bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction between moxifloxacin and Mcl-1 and MITF proteins: the effect on growth inhibition and apoptosis in MDA-MB-231 human triple-negative breast cancer cells
Authors: Beberok Artur , Rok Jakub , Rzepka Zuzanna , Marciniec Krzysztof , Boryczka Stanisław , Wrześniok Dorota
Published: September 2022

Background

Microphthalmia-associated transcription factor (MITF) activates the expression of genes involved in cellular proliferation, DNA replication, and repair, whereas Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing apoptosis. The objective of the present study was to verify whether the interaction between moxifloxacin (MFLX), one of the fluoroquinolones, and MITF/Mcl-1 protein, could affect the viability, proliferation, and apoptosis in human breast cancer using both in silico and in vitro models.

Methods

Molecular docking analysis (in silico), fluorescence image cytometry, and Western blot (in vitro) techniques were applied to assess the contribution of MITF and Mcl-1 proteins in the MFLX-induced anti-proliferative and pro-apoptotic effects on the MDA-MB-231 breast cancer cells.

Results

We indicated the ability of MFLX to form complexes with MITF and Mcl-1 as well as the drug’s capacity to affect the expression of the tested proteins. We also showed that MFLX decreased the viability and proliferation of MDA-MB-231 cells and induced apoptosis via the intrinsic death pathway. Moreover, the analysis of the cell cycle progression revealed that MFLX caused a block in the S and G2/M phases.

Conclusions

We demonstrated for the first time that the observed effects of MFLX on MDA-MB-231 breast cancer cells (growth inhibition and apoptosis induction) could be related to the drug’s ability to interact with MITF and Mcl-1 proteins. Furthermore, the presented results suggest that MITF and Mcl-1 proteins could be considered as the target in the therapy of breast cancer.

Graphical abstract
Introduction to Quantum Field Theory
Authors: Williams Anthony G.
Published: September 2022

This textbook offers a detailed and uniquely self-contained presentation of quantum and gauge field theories. Writing from a modern perspective, the author begins with a discussion of advanced dynamics and special relativity before guiding students steadily through the fundamental principles of relativistic quantum mechanics and classical field theory. This foundation is then used to develop the full theoretical framework of quantum and gauge field theories. The introductory, opening half of the book allows it to be used for a variety of courses, from advanced undergraduate to graduate level, and students lacking a formal background in more elementary topics will benefit greatly from this approach. Williams provides full derivations wherever possible and adopts a pedagogical tone without sacrificing rigour. Worked examples are included throughout the text and end-of-chapter problems help students to reinforce key concepts. A fully worked solutions manual is available online for instructors.
Reading in a Second Language
Authors: Grabe William , Yamashita Junko
Published: September 2022

Understanding reading abilities and their development is fundamental for language comprehension and human cognition. Now in its second edition, this book draws on research from multiple disciplines to explain reading abilities in both L1 and L2, and shows how this research can be applied in practice in order to support reading development. Research into reading has progressed a great deal since the first edition was published, so this edition has been completely updated and revised, in order to reflect these advances. All chapters present updated research studies, and completely new chapters are included on the neurocognition of reading, reading-writing relationships, and digital reading. If you want to know how reading works, no matter the language(s) involved, as well as how it can be taught effectively, this book provides a persuasive research foundation and many practical insights. It is essential reading for academic researchers and students in Applied Linguistics and TESOL.
On q-scale functions of spectrally negative Lévy processes
Authors: Behme Anita , Oechsler David , Schilling René
Published: September 2022

We obtain series expansions of the q-scale functions of arbitrary spectrally negative Lévy processes, including processes with infinite jump activity, and use these to derive various new examples of explicit q-scale functions. Moreover, we study smoothness properties of the q-scale functions of spectrally negative Lévy processes with infinite jump activity. This complements previous results of Chan et al. (Prob. Theory Relat. Fields150, 2011) for spectrally negative Lévy processes with Gaussian component or bounded variation.
Supporting peace negotiations in the Yemen war through machine learning
Authors: Arana-Catania Miguel , van Lier Felix-Anselm , Procter Rob
Published: September 2022

Today’s conflicts are becoming increasingly complex, fluid, and fragmented, often involving a host of national and international actors with multiple and often divergent interests. This development poses significant challenges for conflict mediation, as mediators struggle to make sense of conflict dynamics, such as the range of conflict parties and the evolution of their political positions, the distinction between relevant and less relevant actors in peace-making, or the identification of key conflict issues and their interdependence. International peace efforts appear ill-equipped to successfully address these challenges. While technology is already being experimented with and used in a range of conflict related fields, such as conflict predicting or information gathering, less attention has been given to how technology can contribute to conflict mediation. This case study contributes to emerging research on the use of state-of-the-art machine learning technologies and techniques in conflict mediation processes. Using dialogue transcripts from peace negotiations in Yemen, this study shows how machine-learning can effectively support mediating teams by providing them with tools for knowledge management, extraction and conflict analysis. Apart from illustrating the potential of machine learning tools in conflict mediation, the article also emphasizes the importance of interdisciplinary and participatory, cocreation methodology for the development of context-sensitive and targeted tools and to ensure meaningful and responsible implementation.
Kernels of localities
Authors: Grazian Valentina , Henke Ellen
Published: September 2022

We state a sufficient condition for a fusion system to be saturated. This is then used to investigate localities with kernels: that is, localities that are (in a particular way) extensions of groups by localities. As an application of these results, we define and study certain products in fusion systems and localities, thus giving a new method to construct saturated subsystems of fusion systems.
Photon energy transfer on titanium targets for laser thrusters
Authors: Marcu A. , Stafe M. , Barbuta M. , Ungureanu R. , Serbanescu M. , Calin B. , Puscas N.
Published: September 2022

Using two infrared pulsed lasers systems, a picosecond solid-state Nd:YAG laser with tuneable repetition rate (400 kHz–1 MHz) working in the burst mode of a multi-pulse train and a femtosecond Ti:sapphire laser amplifier with tuneable pulse duration in the range of tens of femtoseconds up to tens of picoseconds, working in single-shot mode (TEWALASS facility from CETAL-NILPRP), we have investigated the optimal laser parameters for kinetic energy transfer to a titanium target for laser-thrust applications. In the single-pulse regime, we controlled the power density by changing both the duration and pulse energy. In the multi-pulse regime, the train’s number of pulses (burst length) and the pulse energy variation were investigated. Heat propagation and photon reflection-based models were used to simulate the obtained experimental results. In the single-pulse regime, optimal kinetic energy transfer was obtained for power densities of about 500 times the ablation threshold corresponding to the specific laser pulse duration. In multi-pulse regimes, the optimal number of pulses per train increases with the train frequency and decreases with the pulse power density. An ideal energy transfer efficiency resulting from our experiments and simulations is close to about 0.0015%.
Birefringent strands drive the flow of viscoelastic fluids past obstacles
Authors: Mokhtari O. , Latché J.-C. , Quintard M. , Davit Y.
Published: September 2022

The flow of polymer solutions past solid obstacles or through porous media gives rise to rich physical phenomena over a wide range of spatial and temporal scales. Viscoelasticity, in particular, can induce a strong nonlinear response with an increase of flow resistance even for a solution whose viscosity decreases in simple shear flow. Various hypotheses have been proposed to explain this phenomenon but a clear picture of the pore-scale mechanisms involved and their impact upon larger scales is still lacking. Here, we show that localized zones of large polymeric stress, known as birefringent strands, drive the flow of an Oldroyd-B fluid through two-dimensional arrays of cylinders. Combining a recently developed numerical scheme with high performance computing, we find that these strands generate a complete reorganization of the flow with an increase of stagnation zones, a reinforcement of preferential paths and a splitting of flow channels. Furthermore, we show that this reorganization is the source of an increase in the viscous dissipation of the solvent and also that the stretching of polymer molecules in the strands is associated with entropy production. Both these phenomena yield a global increase in dissipation that can be directly linked to the increase of flow resistance. Our results demonstrate that the birefringent strands – not the elongational viscosity – drive the flow of viscoelastic fluids through porous media and that the increase of flow resistance can occur even at steady state, before the transition to elastic turbulence.
When More Leads to More: Constitutional Amendments and Interpretation in Mexico 1917-2020
Authors: Pozas-Loyo Andrea , Saavedra-Herrera Camilo , Pou-Giménez Francisca
Published: September 2022

Mexico’s 1917 Constitution has gone through 737 reforms; no other codified constitution has been subjected to such a constant pattern of renewal through amendment. We argue that the study of Mexican patterns offers important theoretical insights for the study of constitutional change by calling into question the generalizability of the thesis—articulated by Donald Lutz and currently endorsed by most specialists in the field—according to which amendment and interpretation are substitute means of constitutional updating. Based on two original data sets containing all constitutional amendments and all Supreme Court precedents on constitutional matters from 1917 to 2020, we find that in Mexico hyper-reformism is correlated to a steep increase in the number and diversity of binding constitutional precedents. Quantitative and qualitative analysis shows that these precedents not only apply the Constitution, but substantively revise it, suggesting that, in Mexico, amendment and interpretation are not alternative but complementary channels of constitutional change. Our account suggests that, in Mexico, hyper-reformism has actually led to innovative constitutional interpretation as a mechanism to cope with its effects. Finally, we discuss the theoretical and comparative insights this case offers for better understanding the nature, causes, and effects of the different modalities of constitutional change.
Copy number variation of WBP1L gene revealed its association with growth traits across Chinese cattle populations
Authors: Zhang Jiaqiang , Zhang Zijing , Liu Xian , Chai Yanan , Yang Peng , Li Jungang , Huang Yajun , Li Lijuan , Huang Weihong , Yang Guojie , Qi Zengfang , Chen Fuying , Li Zhiming , Lei Chuzhao , Shi Qiaoting , Ru Baorui , Wang Eryao , Huang Yongzhen
Published: September 2022

Copy number variation (CNV) is a very common type of gene variation with high frequency. In recent years, CNV has been paid more attention in various fields, especially in livestock and poultry breeding, which has promoted the progress of breeding. WW domain binding protein 1-like (WBP1L) is a protein coding gene, which plays an important role in cattle populations, and its function has been extensively studied, but it is not clear whether the copy number of the gene can affect the growth and development of cattle populations. In this study, CNV of WBP1L gene was detected in 732 cattle of seven breeds (Qinchuan cattle, QC; Pinan cattle, PN; Yuengling cattle, YL; Xianan cattle, XN; Jiaxian cattle, JX; natural Guyuan cattle, NGY; Jian cattle, JA). In addition, the relationship between CNV and growth phenotype of cattle was studied. The experimental data indicate that the copy number of WBP1L was obviously correlated with heart girth of PN cattle (**P < 0.01), rump length (RL) and body weight (BW) of PN cattle (*P < 0.05), withers height (WH), RL, body length, chest depth and BW of JX cattle (*P < 0.05), WH of NGY cattle (*P < 0.05) and WH of JA cattle (*P < 0.05). It was proved that CNV of WBP1L gene could be used as molecular marker locus for genetic breeding of the above four cattle breeds.
Helminth parasites are associated with reduced survival probability in young red deer
Authors: Acerini Claudia I. , Morris Sean , Morris Alison , Kenyon Fiona , McBean David , Pemberton Josephine M. , Albery Gregory F.
Published: September 2022

Helminths are common parasites of wild ungulates that can have substantial costs for growth, mortality and reproduction. Whilst these costs are relatively well documented for mature animals, knowledge of helminths' impacts on juveniles is more limited. Identifying these effects is important because young individuals are often heavily infected, and juvenile mortality is a key process regulating wild populations. Here, we investigated associations between helminth infection and overwinter survival in juvenile wild red deer (Cervus elaphus) on the Isle of Rum, Scotland. We collected fecal samples non-invasively from known individuals and used them to count propagules of 3 helminth taxa (strongyle nematodes,Fasciola hepaticaandElaphostrongylus cervi). Using generalized linear models, we investigated associations between parasite counts and overwinter survival for calves and yearlings. Strongyles were associated with reduced survival in both age classes, andF. hepaticawas associated with reduced survival in yearlings, whilstE. cerviinfection showed no association with survival in either age class. This study provides observational evidence for fitness costs of helminth infection in juveniles of a wild mammal, and suggests that these parasites could play a role in regulating population dynamics.
Toxocara canisinfection worsens the course of experimental autoimmune encephalomyelitis in mice
Authors: Novák Jan , Macháček Tomáš , Majer Martin , Kostelanská Marie , Skulinová Kateřina , Černý Viktor , Kolářová Libuše , Hrdý Jiří , Horák Petr
Published: September 2022

Toxocara canis, a gastrointestinal parasite of canids, is also highly prevalent in many paratenic hosts, such as mice and humans. As with many other helminths, the infection is associated with immunomodulatory effects, which could affect other inflammatory conditions including autoimmune and allergic diseases. Here, we investigated the effect ofT. canisinfection on the course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Mice infected with 2 doses of 100T. canisL3 larvae 5 weeks prior to EAE induction (theTc+EAE group) showed higher EAE clinical scores and greater weight loss compared to the non-infected group with induced EAE (the EAE group). Elevated concentrations of all measured serum cytokines (IL-1α, IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γand TNF-α) were observed in theTc+EAE group compared to the EAE group. In the CNS, the similar number of regulatory T cells (Tregs; CD4+FoxP3+Helios+) but their decreased proportion from total CD4+ cells was found in theTc+EAE group compared to the EAE group. This could indicate that the groupTc+EAE harboured significantly more CD4+ T cells of non-Treg phenotype within the affected CNS. Altogether, our results demonstrate that infection of mice withT. canisworsens the course of subsequently induced EAE. Further studies are, therefore, urgently needed to reveal the underlying pathological mechanisms and to investigate possible risks for the human population, in which exposure toT. canisis frequent.
Roald Amundsen’s route across the polar plateau in 1911–1912
Authors: Lantz Björn
Published: September 2022

Roald Amundsen’s exact route from the top of the Axel Heiberg glacier to the South Pole and back in 1911–1912 has always been somewhat unclear because he never observed his longitude during his southern journey. His approach was simply to steer approximately in a true southerly direction by magnetic compass as long as obstacles did not force him to deviate. The fact that he only knew approximately where he was most of the time on the polar plateau never caused any severe problems for him, but it complicated the search for a depot during the return journey. Based on Amundsen’s bearings of some peaks in the Transantarctic Mountains, in combination with his compass courses adjusted with accurate values for the magnetic declination at the time, this paper elucidates Amundsen’s actual route across the polar plateau in 1911–1912. The main result is that Amundsen must have taken a more easterly route than what previously has been assumed.
Neurofunctional mapping of reward anticipation and outcome for major depressive disorder: a voxel-based meta-analysis
Authors: Yang Xun , Su Yueyue , Yang Fan , Song Yuan , Yan Jiangnan , Luo Ya , Zeng Jianguang
Published: September 2022

Aberrations in how people form expectations about rewards and how they respond to receiving rewards are thought to underlie major depressive disorder (MDD). However, the underlying mechanism linking the appetitive reward system, specifically anticipation and outcome, is still not fully understood. To examine the neural correlates of monetary anticipation and outcome in currently depressed subjects with MDD, we performed two separate voxel-wise meta-analyses of functional neuroimaging studies using the monetary incentive delay task. During reward anticipation, the depressed patients exhibited an increased response in the bilateral middle cingulate cortex (MCC) extending to the anterior cingulate cortex, the medial prefrontal cortex, the left inferior frontal gyrus (IFG), and the postcentral gyrus, but a reduced response in the mesolimbic circuit, including the left striatum, insula, amygdala, right cerebellum, striatum, and IFG, compared to controls. During the outcome stage, MDD showed higher activity in the left inferior temporal gyrus, and lower activity in the mesocortical pathway, including the bilateral MCC, left caudate nucleus, precentral gyrus, thalamus, cerebellum, right striatum, insula, IFG, middle frontal gyrus, and temporal pole. Our findings suggest that cMDD may be characterised by state-dependent hyper-responsivity in cortical regions during the anticipation phase, and hypo-responsivity of the mesocortico-limbic circuit across the two phases of the reward response. Our study showed dissociable neural circuit responses to monetary stimuli during reward anticipation and outcome, which help to understand the dysfunction in different aspects of reward processing, particularly motivational v. hedonic deficits in depression.
Group Ties amid Industrial Change
Authors: Zucker Noah
Published: September 2022

Coethnics often work in the same industries. How does this ethnic clustering affect individuals’ political loyalties amid industrial growth and decline? Focusing on migrant groups, the author contends that ethnic groups’ distribution across industries alters the political allegiances of their members. When a group is concentrated in a growing industry, economic optimism and resources flow between coethnics, bolstering migrants’ confidence in their economic security and dissuading investments in local political incorporation. When a group is concentrated in a declining industry, these gains dissipate, leading migrants to integrate into out-groups with greater access to political rents. Analyses of immigrants near US coal mines in the early twentieth century support this theory. The article shows how ethnic groups’ distribution across industries shapes the evolution of group cleavages and illuminates how decarbonizing transitions away from fossil fuels may reshape identity conflicts.
The Climate Siren
Authors: Stevens Lara , Varney Denise
Published: September 2022

An accomplished dancer, acrobat, and physical theatre performer, Hanna Cormick became ill in 2014 with a trifecta of rare genetic conditions that make her severely allergic to pollutants in the air — smoke, detergents, and food particles — and her bones and internal organs prone to dislocation. In January 2020, during Australia’s summer of unprecedented bushfires, Cormick stagedThe Mermaid, risking her life to make a performance about the climate emergency and how we are all vulnerable bodies at risk in a changing environment.
Treating Knock-On Displacements in Fluctuation Electron Microscopy Experiments
Authors: Radić Dražen , Peterlechner Martin , Posselt Matthias , Bracht Hartmut
Published: September 2022

This work investigates how knock-on displacements influence fluctuation electron microscopy (FEM) experiments. FEM experiments were conducted on amorphous silicon, formed by self-ion implantation, in a transmission electron microscope at 300 kV and 60 kV at various electron doses, two different binnings and with two different cameras, a CCD and a CMOS one. Furthermore, energy filtering has been utilized in one case. Energy filtering greatly enhances the FEM data by removing the inelastic background intensity, leading to an improved speckle contrast. The CMOS camera yields a slightly larger normalized variance than the CCD at an identical electron dose and appears more prone to noise at low electron counts. Beam-induced atomic displacements affect the 300 kV FEM data, leading to a continuous suppression of the normalized variance with increasing electron dose. Such displacements are considerably reduced for 60 kV experiments since the primary electron's maximum energy transfer to an atom is less than the displacement threshold energy of amorphous silicon. The results show that the variance suppression due to knock-on displacements can be controlled in two ways: Either by minimizing the electron dose to the sample or by conducting the experiment at a lower acceleration voltage.
Freedom at the Center
Authors: Whitfield Stephen J.
Published: September 2022

Of course it's brilliant. The Free World represents the hugely ambitious culmination of the efforts of a scholar of exceptional talent to explicate mid-century American culture, and to put it within a broad political and social context. With its immense attention to detail, The Free World frequently offers such fresh readings of a wide variety of topics that perhaps only subspecialists can profess to find familiar the evidence and interpretations that Louis Menand provides. It is emblazoned with bold personal opinions that keep the reader interested. At the Center is a very different book. It is a collective effort, and the authors seem to seek to avoid the kind of personalized style that Menand displays. But the effort that Casey Nelson Blake, Daniel H. Borus, and Howard Brick make to tie the disparate threads together distinguish At the Center from Menand's volume, and therefore offer an invaluable contrast. These books are aimed at different categories of reader, provide divergent temporal and geographic frames, and rarely overlap in attentiveness to the same material. Such variations can make for vigorous scholarly arguments about how to pack thought and culture into American historiography.
Horizontale Feindseligkeit in der Pflege
Authors: Bensch Sandra
Published: September 2022

Zusammenfassung. Horizontale Feindseligkeit ist ein großes Problem in der Pflege. Sie ist überall. Jede Pflegeperson ist fähig, sich horizontal feindselig zu verhalten. Niemand ist davor gefeit, horizontale Feindseligkeit zu erfahren. Faktoren wie Pflexit, Stagnation der Pflegeakademisierung, Auflösung von Fachkraftquoten sowie Nachwuchsmangel zeichnen ein sichtbares Aus für die Professionsentwicklung „Pflege“ in Deutschland. Dies frustriert und fördert die Feindseligkeit untereinander. Das Thema gehört offen angesprochen.
Pflege up to date
Authors: Pech Christina , Look Susanne
Published: September 2022

Zusammenfassung. Um neue Erkenntnisse aus der Pflege- und Versorgungsforschung in den pflegerischen Alltag zu integrieren, werden Pflegende in den meisten Kliniken regelmäßig geschult. Neben der klassischen Präsenzschulung entwickeln sich zunehmend neue digitale Lernformate, die eine Flexibilisierung des Lernens ermöglichen. Wir zeigen ein klinikinternes Schulungskonzept, welches analoge und digitale Lernangebote für Pflegende kombiniert.
Psychologists’ Experiences Who Managed Waitlists in Mental-Health Services During the COVID-19 Lockdown
Authors: McDonnell Darren , Vasiliou Vasilis S. , Lonergan Edgar , Moore Philip
Published: September 2022

Abstract. Introduction: The COVID-19 pandemic increased the demand for mental-health services worldwide. Consequently, it also increased the length of the waitlists for mental-health services, putting a strain on adult mental-health services (AMHS) and the healthcare professionals dealing with these lists. There is little research about how psychologists managed waitlist practices, e.g., scheduling screening appointments, determining clients’ availability in an offered appointment, providing evidence-based bibliotherapy, or using priority waiting scales. It remains unclear what their experiences were with these practices and how effective these practices were during the pandemic. Method: The current convergent, concurrent mixed-method study investigated waitlist-management practices, synthesizing quantitative and qualitative data from an online survey ( n = 20 participants) applied in two local AMHS in Ireland. Results: The most common practices used by psychologists were opt-in systems, maintaining regular contact with clients, informing them about the waiting time, and providing evidence-based bibliotherapy. Screening was the least-used practice. The qualitative analysis highlights the emotional burden psychologists experienced from the use of waitlist practices, particularly when they had to inform the client of the waiting time or put a client back onto a waitlist. Discussion: Psychologists reported a lack of resources and increases in administrative workload as barriers to implementing practices. Managerial, organizational, and policy-based recommendations are proposed.
Irminger Sea Is the Center of Action for Subpolar AMOC Variability
Authors: Chafik L. , Holliday N. P. , Bacon S. , Rossby T.
Published: September 2022

Significant societally important climate impacts can be caused by changes in the strength of the Atlantic Meridional Overturning Circulation (AMOC) at higher latitudes. Focusing on variability and long‐term change of the subpolar North Atlantic (SPNA)—a key AMOC action center—and using eastern OSNAP array observations, we identify a distinct density and sea‐surface height signature of the AMOC strength in the Irminger Sea (2014–2018), reinforced and extended with an ocean reanalysis (1993–2018). Reconstruction of AMOC variability using Irminger Sea density shows strong control by the North Atlantic Oscillation on subpolar overturning on multiple timescales, achieved via the gyre circulation and waters from the Labrador Sea. Furthermore, the observed decrease of Irminger Sea density since the mid‐twentieth century (1950–2019) is suggestive of a long‐term AMOC weakening of 2.2 Sv or 13%, however, this trend remains statistically insignificant due to the large interannual and decadal variability of the SPNA.
Ensemble‐Based Experimental Design for Targeting Data Acquisition to Inform Climate Models
Authors: Dunbar Oliver R. A. , Howland Michael F. , Schneider Tapio , Stuart Andrew M.
Published: September 2022

Data required to calibrate uncertain general circulation model (GCM) parameterizations are often only available in limited regions or time periods, for example, observational data from field campaigns, or data generated in local high‐resolution simulations. This raises the question of where and when to acquire additional data to be maximally informative about parameterizations in a GCM. Here we construct a new ensemble‐based parallel algorithm to automatically target data acquisition to regions and times that maximize the uncertainty reduction, or information gain, about GCM parameters. The algorithm uses a Bayesian framework that exploits a quantified distribution of GCM parameters as a measure of uncertainty. This distribution is informed by time‐averaged climate statistics restricted to local regions and times. The algorithm is embedded in the recently developed calibrate‐emulate‐sample framework, which performs efficient model calibration and uncertainty quantification with only model evaluations, compared with evaluations typically needed for traditional approaches to Bayesian calibration. We demonstrate the algorithm with an idealized GCM, with which we generate surrogates of local data. In this perfect‐model setting, we calibrate parameters and quantify uncertainties in a quasi‐equilibrium convection scheme in the GCM. We consider targeted data that are (a) localized in space for statistically stationary simulations, and (b) localized in space and time for seasonally varying simulations. In these proof‐of‐concept applications, the calculated information gain reflects the reduction in parametric uncertainty obtained from Bayesian inference when harnessing a targeted sample of data. The largest information gain typically, but not always, results from regions near the intertropical convergence zone.
β-Catenin promotes long-term survival and angiogenesis of peripheral blood mesenchymal stem cells via the Oct4 signaling pathway
Authors: Wang Pengzhen , Deng Zhanyu , Li Aiguo , Li Rongsen , Huang Weiguang , Cui Jin , Chen Songsheng , Li Biao , Zhang Shaoheng
Published: September 2022

Stem cell therapy has been extensively studied to improve heart function following myocardial infarction; however, its therapeutic potency is limited by low rates of engraftment, survival, and differentiation. Here, we aimed to determine the roles of the β-catenin/Oct4 signaling axis in the regulation of long-term survival and angiogenesis of peripheral blood mesenchymal stem cells (PBMSCs). These cells were obtained from rat abdominal aortic blood. We showed that β-catenin promotes the self-renewal, antiapoptotic effects, and long-term survival of PBMSCs by activating the Oct4 pathway through upregulation of the expression of the antiapoptotic factors Bcl2 and survivin and the proangiogenic cytokine bFGF and suppression of the levels of the proapoptotic factors Bax and cleaved caspase-3. β-Catenin overexpression increased Oct4 expression. β-Catenin knockdown suppressed Oct4 expression in PBMSCs. However, β-catenin levels were not affected by Oct4 overexpression or knockdown. Chromatin immunoprecipitation assays proved that β-catenin directly regulates Oct4 transcription in PBMSCs. In vivo, PBMSCs overexpressing β-catenin showed high survival in infarcted hearts and resulted in better myocardial repair. Further functional analysis identified Oct4 as the direct upstream regulator of Ang1, bFGF, HGF, VEGF, Bcl2, and survivin, which cooperatively drive antiapoptosis and angiogenesis of engrafted PBMSCs. These findings revealed the regulation of β-catenin in PBMSCs by the Oct4-mediated antiapoptotic/proangiogenic signaling axis and provide a breakthrough point for improving the long-term survival and therapeutic effects of PBMSCs.
Aβ-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation
Authors: Kim Dong Kyu , Jeong Hyobin , Bae Jingi , Cha Moon-Yong , Kang Moonkyung , Shin Dongjin , Ha Shinwon , Hyeon Seung Jae , Kim Hokeun , Suh Kyujin , Choi Mi-Sun , Ryu Hoon , Yu Seong-Woon , Kim Jong-Il , Kim Yeon-Soo , Lee Sang-Won , Hwang Daehee , Mook-Jung Inhee
Published: September 2022

Mitochondria in neural progenitors play a crucial role in adult hippocampal neurogenesis by being involved in fate decisions for differentiation. However, the molecular mechanisms by which mitochondria are related to the genetic regulation of neuronal differentiation in neural progenitors are poorly understood. Here, we show that mitochondrial dysfunction induced by amyloid-beta (Aβ) in neural progenitors inhibits neuronal differentiation but has no effect on the neural progenitor stage. In line with the phenotypes shown in Alzheimer’s disease (AD) model mice, Aβ-induced mitochondrial damage in neural progenitors results in deficits in adult hippocampal neurogenesis and cognitive function. Based on hippocampal proteome changes after mitochondrial damage in neural progenitors identified through proteomic analysis, we found that lysine demethylase 5A (KDM5A) in neural progenitors epigenetically suppresses differentiation in response to mitochondrial damage. Mitochondrial damage characteristically causes KDM5A degradation in neural progenitors. Since KDM5A also binds to and activates neuronal genes involved in the early stage of differentiation, functional inhibition of KDM5A consequently inhibits adult hippocampal neurogenesis. We suggest that mitochondria in neural progenitors serve as the checkpoint for neuronal differentiation via KDM5A. Our findings not only reveal a cell-type-specific role of mitochondria but also suggest a new role of KDM5A in neural progenitors as a mediator of retrograde signaling from mitochondria to the nucleus, reflecting the mitochondrial status.
O-GlcNAc transferase regulates intervertebral disc degeneration by targeting FAM134B-mediated ER-phagy
Authors: Luo Rongjin , Li Gaocai , Zhang Weifei , Liang Huaizhen , Lu Saideng , Cheung Jason Pui Yin , Zhang Teng , Tu Ji , Liu Hui , Liao Zhiwei , Ke Wencan , Wang Bingjin , Song Yu , Yang Cao
Published: September 2022

Both O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) and endoplasmic reticulum-phagy (ER-phagy) are well-characterized conserved adaptive regulatory mechanisms that maintain cellular homeostasis and function in response to various stress conditions. Abnormalities in O-GlcNAcylation and ER-phagy have been documented in a wide variety of human pathologies. However, whether O-GlcNAcylation or ER-phagy is involved in the pathogenesis of intervertebral disc degeneration (IDD) is largely unknown. In this study, we investigated the function of O-GlcNAcylation and ER-phagy and the related underlying mechanisms in IDD. We found that the expression profiles of O-GlcNAcylation and O-GlcNAc transferase (OGT) were notably increased in degenerated NP tissues and nutrient-deprived nucleus pulposus (NP) cells. By modulating the O-GlcNAc level through genetic manipulation and specific pharmacological intervention, we revealed that increasing O-GlcNAcylation abundance substantially enhanced cell function and facilitated cell survival under nutrient deprivation (ND) conditions. Moreover, FAM134B-mediated ER-phagy activation was regulated by O-GlcNAcylation, and suppression of ER-phagy by FAM134B knockdown considerably counteracted the protective effects of amplified O-GlcNAcylation. Mechanistically, FAM134B was determined to be a potential target of OGT, and O-GlcNAcylation of FAM134B notably reduced FAM134B ubiquitination-mediated degradation. Correspondingly, the protection conferred by modulating O-GlcNAcylation homeostasis was verified in a rat IDD model. Our data demonstrated that OGT directly associates with and stabilizes FAM134B and subsequently enhances FAM134B-mediated ER-phagy to enhance the adaptive capability of cells in response to nutrient deficiency. These findings may provide a new option for O-GlcNAcylation-based therapeutics in IDD prevention.
A novel progressive wave gyroscope based on acousto-optic effects
Authors: Tian Lu , Shen Qiang , Chang Honglong
Published: September 2022

We propose and numerically investigate a brand-new, high-sensitivity progressive wave gyroscope based on acousto-optic effects for the measurement of rotational angular velocity. Unlike the traditional surface acoustic wave (SAW) gyroscope, which uses shifts in the SAW frequency to characterize the rotational angular velocity, this study uses acousto-optic effects to detect changes in refractive index caused by mechanical strain, measuring the angular velocity by the output optical power intensity of the optical waveguide. The three-dimensional finite element analysis method is utilized to build an SAW excitation model and optical detection model. We show that the sensitivity of the SAW gyroscope is highly dependent upon geometric parameters of the structure and that the mechanical strain induced by the progressive wave of the SAW can be effectively measured by the optical power intensity under the action of external angular velocity. The superiority of the proposed structure is substantiated by its achievement of a theoretical sensitivity of 1.8647 (mW/m2)/(rad/s) and high impact resistance of 220,000 g. By means of normalization, the sensitivity of the proposed structure can be enhanced by four orders of magnitude compared to the traditional SAW gyroscope. The novel structure combines the advantages of both conventional microscale vibrating gyroscopes and optical gyroscopes, providing a powerful solution for performance enhancement of SAW gyroscopes and, thereby, enabling application in the field of inertial devices.
Integrated analysis reveals FOXA1 and Ku70/Ku80 as targets of ivermectin in prostate cancer
Authors: Lv Shidong , Wu Zeyu , Luo Mayao , Zhang Yifan , Zhang Jianqiang , Pascal Laura E. , Wang Zhou , Wei Qiang
Published: September 2022

Ivermectin is a widely used antiparasitic drug and shows promising anticancer activity in various cancer types. Although multiple signaling pathways modulated by ivermectin have been identified in tumor cells, few studies have focused on the exact target of ivermectin. Herein, we report the pharmacological effects and targets of ivermectin in prostate cancer. Ivermectin caused G0/G1 cell cycle arrest, induced cell apoptosis and DNA damage, and decreased androgen receptor (AR) signaling in prostate cancer cells. Further in vivo analysis showed ivermectin could suppress 22RV1 xenograft progression. Using integrated omics profiling, including RNA-seq and thermal proteome profiling, the forkhead box protein A1 (FOXA1) and non-homologous end joining (NHEJ) repair executer Ku70/Ku80 were strongly suggested as direct targets of ivermectin in prostate cancer. The interaction of ivermectin and FOXA1 reduced the chromatin accessibility of AR signaling and the G0/G1 cell cycle regulator E2F1, leading to cell proliferation inhibition. The interaction of ivermectin and Ku70/Ku80 impaired the NHEJ repair ability. Cooperating with the downregulation of homologous recombination repair ability after AR signaling inhibition, ivermectin increased intracellular DNA double-strand breaks and finally triggered cell death. Our findings demonstrate the anticancer effect of ivermectin in prostate cancer, indicating that its use may be a new therapeutic approach for prostate cancer.
Nintedanib induces senolytic effect via STAT3 inhibition
Authors: Cho Hyun-Ji , Hwang Jeong-A , Yang Eun Jae , Kim Eok-Cheon , Kim Jae-Ryong , Kim Sung Young , Kim Young Zoon , Park Sang Chul , Lee Young-Sam
Published: September 2022

Selective removal of senescent cells, or senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even for reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced the death of primary human dermal fibroblasts undergoing RS. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without inducing cytotoxicity. Interestingly, the mechanism by which nintedanib activated caspase-9 in the intrinsic apoptotic pathway differed from that of ABT263 apoptosis induction; specifically, nintedanib did not decrease the levels of Bcl-2 family proteins in senescent cells. Moreover, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused the drug-induced death of senescent cells. STAT3 knockdown in senescent cells induced caspase activation. Moreover, nintedanib reduced the number of senescence-associated β-galactosidase-positive senescent cells in parallel with a reduction in STAT3 phosphorylation and ameliorated collagen deposition in a mouse model of bleomycin-induced lung fibrosis. Consistently, nintedanib exhibited a senolytic effect through bleomycin-induced senescence of human pulmonary fibroblasts. Overall, we found that nintedanib can be used as a new senolytic agent and that inhibiting STAT3 may be an approach for inducing the selective death of senescent cells. Our findings pave the way for expanding the senolytic toolkit for use in various aging statuses and age-related diseases.
Tuning the density of zero-field skyrmions and imaging the spin configuration in a two-dimensional Fe3GeTe2 magnet
Authors: Ding Bei , Li Xue , Li Zefang , Xi Xuekui , Yao Yuan , Wang Wenhong
Published: September 2022

With the advent of ferromagnetism, two-dimensional (2D) van der Waals (vdW) magnets have attracted particular attention in exploring topological spin textures, such as skyrmions used for next-generation spintronic devices. The discovery of magnetic skyrmions in Fe3GeTe2 (FGT) has sparked interest in investigating the spin configurations of skyrmions in FGT. Here, we used an in situ Lorentz microscope to directly demonstrate the generation and sustainability of Bloch-type skyrmions in a zero magnetic field over a wide temperature range in 2D vdW FGT. By tuning the value of the external magnetic field, the highest-density hexagonal skyrmion lattice emerges after reducing the magnetic field to zero. Moreover, by tilting the FGT nanosheet, we found that the field-free Bloch-type skyrmions in FGT can also represent an invisible contrast when the tilt angle is zero, but a reversed magnetic contrast emerges at a high tilt angle. On the basis of our experiments, we discuss the possible mechanisms for such variable magnetic contrast. These findings offer valuable insights into the spin configurations of skyrmions in 2D vdW FGT and shed light on the identification of spin configurations via Lorentz microscopy.
Global patterns of vascular plant alpha diversity
Authors: Sabatini Francesco Maria , Jiménez-Alfaro Borja , Jandt Ute , Chytrý Milan , Field Richard , Kessler Michael , Lenoir Jonathan , Schrodt Franziska , Wiser Susan K. , Arfin Khan Mohammed A. S. , Attorre Fabio , Cayuela Luis , De Sanctis Michele , Dengler Jürgen , Haider Sylvia , Hatim Mohamed Z. , Indreica Adrian , Jansen Florian , Pauchard Aníbal , Peet Robert K. , Petřík Petr , Pillar Valério D. , Sandel Brody , Schmidt Marco , Tang Zhiyao , van Bodegom Peter , Vassilev Kiril , Violle Cyrille , Alvarez-Davila Esteban , Davidar Priya , Dolezal Jiri , Hérault Bruno , Galán-de-Mera Antonio , Jiménez Jorge , Kambach Stephan , Kepfer-Rojas Sebastian , Kreft Holger , Lezama Felipe , Linares-Palomino Reynaldo , Monteagudo Mendoza Abel , N’Dja Justin K. , Phillips Oliver L. , Rivas-Torres Gonzalo , Sklenář Petr , Speziale Karina , Strohbach Ben J. , Vásquez Martínez Rodolfo , Wang Hua-Feng , Wesche Karsten , Bruelheide Helge
Published: September 2022

Global patterns of regional (gamma) plant diversity are relatively well known, but whether these patterns hold for local communities, and the dependence on spatial grain, remain controversial. Using data on 170,272 georeferenced local plant assemblages, we created global maps of alpha diversity (local species richness) for vascular plants at three different spatial grains, for forests and non-forests. We show that alpha diversity is consistently high across grains in some regions (for example, Andean-Amazonian foothills), but regional ‘scaling anomalies’ (deviations from the positive correlation) exist elsewhere, particularly in Eurasian temperate forests with disproportionally higher fine-grained richness and many African tropical forests with disproportionally higher coarse-grained richness. The influence of different climatic, topographic and biogeographical variables on alpha diversity also varies across grains. Our multi-grain maps return a nuanced understanding of vascular plant biodiversity patterns that complements classic maps of biodiversity hotspots and will improve predictions of global change effects on biodiversity.
Context-dependent function of TSLP and IL-1β in skin allergic sensitization and atopic march
Authors: Segaud Justine , Yao Wenjin , Marschall Pierre , Daubeuf François , Lehalle Christine , German Beatriz , Meyer Pierre , Hener Pierre , Hugel Cécile , Flatter Eric , Guivarch Marine , Clauss Laetitia , Martin Stefan F. , Oulad-Abdelghani Mustapha , Li Mei
Published: September 2022

Atopic diseases, including atopic dermatitis (AD) and asthma, affect a large proportion of the population, with increasing prevalence worldwide. AD often precedes the development of asthma, known as the atopic march. Allergen sensitization developed through the barrier-defective skin of AD has been recognized to be a critical step leading to asthma, in which thymic stromal lymphopoietin (TSLP) was previously shown to be critical. In this study, using a laser-assistant microporation system to disrupt targeted skin layers for generating micropores at a precise anatomic depth of mouse skin, we model allergen exposure superficially or deeply in the skin, leading to epicutaneous sensitization or dermacutaneous sensitization that is associated with a different cytokine microenvironment. Our work shows a differential requirement for TSLP in these two contexts, and identifies an important function for IL-1β, which is independent of TSLP, in promoting allergen sensitization and subsequent allergic asthma.
The Holocene temperature conundrum answered by mollusk records from East Asia
Authors: Dong Yajie , Wu Naiqin , Li Fengjiang , Zhang Dan , Zhang Yueting , Shen Caiming , Lu Houyuan
Published: September 2022

Seasonal biases (the warm-season contribution) of Holocene mean annual temperature (MAT) reconstructions from geological records were proposed as a possible cause of the mismatch with climate simulated temperature. Here we analyze terrestrial mollusk assemblages that best reflect seasonal signals and provide quantitative MAT and four-season temperature records for northern China during the past 20,000 years. The MAT estimated from the seasonal temperatures of a four-season-mean based on mollusks shows a peak during ~9000–4000 years ago, followed by a cooling trend. In general, the contribution of summer and winter temperature to MAT is significantly greater than that of spring and autumn temperatures. The relative contribution of each season varies over time and corresponds roughly with the seasonal insolation in each season. This independent evidence from mollusk records from the mid-latitudes of East Asia does not support the Holocene long-term warming trend observed in climate simulations and the seasonal bias explanation.