bluuebunny/crossref_metadata_2025 huggingface dataset:
Premorbid personality traits as predictors for incident predementia syndromes: a multistate model approach
Authors: Schaeffer Morgan J. , MacDonald Stuart W.S. , Paterson Theone S.E.
Published: January 2024

Objective:

Associations have been found between five-factor model (FFM) personality traits and risk of developing specific predementia syndromes such as subjective cognitive decline (SCD) and mild cognitive impairment (MCI). The aims of this study were to: 1) Compare baseline FFM traits between participants who transitioned from healthy cognition or SCD to amnestic MCI (aMCI) versus non-amnestic MCI (naMCI); and 2) Determine the relationship between FFM traits and risk of transition between predementia cognitive states.

Methods:

Participants were 562 older adults from the Einstein Aging Study, 378 of which had at least one follow-up assessment. Baseline data collected included levels of FFM personality traits, anxiety and depressive symptoms, medical history, performance on a cognitive battery, and demographics. Follow-up cognitive diagnoses were also recorded.

Results:

Mann–Whitney U tests revealed no differences in baseline levels of FFM personality traits between participants who developed aMCI compared to those who developed naMCI. A four-state multistate Markov model revealed that higher levels of conscientiousness were protective against developing SCD while higher levels of neuroticism resulted in an increased risk of developing SCD. Further, higher levels of extraversion were protective against developing naMCI.

Conclusions:

FFM personality traits may be useful in improving predictions of who is at greatest risk for developing specific predementia syndromes. Information on these personality traits could enrich clinical trials by permitting trials to target individuals who are at greatest risk for developing specific forms of cognitive impairment. These results should be replicated in future studies with larger sample sizes and younger participants.
An overview of the nutritional status of childbearing age women, children and adolescents living in a rural area of Madagascar: preliminary results of the Tany Vao project
Authors: Conti Maria Vittori , Itani Leila , Beretta Alice , Bono Edoardo , Yaghi Kassandra , Filosa Asia , Monti Cristina , Cena Hellas
Published: January 2024

Objective:

To describe the food consumption, nutrition knowledge and nutritional assessment of childbearing age women and their children, living in rural villages in Madagascar. The results presented are related to the Tany Vao research study.

Design:

A cross-sectional pilot study.

Setting:

The study was carried out in Ampanitosoha village on Nosy Mitsio island in Madagascar.

Participants:

32 women (14–49 years) and 36 children and adolescents (2–17 years).

Results:

70 % of the women lacked nutrition knowledge and did not reach the Minimum Dietary Diversity Index for Women cut-off. The median BMI was 21·1 kg/m2 but 55·2 % of the women exceeded the cut-off for waist-to-hip ratio, 51·7 % for waist-to-height ratio and 81·2 % for mid-upper arm circumference (MUAC). Almost all had adequate intake of energy, protein and carbohydrates, while 27·6 % had excessive fat intake and 75·9 % of added sugars. Over half of the women did not meet the micronutrients Reference Daily Intake (RDI). For children, the MUAC z-score was lower for boys than for girls (P-value = 0·041).

Conclusions:

These results underline the importance of increasing women’s nutritional knowledge to promote healthy pregnancy and lactation. Moreover, it is fundamental to provide people living in rural areas with sustainable tools to improve dietary diversity and support long-term health.
Comparative analysis of shoulder angles between selected groups of elite and non-achieving event horses
Authors: Whitaker T C , Seabrook J
Published: January 2024

The relationship between conformational structure and function in the equine is thought to be important in the judgement of the future soundness and performance of the horse (Holmstrom et al 1990). Holmstrom et al (ibid ) demonstrated that elite dressage and show jump horses possess a more horizontal shoulder enabling the horse to demonstrate an improved forelimb technique. Holmstom et al (ibid ) further related this difference as a contributory factor to the higher levels of performance observed in the elite groups he studied. Furthermore Holmstrom and Philipsson (1993) showed a positive correlation between ‘good’ gaits and a sloping shoulder. Additionally Holmstrom and Philipsson (1993) found that those horses which had a more vertical position of the scapula and a straighter shoulder joint suffered more concussion and are, therefore, at a greater risk of developing lameness. This study investigated the relationship between shoulder angle and performance within three groups of event horses.
Through the looking glass: the effect of participation in a participatory budget on citizens’ populist attitudes
Authors: Theuwis Marie-Isabel , Kindt Rosa
Published: January 2024

Many citizens feel excluded from political decision-making, which, in their eyes, is dominated by an unresponsive political elite. Citizens with high populist attitudes perceive the world through a populist ‘lens’ and therefore yearn for more popular control and for ‘the people’ to be included in the political process. Participatory budgeting should be particularly suited to address populist demands due to the fact that it is focused on giving citizens actual influence on policy-making. However, so far, no study has examined the effect of participation in a democratic innovation on populist attitudes. This paper empirically assesses if and to what extent participation in a participatory budget affects populist attitudes, and whether citizens with high populist attitudes are affected differently than citizens with low populist attitudes. We analyze panel data on participants of four local participatory budgeting events in the Netherlands before and after participation and find that citizens with high populist attitudes decrease these attitudes significantly after participating in a participatory budget, whereas citizens with low populist attitudes are not significantly affected. Moreover, the significant difference in change between these two groups suggests that citizens with high populist attitudes go ‘through the looking glass’ and become less populist after participating in a participatory budget.
Weed communities after decades of mineral fertilization and tillage treatments in a corn–soybean rotation
Authors: Simard Marie-Josée , Ziadi Noura
Published: January 2024

Soil fertility and disturbance can potentially modify weed dynamics in a corn–soybean rotation. Knowing how added mineral fertilizers and tillage influence weed populations in the long term can provide insight into weed community shifts, which may affect future weed management requirements. The first objective of this study was to evaluate the effect of 24 to 25 years of nitrogen and phosphorus fertilization treatments and tillage (moldboard vs. no-till) on weeds (density, biomass, and composition) before and after herbicide applications in 2016/corn and 2017/soybean. The second objective was to evaluate the effect of the same treatments 6 yr after no postemergence weed management in 2022/corn. Since the last evaluation performed in 2004, weed density, richness, and diversity increased, and more annual grasses were observed under both tillage regimes. No fertilization effect was observed on any weed variables, including composition, except for increased biomass when left to grow all season after crop planting. In managed plots, the density and biomass of annuals and perennials were generally higher in no-till, and discrepancies were highest for annual grass densities before herbicide application. Weed species richness and diversity based on counts were equivalent between tillage regimes, but total biomass was distributed between more species in no-till. Higher weed densities and concurrent weed biomass, observed in no-till, reduced crop yields in 2016/soybean only. The combination of low crop diversity and low use of residual herbicides during the trial potentially led to the observed species shifts and increased weed density.
Adaptations in wild radish (Raphanus raphanistrum) flowering time, Part 2: Harvest weed seed control shortens flowering by twelve days
Authors: Somerville Gayle J. , Ashworth Michael B.
Published: January 2024

Harvest weed seed control (HWSC) is an effective technique for managing wild radish (Raphanus raphanistrum L.), a weed that retains its seed until harvest. However, earlier flowering time (leading to increased seed shedding before harvest) is a risk to HWSC effectiveness. This study investigated the effects of repeated HWSC on the evolution of R. raphanistrum flowering dates, using two methods: an adaptation of the SOMER model that included flowering genes (called SOMEF); and a mathematical calculation of the endpoints of flowering date evolution utilizing the relevant life-history equations. In weed management systems with highly effective herbicides, the additional use of HWSC predicted R. raphanistrum population extinction. Low weed numbers and rapid extinction meant that any gradual evolution in days to first flower (DFF) was insufficient to lead to HWSC evasion. In alternative management systems with less vigorous herbicide control and using HWSC, modeling predicted a maximum 2- to 3-d reduction in DFF. In contrast, mathematical calculations of the phenotypes maximizing seeds returned to the seedbank predicted an endpoint to evolution of 12-d earlier flowering, which matched field observations. However, genetic change postulated by the mathematical calculations was not hampered by a restriction to changing DFF allele frequencies. Unknown accompanying genetic changes could affect germination dates or flowering triggers.

Simulation modeling that included only flowering genes failed to predict the magnitude of an observed 12-d reduction in DFF. Differences between the 12 d observed in the field (and predicted using mathematical calculations) and the modest changes demonstrated in this field-based modeling study are postulated to be due to unaccounted evolutionary changes in R. raphanistrum.
Laboratory Hydrofractures as Analogs to Tectonic Tremors
Authors: Yuan C. , Cochard T. , Denolle M. , Gomberg J. , Wech A. , Xiao L. , Weitz D.
Published: January 2024

The fracture of Earth materials occurs over a wide range of time and length scales. Physical conditions, particularly the stress field and Earth material properties, may condition rupture in a specific fracture regime. In nature, fast and slow fractures occur concurrently: tectonic tremor events are fast enough to emit seismic waves and frequently accompany slow earthquakes, which are too slow to emit seismic waves and are referred to as aseismic slip events. In this study, we generate simultaneous seismic and aseismic processes in a laboratory setting by driving a penny‐shaped crack in a transparent sample with pressurized fluid. We leverage synchronized high‐speed imaging and high‐frequency acoustic emission (AE) sensing to visualize and listen to the various sequences of propagation (breaks) and arrest (sticks) of a fracture undergoing stick‐break instabilities. Slow radial crack propagation is facilitated by fast tangential fractures. Fluid viscosity and pressure regulate the fracture dynamics of slow and fast events, and control the inter‐event time and the energy released during individual fast events. These AE signals share behaviors with observations of episodic tremors in Cascadia, United States; these include: (a) bursty or intermittent slow propagation, and (b) nearly linear scaling of radiated energy with area. Our laboratory experiments provide a plausible model of tectonic tremor as an indicative of hydraulic fracturing facilitating shear slip during slow earthquakes.
A Systems Analysis of Sustainability Impacts of Agricultural Policies in India
Authors: Maji P. , Selin N. E.
Published: January 2024

We apply a systems framework for analyzing the overall sustainability impacts of interventions to a case of the rice‐wheat cropping system of Punjab (India), where agricultural practices lead to air pollution‐related health impacts, over‐exploitation of groundwater, over‐use of fertilizers and reduced local crop diversity. We use this case to quantify how varying degrees of change in interventions result in sustainability impacts using an inclusive wealth‐based approach. We show that either improving the existing cropping system or inducing fundamental changes in the cropping system, can lead to substantial and wide‐ranging sustainability benefits. We also show that interventions that improve human health show the largest quantitative benefit due to the assumed high marginal value of human life. Accurate localized estimates of marginal values of stocks are needed for estimating overall sustainability impacts.
Roles of Continental Mid‐Lithosphere Discontinuity in the Craton Instability Under Variable Tectonic Regimes
Authors: Fu Hui‐Ying , Li Zhong‐Hai
Published: January 2024

The continental mid‐lithosphere discontinuity (MLD) is widely detected within cratons, with the dominant depth range of 70–100 km and a significant reduction of shear‐wave velocity of 2%–12%. However, the formation mechanism and corresponding strength of the MLD are widely debated, which may strongly affect the roles of MLD in craton evolution. The comparisons among variable mechanisms indicate that the strength of the MLD varies from the relatively high viscosity of wet olivine to the rather low viscosity of antigorite. Thus, systematic numerical modeling has been conducted with the MLD of contrasting strengths, that is, the wet olivine‐induced MLD or antigorite‐induced MLD, to investigate the roles of MLD in the craton instability under variable tectonic regimes (stable, extension, compression, mantle flow traction, or mantle plume). The models show that the cratonic lithosphere with wet olivine‐induced MLD maintains its stability under all the tectonic regimes. In contrast, the antigorite‐induced MLD with lowest viscosity could significantly promote the decoupling of lithosphere, and facilitate the lithospheric deformation. However, lithospheric delamination only occurs with the rather weak MLD interacting with the sub‐plate asthenosphere upwelling during craton extension or mantle plume activity. The sufficient amount of melts is essential for this process, which requires a large amount of extension or a mantle plume with rather high temperature anomaly and large size. Therefore, craton destruction is still difficult, and requires additional strict conditions. This may explain the general stability of most cratons with widespread MLDs.
Determinants of Field‐Saturated Soil Hydraulic Conductivity Across Sub‐Saharan Africa: Texture and Beyond
Authors: Bargués‐Tobella Aida , Winowiecki Leigh Ann , Sheil Douglas , Vågen Tor‐Gunnar
Published: January 2024

Soil infiltration is critical for water security and related ecosystem services. This infiltration, the ability of soils to absorb water at their surface, is controlled by the soil hydraulic conductivity. Despite recent efforts in assembling measurements of soil hydraulic conductivity, global databases and derived pedotransfer functions lack coverage in the tropics. Here, we present soil infiltration measurements and other indicators of soil and land health collected systematically in 3,573 plots from 83 100 km2 sites across 19 countries in sub‐Saharan Africa. We use these data to (a) determine field‐saturated hydraulic conductivity (K
fs) and (b) explore which variables best predict variation in K
fs. Our results show that sand content, soil organic carbon (SOC), and woody cover had a positive relationship with K
fs, whereas grazing intensity and soil pH had a negative relationship. Our findings highlight that, despite soil texture being important, structure also plays a critical role. These results indicate considerable potential to improve soil hydrological functioning through management and restoration practices that target soil structure. Enhancing SOC content, limiting animal stocking, promoting trees, shrubs, and other vegetation cover, and preventing soil erosion can increase K
fs and improve water security. This data set can contribute to improving Earth system and land surface models for applications in Africa.
Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia
Authors: Dam Merete , Centanni Maddalena , Friberg Lena E. , Centanni Daniel , Karlsson Mats O. , Stensig Lynggaard Line , Johannsdottir Inga Maria , Wik Hilde Skuterud , Malmros Johan , Vaitkeviciene Goda Elizabeta , Griskevicius Laimonas , Hallböök Helene , Jónsson Ólafur Gísli , Overgaard Ulrik , Schmiegelow Kjeld , Hansen Stefan Nygaard , Heyman Mats , Albertsen Birgitte Klug
Published: January 2024

Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing the risk of relapse. Hypersensitivity reactions include clinical allergies, silent inactivation, or allergy-like responses. We hypothesized that even moderate increases in asparaginase clearance are related to later inactivation. We therefore explored mandatory monitoring of asparaginase enzyme activity (AEA) in patients with ALL aged 1–45 years treated according to the ALLTogether pilot protocol in the Nordic and Baltic countries to relate mean AEA to inactivation, to build a pharmacokinetic model to better characterize the pharmacokinetics of peg-asparaginase and assess whether an increased clearance relates to subsequent inactivation. The study analyzed 1631 real-time AEA samples from 253 patients, identifying inactivation in 18.2% of the patients. This inactivation presented as mild allergy (28.3%), severe allergy (50.0%), or silent inactivation (21.7%). A pharmacokinetic transit compartment model was used to describe AEA-time profiles, revealing that 93% of patients with inactivation exhibited prior increased clearance, whereas 86% of patients without hypersensitivity maintained stable clearance throughout asparaginase treatment. These findings enable prediction of inactivation and options for either dose increments or a shift to alternative asparaginase formulations to optimize ALL treatment strategies.
Design of an automated robotic microinjection system for batch injection of zebrafish embryos and larvae
Authors: Guo Zhongyi , Ai Nana , Ge Wei , Xu Qingsong
Published: January 2024

This paper presents the design of a vision-based automated robotic microinjection system for batch injection of both zebrafish embryos and larvae. A novel visual recognition algorithm based on an automatic threshold and excessive dilatation is introduced to accurately identify the center of zebrafish embryos and larval yolks. A corresponding software system is developed using the producer-consumer model as the framework structure, and a friendly user interface is designed to allow operators to choose from a range of desired functions according to their different needs. In addition, a novel microstructural agarose device is designed and fabricated to simultaneously immobilize mixed batches of embryos and larvae. Moreover, a prototype microinjection system is fabricated by integrating hardware devices with visual algorithms. An experimental study is conducted to verify the performance of the robotic microinjection system. The results show that the reported system can accurately identify zebrafish embryos and larvae and efficiently complete batch microinjection tasks of the mixtures with an injection success rate of 92.05% in 13.88 s per sample. Compared with manual and existing microinjection systems, the proposed system demonstrates the merits of versatility, excellent efficiency, high success rate, high survival rate, and sufficient stability.
RNA processing mechanisms contribute to genome organization and stability in B cells
Authors: Miglierina Emma , Ordanoska Delfina , Le Noir Sandrine , Laffleur Brice
Published: January 2024

RNA processing includes post-transcriptional mechanisms controlling RNA quality and quantity to ensure cellular homeostasis. Noncoding (nc) RNAs that are regulated by these dynamic processes may themselves fulfill effector and/or regulatory functions, and recent studies demonstrated the critical role of RNAs in organizing both chromatin and genome architectures. Furthermore, RNAs can threaten genome integrity when accumulating as DNA:RNA hybrids, but could also facilitate DNA repair depending on the molecular context. Therefore, by qualitatively and quantitatively fine-tuning RNAs, RNA processing contributes directly or indirectly to chromatin states, genome organization, and genome stability. B lymphocytes represent a unique model to study these interconnected mechanisms as they express ncRNAs transcribed from key specific sequences before undergoing physiological genetic remodeling processes, including V(D)J recombination, somatic hypermutation, and class switch recombination. RNA processing actors ensure the regulation and degradation of these ncRNAs for efficient DNA repair and immunoglobulin gene remodeling while failure leads to B cell development alterations, aberrant DNA repair, and pathological translocations. This review highlights how RNA processing mechanisms contribute to genome architecture and stability, with emphasis on their critical roles during B cell development, enabling physiological DNA remodeling while preventing lymphomagenesis.
QL1706 (anti-PD-1 IgG4/CTLA-4 antibody) plus chemotherapy with or without bevacizumab in advanced non-small cell lung cancer: a multi-cohort, phase II study
Authors: Huang Yan , Yang Yunpeng , Zhao Yuanyuan , Zhao Hongyun , Zhou Ningning , Zhang Yaxiong , Chen Likun , Zhou Ting , Chen Gang , Wu Ting , Lu Lu , Xue Shilin , Kang Xiaoyan , Zhang Li , Fang Wenfeng
Published: January 2024

First-line chemoimmunotherapy (with or without bevacizumab) has improved outcomes in advanced non-small cell lung cancer (NSCLC). Here, this open-label, multi-cohort phase II study (NCT05329025) was done to investigate the safety and efficacy of QL1706 (a single bifunctional MabPair product against PD-1 and CTLA-4) and chemotherapy with or without bevacizumab in this population. Patients were enrolled into five different cohorts based on genotype (cohorts 1-4, epidermal growth factor receptor [EGFR] wild-type; cohort 5, EGFR-mutant and progressed on EGFR-tyrosine kinase inhibitors [TKIs]). Between June 11, 2021 and December 29, 2021, 91 patients were enrolled. Most frequent treatment-related adverse events (TRAEs) included decreased appetite (60 [65.9%]), anemia (60 [65.9%]), infusion-related reactions (48 [52.7%]), and pruritus (44 [48.4%]). Grade ≥ 3 TRAEs occurred in 30 (33.0%) patients. Twenty-seven (45%) patients with wild-type EGFR achieved partial response (PR) (objective response rate [ORR] = 45%) and had a median progression-free survival (mPFS) of 6.8 months (95% CI: 5.2-9.7). For 31 patients harboring mutated EGFR, 17 (54.8%) achieved PR (ORR = 54.8%), with an mPFS of 8.5 months (95% CI: 5.72-not evaluable). Overall, QL1706 plus chemotherapy, regardless of having bevacizumab, was generally tolerable and had promising antitumor activity for EGFR wild-type advanced NSCLC in first-line setting. Moreover, QL1706 plus chemotherapy and bevacizumab showed favorable antitumor activity for patients who had EGFR mutated NSCLC but failed in TKI therapy, demonstrating a potential for treating this population.
A phase I study of ATR inhibitor gartisertib (M4344) as a single agent and in combination with carboplatin in patients with advanced solid tumours
Authors: Burris Howard A. , Berlin Jordan , Arkenau Tobias , Cote Gregory M. , Lolkema Martijn P. , Ferrer-Playan Jordi , Kalapur Anup , Bolleddula Jayaprakasam , Locatelli Giuseppe , Goddemeier Thomas , Gounaris Ioannis , de Bono Johann
Published: January 2024

Background

Gartisertib is an oral inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a key kinase of the DNA damage response. We aimed to determine the safety and tolerability of gartisertib ± carboplatin in patients with advanced solid tumours.

Methods

This phase I open-label, multicenter, first-in-human study comprised four gartisertib cohorts: A (dose escalation [DE]; Q2W); A2 (DE; QD/BID); B1 (DE+carboplatin); and C (biomarker-selected patients).

Results

Overall, 97 patients were enroled into cohorts A (n = 42), A2 (n = 26), B1 (n = 16) and C (n = 13). The maximum tolerated dose and recommended phase II dose (RP2D) were not declared for cohorts A or B1. In cohort A2, the RP2D for gartisertib was determined as 250 mg QD. Gartisertib was generally well-tolerated; however, unexpected increased blood bilirubin in all study cohorts precluded further DE. Investigations showed that gartisertib and its metabolite M26 inhibit UGT1A1-mediated bilirubin glucuronidation in human but not dog or rat liver microsomes. Prolonged partial response (n = 1 [cohort B1]) and stable disease >6 months (n = 3) did not appear to be associated with biomarker status. Exposure generally increased dose-dependently without accumulation.

Conclusion

Gartisertib was generally well-tolerated at lower doses; however, unexpected liver toxicity prevented further DE, potentially limiting antitumour activity. Gartisertib development was subsequently discontinued.

ClinicalTrials.gov

NCT02278250.
CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma
Authors: Li Yueshuo , Yang Chenxing , Xie Longlong , Shi Feng , Tang Min , Luo Xiangjian , Liu Na , Hu Xudong , Zhu Yongwei , Bode Ann M. , Gao Qiang , Zhou Jian , Fan Jia , Li Xuejun , Cao Ya
Published: January 2024

Abnormal expression of Cylindromatosis (CYLD), a tumor suppressor molecule, plays an important role in tumor development and treatment. In this work, we found that CYLD binds to class I histone deacetylases (HDAC1 and HDAC2) through its N-terminal domain and inhibits HDAC1 activity. RNA sequencing showed that CYLD-HDAC axis regulates cellular antioxidant response via Nrf2 and its target genes. Then we revealed a mechanism that class I HDACs mediate redox abnormalities in CYLD low-expressing tumors. HDACs are central players in the DNA damage signaling. We further confirmed that CYLD regulates radiation-induced DNA damage and repair response through inhibiting class I HDACs. Furthermore, CYLD mediates nasopharyngeal carcinoma cell radiosensitivity through class I HDACs. Thus, we identified the function of the CYLD-HDAC axis in radiotherapy and blocking HDACs by Chidamide can increase the sensitivity of cancer cells and tumors to radiation therapy both in vitro and in vivo. In addition, ChIP and luciferase reporter assays revealed that CYLD could be transcriptionally regulated by zinc finger protein 202 (ZNF202). Our findings offer novel insight into the function of CYLD in tumor and uncover important roles for CYLD-HDAC axis in radiosensitivity, which provide new molecular target and therapeutic strategy for tumor radiotherapy.
Regulation of ULK1 by WTAP/IGF2BP3 axis enhances mitophagy and progression in epithelial ovarian cancer
Authors: Wang Jiao , Zheng Fei , Wang Dandan , Yang Qing
Published: January 2024

There is a pressing need for innovative therapeutic strategies for patients with epithelial ovarian cancer (EOC). Previous studies have shown that UNC-51-like kinase 1 (ULK1), a serine/threonine kinase, is crucial in regulating cellular autophagy and mitophagy across various tumor types. However, the clinical implications, biological functions, and potential mechanisms of ULK1 in EOC remain poorly understood. This study demonstrates that ULK1 expression is upregulated in EOC tissue samples and EOC cell lines, with increased ULK1 expression correlating with poor prognosis. Functionally, overexpressed ULK1 enhances the proliferation and migration abilities of EOC cells both in vitro and in vivo. Mechanistically, ULK1 was identified as an m6A target of WTAP. WTAP-mediated m6A modification of ULK1 enhanced its mRNA stability in an IGF2BP3-dependent manner, leading to elevated ULK1 expression and enhanced mitophagy in EOC. In summary, our research reveals that the WTAP/IGF2BP3-ULK1 axis significantly influences protective mitophagy in EOC, contributing to its progression. Therefore, the regulatory mechanisms and biological function of ULK1 identify it as a potential molecular target for therapeutic intervention in EOC.
Carfilzomib relieves pancreatitis-initiated pancreatic ductal adenocarcinoma by inhibiting high-temperature requirement protein A1
Authors: Guo Fangyue , Tao Xufeng , Wu Yu , Dong Deshi , Zhu Yanna , Shang Dong , Xiang Hong
Published: January 2024

Pancreatitis is a crucial risk factor for pancreatic ductal adenocarcinoma (PDAC), and our previous study had proved high-temperature requirement protein A1 (HTRA1) exacerbates pancreatitis insult; however, the function and mechanism of HTRA1 in pancreatitis-initiated PDAC is still unclear. In the present paper, we clarified the expression of HTRA1 in PDAC using bioinformatics and immunohistochemistry of tissue chip, and found that HTRA1 is significantly upregulated in PDAC. Moreover, the proliferation, migration, invasion and adhesion of PANC-1 and SW1990 cells were promoted by overexpression of HTRA1, but inhibited by knockdown of HTRA1. Meanwhile, we found that HTRA1 arrested PANC-1 and SW1990 cells at G2/M phase. Mechanistically, HTRA1 interacted with CDK1 protein, and CDK1 inhibitor reversed the malignant phenotype of PANC-1 and pancreatitis-initiated PDAC activated by HTRA1 overexpression. Finally, we discovered a small molecule drug that can inhibit HTRA1, carfilzomib, which has been proven to inhibit the biological functions of tumor cells in vitro and intercept the progression of pancreatitis-initiated PDAC in vivo. In conclusion, the activation of HTRA1-CDK1 pathway promotes the malignant phenotype of tumor cells by blocking the cell cycle at the G2/M phase, thereby accelerating pancreatitis-initiated PDAC. Carfilzomib is an innovative candidate drug that can inhibit pancreatitis-initiated PDAC through targeted inhibition of HTRA1.
ARK5 enhances cell survival associated with mitochondrial morphological dynamics from fusion to fission in human multiple myeloma cells
Authors: Karnan Sivasundaram , Hanamura Ichiro , Ota Akinobu , Vu Lam Quang , Uchino Kaori , Horio Tomohiro , Murakami Satsuki , Mizuno Shohei , Rahman Md Lutfur , Wahiduzzaman Md , Hasan Muhammad Nazmul , Biswas Mrityunjoy , Hyodo Toshinori , Ito Hideaki , Suzuki Atsushi , Konishi Hiroyuki , Tsuzuki Shinobu , Hosokawa Yoshitaka , Takami Akiyoshi
Published: January 2024

5′ adenosine monophosphate–activated protein kinase–related kinase 5 (ARK5) is involved in mitochondrial ATP production and associated with poor prognosis of multiple myeloma (MM). However, the molecular mechanisms of ARK5 in MM remain largely unknown. This study examined the pathogenic role of ARK5 in mitochondria by using genetically modified isogenic cell clones with or without ARK5 in human myeloma cell lines, KMS-11 and Sachi, which overexpress ARK5. The biallelic knockout of ARK5 (ARK5-KO) inhibited cell proliferation, colony formation, and migration with increased apoptosis. Mitochondrial fusion was enhanced in ARK5-KO cells, unlike in ARK5 wild-type (ARK5-WT) cells, which exhibited increased mitochondrial fission. Furthermore, ARK5-KO cells demonstrated a lower phosphorylated dynamin–related protein 1 at serine 616, higher protein expression of mitofusin-1 (MFN1) and MFN2, optic atrophy 1 with a lower level of ATP, and higher levels of lactate and reactive oxygen species than ARK5-WT cells. Our findings suggest that ARK5-enhanced myeloma cells can survive associated mitochondrial fission and activity. This study first revealed the relationship between ARK5 and mitochondrial morphological dynamics. Thus, our outcomes show novel aspects of mitochondrial biology of ARK5, which can afford a more advanced treatment approach for unfavorable MM expressing ARK5.
Identification of oleic acid as an endogenous ligand of GPR3
Authors: Xiong Yangjie , Xu Zhenmei , Li Xinzhi , Wang Yuqin , Zhao Jing , Wang Na , Duan Yaning , Xia Ruixue , Han Zhengbin , Qian Yu , Liang Jiale , Zhang Anqi , Guo Changyou , Inoue Asuka , Xia Yu , Chen Zheng , He Yuanzheng
Published: January 2024

Although GPR3 plays pivotal roles in both the nervous system and metabolic processes, such as cold-induced thermogenesis, its endogenous ligand remains elusive. Here, by combining structural approach (including cryo-electron microscopy), mass spectrometry analysis, and functional studies, we identify oleic acid (OA) as an endogenous ligand of GPR3. Our study reveals a hydrophobic tunnel within GPR3 that connects the extracellular side of the receptor to the middle of plasma membrane, enabling fatty acids to readily engage the receptor. Functional studies demonstrate that OA triggers downstream Gs signaling, whereas lysophospholipids fail to activate the receptor. Moreover, our research reveals that cold stimulation induces the secretion of OA in mice, subsequently activating Gs/cAMP/PKA signaling in brown adipose tissue. Notably, brown adipose tissues from Gpr3 knockout mice do not respond to OA during cold stimulation, reinforcing the significance of GPR3 in this process. Finally, we propose a “born to be activated and cold to enhance” model for GPR3 activation. Our study provides a starting framework for the understanding of GPR3 signaling in cold-stimulated thermogenesis.
Highly loaded bimetallic iron-cobalt catalysts for hydrogen release from ammonia
Authors: Chen Shilong , Jelic Jelena , Rein Denise , Najafishirtari Sharif , Schmidt Franz-Philipp , Girgsdies Frank , Kang Liqun , Wandzilak Aleksandra , Rabe Anna , Doronkin Dmitry E. , Wang Jihao , Friedel Ortega Klaus , DeBeer Serena , Grunwaldt Jan-Dierk , Schlögl Robert , Lunkenbein Thomas , Studt Felix , Behrens Malte
Published: January 2024

Ammonia is a storage molecule for hydrogen, which can be released by catalytic decomposition. Inexpensive iron catalysts suffer from a low activity due to a too strong iron-nitrogen binding energy compared to more active metals such as ruthenium. Here, we show that this limitation can be overcome by combining iron with cobalt resulting in a Fe-Co bimetallic catalyst. Theoretical calculations confirm a lower metal-nitrogen binding energy for the bimetallic catalyst resulting in higher activity. Operando spectroscopy reveals that the role of cobalt in the bimetallic catalyst is to suppress the bulk-nitridation of iron and to stabilize this active state. Such catalysts are obtained from Mg(Fe,Co)2O4 spinel pre-catalysts with variable Fe:Co ratios by facile co-precipitation, calcination and reduction. The resulting Fe-Co/MgO catalysts, characterized by an extraordinary high metal loading reaching 74 wt.%, combine the advantages of a ruthenium-like electronic structure with a bulk catalyst-like microstructure typical for base metal catalysts.
Dorsal hippocampus to nucleus accumbens projections drive reinforcement via activation of accumbal dynorphin neurons
Authors: Ibrahim Khairunisa Mohamad , Massaly Nicolas , Yoon Hye-Jean , Sandoval Rossana , Widman Allie J. , Heuermann Robert J. , Williams Sidney , Post William , Pathiranage Sulan , Lintz Tania , Zec Azra , Park Ashley , Yu Waylin , Kash Thomas L. , Gereau Robert W. , Morón Jose A.
Published: January 2024

The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for episodic, spatial, and associative memory, and has been shown to be necessary for context- and cue-associated reward behaviors. The nucleus accumbens (NAc), a central structure in the mesolimbic reward pathway, integrates the salience of aversive and rewarding stimuli. Despite extensive research on dHPC→NAc direct projections, their sufficiency in driving reinforcement and reward-related behavior remains to be determined. Our study establishes that activating excitatory neurons in the dHPC is sufficient to induce reinforcing behaviors through its direct projections to the dorso-medial subregion of the NAc shell (dmNAcSh). Notably, dynorphin-containing neurons specifically contribute to dHPC-driven reinforcing behavior, even though both dmNAcSh dynorphin- and enkephalin-containing neurons are activated with dHPC stimulation. Our findings unveil a pathway governing reinforcement, advancing our understanding of the hippocampal circuity’s role in reward-seeking behaviors.
Harnessing synthetic active particles for physical reservoir computing
Authors: Wang Xiangzun , Cichos Frank
Published: January 2024

The processing of information is an indispensable property of living systems realized by networks of active processes with enormous complexity. They have inspired many variants of modern machine learning, one of them being reservoir computing, in which stimulating a network of nodes with fading memory enables computations and complex predictions. Reservoirs are implemented on computer hardware, but also on unconventional physical substrates such as mechanical oscillators, spins, or bacteria often summarized as physical reservoir computing. Here we demonstrate physical reservoir computing with a synthetic active microparticle system that self-organizes from an active and passive component into inherently noisy nonlinear dynamical units. The self-organization and dynamical response of the unit are the results of a delayed propulsion of the microswimmer to a passive target. A reservoir of such units with a self-coupling via the delayed response can perform predictive tasks despite the strong noise resulting from the Brownian motion of the microswimmers. To achieve efficient noise suppression, we introduce a special architecture that uses historical reservoir states for output. Our results pave the way for the study of information processing in synthetic self-organized active particle systems.
Supercurrent mediated by helical edge modes in bilayer graphene
Authors: Rout Prasanna , Papadopoulos Nikos , Peñaranda Fernando , Watanabe Kenji , Taniguchi Takashi , Prada Elsa , San-Jose Pablo , Goswami Srijit
Published: January 2024

Bilayer graphene encapsulated in tungsten diselenide can host a weak topological phase with pairs of helical edge states. The electrical tunability of this phase makes it an ideal platform to investigate unique topological effects at zero magnetic field, such as topological superconductivity. Here we couple the helical edges of such a heterostructure to a superconductor. The inversion of the bulk gap accompanied by helical states near zero displacement field leads to the suppression of the critical current in a Josephson geometry. Using superconducting quantum interferometry we observe an even-odd effect in the Fraunhofer interference pattern within the inverted gap phase. We show theoretically that this effect is a direct consequence of the emergence of helical modes that connect the two edges of the sample. The absence of such an effect at high displacement field, as well as in bare bilayer graphene junctions, supports this interpretation and demonstrates the topological nature of the inverted gap.
Risk of introduction and establishment of alien vertebrate species in transboundary neighboring areas
Authors: Zhang Qing , Wang Yanping , Liu Xuan
Published: January 2024

Cross-border neighboring areas could be particularly vulnerable to biological invasions due to short geographic distances and frequent interactions, although the invasion risk remains unevaluated worldwide. Here, based on global datasets of distributions of established alien vertebrates as well as vectors of introduction and establishment, we show that more than one-third of the world’s transboundary neighboring areas are facing high invasion risk of alien vertebrates, especially in Europe, North America, South Asia, and Southeast Asia. The most important predictors of high introduction and establishment risk are bilateral trade, habitat disturbance and the richness of established alien vertebrates. Interestingly, we found that border fences may have limited effects in reducing the risk, as only 7.9% of border fences spatially overlap with hotspots of biological invasion even in the Eurasia areas (13.7% overlap) where physical border barriers are mainly located. We therefore recommend the implementation of immediate and proactive prevention and control measures to cope with cross-border invasions in response to continued globalization.
Effect of solid-electrolyte pellet density on failure of solid-state batteries
Authors: Diallo Mouhamad S. , Shi Tan , Zhang Yaqian , Peng Xinxing , Shozib Imtiaz , Wang Yan , Miara Lincoln J. , Scott Mary C. , Tu Qingsong Howard , Ceder Gerbrand
Published: January 2024

Despite the potentially higher energy density and improved safety of solid-state batteries (SSBs) relative to Li-ion batteries, failure due to Li-filament penetration of the solid electrolyte and subsequent short circuit remains a critical issue. Herein, we show that Li-filament growth is suppressed in solid-electrolyte pellets with a relative density beyond ~95%. Below this threshold value, however, the battery shorts more easily as the density increases due to faster Li-filament growth within the percolating pores in the pellet. The microstructural properties (e.g., pore size, connectivity, porosity, and tortuosity) of $$75\%{{{{{\rm{L}}}}}}{{{{{{\rm{i}}}}}}}_{2}{{{{{\rm{S}}}}}}-25\%{{{{{{\rm{P}}}}}}}_{2}{{{{{{\rm{S}}}}}}}_{5}$$
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with various relative densities are quantified using focused ion beam–scanning electron microscopy tomography and permeability tests. Furthermore, modeling results provide details on the Li-filament growth inside pores ranging from 0.2 to 2 μm in size. Our findings improve the understanding of the failure modes of SSBs and provide guidelines for the design of dendrite-free SSBs.
Catalytic carbon–carbon bond cleavage in lignin via manganese–zirconium-mediated autoxidation
Authors: Palumbo Chad T. , Gu Nina X. , Bleem Alissa C. , Sullivan Kevin P. , Katahira Rui , Stanley Lisa M. , Kenny Jacob K. , Ingraham Morgan A. , Ramirez Kelsey J. , Haugen Stefan J. , Amendola Caroline R. , Stahl Shannon S. , Beckham Gregg T.
Published: January 2024

Efforts to produce aromatic monomers through catalytic lignin depolymerization have historically focused on aryl–ether bond cleavage. A large fraction of aromatic monomers in lignin, however, are linked by various carbon–carbon (C–C) bonds that are more challenging to cleave and limit the yields of aromatic monomers from lignin depolymerization. Here, we report a catalytic autoxidation method to cleave C–C bonds in lignin-derived dimers and oligomers from pine and poplar. The method uses manganese and zirconium salts as catalysts in acetic acid and produces aromatic carboxylic acids as primary products. The mixtures of the oxygenated monomers are efficiently converted to cis,cis-muconic acid in an engineered strain of Pseudomonas putida KT2440 that conducts aromatic O-demethylation reactions at the 4-position. This work demonstrates that autoxidation of lignin with Mn and Zr offers a catalytic strategy to increase the yield of valuable aromatic monomers from lignin.
Identification of a highly conserved neutralizing epitope within the RBD region of diverse SARS-CoV-2 variants
Authors: Wang Yanqun , Yan An , Song Deyong , Duan Maoqin , Dong Chuangchuang , Chen Jiantao , Jiang Zihe , Gao Yuanzhu , Rao Muding , Feng Jianxia , Zhang Zhaoyong , Qi Ruxi , Ma Xiaomin , Liu Hong , Yu Beibei , Wang Qiaoping , Zong Mengqi , Jiao Jie , Xing Pingping , Pan Rongrong , Li Dan , Xiao Juxue , Sun Junbo , Li Ying , Zhang Linfeng , Shen Zhenduo , Sun Baiping , Zhao Yanyan , Zhang Lu , Dai Jun , Zhao Jingxian , Wang Lan , Dou Changlin , Liu Zheng , Zhao Jincun
Published: January 2024

The constant emergence of SARS-CoV-2 variants continues to impair the efficacy of existing neutralizing antibodies, especially XBB.1.5 and EG.5, which showed exceptional immune evasion properties. Here, we identify a highly conserved neutralizing epitope targeted by a broad-spectrum neutralizing antibody BA7535, which demonstrates high neutralization potency against not only previous variants, such as Alpha, Beta, Gamma, Delta and Omicron BA.1-BA.5, but also more recently emerged Omicron subvariants, including BF.7, CH.1.1, XBB.1, XBB.1.5, XBB.1.9.1, EG.5. Structural analysis of the Omicron Spike trimer with BA7535-Fab using cryo-EM indicates that BA7535 recognizes a highly conserved cryptic receptor-binding domain (RBD) epitope, avoiding most of the mutational hot spots in RBD. Furthermore, structural simulation based on the interaction of BA7535-Fab/RBD complexes dissects the broadly neutralizing effect of BA7535 against latest variants. Therapeutic and prophylactic treatment with BA7535 alone or in combination with BA7208 protected female mice from the circulating Omicron BA.5 and XBB.1 variant infection, suggesting the highly conserved neutralizing epitope serves as a potential target for developing highly potent therapeutic antibodies and vaccines.
The nature of carotenoid S* state and its role in the nonphotochemical quenching of plants
Authors: Accomasso Davide , Londi Giacomo , Cupellini Lorenzo , Mennucci Benedetta
Published: January 2024

In plants, light-harvesting complexes serve as antennas to collect and transfer the absorbed energy to reaction centers, but also regulate energy transport by dissipating the excitation energy of chlorophylls. This process, known as nonphotochemical quenching, seems to be activated by conformational changes within the light-harvesting complex, but the quenching mechanisms remain elusive. Recent spectroscopic measurements suggest the carotenoid S* dark state as the quencher of chlorophylls’ excitation. By investigating lutein embedded in different conformations of CP29 (a minor antenna in plants) via nonadiabatic excited state dynamics simulations, we reveal that different conformations of the complex differently stabilize the lutein s-trans conformer with respect to the dominant s-cis one. We show that the s-trans conformer presents the spectroscopic signatures of the S* state and rationalize its ability to accept energy from the closest excited chlorophylls, providing thus a relationship between the complex’s conformation and the nonphotochemical quenching.
Sustainable biomimetic solar distillation with edge crystallization for passive salt collection and zero brine discharge
Authors: Abdelsalam Mohamed A. , Sajjad Muhammad , Raza Aikifa , AlMarzooqi Faisal , Zhang TieJun
Published: January 2024

The urgency of addressing water scarcity and exponential population rise has necessitated the use of sustainable desalination for clean water production, while conventional thermal desalination processes consume fossil fuel with brine rejection. As a promising solution to sustainable solar thermal distillation, we report a scalable mangrove-mimicked device for direct solar vapor generation and passive salt collection without brine discharge. Capillarity-driven salty water supply and continuous vapor generation are ensured by anti-corrosion porous wicking stem and multi-layer leaves, which are made of low-cost superhydrophilic nanostructured titanium meshes. Precipitated salt at the leaf edge forms porous patch during daytime evaporation and get peeled by gravity during night when saline water rewets the leaves, and these salt patches can enhance vaporization by 1.6 times as indicated by our findings. The proposed solar vapor generator achieves a stable photothermal efficiency around 94% under one sun when treating synthetic seawater with a salinity of 3.5 wt.%. Under outdoor conditions, it can produce 2.2 L m−2of freshwater per day from real seawater, which is sufficient for individual drinking needs. This kind of biomimetic solar distillation devices have demonstrated great capability in clean water production and passive salt collection to tackle global water and environmental challenges.