bluuebunny/crossref_metadata_2025 huggingface dataset:
Educational interventions by nurses in caregivers with their elderly patients at home
Authors: Rojas-Ocaña María Jesús , Araujo-Hernández Miriam , Romero-Castillo Rocío , García Navarro E. Begoña
Published: June 2021

Introduction:

The home is the natural setting for the development of informal care. The work that nurses are required to develop in this context (the carer/the elderly dependent/the home) focuses on training and educational activities to assist these two groups, such as demonstrating care activities to help dependent seniors, instruction in self-care techniques and teaching strategies for the use of human and material resources.

Aims:

This article analyzes care education interventions performed by nurses, and the factors that facilitate, or limit, health care training.

Methodological approach:

This is a qualitative, descriptive study designed to be flexible and openly analytical in its approach to the research problem and the dynamic nature of the home environment. Triangulation of the methodological techniques and study subjects was applied.

Results:

Nursing interventions related to professional attitudes, such as encouraging communication and facilitating teaching; communication interventions in health education and counseling; and technical interventions aimed at improving access to health information and support for the informal carer. Lack of will, the advanced age of the carer, emotional state and work overload are factors that undermine care instruction, which if reversed, would become learning facilitators. The lack of time and resources in the home are the major limiting factors on care teaching, according to nurses. Evidence from our study suggests that care in the home is considered a key primary health care strategy, one in which nurses play a significant role.
Mars: a free planet?
Authors: Chon-Torres Octavio A.
Published: June 2021

We are witnessing the enormous breakthroughs of space technology, which will eventually allow us to reach Mars. However, it seems that the technological evolution is expanding at a faster rate than the moral development. Are we ethically ready to take human beings to Mars? Will it be a private company the first one that manages to take us there? Should we colonize Mars or leave it like it is right now? Are astrobiological interests being contemplated when discussing human presence in Mars? These are some of the questions that we must answer since the moment of stepping on Mars does not seem to be far away. Therefore, the objective of this article is to evaluate the idea of Mars being a free planet from any of Earth's governments, and to analyse the idea of colonizing Mars considering that by doing that we could seriously endanger native life. What it proposed is that its unavoidable that we will reach Mars, however, we may not be prepared as humanity and this is something that we must face.
Congresswomen, Legislative Entrepreneurship, and the Basis for Effective Legislating in the U.S. House, 1973–2008
Authors: Kalaf-Hughes Nicole , MacDonald Jason A. , Santoro Lauren M.
Published: June 2021

Research indicates that congresswomen are more effective at moving bills through the lawmaking process than their male counterparts. To investigate why, we discuss what legislative entrepreneurship involves and explain why it can serve as the basis for problem-solving and effective lawmaking in the U.S. Congress. We also examine the entrepreneurial work that members of Congress did on behalf of bills that they sponsored from 1973 to 2008. Among other findings, we observe that congresswomen, especially those in the minority party, are more entrepreneurial than their male colleagues. This finding enhances our understanding of why female lawmakers are more effective lawmakers.
The lived body, everyday and generative powers of war: toward an embodied ontology of war as experience
Authors: Narozhna Tanya
Published: June 2021

This paper examines the emergence of the corporeal turn in International Relations (IR) research on war. It argues that a lack of a sustained ontological investigation leaves open two theoretical gaps, which impedes the development of an embodied theory of war: (1) the core concept of a body and its linkages with war are underdeveloped, and (2) existing research on the embodiment of war slips into discursivism or empiricism. The paper invites the corporeal turn scholarship to bring ontology to the forefront of IR war research and to expand a pool of theoretical resources for analyzing the corporeality of war by turning to existential phenomenology. With the phenomenological concept of the lived body placed at the heart of war ontology, war is conceived as a complex social institution with the generative powers born out of the capacity of the violent politics of injury to disrupt the lived bodies' sense-making and agential capacities, on the one hand, and the potential of individuals and communities to reclaim their interpretive integrity and agency through embodied everyday practices, on the other.
Power-sharing and the quality of democracy
Authors: Bochsler Daniel , Juon Andreas
Published: June 2021

Mounting evidence indicates that power-sharing supports transitions to democracy. However, the resulting quality of democracy remains understudied. Given the increasing global spread of power-sharing, this is a crucial oversight, as prominent critiques accuse it of a number of critical deficiencies. The present article advances this literature in two ways. First, it offers a comprehensive discussion of how power-sharing affects the quality of democracy, going beyond specific individual aspects of democracy. It argues that power-sharing advances some of these aspects while having drawbacks for others. Second, it offers the first systematic, large-Nanalysis of the frequently discussed consequences of power-sharing for the quality of democracy. It relies on a dataset measuring the quality of democracy in 70 countries worldwide, combining it with new fine-grained data for institutional power-sharing. The results indicate that power-sharing is a complex institutional model which privileges a particular set of democratic actors and processes, while deemphasizing others.
Projected Changes to Cool‐Season Storm Tides in the 21st Century Along the Northeastern United States Coast
Authors: Pringle William J. , Wang Jiali , Roberts Keith J. , Kotamarthi Veerabhadra R.
Published: June 2021

This study investigates changes and uncertainties to cool‐season (November‐March) storm tides along the U.S. northeast coast in the 21st century under the high RCP8.5 emission scenario compared to late 20th century. A high‐fidelity (50‐m coastal resolution) hydrodynamic storm tide model is forced with three dynamically downscaled regional climate models (RCMs) over three decadal periods (historical, mid‐21st century, and late‐21st century) to project future changes in peak storm tide elevations at coastal counties in the region. While there is no absolute consensus on future changes to storm tides, for any one future decade two out of the three RCMs project an increase at counties along the Hudson River, Delaware River, and northern Chesapeake Bay due to more intense cyclones that track inland of these locations leading to favorable surge generating conditions. The same RCMs also project a decrease at counties facing the open ocean in the mid‐Atlantic Bight as cyclone densities just offshore of the coastline decrease, particularly by late‐century. The greater tidal range in northern areas of the region leads to uncertainty in the magnitude and sign of the projected changes to storm tide levels due to the arbitrary timing of the local tidal stage and the surge‐producing weather event. This random tide‐weather timing is less important in the Chesapeake Bay and unimportant in Albemarle Sound and Pamlico Sound. Similar to other recent studies, we highlight that sea level rise is likely to be more critical than storm climatology for future changes to the cool‐season coastal flooding potential.
Temperature Gradients Across the Pacific Ocean During the Middle Miocene
Authors: Fox Lyndsey R. , Wade Bridget S. , Holbourn Ann , Leng Melanie J. , Bhatia Rehemat
Published: June 2021

Sea surface temperatures (SSTs) of the tropical Pacific Ocean exert powerful controls on regional and global climates. Previous studies have suggested that during warm climate phases, the east‐west temperature gradient collapsed. To date, there has been no high‐resolution reconstruction of sea surface conditions in both the east and west Pacific Ocean during the Miocene Climate Optimum (MCO) and across the middle Miocene climate transition (MMCT); therefore, our understanding of the mean oceanographic state during this major global climatic shift is limited. Here, we present new SST reconstructions for the eastern Pacific Ocean (15.5–13.3 Ma) which show a clear east‐west temperature gradient of ∼4°C during the warmest interval of the Neogene, implying that the oceanographic processes that produce the modern gradient were present and active. There is no shift in the east‐west gradient across the MMCT indicating that the gradient was not impacted by global cooling and ice growth. We find a 2°C sea surface cooling in the eastern equatorial Pacific, that lags the benthic foraminiferal δ18O positive shift by 150 kyr, indicating that tropical temperature did not decrease synchronously with the expansion of the Antarctic ice sheet. Reconstructed variations in the δ18O composition of seawater, determined by combining our Mg/Ca and δ18O records, reveal a freshening in the eastern Pacific Ocean after 13.8 Ma, suggesting changes in the hydrological cycle and in tropical fronts in response to the new icehouse regime.
Volcanic Unrest at Taupō Volcano in 2019: Causes, Mechanisms and Implications
Authors: Illsley‐Kemp Finnigan , Barker Simon J. , Wilson Colin J. N. , Chamberlain Calum J. , Hreinsdóttir Sigrún , Ellis Susan , Hamling Ian J. , Savage Martha K. , Mestel Eleanor R. H. , Wadsworth Fabian B.
Published: June 2021

Taupō volcano, New Zealand, is a large caldera volcano that has been highly active through the Holocene. It most recently erupted ∼1,800 years ago but there have been multiple periods of historic volcanic unrest. We use seismological and geodetic analysis to show that in 2019 Taupō underwent a period of unrest characterized by increased seismic activity through multiple swarms and was accompanied by ground deformation within the caldera. The earthquakes, which include non‐double‐couple events, serve to outline an aseismic zone beneath the most recent eruptive vents. This aseismic zone is coincident with an inflating source, based on forward modeling of ground deformation data. We infer that this aseismic and deforming region delineates the location of the present day magma reservoir that is ≥250 km3 in volume and has a melt fraction of >20%–30%, inhibiting seismic activity. Our analysis shows that the 2019 unrest at Taupō was volcanic in nature and origin, demonstrating that this is an active and potentially hazardous volcano, and that improving our monitoring and understanding of its behavior is important.
A Two‐Layer Numerical Model for Coastal Sheet‐Flow Sediment Transport
Authors: Tan Weikai , Yuan Jing
Published: June 2021

Sheet‐flow sediment transport is an important topic for coastal sediment research. In this study, a two‐layer numerical model is proposed for coastal sheet‐flow sediment transport. The bottom pick‐up layer, in which sediment motion is usually treated as bedload transport, is resolved in an empirical way, so no bedload model is required. For the suspension layer, the model solves the turbulent diffusion equation for sediment concentration, while the hydrodynamic part is described by Reynolds‐averaged Navier‐Stokes equations. The damping of turbulence due to concentration gradient and the hindered settling effect due to particle‐particle interactions are both incorporated in the present model. A predetermined erosion depth is taken as an input for determining the no‐motion sand bed level. This two‐layer model is capable of describing the detailed spatial‐temporal variations of flow velocity and sediment concentration within the sheet‐flow layer, and the model's fidelity is comparable to that of some two‐phase‐flow models. A large campaign of model validation is carried out to demonstrate that the models works well for wave‐driven sheet‐flow sediment transport.
eLighting up the future
Authors: Lu Ling
Published: June 2021

What will be the cutting-edge photonics research in the coming decade? Prof. Chen and Segev share their perspective by highlighting quantum, topological, and AI photonics on eLight.
Aging mitigates the severity of obesity-associated metabolic sequelae in a gender independent manner
Authors: Moreno-Fernandez Maria E. , Sharma Vishakha , Stankiewicz Traci E. , Oates Jarren R. , Doll Jessica R. , Damen Michelle S. M. A. , Almanan Maha A. T. A. , Chougnet Claire A. , Hildeman David A. , Divanovic Senad
Published: June 2021

Background

Understanding gender-associated bias in aging and obesity-driven metabolic derangements has been hindered by the inability to model severe obesity in female mice.

Methods

Here, using chow- or high fat diet (HFD)-feeding regimens at standard (TS) and thermoneutral (TN) housing temperatures, the latter to model obesity in female mice, we examined the impact of gender and aging on obesity-associated metabolic derangements and immune responsiveness. Analysis included quantification of: (i) weight gain and adiposity; (ii) the development and severity of glucose dysmetabolism and non-alcoholic fatty liver disease (NAFLD); and (iii) induction of inflammatory pathways related to metabolic dysfunction.

Results

We show that under chow diet feeding regimen, aging was accompanied by increased body weight and white adipose tissue (WAT) expansion in a gender independent manner. HFD feeding regimen in aged, compared to young, male mice at TS, resulted in attenuated glucose dysmetabolism and hepatic steatosis. However, under TS housing conditions only aged, but not young, HFD fed female mice developed obesity. At TN however, both young and aged HFD fed female mice developed severe obesity. Independent of gender or housing conditions, aging attenuated the severity of metabolic derangements in HFD-fed obese mice. Tempered severity of metabolic derangements in aged mice was associated with increased splenic frequency of regulatory T (Treg) cells, Type I regulatory (Tr1)-like cells and circulating IL-10 levels and decreased vigor of HFD-driven induction of inflammatory pathways in adipose and liver tissues.

Conclusion

Our findings suggest that aging-associated altered immunological profile and inflammatory vigor may play a dominant role in the attenuation of obesogenic diet-driven metabolic dysfunction.
Drivers and implications of distance decay differ for ectomycorrhizal and foliar endophytic fungi across an anciently fragmented landscape
Authors: Bowman Elizabeth A , Arnold A Elizabeth
Published: June 2021

Fungal communities associated with plants often decrease in similarity as the distance between sampling sites increases (i.e., they demonstrate distance decay). In the southwestern USA, forests occur in highlands separated from one another by warmer, drier biomes with plant and fungal communities that differ from those at higher elevations. These disjunct forests are broadly similar in climate to one another, offering an opportunity to examine drivers of distance decay in plant-associated fungi across multiple ecologically similar yet geographically disparate landscapes. We examined ectomycorrhizal and foliar endophytic fungi associated with a dominant forest tree (Pinus ponderosa) in forests across ca. 550 km of geographic distance from northwestern to southeastern Arizona (USA). Both guilds of fungi showed distance decay, but drivers differed for each: ectomycorrhizal fungi are constrained primarily by dispersal limitation, whereas foliar endophytes are constrained by specific environmental conditions. Most ectomycorrhizal fungi were found in only a single forested area, as were many endophytic fungi. Such regional-scale perspectives are needed for baseline estimates of fungal diversity associated with forest trees at a landscape scale, with attention to the sensitivity of different guilds of fungal symbionts to decreasing areas of suitable habitat, increasing disturbance, and related impacts of climate change.
TRPM2 promotes pancreatic cancer by PKC/MAPK pathway
Authors: Lin Rui , Bao Xunxia , Wang Hui , Zhu Sibo , Liu Zhongyan , Chen Quanning , Ai Kaixing , Shi Baomin
Published: June 2021

The mechanism of pancreatic cancer (PA) is not fully understanded. In our last report, TRPM2 plays a promising role in pancreatic cancer. However, the mechanism of TRPM2 is still unknown in this dismal disease. This study was designed to investigate the role and mechanism of TRPM2 in pancreatic cancer. TRPM2 overexpressed and siRNA plasmid were created and transfected with pancreatic cancer cell line (BxPC-3) to construct the cell model. We employed CCK-8, Transwell, scratch wound, and nude mice tumor-bearing model to investigate the role of TRPM2 in pancreatic cancer. Besides, we collected the clinical data, tumor tissue sample (TT) and para-tumor sample (TP) from the pancreatic cancer patients treated in our hospital. We analyzed the mechanism of TRPM2 in pancreatic cancer by transcriptome analysis, western blot, and PCR. We blocked the downstream PKC/MEK pathway of TRPM2 to investigate the mechanism of TRPM2 in pancreatic cancer by CCK8, scratch wound healing, and transwell assays. Overexpressed TRPM2 could promote pancreatic cancer in proliferation, migration, and invasion ability in no matter the cell model or nude mice tumor-bearing model. TRPM2 level is highly negative correlated to the overall survival and progression-free survival time in PA patients, however, it is significantly increased in PA tissue as the tumor stage increases. The transcriptome analysis, GSEA analysis, western-blot, and PCR results indicate TRPM2 is highly correlated with PKC/MAPK pathways. The experiments of PKC/MEK inhibitors added to TRPM2 overexpressed BxPC-3 cell showed that significant inhibition of PA cells happened in CCK8, transwell, and wound-healing assay. TRPM2 may directly activate PKCα by calcium or indirectly activate PKCε and PKCδ by increased DAG in PA, which promote PA by downstream MAPK/MEK pathway activation.
Long noncoding RNA DGCR5 involves in tumorigenesis of esophageal squamous cell carcinoma via SRSF1-mediated alternative splicing of Mcl-1
Authors: Duan Yuqing , Jia Yunlong , Wang Jiali , Liu Tianxu , Cheng Zishuo , Sang Meixiang , lv Wei , Qin Jing , Liu Lihua
Published: June 2021

Long noncoding RNAs (lncRNAs) emerge as essential roles in the regulation of alternative splicing (AS) in various malignancies. Serine- and arginine-rich splicing factor 1 (SRSF1)-mediated AS events are the most important molecular hallmarks in cancer. Nevertheless, the biological mechanism underlying tumorigenesis of lncRNAs correlated with SRSF1 in esophageal squamous cell carcinoma (ESCC) remains elusive. In this study, we found that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) was upregulated in ESCC clinical samples, which associated with poor prognosis. Through RNA interference and overexpression approaches, we confirmed that DGCR5 contributed to promote ESCC cell proliferation, migration, and invasion while inhibited apoptosis in vitro. Mechanistically, DGCR5 could directly bind with SRSF1 to increase its stability and thus stimulate alternative splicing events. Furthermore, we clarified that SRSF1 regulated the aberrant splicing of myeloid cell leukemia-1 (Mcl-1) and initiated a significant Mcl-1L (antiapoptotic) isoform switch, which contributed to the expression of the full length of Mcl-1. Moreover, the cell-derived xenograft (CDX) model was validated that DGCR5 could facilitate the tumorigenesis of ESCC in vivo. Collectively, our findings identified that the key biological role of lncRNA DGCR5 in alternative splicing regulation and emphasized DGCR5 as a potential biomarker and therapeutic target for ESCC.
Multilevel regulation of Wnt signaling by Zic2 in colon cancer due to mutation of β-catenin
Authors: Xu Zhengshui , Zheng Jianbao , Chen Zilu , Guo Jing , Li Xiaopeng , Wang Xingjie , Qu Chao , Yuan Liyue , Cheng Chen , Sun Xuejun , Yu Junhui
Published: June 2021

Zinc-finger of the cerebellum 2 (Zic2) is widely implicated in cancers, but the role of Zic2 in tumorigenesis is bilateral. A recent study indicated that Zic2 could render colon cancer cells more resistant to low glucose-induced apoptosis. However, the functional roles of Zic2 in colon cancer and the underlying molecular mechanism remain elusive. Herein, we demonstrated that Zic2 was highly expressed in colon cancer tissues and correlated with poor survival. Knockdown of Zic2 inhibited colon cancer cell growth, arrested the cell cycle transition from G0/G1 to S phase, and suppressed tumor sphere formation in vitro; in addition, silencing Zic2 retarded xenograft tumor formation in vivo. Consistently, ectopic expression of Zic2 had the opposite effects. Mechanistically, Zic2 executed its oncogenic role in colon cancer by enhancing Wnt/β-catenin signaling. Zic2 directly binds to the promoter of Axin2 and transcriptionally represses Axin2 expression and subsequently promotes the accumulation and nuclear translocation of β-catenin. Meanwhile, Zic2 could activate Wnt signaling by interacting with β-catenin. Intriguingly, in HCT116 cells with intrinsic Ser45 mutation of β-catenin, which blocks the degradation-related phosphorylation of β-catenin by CK1, modified Zic2 expression did not affect the protein level of β-catenin. Altogether, our findings uncover a novel multilevel mechanism for the oncogenic activity of Zic2 in colon cancer and suggest Zic2 as a potential therapeutic target for colon cancer patients.
HJURP promotes proliferation in prostate cancer cells through increasing CDKN1A degradation via the GSK3β/JNK signaling pathway
Authors: Lai Wenjie , Zhu Weian , Xiao Chutian , Li Xiaojuan , Wang Yu , Han Yuefu , Zheng Jiayu , Li Yingqiu , Li Mingqiang , Wen Xingqiao
Published: June 2021

Genes with cross-cancer aberrations are most likely to be functional genes or potential therapeutic targets. Here, we found a total of 137 genes were ectopically expressed in eight cancer types, of which Holliday junction recognition protein (HJURP) was significantly upregulated in prostate cancer (PCa). Moreover, patients with higher HJURP mRNA and protein levels had poorer outcomes, and the protein levels served as an independent prognosis factor for the overall survival of PCa patients. Functionally, ectopic HJURP expression promoted PCa cells proliferation in vitro and in vivo. Mechanistically, HJURP increased the ubiquitination of cyclin-dependent kinase inhibitor 1 (CDKN1A) via the GSK3β/JNK signaling pathway and decreased its stability. This study investigated the role of HJURP in PCa proliferation and may provide a novel prognostic and therapeutic target for PCa.
Effects of short-chain fatty acids in inhibiting HDAC and activating p38 MAPK are critical for promoting B10 cell generation and function
Authors: Zou Fagui , Qiu Yi , Huang Yilian , Zou Hang , Cheng Xiao , Niu Qingru , Luo Aoxiang , Sun Jianbo
Published: June 2021

B10 cells are regulatory B cells capable of producing IL-10 for maintaining immune homeostasis. Dysregulation of B10 cells occurs in autoimmune and inflammatory diseases. Modulation or adoptive transfer of B10 cells is a promising therapeutic strategy. The short-chain fatty acids (SCFAs), the metabolites of microbiota, play a critical role in maintaining immune homeostasis and are the potential drugs for the modulation of B10 cells. It is not clear whether and how SCFAs upregulate the frequency of B10 cells. Here, we found that SCFAs could promote murine and human B10 cell generation in vitro. Upregulation of B10 cells by butyrate or pentanoate was also observed in either healthy mice, mice with dextran sodium sulfate (DSS)-induced colitis, or mice with collagen-induced arthritis. Moreover, SCFA treatment could ameliorate clinical scores of colitis and arthritis. Adoptive transfer of B cells pretreated with butyrate showed more alleviation of DSS-induced colitis than those without butyrate. A further study demonstrates that SCFAs upregulate B10 cells in a manner dependent on their histone deacetylase (HDAC) inhibitory activity and independent of the G-protein-coupled receptor pathway. Transcriptomic analysis indicated that the MAPK signaling pathway was enriched in B10 cells treated with butyrate. A study with inhibitors of ERK, JNK, and p38 MAPK demonstrated that activating p38 MAPK by butyrate is critical for the upregulation of B10 cells. Moreover, HDAC inhibitor has similar effects on B10 cells. Our study sheds light on the mechanism underlying B10 cell differentiation and function and provides a potential therapeutic strategy with SCFAs and HDAC inhibitors for inflammation and autoimmune diseases.
Are Shockley-Read-Hall and ABC models valid for lead halide perovskites?
Authors: Kiligaridis Alexander , Frantsuzov Pavel A. , Yangui Aymen , Seth Sudipta , Li Jun , An Qingzhi , Vaynzof Yana , Scheblykin Ivan G.
Published: June 2021

Metal halide perovskites are an important class of emerging semiconductors. Their charge carrier dynamics is poorly understood due to limited knowledge of defect physics and charge carrier recombination mechanisms. Nevertheless, classical ABC and Shockley-Read-Hall (SRH) models are ubiquitously applied to perovskites without considering their validity. Herein, an advanced technique mapping photoluminescence quantum yield (PLQY) as a function of both the excitation pulse energy and repetition frequency is developed and employed to examine the validity of these models. While ABC and SRH fail to explain the charge dynamics in a broad range of conditions, the addition of Auger recombination and trapping to the SRH model enables a quantitative fitting of PLQY maps and low-power PL decay kinetics, and extracting trap concentrations and efficacies. However, PL kinetics at high power are too fast and cannot be explained. The proposed PLQY mapping technique is ideal for a comprehensive testing of theories and applicable to any semiconductor.
B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma
Authors: Ruffin Ayana T. , Cillo Anthony R. , Tabib Tracy , Liu Angen , Onkar Sayali , Kunning Sheryl R. , Lampenfeld Caleb , Atiya Huda I. , Abecassis Irina , Kürten Cornelius H. L. , Qi Zengbiao , Soose Ryan , Duvvuri Umamaheswar , Kim Seungwon , Oesterrich Steffi , Lafyatis Robert , Coffman Lan G. , Ferris Robert L. , Vignali Dario A. A. , Bruno Tullia C.
Published: June 2021

Current immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV+), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome. GC TIL-Bs in HPV+ HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a expression is enhanced on GC TIL-Bs present in TLS of HPV+ HNSCC and during the differentiation of TIL-Bs. Our study suggests that therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies.
Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus
Authors: Hasni Sarfaraz A. , Gupta Sarthak , Davis Michael , Poncio Elaine , Temesgen-Oyelakin Yenealem , Carlucci Philip M. , Wang Xinghao , Naqi Mohammad , Playford Martin P. , Goel Rishi R. , Li Xiaobai , Biehl Ann J. , Ochoa-Navas Isabel , Manna Zerai , Shi Yinghui , Thomas Donald , Chen Jinguo , Biancotto Angélique , Apps Richard , Cheung Foo , Kotliarov Yuri , Babyak Ashley L. , Zhou Huizhi , Shi Rongye , Stagliano Katie , Tsai Wanxia Li , Vian Laura , Gazaniga Nathalia , Giudice Valentina , Lu Shajia , Brooks Stephen R. , MacKay Meggan , Gregersen Peter , Mehta Nehal N. , Remaley Alan T. , Diamond Betty , O’Shea John J. , Gadina Massimo , Kaplan Mariana J.
Published: June 2021

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study’s primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, −26.5), cholesterol efflux capacity (p = 0.08, CI 95%: −0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.
A small molecule HIF-1α stabilizer that accelerates diabetic wound healing
Authors: Li Guodong , Ko Chung-Nga , Li Dan , Yang Chao , Wang Wanhe , Yang Guan-Jun , Di Primo Carmelo , Wong Vincent Kam Wai , Xiang Yaozu , Lin Ligen , Ma Dik-Lung , Leung Chung-Hang
Published: June 2021

Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.
The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets
Authors: Nording Henry , Baron Lasse , Haberthür David , Emschermann Frederic , Mezger Matthias , Sauter Manuela , Sauter Reinhard , Patzelt Johannes , Knoepp Kai , Nording Anne , Meusel Moritz , Meyer-Saraei Roza , Hlushchuk Ruslan , Sedding Daniel , Borst Oliver , Eitel Ingo , Karsten Christian M. , Feil Robert , Pichler Bernd , Erdmann Jeanette , Verschoor Admar , Chavakis Emmanouil , Chavakis Triantafyllos , von Hundelshausen Philipp , Köhl Jörg , Gawaz Meinrad , Langer Harald F.
Published: June 2021

Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1−/− mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo.

In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4.
Replicate sequencing libraries are important for quantification of allelic imbalance
Authors: Mendelevich Asia , Vinogradova Svetlana , Gupta Saumya , Mironov Andrey A. , Sunyaev Shamil R. , Gimelbrant Alexander A.
Published: June 2021

A sensitive approach to quantitative analysis of transcriptional regulation in diploid organisms is analysis of allelic imbalance (AI) in RNA sequencing (RNA-seq) data. A near-universal practice in such studies is to prepare and sequence only one library per RNA sample. We present theoretical and experimental evidence that data from a single RNA-seq library is insufficient for reliable quantification of the contribution of technical noise to the observed AI signal; consequently, reliance on one-replicate experimental design can lead to unaccounted-for variation in error rates in allele-specific analysis. We develop a computational approach, Qllelic, that accurately accounts for technical noise by making use of replicate RNA-seq libraries. Testing on new and existing datasets shows that application of Qllelic greatly decreases false positive rate in allele-specific analysis while conserving appropriate signal, and thus greatly improves reproducibility of AI estimates. We explore sources of technical overdispersion in observed AI signal and conclude by discussing design of RNA-seq studies addressing two biologically important questions: quantification of transcriptome-wide AI in one sample, and differential analysis of allele-specific expression between samples.
Reprogramming of microRNA expression via E2F1 downregulation promotes Salmonella infection both in infected and bystander cells
Authors: Aguilar Carmen , Costa Susana , Maudet Claire , Vivek-Ananth R. P. , Zaldívar-López Sara , Garrido Juan J. , Samal Areejit , Mano Miguel , Eulalio Ana
Published: June 2021

Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells’ susceptibility to infection. Here, we show the opposite effect: epithelial cells infected withSalmonellaTyphimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such asShigella flexneriorListeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome ofSalmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promoteSalmonellareplication within infected cells and prime bystander cells for more efficient infection.
RNA structure probing reveals the structural basis of Dicer binding and cleavage
Authors: Luo Qing-Jun , Zhang Jinsong , Li Pan , Wang Qing , Zhang Yue , Roy-Chaudhuri Biswajoy , Xu Jianpeng , Kay Mark A. , Zhang Qiangfeng Cliff
Published: June 2021

It is known that an RNA’s structure determines its biological function, yet current RNA structure probing methods only capture partial structure information. The ability to measure intact (i.e., full length) RNA structures will facilitate investigations of the functions and regulation mechanisms of small RNAs and identify short fragments of functional sites. Here, we present icSHAPE-MaP, an approach combining in vivo selective 2′-hydroxyl acylation and mutational profiling to probe intact RNA structures. We further showcase the RNA structural landscape of substrates bound by human Dicer based on the combination of RNA immunoprecipitation pull-down and icSHAPE-MaP small RNA structural profiling. We discover distinct structural categories of Dicer substrates in correlation to both their binding affinity and cleavage efficiency. And by tertiary structural modeling constrained by icSHAPE-MaP RNA structural data, we find the spatial distance measuring as an influential parameter for Dicer cleavage-site selection.
Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2
Authors: Pack Lindsey R. , Daigh Leighton H. , Chung Mingyu , Meyer Tobias
Published: June 2021

Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical importance, little is known about how CDK4/6 inhibitors affect the stability of CDK4/6 complexes, which bind cyclins and inhibitory proteins such as p21. We develop an assay to monitor CDK complex stability inside the nucleus. Unexpectedly, treatment with CDK4/6 inhibitors—palbociclib, ribociclib, or abemaciclib—immediately dissociates p21 selectively from CDK4 but not CDK6 complexes. This effect mediates indirect inhibition of CDK2 activity by p21 but not p27 redistribution. Our work shows that CDK4/6 inhibitors have two roles: non-catalytic inhibition of CDK2 via p21 displacement from CDK4 complexes, and catalytic inhibition of CDK4/6 independent of p21. By broadening the non-catalytic displacement to p27 and CDK6 containing complexes, next-generation CDK4/6 inhibitors may have improved efficacy and overcome resistance mechanisms.
Pathogen effector recognition-dependent association of NRG1 with EDS1 and SAG101 in TNL receptor immunity
Authors: Sun Xinhua , Lapin Dmitry , Feehan Joanna M. , Stolze Sara C. , Kramer Katharina , Dongus Joram A. , Rzemieniewski Jakub , Blanvillain-Baufumé Servane , Harzen Anne , Bautor Jaqueline , Derbyshire Paul , Menke Frank L. H. , Finkemeier Iris , Nakagami Hirofumi , Jones Jonathan D. G. , Parker Jane E.
Published: June 2021

Plants utilise intracellular nucleotide-binding, leucine-rich repeat (NLR) immune receptors to detect pathogen effectors and activate local and systemic defence. NRG1 and ADR1 “helper” NLRs (RNLs) cooperate with enhanced disease susceptibility 1 (EDS1), senescence-associated gene 101 (SAG101) and phytoalexin-deficient 4 (PAD4) lipase-like proteins to mediate signalling from TIR domain NLR receptors (TNLs). The mechanism of RNL/EDS1 family protein cooperation is not understood. Here, we present genetic and molecular evidence for exclusive EDS1/SAG101/NRG1 and EDS1/PAD4/ADR1 co-functions in TNL immunity. Using immunoprecipitation and mass spectrometry, we show effector recognition-dependent interaction of NRG1 with EDS1 and SAG101, but not PAD4. An EDS1-SAG101 complex interacts with NRG1, and EDS1-PAD4 with ADR1, in an immune-activated state. NRG1 requires an intact nucleotide-binding P-loop motif, and EDS1 a functional EP domain and its partner SAG101, for induced association and immunity. Thus, two distinct modules (NRG1/EDS1/SAG101 and ADR1/EDS1/PAD4) mediate TNL receptor defence signalling.
A multicentre validation study of the diagnostic value of plasma neurofilament light
Authors: Ashton Nicholas J. , Janelidze Shorena , Al Khleifat Ahmad , Leuzy Antoine , van der Ende Emma L. , Karikari Thomas K. , Benedet Andrea L. , Pascoal Tharick A. , Lleó Alberto , Parnetti Lucilla , Galimberti Daniela , Bonanni Laura , Pilotto Andrea , Padovani Alessandro , Lycke Jan , Novakova Lenka , Axelsson Markus , Velayudhan Latha , Rabinovici Gil D. , Miller Bruce , Pariante Carmine , Nikkheslat Naghmeh , Resnick Susan M. , Thambisetty Madhav , Schöll Michael , Fernández-Eulate Gorka , Gil-Bea Francisco J. , López de Munain Adolfo , Al-Chalabi Ammar , Rosa-Neto Pedro , Strydom Andre , Svenningsson Per , Stomrud Erik , Santillo Alexander , Aarsland Dag , van Swieten John C. , Palmqvist Sebastian , Zetterberg Henrik , Blennow Kaj , Hye Abdul , Hansson Oskar
Published: June 2021

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King’s College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
Sam68 promotes hepatic gluconeogenesis via CRTC2
Authors: Qiao Aijun , Zhou Junlan , Xu Shiyue , Ma Wenxia , Boriboun Chan , Kim Teayoun , Yan Baolong , Deng Jianxin , Yang Liu , Zhang Eric , Song Yuhua , Ma Yongchao C. , Richard Stephane , Zhang Chunxiang , Qiu Hongyu , Habegger Kirk M. , Zhang Jianyi , Qin Gangjian
Published: June 2021

Hepatic gluconeogenesis is essential for glucose homeostasis and also a therapeutic target for type 2 diabetes, but its mechanism is incompletely understood. Here, we report that Sam68, an RNA-binding adaptor protein and Src kinase substrate, is a novel regulator of hepatic gluconeogenesis. Both global and hepatic deletions of Sam68 significantly reduce blood glucose levels and the glucagon-induced expression of gluconeogenic genes. Protein, but not mRNA, levels of CRTC2, a crucial transcriptional regulator of gluconeogenesis, are >50% lower in Sam68-deficient hepatocytes than in wild-type hepatocytes. Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination. However, truncated mutants of Sam68 that lack the C- (Sam68ΔC) or N-terminal (Sam68ΔN) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68ΔN mice recapitulate the blood-glucose and gluconeogenesis profile of Sam68-deficient mice. Hepatic Sam68 expression is also upregulated in patients with diabetes and in two diabetic mouse models, while hepatocyte-specific Sam68 deficiencies alleviate diabetic hyperglycemia and improves insulin sensitivity in mice. Thus, our results identify a role for Sam68 in hepatic gluconeogenesis, and Sam68 may represent a therapeutic target for diabetes.
The influence of decision-making in tree ring-based climate reconstructions
Authors: Büntgen Ulf , Allen Kathy , Anchukaitis Kevin J. , Arseneault Dominique , Boucher Étienne , Bräuning Achim , Chatterjee Snigdhansu , Cherubini Paolo , Churakova Olga V. , Corona Christophe , Gennaretti Fabio , Grießinger Jussi , Guillet Sebastian , Guiot Joel , Gunnarson Björn , Helama Samuli , Hochreuther Philipp , Hughes Malcolm K. , Huybers Peter , Kirdyanov Alexander V. , Krusic Paul J. , Ludescher Josef , Meier Wolfgang J.-H. , Myglan Vladimir S. , Nicolussi Kurt , Oppenheimer Clive , Reinig Frederick , Salzer Matthew W. , Seftigen Kristina , Stine Alexander R. , Stoffel Markus , St. George Scott , Tejedor Ernesto , Trevino Aleyda , Trouet Valerie , Wang Jianglin , Wilson Rob , Yang Bao , Xu Guobao , Esper Jan
Published: June 2021

Tree-ring chronologies underpin the majority of annually-resolved reconstructions of Common Era climate. However, they are derived using different datasets and techniques, the ramifications of which have hitherto been little explored. Here, we report the results of a double-blind experiment that yielded 15 Northern Hemisphere summer temperature reconstructions from a common network of regional tree-ring width datasets. Taken together as an ensemble, the Common Era reconstruction mean correlates with instrumental temperatures from 1794–2016 CE at 0.79 (p < 0.001), reveals summer cooling in the years following large volcanic eruptions, and exhibits strong warming since the 1980s. Differing in their mean, variance, amplitude, sensitivity, and persistence, the ensemble members demonstrate the influence of subjectivity in the reconstruction process. We therefore recommend the routine use of ensemble reconstruction approaches to provide a more consensual picture of past climate variability.
High throughput screening identifies SOX2 as a super pioneer factor that inhibits DNA methylation maintenance at its binding sites
Authors: Vanzan Ludovica , Soldati Hadrien , Ythier Victor , Anand Santosh , Braun Simon M. G. , Francis Nicole , Murr Rabih
Published: June 2021

Binding of mammalian transcription factors (TFs) to regulatory regions is hindered by chromatin compaction and DNA methylation of their binding sites. Nevertheless, pioneer transcription factors (PFs), a distinct class of TFs, have the ability to access nucleosomal DNA, leading to nucleosome remodelling and enhanced chromatin accessibility. Whether PFs can bind to methylated sites and induce DNA demethylation is largely unknown. Using a highly parallelized approach to investigate PF ability to bind methylated DNA and induce DNA demethylation, we show that the interdependence between DNA methylation and TF binding is more complex than previously thought, even within a select group of TFs displaying pioneering activity; while some PFs do not affect the methylation status of their binding sites, we identified PFs that can protect DNA from methylation and others that can induce DNA demethylation at methylated binding sites. We call the latter super pioneer transcription factors (SPFs), as they are seemingly able to overcome several types of repressive epigenetic marks. Finally, while most SPFs induce TET-dependent active DNA demethylation, SOX2 binding leads to passive demethylation, an activity enhanced by the co-binding of OCT4. This finding suggests that SPFs could interfere with epigenetic memory during DNA replication.