bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunotherapy of HBV-related advanced hepatocellular carcinoma with short-term HBV-specific TCR expressed T cells: results of dose escalation, phase I trial
Authors: Meng Fanping , Zhao Jinfang , Tan Anthony Tanoto , Hu Wei , Wang Si-Yu , Jin Jiehua , Wu Juan , Li Yuanyuan , Shi Lei , Fu Jun-Liang , Yu Shuangjie , Shen Yingjuan , Liu Limin , Luan Junqing , Shi Ming , Xie Yunbo , Zhou Chun-Bao , Wong Regina Wanju , Lu-En Wai , Koh Sarene , Bertoletti Antonio , Wang Tingting , Zhang Ji-Yuan , Wang Fu-Sheng
Published: November 2021

Background & aims

Immunotherapy with hepatitis B virus (HBV)-specific TCR redirected T (HBV-TCR-T) cells in HBV-related hepatocellular carcinoma (HBV-HCC) patients after liver transplantation was reported to be safe and had potential therapeutic efficacy. We aim to investigate the safety of HBV-TCR-T-cell immunotherapy in advanced HBV-HCC patients who had not met the criteria for liver transplantation.

Methods

We enrolled eight patients with advanced HBV-HCC and adoptively transferred short-lived autologous T cells expressing HBV-specific TCR to perform an open-label, phase 1 dose-escalation study (NCT03899415). The primary endpoint was to evaluate the safety of HBV-TCR-T-cell therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) during the dose-escalation process. The secondary endpoint was to assess the efficacy of HBV-TCR-T-cell therapy by evaluating the anti-tumor responses using RECIST criteria (version 1.1) and the overall survival.

Results

Adverse events were observed in two participants among the 8 patients enrolled. Only one patient experienced a Grade 3 liver-related adverse event after receiving a dose of 1 × 105 HBV-TCR-T cells/kg, then normalized without interventions with immunosuppressive agents. Among the patients, one achieved a partial response lasting for 27.7 months. Importantly, most of the patients exhibited a reduction or stabilization of circulating HBsAg and HBV DNA levels after HBV-TCR-T-cell infusion, indicating the on-target effects.

Conclusions

The adoptive transfer of HBV-TCR-T cells into advanced HBV-HCC patients were generally safe and well-tolerated. Observations of clinical efficacy support the continued development and eventual application of this treatment strategy in patients with advanced HBV-related HCC.

Clinical trials registration

This study was registered at ClinicalTrials.gov (NCT03899415).
Right Heart Morphology of Candidate Patients for Transcatheter Tricuspid Valve Interventions
Authors: Khalique Omar K. , Jelnin Vladimir , Hueske Andreas , Lawlor Mathew , Leon Martin B. , Kodali Susheel K. , Akkoc Deniz , Pettway Eriq , Hahn Rebecca T. , Hamid Nadira B. , George Isaac , Patel Amisha , Ng Vivian , Vahl Torsten P. , Nazif Tamim M. , Siefert Andrew W.
Published: December 2021

Purpose

This study quantitatively evaluated the phasic right heart morphology of candidate patients for a transcatheter tricuspid valve intervention (N=32) and of subjects with trace to no tricuspid regurgitation (N = 14).

Methods

Cardiac computed tomography angiography (CCTA) and transthoracic/transesophageal echocardiography (TTE/TEE) images were analyzed using dedicated research and clinical software. Using CCTA, the phasic right atrial and ventricular volumes, annulus dimensions, annulus-to-right coronary artery (RCA) distances, circumferential topography of the annular tissue shelf, vena cava dimensions (inferior and superior), vena cava positions, axis angles, and annular excursions were quantified. Using TTE/TEE, leaflet geometry, regurgitation, hemodynamics, and heart function were quantified. Measurements within and between groups were quantitatively compared with regression analyses to explore relationships between right heart features.

Results

The phasic position and orientation of the vena cava and the circumferential topography of the annular tissue shelf were quantitatively presented for the first time. The candidate patient group exhibited greater chamber dimensions, enlarged vena cava, distended vena cava positions, positional shallowing of the annular tissue shelf, geometric annular distortion, leaflet distention, moderate or greater regurgitation, and impaired ventricular function. Atrial volume correlated strongly with directional vena cava positions as well as with annular dimensions. Annulus-to-RCA distances and annular excursions were comparable between groups.

Conclusions

This study provides new and further insight to the right heart morphology and functional characteristics of candidate patients for a transcatheter tricuspid valve intervention. These data provide a platform from which these patients can continue to be better understood for further improving transcatheter system design and use.
Degrading permafrost river catchments and their impact on Arctic Ocean nearshore processes
Authors: Mann Paul J. , Strauss Jens , Palmtag Juri , Dowdy Kelsey , Ogneva Olga , Fuchs Matthias , Bedington Michael , Torres Ricardo , Polimene Luca , Overduin Paul , Mollenhauer Gesine , Grosse Guido , Rachold Volker , Sobczak William V. , Spencer Robert G. M. , Juhls Bennet
Published: November 2021

Arctic warming is causing ancient perennially frozen ground (permafrost) to thaw, resulting in ground collapse, and reshaping of landscapes. This threatens Arctic peoples' infrastructure, cultural sites, and land-based natural resources. Terrestrial permafrost thaw and ongoing intensification of hydrological cycles also enhance the amount and alter the type of organic carbon (OC) delivered from land to Arctic nearshore environments. These changes may affect coastal processes, food web dynamics and marine resources on which many traditional ways of life rely. Here, we examine how future projected increases in runoff and permafrost thaw from two permafrost-dominated Siberian watersheds—the Kolyma and Lena, may alter carbon turnover rates and OC distributions through river networks. We demonstrate that the unique composition of terrestrial permafrost-derived OC can cause significant increases to aquatic carbon degradation rates (20 to 60% faster rates with 1% permafrost OC). We compile results on aquatic OC degradation and examine how strengthening Arctic hydrological cycles may increase the connectivity between terrestrial landscapes and receiving nearshore ecosystems, with potential ramifications for coastal carbon budgets and ecosystem structure. To address the future challenges Arctic coastal communities will face, we argue that it will become essential to consider how nearshore ecosystems will respond to changing coastal inputs and identify how these may affect the resiliency and availability of essential food resources.
Exploring Forest Sector Research Subjects and Trends from 2000 to 2019 Using Topic Modeling
Authors: Nummelin T. , Hänninen R. , Kniivilä M.
Published: November 2021

Purpose of Review

This review aims to discover the most common topics and trends in international scientific forest sector research between January 2000 and December 2019 and to test the suitability of a quantitative topic-modeling method to extract topics from the data. The results will be helpful for both researchers and policy decision-makers in identifying emerging research topics and possible research gaps. The analysis framework covers the complete forest wood chain (FWC) with PESTE factors. PESTE is applied to analyze political, economic, social, technological, and ecological/environmental factors affecting the FWC.

Recent findings

In the last two decades, forests and the forest sector have been impacted by several global changes, policies, and megatrends. Previous systematic syntheses of forest sector research reveal that economic, policy, and social research have remained underrepresented in the forest sector literature. Research areas related to forest ecology and climate change have been increasing. More recently, growth has also been detected in social aspects especially related to the increasing literature on forest ecosystem services.

Results

A total of 160 topics were extracted from 14,470 abstracts of 15 leading international peer-reviewed forest science journals. The ecological topics of forest resources and technological topics of industry and products were by far the two largest subject areas. Ecological topics increased, while technological topics slightly decreased, during the period between 2000 and 2019. A clear decline in the share of topics concerning end-product markets was detected. Indeed, changes in end markets drive changes in the entire forest wood chain. To support the goal of a transition from a fossil-based economy to a bioeconomy, it will be important to increase academic research on policy impacts, as well as social and ecological sustainability issues to cover all the stages of the FWC more evenly. The topic-modeling method was a useful tool in data mining, but human intelligence is needed to interpret and classify the topics extracted by this approach.
HPV and Pap testing among white, black, and hispanic women: results from a survey study
Authors: Ventura Ilana M. , Zhong Selena , Bilgen Ipek , Dutwin David , Delgado Jane L.
Published: November 2021

While the Pap test, HPV vaccine, and HPV test are important tools to promote cervical health, the American Cancer Society (ACS) recently updated its cervical cancer prevention recommendations to give primacy to HPV testing for cervical cancer screening. We investigate how women’s health providers view these changes, and the extent to which they have reached American women. To do so, we present results from a novel two-survey study of women’s health providers (N = 558) and White, Black, and Hispanic women (N = 1900). We find that a minority of providers report that the HPV test alone is adequate for cervical cancer screening (18%, CI = 14%, 21%) while 96% (CI = 94%, 97%) indicated that women should regularly have both Pap and HPV screenings. Black (88% CI = 86%, 91%) and Hispanic (87% CI = 84%, 89%) women report lower rates of Pap tests compared to White women (94%, CI = 92%, 96%). Only 35% (CI = 33%, 37%) of women report having had an HPV test, and these levels were similar across groups. White (29%, CI = 25%, 33%) and Hispanic women (26% CI = 23%, 29%) report statistically similar levels of provider recommendation for joint Pap-HPV testing, while Black women report statistically lower rates (22%, CI = 18%, 25%). These patterns hold after controlling for several important socio-demographic variables in logistic regression models. The continued lower rates of Pap tests among Black and Hispanic women, combined with low rates of HPV testing is likely to hinder the ability to reduce cervical cancer incidence and mortality, particularly for Hispanic and Black women.
The Punjab Borderland
Authors: Chattha Ilyas
Published: November 2021

The Punjab Borderland offers a fascinating insight into how the new international boundary between India and Pakistan was made, subverted, and transformed. Dispelling the established historiographical narratives of an increasingly militarised border that presents as the epitome of animosity and a classic example of inter-state tension, this book offers a corrective to these accounts by bringing out narratives of border crossings and social relations built on mutual benefit and trust. It conceptualises the making of the vast contraband as an analytical tool, not merely as borderland societies' modes for evading the state imposition of a partitioned geography on their local lifeworld, but as a catalyst for enabling social mobility and political empowerment for the population involved and a thriving market for consumption in the urban centres. It reveals a 'bottom-up' history of the Punjab border and the invention of the borderland society, narrating a story with local meanings and transnational dimensions.
Nuclear Weapons Law
Authors: Boothby William H. , Heintschel von Heinegg Wolff
Published: November 2021

This book examines the law relating to the possession, threat or use of nuclear weapons. By addressing in logical sequence the law regarding sovereignty, the threat or use of force, the conduct of nuclear hostilities, neutrality, weapons law and war crimes, the book illustrates the topics that an effective national command, control and communications system for nuclear weapons must address. Guidance is given on intractable issues, such as the responsibilities of remote submarine commanders. The continuing relevance of the ICJ's Nuclear Advisory Opinion is assessed, and the prospects for the Treaty on the Prohibition of Nuclear Weapons are discussed. The book has been written in an accessible style so that it will be equally useful to lawyers and practitioners, including relevant commanders, politicians, policy staffs and academics. The objective is to state the law accurately and to explain its implications and provide practical guidance in this most sensitive area. This book is also available as open access.
Discontinuing MRSA and VRE contact precautions: Defining hospital characteristics and infection prevention practices predicting safe de-escalation
Authors: Martin Elise M. , Colaianne Bonnie , Bridge Christine , Bilderback Andrew , Tanner Colleen , Wagester Suzanne , Yassin Mohamed , Pontzer Raymond , Snyder Graham M.
Published: December 2021

Objective:

To define conditions in which contact precautions can be safely discontinued for methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).

Design:

Interrupted time series.

Setting:

15 acute-care hospitals.

Participants:

Inpatients.

Intervention:

Contact precautions for endemic MRSA and VRE were discontinued in 12 intervention hospitals and continued at 3 nonintervention hospitals. Rates of MRSA and VRE healthcare-associated infections (HAIs) were collected for 12 months before and after. Trends in HAI rates were analyzed using Poisson regression. To predict conditions when contact precautions may be safely discontinued, selected baseline hospital characteristics and infection prevention practices were correlated with HAI rate changes, stratified by hospital.

Results:

Aggregated HAI rates from intervention hospitals before and after discontinuation of contact precautions were 0.14 and 0.15 MRSA HAI per 1,000 patient days (P = .74), 0.05 and 0.05 VRE HAI per 1,000 patient days (P = .96), and 0.04 and 0.04 MRSA laboratory-identified (LabID) events per 100 admissions (P = .57). No statistically significant rate changes occurred between intervention and non-intervention hospitals. All successful hospitals had low baseline MRSA and VRE HAI rates and high hand hygiene adherence. We observed no correlations between rate changes after discontinuation and the assessed hospital characteristics and infection prevention factors, but the rate improved with higher proportion of semiprivate rooms (P = .04).

Conclusions:

Discontinuing contact precautions for MRSA/VRE did not result in increased HAI rates, suggesting that contact precautions can be safely removed from diverse hospitals, including community hospitals and those with lower proportions of private rooms. Good hand hygiene and low baseline HAI rates may be conditions permissive of safe removal of contact precautions.
Analyses of wave-phase variation of Reynolds shear stress underneath surface wave using streamline coordinates
Authors: Xuan Anqing , Shen Lian
Published: December 2021

The dependence of Reynolds shear stress on wave phase is investigated for initially isotropic turbulence distorted by a progressive surface wave through direct numerical simulations. A wave-following streamline coordinate frame is used to analyse the turbulence dynamics such that the information of the varying direction of wave orbital motions is embedded into the coordinate system, which helps capture the effect of flow curvature on the turbulence and quantify momentum exchange between the near-surface and deep regions in the wavy domain accurately. It is found that the Reynolds shear stress is enhanced under the backward slope of the wave and can be scaled by the wave steepness and the streamwise velocity fluctuations. Analyses of the budget of Reynolds shear stress indicate that such a variation with the wave phase is caused by the variation in the production of the Reynolds shear stress and the effect of pressure fluctuations. Further investigation shows that the production of the Reynolds shear stress is closely associated with the wave surface curvature. A model that includes a correction term for the curvature effect for the pressure–strain correlation term is examined and is found to agree reasonably well with the simulation result. The correction term is found to make an appreciable contribution to the model, further supporting our finding that the wave curvature plays an important role in the turbulence dynamics near the surface.
Variational characterizations of weighted Hardy spaces and weighted spaces
Authors: Guo Weichao , Wen Yongming , Wu Huoxiong , Yang Dongyong
Published: December 2021

This paper obtains new characterizations of weighted Hardy spaces and certain weighted $BMO$ type spaces via the boundedness of variation operators associated with approximate identities and their commutators, respectively.
Petrogenesis of contrasting magmatic suites in the Abu Kharif area, Northern Eastern Desert, Egypt: implications for Pan-African crustal evolution and tungsten mineralization
Authors: Abdel Wanees Nora G , El-Sayed Mohamed M , Khalil Khalil I , Khamis Hossam A
Published: November 2021

The Abu Kharif area in the Northern Eastern Desert consists of contrasting granitic magma suites: a Cryogenian granodiorite suite (850–635 Ma), an Ediacaran monzogranite suite (635–541 Ma) and a Cambrian alkali riebeckite granite suite (541–485 Ma). Tungsten mineralization occurs within W-bearing quartz veins and a disseminated type confined to the monzogranite.

Whole-rock geochemical data classify the granodiorite as a late-orogenic I-type with calc-alkaline affinity, while the monzogranite and alkali riebeckite granite represent respectively a post-orogenic highly fractionated I-type with calc-alkaline affinity and an anorogenic A1-subtype with alkaline affinity. Geochemical modelling indicates that the three intrusions represent separate magmatic pulses where the granodiorite was generated by ∼75 % batch partial melting of an amphibolitic source followed by fractional crystallization of hornblende, biotite, apatite and titanite. The monzogranite was formed by 62 % batch partial melting of the normal ‘non-metasomatized’ Pan-African crust of calc-alkaline granite composition followed by fractional crystallization of plagioclase, biotite, K-feldspar, magnetite, ilmenite, with minor apatite and titanite. The alkali riebeckite granite was generated by 65 % batch partial melting of metasomatized Pan-African granite source followed by fractional crystallization of plagioclase, K-feldspar, amphibole and biotite with minor magnetite, apatite and titanite. In general, the parent magmas of the three intrusions were originally enriched in W, but with different concentrations. This W-enrichment would be caused by magmatic-related hydrothermal volatile-rich fluids and concentrated within the monzogranite.
Predicting intention to hunt protected wildlife: a case study of Bewick's swan in the European Russian Arctic
Authors: Newth Julia L. , McDonald Robbie A. , Wood Kevin A. , Rees Eileen C. , Semenov Igor , Chistyakov Anton , Mikhaylova Galina , Bearhop Stuart , Cromie Ruth L. , Belousova Anna , Glazov Petr , Nuno Ana
Published: November 2021

Illegal killing of wildlife is a major conservation issue that, to be addressed effectively, requires insight into the drivers of human behaviour. Here we adapt an established socio-psychological model, the theory of planned behaviour, to explore reasons for hunting the Endangered Bewick's swan Cygnus columbianus bewickii in the European Russian Arctic, using responses from hunters to a questionnaire survey. Wider ecological, legal, recreational and economic motivations were also explored. Of 236 hunters who participated overall, 14% harboured intentions to hunt Bewick's swan. Behavioural intention was predicted by all components of the theory of planned behaviour, specifically: hunters' attitude towards the behaviour, perceived behavioural control (i.e. perceived capability of being able to perform the behaviour) and their subjective norms (perception of social expectations). The inclusion of attitude towards protective laws and descriptive norm (perception of whether other people perform the behaviour) increased the model's predictive power. Understanding attitudes towards protective laws can help guide the design of conservation measures that reduce non-compliance. We conclude that conservation interventions should target the socio-psychological conditions that influence hunters' attitudes, social norms and perceived behavioural control. These may include activities that build trust, encourage support for conservation, generate social pressure against poaching, use motivations to prompt change and strengthen peoples' confidence to act. This approach could be applied to inform the effective design, prioritization and targeting of interventions that improve compliance and reduce the illegal killing of wildlife.
Seismic Imaging of a Magma Chamber and Melt Recharge of the Dormant Datong Volcanoes
Authors: He Lipeng , Guo Zhen , Chen Yongshun John , Huang Qinghua , Yang Yingjie
Published: November 2021

The Datong volcanoes erupted episodically from ca. 0.74 to ca 0.10 Ma with the last eruption at ca. 100 ka, and ever since has remained dormant. It remains elusive whether the Datong volcanoes are being recharged and would become active again in the near future. Here, we image the crustal structures beneath the Datong volcanoes using local earthquake data recorded at a newly deployed dense Datong Nodal Array. The high‐resolution 3‐D model reveals, for the first time, the geometry and melt fraction of a shallow crustal magma chamber at the depths of 10–20 km beneath the Datong volcanoes. Here, we suggest a magmatic system beneath the Datong volcanoes that could transport basaltic melt from the uppermost mantle to the shallow crustal magma chamber beneath the Datong volcanoes. Further, the melt‐poor crustal magma chamber (melt fraction of 5%–10%) can explain why the Datong volcanoes are inactive at present, and future eruptions can be expected if melt recharge from a mantle source is sustained.
The pivotal role of the NLRC4 inflammasome in neuroinflammation after intracerebral hemorrhage in rats
Authors: Gan Hui , Zhang Li , Chen Hui , Xiao Han , Wang Lu , Zhai Xuan , Jiang Ning , Liang Ping , Zheng Shuyue , Zhao Jing
Published: November 2021

The NLRC4 inflammasome, a member of the nucleotide-binding and oligomerization domain-like receptor (NLR) family, amplifies inflammation by facilitating the processing of caspase-1, interleukin (IL)–1β, and IL-18. We explored whether NLRC4 knockdown alleviated inflammatory injury following intracerebral hemorrhage (ICH). Furthermore, we investigated whether NLRC4 inflammasome activation can be adjusted by the regulator of G protein signaling 2/leucine-rich repeat kinase-2 pathway. Fifty microliters of arterial blood was drawn and injected into the basal ganglion to simulate the ICH model. NLRC4 small interfering RNAs (siRNAs) were utilized to knockdown NLRC4. An LRRK2 inhibitor (GNE7915) was injected into the abdominal cavity. Short hairpin (sh) RNA lentiviruses and lentiviruses containing RGS2 were designed and applied to knockdown and promote RGS2 expression. Neurological functions, brain edema, Western blot, enzyme-linked immunosorbent, hematoxylin and eosin staining, Nissl staining, immunoprecipitation, immunofluorescence assay and Evans blue dye extravasation and autofluorescence assay were evaluated. It was shown that the NLRC4 inflammasome was activated following ICH injury. NLRC4 knockdown extenuated neuronal death, damage to the blood-brain barrier, brain edema and neurological deficiency 3 days after ICH. NLRC4 knockdown reduced myeloperoxidase (MPO) cells as well as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β and IL-18 following ICH. GNE7915 reduced pNLRC4 and NLRC4 inflammasome activation. RGS2 suppressed the interaction of LRRK2 and NLRC4 and NLRC4 inflammasome activation by regulating pLRRK2. Our study demonstrated that the NLRC4 inflammasome may aggravate the inflammatory injury induced by ICH and that RGS2/LRRK2 may relieve inflammatory injury by restraining NLRC4 inflammasome activation.
Natural killer cell-derived exosomal miR-1249-3p attenuates insulin resistance and inflammation in mouse models of type 2 diabetes
Authors: Wang Ying , Li Mengwei , Chen Lin , Bian Huan , Chen Xiangying , Zheng Huilin , Yang Peiwei , Chen Quan , Xu Hanmei
Published: November 2021

Natural killer (NK) cells have been suggested to be associated with type 2 diabetes by regulating systemic inflammation. However, the mechanism by which NK cells regulate insulin sensitivity remains unknown. This study shows that NK-derived exosomes from lean mice attenuate obesity-induced insulin resistance and inflammation in mice of type 2 diabetes. Moreover, lean NK-derived exosomes enhance insulin sensitivity and relieve inflammation in adipocytes and hepatocytes. MiR-1249-3p, which is significantly upregulated in lean NK-derived exosomes, can be transferred from NK cells to adipocytes and hepatocytes via exosomes. NK-derived exosomal miR-1249-3p dramatically induces cellular insulin sensitivity and relieves inflammation. Mechanistically, exosomal miR-1249-3p directly targets SKOR1 to regulate the formation of ternary complex SMAD6/MYD88/SMURF1, which mediates glucose homeostasis by suppressing the TLR4/NF-κB signaling pathway. This study reveals an emerging role for NK-derived exosomal miR-1249-3p in remission of insulin resistance, and provides a series of potential therapeutic targets in type 2 diabetes.
Gut microbiome and metabolome in a non-human primate model of chronic excessive alcohol drinking
Authors: Piacentino Daria , Grant-Beurmann Silvia , Vizioli Carlotta , Li Xiaobai , Moore Catherine F. , Ruiz-Rodado Victor , Lee Mary R. , Joseph Paule V. , Fraser Claire M. , Weerts Elise M. , Leggio Lorenzo
Published: December 2021

A relationship between the gut microbiome and alcohol use disorder has been suggested. Excessive alcohol use produces changes in the fecal microbiome and metabolome in both rodents and humans. Yet, these changes can be observed only in a subgroup of the studied populations, and reversal does not always occur after abstinence. We aimed to analyze fecal microbial composition and function in a translationally relevant baboon model of chronic heavy drinking that also meets binge criteria (drinking too much, too fast, and too often), i.e., alcohol ~1 g/kg and blood alcohol levels (BALs) ≥ 0.08 g/dL in a 2-hour period, daily, for years. We compared three groups of male baboons (Papio anubis): L = Long-term alcohol drinking group (12.1 years); S = Short-term alcohol drinking group (2.7 years); and C = Control group, drinking a non-alcoholic reinforcer (Tang®) (8.2 years). Fecal collection took place during 3 days of Drinking (D), followed by a short period (3 days) of Abstinence (A). Fecal microbial alpha- and beta-diversity were significantly lower in L vs. S and C (p’s < 0.05). Members of the commensal families Lachnospiraceae and Prevotellaceae showed a relative decrease, whereas the opportunistic pathogen Streptococcus genus showed a relative increase in L vs. S and C (p’s < 0.05). Microbiota-related metabolites of aromatic amino acids, tricarboxylic acid cycle, and pentose increased in L vs. S and C (FDR-corrected p < 0.01), with the latter two suggesting high energy metabolism and enhanced glycolysis in the gut lumen in response to alcohol. Consistent with the long-term alcohol exposure, mucosal damage and oxidative stress markers (N-acetylated amino acids, 2-hydroxybutyrate, and metabolites of the methionine cycle) increased in L vs. S and C (FDR-corrected p < 0.01). Overall, S showed few differences vs. C, possibly due to the long-term, chronic alcohol exposure needed to alter the normal gut microbiota. In the three groups, the fecal microbiome barely differed between conditions D and A, whereas the metabolome shifted in the transition from condition D to A. In conclusion, changes in the fecal microbiome and metabolome occur after significant long-term excessive drinking and are only partially affected by acute forced abstinence from alcohol. These results provide novel information on the relationship between the fecal microbiome and metabolome in a controlled experimental setting and using a unique non-human primate model of chronic excessive alcohol drinking.
Monoclonal gammopathy of undetermined significance and COVID-19: a population-based cohort study
Authors: Rognvaldsson Saemundur , Eythorsson Elias , Thorsteinsdottir Sigrun , Vidarsson Brynjar , Onundarson Pall Torfi , Agnarsson Bjarni A. , Sigurdardottir Margret , Thorsteinsdóttir Ingunn , Olafsson Isleifur , Runolfsdottir Hrafnhildur L. , Helgason Dadi , Emilsdottir Arna R. , Agustsson Arnar S. , Bjornsson Aron H. , Kristjansdottir Gudrun , Thordardottir Asdis Rosa , Indridason Olafur Skuli , Jonsson Asbjorn , Gislason Gauti Kjartan , Olafsson Andri , Steingrimsdottir Hlif , Kampanis Petros , Hultcrantz Malin , Durie Brian G. M. , Harding Stephen , Landgren Ola , Palsson Runolfur , Love Thorvarður Jon , Kristinsson Sigurdur Yngvi
Published: December 2021

Multiple myeloma (MM) patients have increased risk of severe coronavirus disease 2019 (COVID-19) when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM has been associated with immune dysfunction which may lead to severe COVID-19. No systematic data have been published on COVID-19 in individuals with MGUS. We conducted a large population-based cohort study evaluating the risk of SARS-CoV-2 infection and severe COVID-19 among individuals with MGUS. We included 75,422 Icelanders born before 1976, who had been screened for MGUS in the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). Data on SARS-CoV-2 testing and COVID-19 severity were acquired from the Icelandic COVID-19 Study Group. Using a test-negative study design, we included 32,047 iStopMM participants who had been tested for SARS-CoV-2, of whom 1754 had MGUS. Among these participants, 1100 participants, tested positive, 65 of whom had MGUS. Severe COVID-19 developed in 230 participants, including 16 with MGUS. MGUS was not associated with SARS-CoV-2 infection (Odds ratio (OR): 1.05; 95% confidence interval (CI): 0.81–1.36; p = 0.72) or severe COVID-19 (OR: 0.99; 95%CI: 0.52–1.91; p = 0.99). These findings indicate that MGUS does not affect the susceptibility to SARS-CoV-2 or the severity of COVID-19.
Cancer-associated fibroblast-derived exosomal miR-18b promotes breast cancer invasion and metastasis by regulating TCEAL7
Authors: Yan Ziqian , Sheng Zhimei , Zheng Yuanhang , Feng Ruijun , Xiao Qinpei , Shi Lihong , Li Hongli , Yin Chonggao , Luo Hao , Hao Chong , Wang Wenhao , Zhang Baogang
Published: December 2021

Studies have shown that cancer-associated fibroblasts (CAFs) play an irreplaceable role in the occurrence and development of tumors. Therefore, exploring the action and mechanism of CAFs on tumor cells is particularly important. In this study, we compared the effects of CAFs-derived exosomes and normal fibroblasts (NFs)-derived exosomes on breast cancer cells migration and invasion. The results showed that exosomes from both CAFs and NFs could enter into breast cancer cells and CAFs-derived exosomes had a more enhancing effect on breast cancer cells migration and invasion than NFs-derived exosomes. Furthermore, microRNA (miR)-18b was upregulated in CAFs-derived exosomes, and CAFs-derived exosomes miR-18b can promote breast cancer cell migration and metastasis by specifically binding to the 3′UTR of Transcription Elongation Factor A Like 7 (TCEAL7). The miR-18b-TCEAL7 pathway promotes nuclear Snail ectopic activation by activating nuclear factor-kappa B (NF-κB), thereby inducing epithelial-mesenchymal transition (EMT) and promoting cell invasion and metastasis. Moreover, CAFs-derived exosomes miR-18b could promote mouse xenograft model tumor metastasis. Overall, our findings suggest that CAFs-derived exosomes miR-18b promote nuclear Snail ectopic by targeting TCEAL7 to activate the NF-κB pathway, thereby inducing EMT, invasion, and metastasis of breast cancer. Targeting CAFs-derived exosome miR-18b may be a potential treatment option to overcome breast cancer progression.
Generation and characterization of stable pig pregastrulation epiblast stem cell lines
Authors: Zhi Minglei , Zhang Jinying , Tang Qianzi , Yu Dawei , Gao Shuai , Gao Dengfeng , Liu Pengliang , Guo Jianxiong , Hai Tang , Gao Jie , Cao Suying , Zhao Zimo , Li Chongyang , Weng Xiaogang , He Mengnan , Chen Tianzhi , Wang Yingjie , Long Keren , Jiao Deling , Li Guanglei , Zhang Jiaman , Liu Yan , Lin Yu , Pang Daxin , Zhu Qianqian , Chen Naixin , Huang Jingjing , Chen Xinze , Yao Yixuan , Yang Jingcang , Xie Zicong , Huang Xianya , Liu Mengxin , Zhang Ran , Li Qiuyan , Miao Yiliang , Tian Jianhui , Huang Xingxu , Ouyang Hongsheng , Liu Bofeng , Xie Wei , Zhou Qi , Wei Hongjiang , Liu Zhonghua , Zheng Caihong , Li Mingzhou , Han Jianyong
Published: November 2021

Pig epiblast-derived pluripotent stem cells are considered to have great potential and broad prospects for human therapeutic model development and livestock breeding. Despite ongoing attempts since the 1990s, no stably defined pig epiblast-derived stem cell line has been established. Here, guided by insights from a large-scale single-cell transcriptome analysis of pig embryos from embryonic day (E) 0 to E14, specifically, the tracing of pluripotency changes during epiblast development, we developed an in vitro culture medium for establishing and maintaining stable pluripotent stem cell lines from pig E10 pregastrulation epiblasts (pgEpiSCs). Enabled by chemical inhibition of WNT-related signaling in combination with growth factors in the FGF/ERK, JAK/STAT3, and Activin/Nodal pathways, pgEpiSCs maintain their pluripotency transcriptome features, similar to those of E10 epiblast cells, and normal karyotypes after more than 240 passages and have the potential to differentiate into three germ layers. Strikingly, ultradeep in situ Hi-C analysis revealed functional impacts of chromatin 3D-spatial associations on the transcriptional regulation of pluripotency marker genes in pgEpiSCs. In practice, we confirmed that pgEpiSCs readily tolerate at least three rounds of successive gene editing and generated cloned gene-edited live piglets. Our findings deliver on the long-anticipated promise of pig pluripotent stem cells and open new avenues for biological research, animal husbandry, and regenerative biomedicine.
A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells
Authors: Volta Viviana , Pérez-Baos Sandra , de la Parra Columba , Katsara Olga , Ernlund Amanda , Dornbaum Sophie , Schneider Robert J.
Published: November 2021

Regulatory T cells (Treg cells) inhibit effector T cells and maintain immune system homeostasis. Treg cell maturation in peripheral sites requires inhibition of protein kinase mTORC1 and TGF-beta-1 (TGF-beta). While Treg cell maturation requires protein synthesis, mTORC1 inhibition downregulates it, leaving unanswered how Treg cells achieve essential mRNA translation for development and immune suppression activity. Using human CD4+ T cells differentiated in culture and genome-wide transcription and translation profiling, here we report that TGF-beta transcriptionally reprograms naive T cells to express Treg cell differentiation and immune suppression mRNAs, while mTORC1 inhibition impairs translation of T cell mRNAs but not those induced by TGF-beta. Rather than canonical mTORC1/eIF4E/eIF4G translation, Treg cell mRNAs utilize the eIF4G homolog DAP5 and initiation factor eIF3d in a non-canonical translation mechanism that requires cap-dependent binding by eIF3d directed by Treg cell mRNA 5’ noncoding regions. Silencing DAP5 in isolated human naive CD4+ T cells impairs their differentiation into Treg cells. Treg cell differentiation is mediated by mTORC1 downregulation and TGF-beta transcriptional reprogramming that establishes a DAP5/eIF3d-selective mechanism of mRNA translation.
Unravelling strong electronic interlayer and intralayer correlations in a transition metal dichalcogenide
Authors: Whitcher T. J. , Fauzi Angga Dito , Caozheng D. , Chi X. , Syahroni A. , Asmara T. C. , Breese M. B. H. , Neto A. H. Castro , Wee A. T. S. , Majidi M. Aziz , Rusydi A.
Published: November 2021

Electronic correlations play important roles in driving exotic phenomena in condensed matter physics. They determine low-energy properties through high-energy bands well-beyond optics. Great effort has been made to understand low-energy excitations such as low-energy excitons in transition metal dichalcogenides (TMDCs), however their high-energy bands and interlayer correlation remain mysteries. Herewith, by measuring temperature- and polarization-dependent complex dielectric and loss functions of bulk molybdenum disulphide from near-infrared to soft X-ray, supported with theoretical calculations, we discover unconventional soft X-ray correlated-plasmons with low-loss, and electronic transitions that reduce dimensionality and increase correlations, accompanied with significantly modified low-energy excitons. At room temperature, interlayer electronic correlations, together with the intralayer correlations in the c-axis, are surprisingly strong, yielding a three-dimensional-like system. Upon cooling, wide-range spectral-weight transfer occurs across a few tens of eV and in-plane p–d hybridizations become enhanced, revealing strong Coulomb correlations and electronic anisotropy, yielding a two-dimensional-like system. Our result shows the importance of strong electronic, interlayer and intralayer correlations in determining electronic structure and opens up applications of utilizing TMDCs on plasmonic nanolithrography.
Cilia locally synthesize proteins to sustain their ultrastructure and functions
Authors: Hao Kai , Chen Yawen , Yan Xiumin , Zhu Xueliang
Published: November 2021

Cilia are microtubule-based hair-like organelles propelling locomotion and extracellular liquid flow or sensing environmental stimuli. As cilia are diffusion barrier-gated subcellular compartments, their protein components are thought to come from the cell body through intraflagellar transport or diffusion. Here we show that cilia locally synthesize proteins to maintain their structure and functions. Multicilia of mouse ependymal cells are abundant in ribosomal proteins, translation initiation factors, and RNA, including 18 S rRNA and tubulin mRNA. The cilia actively generate nascent peptides, including those of tubulin. mRNA-binding protein Fmrp localizes in ciliary central lumen and appears to function in mRNA delivery into the cilia. Its depletion by RNAi impairs ciliary local translation and induces multicilia degeneration. Expression of exogenous Fmrp, but not an isoform tethered to mitochondria, rescues the degeneration defects. Therefore, local translation defects in cilia might contribute to the pathology of ciliopathies and other diseases such as Fragile X syndrome.
Loss of PRC2 subunits primes lineage choice during exit of pluripotency
Authors: Loh Chet H. , van Genesen Siebe , Perino Matteo , Bark Magnus R. , Veenstra Gert Jan C.
Published: November 2021

Polycomb Repressive Complex 2 (PRC2) is crucial for the coordinated expression of genes during early embryonic development, catalyzing histone H3 lysine 27 trimethylation. Two distinct PRC2 complexes, PRC2.1 and PRC2.2, contain respectively MTF2 and JARID2 in embryonic stem cells (ESCs). In this study, we explored their roles in lineage specification and commitment, using single-cell transcriptomics and mouse embryoid bodies derived fromMtf2andJarid2null ESCs. We observe that the loss ofMtf2results in enhanced and faster differentiation towards cell fates from all germ layers, while theJarid2null cells are predominantly directed towards early differentiating precursors, with reduced efficiency towards mesendodermal lineages. These effects are caused by derepression of developmental regulators that are poised for activation in pluripotent cells and gain H3K4me3 at their promoters in the absence of PRC2 repression. Upon lineage commitment, the differentiation trajectories are relatively similar to those of wild-type cells. Together, our results uncover a major role for MTF2-containing PRC2.1 in balancing poised lineage-specific gene activation, whereas the contribution of JARID2-containing PRC2 is more selective in nature compared to MTF2. These data explain how PRC2 imposes thresholds for lineage choice during the exit of pluripotency.
COVID-19 Flow-Maps an open geographic information system on COVID-19 and human mobility for Spain
Authors: Ponce-de-Leon Miguel , del Valle Javier , Fernandez José María , Bernardo Marc , Cirillo Davide , Sanchez-Valle Jon , Smith Matthew , Capella-Gutierrez Salvador , Gullón Tania , Valencia Alfonso
Published: November 2021

COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, which has spread all over the world leading to a global pandemic. The fast progression of COVID-19 has been mainly related to the high contagion rate of the virus and the worldwide mobility of humans. In the absence of pharmacological therapies, governments from different countries have introduced several non-pharmaceutical interventions to reduce human mobility and social contact. Several studies based on Anonymized Mobile Phone Data have been published analysing the relationship between human mobility and the spread of coronavirus. However, to our knowledge, none of these data-sets integrates cross-referenced geo-localised data on human mobility and COVID-19 cases into one all-inclusive open resource. Herein we present COVID-19 Flow-Maps, a cross-referenced Geographic Information System that integrates regularly updated time-series accounting for population mobility and daily reports of COVID-19 cases in Spain at different scales of time spatial resolution. This integrated and up-to-date data-set can be used to analyse the human dynamics to guide and support the design of more effective non-pharmaceutical interventions.
High-energy synchrotron X-ray tomography coupled with digital image correlation highlights likely failure points inside ITER toroidal field conductors
Authors: Warr Ryan , Jewell Matthew C. , Mitchell Neil , Rack Alexander , Swanson Jack , Tronza Vladimir , Cernik Robert
Published: November 2021

Two sections of heat-treated (HT) and non-heat-treated (NHT) Cable-in-Conduit Conductor (CICC) of a design similar to the ITER tokomak have been imaged using very high energy X-ray tomography at the ESRF beamline ID19. The sample images were collected at four temperatures down to 77 K. These results showed a greater degree of movement, bundle distortion and touching strands in the NHT sample. The HT sample showed non-linear movements with temperature especially close to 77 K; increasing non-circularity of the superconducting fibre bundles towards the periphery of the CICC, and touching bundles throughout the CICC. The images have highlighted where future design might improve potential weakness, in particular at the outer perimeters of the conductor and the individual sub-cable, ‘petal’ wraps.
Factors associated with sunbed use among 3692 outpatients in 18 centers of the Italian Cancer League (LILT)
Authors: Mastroeni Simona , Sampogna Francesca , Salcedo Nidia Melo , Ricci Francesco , Fania Luca , Antonelli Flaminia , Abeni Damiano , Cristofolini Mario
Published: November 2021

Indoor tanning is associated with an increased risk of skin cancer. Nonetheless, its use is still widespread. We aimed to investigate the socio-demographic and clinical characteristics of sunbed users in a group of participants in the skin cancer prevention campaign organized by the Italian Cancer League (LILT). During almost 2 years, 4409 individuals were screened in 18 centers. Participants reported having used sunbeds before the age of 15 years in 2.2% of cases, while after age 15 the prevalence of use was 22.2%. Participants with complete information were 3692. Sunbed users aged > 15 years were significantly more frequently females, young, living in Northern Italy, highly educated, and current or former smokers. They had darker phototype, more common nevi, had used sunbeds more frequently before the age of 15, reported a history of sunburns, and use of sunscreens. Indoor tanning is an important public health issue and a relevant target for primary prevention. However, not all countries have adopted the recommendations issued by the World Health Organization (WHO) on health risks associated with artificial tanning. A deeper insight into the topic may contribute to identify the best prevention strategies.
Metabarcoding analysis of trophic sources and linkages in the plankton community of the Kuroshio and neighboring waters
Authors: Kobari Toru , Tokumo Yusuke , Sato Ibuki , Kume Gen , Hirai Junya
Published: December 2021

Trophic sources and pathways supporting early life stages are crucial for survival of forage fishes recruiting around the oligotrophic and unproductive Kuroshio. However, information is limited for the Kuroshio planktonic food web and its trophodynamics because of its high biodiversity. Here, we explore trophic sources and linkages in the Kuroshio plankton community using metabarcoding analysis of gut-content DNA for 22 mesozooplankton groups. The major prey was dinoflagellates and calanoids for omnivorous groups, and calanoids and gelatinous organisms for carnivorous groups. Larvaceans and hydrozoans were the most frequently appeared prey for both omnivores and carnivores, whereas they were minor constituents of the available prey in water samples. Although calanoids overlapped as major prey items for both omnivores and carnivores because they were the most available, contributions from phytoplankton and gelatinous prey differed among taxonomic groups. Further analysis of the metabarcoding data showed that in addition to omnivorous copepods like calanoids, gelatinous groups like larvaceans and hydrozoans were important hubs in the planktonic food web with their multiple trophic linkages to many components. These findings suggest that gelatinous organisms are important as supplementary prey and provide evidence of niche segregation on trophic sources among mesozooplankton groups in the Kuroshio.
Electromagnetohydrodynamic bioconvective flow of binary fluid containing nanoparticles and gyrotactic microorganisms through a stratified stretching sheet
Authors: Dawar Abdullah , Saeed Anwar , Islam Saeed , Shah Zahir , Kumam Wiyada , Kumam Poom
Published: November 2021

Bioconvection has recently been the subject of dispute in a number of biotechnological fields that depend on fluids and their physical properties. When mixed nanofluids are subjected to heat and mass transmission, the process of bioconvection occurs. This attempt conveys the theoretical analysis of two-dimensional electrically conducting and magnetically susceptible binary fluid containing nanoparticles and gyrotactic microorganisms past a stratified stretching surface. Furthermore binary chemical reaction, thermal radiation, and activation energy are taken into assumptions. The analytical solution based on HAM has been performed. The convergence of HAM is presented with the help of figures. The present study is compared with previously published results and has established an excessive agreement which validate the present study. It is perceived that the presence and absence of an electric field influences the variations in fluid velocities due to presence of magnetic field. The micropolar constant heightens the velocity and microrotation of the fluid flow. The buoyancy parameter and bioconvection Rayleigh number diminish the velocity function while these parameters show dual impact on microrotation function. The skin friction and couple stress escalates with the increasing buoyancy ratio parameter and bioconvection Rayleigh number.