bluuebunny/crossref_metadata_2025 huggingface dataset:
γ-secretase inhibitors augment efficacy of BCMA-targeting bispecific antibodies against multiple myeloma cells without impairing T-cell activation and differentiation
Authors: Chen Hailin , Yu Tengteng , Lin Liang , Xing Lijie , Cho Shih-Feng , Wen Kenneth , Aardalen Kimberly , Oka Adwait , Lam Joni , Daley Mike , Lu Haihui , Munshi Nikhil , Anderson Kenneth C. , Tai Yu-Tzu
Published: August 2022

We here defined the impacts of γ-secretase inhibitors (GSIs) on T-cell-dependent BCMA-specific multiple myeloma (MM) cell lysis and immunomodulatory effects induced by bispecific antibodies (BisAbs). GSIs-induced membrane BCMA (mBCMA) accumulation reached near maximum within 4 h and sustained over 42h-study period on MM cell lines and patient MM cells. GSIs, i.e., 2 nM LY-411575 or 1 μM DAPT, robustly increased mBCMA densities on CD138+ but not CD3+ patient cells, concomitantly with minimum soluble/shed BCMA (sBCMA) in 1 day-culture supernatants. In ex vivo MM-T-cell co-cultures, GSIs overcame sBCMA-inhibited MM cell lysis and further enhanced autologous patient MM cell lysis induced by BCMAxCD3 BisAbs, accompanied by significantly enhanced cytolytic markers (CD107a, IFNγ, IL2, and TNFα) in patient T cells. In longer 7 day-co-cultures, LY-411575 minimally affected BCMAxCD3 BisAb (PL33)-induced transient expression of checkpoint (PD1, TIGIT, TIM3, LAG3) and co-stimulatory (41BB, CD28) proteins, as well as time-dependent increases in % effector memory/central memory subsets and CD8/CD4 ratios in patient T cells. Importantly, LY41157 rapidly cleared sBCMA from circulation of MM-bearing NSG mice reconstituted with human T cells and significantly enhanced anti-MM efficacy of PL33 with prolonged host survival. Taken together, these results further support ongoing combination BCMA-targeting immunotherapies with GSI clinical studies to improve patient outcome.
DNA damage-induced paraspeckle formation enhances DNA repair and tumor radioresistance by recruiting ribosomal protein P0
Authors: Wang Yun-Long , Zhao Wan-Wen , Bai Shao-Mei , Ma Yan , Yin Xin-Ke , Feng Li-Li , Zeng Guang-Dong , Wang Fang , Feng Wei-Xing , Zheng Jian , Wang Ying-Nai , Zeng Bing , Liu Quentin , Hung Mien-Chie , Wan Xiang-Bo
Published: August 2022

Paraspeckles are mammal-specific membraneless nuclear bodies that participate in various biological processes. NONO, a central paraspeckle component, has been shown to play pivotal roles in DNA double-strand breaks (DSB) repair, whereas its underlying mechanism needs to be further disclosed. Here, using co-immunoprecipitation and mass spectrum, we identified ribosomal protein P0 (RPLP0) as a DSB-induced NONO-binding protein; RPLP0 binds to the RRM1 and RRM2 domains of NONO. Similar to NONO, RPLP0 enhances non-homologous end joining-mediated DSB repair, which was ascribed to a ribosome-independent manner. Interestingly, paraspeckles were induced as early as 15 min after irradiation; it further recruited nuclear RPLP0 to enhance its interaction with NONO. Radiation-induced NONO/RPLP0 complex subsequently anchored at the damaged DNA and increased the autophosphorylation of DNA-PK at Thr2609, thereby enhancing DSB repair. Consistently, in vivo and in vitro experiments showed that depletion of NONO sensitizes tumor cells to radiation. For patients with locally advanced rectal cancer, NONO expression was remarkably increased in tumor tissues and correlated with a poor response to radiochemotherapy. Our findings suggest a pivotal role of radiation-induced paraspeckles in DNA repair and tumor radioresistance, and provide a new insight into the ribosome-independent function of ribosomal proteins.
Glycosylated modification of MUC1 maybe a new target to promote drug sensitivity and efficacy for breast cancer chemotherapy
Authors: Xi Xiaomin , Wang Jiting , Qin Yue , Huang Weidong , You Yilin , Zhan Jicheng
Published: August 2022

Breast cancer, the most common cancer in women, usually exhibits intrinsic insensitivity to drugs, even without drug resistance. MUC1 is a highly glycosylated transmembrane protein, overexpressed in breast cancer, contributing to tumorigenesis and worse prognosis. However, the molecular mechanism between MUC1 and drug sensitivity still remains unclear. Here, natural flavonoid apigenin was used as objective due to the antitumor activity and wide availability. MUC1 knockout (KO) markedly sensitized breast cancer cells to apigenin cytotoxicity in vitro and in vivo. Both genetical and pharmacological inhibition significantly enhanced the chemosensitivity to apigenin and clinical drugs whereas MUC1 overexpression conversely aggravated such drug resistance. Constitutively re-expressing wild type MUC1 in KO cells restored the drug resistance; however, the transmembrane domain deletant could not rescue the phenotype. Notably, further investigation discovered that membrane-dependent drug resistance relied on the extracellular glycosylated modification since removing O-glycosylation via inhibitor, enzyme digestion, or GCNT3 (MUC1 related O-glycosyltransferase) knockout markedly reinvigorated the chemosensitivity in WT cells, but had no effect on KO cells. Conversely, inserting O-glycosylated sites to MUC1-N increased the drug tolerance whereas the O-glycosylated deletant (Ser/Thr to Ala) maintained high susceptibility to drugs. Importantly, the intracellular concentration of apigenin measured by UPLC and fluorescence distribution firmly revealed the increased drug permeation in MUC1 KO and BAG-pretreated cells. Multiple clinical chemotherapeutics with small molecular were tested and obtained the similar conclusion. Our findings uncover a critical role of the extracellular O-glycosylation of MUC1-N in weakening drug sensitivity through acting as a barrier, highlighting a new perspective that targeting MUC1 O-glycosylation has great potential to promote drug sensitivity and efficacy.
Loss of FOXA2 induces ER stress and hepatic steatosis and alters developmental gene expression in human iPSC-derived hepatocytes
Authors: Aghadi Maryam , Elgendy Ramy , Abdelalim Essam M.
Published: August 2022

FOXA2 has been known to play important roles in liver functions in rodents. However, its role in human hepatocytes is not fully understood. Recently, we generated FOXA2 mutant induced pluripotent stem cell (FOXA2−/−iPSC) lines and illustrated that loss of FOXA2 results in developmental defects in pancreatic islet cells. Here, we used FOXA2−/−iPSC lines to understand the role of FOXA2 on the development and function of human hepatocytes. Lack of FOXA2 resulted in significant alterations in the expression of key developmental and functional genes in hepatic progenitors (HP) and mature hepatocytes (MH) as well as an increase in the expression of ER stress markers. Functional assays demonstrated an increase in lipid accumulation, bile acid synthesis and glycerol production, while a decrease in glucose uptake, glycogen storage, and Albumin secretion. RNA-sequencing analysis further validated the findings by showing a significant increase in genes associated with lipid metabolism, bile acid secretion, and suggested the activation of hepatic stellate cells and hepatic fibrosis in MH lacking FOXA2. Overexpression of FOXA2 reversed the defective phenotypes and improved hepatocyte functionality in iPSC-derived hepatic cells lacking FOXA2. These results highlight a potential role of FOXA2 in regulating human hepatic development and function and provide a human hepatocyte model, which can be used to identify novel therapeutic targets for FOXA2-associated liver disorders.
USP21 promotes self-renewal and tumorigenicity of mesenchymal glioblastoma stem cells by deubiquitinating and stabilizing FOXD1
Authors: Zhang Qixiang , Chen Zhengxin , Tang Qikai , Wang Zhangjie , Lu Jiacheng , You Yongping , Wang Huibo
Published: August 2022

Recent studies suggest that Forkhead box D1 (FOXD1) plays an indispensable role in maintaining the mesenchymal (MES) properties of glioblastoma (GBM) stem cells (GSCs). Thus, understanding the mechanisms that control FOXD1 protein expression is critical for guiding GBM treatment, particularly in patients with therapy-resistant MES subtypes. In this study, we identify the ubiquitin-specific peptidase 21 (USP21) as a critical FOXD1 deubiquitinase in MES GSCs. We find that USP21 directly interacts with and stabilizes FOXD1 by reverting its proteolytic ubiquitination. Silencing of USP21 enhances polyubiquitination of FOXD1, promotes its proteasomal degradation, and ultimately attenuates MES identity in GSCs, while these effects could be largely restored by reintroduction of FOXD1. Remarkably, we show that disulfiram, a repurposed drug that could block the enzymatic activities of USP21, suppresses GSC tumorigenicity in MES GSC-derived GBM xenograft model. Additionally, we demonstrate that USP21 is overexpressed and positively correlated with FOXD1 protein levels in GBM tissues, and its expression is inversely correlated with patient survival. Collectively, our work reveals that USP21 maintains MES identity by antagonizing FOXD1 ubiquitination and degradation, suggesting that USP21 is a potential therapeutic target for the MES subtype of GBM.
Long noncoding RNA NONMMUT015745 inhibits doxorubicin-mediated cardiomyocyte apoptosis by regulating Rab2A-p53 axis
Authors: Cai Hongjing , Tian Pengchao , Ju Jie , Wang Tao , Chen Xinzhe , Wang Kai , Wang Fei , Yu Xue , Wang Shaocong , Wang Yin , Shan Chan , Li Peifeng
Published: August 2022

Doxorubicin (DOX) is an efficacious and widely used drug for human malignancy treatment, but its clinical application is limited due to side effects, especially cardiotoxicity. Our present study revealed that DOX could induce apoptosis in cardiomyocytes. Herein, we screened the dysregulated long noncoding RNAs (lncRNAs) in DOX-treated cardiomyocytes. Notably, overexpression of lncRNA NONMMUT015745 (lnc5745) could alleviate DOX-induced cardiomyocyte apoptosis both in vitro and in vivo. Conversely, silencing lnc5745 promotes cardiomyocyte apoptosis. Moreover, Rab2A, a direct target of lnc5745, possesses a protective effect in DOX-induced cardiotoxicity once knocked down. Importantly, we verified that the p53-related apoptotic signalling pathway was responsible for the lnc5745-mediated protective role against DOX-induced cardiomyocyte apoptosis. Mechanistically, Rab2A interacts with p53 and phosphorylated p53 on Ser 33 (p53 (Phospho-Ser 33)), promotes p53 phosphorylation, thereby activating the apoptotic pathway. Taken together, our results suggested that lnc5745 protects against DOX-induced cardiomyocyte apoptosis through suppressing Rab2A expression, modifying p53 phosphorylation, thereby regulating p53-related apoptotic signalling pathway. Our findings establish the functional mode of the lnc5745-Rab2A-p53 axis in DOX-induced cardiotoxicity. The development of new strategies targeting the lnc5745-Rab2A-p53 axis could attenuate DOX-induced cardiotoxicity, which is beneficial to its clinical anti-tumour application.
Compound marine heatwaves and ocean acidity extremes
Authors: Burger Friedrich A. , Terhaar Jens , Frölicher Thomas L.
Published: August 2022

Compound MHW-OAX events, during which marine heatwaves (MHWs) co-occur with ocean acidity extreme (OAX) events, can have larger impacts on marine ecosystems than the individual extremes. Using monthly open-ocean observations over the period 1982–2019, we show that globally 1.8 in 100 months (or about one out of five present-day MHW months) are compound MHW-OAX event months under a present-day baseline, almost twice as many as expected for 90th percentile extreme event exceedances if MHWs and OAX events were statistically independent. Compound MHW-OAX events are most likely in the subtropics (2.7 in 100 months; 10°−40° latitude) and less likely in the equatorial Pacific and the mid-to-high latitudes (0.7 in 100 months; >40° latitude). The likelihood pattern results from opposing effects of temperature and dissolved inorganic carbon on [H+]. The likelihood is higher where the positive effect on [H+] from increased temperatures during MHWs outweighs the negative effect on [H+] from co-occurring decreases in dissolved inorganic carbon. Daily model output from a large-ensemble simulation of an Earth system model is analyzed to assess changes in the MHW-OAX likelihood under climate change. The projected long-term mean warming and acidification trends have the largest effect on the number of MHW-OAX days per year, increasing it from 12 to 265 days per year at 2 °C global warming relative to a fixed pre-industrial baseline. Even when long-term trends are removed, an increase in [H+] variability leads to a 60% increase in the number of MHW-OAX days under 2 °C global warming. These projected increases may cause severe impacts on marine ecosystems.
Impedance-based forecasting of lithium-ion battery performance amid uneven usage
Authors: Jones Penelope K. , Stimming Ulrich , Lee Alpha A.
Published: August 2022

Accurate forecasting of lithium-ion battery performance is essential for easing consumer concerns about the safety and reliability of electric vehicles. Most research on battery health prognostics focuses on the research and development setting where cells are subjected to the same usage patterns. However, in practical operation, there is great variability in use across cells and cycles, thus making forecasting challenging. To address this challenge, here we propose a combination of electrochemical impedance spectroscopy measurements with probabilistic machine learning methods. Making use of a dataset of 88 commercial lithium-ion coin cells generated via multistage charging and discharging (with currents randomly changed between cycles), we show that future discharge capacities can be predicted with calibrated uncertainties, given the future cycling protocol and a single electrochemical impedance spectroscopy measurement made immediately before charging, and without any knowledge of usage history. The results are robust to cell manufacturer, the distribution of cycling protocols, and temperature. The research outcome also suggests that battery health is better quantified by a multidimensional vector rather than a scalar state of health.
A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin
Authors: Xiong Jing , Liao Jianming , Liu Xia , Zhang Zhaohui , Adams Jonathan , Pacifici Roberto , Ye Keqiang
Published: August 2022

Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) are expressed in human osteoblasts and mediate fracture healing. BDNF/TrkB signaling activates Akt that phosphorylates and inhibits asparagine endopeptidase (AEP), which regulates the differentiation fate of human bone marrow stromal cells (hBMSC) and is altered in postmenopausal osteoporosis. Here we show that R13, a small molecular TrkB receptor agonist prodrug, inhibits AEP and promotes bone formation. Though both receptor activator of nuclear factor kappa-Β ligand (RANK-L) and osteoprotegerin (OPG) induced by ovariectomy (OVX) remain comparable between WT and BDNF+/− mice, R13 treatment significantly elevates OPG in both mice without altering RANKL, blocking trabecular bone loss. Strikingly, both R13 and anti-RANK-L exhibit equivalent therapeutic efficacy. Moreover, OVX increases RANK-L and OPG in WT and AEP KO mice with RANK-L/OPG ratio lower in the latter than the former, attenuating bone turnover. 7,8-DHF, released from R13, activates TrkB and its downstream effector CREB, which is critical for OPG augmentation. Consequently, 7,8-DHF represses C/EBPβ/AEP pathway, inhibiting RANK-L-induced RAW264.7 osteoclastogenesis. Therefore, our findings support that R13 exerts its therapeutic efficacy toward osteoporosis via inhibiting AEP and escalating OPG.
Two-colour high-purity Einstein-Podolsky-Rosen photonic state
Authors: Brasil Tulio Brito , Novikov Valeriy , Kerdoncuff Hugo , Lassen Mikael , Polzik Eugene S.
Published: August 2022

We report a high-purity Einstein-Podolsky-Rosen (EPR) state between light modes with the wavelengths separated by more than 200 nm. We demonstrate highly efficient EPR-steering between the modes with the product of conditional variances $${{{{{{{{\mathcal{E}}}}}}}}}^{2}=0.11\pm 0.01\ll 1$$

E

2

=
0.11
±
0.01
≪
1
. The modes display − 7.7 ± 0.5 dB of two-mode squeezing and an overall state purity of 0.63 ± 0.16. EPR-steering is observed over five octaves of sideband frequencies from RF down to audio-band. The demonstrated combination of high state purity, strong quantum correlations, and extended frequency range enables new matter-light quantum protocols.
A functional role of meningeal lymphatics in sex difference of stress susceptibility in mice
Authors: Dai Weiping , Yang Mengqian , Xia Pei , Xiao Chuan , Huang Shuying , Zhang Zhan , Cheng Xin , Li Wenchang , Jin Jian , Zhang Jingyun , Wu Binghuo , Zhang Yingying , Wu Pei-hui , Lin Yangyang , Wu Wen , Zhao Hu , Zhang Yan , Lin Wei-Jye , Ye Xiaojing
Published: August 2022

Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to the peripheral immune system. Their potential role in depression-like behaviour has not been investigated. Here, we show in mice, sub-chronic variable stress as a model of depression-like behaviour impairs meningeal lymphatics in females but not in males. Manipulations of meningeal lymphatics regulate the sex difference in the susceptibility to stress-induced depression- and anxiety-like behaviors in mice, as well as alterations of the medial prefrontal cortex and the ventral tegmental area, brain regions critical for emotional regulation. Together, our findings suggest meningeal lymphatic impairment contributes to susceptibility to stress in mice, and that restoration of the meningeal lymphatics might have potential for modulation of depression-like behaviour.
Human supplementation with Pediococcus acidilactici GR-1 decreases heavy metals levels through modifying the gut microbiota and metabolome
Authors: Feng Pengya , Yang Jinfeng , Zhao Shuai , Ling Zhenmin , Han Rong , Wu Ying , Salama Ei-Sayed , Kakade Apurva , Khan Aman , Jin Weilin , Zhang Weibing , Jeon Byong-Hun , Fan Jingjing , Liu Minrui , Mamtimin Tursunay , Liu Pu , Li Xiangkai
Published: August 2022

Exposure to heavy metals (HMs) is a threat to human health. Although probiotics can detoxify HMs in animals, their effectiveness and mechanism of action in humans have not been studied well. Therefore, we conducted this randomized, double-blind, controlled trial on 152 occupational workers from the metal industry, an at-risk human population, to explore the effectiveness of probiotic yogurt in reducing HM levels. Participants were randomly assigned to two groups: one consumed probiotic yogurt containing the HM-resistant strain Pediococcus acidilactici GR-1 and the other consumed conventional yogurt for 12 weeks. Analysis of metal contents in the blood revealed that the consumption of probiotic yogurt resulted in a higher and faster decrease in copper (34.45%) and nickel (38.34%) levels in the blood than the consumption of conventional yogurt (16.41% and 27.57%, respectively). Metagenomic and metabolomic studies identified a close correlation between gut microbiota (GM) and host metabolism. Significantly enriched members of Blautia and Bifidobacterium correlated positively with the antioxidant capacities of GM and host. Further murine experiments confirmed the essential role of GM and protective effect of GR-1 on the antioxidative role of the intestine against copper. Thus, the use of probiotic yogurt may be an effective and affordable approach for combating toxic metal exposure through the protection of indigenous GM in humans.

ClinicalTrials.gov identifier: ChiCTR2100053222
Mapping the dynamics of insulin-responsive pathways in the blood–brain barrier endothelium using time-series transcriptomics data
Authors: Wang Zengtao , Tang Xiaojia , Swaminathan Suresh K. , Kandimalla Karunya K. , Kalari Krishna R.
Published: August 2022

Critical functions of the blood–brain barrier (BBB), including cerebral blood flow, energy metabolism, and immunomodulation, are regulated by insulin signaling pathways. Therefore, endothelial insulin resistance could lead to BBB dysfunction, which is associated with neurodegenerative diseases such as Alzheimer’s disease (AD). The current study aims to map the dynamics of insulin-responsive pathways in polarized human cerebral microvascular endothelial cell (hCMEC/D3) monolayers. RNA-Sequencing was performed on hCMEC/D3 monolayers with and without insulin treatment at various time points. The Short Time-series Expression Miner (STEM) method was used to identify gene clusters with distinct and representative expression patterns. Functional annotation and pathway analysis of genes from selected clusters were conducted using Webgestalt and Ingenuity Pathway Analysis (IPA) software. Quantitative expression differences of 16,570 genes between insulin-treated and control monolayers were determined at five-time points. The STEM software identified 12 significant clusters with 6880 genes that displayed distinct temporal patterns upon insulin exposure, and the clusters were further divided into three groups. Gene ontology (GO) enrichment analysis demonstrated that biological processes protecting BBB functions such as regulation of vascular development and actin cytoskeleton reorganization were upregulated after insulin treatment (Group 1 and 2). In contrast, GO pathways related to inflammation, such as response to interferon-gamma, were downregulated (Group 3). The IPA analyses further identified insulin-responsive cellular and molecular pathways that are associated with AD pathology. These findings unravel the dynamics of insulin action on the BBB endothelium and inform about downstream signaling cascades that are potentially disrupted due to brain insulin resistance prevalent in AD.
Current status of traumatic spinal cord injury caused by traffic accident in Northern China
Authors: Wu Yao , Zhang Zhenrong , Wang Fangyong , Wang Wenjing
Published: August 2022

The study aims to investigate the characteristics of traumatic spinal cord injury (TSCI) caused by motor vehicle collisions (MVCs). The study included 649 cases who experienced MVC-induced TSCI. The mean age was 37.3 years old, ranging from 1 to 82 years old. The male-to-female ratio was 2.7:1. We extracted data of gender, age, occupation, neurological level of injury, fracture level, complications, vehicle type, accident type and other features. The results showed that the most common vehicles involved in accidents were passenger cars (65.1%). Collision was the leading cause of MVCs (35.8%). The lesion level was cervical in 51.6% and thoracic in 42.2%. The most common fracture levels in drivers and passengers were C3–C7, while those in pedestrians were T11–L2. The frequency of tetraplegia (51.6%) was slightly higher than paraplegia (48.4%), and cases with tetraplegia with incomplete injury accounted for 61.2%. MVC-induced TSCI has unique clinical features. Collision was the most common cause. People sitting in cars were more likely to suffer from cervical fractures, while thoracolumbar fractures were more common in pedestrians. Tetraplegic cases were mainly incomplete injuries, while paraplegic cases were mainly complete injuries.
Nanopore metatranscriptomics reveals cryptic catfish species as potential Shigella flexneri vectors in Kenya
Authors: Tighe Andrew J. , Grayson Sean , Byrne John , Hintikka Sanni , Jessen Lisa , Dempsey Jake , Browne Lauren , Kelly-Quinn Mary , Fulanda Bernerd , Ruane Neil M. , Carlsson Jens
Published: August 2022

Bacteria in the Shigella genus remain a major cause of dysentery in sub-Saharan Africa, and annually cause an estimated 600,000 deaths worldwide. Being spread by contaminated food and water, this study highlights how wild caught food, in the form of freshwater catfish, can act as vectors for Shigella flexneri in Southern Kenya. A metatranscriptomic approach was used to identify the presence of Shigella flexneri in the catfish which had been caught for consumption from the Galana river. The use of nanopore sequencing was shown to be a simple and effective method to highlight the presence of Shigella flexneri and could represent a potential new tool in the detection and prevention of this deadly pathogen. Rather than the presence/absence results of more traditional testing methods, the use of metatranscriptomics highlighted how primarily one SOS response gene was being transcribed, suggesting the bacteria may be dormant in the catfish. Additionally, COI sequencing of the vector catfish revealed they likely represent a cryptic species. Morphological assignment suggested the fish were widehead catfish Clarotes laticeps, which range across Africa, but the COI sequences from the Kenyan fish are distinctly different from C. laticeps sequenced in West Africa.
Disentangling influence over group speed and direction reveals multiple patterns of influence in moving meerkat groups
Authors: Averly Baptiste , Sridhar Vivek H. , Demartsev Vlad , Gall Gabriella , Manser Marta , Strandburg-Peshkin Ariana
Published: August 2022

Animals that travel together in groups must constantly come to consensus about both the direction and speed of movement, often simultaneously. Contributions to collective decisions may vary among group members, yet inferring who has influence over group decisions is challenging, largely due to the multifaceted nature of influence. Here we collected high-resolution GPS data from five habituated meerkat groups in their natural habitat during foraging and developed a method to quantify individual influence over both group direction and speed. We find that individual influence over direction and speed are correlated, but also exhibit substantial variation. Comparing patterns across social statuses reveals that dominant females have higher influence than other individuals over both group direction and speed. Individuals with high influence also tend to spend more time in the front of the group. We discuss our results in light of meerkat life-history and current literature on influence during group movement. Our method provides a general approach which can be applied to disentangle individual influence over group direction and speed in a wide range of species with cohesive movement, emphasizing the importance of integrating multiple lines of inquiry when inferring influence in moving animal groups.
CRELD2 is a novel modulator of calcium release and calcineurin-NFAT signalling during osteoclast differentiation
Authors: Duxfield Adam , Munkley Jennifer , Briggs Michael D. , Dennis Ella P.
Published: August 2022

Cysteine rich with epidermal growth factor (EGF)-like domains 2 (CRELD2) is an endoplasmic reticulum (ER) resident chaperone protein with calcium binding properties. CRELD2 is an ER-stress regulated gene that has been implicated in the pathogenesis of skeletal dysplasias and has been shown to play an important role in the differentiation of chondrocytes and osteoblasts. Despite CRELD2 having an established role in skeletal development and bone formation, its role in osteoclasts is currently unknown. Here we show for the first time that CRELD2 plays a novel role in trafficking transforming growth factor beta 1 (TGF-β1), which is linked to an upregulation in the expression of Nfat2, the master regulator of osteoclast differentiation in early osteoclastogenesis. Despite this finding, we show that overexpressing CRELD2 impaired osteoclast differentiation due to a reduction in the activity of the calcium-dependant phosphatase, calcineurin. This in turn led to a subsequent block in the dephosphorylation of nuclear factor of activated T cells 1 (NFATc1), preventing its nuclear localisation and activation as a pro-osteoclastogenic transcription factor. Our exciting results show that the overexpression of Creld2 in osteoclasts impaired calcium release from the ER which is essential for activating calcineurin and promoting osteoclastogenesis. Therefore, our data proposes a novel inhibitory role for this calcium-binding ER-resident chaperone in modulating calcium flux during osteoclast differentiation which has important implications in our understanding of bone remodelling and the pathogenesis of skeletal diseases.
Differences in fluid removal of different open-pore elements for endoscopic negative pressure therapy in the upper gastrointestinal tract
Authors: Jansen Kai Tobias , Hetzel Jürgen , Schulte Carola , Düzenli Nurgül , Fusco Stefano , Zerabruck Emanuel , Schmider Eva , Malek Nisar P. , Königsrainer Alfred , Stüker Dietmar , Werner Christoph R. , Wichmann Dörte
Published: August 2022

Endoscopic negative pressure therapy is an effective treatment strategy for various defects of the gastrointestinal tract. The functional principle is based on an open-pore element, which is placed around a perforated drainage tube and connected to a vacuum source. The resulting open-pore suction device can undergo endoluminal or intracavitary placement. Different open-pore suction devices are used for endoscopic negative pressure therapy of upper gastrointestinal tract defects. Comparative analyses for features and properties of these devices are still lacking. Eight different (six hand-made devices and two commercial devices) open-pore suction devices for endoscopic negative pressure therapy of the upper gastrointestinal tract were used, amount fluid removed was evaluated. The evaluation parameters included the time to reach the target pressure, the time required to remove 100 ml of water, and the material resistance of the device. All open-pore suction devices are able to aspirate the target volume of fluids. The time to reach the target volume varied considerably. Target negative pressure was not achieved with all open-pore suction devices during the aspiration of fluids; however, there was no negative effect on suction efficiency. Of the measurement data, material resistance could be calculated for six open-pore elements. We present a simple experimental, nonphysiologically setup for open-pore suction devices used for endoscopic negative pressure therapy. The expected quantity of fluids secreted into the treated organs should affect open-pore suction device for endoscopic negative pressure therapy.
Effect of prior thyroid cancer on survival of primary liver cancer: a study based on the SEER database
Authors: Liu Hong , Heng Xin , Tian Yuan , Yang Zhongming
Published: August 2022

To explore the effect of prior thyroid cancer on the survival of primary liver cancer (PLC). Eligible PLC patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database during 2004–2016. Propensity score matching (PSM) was used to create a highly comparable control group that PLC patients without prior thyroid cancer. All PLC patients were divided into three groups based on the survival information: (1) PLC-specific death; (2) death due to other causes; (3) alive. The effect sizes were presented by the corresponding hazard ratio (HR) and 95% confidence intervals (CI). Totally, 142 PLC patients with prior thyroid cancer and 1420 PLC patients without prior thyroid cancer were included. During the follow-up period, 714 (45.71%) PLC patients died of liver cancer while 638 (40.85%) PLC patients were alive. Median survival time for PLC patients was 11.00 months, respectively. PLC patients with prior thyroid cancer have a lower risk of death (HR = 0.64; 95% CI: 0.48–0.86). Subgroup analyses stratified by gender displayed the similar relation in female patients with PLC. Prior thyroid cancer may be a protective factor for liver cancer death in PLC patients, especially in female patients.
The use of interdental cleaning devices and periodontal disease contingent on the number of remaining teeth in Korean adults
Authors: Kim Yun-Jeong , Gil Yoon Min , Bae Kwang-Hak , Kim Seon-Jip , Ihm Jungjoon , Cho Hyun-Jae
Published: August 2022

This study aimed to investigate the effect of interdental brushes and dental floss on the prevention of periodontitis in participants with ≥ 20 or < 20 remaining teeth by using the Korea National Health and Nutrition Examination Survey 2016–2018. Data from 11,614 participants were analysed using multivariate logistic regression after adjusting for sociodemographic factors (age and sex), socioeconomic factors (level of education and individual income), oral health-related variables (daily toothbrushing), and systemic health-related variables (smoking, diabetes, and obesity). The adjusted odds ratio (AOR) showed statistically significant results for both floss (AOR, 1.41; 95% confidence interval (CI) 1.22–1.64) and interdental brushes (AOR, 1.16; 95% CI 1.01–1.34). However, no significant difference was found in the subjects with fewer than 20 teeth. The subgroup analysis showed that interdental brushes had a significant preventive effect on women who had more than 20 teeth. Among participants with fewer than 20 teeth, interdental brush users had more periodontitis in men. Regarding those with more than 20 teeth, health inequality was alleviated when floss and interdental brushes were used. The bottom line is that the effect of preventing periodontitis in interdental brushes and dental floss was more evident in participants with ≥ 20 remaining teeth rather than in participants with < 20 remaining teeth.
Non-apoptotic cell death induction via sapogenin based supramolecular particles
Authors: Üner Göklem , Bedir Erdal , Serçinoğlu Onur , Kırmızıbayrak Petek Ballar
Published: August 2022

The discovery of novel chemotherapeutics that act through different mechanisms is critical for dealing with tumor heterogeneity and therapeutic resistance. We previously reported a saponin analog (AG-08) that induces non-canonical necrotic cell death and is auspicious for cancer therapy. Here, we describe that the key element in triggering this unique cell death mechanism of AG-08 is its ability to form supramolecular particles. These self-assembled particles are internalized via a different endocytosis pathway than those previously described. Microarray analysis suggested that AG-08 supramolecular structures affect several cell signaling pathways, including unfolded protein response, immune response, and oxidative stress. Finally, through investigation of its 18 analogs, we further determined the structural features required for the formation of particulate structures and the stimulation of the unprecedented cell death mechanism of AG-08. The unique results of AG-08 indicated that supramolecular assemblies of small molecules are promising for the field of anticancer drug development, although they have widely been accepted as nuisance in drug discovery studies.
Sexually transmitted infections and risk of hypertensive disorders of pregnancy
Authors: DePaoli Taylor Brandie , Hill Ashley V. , Perez-Patron Maria J. , Haggerty Catherine L. , Schisterman Enrique F. , Naimi Ashley I. , Noah Akaninyene , Comeaux Camillia R.
Published: August 2022

Hypertensive disorders of pregnancy (HDP) result in maternal morbidity and mortality but are rarely examined in perinatal studies of sexually transmitted infections. We examined associations between common sexually transmitted infections and HDP among 38,026 singleton pregnancies. Log-binomial regression calculated relative risk (RRs) and 95% confidence intervals (CIs) for associations with gestational hypertension, preeclampsia with severe features, mild preeclampsia, and superimposed preeclampsia. All models were adjusted for insurance type, maternal age, race/ethnicity, and education. Additional adjustments resulted in similar effect estimates. Chlamydia was associated with preeclampsia with severe features (RRadj. 1.4, 95% CI 1.1, 1.9). Effect estimates differed when we examined first prenatal visit diagnosis only (RRadj. 1.3, 95% CI 0.9, 1.9) and persistent or recurrent infection (RRadj. 2.0, 95% CI 1.1, 3.4). For chlamydia (RRadj. 2.0, 95% CI 1.3, 2.9) and gonorrhea (RRadj. 3.0, 95% CI 1.1, 12.2), women without a documented treatment were more likely to have preeclampsia with severe features. Among a diverse perinatal population, sexually transmitted infections may be associated with preeclampsia with severe features. With the striking increasing rates of sexually transmitted infections, there is a need to revisit the burden in pregnant women and determine if there is a link between infections and hypertensive disorders of pregnancy.
Collisions between CO, CO$$_2$$, H$$_2$$O and Ar ice nanoparticles compared by molecular dynamics simulation
Authors: Nietiadi Maureen L. , Rosandi Yudi , Bringa Eduardo M. , Urbassek Herbert M.
Published: August 2022

Molecular dynamics simulations are used to study collisions between amorphous ice nanoparticles consisting of CO, CO$$_2$$

2

, Ar and H$$_2$$

2

O. The collisions are always sticking for the nanoparticle size (radius of 20 nm) considered. At higher collision velocities, the merged clusters show strong plastic deformation and material mixing in the collision zone. Collision-induced heating influences the collision outcome. Partial melting of the merged cluster in the collision zone contributes to energy dissipation and deformation. Considerable differences exist—even at comparable collision conditions—between the ices studied here. The number of ejecta emitted during the collision follows the trend in triple-point temperatures and increases exponentially with the NP temperature.
Natural variants of human SARM1 cause both intrinsic and dominant loss-of-function influencing axon survival
Authors: Ademi Mirlinda , Yang Xiuna , Coleman Michael P. , Gilley Jonathan
Published: August 2022

SARM1 is a central executioner of programmed axon death, and this role requires intrinsic NAD(P)ase or related enzyme activity. A complete absence of SARM1 robustly blocks axon degeneration in mice, but even a partial depletion confers meaningful protection. Since axon loss contributes substantially to the onset and progression of multiple neurodegenerative disorders, lower inherent SARM1 activity is expected to reduce disease susceptibility in some situations. We, therefore, investigated whether there are naturally occurring SARM1 alleles within the human population that encode SARM1 variants with loss-of-function. Out of the 18 natural SARM1 coding variants we selected as candidates, we found that 10 display loss-of-function in three complimentary assays: they fail to robustly deplete NAD in transfected HEK 293T cells; they lack constitutive and NMN-induced NADase activity; and they fail to promote axon degeneration in primary neuronal cultures. Two of these variants are also able to block axon degeneration in primary culture neurons in the presence of endogenous, wild-type SARM1, indicative of dominant loss-of-function. These results demonstrate that SARM1 loss-of-function variants occur naturally in the human population, and we propose that carriers of these alleles will have different degrees of reduced susceptibility to various neurological conditions.
Predicting odor from molecular structure: a multi-label classification approach
Authors: Saini Kushagra , Ramanathan Venkatnarayan
Published: August 2022

Decoding the factors behind odor perception has long been a challenge in the field of human neuroscience, olfactory research, perfumery, psychology, biology and chemistry. The new wave of data-driven and machine learning approaches to predicting molecular properties are a growing area of research interest and provide for significant improvement over conventional statistical methods. We look at these approaches in the context of predicting molecular odor, specifically focusing on multi-label classification strategies employed for the same. Namely binary relevance, classifier chains, and random forests adapted to deal with such a task. This challenge, termed quantitative structure–odor relationship, remains an unsolved task in the field of sensory perception in machine learning, and we hope to emulate the results achieved in the field of vision and auditory perception in olfaction over time.
Peripheral N-methyl-d-aspartate receptor activation contributes to monosodium glutamate-induced headache but not nausea behaviours in rats
Authors: Benbow Tarique , Teja Felisha , Sheikhi Afrooz , Exposto Fernando G. , Svensson Peter , Cairns Brian E.
Published: August 2022

Monosodium glutamate induces behaviors thought to reflect headache and nausea in rats. We explored the effects of the N-methyl-d-aspartate receptor antagonist (2R)-amino-5-phosphonovaleric acid, the inotropic glutamate receptor antagonist kynurenic acid, and the CGRP receptor antagonist olcegepant, on monosodium glutamate-induced increases in nocifensive, headache-like and nausea behaviours. Effects of these antagonists on motor function were examined with a rotarod. The effect of the dopamine receptor antagonist metoclopramide and the serotonin 3 receptor antagonist ondansetron on nausea behaviour was also assessed. (2R)-amino-5-phosphonovaleric acid, and to a lesser extent, kynurenic acid and olcegepant, reduced nocifensive and headache-like behaviours evoked by monosodium glutamate. No alteration in motor function by (2R)-amino-5-phosphonovaleric acid, kynurenic acid or olcegepant was observed. No sex-related differences in the effectiveness of these agents were identified. Nausea behaviour was significantly more pronounced in male than in female rats. Olcegepant, ondansetron and metoclopramide ameliorated this nausea behaviour in male rats. Ondansetron and metoclopramide also reduced headache-like behaviour in male rats. These findings suggest that peripheral N-methyl-d-aspartate receptor activation underlies monosodium glutamate-induced headache-like behaviour but does not mediate the nausea behaviour in rats.
Pinocembrin suppresses oxidized low-density lipoprotein-triggered NLRP3 inflammasome/GSDMD-mediated endothelial cell pyroptosis through an Nrf2-dependent signaling pathway
Authors: Wang Tong , Tian Hua , Pan Tianqi , Yao Shutong , Yu Huayun , Wu Yumei , Wang Shijun
Published: August 2022

Pinocembrin (Pin) has been confirmed to exert anti-inflammatory and antiatherosclerotic effects. Here we have explored whether and how Pin would protect vascular endothelial cells against pyroptosis elicited by the exposure to oxidized low density lipoprotein (oxLDL). Our results showed that Pin preconditioning dose-dependently suppressed oxLDL-stimulated HUVEC injury and pyroptosis, which were manifested by improved cell viability, lower lactate dehydrogenase (LDH) levels and DNA damage as well as decreased expression of pyroptosis-related markers, such as NOD-like receptor pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), pro-Caspase-1, cleaved Caspase-1, N-terminus of Gasdermin D-N (GSDMD-N), pro-interleukins-1β (pro-IL-1β), IL-1β and inflammatory cytokines (IL-18 and IL-1β). All of the effects were similar to those of MCC950 (an NLRP3 inhibitor). As expected, Pin distinctly activated the Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidative signaling pathway assessed through increased expressions of Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Furthermore, after transfection with small interfering RNA of Nrf2, the inhibitory effects of Pin on oxLDL-triggered NLRP3 inflammasome/GSDMD-mediated pyroptosis and oxidative stress in HUVECs were weakened. Additionally, Pin up-regulated Nrf2/HO-1 axis and down-regulated NLRP3 inflammasome/GSDMD-mediated pyroptosis signals in Apoe−/− mice fed with high fat diet. These results contribute to the understanding of the anti-pyroptosis mechanisms of Pin and provide a reference for future research on the anti-atherosclerotic effect of Pin.
Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib
Authors: Zhu Zhou , Turner Nicholas C. , Loi Sherene , André Fabrice , Martin Miguel , Diéras Véronique , Gelmon Karen A. , Harbeck Nadia , Zhang Cathy , Cao Joan Q. , Yan Zhengming , Lu Dongrui R. , Wei Ping , VanArsdale Todd L. , Rejto Paul A. , Huang Xin , Rugo Hope S. , Loibl Sibylle , Cristofanilli Massimo , Finn Richard S. , Liu Yuan
Published: August 2022

While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, combined with endocrine therapy (ET), are becoming the standard-of-care for hormone receptor–positive/human epidermal growth factor receptor 2‒negative metastatic breast cancer, further mechanistic insights are needed to maximize benefit from the treatment regimen. Herein, we conducted a systematic comparative analysis of gene expression/progression-free survival relationship from two phase 3 trials (PALOMA-2 [first-line] and PALOMA-3 [≥second-line]). In the ET-only arm, there was no inter-therapy line correlation. However, adding palbociclib resulted in concordant biomarkers independent of initial ET responsiveness, with shared sensitivity genes enriched in estrogen response and resistance genes over-represented by mTORC1 signaling and G2/M checkpoint. Biomarker patterns from the combination arm resembled patterns observed in ET in advanced treatment-naive patients, especially patients likely to be endocrine-responsive. Our findings suggest palbociclib may recondition endocrine-resistant tumors to ET, and may guide optimal therapeutic sequencing by partnering CDK4/6 inhibitors with different ETs. Pfizer (NCT01740427; NCT01942135).
Mediator-assisted synthesis of WS2 with ultrahigh-optoelectronic performance at multi-wafer scale
Authors: Chen Yu-Siang , Chiu Sheng-Kuei , Tsai De-Liang , Liu Chong-Yo , Ting Hsiang-An , Yao Yu-Chi , Son Hyungbin , Haider Golam , Kalbáč Martin , Ting Chu-Chi , Chen Yang-Fang , Hofmann Mario , Hsieh Ya-Ping
Published: August 2022

The integration of 2D materials into future applications relies on advances in their quality and production. We here report a synthesis method that achieves ultrahigh optoelectronic performance at unprecedented fabrication scales. A mediator-assisted chemical vapor deposition process yields tungsten-disulfide (WS2) with near-unity photoluminescence quantum yield, superior photosensitivity and improved environmental stability. This enhancement is due to the decrease in the density of lattice defects and charge traps brought about by the self-regulating nature of the growth process. This robustness in the presence of precursor variability enables the high-throughput growth in atomically confined stacks and achieves uniform synthesis of single-layer WS2 on dozens of closely packed wafers. Our approach enhances the scientific and commercial potential of 2D materials as demonstrated in producing large-scale arrays of record-breaking optoelectronic devices.