The Hermitian QREM has been used previously as a benchmark model for MBL. The QREM exhibits a size-dependent MBL transition, where the critical value scales as Wc∼LlnL with system size and presenting many-body mobility edges. We reveal that the non-Hermitian QREM with random gain-loss offers a significantly stronger form of localization, evident in the nature of the many-body mobility edges and the value for the transition, which scales as Wc∼ln1/2L with the system size.

Published by the American Physical Society
2024
Conformal field theory approach to parton fractional quantum Hall trial wave functions
Authors: Henderson Greg J. , Sreejith G. J. , Simon Steven H.
Published: May 2024

We show that all lowest Landau-level projected and unprojected chiral parton type fractional quantum Hall ground and edge-state trial wave functions, which take the form of products of integer quantum Hall wave functions, can be expressed as conformal field theory (CFT) correlation functions, where we can associate a chiral algebra to each parton state such that the CFT defined by the algebra is the “smallest” such CFT that can generate the corresponding ground and edge-state trial wave functions (assuming that the corresponding chiral algebra does indeed define a physically “sensible” CFT). A field-theoretic generalization of Laughlin's plasma analogy, known as generalized screening, is formulated for these states. If this holds, along with an additional assumption, we argue that the inner products of edge-state trial wave functions, for parton states where the “densest” trial wave function is unique, can be expressed as matrix elements of an exponentiated local action operator of the CFT, generalizing the result of Dubail [], which implies the equality between edge-state and entanglement level counting to state counting in the corresponding CFT. We numerically test this result in the case of the unprojected ν=2/5 composite fermion state and the bosonic ν=1ϕ22 parton state. We discuss how Read's arguments [] still apply, implying that conformal blocks of the CFT defined by the corresponding chiral algebra are valid quasihole trial wave functions, with the adiabatic braiding statistics given by the monodromy of these functions, assuming the existence of a quasiparticle trapping Hamiltonian. Generalizations of these constructions are discussed, with particular attention given to simple current constructions. It is shown that all chiral composite fermion wave functions can be expressed as CFT correlation functions without explicit symmetrization or antisymmetrization and that the ground, edge, and certain quasihole trial wave functions of the ϕnm parton states can be expressed as the conformal blocks of the U(1)⊗SU(n)m WZW models. Finally, we discuss the relation of the ϕ2k series with the Read-Rezayi series, where several examples of quasihole braiding statistics calculations are given.

Published by the American Physical Society
2024
Impact of JLab data on the determination of GPDs at zero skewness and new insights from transition form factors
N→Δ
Authors: Goharipour Muhammad , Hashamipour Hadi , Irani Fatemeh , Azizi K. ,   The MMGPDs Collaboration
Published: May 2024

It is well-established now that the generalized parton distributions (GPDs) at zero skewness are playing important roles in some physical process such as elastic electron-nucleon scattering, elastic (anti)neutrino-nucleon scattering, and wide-angle Compton scattering (WACS) via various types of form factors (FFs). In this study, we are going to utilize the recent JLab measurements of the elastic electron-nucleon scattering reduced cross section, namely GMp12, as a touchstone to unravel the tension observed between the measurements of the WACS cross section and the data of the proton magnetic FF GMp. We also investigate the impact of GMp12 data on valence unpolarized GPDs Hvq and Evq at zero skewness by performing some χ2 analyses of the related experimental data. By calculating the electric and scalar quadrupole ratios, REM and RSM, and magnetic transition FF GM*/3GD related to the nucleon-to-delta (N→Δ) transition using the extracted GPDs and comparing the results with corresponding experimental measurements, we show that our results are in an excellent consistency with experiments, indicating the universality property of GPDs. We emphasize that the inclusion of these data in the future analysis of GPDs can significantly affect the extracted GPDs especially their uncertainties at smaller values of Q2.

Published by the American Physical Society
2024
ρ
-meson spectroscopy and diffractive production using the holographic light-front Schrödinger equation and the ’t Hooft equation
Authors: Gurjar Bheemsehan , Mondal Chandan , Kaur Satvir
Published: May 2024

We determine the mass spectroscopy and light-front wave functions (LFWFs) of the ρ-meson by solving the holographic Schrödinger equation of light-front chiral QCD along with the ’t Hooft equation of (1+1)-dimensional QCD in the large Nc limit. Subsequently, we utilize the obtained LFWFs in conjunction with the color glass condensate dipole cross section to calculate the cross sections for the diffractive ρ-meson electroproduction. Our spectroscopic results align well with the experimental data. Predictions for the diffractive cross sections demonstrate good consistency with the available experimental data at different energies from H1 and ZEUS collaborations. Additionally, we show that the resulting LFWFs for the ρ-meson can effectively describe various properties, including its decay constant, distribution amplitudes, electromagnetic form factors, charge radius, magnetic and quadrupole moments. Comparative analyses are conducted with experimental measurements and the available theoretical predictions.

Published by the American Physical Society
2024
Doubly charmed pentaquark states in QCD sum rules
Authors: Duan Feng-Bo , Wang Qi-Nan , Yang Zi-Yan , Chen Xu-Liang , Chen Wei
Published: May 2024

We have studied the mass spectra of doubly charmed pentaquark states in the Λc(*)D(*) and Σc(*)D(*) channels with JP=1/2±, 3/2±, and 5/2± within the framework of quantum chromodynamics sum rules. We use the parity projected sum rules to separate the contributions of negative and positive parities from the two-point correlations induced by the pentaquark interpolating currents. Our results show that the bound states of Pcc pentaquarks may exist in the ΛcD(12−), ΣcD(12−), ΣcD*(32−), Λc*D(32−), Λc*D*(52−) channels with negative-parity and ΣcD(12+), ΣcD*(32+), Σc*D(32+) channels with positive-parity, since their masses are predicted to be lower than the corresponding meson-baryon thresholds. However, they are still allowed to decay into the Ξcc(*)π final states via strong interaction. The triply charged Pcc+++(ccuud¯) and neutral Pcc0(ccddu¯) in the isospin quartet would definitely be pentaquark states due to their exotic charges. We suggest searching for these characteristic doubly charmed pentaquark signals in the Pcc+++→Ξcc(*)++π+/ρ+, Σc(*)++D(*)+ and Pcc0→Ξcc(*)+π−/ρ−, Σc(*)0D(*)0 decays in the near future.

Published by the American Physical Society
2024
Extraction of nonperturbative parameters for
D(*)
mesons from lattice data
Authors: Nefediev Alexey
Published: May 2024

Recent data for the masses of D and D* mesons determined using methods of lattice QCD for several values of the charm quark mass different from its physical mass are analyzed in heavy quark effective theory. Nonperturbative parameters are extracted that arise at order O(1/mc) in the heavy quark mass expansion of a heavy-light meson mass. The determined parameters are used to establish the charm quark masses corresponding to the employed lattice sets.

Published by the American Physical Society
2024
Nucleon form factors in
Nf=2+1
lattice QCD at the physical point: Finite lattice spacing effect on the root-mean-square radii
Authors: Tsuji Ryutaro , Aoki Yasumichi , Ishikawa Ken-Ichi , Kuramashi Yoshinobu , Sasaki Shoichi , Sato Kohei , Shintani Eigo , Watanabe Hiromasa , Yamazaki Takeshi ,   PACS Collaboration
Published: May 2024

We present results for the nucleon form factors: electric (GE), magnetic (GM), axial (FA), induced pseudoscalar (FP), and pseudoscalar (GP) form factors, using the second PACS10 ensemble that is one of three sets of 2+1 flavor lattice QCD configurations at physical quark masses in large spatial volumes [exceeding (10  fm)3]. The second PACS10 gauge configurations are generated by the PACS Collaboration with the six stout-smeared O(a) improved Wilson quark action and Iwasaki gauge action at the second gauge coupling β=2.00 corresponding to the lattice spacing of a=0.063  fm. We determine the isovector electric, magnetic and axial radii, and magnetic moment from the corresponding form factors, as well as the axial-vector coupling gA. Combining our previous results for the coarser lattice spacing [E. Shintani , ; ], the finite lattice spacing effects on the isovector radii, magnetic moment, and axial-vector coupling are investigated using the difference between the two results. It was found that the effect on gA is kept smaller than the statistical error of 2% while the effect on the isovector radii was observed as a possible discretization error of about 10%, regardless of the channel. We also report the partially conserved axial-vector current relation using a set of nucleon three-point correlation functions in order to verify the effect by O(a) improvement of the axial-vector current.

Published by the American Physical Society
2024
Ultraheavy atomic dark matter freeze-out through rearrangement
Authors: Qiu Yu-Cheng , Sheng Jie , Tan Liang , Xing Chuan-Yang
Published: May 2024

Atomic dark matter is usually considered to be produced asymmetrically in the early Universe. In this work, we first propose that the symmetric atomic dark matter can be thermally produced through the freeze-out mechanism. The dominant atom antiatom annihilation channel is the atomic rearrangement. It has a geometrical cross section much larger than that of elementary fermions. After the atomic formation, this annihilation process further depletes dark matter particles and finally freezes out. To give the observed dark matter relic, the dark atoms are naturally ultraheavy, ranging from 106 to 1010  GeV.

Published by the American Physical Society
2024