bluuebunny/crossref_metadata_2025_split huggingface dataset:
Infant attachment does not depend on neonatal amygdala and hippocampal structure and connectivity
Authors: Jiménez-Sánchez Lorena , Cabez Manuel Blesa , Vaher Kadi , Corrigan Amy , Thrippleton Michael J. , Bastin Mark E. , Quigley Alan J. , Fletcher-Watson Sue , Boardman James P. 
Published: December 2023

AbstractInfant attachment is an antecedent of later socioemotional abilities, which can be adversely affected by preterm birth. The structural integrity of amygdalae and hippocampi are associated with attachment in childhood. We aimed to investigate associations between neonatal amygdalae and hippocampi structure and their whole-brain connections and attachment behaviours at nine months of age in a sample of infants enriched for preterm birth. In 133 neonates (median gestational age 32 weeks, range 22.14–42.14), we calculated measures of amygdala and hippocampal structure (volume, fractional anisotropy, mean diffusivity, neurite dispersion index, orientation dispersion index) and structural connectivity, and coded attachment behaviours (distress, fretfulness, attentiveness to caregiver) from responses to the Still-Face Paradigm at nine months. After multiple comparisons correction, there were no significant associations between neonatal amygdala or hippocampal structure and structural connectivity and attachment behaviours: standardised β values -0.23 to 0.21, adjusted p-values > 0.34. Findings indicate that the neural basis of infant attachment in term and preterm infants is not contingent on the structure or connectivity of the amygdalae and hippocampi in the neonatal period, which implies that it is more widely distributed in early life and or that network specialisation takes place in the months after hospital discharge.Highlights133 infants had brain MRI and attachment data based on the Still-Face Paradigm.The structure of amygdalae and hippocampi and their brain networks was examined.Neonatal amygdalae/hippocampi structure did not associate with infant attachment.Infant attachment is not contingent on neonatal amygdala/hippocampal connectivity.Graphical abstract
From Text to Tables: A Local Privacy Preserving Large Language Model for Structured Information Retrieval from Medical Documents
Authors: Wiest Isabella C. , Ferber Dyke , Zhu Jiefu , van Treeck Marko , Meyer Sonja K. , Juglan Radhika , Carrero Zunamys I. , Paech Daniel , Kleesiek Jens , Ebert Matthias P. , Truhn Daniel , Kather Jakob Nikolas 
Published: December 2023

AbstractBackground and AimsMost clinical information is encoded as text, but extracting quantitative information from text is challenging. Large Language Models (LLMs) have emerged as powerful tools for natural language processing and can parse clinical text. However, many LLMs including ChatGPT reside in remote data centers, which disqualifies them from processing personal healthcare data. We present an open-source pipeline using the local LLM “Llama 2” for extracting quantitative information from clinical text and evaluate its use to detect clinical features of decompensated liver cirrhosis.MethodsWe tasked the LLM to identify five key clinical features of decompensated liver cirrhosis in a zero- and one-shot way without any model training. Our specific objective was to identify abdominal pain, shortness of breath, confusion, liver cirrhosis, and ascites from 500 patient medical histories from the MIMIC IV dataset. We compared LLMs with three different sizes and a variety of pre-specified prompt engineering approaches. Model predictions were compared against the ground truth provided by the consent of three blinded medical experts.ResultsOur open-source pipeline yielded in highly accurate extraction of quantitative features from medical free text. Clinical features which were explicitly mentioned in the source text, such as liver cirrhosis and ascites, were detected with a sensitivity of 100% and 95% and a specificity of 96% and 95%, respectively from the 70 billion parameter model. Other clinical features, which are often paraphrased in a variety of ways, such as the presence of confusion, were detected only with a sensitivity of 76% and a specificity of 94%. Abdominal pain was detected with a sensitivity of 84% and a specificity of 97%. Shortness of breath was detected with a sensitivity of 87% and a specificity of 96%. The larger version of Llama 2 with 70b parameters outperformed the smaller version with 7b parameters in all tasks. Prompt engineering improved zero-shot performance, particularly for smaller model sizes.ConclusionOur study successfully demonstrates the capability of using locally deployed LLMs to extract clinical information from free text. The hardware requirements are so low that not only on-premise, but also point-of-care deployment of LLMs are possible.Lay summaryWe leveraged the large language model Llama 2 to extract five key features of decompensated liver cirrhosis from medical history texts, simplifying the analysis of complex text-based healthcare data.
Cell-state transitions and frequency-dependent interactions among subpopulations together explain the dynamics of spontaneous epithelial-mesenchymal heterogeneity in breast cancer
Authors: Jain Paras , Kizhuttil Ramanarayanan , Nair Madhav B , Bhatia Sugandha , Thompson Erik W , George Jason T. , Jolly Mohit Kumar 
Published: December 2023

AbstractIndividual cells in a tumour can be distributed among Epithelial (E) and Mesenchymal (M) cell-states, as characterised by the levels of canonical E and M markers. Even after E and M (E-M) subpopulations are isolated and then cultured independently, E-M heterogeneity can re-equilibrate in each population over time, sometimes regaining the initial distribution of the parental cell population. However, it remains unclear which population-level processes give rise to the dynamical changes in E-M heterogeneity observed experimentally, including 1) differential growth, 2) cell-state switching, and 3) frequency-dependent growth or state-transition rates. Here, we analyse the necessity of these three processes in explaining the dynamics of E-M population distributions as observed in PMC42-LA and HCC38 breast cancer cells. We find that growth differences among E and M subpopulations, with and without any frequency-dependent interactions (cooperation or suppression) among E-M sub-populations, are insufficient to explain the observed population dynamics. This insufficiency is ameliorated by including cell-state transitions, albeit at slow rates, in explaining both PMC42-LA and HCC38 cells data. Further, our models predict that treatment of HCC38 cells with TGFβ signalling and JAK2/3 inhibitors could significantly enhance the transition rates from M state to E state, but does not prevent transitions from E to M. Finally, we devise a selection criterion to identify the next most informative time points for which future experimental data can optimally improve the identifiability of our estimated best fit model parameters. Overall, our study identifies the necessary population-level processes shaping the dynamics of E-M heterogeneity in breast cancer cells.
Human monoclonal antibodies reveal subdominant gonococcal and meningococcal cross-protective antigens
Authors: Troisi Marco , Fabbrini Monica , Stazzoni Samuele , Viviani Viola , Carboni Filippo , Abbiento Valentina , Fontana Lucia Eleonora , Tomei Sara , Audagnotto Martina , Santini Laura , Spagnuolo Angela , Antonelli Giada , Paciello Ida , Vacca Fabiola , Cardamone Dario , Marini Eleonora , Mokhtary Pardis , Finetti Francesca , Giusti Fabiola , Bodini Margherita , Torricelli Giulia , Limongi Chiara , Del Vecchio Mariangela , Favaron Sara , Tavarini Simona , Sammicheli Chiara , Rossi Alessandro , Mandelli Andrea Paola , Fortini Pietro , Caffarelli Carla , Gonnelli Stefano , Nuti Ranuccio , Baldari Cosima T. , Sala Claudia , Tagliabue Aldo , Savino Silvana , Brunelli Brunella , Norais Nathalie , Frigimelica Elisabetta , Bardelli Monia , Pizza Mariagrazia , Margarit Immaculada , Delany Isabel , Finco Oretta , Andreano Emanuele , Rappuoli Rino 
Published: December 2023

ABSTRACTGonococcus (Gc), a bacterium resistant to most antibiotics causing more than 80 million cases of gonorrhea annually, is a WHO high priority pathogen. Recently, vaccine development prospects were boosted by reports that licensed meningococcus serogroup B (MenB) vaccines provided partial protection against Gc infection. To determine antigens responsible for cross-protection, memory B cells from 4CMenB vaccinated volunteers were single-cell sorted to identify antibodies that kill Gc in a bactericidal assay. Nine different antibodies, all deriving from the IGHV4-34 germline carrying unusually long HCDR3s, recognized the PorB protein, four recognized the lipooligosaccharide (LOS), and four unknown antigens. One of the PorB antibodies, tested in vivo, provided protection from Gc infection. The identification of PorB and LOS as key antigens of gonococcal and meningococcal immunity provides a mechanistic explanation of the cross-protection observed in the clinic and shows that isolating human monoclonal antibodies from vaccinees can be instrumental for bacterial antigen discovery.
Control of a type III-Dv CRISPR‒Cas system by the transcription factor RpaB and interaction of its leader transcript with the DEAD-box RNA helicase CrhR
Authors: Bilger Raphael , Migur Angela , Wulf Alexander , Steglich Claudia , Urlaub Henning , Hess Wolfgang R. 
Published: December 2023

ABSTRACTCRISPR‒Cas systems in bacteria and archaea provide powerful defense against phages and other foreign genetic elements. The principles of CRISPR‒Cas activity are well understood, but less is known about how their expression is regulated. The cyanobacteriumSynechocystissp. PCC 6803 encodes three different CRISPR‒Cas systems. The expression of one of these, a type III-Dv system, responds to changes in environmental conditions, such as nitrogen starvation or varying light intensities. Here, we found that the promoter of the six-genecasoperon for the type III-Dv system is controlled by the light-and redox-responsive transcription factor RpaB. RpaB binds to an HLR1 motif located 53 to 70 nt upstream of the transcription start site, resulting in transcriptional activation at low light intensities. However, the strong promoter that drives transcription of the cognate repeat-spacer array is not controlled by RpaB. Instead, we found that the 125 nt leader transcript is bound by the redox-sensitive RNA helicase CrhR. Crosslinking coupled to mass spectrometry analysis revealed six residues involved in the CrhR-RNA interaction. Of these, L103, F104, H225, and C371 were predicted to be on the surface of a dimeric CrhR model, while C184 was not on the surface, and P443 could not be assigned to a structural element. These results showed that the expression of the CRISPR‒Cas system is linked to the redox status of the photosynthetic cyanobacterial cell at two different levels. While RpaB affects transcription, CrhR interacts with the leader transcript posttranscription. These results highlight the complex interplay between a CRISPR‒Cas system and its host cell.
Syndrome-informed phenotyping identifies a polygenic background for achondroplasia-like facial variation in the general population
Authors: Vanneste Michiel , Hoskens Hanne , Goovaerts Seppe , Matthews Harold , Aponte Jose D , Cole Joanne , Shriver Mark , Marazita Mary L. , Weinberg Seth M. , Walsh Susan , Richmond Stephen , Klein Ophir D , Spritz Richard A , Peeters Hilde , Hallgrímsson Benedikt , Claes Peter 
Published: December 2023

AbstractHuman craniofacial shape is highly variable yet highly heritable with genetic variants interacting through multiple layers of development. Here, we hypothesize that Mendelian phenotypes represent the extremes of a phenotypic spectrum and, using achondroplasia as an example, we introduce a syndrome-informed phenotyping approach to identify genomic loci associated with achondroplasia-like facial variation in the normal population. We compared three-dimensional facial scans from 43 individuals with achondroplasia and 8246 controls to calculate achondroplasia-like facial scores. Multivariate GWAS of the control scores revealed a polygenic basis for normal facial variation along an achondroplasia-specific shape axis, identifying genes primarily involved in skeletal development. Jointly modeling these genes in two independent control samples showed craniofacial effects approximating the characteristic achondroplasia phenotype. These findings suggest that both complex and Mendelian genetic variation act on the same developmentally determined axes of facial variation, providing new insights into the genetic intersection of complex traits and Mendelian disorders.
O-glycans Expand Lubricin and Attenuate its Viscosity and Shear Thinning
Authors: Boushehri Saber , Holey Hannes , Brosz Matthias , Gumbsch Peter , Pastewka Lars , Aponte-Santamaría Camilo , Gräter Frauke 
Published: December 2023

AbstractLubricin, an intrinsically disordered glycoprotein, plays a pivotal role in facilitating smooth movement and ensuring the enduring functionality of synovial joints. The central domain of this protein serves as a source of this excellent lubrication, and is characterized by its highly glycosylated, negatively charged, and disordered structure. However, the influence of O-glycans on the viscosity of lubricin remains unclear. In this study, we employ molecular dynamics simulations in absence and presence of shear, along with continuum simulations, to elucidate the intricate interplay between O-glycans and lubricin and the impact of O-glycans on lubricin’s conformational properties and viscosity. We find the presence of O-glycans to induce a more extended conformation in fragments of the disordered region of lubricin. These O-glycans contribute to a reduction in solution viscosity but at the same time weaken shear thinning at high shear rates, compared to non-glycosylated systems with the same density. This effect is attributed to the steric and electrostatic repulsion between the fragments, which prevent their conglomeration and structuring. Our computational study yields a mechanistic mechanism underlying previous experimental observations of lubricin and paves the way to more rationally understanding its function in the synovial fluid.
The cryoEM structure of theHendra henipavirusnucleoprotein reveals insights into paramyxoviral nucleocapsid architectures
Authors: Passchier Tim C , White Joshua B R , Maskell Daniel P , Byrne Matthew J , Ranson Neil A , Edwards Thomas A , Barr John N 
Published: December 2023

AbstractWe report the first cryoEM structure of theHendra henipavirusnucleoprotein in complex with RNA, at 3.5 Å resolution, derived from single particle analysis of homotetradecameric RNA-bound N protein rings exhibiting D14 symmetry. The structure of the HeV N protein adopts the common bi-lobed paramyxoviral N protein fold; the N-terminal and C-terminal globular domains are bisected by an RNA binding cleft containing six RNA nucleotides and are flanked by the N-terminal and C-terminal arms, respectively. In common with other paramyxoviral nucleocapsids, the lateral interface between adjacent N and N+1protomers involves electrostatic and hydrophobic interactions mediated primarily through the N-terminal arm and globular domains with minor contribution from the C-terminal arm. However, the HeV N multimeric assembly uniquely identifies an additional interaction between N+1and N-1protomers. The model presented here broadens the understanding of RNA-bound paramyxoviral nucleocapsid architectures and provides a platform for further insight into the molecular biology of HeV, as well as the development of antiviral interventions.
Extracellular vesicles released by keratinocytes regulate melanosome maturation, melanocyte dendricity and pigment transfer
Authors: Prospéri Marie-Thérèse , Giordano Cécile , Gomez-Duro Mireia , Hurbain Ilse , Macé Anne-Sophie , Raposo Graça , D’Angelo Gisela 
Published: December 2023

ABSTRACTExtracellular vesicles (EVs) facilitate the transfer of proteins, lipids and genetic material molecules between cells, and are recognized as an additional mechanism for sustaining intercellular communication. In the epidermis, the communication between melanocytes and keratinocytes is tightly regulated to warrant skin pigmentation. Melanocytes synthetize the melanin pigment in melanosomes that are transported along the dendrites prior to the transfer of melanin pigment to keratinocytes. EVs secreted by keratinocytes modulate pigmentation in melanocytes (Lo Cicero et al., Nat. Comm. 2015). However, whether EVs secreted by keratinocytes contribute to additional processes essential for melanocyte functions remains elusive. Here we show that keratinocyte EVs enhance the ability of melanocytes to generate dendrites, mature melanosomes and their efficient transfer. Further, keratinocyte EVs carrying Rac1 induce important morphological changes, promote dendrite outgrowth, and potentiate melanin transfer to keratinocytes. Hence, in addition to modulate pigmentation, keratinocytes exploit EVs to control melanocyte plasticity and transfer capacity. These data demonstrate that keratinocyte-derived EVs, by regulating melanocyte functions, are major contributors of cutaneous pigmentation and expand our understanding of the mechanism underlying skin pigmentation via a paracrine EV-mediated communication.SIGNIFICANCE STATEMENTOur work uncovers how keratinocyte-derived EVs control melanocyte physiology and functions. By promoting the growth of melanocyte dendrites, maturation, accumulation and peripheral positioning of pigmented melanosomes within the dendrites, and transfer of melanin to keratinocytes, EVs released by keratinocytes control crucial processes in skin photo protection. Importantly, given that dysregulation of these pathways could underlie pigment disorders, melanoma or skin carcinoma, our results open avenues to exploit keratinocyte EVs as tools for the design of new therapies to enhance the ability of melanocytes to provide skin photoprotection, and thus decrease the incidence pigmentary disorders and skin cancers.
Three-dimensional reconstruction of fetal rhesus macaque kidneys at single-cell resolution reveals complex inter-relation of structures
Authors: Dequiedt Lucie , Forjaz André , Lo Jamie O. , McCarty Owen , Wu Pei-Hsun. , Rosenberg Avi , Wirtz Denis , Kiemen Ashley 
Published: December 2023

AbstractKidneys are among the most structurally complex organs in the body. Their architecture is critical to ensure proper function and is often impacted by diseases such as diabetes and hypertension. Understanding the spatial interplay between the different structures of the nephron and renal vasculature is crucial. Recent efforts have demonstrated the value of three-dimensional (3D) imaging in revealing new insights into the various components of the kidney; however, these studies used antibodies or autofluorescence to detect structures and so were limited in their ability to compare the many subtle structures of the kidney at once. Here, through 3D reconstruction of fetal rhesus macaque kidneys at cellular resolution, we demonstrate the power of deep learning in exhaustively labelling seventeen microstructures of the kidney. Using these tissue maps, we interrogate the spatial distribution and spatial correlation of the glomeruli, renal arteries, and the nephron. This work demonstrates the power of deep learning applied to 3D tissue images to improve our ability to compare many microanatomical structures at once, paving the way for further works investigating renal pathologies.
Modulation ofSalmonellavirulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex
Authors: Yu Xiu-Jun , Xie Haixia , Li Yan , Liu Mei , Hou Ruhong , Predeus Alexander V. , Perez Sepulveda Blanca M. , Hinton Jay C. D. , Holden David W. , Thurston Teresa L. M. 
Published: December 2023

AbstractThe injectisome encoded bySalmonellapathogenicity island 2 (SPI-2) had been thought to translocate 28 effectors. Here, we used a proteomic approach to characterise the secretome of a clinical strain of invasive non-typhoidalSalmonella entericaserovar Enteritidis, that had been mutated to cause hyper-secretion of the SPI-2 injectisome effectors. Along with many known effectors, we discovered the novel SseM protein.sseMis widely distributed between the five subspecies ofSalmonella enterica,is found in many clinically-relevant serovars, and is co-transcribed withpipB2, aSPI-2 effector gene. Translocation of SseM required a functional SPI-2 injectisome. Following expression in human cells, SseM interacted with five components of the dystrophin-associated protein complex (DAPC), namely β-2-syntrophin, utrophin/ dystrophin, α-catulin, α-dystrobrevin and β-dystrobrevin. The interaction between SseM and β-2-syntrophin and α-dystrobrevin was verified inS.Typhimurium-infected cells and relied on the PDZ domain of β-2-syntrophin and a sequence corresponding to a PDZ-binding motif (PBM) in SseM. A ΔsseMmutant strain had a small competitive advantage over the wild-type strain in theS.Typhimurium/mouse model of systemic disease. This phenotype was complemented by a plasmid expressing wild type SseM fromS.Typhimurium orS.Enteritidis and was dependent on the PBM of SseM. Therefore, a PBM within aSalmonellaeffector mediates interactions with the DAPC and modulates systemic growth of bacteria in mice.ImportanceInSalmonella enterica, the injectisome machinery encoded bySalmonellapathogenicity island 2 (SPI-2) is conserved among the five subspecies and delivers proteins (effectors) into host cells that are required forSalmonellavirulence. The identification and functional characterisation of SPI-2 injectisome effectors advances our understanding of the interplay betweenSalmonellaand its host(s). Using an optimised method for preparing secreted proteins and a clinical isolate of the invasive non-typhoidal (iNTS)Salmonella entericaserovar Enteritidis strain D24359, we identified 22 known SPI-2 injectisome effectors and one new effector - SseM. SseM modulates bacterial growth during murine infection and has a sequence corresponding to a PDZ-binding motif that is essential for interaction with the PDZ-containing host protein β-2-syntrophin and other components of the dystrophin-associated protein complex (DAPC). To our knowledge, SseM is unique amongSalmonellaeffectors in containing a functional PDZ-binding motif and is the first bacterial protein to target the DAPC.