bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying potential risk genes for clear cell renal cell carcinoma with deep reinforcement learning
Authors: Lu Dazhi , Zheng Yan , Hao Jianye , Zeng Xi , Han Lu , Li Zhigang , Jiao Shaoqing , Ai Jianzhong , Peng Jiajie 
Published: June 2024

AbstractClear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal cell carcinoma. However, our understanding of ccRCC risk genes remains limited. This gap in knowledge poses significant challenges to the effective diagnosis and treatment of ccRCC. To address this problem, we propose a deep reinforcement learning-based computational approach named RL-GenRisk to identify ccRCC risk genes. Distinct from traditional supervised models, RL-GenRisk frames the identification of ccRCC risk genes as a Markov decision process, combining the graph convolutional network and Deep Q-Network for risk gene identification. Moreover, a well-designed data-driven reward is proposed for mitigating the lim-itation of scant known risk genes. The evaluation demonstrates that RL-GenRisk outperforms existing methods in ccRCC risk gene identification. Additionally, RL-GenRisk identifies ten novel ccRCC risk genes. We successfully validated epidermal growth factor receptor (EGFR), corroborated through independent datasets and biological experimentation. This approach may also be used for other diseases in the future.
Infralimbic projections to the basal forebrain mediate extinction learning
Authors: Fernandes-Henriques Carolina , Guetta Yuval , Sclar Mia , Zhang Rebecca , Miura Yuka , Friedman Allyson K. , Likhtik Ekaterina 
Published: June 2024

AbstractFear extinction learning and retrieval are critical for decreasing fear responses to a stimulus that no longer poses a threat. While it is known that the infralimbic region (IL) of the medial prefrontal cortex mediates retrieval of an extinction memory through projections to the basolateral amygdala (BLA), the contribution of the IL to extinction learning is not well-understood. Given the strong projection from the IL to the basal forebrain (BF), a center of attentional processing, we investigated whether this pathway participates in extinction, and compared it to the IL-BLA pathway. Using retrograde tracing, we first demonstrate that projections from the IL to the BF originate from superficial (L2/3) and deep cortical layers (L5), and that they are denser than IL projections to the BLA. Next, combining retrograde tracing with labeling of the immediate early gene cFos, we show increased activity of the L5 IL-BF pathway during extinction learning and increased activity of the L2/3 IL-BLA pathway during extinction retrieval. Ourin vitrorecordings demonstrate that neurons in the IL-BF pathway become more excitable towards the end of extinction learning, but less excitable during extinction retrieval. Finally, using optogenetics we show that inactivation of the IL-BF pathway impairs extinction learning, leaving retrieval intact. We propose that the IL acts as a switchboard operator during extinction, with increased L5 IL-BF communication during learning and increased L2/3 IL-BLA communication during retrieval. Anxiety and stress-related changes in IL physiology could affect one or multiple lines of communication, impairing different aspects of extinction.Significance StatementExtinction of conditioned fear is a widely used behavioral approach to diminish fear, with projections from infralimbic prefrontal cortex to the amygdala known for mediating extinction memory retrieval. However, less is known about infralimbic pathways involved in extinction learning. We use neuroanatomical tracing, behavior, slice recordings, and circuit manipulation to show that infralimbic output to the basal forebrain, an attention processing center, is denser than to the amygdala, and is active during extinction learning rather than retrieval. Neurons in the infralimbic-basal forebrain pathway become more excitable as extinction learning progresses, and then less excitable during extinction retrieval. Moreover, inhibiting this pathway impairs extinction learning. Our findings identify different lines of communication the infralimbic cortex uses for extinction learning and retrieval.
Rare ring conformations in PDB: Facts or wishful thinking?
Authors: Bučeková Gabriela , Doshchenko Viktoriia , Chareshneu Aliaksei , Porubská Jana , Pajtinka Michal , Oleksik Michal , Svoboda Tomáš , Horský Vladimír , Svobodová Radka 
Published: June 2024

Protein structural data are highly valuable for research, and many significant results have been published on their basis. A key point for their credibility and applicability is their quality. An important facet of protein structure quality is the validation of ligands. Some aspects of ligand quality have already been validated by established quality metrics. However, validation of ring conformation has yet to be comprehensively performed despite rings strongly influencing the formation of the ligand’s scaffold and shape. Most rings form several conformations that differ in their stability. The most stable ones occur frequently in nature and should, therefore, be found in Protein Data Bank (PDB) structures.In this article, we examined which conformations of rings occur in PDB structures. Our analysis focused on conformations of all cyclopentane, cyclohexane, and benzene rings in the PDB. Specifically, we examined 123 264 rings of 24 763 distinct ligands, which instances occur in 44 022 protein structures. In general, we found that most of the rings (98.32 %) are in energetically favourable conformations. Surprisingly, the existence of most of the energetically unfavourable ring conformations (2 067 samples, 1.68 %) is not supported by experimental data. Only 291 unfavourable ring conformations (0.24 %) are backed by experimental data that are accurate enough to distinguish the conformation, which shows that the existence of energetically unfavourable ring conformations is rarely supported by structural or experimental evidence.Our results suggest that each occurrence of untypical ring conformation in the PDB may indicate a potential error and should be carefully analysed.
Reward responses to vicarious feeding depend on BMI
Authors: Järvinen Lili , Santavirta Severi , Putkinen Vesa , Karlsson Henry K. , Seppälä Kerttu , Sun Lihua , Hudson Matthew , Hirvonen Jussi , Nuutila Pirjo , Nummenmaa Lauri 
Published: June 2024

AbstractEating is inherently social for humans. Yet, most neuroimaging studies of appetite and food-induced reward have focused on studying brain responses to food intake or viewing pictures of food alone. Here we used functional magnetic resonance imaging (fMRI) to measure haemodynamic responses to “vicarious” feeding. The subjects (n=97) viewed series of short videos representing naturalistic episodes of social eating intermixed with videos without feeding / appetite related content. Viewing the vicarious feeding (versus control) videos activated motor and premotor cortices, thalamus, and dorsolateral prefrontal cortices, consistent with somatomotor and affective engagement. Responses to the feeding videos were also downregulated as a function of the participants’ BMI. Altogether these results suggest that seeing others eating engages the corresponding motor and affective programs in the viewers’ brain, potentially increasing appetite and promoting mutual feeding.
Rab27b promotes lysosomal function and alpha-synuclein clearance in neurons
Authors: Scholz Kasandra , Pattanayak Rudradip , Roschonporn Ekkatine , Pair Frank Sanders , Nobles Amber , Yacoubian Talene A. 
Published: June 2024

ABSTRACTAlpha-synuclein (αsyn) is the key pathogenic protein implicated in synucleinopathies including Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). In these diseases, αsyn is thought to spread between cells where it accumulates and induces pathology; however, mechanisms that drive its propagation or aggregation are poorly understood. We have previously reported that the small GTPase Rab27b is elevated in human PD and DLB and that it can mediate the autophagic clearance and toxicity of αsyn in a paracrine αsyn cell culture neuronal model. Here, we expanded our previous work and further characterized a role for Rab27b in neuronal lysosomal processing and αsyn clearance. We found that Rab27b KD in this αsyn inducible neuronal model resulted in lysosomal dysfunction and increased αsyn levels in lysosomes. Similar lysosomal proteolytic defects and enzymatic dysfunction were observed in both primary neuronal cultures and brain lysates from Rab27b knockout (KO) mice. αSyn aggregation was exacerbated in Rab27b KO neurons upon treatment with αsyn preformed fibrils. We found no changes in lysosomal counts or lysosomal pH in either model, but we did identify defects in acidic vesicle trafficking in Rab27b KO primary neurons which may drive lysosomal dysfunction and promote αsyn aggregation. Rab27b OE enhanced lysosomal activity and reduced insoluble αsyn accumulation. Finally we found elevated Rab27b levels in human postmortem incidental Lewy Body Disease (iLBD) subjects relative to healthy controls. These data suggest a role for Rab27b in neuronal lysosomal activity and identify it as a potential therapeutic target in synucleinopathies.
Divisive attenuation based on noisy sensorimotor predictions accounts for excess variability in self-touch
Authors: Valè Nicola , Tomić Ivan , Gironés Zahara , Wolpert Daniel M , Kilteni Konstantina , Bays Paul M 
Published: June 2024

AbstractWhen one part of the body exerts force on another, the resulting tactile sensation is perceived as weaker than when the same force is applied by an external agent. This phenomenon has been studied using a force matching task, in which observers are first exposed to an external force on a passive finger and then instructed to reproduce the sensation by directly pressing on the passive finger with a finger of the other hand: healthy participants consistently exceed the original force level. However, this exaggeration of the target force is not observed if the observer generates the matching force indirectly, by adjusting a joystick or slider that controls the force output of a motor. Here we present the first detailed computational account of the processes leading to exaggeration of target forces in the force matching task, incorporating attenuation of sensory signals based on motor predictions. The model elucidates previously unappreciated contributions of multiple sources of noise, including memory noise, in determining matching force output. We show that the predictive component can be isolated by quantifying attenuation as the discrepancy between direct and indirect self-generated forces, rather than direct versus externally generated forces. Our computational account makes the prediction that attenuated sensations will display greater trial-to-trial variability than unattenuated ones, because they incorporate additional noise from motor prediction. Quantitative model fitting of force matching data based on close to 500 human participants confirmed the prediction of excess variability in self-generated forces and provided evidence for a divisive rather than subtractive mechanism of attenuation, while highlighting its predictive nature.
The nuclear localization signal of CPSF6 governs post-nuclear import steps of HIV-1 infection
Authors: Rohlfes Nicholas , Radhakrishnan Rajalingam , Singh Parmit K. , Bedwell Gregory J. , Engelman Alan N. , Dharan Adarsh , Campbell Edward M. 
Published: June 2024

AbstractThe early stages of HIV-1 infection include the trafficking of the viral core into the nucleus of infected cells. However, much remains to be understood about how HIV-1 accomplishes nuclear import and the consequences of the import pathways utilized on nuclear events. The host factor cleavage and polyadenylation specificity factor 6 (CPSF6) assists HIV-1 nuclear localization and post-entry integration targeting. Here, we used a CPSF6 truncation mutant lacking a functional nuclear localization signal (NLS), CPSF6-358, and appended heterologous NLSs to rescue nuclear localization. We show that some, but not all, NLSs drive CPSF6-358 into the nucleus. Interestingly, we found that some nuclear localized CPSF6-NLS chimeras supported inefficient HIV-1 infection. We found that HIV-1 still enters the nucleus in these cell lines but fails to traffic to speckle-associated domains (SPADs). Additionally, we show that HIV-1 fails to efficiently integrate in these cell lines. Collectively, our results demonstrate that the NLS of CPSF6 facilitates steps of HIV-1 infection subsequent to nuclear import and additionally identify the ability of canonical NLS sequences to influence cargo localization in the nucleus following nuclear import.Author SummaryDuring HIV-1 infection, the viral capsid, which encloses the viral genome and accessory proteins required for reverse transcription (RT) and integration, traffics towards the nucleus and enters through the nuclear pore complex (NPC). Following entry into the nucleus, RT is completed and viral capsid disassembles releasing the preintegration complex (PIC) to integrate with the host chromosome. In this study, we investigated the early HIV-1 host factor CPSF6, and specifically focused on the C-terminal short amino acid nuclear localization signal (NLS) in CPSF6, in mediating viral nuclear entry and subsequent gene expression. Altering the NLS in CPSF6 with NLS from other proteins, significantly impacted HIV-1’s ability to infect those cells. We further showed this defect in infection occurred at the level of viral integration. This study highlights the importance of the NLS in CPSF6 in dictating the NPC it associates with and its effect on HIV-1 infection. Moreover, our study emphasizes the function of NLS in targeting host cargos to different nuclear entry pathways.
Species identity and composition shape productivity of stony corals
Authors: Vetter Jana , Reichert Jessica , Dietzmann André , Hahn Lisa , Lang Anna E. , Puntin Giulia , Ziegler Maren 
Published: June 2024

AbstractCoral biodiversity has an enhancing but saturating effect on community productivity, however, the direct effects of neighbouring coral colonies on productivity remain poorly understood due to the complex interplay of biotic and abiotic factors. We set up a fully controlled aquarium experiment, in which we quantified the effects of species identity and composition on the productivity of nine stony coral species from three families. Baseline productivity and the response to neighbouring organisms strongly differed between species. Regardless of whether species increased or decreased productivity, the responses were consistently more pronounced and positive towards conspecific than heterospecific neighbours, indicating kin selection effects between closely related species. Species productivity in monoculture and productivity in polyculture were inversely correlated, with inherently less productive species overperforming in polyculture and vice versa. Our results highlight that contact-free interactions in marine animals shape biodiversity-productivity effects otherwise known from plant communities.
Hyperspectral Sensing for High-Throughput Chloride Detection in Grapevines
Authors: Sharma Sadikshya , Wong Christopher , Bhattarai Krishna , Lupo Yaniv , Magney Troy , Diaz-Garcia Luis 
Published: June 2024

AbstractSoil salinity affects major viticultural areas worldwide with chloride ions being the primary source of salt toxicity in grapevines. This toxicity impacts vine health and reduces fruit yield and quality. Current breeding efforts to improve grapevine salinity tolerance are limited by the low throughput of available phenotyping methods, which are time-consuming, labor-intensive, and destructive. This study demonstrated that hyperspectral proximal sensing can be utilized as a high-throughput, non-destructive screening technique to identify salinity-tolerant grapevine germplasm. The predictive abilities of two different hyperspectral devices, which varied in price, resolution, and sensitivity, were compared across 23Vitisaccessions spanning eight species. Prediction models were built using hyperspectral reflectance and leaf chloride content measured with a lab chloridometer. Three distinct approaches were studied: 1) analyzing the correlation between individual wavelengths and chloride content; 2) employing machine learning models, including Partial Least Squares Regression (PLSR), Random Forest (RF), and Support Vector Machine (SVM), utilizing all wavelengths; and 3) classification-based prediction using Partial Least Squares Discriminant Analysis (PLSDA). Multiple regions in the spectrum, including 613-660 nm, 689-696 nm, and 1357-1358 nm, showed a medium correlation (0.30-0.50) with chloride content in the leaves. PLSR was the most effective machine learning approach, demonstrating moderate predictive capability for chloride content (maximumR²= 0.67), though performance varied between the two devices tested. With PLSDA, predictions increased considerably, up to an accuracy of 0.97, depending on the instrument used and the spectral data transformation. Overall, the more expensive and sensitive device with a wider spectral range outperformed the more affordable, shorter-range device. However, when the prediction model was based on classes (chloride excluders vs. non-excluders) rather than chloride content, the differences in prediction abilities were minimal, with both instruments performing very well. This is promising for identifying breeding materials with chloride exclusion capabilities at low cost and high throughput.
ER-associated biogenesis of PINK1 preprotein for neuronal mitophagy
Authors: Hees J. Tabitha , Segura Inmaculada , Schneider Andrea , Schifferer Martina , Misgeld Thomas , Harbauer Angelika B. 
Published: June 2024

AbstractA central role in mitochondrial quality control is played by the Parkinson-related mitochondrial kinase PINK1, whose mRNA is transported in neurons by mitochondrial hitch- hiking. Using a live-cell imaging assay for the translation of the PINK1 precursor, we show that local translation of PINK1 requires a concerted interplay between mitochondria and the ER in neurons. For efficient translation, thePink1mRNA needs to relocate to ribosomes located near endolysosomes and the ER. The ER membrane-tethered chaperone DNAJB6 then shields the PINK1 precursor on transit to mitochondria following the ER-SURF pathway. Loss of DNAJB6 hence leads to persistence of ER/endolysosome-associated PINK1 precursor stores and failure of mitophagy upon mitochondrial damage.
Tumour-intrinsic features shape T-cell differentiation through myeloma disease evolution
Authors: Foster Kane A. , Rees Elise , Ainley Louise , Boyle Eileen M. , Lee Lydia , Ward Gwennan , Galas-Filipowicz Daria , Mikolajczak Anna , Lyon Emma J. , Jankovic Dylan , Rahman Jasmine , Turakhia Mahima , Uddin Imran , Beattie Gordon , Hoade Yvette , Zhu Catherine , Reading James L. , Walker Ieuan , Chapman Michael , Ramasamy Karthik , Herrero Javier , Chain Benny , Quezada Sergio A. , Yong Kwee L. 
Published: June 2024

AbstractThe haematological malignancy multiple myeloma is associated with skewed T-cell activation and function. T-cell alterations are detectable in asymptomatic myeloma precursor conditions and have the potential to identify precursor patients at imminent risk of progression. However, what myeloma-associated T-cells alterations represent mechanistically, how they relate to tumour burden and gene expression, and what influences high inter-patient variability in immune composition remains unknown. Here, we assembled the largest ever dataset of published and newly-generated single-cell RNA and TCR sequencing of the marrow and blood from patients with myeloma, precursor conditions, and age-matched non-cancer controls. We show myeloma is not associated with T-cell exhaustion and instead defined by a pattern of T-cell differentiation resembling antigen-driven terminal memory differentiation. Myeloma-associated T-cell differentiation was dependent on tumour-intrinsic features including tumour burden and tumour expression of antigen-presentation genes. Expanded TCR clones accumulating in myeloma were not enriched for viral specificity and were detected in effector states in highly infiltrated marrows. Together, these results suggest anti-tumour immunity drives a novel form of cancer-associated T-cell memory differentiation in myeloma.
Risk Factors and Outcomes of Pulmonary Hemorrhage in Preterm Infants born before 32 weeks
Authors: Tran Gieng Thi My , Nguyen Nhat Phan Minh , Long Nguyen Phuoc , Nguyen Duc Ninh , Nguyen Thu-Tinh 
Published: June 2024

AbstractBackgroundPulmonary hemorrhage (PH) is a catastrophic event associated with significant morbidity and mortality among preterm infants. Understanding PH risk factors in preterm newborns, particularly those in low-to-middle-income countries like Vietnam, remains limited. This study aimed to investigate the risk factors and short-term outcomes of PH in very preterm infants.MethodsWe conducted an observational study of newborns aged < 72 hours with gestational age < 32 weeks, admitted to our unit from April 1, 2018 to March 31, 2019.ResultsOf 118 recruited newborns, 28 (23.7%) had PH. The logistic regression analysis showed that intubation within 24 first hours, blood transfusion, and coagulation disorders within the first 3 days were risk factors for PH (aOR = 4.594, 95% CI = 1.200-17.593; aOR = 5.394, 95% CI = 1.243-23.395 and aOR = 7.242 95% CI = 1.838-28.542, respectively). Intra-ventricular hemorrhage (IVH) and mortality rates were higher in patients with PH compared to those without (p<0.001). The length of invasive ventilation was longer in the PH group (p<0.001).ConclusionWe have identified intubation, blood transfusion, and coagulation disorders shortly after birth as risk factors for PH in very preterm infants, which was associated with increased mortality and occurrence of IVH.ImpactHigh incidence and mortality of pulmonary hemorrhage in preterm infants < 32 weeks’ gestational age with respiratory distress in a Neonatal Intensive Care Unit in Vietnam.Pulmonary hemorrhage should be considered in the clinical deterioration of preterm infants given invasive ventilation in the first 2-4 days of life.Independent risk factors for pulmonary hemorrhage: intubation in the first 24 hours, coagulation disorders, and transfusion of blood products in the first 3 days of life.Urgent need to seek diagnostic criteria for intraventricular hemorrhage as soon as pulmonary hemorrhage occurs.