bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthetic lethality and the minimal genome size problem
Authors: Rahiminejad Sara , De Sanctis Bianca , Pevzner Pavel , Mushegian Arcady
Published: June 2024

Gene knockout studies suggest that ~300 genes in a bacterial genome and ~1,100 genes in a yeast genome cannot be deleted without loss of viability. These single-gene knockout experiments do not account for negative genetic interactions, when two or more genes can each be deleted without effect, but their joint deletion is lethal. Thus, large-scale single-gene deletion studies underestimate the size of a minimal gene set compatible with cell survival. In yeast
Saccharomyces cerevisiae
, the viability of all possible deletions of gene pairs (2-tuples), and of some deletions of gene triplets (3-tuples), has been experimentally tested. To estimate the size of a yeast minimal genome from that data, we first established that finding the size of a minimal gene set is equivalent to finding the minimum vertex cover in the lethality (hyper)graph, where the vertices are genes and (hyper)edges connect
k
-tuples of genes whose joint deletion is lethal. Using the Lovász-Johnson-Chvatal greedy approximation algorithm, we computed the minimum vertex cover of the synthetic-lethal 2-tuples graph to be 1,723 genes. We next simulated the genetic interactions in 3-tuples, extrapolating from the existing triplet sample, and again estimated minimum vertex covers. The size of a minimal gene set in yeast rapidly approaches the size of the entire genome even when considering only synthetic lethalities in
k
-tuples with small
k
. In contrast, several studies reported successful experimental reductions of yeast and bacterial genomes by simultaneous deletions of hundreds of genes, without eliciting synthetic lethality. We discuss possible reasons for this apparent contradiction.

IMPORTANCE

How can we estimate the smallest number of genes sufficient for a unicellular organism to survive on a rich medium? One approach is to remove genes one at a time and count how many of such deletion strains are unable to grow. However, the single-gene knockout data are insufficient, because joint gene deletions may result in negative genetic interactions, also known as synthetic lethality. We used a technique from graph theory to estimate the size of minimal yeast genome from partial data on synthetic lethality. The number of potential synthetic lethal interactions grows very fast when multiple genes are deleted, revealing a paradoxical contrast with the experimental reductions of yeast genome by ~100 genes, and of bacterial genomes by several hundreds of genes.
Liposomal Fba and Met6 peptide vaccination protects mice from disseminated candidiasis
Authors: Huang Wei-Chiao , Eberle Karen , Colon Jonothan Rosario , Lovell Jonathan F. , Xin Hong
Published: June 2024

Epitopes from the
Candida
cell surface proteins Fba and Met6 are putative vaccine targets for invasive candidiasis. Here, we describe a
Candida
vaccine approach in which short peptides derived from Fba and Met6 are used in spontaneous nanoliposome antigen particle (SNAP) format. SNAP was enabled by the interaction of cobalt porphyrin phospholipid in liposomes with three histidine residues on the N-terminus of synthetic short peptide immunogens from Fba (F-SNAP), Met6 (M-SNAP), or bivalent Fba and Met6 (FM-SNAP). Liposomes were adjuvanted with synthetic monophosphoryl lipid and QS-21. In mice, immunization with F-SNAP, M-SNAP, or FM-SNAP induced antigen-specific IgG responses and mixed Th1/Th2 immunity. The duplex FM-SNAP vaccine elicited stronger antibody responses against each peptide, even at order-of-magnitude lower peptide dosing than a comparable adjuvanted, conjugate vaccine. Enzyme-linked immunosorbent spot analysis revealed the induction of antigen-specific, cytokine-producing T cells. Compared to F-SNAP or M-SNAP, higher production of TNFα, IL-2, and IFNγ was observed with re-stimulation of splenocytes from bivalent FM-SNAP-immunized mice. When vaccinated BALB/c mice were challenged with
Candida auris
, analysis of the fungal burden in the kidneys showed that SNAP vaccination protected from disseminated candidiasis. In a lethal fungal exposure model in A/J mice, F-SNAP, M-SNAP, and FM-SNAP vaccination protected mice from candidiasis challenge. Together, these results show that further investigation into the SNAP adjuvant platform is warranted using Fba and Met6 epitopes for a pan-
Candida
peptide vaccine that provides multifaceted protective immune responses.

IMPORTANCE

This study introduces a promising vaccine strategy against invasive candidiasis, a severe fungal infection, by targeting specific peptides on the surface of
Candida
. Using a novel approach called spontaneous nanoliposome antigen particle (SNAP), we combined peptides from two key
Candida
proteins, Fba and Met6, into a vaccine. This vaccine induced robust immune responses in mice, including the production of protective antibodies and the activation of immune cells. Importantly, mice vaccinated with SNAP were shielded from disseminated candidiasis in experiments. These findings highlight a potential avenue for developing a broad-spectrum vaccine against
Candida
infections, which could significantly improve outcomes for patients at risk of these often deadly fungal diseases.
Genomic insights into the evolution of secondary metabolism of
Escovopsis
and its allies, specialized fungal symbionts of fungus-farming ants
Authors: Berasategui Aileen , Salem Hassan , Moller Abraham G. , Christopher Yuliana , Vidaurre Montoya Quimi , Conn Caitlin , Read Timothy D. , Rodrigues Andre , Ziemert Nadine , Gerardo Nicole
Published: June 2024

The metabolic intimacy of symbiosis often demands the work of specialists. Natural products and defensive secondary metabolites can drive specificity by ensuring infection and propagation across host generations. But in contrast to bacteria, little is known about the diversity and distribution of natural product biosynthetic pathways among fungi and how they evolve to facilitate symbiosis and adaptation to their host environment. In this study, we define the secondary metabolism of
Escovopsis
and closely related genera, symbionts in the gardens of fungus-farming ants. We ask how the gain and loss of various biosynthetic pathways correspond to divergent lifestyles. Long-read sequencing allowed us to define the chromosomal features of representative
Escovopsis
strains, revealing highly reduced genomes composed of seven to eight chromosomes. The genomes are highly syntenic with macrosynteny decreasing with increasing phylogenetic distance, while maintaining a high degree of mesosynteny. An ancestral state reconstruction analysis of biosynthetic pathways revealed that, while many secondary metabolites are shared with non-ant-associated
Sordariomycetes
, 56 pathways are unique to the symbiotic genera. Reflecting adaptation to diverging ant agricultural systems, we observe that the stepwise acquisition of these pathways mirrors the ecological radiations of attine ants and the dynamic recruitment and replacement of their fungal cultivars. As different clades encode characteristic combinations of biosynthetic gene clusters, these delineating profiles provide important insights into the possible mechanisms underlying specificity between these symbionts and their fungal hosts. Collectively, our findings shed light on the evolutionary dynamic nature of secondary metabolism in
Escovopsis
and its allies, reflecting adaptation of the symbionts to an ancient agricultural system.

IMPORTANCE

Microbial symbionts interact with their hosts and competitors through a remarkable array of secondary metabolites and natural products. Here, we highlight the highly streamlined genomic features of attine-associated fungal symbionts. The genomes of
Escovopsis
species, as well as species from other symbiont genera, many of which are common with the gardens of fungus-growing ants, are defined by seven chromosomes. Despite a high degree of metabolic conservation, we observe some variation in the symbionts’ potential to produce secondary metabolites. As the phylogenetic distribution of the encoding biosynthetic gene clusters coincides with attine transitions in agricultural systems, we highlight the likely role of these metabolites in mediating adaptation by a group of highly specialized symbionts.
Distribution and reference values of peripheral perfusion index in neonates from population-wide screening
Authors: Sasikumar Navaneetha , Madhavankutty Nair Sreehari , Gutjahr Georg , Bendapudi Perraju , Moosa Abdulrazak , Prasenan Krishna , Rajan Vishnu Raj , Sudhakar Abish , Kumar Raman Krishna
Published: June 2024

Background

Peripheral perfusion index (PPI) is useful in a variety of neonatal settings. Currently, available reference values are from small numbers and highly variable.

Methods

We sought to generate reference values of PPI by analysing previously collected data from newborns who underwent mandated universal pulse oximetry and PPI screening from 2018 to 2021 using uniform protocol and equipment. Q-Q plots and boxplots were used to visualise distributions. Kernel density estimation for heaped and rounded data was used to estimate percentiles of the distributions.

Results

Data from 388 205 newborns who underwent universal pulse oximetry screening in the first week of life were used for this analysis. Pre and postductal values showed a non-normal distribution and skewed to the left, the former had a thicker tail with more extreme values. Minor, but statistically significant differences were seen in the PPI values from day 1 to 7. Median preductal PPI (2.77, IQR:1.83–3.93) was significantly higher than postductal (2.38 IQR: 1.41–3.55) (p<0.01). PPI values increased with weight and boys had higher PPI. Kernel estimates of the percentiles in the overall sample and subgroups for gender and weight have been provided for preductal and post-ductal values.

Conclusion

This study, based on the largest available dataset, provides reference values for PPI in newborns. A significant influence of gender and birth weight on PPI values in newborns has been identified. Future research on understanding the influence of age, sex, birth weight, gestational age, ambient temperature and genetic factors on PPI is recommended.
Inhibition of receptor interacting protein kinase-1 (RIPK1) in the treatment of murine lupus
Authors: Peng Lin , Wang Pengcheng , Xu Xiaodong , Chen Dacheng , Xu Feng , Yang Fan , Yang Shuying , Xia Hongguang , Liu Zhi-Hong , Qin Weisong
Published: June 2024

Objective

Systemic lupus erythematosus (SLE) is a type of autoimmune disease that involves multiple organs involved as well as cytokine dysregulation. The treatment of SLE is still challenging due to the side effects of the different drugs used. Receptor-interacting protein kinase 1 (RIPK1) is a kinase involved in T cell homeostasis and autoinflammation. Although clinical trials have shown that RIPK1 inhibition exhibits significant efficacy in different autoimmune diseases, its role in SLE remains unclear.

Methods

MRL/lpr lupus-prone mice received RIPK1 inhibitor ZJU37 or vehicle intraperitoneally for 10 weeks. A BM12-induced chronic graft-versus-host-disease (cGVHD) lupus-like model was introduced in RIPK1 D138N mice or C57BL/6 mice. Nephritis, serum autoantibody levels, dysregulation of adaptive immune response and cytokines were compared in treated and untreated mice.

Results

ZJU37 alleviated the clinical features of the MRL/lpr mice including nephritis and anti-dsDNA antibody production. In addition, ZJU37 treatment reduced the proportion of double-negative T cells in the spleen and the cytokines of TNFα, IFN-γ, IL-6, IL-17 and IL-1β in the serum. Moreover, RIPK1 D138N mice were able to prevent the cGVHD lupus-like model from SLE attack, manifesting as anti-dsDNA antibody production, the proliferation of germinal centre B cells, plasma cells, and T follicular helper cells as well as IgG and C3 deposits in kidneys.

Conclusion

RIPK1 inhibition has a protective effect in the mouse model of SLE and can potentially become a new therapeutic target for SLE in humans.
Stochastic Modeling of Nonlinear SIS Epidemic Dynamics with Jump Perturbations
Authors: El Idrissi Mourad , Settati Adel , Lahrouz Aadil , Assadouq Abdelaziz , El Jarroudi Mustapha , Er-Riani Mustapha , Amtout Tarik , Boujoudar Mohamed
Published: June 2024

This research rigorously investigates a stochastic Susceptible-Infectious-Susceptible (SIS) epidemic model incorporating a generalized nonlinear incidence rate. The study further expands the model scope by introducing white and Lévy noise components. Including jumps and noises enhances the likelihood of disease extinction within the population. Initially, we utilized a comprehensive mathematical analysis to establish the global stability of the equilibrium state devoid of the disease. Our findings demonstrate that the system maintains stability even in the presence of the disease. This serves as a fundamental insight into the dynamics of disease transmission. Moreover, we define a collection of adequate criteria that contribute to the continuous presence of the ailment, thereby guaranteeing its non-complete eradication. By identifying the critical factors that contribute to the sustained presence of the disease, we enhance our understanding of the long-term behavior of the epidemic. To validate our theoretical findings, we conduct numerical simulations. These simulations effectively demonstrate the accuracy and reliability of the presented results. By comparing the simulated data with our analytical predictions, we can confidently confirm the validity of our model and its applicability in practical scenarios.
Measuring Cues of Leadership, Cohesion, and Fluidity in Joint Full‐Body Movement to Support Embodied Interaction Design: A Pilot Study
Authors: Gnecco Giorgio , Camurri Antonio , Gasparotti Cora , Ceccaldi Eleonora , Volpe Gualtiero , Bardy Benoît , Bieńkiewicz Marta , Janaqi Stefan
Published: June 2024

Innovative applications of human movement analysis, for example, for mitigating/slowing down certain pathological conditions, have recently emerged from the modeling and automated measurement of full‐body expressive midlevel individual and group movement qualities, at a higher complexity level than movement qualities derived directly from physical signals, still not characterizing any gesture in a specific way. More in general, the availability of automated analysis techniques of midlevel expressive movement qualities can contribute to interaction design incorporating body‐based performance practices inspired by artistic theories in dance and music. This work investigates how such practices and techniques can support embodied interaction design by enabling automated measuring of cues of leadership, cohesion, and fluidity in full‐body movement in group settings. In particular, the dance‐inspired scientific approach, the data collection protocol, and the analysis techniques adopted for assessing movement qualities connected to leadership and cohesion within the group and fluidity of the dancers’ full‐body movement are described. Finally, future developments of this research are outlined.
Shared and Unique Genetic Links between Neuroticism and Gastrointestinal Tract Diseases
Authors: Tian Ye , Zi Jing , Hu Yifan , Zeng Yaxian , Li Haoqi , Luo Hang , Xiong Jingyuan
Published: June 2024

Objective. Association between neuroticism and gastrointestinal tract (GIT) diseases may not be attributable to the genetic overlaps between neuroticism and psychiatric disorders. We aim to explore the genetic links and mechanisms of neuroticism and GIT diseases. Materials and Methods. We obtained European genome‐wide association data of neuroticism (n = 390,278) or subclusters (depressed, n = 357,957; worry, n = 348,219) and six GIT diseases: gastroesophageal reflux disease (GERD, n = 456,327), inflammatory bowel disease (IBD, n = 456,327), peptic ulcer disease (PUD, n = 456,327), irritable bowel syndrome (IBS, n = 486,601), Crohn’s disease (CD, n = 20,883), and ulcerative colitis (UC, n = 21,895). We performed genetic correlation analysis (high‐definition likelihood method and cross‐trait linkage disequilibrium score regression), pairwise pleiotropic analysis, single nucleic acid polymorphism annotation, Bayesian colocalization, gene‐level analysis, transcriptome‐wide association analysis, and gene set enrichment analysis. Results. Neuroticism and its subclusters are associated with most GIT diseases (15 of 18 trait‐pairs). GERD and PUD were highly correlated with depressed affect. We identified pleiotropic loci 11q23.2 (mapped gene: NCAM1/DRD2) and 18q12.2 (mapped gene: CELF4) in neuroticism and IBS/GERD, supporting the genetic overlap between neuroticism and depression. We found that 16q12.1 (mapped gene: NKD1/ZNF423/NOD2) and 2q37.1 (mapped gene: ATG16L1/SP140) are only highlighted in depressed/neuroticism CD, revealing pleiotropic loci with dissimilarities between neuroticism and different GIT diseases. MR analysis suggested that genetic liability to neuroticism is associated with increased risks of IBS, PUD, and GERD. Conclusion. Our findings document the genetic links between neuroticism and six GIT diseases, highlighting the genetic overlaps and heterogeneity between neuroticism and psychiatric disorders in the context of gastrointestinal disorders. Both the shared and unique pleiotropic loci identified between neuroticism and different GIT diseases could facilitate mechanistic understandings and may stimulate further translational implications.
A Novel Method of Pure Output Modal Identification Based on Multivariate Variational Mode Decomposition
Authors: Li Tao , Hou Rui , Zheng Kangkang , Li Lingfeng , Liu Bo
Published: June 2024

This paper proposes a novel parameterized frequency‐domain modal parameter identification method, called direct modal variational mode decomposition (DMVMD), based on the multivariate variational mode decomposition (MVMD) framework and the principle of modal superposition. Under the constraint of normalized mode shapes, this paper theoretically derives the relationship between multivariate variational mode decomposition and the natural frequencies and mode shapes of structural systems. The aim is to extract K response modes and their corresponding mode shapes from the excited C‐dimensional vibration signals of the measured component’s response. First, the measured multichannel vibration signals are decomposed into IMFs aligned with K‐order natural frequencies using multivariate variational mode decomposition (MVMD). Then, the Hilbert equations and mode shape normalization constraints are used to solve the structural natural frequencies and mode shapes. Furthermore, the proposed multimodal identification algorithm has been validated through numerical simulations and experimental examples, demonstrating its high accuracy and robustness in modal identification. Compared to the existing multimodal algorithms related to variational mode decomposition, the proposed method is more direct and elegant. This method has been successfully applied to the modal parameter identification of subway tunnel structures, enabling accurate determination of the location of tunnel damage through analysis of the identified modal parameters.
Traditional Cardiovascular Risk Factors Associated with Diagonal Earlobe Crease (Frank Sign) in Mexican Adults: Aging, Obesity, Arterial Hypertension, and Being Male Are the Most Important
Authors: Molina-Gallardo Rogelio , Aurelien-Cabezas Nomely S. , Tiburcio-Jimenez Daniel , Plata-Florenzano Jorge E. , Guzman-Esquivel Jose , Rodriguez-Sanchez Iram P. , Martinez-Fierro Margarita L. , Molina-Osorio Roque , De-la-Madrid-Cernas Adrian A. , Barriguete-Melendez Jorge Armando , Delgado-Enciso Ivan
Published: June 2024

Introduction. Cardiovascular risk factors such as obesity, type 2 diabetes, hypertension, smoking, and dyslipidemia enfold heart disease morbimortality. Diagonal earlobe crease has been proposed as a prognostic marker of extension and severity of illness in patients with acute coronary syndrome. But its usefulness remains unclear in patients with or without coronary disease. Methods. A case‐control study was carried out on a total of 805 patients with and without cardiovascular risk factors or acute coronary syndrome. Univariate and multivariate binary logistic regression analyses were used to determine the probability of having diagonal earlobe crease with the presence of cardiovascular risk factors and acute coronary syndrome. Data were summarized as odds ratio with 95% confidence intervals and P values. Results. An unadjusted (univariate) analysis showed that being male, being older than 55 years, obesity, type 2 diabetes mellitus, arterial hypertension, smoking, and dyslipidemia, as well as having acute coronary syndrome, were associated with the presence of diagonal earlobe crease. The multivariate analysis showed that men (OR 1.6, 95% IC 1.1–2.4, P = 0.007), being over 55 years old (OR 4.8, 95% IC 3.2–7.2, P < 0.001), being obese (OR 2.1, 95% IC 1.4–3.1, P < 0.001), having arterial hypertension (1.5, 95% IC 1.1–2.3, P = 0.025), or suffering from acute coronary syndrome (OR 5.3, 95% IC 2.5–11.1, P < 0.001), were independent factors associated with diagonal earlobe crease. The rest of cardiovascular risk factors were not relevant in the multivariate model. Conclusions. In Mexican adults, having an acute coronary syndrome is not the only factor associated with diagonal earlobe crease but also being a man, older than 55 years, having high blood pressure and obesity. Diagonal earlobe crease may simply be caused by changes in the skin and connective tissues of the ears because of the aging process, obesity, and/or being male. These factors, by themselves, enfold cardiovascular risk due to well‐known pathophysiological causes.
Lobe‐Based Hepatic Uptake Index of Gd‐EOB‐DTPA on Contrast‐Enhanced MRI to Quantitatively Discriminate between Compensated and Decompensated Hepatitis B‐Related Cirrhosis
Authors: Lu Fulin , Tan Bangguo , Huang Yucheng , Xu Lin , Wu Changqiang , Zhou Haiying , Li Rui , Zhang Xiaoming , Chen Tianwu , Li Hongjun
Published: June 2024

Purpose. To use hepatic uptake index (HUI) of liver lobes on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd‐EOB‐DTPA)‐enhanced magnetic resonance imaging (MRI) to discriminate between patients with hepatitis B‐related cirrhosis in compensated and decompensated statuses. Methods. Forty‐four consecutive patients with hepatitis B‐related cirrhosis who underwent Gd‐EOB‐DTPA‐enhanced MRI were divided into compensated and decompensated statuses based on clinical evaluation. Volume and signal intensity of individual lobes were retrospectively measured to calculate HUI of the right liver lobe (RHUI), medial (MHUI) and lateral (LHUI) left liver lobes, and caudate lobe (CHUI). Spearman’s rank correlation analyses were performed to evaluate relationships of lobe‐based HUI with Child–Pugh and model for end‐stage liver disease (MELD) scoring system scores in compensated and decompensated statuses. The Mann–Whitney U‐test was used to compare the lobe‐based HUI between compensated and decompensated statuses. The performance of lobe‐based HUI in distinguishing cirrhosis was evaluated using receiver operating characteristic (ROC) analysis, and the area under the ROC curve (AUC) was calculated as a measure of accuracy. Delong’s method was used for statistical analysis to elucidate which HUI is optimal. Results. Compensated and decompensated liver cirrhosis were confirmed in 25 (56.82%) and 19 (43.18%) patients, respectively. According to Spearman’s rank correlation analysis, RHUI, MHUI, LHUI, and CHUI were all significantly associated with Child–Pugh and MELD scores (all P values <0.05). Receiver operating characteristic analysis demonstrated that among all lobe‐based HUI parameters, RHUI could best perform the previous discrimination with a cut‐off of 485.73 and obtain an AUC of 0.867. The AUC of RHUI improved and was significantly different from that of MHUI, LHUI, and CHUI (P = 0.03, P = 0.007, and P < 0.001, respectively, Delong’s test). Conclusions. The RHUI could help quantitatively discriminate hepatitis B‐related cirrhosis between compensated and decompensated statuses.
Supplementary Table 4 from Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response
Authors: Norgard Robert J. , Budhani Pratha , O'Brien Sarah A. , Xia Youli , Egan Jessica N. , Flynn Brianna , Tagore Joshua R. , Seco Joseph , Peet Gregory W. , Mikucka Ania , Wasti Ruby , Chan Li-Chuan , Hinkel Melanie , Martinez-Morilla Sandra , Pignatelli Jeanine , Trapani Francesca , Corse Emily , Feng Di , Kostyrko Kaja , Hofmann Marco H. , Liu Kang , Kashyap Abhishek S.
Published: June 2024

Supplementary Table 4
Supplementary Table 1 from Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response
Authors: Norgard Robert J. , Budhani Pratha , O'Brien Sarah A. , Xia Youli , Egan Jessica N. , Flynn Brianna , Tagore Joshua R. , Seco Joseph , Peet Gregory W. , Mikucka Ania , Wasti Ruby , Chan Li-Chuan , Hinkel Melanie , Martinez-Morilla Sandra , Pignatelli Jeanine , Trapani Francesca , Corse Emily , Feng Di , Kostyrko Kaja , Hofmann Marco H. , Liu Kang , Kashyap Abhishek S.
Published: June 2024

Supplementary Table 1
Supplementary Figure 8 from Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response
Authors: Norgard Robert J. , Budhani Pratha , O'Brien Sarah A. , Xia Youli , Egan Jessica N. , Flynn Brianna , Tagore Joshua R. , Seco Joseph , Peet Gregory W. , Mikucka Ania , Wasti Ruby , Chan Li-Chuan , Hinkel Melanie , Martinez-Morilla Sandra , Pignatelli Jeanine , Trapani Francesca , Corse Emily , Feng Di , Kostyrko Kaja , Hofmann Marco H. , Liu Kang , Kashyap Abhishek S.
Published: June 2024

Supplementary Figure 8
Supplementary Figure 5 from Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response
Authors: Norgard Robert J. , Budhani Pratha , O'Brien Sarah A. , Xia Youli , Egan Jessica N. , Flynn Brianna , Tagore Joshua R. , Seco Joseph , Peet Gregory W. , Mikucka Ania , Wasti Ruby , Chan Li-Chuan , Hinkel Melanie , Martinez-Morilla Sandra , Pignatelli Jeanine , Trapani Francesca , Corse Emily , Feng Di , Kostyrko Kaja , Hofmann Marco H. , Liu Kang , Kashyap Abhishek S.
Published: June 2024

Supplementary Figure 5
Data from Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response
Authors: Norgard Robert J. , Budhani Pratha , O'Brien Sarah A. , Xia Youli , Egan Jessica N. , Flynn Brianna , Tagore Joshua R. , Seco Joseph , Peet Gregory W. , Mikucka Ania , Wasti Ruby , Chan Li-Chuan , Hinkel Melanie , Martinez-Morilla Sandra , Pignatelli Jeanine , Trapani Francesca , Corse Emily , Feng Di , Kostyrko Kaja , Hofmann Marco H. , Liu Kang , Kashyap Abhishek S.
Published: June 2024

Abstract
KRAS inhibitors have demonstrated exciting preclinical and clinical responses, although resistance occurs rapidly. Here, we investigate the effects of KRAS-targeting therapies on the tumor microenvironment using a library of KrasG12D, p53-mutant, murine pancreatic ductal adenocarcinoma–derived cell lines (KPCY) to leverage immune-oncology combination strategies for long-term tumor efficacy. Our findings show that SOS1 and MEK inhibitors (SOS1i+MEKi) suppressed tumor growth in syngeneic models and increased intratumoral CD8+ T cells without durable responses. Single-cell RNA sequencing revealed an increase in inflammatory cancer-associated fibroblasts (iCAF), M2 macrophages, and a decreased dendritic cell (DC) quality that ultimately resulted in a highly immunosuppressive microenvironment driven by IL6+ iCAFs. Agonist CD40 treatment was effective to revert macrophage polarization and overcome the lack of mature antigen-presenting DCs after SOS1i+MEKi therapy. Treatment increased the overall survival of KPCY tumor-bearing mice. The addition of checkpoint blockade to SOS1i+MEKi combination resulted in tumor-free mice with established immune memory. Our data suggest that KRAS inhibition affects myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong antitumor effects.
Significance:
Combination of SOS1 and MEK inhibitors increase T cell infiltration while blunting pro-immune myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong anti-tumor effects.
Impact of Duration of Diabetes Mellitus on Long-Term Outcome in Type 2 Diabetic Patients with Primary Percutaneous Coronary Intervention after the First Myocardial Infarction
Authors: Yaliqin Nazila , Aimaier Salamaiti , Adi Dilare , Ma Yi-Tong , Yu Zi-Xiang
Published: June 2024

Background: Diabetes mellitus (DM) increases the risk of mortality in patients with acute myocardial infarction (AMI). The impact of the diabetes duration on the long-term outcome of those with percutaneous coronary intervention (PCI) after the first AMI is unclear. In this study, we evaluated the predictive value of diabetes duration in the occurrence of major adverse cardiovascular and cerebrovascular events (MACCEs). Methods: A total of 394 type 2 DM patients with PCI after the first AMI were enrolled and were divided into two groups by the diabetes duration: a short-DM group with diabetes duration of <5 years and a long-DM group with a duration of ≥5 years. The clinical endpoint was MACCEs. Results: Multivariate Cox regression analysis found that the diabetes duration was independently associated with increased occurrence of MACCEs (HR: 1.512, 95% CI: 1.033, 2.215, p = 0.034), along with hypertension, Killip class III or IV, creatinine, multivessel disease, and continuous hypoglycemic therapy. After adjusting for the confounding variables, a nested Cox model showed that diabetes duration was still an independent risk factor of MACCEs (HR: 1.963, 95% CI: 1.376, 2.801, p < 0.001). The Kaplan-Meier survival curve illustrated a significantly high risk of MACCEs (HR: 2.045, p < 0.0001) in long-duration DM patients. After propensity score matching, a longer diabetes duration was associated with an increased risk of MACCE occurrence. Conclusion: Long-duration diabetes was independently associated with poor clinical outcomes after PCI in patients with their first myocardial infarction. Despite the diabetes duration, continuous hypoglycemic therapy significantly improved long-term clinical outcomes.
Deep Brain Stimulation with Double Targeting of the VIM and PSA for the Treatment of Rare Tremor Syndromes
Authors: Yilmaz Atilla , Eray Halit Anıl , Cakir Murtaza , Ceylan Mustafa , Blomstedt Patric
Published: June 2024

Introduction: In tremor syndromes, pharmacological therapy is the primary treatment, but deep brain stimulation (DBS) is used when it is insufficient. We explore the use of DBS, focusing on the globus pallidus internus for dystonia and the ventral intermediate nucleus (VIM) for tremor conditions. We introduce the posterior subthalamic area (PSA) as a potential target, suggesting its efficacy in tremor reduction, particularly in rare tremor syndromes. We aim to evaluate the efficacy and safety of double targeting the VIM and PSA in rare tremor conditions, highlighting the limited existing data on this. Methods: Between 2019 and 2023, 22 patients with rare tremor syndromes were treated with bilateral DBS of the VIM and PSA. This case series consisted of 7 isolated head tremor, 1 hepatic encephalopathic tremor due to Abernethy syndrome, 2 voice tremor, 4 dystonic tremor, and 8 Holmes tremor (2 multiple sclerosis, 2 cerebellar insult, and 4 posttraumatic) patients. Patients’ preoperative and 12-month postoperative tremor scores were compared, and the optimum VIM and PSA stimulation areas were investigated. Results: There was a significant reduction in the mean TRS score from 3.70 (±0.57) to 0.45 (±0.68) after 12 months of surgery. Specific outcomes for different indications were observed: for head tremor, 6 of 7 patients showed a reduction in TRS scores to 0 points; the vocal tremor patients demonstrated improvement; this change was not statistically significant, which is likely to be due to the low number of patients in this subgroup; the dystonic tremor patients showed either complete tremor abolition or a reduction in TRS scores; the Holmes tremor patients showed an 80% reduction in TRS scores; and the hepatic encephalopathy tremor and Abernethy syndrome patients showed a 75% improvement in TRS scores. The stimulation parameters converged on the VIM and dorsal PSA. Complications included the need for electrode repositioning, infections requiring electrode removal and re-implantation, dysarthria, and stimulation-induced ataxia, which was resolved by adjusting the stimulation parameters. Discussion: The literature on DBS for rare tremors is limited. Double targeting of the VIM and PSA appears to produce promising improvements on the outcomes reported in the existing literature on VIM-only DBS. The proximity of the VIM and PSA allows for flexible electrode placement, contributing to the potential success of the dual-target approach. We also discuss the theoretical advantages of targeting the PSA based on the distribution of tremor circuits, emphasizing the need for further research and electrophysiological studies.
“Real Time Story Telling”: A Performance-Art Festival in the Context of International Networks during the Transitional Period in Poland before and after 1989
Authors: Kaźmierczak Małgorzata
Published: June 2024

The article explains the situation of performance artists in Poland during the transition period before and after 1989. Then it focuses on the first large performance art festival in Poland after 1989, Real Time Story Telling. It was organized in Sopot and Gdańsk in 1991 by Galeria Działań and curated by the outstanding artist and art theorist Jan Świdziński. The article explains the idea of the festival and briefly describes the curatorial activity of the invited international performance artists. The article also outlines the international network of connections between performance art festivals, which depended on the personal relationships between artists who organized them. Finally, it shows how the festival influenced the introduction of Polish performance artists to the international circuit and how it influenced the development of the festival network in Poland.
Developmental Dilemmas
Authors: Noor Tausif
Published: June 2024

Three recent volumes on the economic, infrastructural, and international networks of modernism reveal the extent to which notions of development have shaped the trajectory of modernist art practice outside the Western world, and Sarah-Neel Smith's Metrics of Modernity: Art and Development in Postwar Turkey (2022) considers how efforts by the Turkish state to join the new global political economy in the 1950s prompted artists and art administrators to synthesize the language of economic development into artistic discourse and institutional infrastructure. Devika Singh's International Departures: Art in India After Independence (2024) situates modernist artistic practice in India in the Nehruvian decades, wherein the state's developmental aspirations led to major upheavals and connections across international networks. Karin Zitzewitz's Infrastructure and Form: The Global Networks of Indian Contemporary Art, 1991–2008 (2022) examines an efflorescence of Indian contemporary art between economic liberalization in 1991 through the 2008 global financial crisis, marking shifts in the production, circulation, and discourse of art through a wide-ranging array of examples. Each of these texts move away from art history's fixation with self-contained nationalist histories toward a more critical apprehension of how relations between the state and international non-state actors within international political economy shaped the trajectory of visual art. The review considers how the authors combine sociopolitical discourse and economic changes with formal examinations of specific artworks in their local, national, and international contexts and addresses the importance of institution-building and the processes of legitimization for these authors' arguments.
Kim Il-sung in the Soviet Army, 1940–1945: His Experience and Its Future Impact on the North Korean State and Armed Forces
Authors: Tertitski Konstantin , Tertitskiy Fyodor
Published: June 2024

This article traces the origins of North Korea's militarized, repressive political system. It shows that the policies of the country's founder, Kim Il-sung, were heavily influenced by his personal experience in the USSR, or, more precisely, in the Soviet armed forces in the early 1940s. This factor has been largely overlooked by the academic community up to now. Drawing on a wealth of new sources in Chinese, Korean, and Russian, the article discusses how Kim's service as a Soviet military officer shaped his worldview and approach to governing North Korea. Through a multifaceted analysis of the North Korean military, the article reveals how its size, doctrine, economic role, and political education system were all influenced by Kim's experiences and those of his fellow soldiers in the USSR's Red Army. This insight has broader implications for understanding North Korean civilian society. By shedding light on the formative experiences that shaped Kim's approach to governance, the article offers a new lens through which to view the country's political and social structures.
Beginning of Winter: The George H.W. Bush Administration, the Nagorno-Karabakh Conflict, and the Emergence of the Post–Cold War World
Authors: Stocker James R.
Published: June 2024

The conflict that arose between Soviet Armenia and Soviet Azerbaijan over Nagorno-Karabakh in 1988 festered throughout the final years of the Soviet Union and sparked a major war between the newly independent Armenia and Azerbaijan in 1992–1994. Most accounts of this period have suggested that the administration of George H. W. Bush took a largely hands-off approach to the Nagorno-Karabakh conflict, but this article shows that in fact the Bush administration pursued a much more active policy that reflected support for the Soviet Union and then Russia, a strong domestic Armenian-American lobby, and regional priorities, as well as a growing awareness of the West's failure to stem violence in Yugoslavia. The Bush administration was hoping to prevent all-out war between Armenia and Azerbaijan, but after the war began, the administration did what it could to try to limit and halt the violence.
Cold War Détente?: The Role of China in the Aftermath of Malaya's Failed Peace Talks in 1955
Authors: Yanqing He , Cheok Cheong Kee , Ran Li
Published: June 2024

After World War II, the struggle for independence in Southeast Asia was complicated by the onset of the Cold War and the involvement of major external powers in the region, especially the People's Republic of China (PRC). Amid Cold War tensions, an opportunity arose for détente in Malaya in the early 1950s, despite the failure of peace talks between the Malayan Communist Party (MCP) and the Malayan government. This opportunity arose from the PRC's proclaimed embrace of peaceful coexistence. Chinese leaders adopted the policy in the expectation that the new Malayan government would defer to China's wishes. This expectation proved unfounded; the government of independent Malaya had no desire to be subservient to the PRC. The adverse turn of events for China, and the subsequent emergence of a rift between Moscow and Beijing, thwarted efforts to establish formal ties between the MCP and the Malayan government, prompting the Malayan Communists to resume their campaign of guerrilla warfare.
Overcoming a Cold War Mindset: Encounters with Soviet Musical Expertise in a Finnish Town
Authors: Mikkonen Simo , Okko Antti
Published: June 2024

This article examines how a music festival in a regional Finnish town managed to overcome concrete and imagined Cold War limitations to become a venue for sustained encounters between Soviet and Western musicians starting in the mid-1960s. It explains how the Jyväskylä Summer Festival, which began in 1956 as one of the first festivals of its kind in the Nordic countries, acted as an intermediary and managed to secure contracts for several high-profile Soviet musicians to perform and provide master classes for up to a month, with relatively little surveillance from the Soviet state security apparatus, allowing for deeper interaction among Eastern and Western participants. Although many obstacles and challenges had to be overcome, the use of music and art to ease Cold War tensions proved beneficial to both the USSR and Finland and helped reduce cultural stereotypes, introduce new forms of music, improve performer agency, promote careers, and open doors to opportunities for long-term cooperation between previously separated societies.
The spatiotemporal profile and adaptation determine the joint effects and interactions of multiple stressors
Authors: Streib Lucas , Spaak Jurg W. , Kloft Marius , Schäfer Ralf B.
Published: June 2024

Background

Biodiversity is declining worldwide as ecosystems are increasingly threatened by multiple stressors associated with anthropogenic global change. Stressors frequently co-occur across scales spatially and temporally, resulting in joint effects that are additive or non-additive, i.e., antagonism or synergism. Forecasting and counteracting threats from intensifying stressors requires improved mechanistic understanding of joint effects, which is currently relatively low. To date, research on multiple stressors has been biased toward simplified scenarios, emphasized classification of interactions over realized joint effects, and mostly ignored adaptation (i.e., phenotypic plasticity or evolving life-history traits) of organisms. To investigate if more a realistic scenarios design incorporating complex spatiotemporal stressor profiles and adaption change joint effects and interactions of multiple stressors compared to simplified scenarios, we modified a spatially explicit meta-population model for a generic freshwater insect. We used the model to simulate different, hypothetical spatiotemporal profiles of a continuous and a discrete stressor and evaluated their joint effects and interactions. Agricultural land use represented the continuous stressor impacting meta-population patch quality and network connectivity and related scenarios implied different trajectories. Climatic events represented the discrete stressor impacting all patches simultaneously by temporary mortality events, with related scenarios implying different event severity. Adaptation mitigated the effects of climatic events based on previous events.

Results

Excluding adaptation, we found that at higher levels of the discrete stressor (i.e., strong and frequent climatic events) it strongly dominates the joint effects, while at a low level (i.e., weak and infrequent climatic events) of the discrete stressor, the continuous stressor (i.e., land use) dominates. Yet, the continuous stressor always defined the interaction type, with decreasing land use stress leading to antagonism, and increasing land use stress leading to synergism. Adaptation reduced joint effects under decreasing land use stress, yet had little compensatory influence under increasing land use stress. Moreover, adaptation changed interaction sizes inconsistently across the different land use and climate scenarios, with change depending on the climate scenario. Here, interactions decreased in the moderate scenario but increased in the severe and intense scenarios.

Conclusions

We highlight that realistic stressor scenarios accounting for potential adaptation are critical for a mechanistic understanding of how species respond to global change. To our knowledge, this is the first modeling study to show that stressor interactions depend on complex spatiotemporal stressor profiles and adaptation, following general principles.
Advancements in understanding the role of intestinal dysbacteriosis mediated mucosal immunity in IgA nephropathy
Authors: Fan Yitao , Wang Yan , Xiao Han , Sun Hui
Published: June 2024

IgA nephropathy, presently recognized as the foremost primary glomerular disorder, emerges as a principal contributor to renal failure globally, with its pathogenesis yet to be fully elucidated. Extensive research has highlighted the critical role of gut microbiome in the onset and progression of IgA nephropathy, underscoring its importance in accurately delineating the disease’s etiology. For example, gut microbiome dysbacteriosis can lead to the production of nephritogenic IgA1 antibodies, which form immune complexes that deposit in the kidneys, causing inflammation and damage. The gut microbiome, a source of numerous bioactive compounds, interacts with the host and plays a regulatory role in gut-immune axis modulation, earning it the moniker of the “second brain.” Recent investigations have particularly emphasized a significant correlation between IgA nephropathy and gut microbiome dysbacteriosis. This article offers a detailed overview of the pathogenic mechanisms of IgA nephropathy, specifically focusing on elucidating how alterations in the gut microbiome are associated with anomalies in the intestinal mucosal system in IgA nephropathy. Additionally, it describes the possible influence of gut microbiome on recurrent IgA nephropathy following kidney transplantation. Furthermore, it compiles potential therapeutic interventions, offering both theoretical and practical foundations for the management of IgA nephropathy. Lastly, the challenges currently faced in the therapeutic approaches to IgA nephropathy are discussed.