bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting survival time for critically ill patients with heart failure using conformalized survival analysis
Authors: Wang Xiaomeng , Ren Zhimei , Ye Jiancheng 
Published: September 2024

AbstractHeart failure (HF) is a serious public health issue, particularly for critically ill patients in intensive care units (ICUs). Predicting survival outcomes of critically ill patients with calibrated uncertainty calibration is a difficult yet crucially important task for timely treatment. This study applies a novel approach, conformalized survival analysis (CSA), to predicting the survival time to critically ill HF patients. CSA quantifies the uncertainty of point prediction by accompanying each predicted value with a lower bound guaranteed to cover the true survival time. Utilizing the MIMIC-IV dataset, we demonstrate that CSA delivers calibrated uncertainty quantification for the predicted survival time, while the methods based on parametric models (e.g., Cox model or the Accelerated Failure Time model) fail to do so. By applying CSA to a large, real-world dataset, the study highlights its potential to improve decision-making in critical care, offering a more nuanced and accurate tool for prognostication in a setting where precise predictions and calibrated uncertainty quantification can significantly influence patient outcomes.
Antigen specificity of clonally-enriched CD8+ T cells in multiple sclerosis
Authors: Mittl Kristen , Hayashi Fumie , Dandekar Ravi , Schubert Ryan D. , Gerdts Josiah , Oshiro Lindsay , Loudermilk Rita , Greenfield Ariele , Augusto Danillo G. , Ramesh Akshaya , Tran Edwina , Koshal Kaniskha , Kizer Kerry , Dreux Joanna , Cagalingan Alaina , Schustek Florian , Flood Lena , Moore Tamson , Kirkemo Lisa L. , Cooper Tiffany , Harms Meagan , Gomez Refujia ,   University of California, San Francisco MS-EPIC Team, Sibener Leah , Cree Bruce A. C. , Hauser Stephen L. , Hollenbach Jill A. , Gee Marvin , Wilson Michael R. , Zamvil Scott S. , Sabatino Joseph J. 
Published: September 2024

AbstractCD8+ T cells are the dominant lymphocyte population in multiple sclerosis (MS) lesions where they are highly clonally expanded. The clonal identity, function, and antigen specificity of CD8+ T cells in MS are not well understood. Here we report a comprehensive single-cell RNA-seq and T cell receptor (TCR)-seq analysis of the cerebrospinal fluid (CSF) and blood from a cohort of treatment-naïve MS patients and control participants. A small subset of highly expanded and activated CD8+ T cells were enriched in the CSF in MS that displayed high activation, cytotoxicity and tissue-homing transcriptional profiles. Using a combination of unbiased and targeted antigen discovery approaches, MS-derived CD8+ T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and multiple novel mimotopes were identified. These findings shed vital insight into the role of CD8+ T cells in MS and pave the way towards disease biomarkers and therapeutic targets.Graphical SummaryCreated in BioRender. Sabatino, J. (2024)BioRender.com/e66l598
Engineering elephant models of cold-adaptation and cancer resistance
Authors: Karpinski Emil , Badey Nikil , Mintzer Esther , Ashkenazy-Titelman Asaf , Li Li , Church George M. 
Published: September 2024

AbstractThroughout their evolution, proboscideans have gotten larger and spread to occupy novel environments throughout the world. These phenotypic changes have been accompanied by a suite of genetic changes including those responsible for tumor suppression and environmental adaptation. Here we examine a handful of woolly mammoth-specific deletions, and their potential contributions to arctic adaptation, as well as the expanded TP53 genetic repertoire in elephants. We use CRISPR-Cas9 to introduce mammoth-specific noncoding deletions as well as knockouts of TP53, all 29 TP53 retrogenes, or both in combination in Asian elephant cell lines, and examine the transcriptomic response. We find that many of the mammoth-specific deletions likely contribute to various arctic phenotypes including vascular development, metabolism and thermogenesis, and hair and skin adaptations. Additionally, we find that while there is considerable overlap in the DNA damage responses of the TP53 and retrogene knockouts, there are also many unique pathways enriched in both. In particular, the retrogene knockouts exhibit strong enrichment of many extracellular pathways suggesting they may play a role in the tumor microenvironment and mitigating metastatic growth. This highlights the usability of cell culture models to disentangle the effects of regulatory mutations or complex genetic systems, especially in non-model species where the generation of animal models is not possible.
Protein degradation by small tag artificial bacterial E3 ligase
Authors: Liu Zhenyi , Tsai Ming-Chi , Ghosh Soumitra , Lawrence Jessica , Chu Sarah , Bingol Baris , Warming Søren 
Published: September 2024

ABSTRACTTargeting of proteins for degradation in a reversible manner is a powerful approach to decipher gene function and mimic drug effects, with great potential for drug target discovery and validation. A generalized approach is to tag a protein of interest and then use this tag to recruit an endogenously or exogenously expressed E3 ligase for its polyubiquitination and subsequent degradation via 26S proteasome. However, the often bulky size of the tag and the great variability of substrate-dependent degradation efficiency of mammalian E3 ligases pose great challenges in practice. Here we show that small tags (10-15 amino acids) can be used to efficiently tag endogenous proteins for degradation when coupled with an exogenously expressedartificialbacterialE3 ligase (ABEL) consisting of a tag-interacting moiety and the catalytic domain of the bacterial E3 ligase IpaH9.8. We name this versatile and efficient platformdegradation bysmall tagABEL(DESTABEL). Furthermore, we show that an ABEL containing a nanobody against human α-synuclein mediates efficient degradation in primary neurons as well as in the adult mouse brain. Taken together, our data show that tag-dependent and independent ABELs are powerful yet flexible tools for studies of protein function and drug target validation.
Pentose Phosphate Pathway ProtectsE. colifrom Antibiotic Lethality
Authors: Seregina Tatyana , Shakulov Rustem , Shatalin Konstantin , Sklyarova Svetlana , Petrushanko Irina , Mitkevich Vladimir , Makarov Alexander , Mironov Alexander S. , Nudler Evgeny 
Published: September 2024

ABSTRACTDisruption of both branches of the canonical pentose phosphate pathway (PPP) inE. coliby combined inactivation of thezwfandtalABgenes provokes the restoration of the ancient anabolic variant of PPP (aPPP). In the aPPP, pentose-5-phosphates are synthesized unidirectionally from fructose-6-phosphate and glyceraldehyde-3-phosphate by transketolase B, aldolase A, and phosphatase GlpX, converting sedoheptulose-1,7-bisphosphate to sedoheptulose-7-phosphate. Unexpectedly, the doublezwf talABmutant exhibits decreased survival after treatment by diverse classes of antibiotics with little effect on the minimal inhibitory concentration. Simultaneously, we found that killing effect of antimicrobials on thezwf talABmutant could be reversed by the inactivation of eitherpurRordeoBgenes, both responsible for ribose-5-phosphate content in the mutant strain. Enhanced biosynthesis of the cell wall component ADP-heptose from sedoheptulose-7-phosphate also suppressed killing effect of antibiotics on thezwf talABmutant. Furthermore, the inactivation of the Entner-Doudoroff pathway (Δedd) or shifting the metabolic equilibrium by the addition of exogenous phosphogluconate reverts aPPP to glycolysis, preventing the accumulation of excess pentose phosphates and the occurrence of the futile cycle inzwf talABcells, thus desensitizing them to antibiotics. Our findings show that ribose-5-phosphate metabolism plays a crucial role in bacterial tolerance to a wide range of bactericidal antibiotics. We propose that targeting PPP could be a promising strategy for developing new therapeutic agents aimed at potentiating clinically significant antimicrobials.IMPORTANCERecent studies have revealed the crucial role of bacterial cell’s metabolic status in its susceptibility to the lethal action of antibacterial drugs. However, there is still no clear understanding of which key metabolic nodes are optimal targets to improve the effectiveness of bacterial infection treatment. Our study establishes that the disruption of the canonical pentose phosphate pathway induces one-way anabolic synthesis of pentose phosphates (aPPP) inE. colicells, significantly increasing the killing efficiency of various antibiotics. It is also demonstrated that the activation of ribose-5-phosphate utilization processes restores bacterial tolerance to antibiotics. We consider the synthesis of ribose-5-phosphate to be one of the determining factors of bacterial cell stress resistance. Understanding bacterial metabolic pathways, particularly the aPPP’s role in antibiotic sensitivity, offers insights for developing novel adjuvant therapeutic strategies to enhance antibiotic potency.
Structural basis for sequence context-independent single-stranded DNA cytosine deamination by the bacterial toxin SsdA
Authors: Yin Lulu , Shi Ke , Chen Yanjun , Harris Reuben S. , Aihara Hideki 
Published: September 2024

AbstractDNA deaminase toxins are involved in interbacterial antagonism and the generation of genetic diversity in surviving bacterial populations. These enzymes have also been adopted as genome engineering tools. The single-stranded (ss)DNA deaminase SsdA represents the bacterial deaminase toxin family-2 (BaDTF2) and it deaminates ssDNA cytosines with little sequence context dependence, which contrasts with the AID/APOBEC family of sequence-selective ssDNA cytosine deaminases.Here we report the crystal structure of SsdA in complex with a ssDNA substrate. The structure reveals a unique mode of substrate binding, in which a cluster of aromatic residues of SsdA engages ssDNA in a V-shaped conformation sharply bent across the target cytosine. The bases 5’ or 3’ to the target cytosine are stacked linearly and make few sequence-specific protein contacts, thus explaining the broad substrate selectivity of SsdA. Unexpectedly, SsdA contains a β-amino acid isoaspartate, which is important for enzymatic activity and may contribute to the stability of SsdA as a toxin. Structure- function studies helped to design SsdA mutants active in human cells, which could lead to future applications in genome engineering.
Templated trimerization of the phage L decoration protein on capsids
Authors: Woodbury Brianna M. , Newcomer Rebecca L. , Alexandrescu Andrei T. , Teschke Carolyn M. 
Published: September 2024

ABSTRACTThe 134-residue phage L decoration protein (Dec) forms a capsid-stabilizing homotrimer that has an asymmetric tripod-like structure when bound to phage L capsids. The N-termini of the trimer subunits consist of spatially separated globular OB-fold domains that interact with the virions of phage L or the related phage P22. The C-termini of the trimer form a three-stranded intertwined spike structure that accounts for nearly all the interactions that stabilize the trimer. A Dec mutant with the spike residues 99-134 deleted (Dec1-98) was used to demonstrate that the stable globular OB-fold domain folds independently of the C-terminal residues. However, Dec1-98was unable to bind phage P22 virions, indicating the C-terminal spike is essential for stable capsid interaction. The full-length Dec trimer is disassembled into monomers by acidification to pH <2. These monomers retain the folded globular OB-fold domain structure, but the spike is unfolded. Increasing the pH of the Dec monomer solution to pH 6 allowed for slow trimer formationin vitroover the course of days. The infectious cycle of phage L is only around an hour, however, implying Dec trimer assemblyin vivois templated by the phage capsid. The Thermodynamic Hypothesis holds that protein folding is determined by the amino acid sequence. Dec serves as an unusual example of an oligomeric folding step that is kinetically accelerated by a viral capsid template. The capsid templating mechanism could satisfy the flexibility needed for Dec to adapt to the unusual quasi-symmetric binding site on the mature phage L capsid.
SME supply chain resilience in disruptive times: the effects of supply chain robustness, access to government assistance and disruption intensity
Authors: Nakandala Dilupa , Chen Jiahe , Chikweche Tendai 
Published: September 2024

PurposeThis study investigates the antecedents of supply chain resilience of small and medium-sized enterprises (SMEs) and the effects of government assistance and disruption intensity in long-term disruptions.Design/methodology/approachThis study collected data from 626 SMEs in Australia in 2022 and analysed data using partial least squares structural equation modelling.FindingsThe study empirically confirms that digital capabilities, prior experience in disruptions, supplier proximity and relationships are antecedents of supply chain resilience of SMEs, with supply chain robustness as a mediator. It further confirms that SMEs' access to government assistance positively moderates the relationship between digital capabilities and supply chain robustness. The disruption intensity moderates the relationships between supplier proximity and supply chain robustness with supply chain resilience. Severe disruptions weaken the effects of prior disruption experiences and supplier relationships on supply chain resilience.Practical implicationsThe findings inform SME practitioners of the importance of building supply chain robustness, leveraging their prior experience, supplier proximity and relationships and capabilities and flexibility for dynamic supply chain structures when disruptions are intense.Originality/valueThe novelty of our study is the use of the Contingent Resource-Based View to understand the effects of firm and supply chain-level antecedents on supply chain robustness and resilience, considering the contextual contingencies of disruption intensity and government assistance. The focus on long-term disruptions extends the conventional supply chain resilience studies on supply and demand disruptions of small scale. We also explore the firm-level effects of government assistance, which extends the commonly tested economic-level effects. Furthermore, we investigate supply chain robustness and resilience as different but connected constructs, deviating from common approaches. The finding that the relationship between digital capabilities and supply chain robustness, not the relationship between digital capabilities and supply chain resilience, becomes stronger with higher access to government support shows the importance of this approach to investigating specific effects.
Digital technologies and food supply chain: a scoping view from 2010 to 2024
Authors: Panigrahi Rashmi Ranjan , Singh Neha , Muduli Kamalakanta 
Published: September 2024

PurposeThis paper aims to deepen the understanding of robust food supply chains (FSC) in SMEs by exploring and analyzing the literature through the lenses of digital technologies.Design/methodology/approachThe study collected data from Scopus spanning from 2010 to 2024, employing selected keywords, and processed it using VOS-viewer and Biblioshiny to derive valid inferences and theoretical arguments.FindingsThe review paper identified several key themes shaping the future of supply chain management – Sustainability in SCM, Industry 4.0, Digitalization with FSCM, Circular Economy, Food Waste with Supply Chain, Food Security and Climate Change. These themes collectively bring transformative opportunities for both the adoption of digital technologies and sustainable practices in food supply chains.Research limitations/implicationsThe review found limitations are rooted in financial constraints, institutional barriers and expertise-related challenges encountered within the realm of Digitalization and FSC. Government and corporate houses should focus on these limitations as well as convert them to strengthen the SMEs of FSC.Originality/valueThe study stands out as a pioneering review that not only explores Digitalization in FSC but also explores the link and evidence of SMEs in the unorganized sector, providing unique insights into a previously underexplored area.
Influencing search
Authors: Janssen Maarten C. W. , Williams Cole 
Published: September 2024

AbstractWe show that in search markets an influencer who recommends a product to her followers improves consumer surplus and total welfare despite the firm paying for her recommendation. As consumers learn their value for the product upon search, they will not buy at the recommended firm if they learn their value is low. The threat of search incentivizes firms to offer the influencer a financial contract involving a commission and incentivizes the influencer to be honest in her recommendation. Provided the influencer's search cost is not too high, she also has an incentive to acquire information and give informative recommendations. These informative equilibria are more difficult to sustain if influencers compete with each other.
A phase I drug–drug interaction study to assess the effect of futibatinib on P‐gp and BCRP substrates and of P‐gp inhibition on the pharmacokinetics of futibatinib
Authors: Long Amanda , Yamamiya Ikuo , Valentine Michelle , Machnes Ziv , Hangai Nanae , Anderson Bailey , Wacheck Volker , Gao Ling 
Published: September 2024

AbstractFutibatinib, an inhibitor of fibroblast growth factor receptor 1–4, is approved for the treatment of patients with advanced cholangiocarcinoma with FGFR2 fusions/rearrangements. In this phase I drug–drug interaction study, the effects of futibatinib on P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) substrates, and of P‐gp inhibition on futibatinib pharmacokinetics (PK) were investigated in healthy adults aged 18–55 years. In part 1, 20 participants received digoxin (P‐gp substrate) and rosuvastatin (BCRP substrate). Following a ≥10‐day washout, futibatinib was administered for 7 days, with digoxin and rosuvastatin coadministered on the third day. In part 2, 24 participants received futibatinib. Following a ≥3‐day washout, quinidine (P‐gp inhibitor) was administered for 4 days, with futibatinib coadministered on day 4. Blood samples were collected predose and for 24 (futibatinib), 72 (rosuvastatin), and 120 h (digoxin) postdose. Urine samples (digoxin) were collected predose and for 120 h postdose. PK parameters were compared between treatments using analysis of variance. Coadministration with futibatinib had no effect on the PK of digoxin and rosuvastatin, and coadministration with quinidine had minimal effects on the PK of futibatinib. Differences in Cmax and AUC with and without futibatinib and quinidine, respectively, were <20%. The most common treatment‐emergent adverse events were diarrhea (80%) and increased blood phosphorous (75%) in part 1 and prolonged electrocardiogram QT interval (38%) in part 2. The data show that futibatinib has no clinically meaningful effects on the PK of P‐gp or BCRP substrates and that the effect of P‐gp inhibition on futibatinib PK is not clinically relevant.
Vonoprazan Dual or Triple Therapy Versus Bismuth‐Quadruple Therapy as First‐Line Therapy for Helicobacter pylori Infection: A Three‐Arm, Randomized Clinical Trial
Authors: Cheung Ka Shing , Lyu Tao , Deng Zijie , Han Shaowei , Ni Li , Wu Juan , Tan Jing Tong , Qin Jian , Ng Ho Yu , Leung Wai K. , Seto Wai‐Kay 
Published: September 2024

ABSTRACTBackgroundWe compared efficacy of vonoprazan‐dual or triple therapies and bismuth‐quadruple therapy for treatment‐naive Helicobacter pylori (HP) infection in Southern China, where primary resistance rates of clarithromycin and levofloxacin are >30%.MethodsThis was an investigator‐initiated, three‐arm, randomized clinical trial in Southern China. Between March 2022 and August 2023, treatment‐naïve HP‐infected adults were randomly assigned to receive one of three 14‐day regimens (1:1:1 ratio): vonoprazan‐dual (VA‐dual; vonoprazan 20 mg twice daily and amoxicillin 1 g thrice daily), vonoprazan‐triple (VAC‐triple; vonoprazan 20 mg/amoxicillin 1 g/clarithromycin 500 mg twice daily), or bismuth‐quadruple therapy containing bismuth, esomeprazole, tetracycline, and metronidazole. Primary outcome was noninferiority in HP eradication, evaluated by UBT 4–6 weeks post‐treatment by intention‐to‐treat (ITT) and per‐protocol (PP) analysis (based on subjects who completed 14‐day treatment and rechecked UBT). Bonferroni‐adjusted p‐value of <0.017 was used to determine statistical significance.ResultsA total of 298 subjects (mean age: 35.7 ± 8.4 years; male: 134 [45.0%]; VC‐dual: 100, VAC‐triple: 98, bismuth‐quadruple: 100) were enrolled, and 292 (98.0%) had UBT rechecked. ITT analysis showed that both VA‐dual (eradication rate of 96.0%) and VAC‐triple therapies (95.9%) were noninferior to bismuth‐quadruple therapy (92.0%) (difference: 4.0%, 95% CI: −2.9% to 11.5%, p < 0.001; and 3.9%, 95% CI: −3.1% to 11.5%, p < 0.001, respectively). PP analysis also revealed noninferiority (96.7% or 96.7% vs. 97.4%, with difference: −2.9% and −2.9%, p = 0.009 and 0.010, respectively). The frequency of adverse events was 39.0%, 56.1%, and 71.0% in VA‐dual, VAC‐triple, and bismuth‐quadruple therapies, respectively.ConclusionsVA‐dual and VA‐triple therapies are highly effective and noninferior to bismuth‐quadruple therapy in Southern China. Given the lower adverse effects and fewer antibiotic use, VA‐dual therapy is the preferred first‐line treatment for HP infection.Trial RegistrationChinese Clinical Trial Registry (No. ChiCTR2200056375). Registered on February 4, 2022, https://www.chictr.org.cn/showproj.aspx?proj=14131.
Circular and return migration of Egyptian migrant workers in Libya
Authors: Elsayeh Mohamed 
Published: September 2024

AbstractThe return of Egyptian migrants to Egypt following the onset of crisis in Libya in 2011 raises important questions about their classification as “returnees.” This article demonstrates the impact of the crisis on Egyptians' livelihoods. Field research conducted in Egypt in 2016 reveals that, at least in part, from 2011 onwards Egyptians were engaged in circular migration to and from Libya as a livelihood strategy because of failed reintegration in Egypt. The Egyptian government, intergovernmental and non‐governmental organisations provided varied levels of protection and assistance in evacuating migrants; however, they lacked awareness about returnees' socio‐economic needs. Egyptians were largely unsupported by state and non‐state institutions upon their return and therefore remained reliant on families and social networks. Initiatives aimed at providing aid to returnees, such as those introduced in Ghana and Niger, were generally absent in the Egyptian context. The absence of support had other unintended consequences, including increased levels of domestic violence and reduced educational opportunities for children in households hosting returnees.