bluuebunny/crossref_metadata_2025_split huggingface dataset:
External Validation of Mortality Prediction Models for Critical Illness Reveals Preserved Discrimination but Poor Calibration
Authors: Cox Eline G. M. , Wiersema Renske , Eck Ruben J. , Kaufmann Thomas , Granholm Anders , Vaara Suvi T. , Møller Morten Hylander , van Bussel Bas C. T. , Snieder Harold , Pleijhuis Rick G. , van der Horst Iwan C. C. , Keus Frederik 
Published: November 2022

OBJECTIVES:
In a recent scoping review, we identified 43 mortality prediction models for critically ill patients. We aimed to assess the performances of these models through external validation.

DESIGN:
Multicenter study.

SETTING:
External validation of models was performed in the Simple Intensive Care Studies-I (SICS-I) and the Finnish Acute Kidney Injury (FINNAKI) study.

PATIENTS:
The SICS-I study consisted of 1,075 patients, and the FINNAKI study consisted of 2,901 critically ill patients.

MEASUREMENTS AND MAIN RESULTS:
For each model, we assessed: 1) the original publications for the data needed for model reconstruction, 2) availability of the variables, 3) model performance in two independent cohorts, and 4) the effects of recalibration on model performance. The models were recalibrated using data of the SICS-I and subsequently validated using data of the FINNAKI study. We evaluated overall model performance using various indexes, including the (scaled) Brier score, discrimination (area under the curve of the receiver operating characteristics), calibration (intercepts and slopes), and decision curves. Eleven models (26%) could be externally validated. The Acute Physiology And Chronic Health Evaluation (APACHE) II, APACHE IV, Simplified Acute Physiology Score (SAPS)-Reduced (SAPS-R)‚ and Simplified Mortality Score for the ICU models showed the best scaled Brier scores of 0.11‚ 0.10‚ 0.10‚ and 0.06‚ respectively. SAPS II, APACHE II, and APACHE IV discriminated best; overall discrimination of models ranged from area under the curve of the receiver operating characteristics of 0.63 (0.61–0.66) to 0.83 (0.81–0.85). We observed poor calibration in most models, which improved to at least moderate after recalibration of intercepts and slopes. The decision curve showed a positive net benefit in the 0–60% threshold probability range for APACHE IV and SAPS-R.

CONCLUSIONS:
In only 11 out of 43 available mortality prediction models, the performance could be studied using two cohorts of critically ill patients. External validation showed that the discriminative ability of APACHE II, APACHE IV, and SAPS II was acceptable to excellent, whereas calibration was poor.
Novel proresolving lipid mediator mimetic 3-oxa-PD1n-3 docosapentaenoic acid reduces acute and chronic itch by modulating excitatory and inhibitory synaptic transmission and astroglial secretion of lipocalin-2 in mice
Authors: Furutani Kenta , Chen Ouyang , McGinnis Aidan , Wang Yuqing , Serhan Charles N. , Hansen Trond Vidar , Ji Ru-Rong 
Published: November 2022

Abstract
Specialized proresolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch are currently unknown. Recently, n-3 docosapentaenoic acid (DPA) was found to be a substrate for the biosynthesis of several novel families of SPMs and 3-oxa-PD1n-3 DPA (3-oxa-PD1) is an oxidation-resistant metabolic stable analogue of the n-3 DPA-derived protectin D1 (PD1). In this article, we demonstrate that 3-oxa-PD1 effectively reduces both acute and chronic itch in mouse models. Intrathecal injection of 3-oxa-PD1 (100 ng) reduced acute itch induced by histamine, chloroquine, or morphine. Furthermore, intrathecal 3-oxa-PD1 effectively reduced chronic itch, induced by cutaneous T-cell lymphoma (CTCL), allergic contact dermatitis with dinitrofluorobenzene, and psoriasis by imiquimod. Intratumoral injection of 3-oxa-PD1 also suppressed CTCL-induced chronic itch. Strikingly, the antipruritic effect lasted for several weeks after 1-week intrathecal 3-oxa-PD1 treatment. Whole-cell recordings revealed significant increase in excitatory postsynaptic currents in spinal dorsal horn (SDH) neurons of CTCL mice, but this increase was blocked by 3-oxa-PD1. 3-oxa-PD1 further increased inhibitory postsynaptic currents in SDH neurons of CTCL mice. Cutaneous T-cell lymphoma increased the spinal levels of lipocalin-2 (LCN2), an itch mediator produced by astrocytes. 3-oxa-PD1 suppressed LCN2 production in CTCL mice and LCN2 secretion in astrocytes. Finally, CTCL-induced anxiety was alleviated by intrathecal 3-oxa-PD1. Our findings suggest that 3-oxa-PD1 potently inhibits acute and chronic itch through the regulation of excitatory or inhibitory synaptic transmission and astroglial LCN2 production. Therefore, stable SPM analogs such as 3-oxa-PD1 could be useful to treat pruritus associated with different skin injuries.
Mapping glioma heterogeneity using multiparametric 18F-choline PET/MRI in childhood and teenage-young adults
Authors: Ferrazzoli Valentina , Shankar Ananth , Cockle Julia V. , Tang Christine , Al-Khayfawee Ahmed , Bomanji Jamshed , Fraioli Francesco , Hyare Harpreet 
Published: November 2022

Objective
The heterogeneity of post-treatment imaging remains a significant challenge in children and teenagers/young adults (TYA) diagnosed with glioma. The aim of this study was to evaluate the utility of 18F-choline PET/MRI in determining intratumoural heterogeneity in paediatric and TYA gliomas.

Methods
Twenty-six patients (mean age 16 years, range 8–22 years) with suspected glioma disease progression were evaluated with 18F-choline PET/MRI. Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC) and maximum standardised uptake values (SUVmax) in enhancing (enh) and non-enhancing (ne) tumour volumes and normal-appearing white matter (wm) were calculated (rCBVenh, rCBVne, rCBVwm, ADCenh, ADCne, ADCwm, SUVenh, SUVne and SUVwm).

Results
Significantly higher SUVenh and SUVne compared with SUVwm were observed [SUVenh 0.89 (0.23–1.90), SUVne 0.36 (0.16–0.78) versus SUVwm 0.15 (0.04–1.19); P < 0.001 and P = 0.004, respectively]. Equivalent results were observed for ADV and rCBV (ADCenh, ADCne: P < 0.001 versus ADCwm; rCBVenh, rCBVne: P < 0.001 versus rCBVwm). The highest values for mean SUVmax [0.89 (0.23–1.90)] and mean rCBV [2.1 (0.74–5.08)] were in the enhancing component, while the highest values for ADC [1780 mm2/s (863–2811)] were in the necrotic component.

Conclusion

18F-choline PET/MRI is able map imaging heterogeneity in paediatric and TYA gliomas, detecting post-treatment enhancing, non-enhancing, and necrotic tumour components equivalent to ADC and DSC-derived rCBV. This offers potential in the response assessment of diffuse non-enhancing gliomas and in selected cases such as posterior fossa tumours where quantitative MRI is technically difficult.
Strategies for Mitigating Antibody-Drug Conjugate Related Adverse Events for Precision Therapy
Authors: Gouda Mohamed A. , Subbiah Vivek 
Published: November 2022

Abstract
Antibody-drug conjugates (ADCs) have been revolutionary in improving personalized therapy of cancer. Through combining monoclonal antibodies, which are targeted to tumor-specific antigens, and cytotoxic agents, ADCs lead to selective delivery of active components, also called payloads, to cancerous cells while sparing healthy body cells from possible collateral damage. Adverse events, however, can still develop because of early release of the payload or cross-expression of targets by normal cells leading to collateral damage. In this review, we elaborate on the common and serious adverse events for the currently US Food and Drug Administration–approved ADCs in solid tumors and discuss mitigating strategies and dose modification guidance for optimizing efficacy and toxicity.
Antibody-Drug Conjugates in Breast Cancer: What Is Beyond HER2?
Authors: Nicolò Eleonora , Repetto Matteo , Boscolo Bielo Luca , Tarantino Paolo , Curigliano Giuseppe 
Published: November 2022

Abstract
The therapeutic landscape of patients with breast cancer has changed significantly with the introduction of antibody-drug conjugates (ADCs). Although human epidermal growth factor receptor 2 (HER2) has been the centerpiece of ADC development, potentially any surface antigen with differential expression between tumor and normal cells may be suitable for targeting with ADCs. Exploration of new targets is critical to expand the fraction of patients who can benefit from ADCs. Sacituzumab govitecan, an anti–trophoblast cell surface antigen 2 ADC, is the only non–anti-HER2 ADC approved for breast cancer to date, with several novel ADCs directed against novel targets (e.g., HER3, LIV-1) at various stages of preclinical and clinical development. The aim of this review is to provide an overview of clinical trials investigating ADCs targeting novel antigens. We discuss the optimal characteristics of the target to be exploited in ADCs' design and potential future challenges in the evolving field of ADCs such as biomarker assessment, patient selection, and sequencing of ADCs.
Highly Realistic Whole Transcriptome Synthesis through Generative Adversarial Networks
Authors: Fu Suneng 
Published: November 2022

AbstractThe transcriptome is the most extensive and standardized among all biological data, but its lack of inherent structure impedes the application of deep learning tools. This study resolves the neighborhood relationship of protein-coding genes through uniform manifold approximation and projection (UMAP) of high-quality gene expression data. The resultant transcriptome image is conducive to classification tasks and generative learning. Convolutional neural networks (CNNs) trained with full or partial transcriptome images differentiate normal versus lung squamous cell carcinoma (LUSC) and LUSC versus lung adenocarcinoma (LUAD) with over 96% accuracy, comparable to XGBoost. Meanwhile, the generative adversarial network (GAN) model trained with 93 TcgaTargetGtex transcriptome classes synthesizes highly realistic and diverse tissue/cancer-specific transcriptome images. Comparative analysis of GAN-synthesized LUSC and LUAD transcriptome images show selective retention and enhancement of epithelial identity gene expression in the LUSC transcriptome. Further analyses of synthetic LUSC transcriptomes identify a novel role for mitochondria electron transport complex I expression in LUSC stratification and prognosis. In summary, this study provides an intuitive transcriptome embedding compatible with generative deep learning and realistic transcriptome synthesis.Significance StatementDeep learning is most successful when the subject is structured. This study provides a novel way of converting unstructured gene expression lists to 2D-structured transcriptome portraits that are intuitive and compatible with a generative adversarial network (GAN)-based deep learning. The StyleGAN generator trained with transcriptome portrait libraries synthesizes tissue- and disease-specific transcriptomes with significant diversity. Detailed analyses of the synthetic transcriptomes reveal selective enhancement of clinically significant features not apparent in the original transcriptome. Therefore, transcriptome-image-based generative learning may become a significant source of de novo insight generation.
Selective brain cooling monitored by CT perfusion as adjuvant therapy in a porcine model of severe ischemic stroke
Authors: Tong Olivia L.H. , Chung Kevin J. , Hadway Jennifer , Morrison Laura , Desjardins Lise , Tyler Susan , Flamminio Marcus , Keenliside Lynn , Lee Ting-Yim 
Published: November 2022

AbstractDespite the advances in ischemic stroke treatment, not all patients are eligible for or fully recovered after recanalization therapies. Therapeutic hypothermia could be adjuvant therapy that optimizes the beneficial effect of reperfusion. While conventional whole-body cooling has severe adverse effects, selective brain cooling has emerged as an attractive alternative. However, clinical application is limited by the lack of optimal delivery methods and unknown treatment parameters. Optimal parameters may depend on injury levels and monitoring cerebral perfusion may provide valuable information. Here, we show that selective brain cooling via our in-house developed Vortex tube IntraNasal Cooling Instrument (VINCI), even with a clinically relevant delay in treatment, can attenuate subacute injuries in animals with severe ischemic stroke. The treatment responses of selective brain cooling were characterized by CT Perfusion (CTP). The predicted lesion volume by CTP matched the true infarct volume by histology when the brain temperature was decreased by 5°C from normothermia. More importantly, we found that global hyperemia (high cerebral blood flow) before rewarming could be an early manifestation of poor treatment outcomes. Altogether, our study shows that VINCI-enabled brain cooling could be guided by CTP imaging as adjuvant therapy for severe ischemic stroke. This work lays the groundwork toward individualized selective brain cooling.Significance StatementNot all patients suffering from ischemic stroke are eligible or fully recovered after recanalization therapies. Therapeutic hypothermia could be an adjuvant therapy, but the clinical application is hindered by the delivery methods. The optimum treatment depth and duration are also unknown, and they may depend on the injury level. We developed a non-invasive selective brain cooling device, Vortex tube IntraNasal Cooling Instrument (VINCI). The treatment responses were characterized by CT Perfusion (CTP). Global hyperemia (high cerebral blood flow) was identified and could be an early manifestation of poor treatment outcomes. Our work shows that VINCI-enabled brain cooling could be guided by CTP imaging as adjuvant therapy for ischemic stroke. This work also lays the groundwork toward individualized selective brain cooling.
Systematic identification and characterization of novel genes in the regulation and biogenesis of photosynthetic machinery
Authors: Kafri Moshe , Patena Weronika , Martin Lance , Wang Lianyong , Gomer Gillian , Sirkejyan Arthur K , Goh Audrey , Wilson Alexandra T. , Gavrilenko Sophia E , Breker Michal , Roichman Asael , McWhite Claire D. , Rabinowitz Joshua D. , Cross Frederick R , Wühr Martin , Jonikas Martin C. 
Published: November 2022

SUMMARYPhotosynthesis is central to food production and the Earth’s biogeochemistry, yet the molecular basis for its regulation remains poorly understood. Here, using high-throughput genetics in the model eukaryotic algaChlamydomonas reinhardtii, we identify with high confidence (FDR<0.11) 70 previously-uncharacterized genes required for photosynthesis. We then provide a resource of mutant proteomes that enables functional characterization of these novel genes by revealing their relationship to known genes. The data allow assignment of 34 novel genes to the biogenesis or regulation of one or more specific photosynthetic complexes. Additional analysis uncovers at least seven novel critical regulatory proteins, including five Photosystem I mRNA maturation factors and two master regulators: MTF1, which impacts chloroplast gene expression directly; and PMR1, which impacts expression via nuclear-expressed factors. Our work provides a rich resource identifying novel regulatory and functional genes and placing them into pathways, thereby opening the door to a system-level understanding of photosynthesis.HighlightsHigh-confidence identification of 70 previously-uncharacterized genes required for photosynthesisProteomic analysis of mutants allows assignment of function to novel genesCharacterization of 5 novel Photosystem I mRNA maturation factors validates this resourceMTF1 and PMR1 identified as master regulators of photosynthesis
Neisseria meningitidissibling small regulatory RNAs connect metabolism with colonization by controlling propionate use
Authors: Man-Bovenkerk Sandra , Schipper Kim , van Sorge Nina M. , Speijer Dave , van der Ende Arie , Pannekoek Yvonne 
Published: November 2022

ABSTRACTNeisseria meningitidis(the meningococcus) colonizes the human nasopharynx, primarily as a commensal, but sporadically causing septicemia and meningitis. During colonization and invasion, it encounters different niches with specific nutrient compositions. Small non-coding RNAs (sRNAs) are used to fine-tune expression of genes allowing adaptation to their physiological differences. We have previously characterized sRNAs (Neisseria metabolic switch regulators [NmsRs]) controlling switches between cataplerotic and anaplerotic metabolism. Here we extend the NmsRs regulon by studying methylcitrate lyase (PrpF) and propionate kinase (AckA-1) involved in the methylcitrate cycle, and serine hydroxymethyltransferase (GlyA) and 3-hydroxyacid dehydrogenase (MmsB) involved in protein degradation. These proteins were previously shown to be dysregulated in a ΔnmsRsstrain. Levels of transcription of target genes and NmsRs were assessed by RT-qPCR. We also used a novel gene-reporter system, in which the 5’UTR of the target gene is fused to mcherry to study NmsRs-target gene interaction in the meningococcus.Under nutrient-rich conditions, NmsRs downregulate expression of PrpF and AckA-1, by direct interaction with the 5’ UTR of their mRNA. Overexpression of NmsRs impaired growth under nutrient-limiting growth conditions with pyruvate and propionic acid as the only carbon sources. Our data strongly suggest that NmsRs downregulate propionate metabolism by lowering methylcitrate enzyme activity under nutrient-rich conditions. Under nutrient-poor conditions, NmsRs are downregulated, increasing propionate metabolism, resulting in higher tricarboxylic acid (TCA) activities. This allows metabolism to support nasopharynx colonization with breakdown products of amino acids functioning as anaplerotic substrates, as highlighted by NmsRs regulation of GlyA and MmsB.SIGNIFICANCENeisseria meningitidiscolonizes the human adult nasopharynx, forming a reservoir for the sporadic occurrence of epidemic invasive meningococcal disease like septicemia and meningitis. Propionic acid generated by other bacteria that co-inhabit the human adolescent/adult nasopharynx can be utilized by meningococci for replication in this environment. Here we showed that the sibling small RNAs designated NmsRs (Neisseria metabolic switch regulators) riboregulate propionic acid utilization by meningococci, and thus, colonization. Under conditions mimicking the nasopharyngeal environment, NmsRs upregulated expression of enzymes of the methylcitrate cycle. This leads to the conversion of propionic acid to pyruvate and succinate, resulting in higher tricarboxylic acid cycle activity, allowing colonization of the nasopharynx. NmsRs link metabolic state with colonization, which is a crucial step on the trajectory to invasive meningococcal disease.
De novodesign of modular peptide binding proteins by superhelical matching
Authors: Wu Kejia , Bai Hua , Chang Ya-Ting , Redler Rachel , McNally Kerrie E. , Sheffler William , Brunette TJ , Hicks Derrick R. , Morgan Tomos E , Stevens Tim J , Broerman Adam , Goreshnik Inna , DeWitt Michelle , Chow Cameron M. , Shen Yihang , Stewart Lance , Derivery Emmanuel , Silva Daniel Adriano , Bhabha Gira , Ekiert Damian , Baker David 
Published: November 2022

AbstractGeneral approaches for designing sequence-specific peptide binding proteins would have wide utility in proteomics and synthetic biology. Although considerable progress has been made in designing proteins which bind to other proteins, the general peptide binding problem is more challenging as most peptides do not have defined structures in isolation, and to offset the loss in solvation upon binding the protein binding interface has to provide specific hydrogen bonds that complement the majority of the buried peptide’s backbone polar groups (1–3). Inspired by natural repeat protein-peptide complexes, and engineering efforts to alter their specificity (4–11), we describe a general approach forde novodesign of proteins made out of repeating units that bind peptides with repeating sequences such that there is a one to one correspondence between repeat units on the protein and peptide. We develop a rapid docking plus geometric hashing method to identify protein backbones and protein-peptide rigid body arrangements that are compatible with bidentate hydrogen bonds between side chains on the protein and the backbone of the peptide (12); the remainder of the protein sequence is then designed using Rosetta to incorporate additional interactions with the peptide and drive folding to the desired structure. We use this approach to design, from scratch, alpha helical repeat proteins that bind six different tripeptide repeat sequences--PLP, LRP, PEW, IYP, PRM and PKW--in near polyproline 2 helical conformations. The proteins are expressed at high levels in E. coli, are hyperstable, and bind peptides with 4-6 copies of the target tripeptide sequences with nanomolar to picomolar affinities both in vitro and in living cells. Crystal structures reveal repeating interactions between protein and peptide interactions as designed, including a ladder of protein sidechain to peptide backbone hydrogen bonds. By redesigning the binding interfaces of individual repeat units, specificity can be achieved for non-repeating sequences, and for naturally occuring proteins containing disordered regions. Our approach provides a general route to designing specific binding proteins for a broad range of repeating and non-repetitive peptide sequences.
Firing rate adaptation affords place cell theta sweeps, phase precession and procession
Authors: Chu Tianhao , Ji Zilong , Zuo Junfeng , Mi Yuanyuan , Zhang Wen-hao , Huang Tiejun , Bush Daniel , Burgess Neil , Wu Si 
Published: November 2022

AbstractHippocampal place cells in freely moving rodents display both theta phase precession and procession, which is thought to play important roles in cognition, but the neural mechanism for producing theta phase shift remains largely unknown. Here we show that firing rate adaptation within a continuous attractor neural network causes the neural activity bump to oscillate around the external input, resembling theta sweeps of decoded position during locomotion. These forward and backward sweeps naturally account for theta phase precession and procession of individual neurons, respectively. By tuning the adaptation strength, our model explains the difference between “bimodal cells” showing interleaved phase precession and procession, and “unimodal cells” in which phase precession predominates. Our model also explains the constant cycling of theta sweeps along different arms in a T-maze environment, the speed modulation of place cells’ firing frequency, and the continued phase shift after transient silencing of the hippocampus. We hope that this study will aid an understanding of the neural mechanism supporting theta phase coding in the brain.