bluuebunny/crossref_metadata_2025 huggingface dataset:
Does Relationship Conflict Predicts Psychological Distress or Vice Versa? A Cross-Lagged Panel Model
Authors: Özdemir Yalçın , Sağkal Ali Serdar
Published: February 2021

The present study examines the directionality of links between romantic relationship conflict and psychological distress in premarital relationships of emerging adults. A total of 182 participants (Mage = 21.23; SDage = 1.62; 85.16% female) provided data at both Time 1 (T1) and Time 2 (T2). Participants responded to a battery of questions related to romantic relationship conflict and psychological distress. The data for the present study were collected at two time points during spring semester of 2018: First week (Time 1) and the last week of the semester, Week 14 (Time 2). A two-wave two variable cross-lagged autoregressive panel model was conducted to examine the links between relationship conflict and psychological distress over time in emerging adults. Using a latent cross-lagged panel model, we found that romantic relationship conflict at T1 significantly predicted psychological distress at T2, but psychological distress at T1 was not associated with subsequent romantic relationship conflict at T2, after controlling for autoregressive effects. The results highlighted the key role of romantic relationship conflict in predicting later psychological distress. Limitations and implications are discussed and future directions are suggested.
Extremely Collimated Electron Beams in the High Latitude Magnetosphere Observed by Arase
Authors: Kazama Y. , Kojima H. , Miyoshi Y. , Kasahara Y. , Kasahara S. , Usui H. , Wang B.‐J. , Wang S.‐Y. , Tam S. W. Y. , Chang T.‐F. , Asamura K. , Kasaba Y. , Matsuda S. , Shoji M. , Matsuoka A. , Teramoto M. , Takashima T. , Shinohara I.
Published: February 2021

This report describes electron beams observed at high latitudes in the magnetosphere by the Arase satellite. According to fine angular channel measurements, beam electrons are mainly flowing away from the Earth, and are well collimated to within a few degrees. A statistical study indicates that the beams are seen when Arase is located at Lm > ∼5, and more frequently as the magnetosphere becomes active. The field lines of the beam events are traced back to the typical auroral ovals. The statistical properties of the beams are consistent with the interpretation that ionospheric electrons are accelerated by a parallel electric field of an auroral potential structure and are streaming upward to the high latitude magnetosphere.
Tangent Directions of the Cusp Boundary Derived From the Simulated Soft X‐Ray Image
Authors: Sun Tianran , Wang Xue , Wang Chi
Published: February 2021

The magnetospheric cusp plays an essential role in mass and energy transportation from the solar wind to the geo‐space environment. Recent development of the X‐ray imaging technique makes it possible to study the large scale properties of the cusp region from a global view. As the detected X‐ray signals will be integrated along the line‐of‐sight (LOS), it is a challenging task to derive the information about the 3D cusp region from a 2D X‐ray image. Based on global magnetohydrodynamic (MHD) code, this paper simulated and analyzed the X‐ray image of cusp. An approach was developed to present the following aspects related to the morphology of cusp from the X‐ray image: (1) The tangent direction of the cusp boundary is the direction with appreciable increase of local standard deviation in X‐ray intensity, and (2) the direction running through the cusp center is the direction with peak X‐ray intensity. Lack of knowledge on radial distribution of X‐ray signal along the line‐of‐sight, exact position of cusp cannot be further derived without assumptions. Nevertheless, under special solar wind conditions such as zero Interplanetary Magnetic Field (IMF) By, it is reasonable to assume that the cusp center is in the noon‐midnight meridian plane. Therefore, position of the cusp center can be reconstructed. Based on MHD simulations, the above conclusions have been validated with different viewing geometries and solar wind conditions. With reasonable assumptions, the large‐scale cusp features in response to the solar wind variations can be clearly revealed by analyzing X‐ray images.
Anomalous Electron Temperature Increases in the Evening Equatorial Ionosphere
Authors: Fejer B. G. , Hysell D. L. , Navarro L. A.
Published: February 2021

We use novel radar observations at the Jicamarca Radio Observatory to study the first observations of highly enhanced plasma temperatures in the evening equatorial ionosphere. These short‐lived solstice evening events occurred following large upward plasma drifts and sharply reduced plasma densities. The electron temperatures increase during the August 5 and 6, 2011 moderate solar event reached peak values of about 1,000 K near 350 km. Smaller electron temperature increases were observed to altitudes up to about 500 km. There were also smaller concurrent ion temperature enhancements. During the very low solar flux January 20 and 21, 2020 event, a peak electron temperature increase of about 700 K occurred at an altitude of about 270 km. We also show that SAMI2‐PE simulations using the measured vertical plasma drifts reproduce the main characteristics of the measured plasma densities and temperatures up to 300 km, but not at higher altitudes. These simulations indicate that the evening anomalous plasma heating below about 300 km is due to the decrease in the electron‐ion cooling rate resulting from upward plasma drift driven decrease in the plasma density. Plasma transport and reduced cooling rate is a potential source of higher altitude heating.
Bottom Boundary Layer Oxygen Fluxes During Winter on the Oregon Shelf
Authors: Reimers Clare E. , Fogaren Kristen E.
Published: February 2021

In this study, lander‐based eddy covariance measurements made 30 cm above a sandy seafloor are combined with ocean‐observing and ship‐based measurements to evaluate magnitudes of oxygen fluxes within the bottom boundary layer (BBL) during winter on the Oregon shelf. The total oxygen fluxes observed at a mid‐shelf station were −12.3 ± 7.6 and −18.6 ± 16.9 mmol m−2d−1 during February 2018 and January 2019 deployments, respectively, and −51.8 ± 34.9 mmol m−2d−1 during a deployment on the inner shelf in January 2019. These mean (±SD) flux derivations are greater than fluxes determined previously at nearly the same locations during the summer upwelling season, which points to the activation of benthic respiration by winter wave‐dominated BBL dynamics. To determine the direct flux contributions (or potential bias) at wave frequencies, a phase‐based method of spectral decomposition was applied to separate wave‐induced and turbulence‐induced components of velocity and dissolved oxygen time‐series. This approach identified 25.4, 18.6, and 23.3% of the average total EC oxygen fluxes from the three deployments as carried by waves or possibly turbulence stretched by waves. Additionally, we observed evidence of large waves regularly resuspending sediments and transporting entrained particles past the EC sensors. We apply this evidence to infer that wave frequencies must also contribute significantly to the real spectral domain of benthic oxygen fluxes and that the total fluxes of this study reflect elevated oxygen consumption rates without artifacts. This assessment may not be true for all data sets and may be dependent on wave properties and the quality and treatment of the measurements.
The Southern Annular Mode in 6th Coupled Model Intercomparison Project Models
Authors: Morgenstern O.
Published: February 2021

I analyze trends in the Southern Annular Mode (SAM) in CMIP6 simulations. For the period 1957–2014, simulated linear trends are generally consistent with two observational references but seasonally in disagreement with two other representations of the SAM. Using a regression analysis applied to model simulations with interactive ozone chemistry, a strengthening of the SAM in summer is attributed nearly completely to ozone depletion because a further strengthening influence due to long‐lived greenhouse gases is almost fully counterbalanced by a weakening influence due to stratospheric ozone increases associated with these greenhouse gas increases. Ignoring such ozone feedbacks would yield comparable contributions from these two influences, an incorrect result. In winter, trends are smaller but an influence of greenhouse gas‐mediated ozone feedbacks is also identified. The regression analysis furthermore yields significant differences in the attribution of SAM changes to the two influences between models with and without interactive ozone chemistry, with ozone depletion and GHG increases playing seasonally a stronger and weaker, respectively, role in the chemistry models versus the no‐chemistry ones.
Hydrogeochemical Constraints Shape Hot Spring Microbial Community Compositions: Evidence From Acidic, Moderate‐Temperature Springs and Alkaline, High‐Temperature Springs, Southwestern Yunnan Geothermal Areas, China
Authors: Guo Liang , Wang Guangcai , Sheng Yizhi , Shi Zheming
Published: February 2021

Environmental factors (e.g., temperature and pH) shaping the distribution of microbial communities in hot springs have been extensively studied, whereas how hydrochemical formation mechanisms and hydrological circulation processes affect microbial community composition is not comprehensively elucidated. In the present study, hydrochemical, isotopic, and high‐throughput sequencing methods were employed to investigate hydrochemical characteristics and evolution of springwater as well as their underlying roles in shaping the microbial community in multiple acidic and alkaline hot springs in southwestern Yunnan, China. Distinct hydrochemical (e.g., pH, temperature, sulfate, SiO2, and trace metals) and isotopic (δ2H and δ18O) characteristics revealed the recharge sources and circulation processes of springwater were different in alkaline, high‐temperature and acidic, moderate‐temperature hot springs. Two acidic, moderate‐temperature springs (43°C–55°C), characterized by high sulfate, showed shallow circulation depths and were potentially heated by upwelling hot, high H2S abundance gases, and sulfur oxidation might be one of the main underlying hydrochemical processes. Seven alkaline, high‐temperature springs (>70°C), in contrast, which originated from a different recharge source as indicated by the lighter isotopic compositions (δ2H and δ18O), showed characteristics of deeper circulation. Hydrogenobacter sp. is the most abundant microorganism in alkaline, high‐temperature springs, whereas acidic, moderate‐temperature springs are mainly composed of Chlorobiaceae, Thiomonas sp., Halothiobacillus sp., Sulfurihydrogenibium sp., and Hydrogenobaculum sp. which have been reported to possess the potentials to cycle sulfur. The hydrochemical constraints on shaping microbial communities may help us better understand biogeochemical cycles across a range of temperatures in acidic and alkaline springs.
A Peculiar ICME Event in August 2018 Observed With the Global Muon Detector Network
Authors: Kihara W. , Munakata K. , Kato C. , Kataoka R. , Kadokura A. , Miyake S. , Kozai M. , Kuwabara T. , Tokumaru M. , Mendonça R. R. S. , Echer E. , Lago A. Dal , Rockenbach M. , Schuch N. J. , Bageston J. V. , Braga C. R. , Al Jassar H. K. , Sharma M. M. , Duldig M. L. , Humble J. E. , Evenson P. , Sabbah I. , Kóta J.
Published: February 2021

We demonstrate that global observations of high‐energy cosmic rays contribute to understanding unique characteristics of a large‐scale magnetic flux rope causing a magnetic storm in August 2018. Following a weak interplanetary shock on August 25, 2018, a magnetic flux rope caused an unexpectedly large geomagnetic storm. It is likely that this event became geoeffective because the flux rope was accompanied by a corotating interaction region and compressed by high‐speed solar wind following the flux rope. In fact, a Forbush decrease was observed in cosmic‐ray data inside the flux rope as expected, and a significant cosmic‐ray density increase exceeding the unmodulated level before the shock was also observed near the trailing edge of the flux rope. The cosmic‐ray density increase can be interpreted in terms of the adiabatic heating of cosmic rays near the trailing edge of the flux rope, as the corotating interaction region prevents free expansion of the flux rope and results in the compression near the trailing edge. A northeast‐directed spatial gradient in the cosmic‐ray density was also derived during the cosmic‐ray density increase, suggesting that the center of the heating near the trailing edge is located northeast of Earth. This is one of the best examples demonstrating that the observation of high‐energy cosmic rays provides us with information that can only be derived from the cosmic ray measurements to observationally constrain the three‐dimensional macroscopic picture of the interaction between coronal mass ejections and the ambient solar wind, which is essential for prediction of large magnetic storms.
Orexin receptor antagonists reverse aberrant dopamine neuron activity and related behaviors in a rodent model of stress-induced psychosis
Authors: Elam Hannah B. , Perez Stephanie M. , Donegan Jennifer J. , Lodge Daniel J.
Published: February 2021

Post-traumatic stress disorder (PTSD) is a prevalent condition affecting approximately 8% of the United States population and 20% of United States combat veterans. In addition to core symptoms of the disorder, up to 64% of individuals diagnosed with PTSD experience comorbid psychosis. Previous research has demonstrated a positive correlation between symptoms of psychosis and increases in dopamine transmission. We have recently demonstrated projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) can regulate dopamine neuron activity in the ventral tegmental area (VTA). Specifically, inactivation of the PVT leads to a reversal of aberrant dopamine system function and psychosis-like behavior. The PVT receives dense innervation from orexin containing neurons, therefore, targeting orexin receptors may be a novel approach to restore dopamine neuron activity and alleviate PTSD-associated psychosis. In this study, we induced stress-related pathophysiology in male Sprague Dawley rats using an inescapable foot-shock procedure. We observed a significant increase in VTA dopamine neuron population activity, deficits in sensorimotor gating, and hyperresponsivity to psychomotor stimulants. Administration of selective orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) antagonists (SB334867 and EMPA, respectively) or the FDA-approved, dual-orexin receptor antagonist, Suvorexant, were found to reverse stress-induced increases in dopamine neuron population activity. However, only Suvorexant and SB334867 were able to reverse deficits in behavioral corelates of psychosis. These results suggest that the orexin system may be a novel pharmacological target for the treatment of comorbid psychosis related to PTSD.
Correction to: Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence
Authors: Mocking Roel J. T. , Naviaux Jane C. , Li Kefeng , Wang Lin , Monk Jonathan M. , Bright A. Taylor , Figueroa Caroline A. , Schene Aart H. , Ruhé Henricus G. , Assies Johanna , Naviaux Robert K.
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41398-021-01239-4
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

Long 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

Alteration 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

Through 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

There 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

A 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

ATP-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

Statins 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

The 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

MicroRNAs 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

The 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

Gravity 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

Analysis 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

We 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

Storms 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

18Ni-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.
Frequency-induced negative magnetic susceptibility in epoxy/magnetite nanocomposites
Authors: Chang Che-Hao , Su Shih-Chieh , Chang Tsun-Hsu , Chang Ching-Ray
Published: February 2021

The epoxy/magnetite nanocomposites express superparamagnetism under a static or low-frequency electromagnetic field. At the microwave frequency, said the X-band, the nanocomposites reveal an unexpected diamagnetism. To explain the intriguing phenomenon, we revisit the Debye relaxation law with the memory effect. The magnetization vector of the magnetite is unable to synchronize with the rapidly changing magnetic field, and it contributes to diamagnetism, a negative magnetic susceptibility for nanoparticles. The model just developed and the fitting result can not only be used to explain the experimental data in the X-band but also can be used to estimate the transition frequency between paramagnetism and diamagnetism.
Sex-dependent alterations in behavior, drug responses and dopamine transporter expression in heterozygous DAT-Cre mice
Authors: Costa Kauê Machado , Schenkel Daniela , Roeper Jochen
Published: February 2021

Heterozygous mice that express Cre-recombinase under the dopamine transporter promoter (DAT-Cre knock in mice, or KI) are widely used for targeting midbrain dopamine neurons, under the assumption that their constitutive physiology is not affected. We report here that these mice display striking sex-dependent behavioral and molecular differences in relation to wildtypes (WT). Male and female KI mice were constitutively hyperactive, and male KI mice showed attenuated hyperlocomotor responses to amphetamine. In contrast, female KIs displayed a marked reduction in locomotion (“calming” effect) in response to the same dose of amphetamine. Furthermore, male and female DAT-Cre KI mice showed opposing differences in reinforcement learning, with females showing faster conditioning and males showing slower extinction. Other behavioral variables, including working memory and novelty preference, were not changed compared to WT. These effects were paralleled by differences in striatal DAT expression that disproportionately affected female KI mice. Our findings reveal clear limitations of the DAT-Cre line that must be considered when using this model.
Watching synchronous mitochondrial respiration in the retina and its instability in a mouse model of macular degeneration
Authors: Kaynezhad Pardis , Tachtsidis Ilias , Aboelnour Asmaa , Sivaprasad Sobha , Jeffery Glen
Published: February 2021

Mitochondrial function declines with age and in some diseases, but we have been unable to analyze this in vivo. Here, we optically examine retinal mitochondrial function as well as choroidal oxygenation and hemodynamics in aging C57 and complement factor H (CFH−/−) mice, proposed models of macular degeneration which suffer early retinal mitochondrial decline. In young C57s mitochondrial populations respire in coupled oscillatory behavior in cycles of ~ 8 min, which is phase linked to choroidal oscillatory hemodynamics. In aging C57s, the oscillations are less regular being ~ 14 min and more dissociated from choroidal hemodynamics. The mitochondrial oscillatory cycles are extended in CFH−/− mice being ~ 16 min and are further dissociated from choroidal hemodynamics. Mitochondrial decline occurs before age-related changes to choroidal vasculature, hence, is the likely origin of oscillatory disruption in hemodynamics. This technology offers a non-invasive technique to detect early retinal disease and its relationship to blood oxygenation in vivo and in real time.
Speciation and milk adulteration analysis by rapid ambient liquid MALDI mass spectrometry profiling using machine learning
Authors: Piras Cristian , Hale Oliver J. , Reynolds Christopher K. , Jones A. K. , Taylor Nick , Morris Michael , Cramer Rainer
Published: February 2021

Growing interest in food quality and traceability by regulators as well as consumers demands advances in more rapid, versatile and cost-effective analytical methods. Milk, as most food matrices, is a heterogeneous mixture composed of metabolites, lipids and proteins. One of the major challenges is to have simultaneous, quantitative detection (profiling) of this panel of biomolecules to gather valuable information for assessing food quality, traceability and safety. Here, for milk analysis, atmospheric pressure matrix-assisted laser desorption/ionization employing homogenous liquid sample droplets was used on a Q-TOF mass analyzer. This method has the capability to produce multiply charged proteinaceous ions as well as highly informative profiles of singly charged lipids/metabolites. In two examples, this method is coupled with user-friendly machine-learning software. First, rapid speciation of milk (cow, goat, sheep and camel) is demonstrated with 100% classification accuracy. Second, the detection of cow milk as adulterant in goat milk is shown at concentrations as low as 5% with 92.5% sensitivity and 94.5% specificity.
In silico identification of natural products from Traditional Chinese Medicine for cancer immunotherapy
Authors: Cai Chuipu , Wu Qihui , Hong Honghai , He Liying , Liu Zhihong , Gu Yong , Zhang Shijie , Wang Qi , Fan Xiude , Fang Jiansong
Published: February 2021

Advances in immunotherapy have revolutionized treatments in many types of cancer. Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant application against cancer, is emerging as an important medical resource for developing innovative cancer treatments, including immunotherapy. In this study, we developed a quantitative and systems pharmacology-based framework to identify TCM-derived natural products for cancer immunotherapy. Specifically, we integrated 381 cancer immune response-related genes and a compound-target interaction network connecting 3273 proteins and 766 natural products from 66 cancer-related herbs based on literature-mining. Via systems pharmacology-based prediction, we uncovered 182 TCM-derived natural products having potential anti-tumor immune responses effect. Importantly, 32 of the 49 most promising natural products (success rate = 65.31%) are validated by multiple evidence, including published experimental data from clinical studies, in vitro andin vivoassays. We further identified the mechanism-of-action of TCM in cancer immunotherapy using network-based functional enrichment analysis. We showcased that three typical natural products (baicalin, wogonin, and oroxylin A) inHuangqin(Scutellaria baicalensis Georgi) potentially overcome resistance of known oncology agents by regulating tumor immunosuppressive microenvironments. In summary, this study offers a novel and effective systems pharmacology infrastructure for potential cancer immunotherapeutic development by exploiting the medical wealth of natural products in TCM.
The protective role of daidzein in intestinal health of turbot (Scophthalmus maximus L.) fed soybean meal-based diets
Authors: Yu Guijuan , Liu Yang , Ou Weihao , Dai Jihong , Ai Qinghui , Zhang Wenbing , Mai Kangsen , Zhang Yanjiao
Published: February 2021

Soybean meal-induced enteropathy (SBMIE) is prevalent in aquaculture. The aim of this study is to evaluate the role of daidzein on SBMIE of juvenile turbot (Scophthalmus maximus L.) by feeding with fish meal diet (FM), soybean meal diet (SBM, 40% fish meal protein in FM replaced by soybean meal protein) and daidzein diet (DAID, 40 mg/kg daidzein supplemented to SBM) for 12 weeks. We found that daidzein supplementation elevated the gene expression of anti-inflammatory cytokine TGF-β, decreased gene expression of pro-inflammatory cytokines TNF-α and signal molecules p38, JNK and NF-κB. SBM up-regulated the genes expression related to oxidative stress and apoptosis, but dietary daidzein restored it to the similar level with that in FM group. Moreover, dietary daidzein up-regulated gene expression of tight junction protein, and modified the intestinal microbial profiles with boosted relative abundance of phylum Proteobacteria and Deinococcus–Thermus, genera Sphingomonas and Thermus, species Lactococcus lactis, and decreased abundance of some potential pathogenic bacteria. In conclusion, dietary daidzein could ameliorate SBM-induced intestinal inflammatory response, oxidative stress, mucosal barrier injury and microbiota community disorder of turbot. Moreover, p38, JNK and NF-κB signaling might be involved in the anti-inflammatory process of daidzein, and daidzein itself might act as an antioxidant to resist SBM-induced oxidative damage.