bluuebunny/crossref_metadata_2025 huggingface dataset:
Tungsten in barium stars
Authors: Roriz M P , Lugaro M , Junqueira S , Sneden C , Drake N A , Pereira C B
Published: January 2024

Classical barium stars are red giants that receive from their evolved binary companions material exposed to the slow neutron-capture nucleosynthesis, i.e. the s-process. Such a mechanism is expected to have taken place in the interiors of Thermally-Pulsing Asymptotic Giant Branch (TP-AGB) stars. As post-interacting binaries, barium stars figure as powerful tracers of the s-process nucleosynthesis, evolution of binary systems, and mechanisms of mass transfer. The present study is the fourth in a series of high-resolution spectroscopic analyses on a sample of 180 barium stars, for which we report tungsten (W, Z = 74) abundances. The abundances were derived from synthetic spectrum computations of the W i absorption features at 4843.8 and 5224.7 Å. We were able to extract abundances for 94 stars; the measured [W/Fe] ratios range from ∼0.0 to 2.0 dex, increasing with decreasing metallicity. We noticed that in the plane [W/Fe] versus [s/Fe], barium stars follow the same trend observed in post-AGB stars. The observational data were also compared with predictions of the FRUITY and Monash AGB nucleosynthesis models. These expect values between −0.20 and +0.10 dex for the [W/hs] ratios, whereas a larger spread is observed in the program stars, with [W/hs] ranging from −0.40 to +0.60 dex. The stars with high [W/hs] ratios may represent evidence for the operation of the intermediate neuron-capture process at metallicities close to solar.
Torque-dependent orbital modulation of X-ray pulsar Cen X-3
Authors: Liao Zhenxuan , Liu Jiren
Published: January 2024

Cen X-3 shows alternate spin-up/spin-down episodes lasting for tens of days. We study the orbital profiles and spectra of Cen X-3 during these spin-up/spin-down intervals, using long-term data monitored by Fermi/Gamma-ray Burst Monitor (GBM), Swift/Burst Alert Telescope (BAT), and Monitor of All-sky X-ray Image (MAXI)/Gas Slit Camera (GSC). In spin-up intervals, its orbital profile in 2–10 keV is symmetrically peaked around orbital phase 0.42, while in spin-down intervals of similar fluxes and similar magnitudes of spin change rate, its profile reaches a peak around orbital phase 0.22 and then declines gradually. Such a distinct orbital difference between spin-up and spin-down states of similar flux is hard to explain in the standard disc model and indicates that its torque reversals are related to processes on the orbital scale. The durations of continuous spin-up/spin-down trend (tens of days) also point to a superorbital variation. One possible scenario is the irradiation-driven warping disc instability, which may produce a flipped inner disc for tens of days.
Genetically Encoded Lizard Color Divergence for Camouflage and Thermoregulation
Authors: Sun Bao-Jun , Li Wei-Ming , Lv Peng , Wen Guan-Nan , Wu Dan-Yang , Tao Shi-Ang , Liao Ming-Ling , Yu Chang-Qing , Jiang Zhong-Wen , Wang Yang , Xie Hong-Xin , Wang Xi-Feng , Chen Zhi-Qiang , Liu Feng , Du Wei-Guo
Published: January 2024

Local adaptation is critical in speciation and evolution, yet comprehensive studies on proximate and ultimate causes of local adaptation are generally scarce. Here, we integrated field ecological experiments, genome sequencing, and genetic verification to demonstrate both driving forces and molecular mechanisms governing local adaptation of body coloration in a lizard from the Qinghai-Tibet Plateau. We found dark lizards from the cold meadow population had lower spectrum reflectance but higher melanin contents than light counterparts from the warm dune population. Additionally, the colorations of both dark and light lizards facilitated the camouflage and thermoregulation in their respective microhabitat simultaneously. More importantly, by genome resequencing analysis, we detected a novel mutation in Tyrp1 that underpinned this color adaptation. The allele frequencies at the site of SNP 459# in the gene of Tyrp1 are 22.22% G/C and 77.78% C/C in dark lizards and 100% G/G in light lizards. Model-predicted structure and catalytic activity showed that this mutation increased structure flexibility and catalytic activity in enzyme TYRP1, and thereby facilitated the generation of eumelanin in dark lizards. The function of the mutation in Tyrp1 was further verified by more melanin contents and darker coloration detected in the zebrafish injected with the genotype of Tyrp1 from dark lizards. Therefore, our study demonstrates that a novel mutation of a major melanin-generating gene underpins skin color variation co-selected by camouflage and thermoregulation in a lizard. The resulting strong selection may reinforce adaptive genetic divergence and enable the persistence of adjacent populations with distinct body coloration.
Gut flora metagenomic analysis coupled with metabolic and deep immune profiling in chronic kidney disease
Authors: Wu I-Wen , Chang Lun-Ching , Wu Yi-Lun , Yang Huang-Yu , Twu Yuh-Ching , Tsai Po-Yu , Paulus Skyler , Resnick Rhian , Chung Wen-Hung , Yang Chih-Wei , Hsieh Wen-Ping , Su Shih-Chi
Published: January 2024

Background

Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation.

Methods

To clarify the underlying host–microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome and deep immunotyping, in a cohort of patients and non-CKD controls.

Results

Our analyses on functional profiles of the gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme and virulence factor genes in CKD. Moreover, models generated using measurements of serum metabolites (amino acids, bile acids and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of the functional profiles derived from gut microbiota, with the CAZyme genes being the top-performing model to accurately predict the early stage of diseases. In addition, co-occurrence analyses revealed coordinated host–microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g. B cell cluster tryptophan and B cell cluster tryptophan metabolism).

Conclusion

Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host–microbe co-metabolites and renal function, which may have aetiological and diagnostic implications in CKD.
Hyperkalaemia-related reduction of RAASi treatment associates with more subsequent inpatient care
Authors: Svensson Maria K , Murohara Toyoaki , Lesén Eva , Arnold Matthew , Cars Thomas , Järbrink Krister , Chen Gengshi , Morita Naru , Venkatesan Sudhir , Kanda Eiichiro
Published: January 2024

Background

Hyperkalaemia is a barrier to achieving optimal, guideline-directed treatment with renin–angiotensin–aldosterone system inhibitors (RAASis) in patients with chronic kidney disease (CKD) and/or heart failure (HF). This study describes the association between hyperkalaemia-related RAASi treatment reduction and the number of hospitalized days in patients with CKD and/or HF in Sweden and Japan.

Methods

Using data from health registers and hospital medical records, patients with CKD and/or HF currently receiving RAASis who experienced an index hyperkalaemia episode were identified and categorized as having maintained or reduced RAASi treatment post-index; propensity score matching (1:1) was applied to balance the groups in terms of baseline characteristics. Changes in the number of all-cause, CKD- and HF-related hospitalized days per patient-year during 6 months pre- versus post-index and the number of days alive and out of hospital (DAOH) during 6 months post-index were described.

Results

Overall, 20 824 and 7789 patients were included from Sweden and Japan, respectively, 42% and 38% of whom reduced their RAASi treatment after the index hyperkalaemia episode. During the 6 months post-index, all-cause hospitalization increased by 18.2 days [95% confidence interval (CI) 17.0–19.2] per person-year in Sweden and 17.9 days (95% CI 17.4–18.5) per person-year in Japan among patients with reduced RAASi treatment compared with increases of 9.4 days (95% CI 8.6–10.4) and 8.5 days (95% CI 8.0–9.0) per person-year, respectively, among patients with maintained RAASi treatment. The mean DAOH was 121.5 [standard deviation (SD) 75.0] in Sweden and 141.7 (SD 54.5) in Japan among patients with reduced RAASi treatment compared with 154.0 (SD 51.3) and 157.5 (SD 31.6), respectively, among patients with maintained RAASi treatment.

Conclusion

Patients whose RAASi treatment was reduced after a hyperkalaemia episode had more hospitalized days and fewer DAOH compared with patients whose RAASi treatment was maintained.
Fluorescein-stained confocal laser endomicroscopy versus conventional frozen section for intraoperative histopathological assessment of intracranial tumors
Authors: Wagner Arthur , Brielmaier Maria Charlotte , Kampf Charlotte , Baumgart Lea , Aftahy Amir Kaywan , Meyer Hanno S , Kehl Victoria , Höhne Julius , Schebesch Karl-Michael , Schmidt Nils O , Zoubaa Saida , Riemenschneider Markus J , Ratliff Miriam , Enders Frederik , von Deimling Andreas , Liesche-Starnecker Friederike , Delbridge Claire , Schlegel Juergen , Meyer Bernhard , Gempt Jens
Published: January 2024

Background

The aim of this clinical trial was to compare Fluorescein-stained intraoperative confocal laser endomicroscopy (CLE) of intracranial lesions and evaluation by a neuropathologist with routine intraoperative frozen section (FS) assessment by neuropathology.

Methods

In this phase II noninferiority, prospective, multicenter, nonrandomized, off-label clinical trial (EudraCT: 2019-004512-58), patients above the age of 18 years with any intracranial lesion scheduled for elective resection were included. The diagnostic accuracies of both CLE and FS referenced with the final histopathological diagnosis were statistically compared in a noninferiority analysis, representing the primary endpoint. Secondary endpoints included the safety of the technique and time expedited for CLE and FS.

Results

A total of 210 patients were included by 3 participating sites between November 2020 and June 2022. Most common entities were high-grade gliomas (37.9%), metastases (24.1%), and meningiomas (22.7%). A total of 6 serious adverse events in 4 (2%) patients were recorded. For the primary endpoint, the diagnostic accuracy for CLE was inferior with 0.87 versus 0.91 for FS, resulting in a difference of 0.04 (95% confidence interval −0.10; 0.02; P = .367). The median time expedited until intraoperative diagnosis was 3 minutes for CLE and 27 minutes for FS, with a mean difference of 27.5 minutes (standard deviation 14.5; P < .001).

Conclusions

CLE allowed for a safe and time-effective intraoperative histological diagnosis with a diagnostic accuracy of 87% across all intracranial entities included. The technique achieved histological assessments in real time with a 10-fold reduction of processing time compared to FS, which may invariably impact surgical strategy on the fly.
Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas
Authors: Galbraith Kristyn , Garcia Mekka , Wei Siyu , Chen Anna , Schroff Chanel , Serrano Jonathan , Pacione Donato , Placantonakis Dimitris G , William Christopher M , Faustin Arline , Zagzag David , Barbaro Marissa , Eibl Maria Del Pilar Guillermo Prieto , Shirahata Mitsuaki , Reuss David , Tran Quynh T , Alom Zahangir , von Deimling Andreas , Orr Brent A , Sulman Erik P , Golfinos John G , Orringer Daniel A , Jain Rajan , Lieberman Evan , Feng Yang , Snuderl Matija
Published: January 2024

Background

Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma.

Methods

We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts.

Results

There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534).

Conclusions

The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.
Phase 1 trial of TPI 287, a microtubule stabilizing agent, in combination with bevacizumab in adults with recurrent glioblastoma
Authors: Goldlust Samuel A , Nabors Louis B , Hsu Sigmund , Mohile Nimish , Duic Paul J , Benkers Tara , Singer Samuel , Rao Mayank , Cappello Lori , Silberman Sandra L , Farmer George
Published: January 2024

Background

Recurrent glioblastoma (rGBM) has limited treatment options. This phase 1 protocol was designed to study the safety and preliminary efficacy of TPI 287, a central nervous system penetrant microtubule stabilizer, in combination with bevacizumab (BEV) for the treatment of rGBM.

Methods

GBM patients with up to 2 prior relapses without prior exposure to anti-angiogenic therapy were eligible. A standard 3 + 3 design was utilized to determine the maximum tolerated dose (MTD) of TPI 287. Cohorts received TPI 287 at 140–220 mg/m2 every 3 weeks and BEV 10 mg/kg every 2 weeks during 6-week cycles. An MRI was performed after each cycle, and treatment continued until progression as determined via response assessment in neuro-oncology criteria.

Results

Twenty-four patients were enrolled at 6 centers. Treatment was generally well tolerated. Fatigue, myelosuppression, and peripheral neuropathy were the most common treatment emergent adverse events. Dose-limiting toxicity was not observed, thus the MTD was not determined. Twenty-three patients were evaluable for median and 6-month progression-free survival, which were 5.5 months (mo) and 40%, respectively. Median and 12-month overall survival were 13.4 mo and 64%, respectively. The optimal phase 2 dose was determined to be 200 mg/m2.

Conclusions

TPI 287 can be safely combined with BEV for the treatment of rGBM and preliminary efficacy supports further investigation of this combination.
Plasma Oxidative State Induced by Exercise in Young Heat-Not-Burn Cigarette Users
Authors: Takagi Aoi , Hamada Hironobu , Sekikawa Kiyokazu , Ueoka Hatsumi , Namba Haruchi , Sato Yoshinobu M , Kanda Naoto , Miyazaki Ryosuke
Published: January 2024

Introduction

Oxidative state, a risk factor for several diseases, is increased by habitual conventional cigarette (CC) smoking. Reports have demonstrated that heat-not-burn cigarettes (HNBCs), which have recently become popular among smokers, generate less oxidative state than CC in smokers with a long smoking history. However, no previous study has examined oxidative state in young HNBC users. Previously, we reported that exercise induces a greater oxidative state in young CC smokers than in never-smokers of similar age, but there was no difference in resting oxidative state. This study aimed to clarify the resting and exercise-induced oxidative states in young HNBC users, compared with those in never-smokers and CC users of similar age.

Methods

Healthy young never-smokers, HNBC users, and CC users were recruited, and they underwent the Wingate anaerobic test. Blood samples were collected before and after exercise, and the plasma hydroperoxide concentration, a marker of oxidative state, was measured.

Results

No significant differences in pre-exercise plasma hydroperoxide concentrations were detected among never-smokers, HNBC users, and CC users (n = 10 each). Plasma hydroperoxide concentration was significantly increased after exercise in all participants. The exercise induced a significant increase in plasma hydroperoxide concentration in HNBC users compared with that in never-smokers (p < .005), but it was significantly decreased compared with that in CC users (p < .01).

Conclusions

The use of HNBC increased exercise-induced plasma oxidative state compared with that in never-smokers, indicating that HNBC may lead to the risk of oxidative damage.

Implications

This study, for the first time, reports exercise-induced oxidative state in young HNBC users compared with never-smokers and CC users. The exercise-induced oxidative state in HNBC users was higher than that in never-smokers and lower than that in CC users. Our study suggests that the use of HNBCs increases the risk of acute oxidative damage.
Utility of Low-Dose Duvelisib for Advanced Mycosis Fungoides: A Single-Institution Study
Authors: Bazewicz Christopher , Verardi Nicolena , Akilov Oleg
Published: January 2024

Duvelisib, a small-molecule phosphatidylinositol 3-kinase-δ,γ inhibitor, has shown efficacy for mycosis fungoides (MF) at dosage ranges of 25-100 mg twice daily (BID), but with significant toxicity. We conducted a retrospective cohort study of patients with advanced MF treated with low-dose duvelisib (15 mg every other day to BID), in an effort to minimize toxicity. A total of 7 patients were included. The overall response rate on duvelisib was 71%, with the remaining patients maintaining stable disease. Mean modified Severity Weighted Assessment Tool score improved by 57.4% and mean percent body surface area involved improved by 52%. Median progression-free survival was 10.3 months. Adverse events occurred in 4 of 7 patients, the most common being fatigue (2/7; grades 1-2), nausea (2/7; grades 1-2), and transaminitis (2/7; grade 3). Overall, low-dose duvelisib showed efficacy for advanced MF with less toxicity, providing a rationale for its use as monotherapy and potentially combinatorial therapy.
Ribociclib-Induced Cutaneous Adverse Events in Metastatic HR+/HER2− Breast Cancer: Incidence, Multidisciplinary Management, and Prognostic Implication
Authors: Borroni Riccardo Giovanni , Bartolini Michela , Gaudio Mariangela , Jacobs Flavia , Benvenuti Chiara , Gerosa Riccardo , Tiberio Paola , Manara Sofia Ada Assunta Maria , Solferino Alessandra , Santoro Armando , De Sanctis Rita
Published: January 2024

Background

Ribociclib is approved for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) advanced breast cancer (ABC) treatment, in combination with endocrine therapy. Hematological, hepatic, and cardiac adverse events (AEs) emerged from pivotal trials, but little is known about cutaneous adverse events (CAEs).

Patients and Methods

We report data from a retrospective cohort study of all patients with HR+/HER2− ABC treated with ribociclib at Humanitas Cancer Center between June 2017 and December 2022. We recorded clinical-pathological data, the incidence, and treatment of ribociclib-related CAEs. These were evaluated according to the NCI-CTCAE v5.0 classification. Progression-free survival (PFS) was estimated by Kaplan-Meier method and the log-rank test was used to analyze differences between groups.

Results

Thirteen of 91 patients (14.3%) experienced treatment-related CAEs (mean time to the occurrence: 3.9 months). The most frequent CAEs were eczematous dermatitis (53.8%) and maculo-papular reaction (15.4%). Itch was reported by all 13 patients. The grade was G3 in 8 cases, G2 in 4, and G1 in 1. An integrated approach based on ribociclib dose modulation and dermatological interventions (oral antihistamine, moisturized cream, topical, and/or systemic steroids) could prevent ribociclib discontinuation in most patients. At a median follow-up of 20 months, the median PFS was 13 months (range, 1-66) with a better PFS curves for patients experiencing CAEs (P = .04).

Conclusion

We mapped frequency and types of ribociclib-induced CAEs. An interdisciplinary management of CAEs incorporated into routine care may reduce the rate of drug discontinuation thus potentially contributing to better long-term outcomes.
SUPPRESSOR OF MAX2 1-LIKE (SMXL) homologs are MAX2-dependent repressors of Physcomitrium patens growth
Authors: Guillory Ambre , Lopez-Obando Mauricio , Bouchenine Khalissa , Le Bris Philippe , Lécureuil Alain , Pillot Jean-Paul , Steinmetz Vincent , Boyer François-Didier , Rameau Catherine , de Saint Germain Alexandre , Bonhomme Sandrine
Published: January 2024

SUPPRESSOR OF MAX2 (SMAX)1-LIKE (SMXL) proteins are a plant-specific clade of type I HSP100/Clp-ATPases. SMXL genes are present in virtually all land plant genomes. However, they have mainly been studied in angiosperms. In Arabidopsis (Arabidopsis thaliana), 3 functional SMXL subclades have been identified: SMAX1/SMXL2, SMXL345, and SMXL678. Of these, 2 subclades ensure endogenous phytohormone signal transduction. SMAX1/SMXL2 proteins are involved in KAI2 ligand (KL) signaling, while SMXL678 proteins are involved in strigolactone (SL) signaling. Many questions remain regarding the mode of action of these proteins, as well as their ancestral roles. We addressed these questions by investigating the functions of the 4 SMXL genes in the moss Physcomitrium patens. We demonstrate that PpSMXL proteins are involved in the conserved ancestral MAX2-dependent KL signaling pathway and negatively regulate growth. However, PpSMXL proteins expressed in Arabidopsis cannot replace SMAX1 or SMXL2 function in KL signaling, whereas they can functionally replace SMXL4 and SMXL5 and restore root growth. Therefore, the molecular functions of SMXL proteins are conserved, but their interaction networks are not. Moreover, the PpSMXLC/D clade positively regulates SL signal transduction in P. patens. Overall, our data reveal that SMXL proteins in moss mediate crosstalk between the SL and KL signaling pathways.
Degradation of FATTY ACID EXPORT PROTEIN1 by RHOMBOID-LIKE PROTEASE11 contributes to cold tolerance in Arabidopsis
Authors: John Annalisa , Krämer Moritz , Lehmann Martin , Kunz Hans-Henning , Aarabi Fayezeh , Alseekh Saleh , Fernie Alisdair , Sommer Frederik , Schroda Michael , Zimmer David , Mühlhaus Timo , Peisker Helga , Gutbrod Katharina , Dörmann Peter , Neunzig Jens , Philippar Katrin , Neuhaus Horst Ekkehard
Published: January 2024

Plants need to acclimate to different stresses to optimize growth under unfavorable conditions. In Arabidopsis (Arabidopsis thaliana), the abundance of the chloroplast envelope protein FATTY ACID EXPORT PROTEIN1 (FAX1) decreases after the onset of low temperatures. However, how FAX1 degradation occurs and whether altered FAX1 abundance contributes to cold tolerance in plants remains unclear. The rapid cold-induced increase in RHOMBOID-LIKE PROTEASE11 (RBL11) transcript levels, the physical interaction of RBL11 with FAX1, the specific FAX1 degradation after RBL11 expression, and the absence of cold-induced FAX1 degradation in rbl11 loss-of-function mutants suggest that this enzyme is responsible for FAX1 degradation. Proteomic analyses showed that rbl11 mutants have higher levels of FAX1 and other proteins involved in membrane lipid homeostasis, suggesting that RBL11 is a key element in the remodeling of membrane properties during cold conditions. Consequently, in the cold, rbl11 mutants show a shift in lipid biosynthesis toward the eukaryotic pathway, which coincides with impaired cold tolerance. To test whether cold sensitivity is due to increased FAX1 levels, we analyzed FAX1 overexpressors. The rbl11 mutants and FAX1 overexpressor lines show superimposable phenotypic defects upon exposure to cold temperatures. Our re­sults show that the cold-induced degradation of FAX1 by RBL11 is critical for Arabidop­sis to survive cold and freezing periods.
Heritable, multinucleotide deletions in plants using viral delivery of a repair exonuclease and guide RNAs
Authors: Liu Degao , Myers Erik A , Xuan Shuya , Prichard Lynn E , Donahue Lilee I , Ellison Evan E , Starker Colby G , Voytas Daniel F
Published: January 2024

CRISPR/Cas9-mediated mutagenesis typically results in short insertion/deletion mutations, which are often too small to disrupt the function of cis-acting regulatory elements. Here, we describe a highly efficient in planta gene editing approach called VirTREX2-HLDel that achieves heritable multinucleotide deletions in both protein-coding genes and noncoding DNA regulatory elements. VirTREX2-HLDel uses RNA viruses to deliver both the 3 prime repair exonuclease 2 (TREX2) and single-guide RNAs. Our method enables recovery of multiplexed heritable deletions and increases the heritable gene editing frequency at poorly edited sites. We identified functional conservation and divergence of MICRORNA164 (miR164) in Nicotiana benthamiana and tomato (Solanum lycopersicum) using VirTREX2-HLDel and observed previously uncharacterized phenotypes in plants with large deletions at this locus. Our viral delivery method reduces the need for tissue culture and will accelerate the understanding of protein-coding and regulatory regions in plants.
Valsa mali effector Vm_04797 interacts with adaptor protein MdAP-2β to manipulate host autophagy
Authors: Sun Yubo , Luo Danyan , Liu Yuerong , Tu Wenyan , Che Runmin , Feng Hao , Huang Lili , Ma Fengwang , Liu Changhai
Published: January 2024

Apple Valsa canker, caused by the ascomycete fungus Valsa mali, employs virulence effectors to disturb host immunity and poses a substantial threat to the apple industry. However, our understanding of how V. mali effectors regulate host defense responses remains limited. Here, we identified the V. mali effector Vm_04797, which was upregulated during the early infection stage. Vm_04797, a secreted protein, suppressed Inverted formin 1 (INF1)-triggered cell death in Nicotiana benthamiana and performed virulence functions inside plant cells. Vm_04797 deletion mutants showed substantially reduced virulence toward apple. The adaptor protein MdAP-2β positively regulated apple Valsa canker resistance and was targeted and degraded by Vm_04797 via the ubiquitination pathway. The in vitro analysis suggested that Vm_04797 possesses E3 ubiquitin ligase activity. Further analysis revealed that MdAP-2β is involved in autophagy by interacting with Malus domestica autophagy protein 16 MdATG16 and promoting its accumulation. By degrading MdAP-2β, Vm_04797 inhibited autophagic flux, thereby disrupting the defense response mediated by autophagy. Our findings provide insights into the molecular mechanisms employed by the effectors of E3 ubiquitin ligase activity in ascomycete fungi to regulate host immunity.
ELONGATED HYPOTCOTYL5 and SPINE BASE SIZE1 together mediate light-regulated spine expansion in cucumber
Authors: Zhao Lijun , Fan Pengfei , Wang Yueling , Xu Nana , Zhang Minjuan , Chen Mingyue , Zhang Mengyao , Dou Junling , Liu Dongming , Niu Huanhuan , Zhu Huayu , Hu Jianbin , Sun Shouru , Yang Luming , Yang Sen
Published: January 2024

Plant trichome development is influenced by diverse developmental and environmental signals, but the molecular mechanisms involved are not well understood in most plant species. Fruit spines (trichomes) are an important trait in cucumber (Cucumis sativus L.), as they affect both fruit smoothness and commercial quality. Spine Base Size1 (CsSBS1) has been identified as essential for regulating fruit spine size in cucumber. Here, we discovered that CsSBS1 controls a season-dependent phenotype of spine base size in wild-type plants. Decreased light intensity led to reduced expression of CsSBS1 and smaller spine base size in wild-type plants, but not in the mutants with CsSBS1 deletion. Additionally, knockout of CsSBS1 resulted in smaller fruit spine base size and eliminated the light-induced expansion of spines. Overexpression of CsSBS1 increased spine base size and rescued the decrease in spine base size under low light conditions. Further analysis revealed that ELONGATED HYPOTCOTYL5 (HY5), a major transcription factor involved in light signaling pathways, directly binds to the promoter of CsSBS1 and activates its expression. Knockout of CsHY5 led to smaller fruit spine base size and abolished the light-induced expansion of spines. Taken together, our study findings have clarified a CsHY5–CsSBS1 regulatory module that mediates light-regulated spine expansion in cucumber. This finding offers a strategy for cucumber breeders to develop fruit with stable appearance quality under changing light conditions.
Perceptual integration of bodily and facial emotion cues in chimpanzees and humans
Authors: Heesen Raphaela , Kim Yena , Kret Mariska E , Clay Zanna
Published: January 2024

For highly visual species like primates, facial and bodily emotion expressions play a crucial role in emotion perception. However, most research focuses on facial expressions, while the perception of bodily cues is still poorly understood. Using a novel comparative priming eye-tracking design, we examined whether our close primate relatives, the chimpanzees (Pan troglodytes), and humans infer emotions from bodily cues through subsequent perceptual integration with facial expressions. In experiment 1, we primed chimpanzees with videos of bodily movements of unfamiliar conspecifics engaged in social activities of opposite valence (play and fear) against neutral control scenes to examine attentional bias toward succeeding congruent or incongruent facial expressions. In experiment 2, we assessed the same attentional bias in humans yet using stimuli showing unfamiliar humans. In experiment 3, humans watched the chimpanzee stimuli of experiment 1, to examine cross-species emotion perception. Chimpanzees exhibited a persistent fear-related attention bias but did not associate bodily with congruent facial cues. In contrast, humans prioritized conspecifics' congruent facial expressions (matching bodily scenes) over incongruent ones (mismatching). Nevertheless, humans exhibited no congruency effect when viewing chimpanzee stimuli, suggesting difficulty in cross-species emotion perception. These results highlight differences in emotion perception, with humans being greatly affected by fearful and playful bodily cues and chimpanzees being strongly drawn toward fearful expressions, regardless of the preceding bodily priming cue. These data advance our understanding of the evolution of emotion signaling and the presence of distinct perceptual patterns in hominids.
Detecting Artificial Intelligence-Generated Personal Statements in Professional Physical Therapist Education Program Applications: A Lexical Analysis
Authors: Hollman John H , Cloud-Biebl Beth A , Krause David A , Calley Darren Q
Published: January 2024

Objective

The objective of this study was to compare the lexical sophistication of personal statements submitted by professional physical therapist education program applicants with those generated by OpenAI’s Chat Generative Pretrained Transformer (ChatGPT).

Methods

Personal statements from 152 applicants and 20 generated by ChatGPT were collected, all in response to a standardized prompt. These statements were coded numerically, then analyzed with recurrence quantification analyses (RQAs). RQA indices including recurrence, determinism, max line, mean line, and entropy were compared with t-tests. A receiver operating characteristic curve analysis was used to examine discriminative validity of RQA indices to distinguish between ChatGPT and human-generated personal statements.

Results

ChatGPT-generated personal statements exhibited higher recurrence, determinism, mean line, and entropy values than did human-generated personal statements. The strongest discriminator was a 13.04% determinism rate, which differentiated ChatGPT from human-generated writing samples with 70% sensitivity and 91.4% specificity (positive likelihood ratio = 8.14). Personal statements with determinism rates exceeding 13% were 8 times more likely to have been ChatGPT than human generated.

Conclusion

Although RQA can distinguish artificial intelligence (AI)-generated text from human-generated text, it is not absolute. Thus, AI introduces additional challenges to the authenticity and utility of personal statements. Admissions committees along with organizations providing guidelines in professional physical therapist education program admissions should reevaluate the role of personal statements in applications.

Impact

As AI-driven chatbots like ChatGPT complicate the evaluation of personal statements, RQA emerges as a potential tool for admissions committees to detect AI-generated statements.
Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study
Authors: Byrne Jonah F , Healy Colm , Föcking Melanie , Susai Subash Raj , Mongan David , Wynne Kieran , Kodosaki Eleftheria , Heurich Meike , de Haan Lieuwe , Hickie Ian B , Smesny Stefan , Thompson Andrew , Markulev Connie , Young Alison Ruth , Schäfer Miriam R , Riecher-Rössler Anita , Mossaheb Nilufar , Berger Gregor , Schlögelhofer Monika , Nordentoft Merete , Chen Eric Y H , Verma Swapna , Nieman Dorien H , Woods Scott W , Cornblatt Barbara A , Stone William S , Mathalon Daniel H , Bearden Carrie E , Cadenhead Kristin S , Addington Jean , Walker Elaine F , Cannon Tyrone D , Cannon Mary , McGorry Pat , Amminger Paul , Cagney Gerard , Nelson Barnaby , Jeffries Clark , Perkins Diana , Cotter David R
Published: January 2024

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.
The chromatographic fingerprinting study and genotoxicity evaluation of aqueous extract from Cyclocarya paliurus leaves
Authors: Zhao Hongwei , Yang Xiaobing , Wang Lei , Huang Xianju
Published: January 2024

Cyclocarya paliurus leaf is a medicinal and edible homologous plant, which possess various bioactive components with significant health benefits. However, the quality and safety of the aqueous extract from Cyclocarya paliurus leaves (CPLAE) vary greatly due to the raw materials and preparation technology. At present, chromatographic fingerprinting has been widely used for qualitative and quantitative analysis of traditional Chinese medicine (TCM). In this study, a method combining high performance liquid chromatography (HPLC) fingerprint with quantitative analysis was established and successfully applied to the characterization and quality evaluation of the CPLAE. In addition, the genetic safety of the CPLAE was evaluated by genotoxicity tests, including Ames test, chromosomal aberration test of Chinese hamster lung (CHL) cell in vitro, and bone marrow micronucleus test in mice. The results showed that 10 batches of CPLAE samples were analyzed by high performance liquid chromatography coupled with mass spectrometry (HPLC-MS), and the similarity of chromatographic fingerprint of each batch was above 0.961, indicating good similarity. At the same time, the 6 compounds with high absorption strength in the chromatogram were quantitatively analyzed. The results showed that all 6 compounds had good regression (R2=1.000) in the test range, and the recoveries ranged from 96.25% to 102.46%. The results of the 3 genotoxicity tests showed that the highest dose of CPLAE had no genotoxicity. In conclusion, the newly established chromatographic fingerprint and multi-component quantitative analysis method is stable and accurate, and can be used for the identification and quality evaluation of the CPLAE. Moreover, the CPLAE has the characteristics of safety and high quality as functional materials in food.
The sphingosine‐1‐phosphate receptor 1 modulator ponesimod repairs cuprizone‐induced demyelination and induces oligodendrocyte differentiation
Authors: Willems Emily , Schepers Melissa , Piccart Elisabeth , Wolfs Esther , Hellings Niels , Ait‐Tihyaty Maria , Vanmierlo Tim
Published: January 2024

Sphingosine‐1‐phosphate receptor (S1PR) modulators are clinically used to treat relapse‐remitting multiple sclerosis (MS) and the early phase of progressive MS when inflammation still prevails. In the periphery, S1PR modulators prevent lymphocyte egress from lymph nodes, hence hampering neuroinflammation. Recent findings suggest a role for S1PR modulation in remyelination. As the Giα‐coupled S1P1 subtype is the most prominently expressed S1PR in oligodendrocyte precursor cells (OPCs), selective modulation (functional antagonism) of S1P1 may have direct effects on OPC functionality. We hypothesized that functional antagonism of S1P1 by ponesimod induces remyelination by boosting OPC differentiation. In the cuprizone mouse model of demyelination, we found ponesimod to decrease the latency time of visual evoked potentials compared to vehicle conditions, which is indicative of functional remyelination. In addition, the Y maze spontaneous alternations test revealed that ponesimod reversed cuprizone‐induced working memory deficits. Myelin basic protein (MBP) immunohistochemistry and transmission electron microscopy of the corpus callosum revealed an increase in myelination upon ponesimod treatment. Moreover, treatment with ponesimod alone or in combination with A971432, an S1P5 monoselective modulator, significantly increased primary mouse OPC differentiation based on O4 immunocytochemistry. In conclusion, S1P1 functional antagonism by ponesimod increases remyelination in the cuprizone model of demyelination and significantly increases OPC differentiation in vitro.
KAT8 functions in redox homeostasis and mitochondrial dynamics during mouse oocyte meiosis progression
Authors: Wu Xuan , Wang Shiwei , Guo Yajun , Song Shuang , Zeng Shenming
Published: January 2024

As a histone acetyltransferase, lysine acetyltransferase 8 (KAT8) participates in diverse biological processes. However, the effect of KAT8 on oocyte maturation in mice remains unclear. In this study, we found that mouse oocytes overexpressing Kat8‐OE induced maturation failure manifested reduced rates of GVBD and first polar body emission. In addition, immunostaining results revealed that Kat8 overexpressing oocytes showed inappropriate mitochondrial distribution patterns, overproduction of reactive oxygen species (ROS), accumulation of phosphorylated γH2AX, hyperacetylation of α‐tubulin, and severely disrupted spindle/chromosome organization. Moreover, we revealed that Kat8 overexpression induced a decline in SOD1 proteins and KAT8's interaction with SOD1 in mouse ovaries via immunoprecipitation. Western blotting data confirmed that Kat8‐OE induced downregulation of SOD1 expression, which is a key factor for the decline of oocyte quality in advanced maternal age. Also, the injection of Myc‐Sod1 cRNA could partially rescue maternal age‐induced meiotic defects in oocytes. In conclusion, our data demonstrated that high level of KAT8 inhibited SOD1 activity, which in turn induced defects of mitochondrial dynamics, imbalance of redox homeostasis, and spindle/chromosome disorganization during mouse oocyte maturation.
Development of a novel HER2-CAR monocyte cell therapy with controllable proliferation and enhanced anti-tumor efficacy
Authors: Yang Bing , Wang Xiaoxue , Wei Xundong , Ma Jie
Published: January 2024

Background:

One of the significant challenges for cell therapies, such as chimeric antigen receptor (CAR)-T cell therapy, is the poor infiltration of immune cells into tumor tissues. CAR-monocytes/macrophages (CAR-M) are promising therapies because of their enrichment in the tumor microenvironment. Thus, we constructed a novel CAR-M to facilitate the infiltration of T cells and other immune cells.

Methods:

The suicide gene inducible caspase-9 (iCasp9) and anti-erb-b2 receptor tyrosine kinase 2 (HER2) CAR elements were transfected into THP1 (an immortalized human monocyte cell line) by lentivirus. The suicide efficiency and specific anti-tumor efficacy were assessed using flow cytometry, inCucyte, and tumor-bearing BALB/c-nude mouse models. The activation of related signaling pathways in CAR-THP1 activation was explored by transcriptome sequencing. Finally, the synergistic therapeutic efficacy of CAR-THP1 combined with RAK cell treatment was demonstrated in tumor-bearing NOD.CB17-Prkdcscid Il2rgtm1/Bcgen mouse models.

Results:

We developed a novel CAR-THP1, which incorporated iCasp9, CD3ζ, and CD147 intracellular segments, based on the first-generation HER2-CAR backbone. By constructing and comparing a series of CARs with different permutations, CAR-CD3ζ-CD147-iCasp9-THP1 was selected as the optimal combination. CAR-CD3ζ-CD147-iCasp9-THP1 initiated suicide quickly and efficiently under the control of iCasp9 gene, which enabled us to achieve controlled proliferation of CAR-THP1. CAR-THP1 also exhibited robust specific anti-tumor efficacy independently of T cells in vitro and in vivo. Through transcriptional sequencing, we found that CAR-THP1 tended to differentiate into the M1 phenotype and bridged innate and adaptive immunity. A combination of CAR-THP1 and Retronectin actived killer cells (RAKs) showed better therapeutic efficiency, as the metalloproteinases (MMPs) secreted by CAR-THP1 facilitated the degradation of the dense tumor matrix. This further assisted intratumoral infiltration of T cells and augmented the anti-tumor immune response.

Conclusion:

CAR-THP1 might be effective against HER2-positive tumor cells and has great potential for combination therapy with other immune cells.
GRK2–YAP signaling is implicated in pulmonary arterial hypertension development
Authors: Ye Peng , Deng Yunfei , Gu Yue , Liu Pengfei , Luo Jie , Pu Jiangqin , Chen Jingyu , Huang Yu , Wang Nanping , Ji Yong , Chen Shaoliang
Published: January 2024

Background:

Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of small pulmonary arterial vascular smooth muscle cells (PASMCs), endothelial dysfunction, and extracellular matrix remodeling. G protein-coupled receptor kinase 2 (GRK2) plays an important role in the maintenance of vascular tone and blood flow. However, the role of GRK2 in the pathogenesis of PAH is unknown.

Methods:

GRK2 levels were detected in lung tissues from healthy people and PAH patients. C57BL/6 mice, vascular smooth muscle cell-specific Grk2-knockout mice (Grk2
Δ
SM22), and littermate controls (Grk2
flox/flox) were grouped into control and hypoxia mice (n = 8). Pulmonary hypertension (PH) was induced by exposure to chronic hypoxia (10%) combined with injection of the SU5416 (cHx/SU). The expression levels of GRK2 and Yes-associated protein (YAP) in pulmonary arteries and PASMCs were detected by Western blotting and immunofluorescence staining. The mRNA expression levels of Grk2 and Yes-associated protein (YAP) in PASMCs were quantified with real-time polymerase chain reaction (RT-PCR). Wound-healing assay, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, and 5-Ethynyl-2′-deoxyuridine (EdU) staining were performed to evaluate the proliferation and migration of PASMCs. Meanwhile, the interaction among proteins was detected by immunoprecipitation assays.

Results:

The expression levels of GRK2 were upregulated in the pulmonary arteries of patients with PAH and the lungs of PH mice. Moreover, cHx/SU-induced PH was attenuated in Grk2
Δ
SM22 mice compared with littermate controls. The amelioration of PH in Grk2
Δ
SM22 mice was accompanied by reduced pulmonary vascular remodeling. In vitro study further confirmed that GRK2 knock-down significantly altered hypoxia-induced PASMCs proliferation and migration, whereas this effect was severely intensified by overexpression of GRK2. We also identified that GRK2 promoted YAP expression and nuclear translocation in PASMCs, resulting in excessive PASMCs proliferation and migration. Furthermore, GRK2 is stabilized by inhibiting phosphorylating GRK2 on Tyr86 and subsequently activating ubiquitylation under hypoxic conditions.

Conclusion:

Our findings suggest that GRK2 plays a critical role in the pathogenesis of PAH, via regulating YAP expression and nuclear translocation. Therefore, GRK2 serves as a novel therapeutic target for PAH treatment.
Effects of the Need for Support From the Workplace and Resilience on Psychological Distress in Japanese Employees
Authors: Eguchi Hisashi , Inoue Akiomi , Mafune Kosuke , Tsuji Mayumi , Tateishi Seiichiro , Ikegami Kazunori , Nagata Tomohisa , Matsugaki Ryutaro , Fujino Yoshihisa ,   for the CORoNaWork project
Published: January 2024

Purpose

This study examines workplace support and resilience’s influence on psychological distress in Japanese employees.

Method

A 1-year prospective online cohort study was conducted. Logistic regression analyzed prevalence odds ratios and 95% confidence intervals for psychological distress. Participants were grouped based on their support and resilience levels.

Results

Prevalence odds ratios for psychological distress followed this pattern for low and high resilience groups: “necessary but not received” (prevalence odds ratio and 95% confidence interval for low/high resilience: 9.71, 6.88–13.69 and 4.72, 2.97–7.52, respectively), “received” (6.65, 4.29–10.29 and 2.27, 1.21–4.25), and “not necessary” (4.43, 3.30–5.95 and reference). Workplace support had a stronger impact on psychological distress in low-resilience employees.

Conclusions

We provided evidence that the combination of the need for support from the workplace and resilience affects psychological distress in employees.