bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of an enigmatic tubular ultrastructure in the bacterial defensive symbiont of the Asian citrus psyllid
Authors: Song Chihong , Maruyama Junnosuke , Murata Kazuyoshi , Suzaki Toshinobu , Nakabachi Atsushi 
Published: February 2025

Abstract“CandidatusProfftella armatura” (Betaproteobacteria) is a unique organelle-like defensive symbiont harbored intracellularly within the symbiotic organ of a devastating citrus pest, the Asian citrus psyllidDiaphorina citri(Insecta: Hemiptera). Our previous two-dimensional transmission electron microscopy identified an unprecedented ultrastructure that appeared tubular inProfftella, but their detailed architecture, three-dimensional arrangement, and components were unknown. To address these issues, this study conducted serial block-face scanning electron microscopy, high-voltage electron tomography, and fluorescencein situhybridization. The results revealed that highly elongated (2.8–136 µm observed), string-shapedProfftellacells contain tubes of various numbers (1–43 per cell observed) and length (up to 45 μm observed), depending on the cell length. The tubes were evenly distributed throughout the cells, occupying an average of 6.3% of the total cell volume. Each tube consisted of five or six thin fibers twisted into a right-handed helix, maintaining a consistent diameter of approximately 230 nm along its entire length. Even without fixation or embedding, the tubes retained their shape under high vacuum conditions in electron microscopes, demonstrating their remarkable stability and robustness. These findings suggest that the tubes may help provide mechanical stability to the highly elongated and potentially vulnerableProfftellacells. Further analysis showed that the tubes are closely associated with ribosomes, suggesting a role in protein synthesis. Overall, these results offer new insights into the structural and functional evolution of bacteria, with potential implications for developing novel pest control strategies.Significance statementBacteria generally have simple intracellular structures, lacking organelles. Here, we report a highly elongated, elaborate organelle-like structure with a tubular shape in a bacterial symbiont of an important agricultural pest. The tube, which exhibits high durability and robustness, may contribute to the mechanical stability of the notably elongated symbiont cell. They are closely associated with numerous ribosomes, suggesting a potential role in gene expression. These findings not only enhance our understanding of bacterial evolution but may also provide clues for developing novel strategies for pest control.
Keratinocyte Arginase1 Deficiency Impairs Healing and Antimicrobial Defence againstPseudomonas aeruginosaInfection
Authors: Crompton Rachel A. , Szondi Denis C. , Doherty Christopher , Thomason Helen A. , Lee Sze Han , Loh Yan Ping , O’Neill Catherine A. , Vardy Leah , McBain Andrew J. , Cruickshank Sheena M. 
Published: February 2025

SUMMARYWound infection is a major disruptor of wound healing. Keratinocytes, critical in repair and microbial responses, require the L-arginine hydrolysing enzyme arginase1, for effective healing. Wound pathogens such asPseudomonas aeruginosamay also need L-arginine. We therefore investigated host-microbial interactions in the context of wound healing and L-arginine metabolism. Arginase-inhibited murine wounds challenged withP. aeruginosa,exhibited significantly delayed re-epithelialisation. This finding was recapitulatedin vitrousingP. aeruginosa-challenged, arginase1 deficient (shARG1)keratinocytes, associated with reduced epithelial proliferation and viability, and heightened inflammation. WhilstP. aeruginosachallenge promoted host metabolism of L-arginine, this was perturbed in woundedshARG1keratinocytes. There was, however, heightened downstream polyamine metabolism inshARG1cells when underP. aeruginosachallenge. Host keratinocyte arginase1 deficiency promoted bacterial growthin vitro, in line with a failure to upregulate the anti-microbial peptides,β-defensins,inshARG1scratches. This work demonstrates a pivotal role for keratinocyte arginase1 in wound infection.HIGHLIGHTSHost arginase is required for effective healing underP. aeruginosachallenge.P. aeruginosaenhances host keratinocyte L-arginine metabolism upon scratch.P. aeruginosapromotes polyamine metabolism in arginase1 deficient woundsin vitro.Arginase1 is required for keratinocyte anti-microbial defence againstP. aeruginosa.
Breast cancer multigene germline panel testing in mainstream oncology based on clinical-public health utility (cancer mortality benefit): ESMO Precision Oncology Working Group recommendations
Authors: Turnbull C. , Achatz M.I. , Balmaña J. , Castro E. , Curigliano G. , Cybulski C. , Domchek S.M. , Evans D.G. , Hanson H. , Hoogerbrugge N. , James P.A. , Krause A. , Nathanson K. L. , Yie J. Ngeow Yuen , Robson M. , Tischkowitz M. , Westphalen B. , Foulkes W.D. 
Published: February 2025

AbstractBackgroundWith widening therapeutic indications, germline genetic testing is offered to an increasing proportion of patients with breast cancer (BC) via mainstream oncology services. However, the gene set tested varies widely from just BRCA1/BRCA2 through to ‘pan-cancer’ panels of near 100 genes. If a germline pathogenic variant (GPV) is detected, the BC proband and other family GPV-carriers may be offered interventions such as risk-reducing surgery and decades of intensive surveillance for the various cancers linked to that gene.MethodsESMO’s Precision Oncology Working Group established an international expert group in breast cancer germline genetics. This group firstly established a framework of criteria by which to evaluate each breast cancer susceptibility gene (BCSG) for inclusion on a breast cancer multigene panel test (BC-MGPT) for universal mainstream testing for BC cases. Next the panel scored BCSGs for gene utility regarding (i) BC risk estimation, (ii) clinical actionability (iii) evidence of impact on cancer-specific mortality (and/or morbidity).ResultsThe group agreed genes should be included on the BC-MGPT based on potential cancer-specific mortality (and/or morbidity) benefit. Judged as of high or moderate utility on this basis were 7 genes:BRCA1, BRCA2, PALB2, RAD51C, RAD51DandTP53(for BC diagnosed <40 years), withBRIP1later added. Whilst potentially informative for BC risk estimation,CHEK2andATMwere judged to offer insufficient evidence for improving cancer-specific mortality. The expert group recommended strongly against inclusion of ‘syndromic’ genes such asSTK11, PTEN, NF1andCDH1.ConclusionWith expanded germline testing in patients with BC (and cascade testing into families), the number and nature of resultant GPV carriers identified will be dictated by the genes included on the upfront BC-MGPT. The potential harms, opportunity and economic costs of decades of surveillance of multiple organs and risk-reducing surgeries should be outweighed by strong evidence of meaningful benefit, improved cancer-specific mortality (and/or morbidity).HighlightsESMO expert panel settled a list of genes for inclusion on a BC-MGPT based on potential cancer-specific mortality benefitThis BC-MGPT should include 7 genes:BRCA1, BRCA2, PALB2, RAD51C, RAD51D, BRIP1andTP53(for BC diagnosed <40 years)This BC-MGPT would service urgent diagnostic mainstreaming germline testing requirements for all eligible BC cases‘Syndromic’ genes such asSTK11, PTEN, NF1andCDH1should only be tested downstream post expert review in a minority of BCThe mortality benefit was deemed equivocal forATMandCHEK2, being primarily of intermediate penetrance for ER-positive BC
New Insights into Epileptic Spasm Generation and Treatment from the TTX Animal Model
Authors: Swann John W. , Ballester-Rosado Carlos J. , Lee Chih-Hong 
Published: February 2025

SummaryCurrently, we have an incomplete understanding of the mechanisms underlying infantile epileptic spasms syndrome (IESS). However, over the past decade, significant efforts have been made to develop IESS animal models to provide much-needed mechanistic information for therapy development. Our laboratory has focused on the TTX model, in which tetrodotoxin (TTX) is infused into the neocortex of infant rats, producing a lesion at the infusion site and mimicking IESS resulting from acquired structural brain abnormalities. Subsequent electrophysiological studies showed that the epileptic spasms originate from neocortical layer V pyramidal cells. Importantly, experimental maneuvers that increase the excitability of these cells produce focal seizures in non-epileptic control animals but never produce them in TTX-infused epileptic rats; instead, epileptic spasms are produced in epileptic rats, indicating a significant transformation in the operations of neocortical networks. At the molecular level, studies showed that the expression of insulin-like growth factor 1 was markedly reduced in the cortex and this corresponded with a loss of presynaptic GABAergic nerve terminals. Very similar observations were made in surgically resected tissue from IESS patients with a history of perinatal strokes. Other experiments in conditional knockout mice indicated that IGF-1 plays a critical role in the maturation of neocortical inhibitory connectivity. This finding led to our hypothesis that the loss of IGF-1 in epileptic animals impairs inhibitory interneuron synaptogenesis and is responsible for spasms. To test this idea, we treated epileptic rats with the IGF-1-derived tripeptide (1-3)IGF-1, which was shown to act through IGF-1’s receptor. (1-3)IGF-1 rescued inhibitory interneuron connectivity, restored IGF-1 levels, and abolished spasms. Thus (1-3)IGF-1 or its analogues are potential novel treatments for IESS following perinatal brain injury. We conclude by discussing our findings in the broader context of the often-debated final common pathway hypothesis for IESS.We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.Plain Language SummaryWe review recent findings from the TTX animal model of infantile epileptic spasms syndrome, which show that these seizures come from an area of the brain called the neocortex. In this area, the amount of an important growth factor called IGF-1 is reduced, as is the number of inhibitory synapses that play an important role in preventing seizures. Other results indicate that the loss of IGF-1 prevents the normal development of these inhibitory synapses. Treatment of epileptic animals with (1-3)IGF-1 restored IGF-1 levels and inhibitory synapses and abolished spasms. Thus, (1-3)IGF-1 or an analogue are potential new therapies for epileptic spasms.
Egress-enhancing mutation reveals inefficiency of non-enveloped virus cell exit
Authors: Rodriguez-Irizarry Valerie J. , Maples Robert W. , Pfeiffer Julie K. 
Published: February 2025

AbstractViruses encounter a range of selective pressures, but inefficiencies during replication can be masked. To uncover factors that limit viral replication, we used forward genetics to enrich for a murine norovirus (MNV) mutant with faster replication. We sequentially harvested the earliest progeny in cultured cells and identified a single amino acid change in the viral NS3 protein, K40R, that was sufficient to enhance replication speed. We found that the NS3-K40R virus induced earlier cell death and viral egress compared with wild-type virus. Mechanistically, NS3-K40R protein disrupted membranes more efficiently than wild-type NS3 protein, potentially contributing to increased mitochondrial dysfunction and cell death. Mice infected with NS3-K40R virus had increased titers, suggesting that increasing egress did not reduce fitnessin vivo. Overall, by using a forward genetic approach, we identified a previously unknown inefficiency in norovirus egress and provide new insights into selective pressures that influence viral replication and evolution.
Mass mortality events in the sub-Antarctic Indian Ocean caused by long-distance circumpolar spread of highly pathogenic avian influenza H5N1 clade 2.3.4.4b
Authors: Clessin Augustin , Briand François-Xavier , Tornos Jérémy , Lejeune Mathilde , Pasquale Camille De , Fischer Romain , Souchaud Florent , Hirchaud Edouard , Bralet Tristan , Guinet Christophe , McMahon Clive R. , Grasland Béatrice , Baele Guy , Boulinier Thierry 
Published: February 2025

AbstractSince 2020, the outbreak of highly pathogenic avian influenza (HPAI) virus clade 2.3.4.4b has turned into the largest documented panzootic to date, reaching the sub-Antarctic region and Antarctica via the tip of South America in 2023. Here, we describe its recent arrival into the Indian Ocean sub-Antarctic archipelagos of Crozet and Kerguelen, where we first detected the virus in October 2024 in dead southern elephant seals, king penguins, gentoo penguins, brown skuas and kelp gulls. While the panzootic is ongoing, it has already caused unprecedented and alarming mortalities of southern elephant seals. We collected brain swabs from various seal and bird carcasses, subsequently isolated the virus and obtained 25 novel HPAI H5N1 clade 2.3.4.4b sequences. Our phylogenetic and phylogeographic analyses show that there have been independent introductions of the virus to Crozet and Kerguelen, from the distant South Georgia Islands in the Southern Atlantic, and not from the more nearby coasts of South Africa. Our results point to a year-long gap in genomic surveillance in the south polar region, obscuring how HPAI H5N1 clade 2.3.4.4b is spreading in the sub-Antarctic and illustrating the difficulties in tracking pathogen dispersal in the region. Locally, our phylogenetic analyses show that the virus is transmitted between different species. Moreover, our serological analyses show that some southern elephant seal pups had mounted an anti-H5 antibody response. With the spread to Crozet and Kerguelen, HPAI H5N1 2.3.4.4b is moving ever closer to Australia and New Zealand, which currently remain free from infections with this strain, and represents a major threat to the sub-Antarctic wildlife. Our results provide key elements to enable stakeholders to anticipate the arrival and spread of the virus in remote areas of critical wildlife conservation concerns.
MsyB-HU Interaction Modulates a Two-Tiered Bacterial Stress Response by Regulating DNA Supercoiling
Authors: Chen Huan , Yang Yanan , Chen Xinrui , Zhou Haolong , He Yingli , Li Mengzhe , Lin Wei , Yuan Zuyi , Wang Yawen , Matthews Steve , Yuan Shuai , Wang Hongliang , Liu Bing 
Published: February 2025

ABSTRACTBacteria respond to stressful conditions through multiple pathways, including changes in gene expression patterns and mutations for adaptation. DNA supercoiling is a fundamental regulatory principle of bacterial gene expression, controlled antagonistically by DNA gyrase and topoisomerase I. Nucleoid-associated proteins, such as HU, also regulate supercoiling through interactions with DNA. Here, we identifyEscherichia coliprotein MsyB as a HU inhibitor and a β-clamp binder. MsyB is fine-tuned under various stressful conditions, where it modulates the population of DNA-bound HU by forming a HU-MsyB complex. Consequently, the balance between DNA-bound HU and MsyB-bound HU adjusts the DNA supercoiling state, thereby influencing transcription for adaptation. Additionally, under prolonged starvation during the stationary phase, sustained high level of MsyB increases DNA exposure to damaging factors, acting as a damage inducer. The HU/MsyB/β-clamp interaction suggests a model in which MsyB coordinates with HU and the β-clamp to facilitate damage acquisition and error-prone DNA repair. Thus, MsyB-dependent supercoiling regulation represents a novel two-tiered bacterial stress response mechanism in gene expression and adaptive mutation. Our findings reveal a previously unrecognized regulatory mechanism of bacterial supercoiling, positioning HU as a promising antibiotic target.
Derivation and analysis of human somatic sensory neuron subtypes facilitated through fluorescent hPSC reporters
Authors: Malka-Gibor Eti , Oliver Katherine M. , Chen Shirley , Garcia-Diaz Alejandro , Williams Damian , Corneo Barbara , de Nooij Joriene C. 
Published: February 2025

SummaryPeripheral sensory neuropathy (PSN) is associated with several devastating neurological conditions, yet effective strategies to prevent or alleviate the consequences of PSN are nearly non-existent. A major challenge in the development of better therapeutic interventions is the lack of appropriate human model systems. Human induced pluripotent stem cell (hiPSC)-derived somatosensory neurons present a promising strategy to overcome this issue but remain of limited translational utility, in part due to the low efficiency and lack of sensory subtype selectivity of the existing sensory neuron derivation protocols. To improve upon iPSC-based somatosensory disease models, we here describe the generation and validation of a genetic toolset to fluorescently label all or distinct (nociceptor, low threshold mechanoreceptor, and proprioceptor) somatosensory subtypes. These new resources will be transformative for hPSC-based approaches in PSN disease modeling - a critical step towards translating new findings into clinically relevant therapeutic strategies.
Relationships between GABA+ and Glx concentrations with age and inhibition in healthy older adults
Authors: Treacy Ciara , Andrews Sophie C. , Levenstein Jacob M. 
Published: February 2025

AbstractInhibition represents a core executive function which underlies the ability to suppress interfering and/or distracting stimuli, thereby building resistance against task-irrelevant information. However, the impact of ageing on inhibitory functioning and the potential role of neuroplasticity - largely driven by predominant excitatory (glutamatergic) and inhibitory (GABAergic) neurochemicals – remains poorly understood. In this study, we investigated age relationships with neurochemical concentrations (GABA+ and Glx) and examined the associations between these neurochemicals and inhibitory sub-components in the context of healthy ageing. To this end, participants completed three inhibition tasks (i.e., flanker, Stroop and go/no-go), each measuring a different sub-component process, via the PsyToolkit platform. MRS data was acquired in the sensorimotor (SM1; n=71, mean age (SD) = 68.3 (±9.7) years, 39 females) and prefrontal (PFC; n=58, mean age (SD) = 67.6 (±9.6) years, 30 females) regions using a HERMES sequence and analysed using OSPREY’s pipeline. After correcting for gender and education, semi-partial correlations (rho) revealed no significant relationships between age and GABA+ or Glx concentrations in either the SM1 or PFC regions. Furthermore, through partial correlations (rho), after correcting for age, gender and education, we identified a significant negative relationship between SM1 Glx concentrations and go/no-go error rates, such that greater concentrations of Glx in the SM1 region were associated with greater accuracy on the go/no-go task. The null age-neurochemical results suggest that GABA+ and Glx may not uniformly decline during healthy ageing. This finding suggests that the relationship between older age and neurochemistry may be more nuanced than previously reported. In addition, our neurochemical-behavioural findings provide neurochemically-and-spatially specific evidence that SM1 Glx concentrations may be important for response inhibition. This result indicates a role for the glutamatergic system in supporting inhibition over the normal course of ageing.
Interpersonal synchronization as an objective measure of listening engagement
Authors: Lambrechts Lotte , Accou Bernd , Vanthornhout Jonas , Boets Bart , Francart Tom 
Published: February 2025

AbstractListening engagement has received increasing attention for its role in effective communication and knowledge transfer. It encompasses a state of deep listening in which a person not only pays attention to a stimulus but is fully absorbed in it. Behavioral measures have been used to assess listening engagement; however, they have limitations and do not fully capture this multidimensional state. Measuring listening engagement objectively using brain and body signals is a compelling alternative. In particular, interpersonal synchronization—observed through synchronized physiological responses among listeners—offers a promising objective measure of this phenomenon. We measured brain, heart rate, and electrodermal activity synchronization between people who listened to engaging and non-engaging stories. As a ground truth, we also measured subjective listening engagement through a questionnaire. Results showed higher synchronization when participants listened to an engaging stimulus compared to a non-engaging one across different modalities of objective response. Furthermore, we found a significant correlation between synchronization measures and subjective engagement ratings. These results confirm that synchronization may serve as a reliable measure of listening engagement.
Neural variability reliably and selectively encodes pain discriminability
Authors: Zhang Libo , Geng Xinyi , Hu Li 
Published: February 2025

AbstractNeural activity varies dramatically across time. While such variability has been associated with cognition, its relationship with pain remains largely unexplored. Here, we systematically investigated the relationship between neural variability and pain, particularly pain discriminability, in five large electroencephalography (EEG) datasets (total N = 489), collected from healthy individuals (Datasets 1–4) and patients with postherpetic neuralgia (PHN; Dataset 5) who had received painful or nonpainful sensory stimuli. We found robust correlations between neural variability and interindividual pain discriminability. These correlations were (1) replicable in multiple datasets, (2) pain selective, as no significant correlations were observed in nonpain modalities, and (3) clinically relevant, as they were partly disrupted in patients with PHN. Importantly, variability and amplitude of EEG signals were mutually independent and had distinct temporal and oscillatory profiles in encoding pain discriminability. These findings demonstrate that neural variability is a replicable and selective indicator of pain discriminability above and beyond amplitude, thereby enhancing the understanding of neural encoding of pain discriminability and underscoring the value of neural variability in pain studies.