bluuebunny/crossref_metadata_2025_split huggingface dataset:
Probiotic neoantigen delivery vectors for precision cancer immunotherapy
Authors: Redenti Andrew , Im Jongwon , Redenti Benjamin , Li Fangda , Rouanne Mathieu , Sheng Zeren , Sun William , Gurbatri Candice R. , Huang Shunyu , Komaranchath Meghna , Jang YoungUk , Hahn Jaeseung , Ballister Edward R. , Vincent Rosa L. , Vardoshivilli Ana , Danino Tal , Arpaia Nicholas 
Published: October 2023

AbstractMicrobial systems have been synthetically engineered to deploy therapeutic payloadsin vivo1–4. With emerging evidence that bacteria naturally home to tumors5–7and modulate anti-tumor immunity8,9, one promising application is the development of bacterial vectors as precision cancer vaccines10–12. In this study, we engineered probioticE. coliNissle 1917 (EcN) as an anti-tumor vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system which drives potent and specific T cell–mediated anti-cancer immunity that effectively controls or eliminates tumor growth and extends survival in advanced murine primary and metastatic solid tumors. We demonstrate that the elicited anti-tumor immune response involves extensive priming and activation of neoantigen-specific CD4+and CD8+T cells, broader activation of both T and NK cells, and a reduction of tumor-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumor-specific neoantigen–derived epitopes within the optimal context to induce specific, effective, and durable systemic anti-tumor immunity.
SalmonellaTyphimurium employ spermidine to exert protection against ROS-mediated cytotoxicity and rewires host polyamine metabolism to ameliorate its survival in macrophages
Authors: Nair Abhilash Vijay , Singh Anmol , Rajamani R. S. , Chakravortty Dipshikha 
Published: October 2023

AbstractSalmonellainfection involves a cascade of attacks and defence measures. After breaching the intestinal epithelial barrier,Salmonellais phagocytosed by the macrophages, inside which, the bacteria face multiple stresses and, consequently, employ appropriate countermeasures. We show that, inSalmonella, the polyamine spermidine activates a stress response mechanism by regulating critical antioxidant genes.SalmonellaTyphimurium mutants for spermidine transport and synthesis cannot mount an antioxidative response, resulting in high intracellular ROS levels. These mutants are also compromised in their ability to be phagocytosed by macrophages. Furthermore, it regulates a novel enzyme inSalmonella, Glutathionyl-spermidine synthetase (GspSA), which is known to prevent the oxidation of proteins inE.coli. Moreover, the spermidine mutants and the GspSA mutant show significantly reduced survival in the presence of hydrogen peroxidein vitro, and lesser organ burden in the mouse model ofSalmonellainfection. Conversely, in macrophages isolated fromgp91phox-/-mice, we observed a rescue in the attenuated fold proliferation previously observed upon infection. Interestingly,Salmonellaupregulates polyamine biosynthesis in the host through its effectors from SPI-1 and SPI-2, which also solves the mystery of the attenuated proliferation observed in spermidine transport mutants. Thus, inhibition of this pathway in the host abrogates the proliferation ofSalmonellaTyphimurium in macrophages. From a therapeutic perspective, inhibiting host polyamine biosynthesis using an FDA-approved chemopreventive drug, D,L-α-difluoromethylornithine (DFMO), reducesSalmonellacolonization and tissue damage in the mouse model of infection, while enhancing the survival of infected mice. Therefore, our work provides a mechanistic insight into the critical role of spermidine in stress resistance ofSalmonella. It also reveals a strategy of the bacteria in modulating host metabolism to promote their intracellular survival and shows the potential of DFMO to curb Salmonellainfection.
Replicated Functional Evolution in Cichlid Adaptive Radiations
Authors: Martinez Christopher M. , Corn Katherine A. , Williamson Sarah , Satterfield Darien , Roberts-Hugghis Alexus S. , Barley Anthony , Borstein Samuel R. , McGee Matthew D. , Wainwright Peter C. 
Published: October 2023

ABSTRACTAdaptive radiations highlight the mechanisms by which species and traits diversify and the extent to which these patterns are predictable. We used 1,110 high-speed videos of suction feeding to study functional and morphological diversification in 300 cichlid species from three African Great Lake radiations of varying ages (Tanganyika, Malawi and Victoria) and an older, spatially dispersed continental radiation in the Neotropics. Among African radiations, standing diversity was reflective of time. Morphological and functional variance in Lake Victoria, the youngest radiation, was a subset of that within Lake Malawi, which itself was nested within the older Tanganyikan radiation. However, functional diversity in Neotropical cichlids was often lower than in Lake Tanganyika, despite being at least 25 My older. These two radiations broadly overlapped, but each diversified into novel trait spaces not found in the youngest lake radiations. Evolutionary rates across radiations were inversely related to age, suggesting, at least for lake radiations, extremely rapid trait evolution at early stages. Despite this support for early bursts, other patterns of trait diversity were inconsistent with expectations of adaptive radiations. This work suggests that cichlid functional evolution has played out in strikingly similar fashion in different radiations, with contingencies eventually resulting in lineage-specific novelties.
A native phosphoglycolate salvage pathway of the synthetic autotrophic yeastKomagataella phaffii
Authors: Baumschabl Michael , Mitic Bernd M. , Troyer Christina , Hann Stephan , Ata Özge , Mattanovich Diethard 
Published: October 2023

AbstractSynthetic autotrophs can serve as chassis strains for bioproduction from CO2as a feedstock to take measures against the climate crisis. Integration of the Calvin–Benson–Bassham (CBB) cycle into the methylotrophic yeastKomagataella phaffii(Pichia pastoris) enabled it to use CO2as the sole carbon source. The key enzyme in this cycle is ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) catalyzing the carboxylation step. However, this enzyme is error prone to perform an oxygenation reaction leading to the production of toxic 2-phosphoglycolate. Native autotrophs have evolved different recycling pathways for 2-phosphoglycolate. However, for synthetic autotrophs, no information is available for the existence of such pathways. Deletion ofCYB2in the autotrophicK. phaffiistrain led to the accumulation of glycolate, an intermediate in phosphoglycolate salvage pathways, suggesting that such a pathway is enabled by nativeK. phaffiienzymes.13C tracer analysis with labeled glycolate indicated that the yeast pathway recycling phosphoglycolate is similar to the plant salvage pathway. This orthogonal yeast pathway may serve as a sensor for RuBisCO oxygenation, and as an engineering target to boost autotrophic growth rates inK. phaffii.
Structural and quantum chemical basis for OCP-mediated quenching of phycobilisomes
Authors: Sauer Paul V. , Cupellini Lorenzo , Sutter Markus , Bondanza Mattia , Domínguez Martin María Agustina , Kirst Henning , Bína David , Koh Adrian Fujiet , Kotecha Abhay , Greber Basil J , Nogales Eva , Polívka Tomáš , Mennucci Benedetta , Kerfeld Cheryl A. 
Published: October 2023

AbstractCyanobacteria employ large antenna complexes called phycobilisomes (PBS) for light harvesting. However, intense light triggers non-photochemical quenching, where the Orange Carotenoid Protein (OCP) binds to PBS, dissipating excess energy as heat. The mechanism of efficiently transferring energy from phycocyanobilins in PBS to canthaxanthin in OCP remains insufficiently understood. Using advanced cryogenic-electron microscopy, we unveiled the OCP-PBS complex structure at 1.6-2.1 Å resolution, showcasing its inherent flexibility. Employing multiscale quantum chemistry, we disclosed the quenching mechanism. Identifying key protein residues, we clarified how canthaxanthin’s transition dipole moment in its lowest-energy dark state becomes large enough for efficient energy transfer from phycocyanobilins. Our energy transfer model offers a detailed understanding of the atomic determinants of light harvesting regulation and antenna architecture in cyanobacteria.One sentence summaryHigh-resolution cryo-EM structure of the OCP-PBS complex reveals intrinsic motions and enables the atomic simulation of the quenching mechanism
Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors
Authors: Frank Anderson R , Vandiver Florentina , McFadden David G 
Published: October 2023

ABSTRACTAltered metabolism is a hallmark of cancer; however, it has been difficult to specifically target metabolism in cancer for therapeutic benefit. Cancers with genetically defined defects in metabolic enzymes constitute a subset of cancers where targeting metabolism is potentially accessible. Hürthle cell carcinoma of the thyroid (HTC) tumors frequently harbor deleterious mitochondrial DNA (mtDNA) mutations in subunits of complex I of the mitochondrial electron transport chain (ETC). Previous work has shown that HTC models with deleterious mtDNA mutations exhibit mitochondrial ETC defects that expose lactate dehydrogenase (LDH) as a therapeutic vulnerability. Here, we performed forward genetic screens to identify mechanisms of resistance to small molecule LDH inhibitors. We identified two distinct mechanisms of resistance: upregulation of an LDH isoform and a compound-specific resistance mutation. Using these tools, we demonstrate that the anti-cancer activity of LDH inhibitors in cell line and xenograft models of complex I-mutant HTC is through on-target LDH inhibition.
DegCre: Probabilistic association of differential gene expression with regulatory regions
Authors: Roberts Brian S. , Cooper Gregory M. , Myers Richard M. 
Published: October 2023

AbstractDifferential gene expression in response to perturbations is mediated at least in part by changes in binding of transcription factors (TFs) and other proteins at specific genomic regions. Association of these cis-regulatory elements (CREs) with their target genes is a challenging task that is essential to address many biological and mechanistic questions. Many current approaches rely on chromatin conformation capture techniques that identify spatial proximity between genomic sites to establish CRE-to-gene associations. These methods can be effective but have limitations, including resolution, minimal detectable interaction distance, and cost. As an alternative, we have developed DegCre, a non-parametric method that evaluates correlations between measurements of perturbation-induced differential gene expression and differential regulatory signal at CREs to score possible CRE-to-gene associations. It has several unique features, including the ability to: use any type of CRE activity measurement; yield probabilistic scores for CRE-to-gene pairs; and assess CRE-to-gene pairings across a wide range of sequence distances. We apply DegCre to three data sets, each employing different perturbations and containing a variety of regulatory signal measurements, including chromatin openness, histone modifications, and TF occupancy. To test their efficacy, we compare DegCre associations to HiC loop calls and to CRISPR validated interactions, with both yielding good agreement. We demonstrate the identification of perturbation direct target genes with DegCre confirm the results with previous reports. DegCre is a novel approach to the association of CREs to genes from a perturbation-differential perspective, with strengths that are complementary to existing approaches and allow for new insights into gene regulation.
A prospective comparison of a modified miniaturised hand‐held epifluorescence microscope and touch imprint cytology for evaluation of axillary sentinel lymph nodes intraoperatively in breast cancer patients
Authors: Chen Jia‐jian , Yu Bao‐hua , Shen Ti‐jing , Wang Ying , Ren Fei , Yang Li‐rui , Dong Yuan , Zheng Ming‐jie , Hao Shuang , Yang Wen‐tao , Wu Jiong 
Published: October 2023

AbstractBackgroundThe management of axillary lymph nodes in early‐stage breast cancer patients has changed considerably, with the primary focus shifting from the examination of sentinel lymph nodes (SLNs) to toward the detection of all macro‐metastases. However, current methods, such as touch imprint cytology (TIC) and frozen sections, are inadequate for clinical needs. To address this issue, we proposed a novel miniaturised epifluorescence widefield microscope (MEW‐M) to assess SLN status intraoperatively for improved diagnostic efficiency.MethodsA prospective, side‐by‐side comparison of intraoperative SLN evaluation between MEW‐M and TIC was performed.ResultsA total of 73 patients with 319 SLNs consecutive enrolled in this study. MEW‐M showed significantly superior image quality compared to TIC (median score 3.1 vs 2.1, p < 0.0001) and had a shorter time to issue results (10.3 vs 19.4 min, p < 0.0001). Likelihood ratio analysis illustrated that the positive likelihood ratio value of MEW‐M compared with TIC was infinitely great vs 52.37 (95% CI, 21.96‐124.90) in model 1 (classifying results into negative/positive), infinitely great vs 52.37 (95% CI, 21.96‐124.90) in model 2 (classifying results into macro‐metastasis/others, and TIC results followed the same classification as model 1), respectively. Similarly, the negative likelihood ratio values of MEW‐M compared with TIC were 0.055 (95% CI, 0.018‐0.160) and 0.074 (95% CI, 0.029‐0.190) in model 1; and 0.019 (95% CI, 0.003‐0.130) vs 0.020 (95% CI, 0.003‐0.140) in model 2, respectively.ConclusionsMEW‐M is a promising technique that can be utilised to provide a rapid and accurate intraoperative assessment of SLN in a clinical setting to help improve decision‐making in axillary surgery.
Understanding how self‐management education and support programmes for type 2 diabetes are expected to change behaviour: A document analysis of two programmes
Authors: Carvalho Márcia , Byrne Molly , Kenny Eanna , Caba Molly , Hadjiconstantinou Michelle , Dunbar Jenny , Powell Sinéad , McSharry Jenny 
Published: October 2023

AbstractAimsAttendance at diabetes self‐management education and support (DSMES) programmes for type 2 diabetes is associated with positive outcomes, but the impact on some outcomes is inconsistent and tends to decline over time. Understanding the active ingredients of effective programmes is essential to optimise their effectiveness. This study aimed to (1) retrospectively identify behaviour change techniques (BCTs), mechanisms of action (MoAs) and intervention functions in two DSMES programmes, the Community‐Oriented Diabetes Education and the Diabetes Education and Self‐Management for Ongoing and Newly Diagnosed and (2) examine variation in content between programmes.MethodsA multiple case study approach, including a documentary analysis of the programme materials, was conducted. Materials were coded using the BCT Taxonomy v1, the Mode of Delivery Ontology v1 and the Intervention Source Ontology v1. The Behaviour Change Wheel guidance and the Theory and Techniques tool were used to identify intervention functions and MoAs. Programme stakeholders provided feedback on the findings.ResultsThirty‐four BCTs were identified across the programmes, with 22 common to both. The identified BCTs were frequently related to ‘goals and planning’, ‘feedback and monitoring’ and ‘natural consequences’. BCTs were linked with 15 MoAs, predominantly related to reflective motivation (‘beliefs about capabilities’ and ‘beliefs about consequences’) and psychological capability (‘knowledge’). BCTs served six intervention functions, most frequently ‘education’, ‘enablement’ and ‘persuasion’.ConclusionsAlthough both programmes included several BCTs, some BCTs were rarely or never used. Additional BCTs could be considered to potentially enhance effectiveness by addressing a wider range of barriers.
Use of the synergist piperonyl butoxide can slow the development of alpha‐cypermethrin resistance in the whitefly Bemisia tabaci
Authors: Zimmer C. T. , Panini M. , Singh K. S. , Randall E. L. , Field L. M. , Roditakis E. , Mazzoni E. , Bass C. 
Published: October 2023

AbstractThe development of insecticide resistance in insect pests of crops is a growing threat to sustainable food production, and strategies that slow the development of resistance are therefore urgently required. The insecticide synergist piperonyl butoxide (PBO) inhibits certain insect detoxification systems and so may delay the evolution of metabolic resistance. In the current study we characterized resistance development in the silverleaf whitefly, Bemisia tabaci, after selection with either a neonicotinoid (thiacloprid) or pyrethroid (alpha‐cypermethrin) insecticide alone or in combination with PBO. Resistance development was significantly suppressed (> 60%) in the line selected with alpha‐cypermethrin + PBO compared to the line selected with alpha‐cypermethrin alone. RNA sequencing (RNAseq) analyses revealed an increase in frequency of a knock‐down resistance mutation but no differentially expressed genes were identified that could explain the sensitivity shift. No significant difference was observed in the level of resistance between the thiacloprid and thiacloprid + PBO selected lines, and RNA sequencing (RNAseq) analyses revealed that the cytochrome P450 monooxygenase CYP6CM1, known to metabolize neonicotinoids, was significantly upregulated (>10‐fold) in both lines. The findings of this study demonstrate that PBO used in combination with certain insecticides can suppress the development of resistance in a laboratory setting; however, the mechanism by which PBO supresses resistance development remains unclear.
Corporate Governance in China
Authors: Morck Randall , Yeung Bernard 
Published: October 2023

Since the death of Mao Tse Tung in 1976, China has achieved unprecedented economic growth. Per capita GDP has increased from one of the lowest in the world to a level that is firmly in the middle of the international ranks. But can China continue on the growth path of the last four decades? The question arises because of the tendency of developing economies, having achieved periods of “catch‐up” growth, to become mired in a “middle‐income trap” that appears to stem from a variety of factors, including the tendency for elites and oligarchs to protect their own interests by blocking competition.China's success to date has come without many of the key institutions—notably, private property rights, shareholder‐centered corporate governance, and a well‐functioning impartial legal system—that most Western economists believe essential to long‐term success. China's description of its system as “market socialism with Chinese characteristics” is an accurate one. Markets, not decrees, set most prices, while the state, in the form of the Communist Party, continues to control the careers of SOEs' senior executives, regulators, and government officials, and retains “options” to intervene in a large variety of financial and corporate affairs as well as judicial processes and decisions.Chinese history underpins the system in the sense that the Party is, at least in some respects, a genuine meritocracy reminiscent of the imperial civil service of past eras. And the authors raise the possibility that the Party's Leading Role has actually contributed to China's extraordinary growth not only by fostering such a meritocracy, but by initiating and presiding over what development economists describe as a “Big Push,” a coordinated simultaneous development of many firms in multiple industries that was necessary to transform a subsistence agricultural economy into a modern industrial one.But for all the effectiveness of China's “Big Push,” the authors close by expressing doubt that China can continue to rise into the world's economic upper ranks until it adopts the substance as well as the form of those missing institutions that, they argue, are the only well‐marked path to high‐income status.
CARE Conference Hong Kong Polytechnic University, June 9, 2014: Equity Financing for Early‐Stage Companies in China
Authors: Jia Ning 
Published: October 2023

Many of the smaller private‐sector Chinese companies in their entrepreneurial growth stage are now being funded by Chinese venture capital (VC) and private equity (PE) firms. In contrast to western VC markets, where institutional investors such as pension funds and endowments have been the main providers of capital, in China most capital for domestic funds has come from private business owners and high net worth individuals. As relatively new players in the market who are less accustomed to entrusting their capital to fund managers for a lengthy period of time, Chinese VCs and their investors have shown a shorter investment horizon and demanded a faster return of capital and profits.In an attempt to explain this behavior, Paul Gompers and Josh Lerner of Harvard Business School have offered a “grandstanding hypothesis” that focuses on the incentives of younger, less established VCs to push their portfolio companies out into the IPO market as early as they can—and thus possibly prematurely—to establish a track record and facilitate future fundraising. This explanation is supported by the under‐performance of Chinese VC‐backed IPOs that has been documented by the author's recent research.Although they continue to offer significant opportunities for global investors, China's VC and PE markets still face many challenges. The supervisory system and legal environment need further improvement, and Chinese funds need to find a way to attract more institutional investors—a goal that can and likely will be promoted through government inducements.
Research Reviews: Advances in methods for evaluating child and adolescent mental health interventions
Authors: Pickles Andrew , Edwards Danielle , Horvath Levente , Emsley Richard 
Published: October 2023

BackroundThe evidence base for interventions for child mental health and neurodevelopment is weak and the current capacity for rigorous evaluation limited. We describe some of the challenges that make this field particularly difficult and expensive for evaluation studies.MethodsWe describe and review the use of novel study designs and analysis methodology for their potential to improve this situation.ResultsWhile several novel designs appeared ill‐suited to our field, systematic review found others that offered potential but had yet to be widely adopted, some not at all.ConclusionsWhile funding is inevitably a constraint, we argue that improvements in the evidence base of both current and new treatments will only be achieved by the adoption of a number of these new technologies and study designs, the consistent application of rigorous constructive but demanding standards, and the engagement of the public, patients, clinical and research services to build a design, recruitment, and analysis infrastructure.