bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroprotective effects of maternal melatonin administration in early-onset placental insufficiency and fetal growth restriction
Authors: Malhotra Atul , Rocha Anna K. A. A. , Yawno Tamara , Sutherland Amy E. , Allison Beth J. , Nitsos Ilias , Pham Yen , Jenkin Graham , Castillo-Melendez Margie , Miller Suzanne L. 
Published: January 2024

Abstract
Background
Early-onset fetal growth restriction (FGR) is associated with adverse outcomes. We hypothesised that maternal melatonin administration will improve fetal brain structure in FGR.

Methods
Surgery was performed on twin-bearing ewes at 88 days (0.6 gestation), and FGR induced in one twin via single umbilical artery ligation. Melatonin was administered intravenously (6 mg/day) to a group of ewes commencing on day of surgery until 127 days (0.85 gestation), when the ewe/fetuses were euthanized, and fetal brains collected.

Results
Study groups were control (n = 5), FGR (n = 5), control+melatonin (control+MLT; n = 6) and FGR+melatonin (FGR + MLT; n = 6). Melatonin administration did not significantly alter fetal body or brain weights. Myelin (CNPase+) fibre density was reduced in FGR vs. control animals in most brain regions examined (p < 0.05) and melatonin treatment restored CNPase fibre density. Similar but less pronounced effect was seen with mature myelin (MBP+) staining. Significant differences in activated microglia (Iba-1) activity were seen between lamb groups (MLT mitigated FGR effect) in periventricular white matter, subventricular zone and external capsule (p < 0.05). Similar effects were seen in astrogliosis (GFAP) in intragyral white matter and cortex.

Conclusions
Maternal melatonin administration in early onset FGR led to improved myelination of white matter brain regions, possibly mediated by decreased inflammation.

Impact

Maternal melatonin administration might lead to neuroprotection in the growth-restricted fetus, possibly via dampening neuroinflammation and enhancing myelination.

This preclinical study adds to the body of work on this topic, and informs clinical translation.

Neuroprotection likely to improve long-term outcomes of this vulnerable infant group.
Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis
Authors: Zhang Yun , Du Lijun , Wang Chenxi , Jiang Zhangsheng , Duan Qingchi , Li Yiping , Xie Zhijun , He Zhixing , Sun Yi , Huang Lin , Lu Liwei , Wen Chengping 
Published: January 2024

AbstractSystemic lupus erythematosus (SLE), a severe autoimmune disorder, is characterized by systemic inflammatory response, autoantibody accumulation and damage to organs. The dysregulation of double-negative (DN) T cells is considered as a crucial commander during SLE. Neddylation, a significant type of protein post-translational modification (PTM), has been well-proved to regulate T cell-mediated immune response. However, the function of neddylation in SLE is still unknown. Here, we reported that neddylation inactivation with MLN4924, a specific inhibitor of NEDD8-activating enzyme E1 (NAE1), or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development. Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells, contributing to the apoptosis of the accumulated DN T cells in lupus mice. Then double knockout (KO) lupus-prone mice (Ube2m-/-Bim-/-lpr) were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression. Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression. Clinically, we also found that in SLE patients, the proportion of DN T cells was raised and their apoptosis was reduced. Moreover, compared to healthy groups, SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels. Meantime, the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients. Altogether, our findings provide the direct evidence about the function of neddylation during lupus, suggesting a promising therapeutic approach for this disease.
Chimeric antigen receptor-based natural killer cell immunotherapy in cancer: from bench to bedside
Authors: Zhang Beibei , Yang Mengzhe , Zhang Weiming , Liu Ning , Wang Daogang , Jing Liangfang , Xu Ning , Yang Na , Ren Tao 
Published: January 2024

AbstractImmunotherapy has rapidly evolved in the past decades in the battle against cancer. Chimeric antigen receptor (CAR)-engineered T cells have demonstrated significant success in certain hematologic malignancies, although they still face certain limitations, including high costs and toxic effects. Natural killer cells (NK cells), as a vital component of the immune system, serve as the “first responders” in the context of cancer development. In this literature review, we provide an updated understanding of NK cell development, functions, and their applications in disease therapy. Furthermore, we explore the rationale for utilizing engineered NK cell therapies, such as CAR-NK cells, and discuss the differences between CAR-T and CAR-NK cells. We also provide insights into the key elements and strategies involved in CAR design for engineered NK cells. In addition, we highlight the challenges currently encountered and discuss the future directions in NK cell research and utilization, including pre-clinical investigations and ongoing clinical trials. Based on the outstanding antitumor potential of NK cells, it is highly likely that they will lead to groundbreaking advancements in cancer treatment in the future.
Cell-free chromatin particles released from dying cells inflict mitochondrial damage and ROS production in living cells
Authors: Raghuram Gorantla V. , Tripathy Bhabesh Kumar , Avadhani Kartikeya , Shabrish Snehal , Khare Naveen Kumar , Lopes Relestina , Pal Kavita , Mittra Indraneel 
Published: January 2024

AbstractMitochondrial damage and the resultant oxidative stress are associated with neurodegenerative diseases, ageing, and cancer. However, the triggers of mitochondrial damage remain unclear. We previously reported that cell-free chromatin particles (cfChPs) released from the billions of cells that die in the body every day can readily enter healthy cells and damage their DNA. Here, we show that cfChPs isolated from the sera of healthy individuals, when applied to NIH3T3 mouse fibroblast cells, cause physical damage to mitochondrial DNA (mtDNA). cfChPs also induce ultrastructural changes, increase mitochondrial mass, alter mitochondrial shape, upregulate mitochondrial outer membrane protein translocase of the outer membrane 20, and change mitochondrial membrane potential. Furthermore, a marked increase was observed in mitochondrial superoxide (ROS) production, as detected by MitoSOX Red, and intracellular superoxide dismutase-1 activation. ROS production was also activated when a conditioned medium containing cfChPs released from hypoxia-induced dying NIH3T3 cells was applied to healthy NIH3T3 cells. ROS activation was significantly reduced when the conditioned medium was pre-treated with three different cfChP-deactivating agents: anti-histone antibody-complexed nanoparticles, DNase I, and the novel pro-oxidant combination of the nutraceuticals resveratrol and copper. Given that 1 × 109–1 × 1012 cells die in the body every day, we hypothesise that cfChPs from dying cells are the major physiological triggers for mtDNA damage and ROS production. Deactivation of cfChPs may provide a novel therapeutic approach to retard ageing and associated degenerative conditions linked to oxidative stress.
LINC complex protein nesprin-2 has pro-apoptotic activity via Bcl-2 family proteins
Authors: Lindenboim Liora , Zohar Hila , Gundersen Gregg G. , Worman Howard J. , Stein Reuven 
Published: January 2024

AbstractThe apoptotic intrinsic pathway is initiated by perforation of the mitochondrial outer membrane by the effector pro-apoptotic proteins of the Bcl-2 family, Bax and Bak. Bax and Bak need to be activated, a process facilitated by the action of BH3-only pro-apoptotic members of the Bcl-2 family. The latter either directly activates the effector proteins or antagonizes the action of pro-survival Bcl-2 family members such as Bcl-xL. The nuclear envelope is a known target of the apoptotic machinery; however, it may also act as mediator of apoptosis. We showed previously that the nuclear envelope protein nesprin-2, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex, can bind to Bax in close proximity to the mitochondria and that the binding increases in apoptotic cells. We now show that depleting nesprin-2 inhibits the apoptotic mitochondrial pathway as measured by Bax and Bak activation and cytochrome c release. This survival effect was Bcl-xL-dependent. Nesprin-2 depletion also inhibited spontaneous exposure of the N-terminus of Bak in cells lacking Bcl-xL and increased the presence of Bcl-xL and Bax in the mitochondria. These results indicate that nesprin-2 promotes Bak activation and regulates mitochondrial translocation/retrotranslocation of Bcl-2 family proteins. Our findings demonstrate a new apoptotic pathway whereby the nuclear envelope, via nesprin-2, regulates apoptosis.
α-Ketoglutarate supplementation and NAD+ modulation enhance metabolic rewiring and radiosensitization in SLC25A1 inhibited cancer cells
Authors: Xiang Kexu , Kunin Mikhail , Larafa Safa , Busch Maike , Dünker Nicole , Jendrossek Verena , Matschke Johann 
Published: January 2024

AbstractMetabolic rewiring is the result of the increasing demands and proliferation of cancer cells, leading to changes in the biological activities and responses to treatment of cancer cells. The mitochondrial citrate transport protein SLC25A1 is involved in metabolic reprogramming offering a strategy to induce metabolic bottlenecks relevant to radiosensitization through the accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) upon SLC25A1 inhibition (SLC25A1i). Previous studies have revealed the comparative effects of SLC25A1i or cell-permeable D-2HG (octyl-D-2HG) treatments on DNA damage induction and repair, as well as on energy metabolism and cellular function, which are crucial for the long-term survival of irradiated cells. Here, α-ketoglutarate (αKG), the precursor of D-2HG, potentiated the effects observed upon SLC25A1i on DNA damage repair, cell function and long-term survival in vitro and in vivo, rendering NCI-H460 cancer cells more vulnerable to ionizing radiation. However, αKG treatment alone had little effect on these phenotypes. In addition, supplementation with nicotinamide (NAM), a precursor of NAD (including NAD+ and NADH), counteracted the effects of SLC25A1i or the combination of SLC25A1i with αKG, highlighting a potential importance of the NAD+/NADH balance on cellular activities relevant to the survival of irradiated cancer cells upon SLC25A1i. Furthermore, inhibition of histone lysine demethylases (KDMs), as a major factor affected upon SLC25A1i, by JIB04 treatment alone or in combination with αKG supplementation phenocopied the broad effects on mitochondrial and cellular function induced by SLC25A1i. Taken together, αKG supplementation potentiated the effects on cellular processes observed upon SLC25A1i and increased the cellular demand for NAD to rebalance the cellular state and ensure survival after irradiation. Future studies will elucidate the underlying metabolic reprogramming induced by SLC25A1i and provide novel therapeutic strategies for cancer treatment.
Predictive Minisci late stage functionalization with transfer learning
Authors: King-Smith Emma , Faber Felix A. , Reilly Usa , Sinitskiy Anton V. , Yang Qingyi , Liu Bo , Hyek Dennis , Lee Alpha A. 
Published: January 2024

AbstractStructural diversification of lead molecules is a key component of drug discovery to explore chemical space. Late-stage functionalizations (LSFs) are versatile methodologies capable of installing functional handles on richly decorated intermediates to deliver numerous diverse products in a single reaction. Predicting the regioselectivity of LSF is still an open challenge in the field. Numerous efforts from chemoinformatics and machine learning (ML) groups have made strides in this area. However, it is arduous to isolate and characterize the multitude of LSF products generated, limiting available data and hindering pure ML approaches. We report the development of an approach that combines a message passing neural network and 13C NMR-based transfer learning to predict the atom-wise probabilities of functionalization for Minisci and P450-based functionalizations. We validated our model both retrospectively and with a series of prospective experiments, showing that it accurately predicts the outcomes of Minisci-type and P450 transformations and outperforms the well-established Fukui-based reactivity indices and other machine learning reactivity-based algorithms.
Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity
Authors: Hall Liam G. , Czeczor Juliane K. , Connor Timothy , Botella Javier , De Jong Kirstie A. , Renton Mark C. , Genders Amanda J. , Venardos Kylie , Martin Sheree D. , Bond Simon T. , Aston-Mourney Kathryn , Howlett Kirsten F. , Campbell James A. , Collier Greg R. , Walder Ken R. , McKenzie Matthew , Ziemann Mark , McGee Sean L. 
Published: January 2024

AbstractThere are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer’s disease. The role of amyloid beta 42 (Aβ42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aβ42, which is increased from adipose tissue of male mice with obesity and is associated with higher plasma Aβ42. Increasing circulating Aβ42 levels in male mice without obesity has no effect on systemic glucose homeostasis but has obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. The closely related Aβ40 isoform does not have these same effects on the heart. Administration of an Aβ-neutralising antibody prevents obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Aβ-neutralising antibody administration in established obesity prevents further deterioration of cardiac function. Multi-contrast transcriptomic analyses reveal that Aβ42 impacts pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aβ42 inhibits mitochondrial complex I. These data reveal a role for systemic Aβ42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer’s disease could be effective in combating obesity-induced heart failure.
Encoding of multi-modal emotional information via personalized skin-integrated wireless facial interface
Authors: Lee Jin Pyo , Jang Hanhyeok , Jang Yeonwoo , Song Hyeonseo , Lee Suwoo , Lee Pooi See , Kim Jiyun 
Published: January 2024

AbstractHuman affects such as emotions, moods, feelings are increasingly being considered as key parameter to enhance the interaction of human with diverse machines and systems. However, their intrinsically abstract and ambiguous nature make it challenging to accurately extract and exploit the emotional information. Here, we develop a multi-modal human emotion recognition system which can efficiently utilize comprehensive emotional information by combining verbal and non-verbal expression data. This system is composed of personalized skin-integrated facial interface (PSiFI) system that is self-powered, facile, stretchable, transparent, featuring a first bidirectional triboelectric strain and vibration sensor enabling us to sense and combine the verbal and non-verbal expression data for the first time. It is fully integrated with a data processing circuit for wireless data transfer allowing real-time emotion recognition to be performed. With the help of machine learning, various human emotion recognition tasks are done accurately in real time even while wearing mask and demonstrated digital concierge application in VR environment.
Unified metal-free intermolecular Heck-type sulfonylation, cyanation, amination, amidation of alkenes by thianthrenation
Authors: Liu Ming-Shang , Du Hai-Wu , Meng Huan , Xie Ying , Shu Wei 
Published: January 2024

AbstractDirect and site-selective C-H functionalization of alkenes under environmentally benign conditions represents a useful and attractive yet challenging transformation to access value-added molecules. Herein, a unified protocol for a variety of intermolecular Heck-type functionalizations of Csp2-H bond of alkenes has been developed by thianthrenation. The reaction features metal-free and operationally simple conditions for exclusive cine-selective C-H functionalization of aliphatic and aryl alkenes to forge C-C, C-N, C-P, and C-S bonds at room temperature, providing a general protocol for intermolecular Heck-type reaction of alkenes with nucleophiles (Nu = sulfinates, cyanides, amines, amides). Alkenes undergo cine-sulfonylation, cyanation, amination to afford alkenyl sulfones, alkenyl nitriles and enamines.
Unconventionally fast transport through sliding dynamics of rodlike particles in macromolecular networks
Authors: Zhang Xuanyu , Dai Xiaobin , Habib Md Ahsan , Gao Lijuan , Chen Wenlong , Wei Wenjie , Tang Zhongqiu , Qi Xianyu , Gong Xiangjun , Jiang Lingxiang , Yan Li-Tang 
Published: January 2024

AbstractTransport of rodlike particles in confinement environments of macromolecular networks plays crucial roles in many important biological processes and technological applications. The relevant understanding has been limited to thin rods with diameter much smaller than network mesh size, although the opposite case, of which the dynamical behaviors and underlying physical mechanisms remain unclear, is ubiquitous. Here, we solve this issue by combining experiments, simulations and theory. We find a nonmonotonic dependence of translational diffusion on rod length, characterized by length commensuration-governed unconventionally fast dynamics which is in striking contrast to the monotonic dependence for thin rods. Our results clarify that such a fast diffusion of thick rods with length of integral multiple of mesh size follows sliding dynamics and demonstrate it to be anomalous yet Brownian. Moreover, good agreement between theoretical analysis and simulations corroborates that the sliding dynamics is an intermediate regime between hopping and Brownian dynamics, and provides a mechanistic interpretation based on the rod-length dependent entropic free energy barrier. The findings yield a principle, that is, length commensuration, for optimal design of rodlike particles with highly efficient transport in confined environments of macromolecular networks, and might enrich the physics of the diffusion dynamics in heterogeneous media.
Generation and optimization of off-the-shelf immunotherapeutics targeting TCR-Vβ2+ T cell malignancy
Authors: Ren Jingjing , Liao Xiaofeng , Lewis Julia M. , Chang Jungsoo , Qu Rihao , Carlson Kacie R. , Foss Francine , Girardi Michael 
Published: January 2024

AbstractCurrent treatments for T cell malignancies encounter issues of disease relapse and off-target toxicity. Using T cell receptor (TCR)Vβ2 as a model, here we demonstrate the rapid generation of an off-the-shelf allogeneic chimeric antigen receptor (CAR)-T platform targeting the clone-specific TCR Vβ chain for malignant T cell killing while limiting normal cell destruction. Healthy donor T cells undergo CRISPR-induced TRAC, B2M and CIITA knockout to eliminate T cell-dependent graft-versus-host and host-versus-graft reactivity. Second generation 4-1BB/CD3zeta CAR containing high affinity humanized anti-Vβ scFv is expressed efficiently on donor T cells via both lentivirus and adeno-associated virus transduction with limited detectable pre-existing immunoreactivity. Our optimized CAR-T cells demonstrate specific and persistent killing of Vβ2+ Jurkat cells and Vβ2+ patient derived malignant T cells, in vitro and in vivo, without affecting normal T cells. In parallel, we generate humanized anti-Vβ2 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) by Fc-engineering for NK cell ADCC therapy.
MBD2 couples DNA methylation to transposable element silencing during male gametogenesis
Authors: Wang Shuya , Wang Ming , Ichino Lucia , Boone Brandon A. , Zhong Zhenhui , Papareddy Ranjith K. , Lin Evan K. , Yun Jaewon , Feng Suhua , Jacobsen Steven E. 
Published: January 2024

AbstractDNA methylation is an essential component of transposable element (TE) silencing, yet the mechanism by which methylation causes transcriptional repression remains poorly understood1–5. Here we study the Arabidopsis thaliana Methyl-CpG Binding Domain (MBD) proteins MBD1, MBD2 and MBD4 and show that MBD2 acts as a TE repressor during male gametogenesis. MBD2 bound chromatin regions containing high levels of CG methylation, and MBD2 was capable of silencing the FWA gene when tethered to its promoter. MBD2 loss caused activation at a small subset of TEs in the vegetative cell of mature pollen without affecting DNA methylation levels, demonstrating that MBD2-mediated silencing acts strictly downstream of DNA methylation. TE activation in mbd2 became more significant in the mbd5 mbd6 and adcp1 mutant backgrounds, suggesting that MBD2 acts redundantly with other silencing pathways to repress TEs. Overall, our study identifies MBD2 as a methyl reader that acts downstream of DNA methylation to silence TEs during male gametogenesis.
Titanium-rich basaltic melts on the Moon modulated by reactive flow processes
Authors: Klaver Martijn , Klemme Stephan , Liu Xiao-Ning , Hin Remco C. , Coath Christopher D. , Anand Mahesh , Lissenberg C. Johan , Berndt Jasper , Elliott Tim 
Published: January 2024

AbstractThe origin of titanium-rich basaltic magmatism on the Moon remains enigmatic. Ilmenite-bearing cumulates in the lunar mantle are often credited as the source, but their partial melts are not a compositional match and are too dense to enable eruption. Here we use petrological reaction experiments to show that partial melts of ilmenite-bearing cumulates react with olivine and orthopyroxene in the lunar mantle, shifting the melt composition to that of the high-Ti suite. New high-precision Mg isotope data confirm that high-Ti basalts have variable and isotopically light Mg isotope compositions that are inconsistent with equilibrium partial melting. We employ a diffusion model to demonstrate that kinetic isotope fractionation during reactive flow of partial melts derived from ilmenite-bearing cumulates can explain these anomalously light Mg isotope compositions, as well as the isotope composition of other elements such as Fe, Ca and Ti. Although this model does not fully replicate lunar melt–solid interaction, we suggest that titanium-rich magmas erupted on the surface of the Moon can be derived through partial melting of ilmenite-bearing cumulates, but melts undergo extensive modification of their elemental and isotopic composition through reactive flow in the lunar mantle. Reactive flow may therefore be the critical process that decreases melt density and allows high-Ti melts to erupt on the lunar surface.