bluuebunny/crossref_metadata_2025_split huggingface dataset:
p75NTR modulation by LM11A-31 counteracts oxidative stress and cholesterol dysmetabolism in a rotenone-induced cell model of Parkinson’s disease
Authors: Pensabene Daniele , Martella Noemi , Scavo Giuseppe , Varone Michela , Bisesto Emanuele , Cavicchia Francesca , Colardo Mayra , Moreno Sandra , Segatto Marco 
Published: December 2024

AbstractNeurotrophins play pivotal roles in the development and proper functioning of the nervous system. The effects of these growth factors are mediated through the binding of high-affinity receptors, known as Trks, as well as the low-affinity receptor p75NTR. The latter has the capacity to induce complex signal pathways, as it favors both pro-survival and pro-apoptotic cascades depending on the physiopathological condition. Recent findings have indicated that p75NTR expression is increased in post-mortem Parkinson’s disease (PD) brains, and this upregulation is associated with a significant reduction in neuroprotection. Given its double-edged sword nature, p75NTR has recently been identified as a promising therapeutic target to counteract neurodegenerative events. The present study aims to assess the neuroprotective effects of p75NTR modulation in a rotenone-induced neuronal model of PD. To this end, differentiated SH-SY5Y cells were exposed to rotenone to mimic the PD phenotype, and the small molecule LM11A-31 was used to modulate p75NTR activity. The main results revealed that LM11A-31 significantly mitigated the hallmarks of PD, including cell death, neuromorphological aberrations, and α-synuclein accumulation. Pharmacological manipulation of p75NTR also reduced oxidative damage by increasing the expression of transcriptional factors that regulate the antioxidant response and by decreasing the expression of the pro-oxidant NADPH-oxidase modulatory subunits. Furthermore, LM11A-31 hampered cholesterol buildup induced by rotenone, normalizing the expression of proteins involved in cholesterol biosynthesis, uptake and intracellular trafficking. Taken together, these findings suggest that p75NTR modulation may represent a novel approach to counteracting PD abnormalities of redox and cholesterol metabolism.
Implementing Trust in Non-Small Cell Lung Cancer Diagnosis with a Conformalized Uncertainty-Aware AI Framework in Whole-Slide Images
Authors: Zhang Xiaoge , Wang Tao , Yan Chao , Najdawi Fedaa , Zhou Kai , Ma Yuan , Cheung Yiu-ming , Malin Bradley A. 
Published: December 2024

ABSTRACTEnsuring trustworthiness is fundamental to the development of artificial intelligence (AI) that is considered societally responsible, particularly in cancer diagnostics, where a misdiagnosis can have dire consequences. Current digital pathology AI models lack systematic solutions to address trustworthiness concerns arising from model limitations and data discrepancies between model deployment and development environments. To address this issue, we developed TRUECAM, a framework designed to ensure both data and model trustworthiness in non-small cell lung cancer subtyping with whole-slide images. TRUECAM integrates 1) a spectral-normalized neural Gaussian process for identifying out-of-scope inputs and 2) an ambiguity-guided elimination of tiles to filter out highly ambiguous regions, addressing data trustworthiness, as well as 3) conformal prediction to ensure controlled error rates. We systematically evaluated the framework across multiple large-scale cancer datasets, leveraging both task-specific and foundation models, illustrate that an AI model wrapped with TRUECAM significantly outperforms models that lack such guidance, in terms of classification accuracy, robustness, interpretability, and data efficiency, while also achieving improvements in fairness. These findings highlight TRUECAM as a versatile wrapper framework for digital pathology AI models with diverse architectural designs, promoting their responsible and effective applications in real-world settings.
NeoPhAR: Next-generation Phage Therapy for Antimicrobial Resistance
Authors: Rivera-Orellana Sebastián , Yeager Justin , Tejera Eduardo , López-Cortés Andrés 
Published: December 2024

ABSTRACTGrowing antimicrobial resistance (AMR) infections are among the top contemporary concerns in public healthcare systems which can place considerable burdens on healthcare systems. Phage therapy has long been considered a viable option to help combat AMR infections, including on broad geographic scales. One bottleneck in the application of phage therapy is the accurate matching of host-specific phages to bacterial strains, which is traditionally done using molecular techniques. Here we present an open-access deep learning-based model that shows incredible potential to accurately predict phages for therapeutic use. Our goal is to attenuate the matching process so that specific phages, or a cocktail of phages can be prepared for patients with a high probability of therapeutic success, helping to democratize phage therapy treatments even in low to middle-income countries where genomic resources can be limited, costly, or time prohibitive. We feel this is an important first step towards incorporating and applying bioinformatic practices in promising fields such as phage therapy.
The Arp2/3 complex maintains genome integrity and survival of epidermal Langerhans cells
Authors: Delgado Maria-Graciela , Burkhart Ann-Kathrin , Villar Javiera , Amadio Roberto , Racz Vanessa S. , Sanséau Doriane , De Silva Nilushi , Mariano Livia Lacerda , Shmakova Anna , Chipont Anna , San Roman Mabel , Bracchetti Giulia , Calmettes Vincent , Alraies Zahraa , Maurin Mathieu , Dauphin Aurelien , Guerin Coralie , Ginhoux Florent , Manel Nicolas , Fachinetti Daniele , Benvenuti Federica , Iden Sandra , Lennon-Duménil Ana-Maria 
Published: December 2024

ABSTRACTMyeloid cells use intracellular actin networks for key cellular processes, including cell migration and chemotaxis, phagocytosis or macropinocytosis, as well as immune synapse formation. However, whether these networks play any role in the development and/or survival of myeloid cells in tissues remains open. Here, we found that the Arp2/3 complex, which is responsible for the nucleation of branched actin networks, is needed for thein vivomaintenance of epidermal Langerhans cells (LCs) throughout life. Mice harboring a genetic deletion of the Arpc4 subunit of the complex form LC networks at birth, but these cells decline in numbers following a process reminiscent of premature cellular aging. By combiningin vivoanalyses of LCs within vitroexperiments on bone-marrow-derived dendritic cells, we found that Arpc4-deficient cells manage to progress through the cell cycle but accumulate DNA damage associated with aberrant nuclear shapes and events of nuclear envelope rupture. These results provide the first evidence for a physiological role of Arp2/3 in maintenance of genome integrity and survival of immune cells in tissues.
Auxin fluctuation and PIN polarization in moss leaf cell reprogramming
Authors: Tang Han , Chen Li-Hang , Friml Jiří 
Published: December 2024

AbstractAuxin and its PIN-FORMED (PIN) exporters are essential for tissue repair and regeneration in flowering plants. To gain insight into the evolution of this mechanism, we investigated their roles in leaves excised fromPhyscomitrium patens, a bryophyte known for its remarkable cell reprogramming capacity. We used various approaches to manipulate auxin levels, including exogenous application, pharmacological manipulations, and auxin biosynthesis mutants. We observed no significant effect on the rate of cell reprogramming. Rather, our analysis of auxin dynamics revealed a decrease in auxin levels upon excision, which was followed by a local increase before the reprogramming process began. Mutant analysis revealed that PpPINs are required for effective cell reprogramming, and endogenously expressed PpPINA-GFP accumulates polarly at sites that will develop into future filamentous stem cells. In addition, hyperpolarized PpPINA variants carrying mutated phosphorylation sites showed a marked delay in reprogramming, whereas endogenous or non-polar versions do not have this effect. These results underscore that both, the levels and the polarity of PpPINA are important for efficient cell reprogramming. Overall, these findings highlight the pivotal role of PIN polarity in plant regeneration. Furthermore, they suggest that understanding polarity mechanisms could have broader implications for improving regenerative processes across various plant species.
JMJD6 and YBX1 physically interact and regulate HOTAIR proximal promoter
Authors: Gupta Aritra , Bhardwaj Siddharth , Desai Kartiki V. 
Published: December 2024

AbstractIn a previous study, we showed JMJD6 interacted with HOTAIR promoter (−123 to -103 bp upstream of TSS, JIR) and augmented its transcription. Maximal JMJD6 mediated induction required (−216 to -123 bp) region.In silicoprediction and ENCODE data suggested that YBX1 could be that potential candidate and in this study the region is designated as YBX1 interacting region (YIR). In breast cancer cell lines, we show that JMJD6 and YBX1 regulate each other’s expression and physically interact with each other when recombinantly expressed, as endogenous proteins and when synthesizedin vitro.Domain mapping indicated that A/P domain of YBX1 interacted with JMJC domain of JMJD6. Luciferase activity of HOTAIR promoter constructs, pHP216 and pHP123, increased in presence of YBX1 in MCF7, Vec and JMJD6 overexpressing JOE cells but was lost in the presence of JMJD6 and YBX1 siRNAs. Interestingly, activity of pHP123 that lacks YIR also decreased upon YBX1 knock out (YKO). Next, by individual JMJD6, YBX1 and ChIP-re-ChIP assays we demonstrate that both proteins co-occupy this promoter region. Further, electrophoretic mobility shift assays showed that YIR probes retarded two complexes, which lost intensity in YKO cells. Interestingly, JIR-protein complex disappeared in YKO cells. Together these data imply that YBX1 not only enhanced promoter activity but may also be involved in JMJD6 recruitment. Taken together, our data proposes that the interaction and positive feed forward loop perpetuated by JMJD6 and YBX1 may culminate in HOTAIR induction, which in turn is known to drive tumor progression.
Type 1 lymphocytes and interferon-γ accumulate in the thalamus and restrict seizure susceptibility after traumatic brain injury
Authors: Mroz Nicholas M. , Ciesielska Agnieszka , Ewing-Crystal Nathan A. , Dorman Leah C. , Han Rafael T. , Barron Jerika J. , Silva Nicholas J. , Molofsky Anna V. , Molofsky Ari B. , Paz Jeanne T. 
Published: December 2024

ABSTRACTTraumatic brain injury (TBI) is a leading cause of mortality and disability worldwide and can lead to secondary sequelae such as increased seizure susceptibility. Emerging work suggests that the thalamus, the relay center of the brain that undergoes secondary damage after cortical TBI, is involved with heightened seizure risks after TBI. TBI also induces the recruitment of peripheral immune cells, including T cells, to the site(s) of injury, but it is unclear how these cells impact neurological sequelae post-TBI. Here, we characterize the identities and kinetics of lymphocytic infiltrates into the cortex and thalamus using a mouse model of cortical TBI. We identify a population of IFNγ-producing type 1 lymphocytes that infiltrate specific thalamic subregions over weeks following injury, where they elicit a local IFNγ response in microglia and neuronal subset(s). Depletion of CD4+T cells protects mice from TBI-induced seizure susceptibility by de-repressing other non-CD4+type 1 lymphocytes and disease-associated microglia (DAMs) in the thalamus. Strikingly, we find that a single dose of IFNγ prior to challenge with a proconvulsant agent was sufficient to reduce TBI-induced seizure incidence, severity, and mortality. This work identifies IFNγ as a direct modulator of TBI-associated seizure susceptibility, which could have therapeutic implications for the treatment of TBI patients.
Unraveling genetic mysteries: phenotype-shaping profiles in chronic sarcoidosis
Authors: Kullberg Susanna , Darlington Pernilla , Ellinghaus David , Prasse Antje , Iseda Tomoko , Chuquimia Olga , Eklund Anders , Schreiber Stefan , Müller-Quernheim Joachim , Kockum Ingrid , Wheelock Åsa , Padyukov Leonid , Mirsaeidi Mehdi S. , Spagnolo Paolo , Rivera Natalia V. 
Published: December 2024

ABSTRACTBackgroundSarcoidosis represents a complex inflammatory condition of unknown origin, characterized by diverse clinical profiles, particularly identifiable as Löfgren’s syndrome (LS) and non-LS cases. Delving into the genetic underpinnings of chronic sarcoidosis phenotypes is essential for advancing our understanding and treatment of this disease.MethodsTo classify chronicity, pulmonologists evaluated sarcoidosis phenotypes over a follow-up period of two years, distinguishing between chronic and nonchronic classifications. We assessed the genetics of these chronicity phenotypes in a Swedish cohort of 1,515 sarcoidosis cases (679 nonchronic and 836 chronic) alongside 3,085 controls using the Immunochip array. To confirm our findings, replication analysis was conducted in a German cohort of 1,216 sarcoidosis cases (485 nonchronic and 731 chronic) and 3,042 controls. A comprehensive meta-analysis of significant SNPs (p < 5e-8) was carried out using inverse variance weighting. Additionally, we employed gene-based analysis, enrichment mapping, and pathway analysis to gain deeper functional insights.ResultsOur meta-analysis uncovered significant genetic associations with chronic sarcoidosis phenotypes, including LS nonchronic (rs3135356; OR = 3.13, 95% CI: 2.38 - 4.12), non-LS nonchronic (rs2395162; OR = 2.34, 95% CI: 1.96 - 2.85), and non-LS chronic cases (rs1049550; OR = 0.68, 95% CI: 0.59 - 0.76). Specifically, gene-based analysis revealed thatCLIC1is associated with nonchronic forms, whileANXA11is linked to the chronic phenotype. Our enrichment analysis highlighted the expression of quantitative trait loci (eQTLs) in immune cells, whole blood, and lung tissues. The pathway analysis pinpointed the antigen presentation pathway as vital to understanding chronicity phenotypes.ConclusionsThis study illuminates the distinct genomic features that differentiate chronic sarcoidosis phenotypes, underscoring the critical involvement of immune-related genes and regulatory networks. By advancing the knowledge of sarcoidosis chronicity, these findings pave the way for targeted therapeutic interventions and personalized treatment strategies that can significantly improve patient outcomes.
Coancestry superposed on admixed populations yields measures of relatedness at individual-level resolution
Authors: Chen Danfeng , Storey John D. 
Published: December 2024

AbstractThe admixture model is widely applied to estimate and interpret population structure among individuals. Here we consider a “standard admixture” model that assumes the admixed populations are unrelated and also a generalized model, where the admixed populations themselves are related via coancestry (or covariance) of allele frequencies. The generalized model yields a potentially more realistic and substantially more flexible model that we call “super admixture”. This super admixture model provides a one-to-one mapping in terms of probability moments with the population-level kinship model, the latter of which is a general model of genome-wide relatedness and structure based on identity-by-descent. We introduce a method to estimate the super admixture model that is based on method of moments, does not rely on likelihoods, is computationally efficient, and scales to massive sample sizes. We apply the method to several human data sets and show that the admixed populations are indeed substantially related, implying the proposed method captures a new and important component of evolutionary history and structure in the admixture model. We show that the fitted super admixture model estimates relatedness between all pairs of individuals at a resolution similar to the kinship model. The super admixture model therefore provides a tractable, forward generating probabilistic model of complex structure and relatedness that should be useful in a variety of scenarios.
Induction of Senescence During Postpartum Mammary Gland Involution supports tissue remodeling and promotes postpartum tumorigenesis
Authors: Chiche Aurelie , Charifou Elsa , Djoual Lamia , Wang Shuoyang , Temime Laurianne , Saclier Marielle , Wang Shaoxiang , Chantrel Jeremy , Li Han 
Published: December 2024

ABSTRACTCellular senescence is an evolutionarily conserved stress response1, yet its roles during physiological processes remain underexplored2,3. Senescent cells are known to promote tissue repair4,5and suppress tumorigenesis6, but their accumulation contributes to various pathological and physiological processes, including cancer and ageing7–9. However, it is currently unknown whether physiological senescence can be co-opted by oncogenic events to promote tumorigenesis. Postpartum mammary gland involution is a major tissue remodelling event in adulthood10,11, resembling the wound healing process, and is closely linked to postpartum breast cancer (PPBC)12providing a compelling context to investigate this question. Here, we show that senescence is induced in alveolar luminal cells during involution in a p16-dependent manner. Reducing senescent cells hinders tissue remodeling and delays involution, underscoring their physiological importance. However, using a PPBC mouse model where the oncogenic event coincides with involution, we demonstrate that eliminating involution-associated senescent cells markedly extended the cancer latency. Mechanistically, we reveal that senescent cells enhance tumor-initiating cell plasticity in a paracrine manner, promoting tumor invasion and metastasis. Collectively, our findings uncover a dual role of senescence in mediating postpartum tissue remodeling and promoting tumorigenesis, highlighting a scenario where physiological senescence is hijacked to drive cancer progression. This work underscores that senescence might be a unifying mechanism linking tissue repair to tumorigenesis.
Can we infer excitation-inhibition balance from the spectrum of population activity?
Authors: Chakravarty Kingshuk , Roy Sangheeta , Sinha Aniruddha , Kumar Arvind 
Published: December 2024

AbstractNetworks in the brain operate in an excitation-inhibition (EI) balanced state. Altered EI balance underlies aberrant dynamics and impaired information processing. Given its importance, it is crucial to establish non-invasive measures of the EI balances. Previous studies have suggested that relative EI balance can be inferred from the spectrum of the population signals such as Local Field Potentials, Electroencephalogram and Magnetoencephalography. This idea exploits the fact that in most cases excitatory and inhibitory synapses have quite different time constants. However, it is not clear to what extent spectral slope of population activity is related to the network parameters that define the EI balance e.g. excitatory and inhibitory conductance. To address this question we simulated two different types of recurrent networks and measured spectral slope for a wide range of parameters. Our results show that the slope of the spectrum cannot predict the ratio of excitatory and inhibitory synaptic conductance. Only in a small set of simulations a change in the spectral slope was consistent with the corresponding change in the synaptic weights or inputs to the network. Thus, our results show that we should be careful in interpreting the change in the slope of the population activity spectrum.Significant statementNon-invasive signals such as electroencephalogram (EEG) and magneto-encephalogram (MEG) are routine acquired from human subjects in different functional and dysfunctional states. It is of great interest to relate properties of EEG/MEG to the underlying physiology and network properties. In this regard, recently it was proposed that the slope of the EEG/MEG spectrum can be related to excitation-inhibition balance: steeper slopes indicate higher inhibition. Here we show that such an explanation holds only for a small set of conditions. In most cases spectral slope is not informative of underlying excitation-inhibition balance. Thus, we argue that while spectral slope may be a good biomarker of brain state, it is not informative about the underlying excitation-inhibition balance or network parameters.
Evaluation of Immunopharmacological Efficacy of LiveLeishmania donovaniOverexpressing Ld_ζ1domainfor Protection Against Experimental Human Visceral Leishmaniasis
Authors: Bansal Ruby , Shafi Sadat , Garg Prachi , Srivastava Aakriti , Garg Swati , Jha Neha , Singhal Jhalak , Deethamvali Ghouse Peer Gajala , Pati Pandey Ramendra , Basu Subhajit , Singh Shailja 
Published: December 2024

AbstractObjectiveTo evaluate the efficacy and immunogenicity of the zeta domain over-expressingLeishmania donovani(Ld_ζ1domain) as a vaccination candidate against visceral leishmaniasis (VL).MethodsIn this study,Leishmaniaoverexpressor Ld_ζ1domain(OE) were transformed by electroporation using a GFP-tagged Ld_ζ1domainrecombinant plasmid. The resulting overexpressing cells were analysedin vitroto assess their growth dynamics and infectivity. We also investigated the immune-protective potential of these overexpressor in a mouse model challenged withLeishmania donovani. The immune response, including Th1 and Th2 pathways, was thoroughly characterized using RT-PCR and ELISA assays. In addition, the study conducted a thorough evaluation of the mouse’s spleen and liver parasites, as well as quantitative evaluation of tissue pathological changes.ResultsLd_ζ1domain(OE) parasites exhibited significantly lower viability and replication rates than WT parasites, andin vivostudies showed that mice immunized with the Ld_ζ1(OE)domainhad lower parasite numbers than mice infected with LdWT. Spleen and liver showed significant histological changes suggestive of protection. Parasite burden in the spleen and liver of vaccinated mice were significantly reduced. The immune response showed increased IFN-γ levels and lower IL-10 production, resulting in a greater IFN-γ/IL-10 ratio, indicating parasite elimination. The vaccination also caused a significant IgG humoral response and increased nitric oxide production in immunized mice.ConclusionOur findings demonstrated that overexpressing the zeta toxin resulted in controlled parasite attenuation, lowering pathogenicity while retaining immunogenic features. Our work established the zeta over-expressor’s protective efficacy, immunogenicity, and proliferation in response to aLeishmaniachallengein vitroandin vivo. This preliminary prototype study suggested that Ld_ζ1domain(OE) parasites may be suitable for developing an attenuated vaccine against leishmaniasis.Graphical representationA schematic representation on the protective effectiveness, immunogenicity, and proliferation of the zeta over-expressor in response toLeishmaniachallengein vitroandin vivomodel.