bluuebunny/crossref_metadata_2025_split huggingface dataset:
A degron system targeting endogenous PD-1 inhibits the growth of tumor cells in mice
Authors: Naruse Chie , Sugihara Kazushi , Miyazaki Tatsuhiko , Pan Xuchi , Sugiyama Fumihiro , Asano Masahide 
Published: June 2022

Abstract
Recently, targeted protein degradation systems have been developed using the ubiquitin-proteasome system. Here, we established Programmed cell death-1 (PD-1) knockdown mice as a model system for subjecting endogenous mouse proteins to the small molecule-assisted shutoff (SMASh) degron system. SMASh degron-tagged PD-1-mCherry in Jurkat cells and CD3+ splenocytes were degraded by the NS3/4A protease inhibitors, asunaprevir (ASV) or grazoprevir (GRV). Growth of MC-38 colon adenocarcinoma cells injected in Pdcd1-mCherry-SMASh homozygous knock-in (KI) mice was repressed by ASV or GRV. Moreover, growth of MC-38 cells was suppressed in wild-type mice transplanted with KI bone marrow cells after GRV treatment. This is the first study to use a degron tag targeting an endogenous mouse protein in vivo. Our experimental system using the SMASh degron may be employed for treating diseases and characterizing the cellular functions of essential proteins.
Phase I trial of sargramostim/pelareorep therapy in pediatric patients with recurrent or refractory high-grade brain tumors
Authors: Schuelke Matthew R , Gundelach Justin H , Coffey Matt , West Emma , Scott Karen , Johnson Derek R , Samson Adel , Melcher Alan , Vile Richard G , Bram Richard J 
Published: June 2022

Abstract

Background
Brain tumors are the leading cause of cancer death for pediatric patients. Pelareorep, an immunomodulatory oncolytic reovirus, has intravenous efficacy in preclinical glioma models when preconditioned with GM-CSF (sargramostim). We report a phase I trial with the primary goal of evaluating the safety of sargramostim/pelareorep in pediatric patients with recurrent or refractory high-grade brain tumors and a secondary goal of characterizing immunologic responses.

Methods
The trial was open to pediatric patients with recurrent or refractory high-grade brain tumors (3 + 3 cohort design). Each cycle included 3 days of subcutaneous sargramostim followed by 2 days of intravenous pelareorep. Laboratory studies and imaging were acquired upon recruitment and periodically thereafter.

Results
Six patients participated, including three glioblastoma, two diffuse intrinsic pontine glioma, and one medulloblastoma. Two pelareorep dose levels of 3 × 108 and 5 × 108 tissue culture infectious dose 50 (TCID50) were assessed. One patient experienced a dose limiting toxicity of persistent hyponatremia. Common low-grade (1 or 2) adverse events included transient fatigue, hypocalcemia, fever, flu-like symptoms, thrombocytopenia, and leukopenia. High-grade (3 or 4) adverse events included neutropenia, lymphopenia, leukopenia, hypophosphatemia, depressed level of consciousness, and confusion. All patients progressed on therapy after a median of 32.5 days and died a median of 108 days after recruitment. Imaging at progression did not show evidence of pseudoprogression or inflammation. Correlative assays revealed transient but consistent changes in immune cells across patients.

Conclusions
Sargramostim/pelareorep was administered to pediatric patients with recurrent or refractory high-grade brain tumors. Hyponatremia was the only dose limiting toxicity (DLT), though maximum tolerated dose (MTD) was not determined.
Energy landscape decomposition for cell differentiation with proliferation effect
Authors: Shi Jifan , Aihara Kazuyuki , Li Tiejun , Chen Luonan 
Published: June 2022

AbstractComplex interactions between genes determine the development and differentiation of cells. We establish a landscape theory for cell differentiation with proliferation effect, in which the developmental process is modeled as a stochastic dynamical system with a birth-death term. We find that two different energy landscapes, denoted U and V, collectively contribute to the establishment of non-equilibrium steady differentiation. The potential U is known as the energy landscape leading to the steady distribution, whose metastable states stand for cell types, while V indicates the differentiation direction from pluripotent to differentiated cells. This interpretation of cell differentiation is different from the previous landscape theory without the proliferation effect. We propose feasible numerical methods and a mean-field approximation for constructing landscapes U and V. Successful applications to typical biological models demonstrate the energy landscape decomposition's validity and reveal biological insights into the considered processes.
US County-Level COVID-19 Vaccine Uptake and Rates of Omicron Cases and Deaths
Authors: McLaughlin John M , Wiemken Timothy L , Khan Farid , Jodar Luis 
Published: June 2022

Abstract
The population-level impact of vaccination on Omicron-related disease is not well described. We fit negative binomial models to estimate the relationship between US county-level vaccine coverage and rates of coronavirus disease 2019. Increased booster dose uptake was associated with lower rates of Omicron cases and deaths and is critical to combat future severe acute respiratory syndrome coronavirus 2 waves.
Rates of Medically Attended RSV Among US Adults: A Systematic Review and Meta-analysis
Authors: McLaughlin John M , Khan Farid , Begier Elizabeth , Swerdlow David L , Jodar Luis , Falsey Ann R 
Published: June 2022

Abstract

Background
Adult respiratory syncytial virus (RSV) vaccines are in the late stages of development. A comprehensive synthesis of adult RSV burden is needed to inform public health decision-making.

Methods
We performed a systematic review and meta-analysis of studies describing the incidence of medically attended RSV (MA-RSV) among US adults. We also identified studies reporting nasopharyngeal (NP) or nasal swab reverse transcription polymerase chain reaction (RT-PCR) results with paired serology (4-fold-rise) or sputum (RT-PCR) to calculate RSV detection ratios quantifying improved diagnostic yield after adding a second specimen type (ie, serology or sputum).

Results
We identified 14 studies with 15 unique MA-RSV incidence estimates, all based on NP or nasal swab RT-PCR testing alone. Pooled annual RSV-associated incidence per 100 000 adults ≥65 years of age was 178 (95% CI, 152‒204; n = 8 estimates) hospitalizations (4 prospective studies: 189; 4 model-based studies: 157), 133 (95% CI, 0‒319; n = 2) emergency department (ED) admissions, and 1519 (95% CI, 1109‒1929; n = 3) outpatient visits. Based on 6 studies, RSV detection was ∼1.5 times higher when adding paired serology or sputum. After adjustment for this increased yield, annual RSV-associated rates per 100 000 adults age ≥65 years were 267 hospitalizations (uncertainty interval [UI], 228‒306; prospective: 282; model-based: 236), 200 ED admissions (UI, 0‒478), and 2278 outpatient visits (UI, 1663‒2893). Persons &lt;65 years with chronic medical conditions were 1.2−28 times more likely to be hospitalized for RSV depending on risk condition.

Conclusions
The true burden of RSV has been underestimated and is significant among older adults and individuals with chronic medical conditions. A highly effective adult RSV vaccine would have substantial public health impact.
Tree Peony R2R3-MYB Transcription Factor PsMYB30 Promotes Petal Blotch Formation by Activating the Transcription of the Anthocyanin Synthase Gene
Authors: Luan Yuting , Tang Yuhan , Wang Xin , Xu Cong , Tao Jun , Zhao Daqiu 
Published: June 2022

Abstract
Petal blotches are commonly observed in many angiosperm families and not only influence plant–pollinator interactions but also confer high ornamental value. Tree peony (Paeonia suffruticosa Andr.) is an important cut flower worldwide, but few studies have focused on its blotch formation. In this study, anthocyanins were found to be the pigment basis for blotch formation of P. suffruticosa, and peonidin-3,5-di-O-glucoside (Pn3G5G) was the most important component of anthocyanins, while the dihydroflavonol-4-reductase gene was the key factor contributing to blotch formation. Then, the R2R3-myeloblastosis (MYB) transcription factor PsMYB30 belonging to subgroup 1 was proven as a positive anthocyanin regulator with transcriptional activation and nuclear expression. Furthermore, silencing PsMYB30 in P. suffruticosa petals reduced blotch size by 37.9%, faded blotch color and decreased anthocyanin and Pn3G5G content by 23.6% and 32.9%, respectively. Overexpressing PsMYB30 increased anthocyanin content by 14.5-fold in tobacco petals. In addition, yeast one-hybrid assays, dual-luciferase assays and electrophoretic mobility shift assays confirmed that PsMYB30 could bind to the promoter of the anthocyanin synthase (ANS) gene and enhance its expression. Altogether, a novel MYB transcription factor, PsMYB30, was identified to promote petal blotch formation by activating the expression of PsANS involved in anthocyanin biosynthesis, which provide new insights for petal blotch formation in plants.
The Key to the Future Lies in the Past: Insights from Grain Legume Domestication and Improvement Should Inform Future Breeding Strategies
Authors: Bohra Abhishek , Tiwari Abha , Kaur Parwinder , Ganie Showkat Ahmad , Raza Ali , Roorkiwal Manish , Mir Reyazul Rouf , Fernie Alisdair R , Smýkal Petr , Varshney Rajeev K 
Published: June 2022

Abstract
Crop domestication is a co-evolutionary process that has rendered plants and animals significantly dependent on human interventions for survival and propagation. Grain legumes have played an important role in the development of Neolithic agriculture some 12,000 years ago. Despite being early companions of cereals in the origin and evolution of agriculture, the understanding of grain legume domestication has lagged behind that of cereals. Adapting plants for human use has resulted in distinct morpho-physiological changes between the wild ancestors and domesticates, and this distinction has been the focus of several studies aimed at understanding the domestication process and the genetic diversity bottlenecks created. Growing evidence from research on archeological remains, combined with genetic analysis and the geographical distribution of wild forms, has improved the resolution of the process of domestication, diversification and crop improvement. In this review, we summarize the significance of legume wild relatives as reservoirs of novel genetic variation for crop breeding programs. We describe key legume features, which evolved in response to anthropogenic activities. Here, we highlight how whole genome sequencing and incorporation of omics-level data have expanded our capacity to monitor the genetic changes accompanying these processes. Finally, we present our perspective on alternative routes centered on de novo domestication and re-domestication to impart significant agronomic advances of novel crops over existing commodities. A finely resolved domestication history of grain legumes will uncover future breeding targets to develop modern cultivars enriched with alleles that improve yield, quality and stress tolerance.
Universal critical behavior of transition to chaos: Intermittency route
Authors: Okubo Ken-ichi , Umeno Ken 
Published: June 2022

Abstract
The robustness of the universality class concept of the chaotic transition was investigated by analytically obtaining its critical exponent for a wide class of maps. In particular, we extended the existing one-dimensional chaotic maps, thereby generalizing the invariant density function from the Cauchy distribution by adding one parameter. This generalization enables the adjustment of the power exponents of the density function and superdiffusive behavior. We proved that these generalized one-dimensional chaotic maps are exact (a stronger condition than ergodicity) to obtain the critical exponent of the Lyapunov exponent from the phase average. Furthermore, we proved that the critical exponent of the Lyapunov exponent is $\frac{1}{2}$ regardless of the power exponent of the density function and is thus universal. This result can be considered as rigorous proof of the universality of the critical exponent of the Lyapunov exponent for a countably infinite number of maps.
An amelogenin-based peptide hydrogel promoted the odontogenic differentiation of human dental pulp cells
Authors: Li Xinxin , Yu Zhaoxia , Jiang Shihui , Dai Xiaohua , Wang Guanhua , Wang Yue , Yang Zhimou , Gao Jie , Zou Huiru 
Published: June 2022

Abstract
Amelogenin can induce odontogenic differentiation of human dental pulp cells (HDPCs), which has great potential and advantages in dentine-pulp complex regeneration. However, the unstability of amelogenin limits its further application. This study constructed amelogenin self-assembling peptide hydrogels (L-gel or D-gel) by heating-cooling technique, investigated the effects of these hydrogels on the odontogenic differentiation of HDPCs and explored the underneath mechanism. The critical aggregation concentration, conformation, morphology, mechanical property and biological stability of the hydrogels were characterized, respectively. The effects of the hydrogels on the odontogenic differentiation of HDPCs were evaluated via alkaline phosphatase activity measurement, quantitative reverse transcription polymerase chain reaction, western blot, Alizarin red staining and scanning electron microscope. The mechanism was explored via signaling pathway experiments. Results showed that both the L-gel and D-gel stimulated the odontogenic differentiation of HDPCs on both Day 7 and Day 14, while the D-gel showed the highest enhancement effects. Meanwhile, the D-gel promoted calcium accumulation and mineralized matrix deposition on Day 21. The D-gel activated MAPK-ERK1/2 pathways in HDPCs and induced the odontogenic differentiation via ERK1/2 and transforming growth factor/smad pathways. Overall, our study demonstrated that the amelogenin peptide hydrogel stimulated the odontogenic differentiation and enhanced mineralization, which held big potential in the dentine-pulp complex regeneration.
Linking Salience Signaling With Early Adversity and Affective Distress in Individuals at Clinical High Risk for Psychosis: Results From an Event-Related fMRI Study
Authors: Millman Zachary B , Schiffman Jason , Gold James M , Akouri-Shan LeeAnn , Demro Caroline , Fitzgerald John , Rakhshan Rouhakhtar Pamela J , Klaunig Mallory , Rowland Laura M , Waltz James A 
Published: June 2022

Abstract
Evidence suggests dysregulation of the salience network in individuals with psychosis, but few studies have examined the intersection of stress exposure and affective distress with prediction error (PE) signals among youth at clinical high-risk (CHR). Here, 26 individuals at CHR and 19 healthy volunteers (HVs) completed a monetary incentive delay task in conjunction with fMRI. We compared these groups on the amplitudes of neural responses to surprising outcomes—PEs without respect to their valence—across the whole brain and in two regions of interest, the anterior insula and amygdala. We then examined relations of these signals to the severity of depression, anxiety, and trauma histories in the CHR group. Relative to HV, youth at CHR presented with aberrant PE-evoked activation of the temporoparietal junction and weaker deactivation of the precentral gyrus, posterior insula, and associative striatum. No between-group differences were observed in the amygdala or anterior insula. Among youth at CHR, greater trauma histories were correlated with stronger PE-evoked amygdala activation. No associations were found between affective symptoms and the neural responses to PE. Our results suggest that unvalenced PE signals may provide unique information about the neurobiology of CHR syndromes and that early adversity exposure may contribute to neurobiological heterogeneity in this group. Longitudinal studies of young people with a range of risk syndromes are needed to further disentangle the contributions of distinct aspects of salience signaling to the development of psychopathology.
A new perspective on the evolution and diversity of the genus Amdoparvovirus (family Parvoviridae) through genetic characterization, structural homology modeling, and phylogenetics
Authors: Canuti Marta , Pénzes Judit J , Lang Andrew S 
Published: June 2022

Abstract
Amdoparvoviruses (genus Amdoparvovirus, family Parvoviridae) are primarily viruses of carnivorans, but recent studies have indicated that their host range might also extend to rodents and chiropterans. While their classification is based on the full sequence of the major nonstructural protein (NS1), several studies investigating amdoparvoviral diversity have been focused on partial sequences, leading to difficulties in accurately determining species demarcations and leaving several viruses unclassified. In this study, while reporting the complete genomic sequence of a novel amdoparvovirus identified in an American mink (British Columbia amdoparvovirus, BCAV), we studied the phylogenetic relationships of all amdoparvovirus-related sequences and provide a comprehensive reevaluation of their diversity and evolution. After excluding recombinant sequences, phylogenetic and pairwise sequence identity analyses allowed us to define fourteen different viruses, including the five currently classified species, BCAV, and four additional viruses that fulfill the International Committee on Taxonomy of Viruses criteria to be classified as species. We show that the group of viruses historically known as Aleutian mink disease virus (species Carnivore amdoparvovirus 1) should be considered as a cluster of at least four separate viral species that have been co-circulating in mink farms, facilitating the occurrence of inter-species recombination. Genome organization, splicing donor and acceptor sites, and protein sequence motifs were surprisingly conserved within the genus. The sequence of the major capsid protein virus protein 2 (VP2) was significantly more conserved between and within species compared to NS1, a phenomenon possibly linked to antibody-dependent enhancement (ADE). Homology models suggest a remarkably high degree of conservation of the spikes located near the icosahedral threefold axis of the capsid, comprising the surface region associated with ADE. A surprisingly high number of divergent amino acid positions were found in the luminal threefold and twofold axes of the capsid, regions of hitherto unknown function. We emphasize the importance of complete genome analyses and, given the marked phylogenetic inconsistencies across the genome, advise to obtain the complete coding sequences of divergent strains. Further studies on amdoparvovirus biology and structure as well as epidemiological and virus discovery investigations are required to better characterize the ecology and evolution of this important group of viruses.
Embryonic heat conditioning in chicks induces transgenerational heat/immunological resilience via methylation on regulatory elements
Authors: Rosenberg Tali , Marco Asaf , Kisliouk Tatiana , Haron Amit , Shinder Dmitry , Druyan Shelly , Meiri Noam 
Published: June 2022

AbstractThe question of whether behavioral traits are heritable is under debate. An obstacle in demonstrating transgenerational inheritance in mammals originates from the maternal environment's effect on offspring phenotype. Here, we used in ovo embryonic heat conditioning (EHC) of first‐generation chicks, demonstrating heredity of both heat and immunological resilience, confirmed by a reduced fibril response in their untreated offspring to either heat or LPS challenge. Concordantly, transcriptome analysis confirmed that EHC induces changes in gene expression in the anterior preoptic hypothalamus (APH) that contribute to these phenotypes in the offspring. To study the association between epigenetic mechanisms and trait heritability, DNA‐methylation patterns in the APH of offspring of control versus EHC fathers were evaluated. Genome‐wide analysis revealed thousands of differentially methylated sites (DMSs), which were highly enriched in enhancers and CCCTC‐binding factor (CTCF) sites. Overlap analysis revealed 110 differentially expressed genes that were associated with altered methylation, predominantly on enhancers. Gene‐ontology analysis shows pathways associated with immune response, chaperone‐mediated protein folding, and stress response. For the proof of concept, we focused on HSP25 and SOCS3, modulators of heat and immune responses, respectively. Chromosome conformational capture (3C) assay identified interactions between their promoters and methylated enhancers, with the strongest frequency on CTCF binding sites. Furthermore, gene expression corresponded with the differential methylation patterns, and presented increased CTCF binding in both hyper‐ and hypomethylated DMSs. Collectively, we demonstrate that EHC induces transgenerational thermal and immunological resilience traits. We propose that one of the mechanisms underlying inheritance depends on three‐dimensional (3D) chromatin reorganization.
The hypoxia‐induced changes in miRNA‐mRNA in RNA‐induced silencing complexes and HIF‐2 induced miRNAs in human endothelial cells
Authors: Moszyńska Adrianna , Jaśkiewicz Maciej , Serocki Marcin , Cabaj Aleksandra , Crossman David K. , Bartoszewska Sylwia , Gebert Magdalena , Dąbrowski Michał , Collawn James F. , Bartoszewski Rafal 
Published: June 2022

AbstractThe cellular adaptive response to hypoxia relies on the expression of hypoxia‐inducible factors (HIFs), HIF‐1 and HIF‐2. HIFs regulate global gene expression changes during hypoxia that are necessary for restoring oxygen homeostasis and promoting cell survival. In the early stages of hypoxia, HIF‐1 is elevated, whereas at the later stages, HIF‐2 becomes the predominant form. What governs the transition between the two HIFs (the HIF switch) and the role of miRNAs in this regulation are not completely clear. Genome‐wide expression studies on the miRNA content of RNA‐induced silencing complexes (RISC) in HUVECs exposed to hypoxia compared to the global miRNA‐Seq analysis revealed very specific differences between these two populations. We analyzed the miRNA and mRNA composition of RISC at 2 h (mainly HIF‐1 driven), 8 h (HIF‐1 and HIF‐2 elevated), and 16 h (mainly HIF‐2 driven) in a gene ontology context. This allowed for determining the direct impact of the miRNAs in modulating the cellular signaling pathways involved in the hypoxic adaptive response. Our results indicate that the miRNA‐mRNA RISC components control the adaptive responses, and this does not always rely on the miRNA transcriptional elevations during hypoxia. Furthermore, we demonstrate that the hypoxic levels of the vast majority of HIF‐1‐dependent miRNAs (including miR‐210‐3p) are also HIF‐2 dependent and that HIF‐2 governs the expression of 11 specific miRNAs. In summary, the switch from HIF‐1 to HIF‐2 during hypoxia provides an important level of miRNA‐driven control in the adaptive pathways in endothelial cells.