bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progress in understanding the role of lncRNA in programmed cell death
Authors: Jiang Na , Zhang Xiaoyu , Gu Xuejun , Li Xiaozhuang , Shang Lei 
Published: February 2021

AbstractLong non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but not translated into proteins. LncRNAs regulate gene expressions at multiple levels, such as chromatin, transcription, and post-transcription. Further, lncRNAs participate in various biological processes such as cell differentiation, cell cycle regulation, and maintenance of stem cell pluripotency. We have previously reported that lncRNAs are closely related to programmed cell death (PCD), which includes apoptosis, autophagy, necroptosis, and ferroptosis. Overexpression of lncRNA can suppress the extrinsic apoptosis pathway by downregulating of membrane receptors and protect tumor cells by inhibiting the expression of necroptosis-related proteins. Some lncRNAs can also act as competitive endogenous RNA to prevent oxidation, thereby inhibiting ferroptosis, while some are known to activate autophagy. The relationship between lncRNA and PCD has promising implications in clinical research, and reports have highlighted this relationship in various cancers such as non-small cell lung cancer and gastric cancer. This review systematically summarizes the advances in the understanding of the molecular mechanisms through which lncRNAs impact PCD.
Inhibition of JNK increases the sensitivity of hepatocellular carcinoma cells to lysosomotropic drugs via LAMP2A destabilization
Authors: Desideri Enrico , Ciriolo Maria Rosa 
Published: February 2021

AbstractAlteration of lysosomal homeostasis is common in cancer cells, which often feature an enlarged and peripheral distributed lysosomal compartment and the overexpression of cathepsins. These alterations accelerate the production of building blocks for the de novo synthesis of macromolecules and contribute to the degradation of the extracellular matrix, thus contributing to tumor growth and invasion. At the same time, they make lysosomes more fragile and more prone to lysosomal membrane permeabilization, a condition that can cause the release of proteases into the cytosol and the activation of cell death. Therefore, lysosomes represent a weak spot of cancer cells that can be targeted for therapeutic purposes. Here, we identify a novel role of the kinase JNK as keeper of lysosomal stability in hepatocellular carcinoma cells. JNK inhibition reduces the stability of LAMP2A, a lysosomal membrane protein responsible for the stability of the lysosomal membrane, promoting its degradation by the proteasome. LAMP2A decrease enhances the lysosomal damage induced by lysosomotropic agents, ultimately leading to cell death. The effect is cancer-specific, as JNK inhibition does not decrease LAMP2A in non-tumoral liver cells and does not alter their sensitivity to lysosomotropic drugs. Our finding on the new role of JNK as cancer-specific keeper of lysosomal homeostasis lays the ground for future evaluation of the efficacy of the combination of JNK inhibition and lysosomotropic agents as a potential therapeutic strategy in hepatocellular carcinoma.
Incorporation of sensing modalities into de novo designed fluorescence-activating proteins
Authors: Klima Jason C. , Doyle Lindsey A. , Lee Justin Daho , Rappleye Michael , Gagnon Lauren A. , Lee Min Yen , Barros Emilia P. , Vorobieva Anastassia A. , Dou Jiayi , Bremner Samantha , Quon Jacob S. , Chow Cameron M. , Carter Lauren , Mack David L. , Amaro Rommie E. , Vaughan Joshua C. , Berndt Andre , Stoddard Barry L. , Baker David 
Published: February 2021

AbstractThrough the efforts of many groups, a wide range of fluorescent protein reporters and sensors based on green fluorescent protein and its relatives have been engineered in recent years. Here we explore the incorporation of sensing modalities into de novo designed fluorescence-activating proteins, called mini-fluorescence-activating proteins (mFAPs), that bind and stabilize the fluorescent cis-planar state of the fluorogenic compound DFHBI. We show through further design that the fluorescence intensity and specificity of mFAPs for different chromophores can be tuned, and the fluorescence made sensitive to pH and Ca2+ for real-time fluorescence reporting. Bipartite split mFAPs enable real-time monitoring of protein–protein association and (unlike widely used split GFP reporter systems) are fully reversible, allowing direct readout of association and dissociation events. The relative ease with which sensing modalities can be incorporated and advantages in smaller size and photostability make de novo designed fluorescence-activating proteins attractive candidates for optical sensor engineering.
Rapid decline of neutralizing antibodies against SARS-CoV-2 among infected healthcare workers
Authors: Marot Stéphane , Malet Isabelle , Leducq Valentin , Zafilaza Karen , Sterlin Delphine , Planas Delphine , Gothland Adélie , Jary Aude , Dorgham Karim , Bruel Timothée ,   the Sorbonne Université SARS-CoV-2 Neutralizing Antibodies Study Group, Attali Valérie , Baresse Isabelle , Beurton Alexandra , Boddaert Jacques , Bourmaleau Julie , Catala Martin , Demoule Alexandre , Dunoyer Violaine , Esteban-Amarilla Cristina , Hausfater Pierre , Haziot Noémie , Ip Queyras , Kubis Nathalie , Lhoest Laurence , Lubetzki Catherine , Marion Fabienne , Morawiec Elise , Mourtada Leila , Orcel Brigitte , Morelot-Panzini Capucine , Raux Mathieu , Reinhard Christophe , Riquier Claire , Roubertier Xavier , Weiss Nicolas , Zalc Bernard , Burrel Sonia , Boutolleau David , Schwartz Olivier , Gorochov Guy , Calvez Vincent , Marcelin Anne-Geneviève 
Published: February 2021

AbstractThere are only few data concerning persistence of neutralizing antibodies (NAbs) among SARS-CoV-2-infected healthcare workers (HCW). These individuals are particularly exposed to SARS-CoV-2 infection and at potential risk of reinfection. We followed 26 HCW with mild COVID-19 three weeks (D21), two months (M2) and three months (M3) after the onset of symptoms. All the HCW had anti-receptor binding domain (RBD) IgA at D21, decreasing to 38.5% at M3 (p < 0.0001). Concomitantly a significant decrease in NAb titers was observed between D21 and M2 (p = 0.03) and between D21 and M3 (p < 0.0001). Here, we report that SARS-CoV-2 can elicit a NAb response correlated with anti-RBD antibody levels. However, this neutralizing activity declines, and may even be lost, in association with a decrease in systemic IgA antibody levels, from two months after disease onset. This short-lasting humoral protection supports strong recommendations to maintain infection prevention and control measures in HCW, and suggests that periodic boosts of SARS-CoV-2 vaccination may be required.
Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models
Authors: Liu Yuanjing , Dodart Jean-Cosme , Tran Helene , Berkovitch Shaunna , Braun Maurine , Byrne Michael , Durbin Ann F. , Hu Xiao Shelley , Iwamoto Naoki , Jang Hyun Gyung , Kandasamy Pachamuthu , Liu Fangjun , Longo Kenneth , Ruschel Jörg , Shelke Juili , Yang Hailin , Yin Yuan , Donner Amy , Zhong Zhong , Vargeese Chandra , Brown Robert H. 
Published: February 2021

AbstractA large G4C2-repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal degeneration associated with this expansion arises from a loss of C9orf72 protein, the accumulation of RNA foci, the expression of dipeptide repeat (DPR) proteins, or all these factors. We report the discovery of a new targeting sequence that is common to all C9orf72 transcripts but enables preferential knockdown of repeat-containing transcripts in multiple cellular models and C9BAC transgenic mice. We optimize stereopure oligonucleotides that act through this site, and we demonstrate that their preferential activity depends on both backbone stereochemistry and asymmetric wing design. In mice, stereopure oligonucleotides produce durable depletion of pathogenic signatures without disrupting protein expression. These oligonucleotides selectively protect motor neurons harboring C9orf72-expansion mutation from glutamate-induced toxicity. We hypothesize that targeting C9orf72 with stereopure oligonucleotides may be a viable therapeutic approach for the treatment of C9orf72-associated neurodegenerative disorders.
Mechanism of the small ATP-independent chaperone Spy is substrate specific
Authors: Mitra Rishav , Gadkari Varun V. , Meinen Ben A. , van Mierlo Carlo P. M. , Ruotolo Brandon T. , Bardwell James C. A. 
Published: February 2021

AbstractATP-independent chaperones are usually considered to be holdases that rapidly bind to non-native states of substrate proteins and prevent their aggregation. These chaperones are thought to release their substrate proteins prior to their folding. Spy is an ATP-independent chaperone that acts as an aggregation inhibiting holdase but does so by allowing its substrate proteins to fold while they remain continuously chaperone bound, thus acting as a foldase as well. The attributes that allow such dual chaperoning behavior are unclear. Here, we used the topologically complex protein apoflavodoxin to show that the outcome of Spy’s action is substrate specific and depends on its relative affinity for different folding states. Tighter binding of Spy to partially unfolded states of apoflavodoxin limits the possibility of folding while bound, converting Spy to a holdase chaperone. Our results highlight the central role of the substrate in determining the mechanism of chaperone action.
Structural basis for the biosynthesis of lovastatin
Authors: Wang Jialiang , Liang Jingdan , Chen Lu , Zhang Wei , Kong Liangliang , Peng Chao , Su Chen , Tang Yi , Deng Zixin , Wang Zhijun 
Published: February 2021

AbstractStatins are effective cholesterol-lowering drugs. Lovastatin, one of the precursors of statins, is formed from dihydromonacolin L (DML), which is synthesized by lovastatin nonaketide synthase (LovB), with the assistance of a separate trans-acting enoyl reductase (LovC). A full DML synthesis comprises 8 polyketide synthetic cycles with about 35 steps. The assembling of the LovB–LovC complex, and the structural basis for the iterative and yet permutative functions of the megasynthase have remained a mystery. Here, we present the cryo-EM structures of the LovB–LovC complex at 3.60 Å and the core LovB at 2.91 Å resolution. The domain organization of LovB is an X-shaped face-to-face dimer containing eight connected domains. The binding of LovC laterally to the malonyl-acetyl transferase domain allows the completion of a L-shaped catalytic chamber consisting of six active domains. This architecture and the structural details of the megasynthase provide the basis for the processing of the intermediates by the individual catalytic domains. The detailed architectural model provides structural insights that may enable the re-engineering of the megasynthase for the generation of new statins.
The mechanosensitive Piezo1 channel mediates heart mechano-chemo transduction
Authors: Jiang Fan , Yin Kunlun , Wu Kun , Zhang Mingmin , Wang Shiqiang , Cheng Heping , Zhou Zhou , Xiao Bailong 
Published: February 2021

AbstractThe beating heart possesses the intrinsic ability to adapt cardiac output to changes in mechanical load. The century-old Frank–Starling law and Anrep effect have documented that stretching the heart during diastolic filling increases its contractile force. However, the molecular mechanotransduction mechanism and its impact on cardiac health and disease remain elusive. Here we show that the mechanically activated Piezo1 channel converts mechanical stretch of cardiomyocytes into Ca2+ and reactive oxygen species (ROS) signaling, which critically determines the mechanical activity of the heart. Either cardiac-specific knockout or overexpression of Piezo1 in mice results in defective Ca2+ and ROS signaling and the development of cardiomyopathy, demonstrating a homeostatic role of Piezo1. Piezo1 is pathologically upregulated in both mouse and human diseased hearts via an autonomic response of cardiomyocytes. Thus, Piezo1 serves as a key cardiac mechanotransducer for initiating mechano-chemo transduction and consequently maintaining normal heart function, and might represent a novel therapeutic target for treating human heart diseases.
The GSK3β-β-catenin-TCF1 pathway improves naive T cell activation in old adults by upregulating miR-181a
Authors: Ye Zhongde , Gould Timothy M. , Zhang Huimin , Jin Jun , Weyand Cornelia M. , Goronzy Jörg J. 
Published: February 2021

AbstractMicroRNAs play an important role in the regulation of T cell development, activation, and differentiation. One of the most abundant microRNAs in lymphocytes is miR-181a, which controls T cell receptor (TCR) activation thresholds in thymic selection as well as in peripheral T cell responses. We previously found that miR-181a levels decline in T cells in the elderly. In this study, we identified TCF1 as a transcriptional regulator of pri-miR-181a. A decline in TCF1 levels in old individuals accounted for the reduced miR-181a expression impairing TCR signaling. Inhibition of GSK3ß restored expression of miR-181a by inducing TCF1 in T cells from old adults. GSK3ß inhibition enhanced TCR signaling to increase downstream expression of activation markers and production of IL-2. The effect involved the upregulation of miR-181a and the inhibition of DUSP6 expression. Thus, inhibition of GSK3ß can restore responses of old T cells by inducing miR-181a expression through TCF1.
Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer
Authors: Foldi Julia , Silber Andrea , Reisenbichler Emily , Singh Kamaljeet , Fischbach Neal , Persico Justin , Adelson Kerin , Katoch Anamika , Horowitz Nina , Lannin Donald , Chagpar Anees , Park Tristen , Marczyk Michal , Frederick Courtney , Burrello Trisha , Ibrahim Eiman , Qing Tao , Bai Yalai , Blenman Kim , Rimm David L. , Pusztai Lajos 
Published: February 2021

AbstractThe goal of this Phase I/II trial is to assess the safety and efficacy of administering durvalumab concurrent with weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide (ddAC) neoadjuvant therapy for stages I–III triple-negative breast cancer. The primary endpoint is pathologic complete response (pCR:ypT0/is, ypN0). The response was correlated with PDL1 expression and stromal tumor-infiltrating lymphocytes (sTILs). Two dose levels of durvalumab (3 and 10 mg/kg) were assessed. PD-L1 was assessed using the SP263 antibody; ≥1% immune and tumor cell staining was considered positive; sTILs were calculated as the area occupied by mononuclear inflammatory cells over the total intratumoral stromal area. 59 patients were evaluable for toxicity and 55 for efficacy in the Phase II study (10 mg/kg dose). No dose-limiting toxicities were observed in Phase I. In Phase II, pCR rate was 44% (95% CI: 30–57%); 18 patients (31%) experienced grade 3/4 treatment-related adverse events (AE), most frequently neutropenia (n = 4) and anemia (n = 4). Immune-related grade 3/4 AEs included Guillain–Barre syndrome (n = 1), colitis (n = 2), and hyperglycemia (n = 2). Of the 50 evaluable patients for PD-L1, 31 (62%) were PD-L1 positive. pCR rates were 55% (95% CI: 0.38–0.71) and 32% (95% CI: 0.12–0.56) in the PD-L1 positive and negative groups (p = 0.15), respectively. sTIL counts were available on 52 patients and were significantly higher in the pCR group (p = 0.0167). Concomitant administration of durvalumab with sequential weekly nab-paclitaxel and ddAC neoadjuvant chemotherapy resulted in a pCR rate of 44%; pCR rates were higher in sTIL-high cancers.
Gravity sensing in plant and animal cells
Authors: Takahashi Ken , Takahashi Hideyuki , Furuichi Takuya , Toyota Masatsugu , Furutani-Seiki Makoto , Kobayashi Takeshi , Watanabe-Takano Haruko , Shinohara Masahiro , Numaga-Tomita Takuro , Sakaue-Sawano Asako , Miyawaki Atsushi , Naruse Keiji 
Published: February 2021

AbstractGravity determines shape of body tissue and affects the functions of life, both in plants and animals. The cellular response to gravity is an active process of mechanotransduction. Although plants and animals share some common mechanisms of gravity sensing in spite of their distant phylogenetic origin, each species has its own mechanism to sense and respond to gravity. In this review, we discuss current understanding regarding the mechanisms of cellular gravity sensing in plants and animals. Understanding gravisensing also contributes to life on Earth, e.g., understanding osteoporosis and muscle atrophy. Furthermore, in the current age of Mars exploration, understanding cellular responses to gravity will form the foundation of living in space.
Simultaneous experimental evaluation of pulse shape and deadtime phenomenon of GM detector
Authors: Almutairi Bader , Alam Syed , Goodwin Cameron S. , Usman Shoaib , Akyurek Tayfun 
Published: February 2021

AbstractAnalysis of several pulse shape properties generated by a Geiger Mueller (GM) detector and its dependence on applied voltage was performed. The two-source method was utilized to measure deadtime while simultaneously capturing pulse shape parameters on an oscilloscope. A wide range of operating voltages (600–1200 V) beyond the recommended operating voltage of 900 V was investigated using three radioactive sources (204Tl, 137Cs, 22Na). This study investigates the relationship between operating voltage, pulse shape properties, and deadtime of the detector. Based on the data, it is found that deadtime decreases with increasing voltage from 600 to 650 V. At these low voltages (600–650 V), the collection time was long, allowing sufficient time for some recombination to take place. Increasing the voltage in this range decreased the collection time, and hence deadtime decreased. It is also observed that rise and fall time were at their highest at these applied voltages. Increasing the voltage further would result in gas multiplication, where deadtime and pulse width are observed to be increasing. After reaching the maximum point of deadtime (~ 250 µs at ~ 700 V), deadtime started to exponentially decrease until a plateau was reached. In this region, it is observed that detector deadtime and operating voltage show a strong correlation with positive pulse width, rise and fall time, cycle mean, and area. Therefore, this study confirms a correlation between detector deadtime, operating voltage, and pulse shape properties. The results will validate our hypothesis that deadtime phenomena at different operating voltages are phenomenologically different.
The origin of the expressed retrotransposed gene ACTBL2 and its influence on human melanoma cells’ motility and focal adhesion formation
Authors: Malek Natalia , Michrowska Aleksandra , Mazurkiewicz Ewa , Mrówczyńska Ewa , Mackiewicz Paweł , Mazur Antonina J. 
Published: February 2021

AbstractWe have recently found that β-actin-like protein 2 (actbl2) forms complexes with gelsolin in human melanoma cells and can polymerize. Phylogenetic and bioinformatic analyses showed that actbl2 has a common origin with two non-muscle actins, which share a separate history from the muscle actins. The actin groups’ divergence started at the beginning of vertebrate evolution, and actbl2 actins are characterized by the largest number of non-conserved amino acid substitutions of all actins. We also discovered thatACTBL2is expressed at a very low level in several melanoma cell lines, but a small subset of cells exhibited a highACTBL2expression. We found that clones with knocked-outACTBL2(CR-ACTBL2) or overexpressing actbl2 (OE-ACTBL2) differ from control cells in the invasion, focal adhesion formation, and actin polymerization ratio, as well as in the formation of lamellipodia and stress fibers. Thus, we postulate that actbl2 is the seventh actin isoform and is essential for cell motility.
Seasonal characteristics of storms over the Indian subcontinent
Authors: Sindhu Kapil Dev , Bhat G. S. 
Published: February 2021

AbstractStorms are convective cells responsible for the major fraction of convective precipitation. Here, the pre-monsoon and monsoon season characteristics of storms are reported at Lucknow, Patna, Bhopal, and Nagpur in India using equivalent radar reflectivity factor ($$\hbox {Z}_e$$

Z
e

) given at these radar locations. It is observed that the lifetime, speed of propagation, area, volume, echo top height and thickness lie in ranges 0.3–3 h, 5–60 km $$\hbox {h}^{-1}$$

h

-
1

, 4–184 $$\hbox {km}^2$$

km
2

, 8–1600 $$\hbox {km}^3$$

km
3

, 2–14 km, and 0.5–16 km respectively. For both seasons, the relationships between radar estimated rain volume (RERV; range $$10^4$$

10
4

–$$10^7$$

10
7

$$\hbox {m}^3$$

m
3

) and area-time integral (ATI; range 1–100 $$\hbox {km}^2$$

km
2

h) are established which are considered as a representative of total precipitation resulted from an individual storm during its life cycle. The results from statistical analysis of RERV-ATI pairs suggest that storms at Lucknow have similar seasonal characteristics at 87% confidence interval while other locations exhibit dissimilarities. In addition, the vertical profiles of radar reflectivity (VPRRs) of storms are constructed at their life phases, namely cumulus, mature and dissipation. It is concluded that the vertical $$\hbox {Z}_e$$

Z
e

gradient in mixed-phase region (5–8 km) is lower (2–2.9 dBZ $$\hbox {km}^{-1}$$

km

-
1

) at cumulus and dissipation phases than at mature phase (3.6–4.4 dBZ $$\hbox {km}^{-1}$$

km

-
1

) in monsoon season. For pre-monsoon season, this gradient lies between 3.3–5.2 dBZ $$\hbox {km}^{-1}$$

km

-
1

at mature phase. Our results are of great importance for advancing knowledge about storm-scale, which has implications in short-range weather forecasting as well as developing new convective parametrization schemes.
Use of plasma nitriding to improve the wear and corrosion resistance of 18Ni-300 maraging steel manufactured by selective laser melting
Authors: Godec M. , Podgornik B. , Kocijan A. , Donik Č. , Balantič D. A. Skobir 
Published: February 2021

Abstract18Ni-300 maraging steel manufactured by selective laser melting was plasma nitrided to improve its wear and corrosion resistance. The effects of a prior solution treatment, aging and the combination of both on the microstructure and the properties after nitriding were investigated. The results were compared with conventionally produced 18Ni-300 counterparts subjected to the same heat- and thermo-chemical treatments. The plasma nitriding was performed under the same conditions (temperature of 520 °C and time of 6 h) as the aging in order to investigate whether the nitriding and the aging could be carried out simultaneously in a single step. The aim of this work was to provide a better understanding of the morphology and chemical composition of the nitrided layer in the additive-manufactured maraging steel as a function of the prior heat treatments and to compare the wear and corrosion resistance with those of conventional maraging steel. The results show that nitriding without any prior aging leads to cracks in the compound layer, while nitriding of the prior-heat-treated additive-manufactured maraging steel leads to benefits from the thermochemical treatment in terms of wear and corrosion resistance. Some explanations for the origins of the cracks and pores in the nitride layers are provided.