bluuebunny/crossref_metadata_2025 huggingface dataset:
Three-Dimensional Membrane Imaging with X-ray Ptychography: Determination of Membrane Transport Properties for Membrane Distillation
Authors: Cramer Kerstin , Prasianakis Nikolaos I. , Niceno Bojan , Ihli Johannes , Holler Mirko , Leyer Stephan
Published: May 2021

Membrane distillation (MD) is a desalination technique that uses a membrane to thermally separate potable water from sea or brackish water. The mass transport processes through the membrane are commonly described by the dusty gas model. These processes are modeled assuming uniform, ideally cylindrical capillaries and are adjusted for the membrane geometry by including porosity and tortuosity. The tortuosity is usually set to 2 or is used as an adjusting parameter to fit theoretical models to experimentally measured data. In this work, ptychographic X-ray computed tomography is employed to map the three-dimensional (3D) structure of three commercial state-of-the-art PTFE membranes in MD. The porosity, tortuosity and permeability (viscous flow coefficient) of the samples are computed using the lattice Boltzmann method. The intrinsic permeability is compared to the dusty gas model and an apparent permeability is proposed which is corrected for Knudsen slip effects at the membrane structure.

Article Highlights

3D structure of membranes for distillation measured at full height at an unprecedented detail using X-ray ptychography for the first time.

Comparison of the dusty gas model to 3D direct numerical simulation: permeability and Knudsen effects.

Membrane characterization and calculation of the hydraulic tortuosity factor from 3D flow field simulations.
Legalized Identities
Authors: Lixinski Lucas
Published: May 2021

Cultural heritage is a feature of transitioning societies, from museums commemorating the end of a dictatorship to adding places like the Auschwitz-Birkenau concentration camp to the World Heritage List. These processes are governed by specific laws, and yet transitional justice discourses tend to ignore law's role, assuming that memory in transition emerges organically. This book debunks this assumption, showing how cultural heritage law is integral to what memory and cultural identity is possible in transition. Lixinski attempts to reengage with the original promise of transitional justice: to pragmatically advance societies towards a future where atrocities will no longer happen. The promise in the UNESCO Constitution of lasting peace through cultural understanding is possible through focusing on the intersection of cultural heritage law and transitional justice, as Lixinski shows in this ground-breaking book.
Effective suppression of mode distortion induced by stimulated Raman scattering in high-power fiber amplifiers
Authors: Gao Wei , Fan Wenhui , Ju Pei , Li Gang , Zhang Yanpeng , He Aifeng , Gao Qi , Li Zhe
Published: May 2021

Mode distortion induced by stimulated Raman scattering (SRS) has become a new obstacle for the further development of high-power fiber lasers with high beam quality. Here, an approach for effective suppression of the SRS-induced mode distortion in high-power fiber amplifiers has been demonstrated experimentally by adjusting the seed power (output power of seed source) and forward feedback coefficient of the rear port in the seed source. It is shown that the threshold power of the SRS-induced mode distortion can be increased significantly by reducing the seed power or the forward feedback coefficient. Moreover, it has also been found that the threshold power is extremely sensitive to the forward feedback power value from the rear port. The influence of the seed power on the threshold power can be attributed to the fact that the seed power plays an important role in the effective length of the gain fiber in the amplifier. The influence of the forward feedback coefficient on the threshold power can be attributed to the enhanced SRS configuration because the end surface of the rear port together with the fiber in the amplifier constitutes a half-opening cavity. This suppression approach will be very helpful to further develop the high-power fiber amplifiers with high beam quality.
Surgeons’ mental models of surgical site infection: Insights into adherence with complex prevention bundles
Authors: Pop-Vicas Aurora E. , Young Amanda , Knobloch Mary-Jo , Heise Charles , Bowers Barbara , Safdar Nasia
Published: May 2021

Of 10 surgeons interviewed in a descriptive qualitative study, 6 believed that surgical site infections are inevitable. Bundle adherence was felt to be more likely with strong evidence-based measures developed by surgical leaders. The intrinsic desire to excel was viewed as the main adherence motivator, rather than “pay-for-performance” models.
Physics of unsteady cylinder-induced shock-wave/transitional boundary-layer interactions
Authors: Murphree Zachary R. , Combs Christopher S. , Yu Wesley M. , Dolling David S. , Clemens Noel T.
Published: May 2021

Given the current lack of experimental data for shock waves interacting with incoming transitional boundary layers, the goal of this study was to characterize the dynamics of such an interaction to better understand the fundamental fluid physics of these complex phenomena. Here, the mean flow field and time-dependent characteristics of a three-dimensional Mach 5 cylinder-induced shock-wave/boundary-layer interaction where the upstream boundary layer is transitional, have been studied experimentally. The interactions were generated with a right circular cylinder mounted on a flat plate. Streamwise–spanwise planar laser scattering from a condensed alcohol fog and schlieren imaging were used to characterize the mean and instantaneous structure of the interaction, and fast-response wall-pressure measurements on the centreline upstream of the cylinder enabled characterization of the unsteadiness. The pressure measurements show a mean pressure profile that resembles a composite of an upstream laminar profile and a downstream turbulent profile. The upstream influence location of the transitional interaction was approximately 8.5 diameters (

$d$

) upstream of the cylinder leading edge, which is between that of a laminar and a turbulent interaction, and is followed by a plateau region to approximately

$4d$

upstream of the cylinder. The plateau region is a region with a thicker boundary layer and possible flow separation. The plateau pressure was within 7 % of the value predicted by Hill's correlation for free-interaction phenomena. Furthermore, a statistical analysis of the pressure histories suggests that the entire interaction stretches and contracts in concert. Power spectral densities of the pressure fluctuations showed unsteadiness throughout the interaction with energy content primarily centred between a region defined by a separation-length-based Strouhal number

$St_{L} = 0.05\text {--}0.2$

, comparing well with other related studies of cylinder-induced interactions. Cross-correlations and coherence functions in the interaction suggest that the unsteadiness in the laminar region may be due to the entire ‘laminar’ region oscillating in response to the ‘turbulent’ unsteadiness of the intermittent region.
Feminism as Epic Theory
Authors: Phelan Kate M.
Published: May 2021

Sheldon Wolin identifies a particular tradition within political theory that he calls ‘epic theory’. Epic theory, he explains, is political theory's equivalent of the Kuhnian scientific revolution. This article takes up the analogy between epic theory and scientific revolution to show that feminism is an epic theory in the truest sense of the term, a sense not fully grasped by Wolin. It is so for two reasons. First, it is a theory of the whole. Second, it is less a discovery than an invention of the world. The author seeks to account for the existence of feminism in the face of its impossibility, and to demonstrate the magnitude of the achievement that feminism represents.
Efficacy of topical application of autologous platelet-rich plasma in adult tonsillectomy patients: a randomised control study
Authors: Nanditha S , Gopalakrishnan S , Karthikeyan P , Singh Bakshi S
Published: May 2021

Objective

Tonsillectomy is a painful surgery performed in cases of recurrent tonsillitis. Application of platelet-rich plasma to diminish the pain and morbidity post-tonsillectomy is gaining importance. This study evaluated post-operative pain and morbidity after autologous platelet-rich plasma application on the tonsil beds during tonsillectomy.

Method

Participants were randomised into group 1 (n = 28, peri-operative platelet-rich plasma intervention) and group 2 (n = 28, control). Post-tonsillectomy, patients were assessed (day 0, 1, 2, 3, 7 and 14) for pain, healing and time taken to return to normal activity. Data were analysed by independent t-test and chi-square test with p ≤ 0.05 as the significance level.

Results

A significant decrease in the mean pain score up to day 7 (p < 0.05) and tonsillar fossae healing on days 2 and 3 (p < 0.05) post-tonsillectomy was noted. The majority of the patients returned to their routine activities after a week post-tonsillectomy.

Conclusion

Platelet-rich plasma application was effective in accentuating healing and reducing post-tonsillectomy pain and morbidity.
Functional connexin35 increased in the myopic chicken retina
Authors: Banerjee Seema , Wang Qing , Tang George , So ChungHim , Shan Sze Wan , Li King Kit , Do Chi-Wai , Pan Feng
Published: May 2021

Our previous research showed that increased phosphorylation of connexin (Cx)36 indicated extended  coupling of AII amacrine cells (ACs) in the rod-dominant mouse myopic retina. This research will determine whether phosphorylation at serine 276 of Cx35-containing gap junctions increased in the myopic chicken, whose retina is cone-dominant. Refractive errors and ocular biometric dimensions of 7-days-old chickens were determined following 12 h and 7 days induction of myopia by a −10D lens. The expression pattern and size of Cx35-positive plaques were examined in the early (12 h) and compensated stages (7 days) of lens-induced myopia (LIM). At the same time, phosphorylation at serine 276 (functional assay) of Cx35 in strata 5 (S5) of the inner plexiform layer was investigated. The axial length of the 7 days LIM eyes was significantly longer than that of non-LIM controls (P < 0.05). Anti-phospho-Ser276 (Ser276-P)-labeled plaques were significantly increased in LIM retinas at both 12 h and 7 days. The density of Ser276-P of Cx35 was observed to increase after 12 h LIM. In the meanwhile, the areas of existing Cx35 plaques did not change. As there was more phosphorylation of connexin35 at Ser276 at both the early and late stages (12 h) and 7 days of LIM chicken retinal activity, the coupling with ACs could be increased in myopia development of the cone-dominated chicken retina.
Interference of fixatives and fixation period on the morphologic analysis of ovarian preantral follicles
Authors: Brito D.C.C. , Ñaupas L.V.S. , Souza S.S. , Alcântara G.L.H. , Figueiredo J.R. , Santos R.R. , Rodrigues A.P.R.
Published: May 2021

Ovine ovarian fragments (3 × 3 × 1 mm) were fixed in neutral buffered formalin (NBF), Carnoy’s solution (CAR), Davidson’s solution (DAV), or paraformaldehyde (PFA) for 12 h or 24 h. After this fixation time, each fragment was prepared for histological analysis. Although fixative and fixation period did not affect follicular and stromal cells density, the percentages of morphologically normal primordial and primary follicles was affected by the fixative type and period of fixation. Paraformaldehyde was not indicated as a fixative for ovarian fragments. Formalin was a suitable fixative only when the period of fixation was 12 h, while Carnoy was efficient after a fixation period of 24 h. In conclusion, the most indicated fixative for the morphological evaluation of ovarian preantral follicles was DAV, regardless of the fixation period, that is 12 or 24 h.
Chest tube drainage placement may not be a necessity in paediatric thoracoscopic surgery: a retrospective study
Authors: Zhang Gang , Liu Dandan , Kuang Ruiming , Cai Chun , Li Xiao , Yu Gang , Fan Xiujing
Published: May 2021

Objective:

Chest tube drainage placement, a standard procedure in video-assisted thoracoscopic surgery, was reported to cause perioperative complications like pain and increased risk of infection. The present study was designed to evaluate the necessity of chest tube drainage inpaediatric thoracoscopic surgery.

Methods:

Thirty children admitted to our hospital from April 2018 to April 2020 were included in the current study and were grouped as the tube group (children receiving video-assisted thoracoscopic surgery with chest tube drainage) and the non-tube group (children receiving video-assisted thoracoscopic surgery without chest tube drainage). Laboratory hemogram index, length of hospitalisation, post-operative performance of involved children, and psychological acceptance of indicated therapy by guardians of the involved children were investigated.

Results:

Laboratory examination revealed that the mean corpuscular haemoglobin concentration in the non-tube group was significantly higher than that in the tube group on post-operative day 1 (p < 0.05). Children in the non-tube group had a shorter length of hospitalisation (7–9 days) than that of patients from the tube group. Additionally, the frequency of crying of children was decreased and psychological acceptance by patients’ guardians was improved in the non-tube group when compared with the tube group.

Conclusion:

This study showed that chest tube drainage placement may not be necessary in several cases of paediatric video-assisted thoracoscopic surgery. Rapid recovery with decreased perioperative complications in children operated by video-assisted thoracoscopic surgery without tube placement could also reduce the burden of the family and society both economically and psychologically.
Leveling the Field: Gender Inequity in Academia During COVID-19
Authors: Shalaby Marwa , Allam Nermin , Buttorff Gail J.
Published: May 2021

This article explores the differential impact of the COVID-19 pandemic on the productivity of male and female academics and whether the ongoing health crisis will exacerbate further the existing gender gap in academia in both the short and long terms. We present early evidence of the pandemic’s disproportionate effect on women’s research productivity using online survey data supplemented by interview data with regional and international female political scientists. The interviews and survey findings reveal gender disparities in perceived research productivity and service workloads during the pandemic. The results also shed initial light on the pandemic’s impact on the research productivity of academics who are parents, especially among women.
Who Says Yes or No? Models of Ethical and Safety Oversight for Student-Led Political Violence Research
Authors: Eck Kristine , Cohen Dara Kay
Published: May 2021

The ethical risks inherent in student research on political violence that involve human participants are myriad. Undergraduate and master’s students face constraints that are different than those for many doctoral students and faculty researchers, and it is the responsibility of educators and academic institutions to ensure that students engage in ethical practices and to mitigate risks. This article focuses on formal mechanisms of oversight. Drawing on discussions with colleagues across the globe, we describe how institutions can design oversight mechanisms to manage student research. We present five distinct models for how ethical oversight of student research is provided in academic programs around the world, considering the costs and benefits of each model. The article concludes that whereas the creation of oversight systems can seem daunting, it is useful to start small—indeed, moving from no oversight to some oversight is a significant improvement. Programs and academic units then can build on these early efforts, experiment with other systems, and eventually develop a system that is adapted to an institution through iterative improvements based on student and faculty experiences.
Ritual and ritual text in the Zoroastrian tradition: The extent of Yasna 41
Authors: ZEINI ARASH
Published: May 2021

This article examines the extent of the concluding section (Y 41) of the Yasna Haptaŋhāiti in light of the manuscript evidence and the section's divergent reception in a Middle Persian text known as the “Supplementary Texts to the Šāyest nē Šāyest” (Suppl.ŠnŠ). This investigation will entertain the possibility of an alternative ritual being described in the Suppl.ŠnŠ. Moreover, it argues that the manuscripts transmit the ritual text along with certain variations and repetitions while the descriptions of the extent of each section preserve the necessary boundaries of the text as a textual composition or unit.
Using vignettes to improve understanding of Social Security and annuities
Authors: Samek Anya , Kapteyn Arie , Gray Andre
Published: May 2021

Evidence shows that people have difficulty understanding complex aspects of retirement planning, which leads them to under-utilize annuities and claim Social Security benefits earlier than is optimal. To target this problem, we developed vignettes about the consequences of different annuitization and claiming decisions. We evaluated our vignettes using an experiment with a representative online panel of nearly 2,000 Americans. In our experiment, respondents were either assigned to a control group with no vignette, to a written vignette, or to a video vignette. They were then asked to give advice to hypothetical persons on annuitization or Social Security claiming, and were asked factual questions about these concepts. We found evidence that being exposed to vignettes led respondents to give better advice. For example, the gap between advised claim age for a relatively healthy person versus a relatively sick person was larger by nearly a year in the vignette treatments than in the control group. Furthermore, the vignettes increased financial literacy related to these concepts by 10–15 percentage points. Interestingly, the mode of communication did not have a significant impact – the video and written vignettes were equally effective.
Why were there no war crimes trials for the Korean War?
Authors: Wilson Sandra
Published: May 2021

In the Korean War of 1950-53, U.S. authorities were determined to pursue atrocities perpetrated by North Korean and Communist Chinese forces through legal channels, in keeping with the standards they believed they had set after the Second World War. Yet, their plans foundered in Korea, despite extensive groundwork for prosecutions. Four factors were responsible. First, it was difficult to find reliable evidence and to identify and apprehend suspects. Second, U.S. officials rapidly lost confidence in the idea of prosecuting national leaders. Third, the lack of clear-cut victory in the conflict necessitated a diplomatic solution, which was incompatible with war crimes trials. Fourth, the moral standing of the West, and hence its authority to run trials, was undermined by the large number of atrocities committed by the United Nations side. Thus, the U.S. plan for war crimes trials was dropped without fanfare, to be replaced by an anti-Communist propaganda campaign.
Heat Flux From a Vapor‐Dominated Hydrothermal Field Beneath Yellowstone Lake
Authors: Favorito Julia E. , Harris Robert N. , Sohn Robert A. , Hurwitz Shaul , Luttrell Karen M.
Published: May 2021

We report results from 149 heat flux measurements made over an ∼2‐year interval at sites in and around a vapor‐dominated geothermal field located at water depths of ∼100–120 m in Yellowstone Lake, Wyoming. Measurements of both in situ temperature and thermal conductivity as a function of depth were made with a 1 m probe via a remotely operated vehicle, and are combined to compute the vertical conductive heat flux. Inside the ∼55.5 × 103 m2 bathymetric depression demarcating the vapor‐dominated field, the median conductive flux is 13 W m−2, with a conductive output of 0.72 MW. Outside the thermal field, the median conductive flux is 3.5 W m−2. We observed 49 active vents inside the thermal field, with an estimated mass discharge rate of 56 kg s−1, a median exit‐fluid temperature of 132°C, and a total heat output of 29 MW. We find evidence for relatively weak secondary convection with a total output of 0.09 MW in thermal area lake floor sediments. Our data indicate that vapor beneath the thermal field is trapped by a low‐permeability cap at a temperature of ∼189°C and a depth of ∼15 m below the lake floor. The thermal output of the Deep Hole is among the highest of any vapor‐dominated field in Yellowstone, due in part to the high boiling temperatures associated with the elevated lake floor pressures.
Eastward‐Propagating Planetary Waves Prior to the January 2009 Sudden Stratospheric Warming
Authors: Rhodes Christian T. , Limpasuvan Varavut , Orsolini Yvan J.
Published: May 2021

Eastward‐propagating planetary waves (EPWs) were investigated prior to the boreal January 2009 major sudden stratospheric warming (SSW) event simulated by the National Center for Atmospheric Research's Whole Atmosphere Community Climate Model with specified dynamics. About 22 days before SSW onset, a background flow with jet maxima around the upper polar stratosphere and subtropical mesosphere developed due to the net forcing by gravity and planetary waves. The mesospheric wind structure was largely unstable and supported a wave geometry conducive to overreflection. With a zonal phase speed of ∼10 m s−1, EPWs appeared near their turning and critical layers as wavenumber‐2 perturbations in the stratosphere and mesosphere. Accompanied by upward EPW activity from the lower stratosphere, EPW growth exhibited characteristics of wave instability and overreflection.
Role of Surface Gravity Waves in Aquaplanet Ocean Climates
Authors: Studholme Joshua H. P. , Markina Margarita Y. , Gulev Sergey K.
Published: May 2021

We present a set of idealized numerical experiments of a solstitial aquaplanet ocean and examine the thermodynamic and dynamic implications of surface gravity waves (SGWs) upon its mean state. The aquaplanet's oceanic circulation is dominated by an equatorial zonal jet and four Ekman driven meridional overturning circulation (MOC) cells aligned with the westerly atmospheric jet streams and easterly trade winds in both hemispheres. Including SGW parameterization (representing modulations of air‐sea momentum fluxes, Langmuir circulation, and Stokes‐Coriolis force) increases mixed layer vertical momentum diffusivity by ∼40% and dampens surface momentum fluxes by ∼4%. The correspondingly dampened MOC impacts the oceanic density structure to 1 km depth by lessening the large‐scale advective transports of heat and salt, freshening the equatorial latitudes (where evaporation minus precipitation [E − P] is negative) and increasing salinity in the subtropics (where E − P is positive) by ∼1%. The midlatitude pycnocline in both hemispheres is deepened by the inclusion of SGWs. Including SGWs into the aquaplanet ocean model acts to increase mixed layer depth by ∼10% (up to 20% in the wintertime in midlatitudes), decrease vertical shear in the upper 200 m and alter local midlatitude buoyancy frequency. Generally, the impacts of SGWs upon the aquaplanet ocean are found to be consistent across cooler and warmer climates. We suggest that the implications of these simulations could be relevant to understanding future projections of SGW climate, exoplanetary oceans, and the dynamics of the Southern Ocean mixed layer.
A Vector‐Based River Routing Model for Earth System Models: Parallelization and Global Applications
Authors: Mizukami Naoki , Clark Martyn P. , Gharari Shervan , Kluzek Erik , Pan Ming , Lin Peirong , Beck Hylke E. , Yamazaki Dai
Published: May 2021

A vector‐river network explicitly uses realistic geometries of river reaches and catchments for spatial discretization in a river model. This enables improving the accuracy of the physical properties of the modeled river system, compared to a gridded river network that has been used in Earth System Models. With a finer‐scale river network, resolving smaller‐scale river reaches, there is a need for efficient methods to route streamflow and its constituents throughout the river network. The purpose of this study is twofold: (1) develop a new method to decompose river networks into hydrologically independent tributary domains, where routing computations can be performed in parallel; and (2) perform global river routing simulations with two global river networks, with different scales, to examine the computational efficiency and the differences in discharge simulations at various temporal scales. The new parallelization method uses a hierarchical decomposition strategy, where each decomposed tributary is further decomposed into many sub‐tributary domains, enabling hybrid parallel computing. This parallelization scheme has excellent computational scaling for the global domain where it is straightforward to distribute computations across many independent river basins. However, parallel computing for a single large basin remains challenging. The global routing experiments show that the scale of the vector‐river network has less impact on the discharge simulations than the runoff input that is generated by the combination of land surface model and meteorological forcing. The scale of vector‐river networks needs to consider the scale of local hydrologic features such as lakes that are to be resolved in the network.
The Space Weather Modeling Framework Goes Open Access
Authors: Pulkkinen Tuija , Gombosi Tamas , Ridley Aaron , Toth Gabor , Zou Shasha
Published: May 2021

A versatile suite of computational models, already used to forecast magnetic storms and potential power grid and telecommunications disruptions, is preparing to welcome a larger group of users.
The arachidonic acid metabolite 11,12-epoxyeicosatrienoic acid alleviates pulmonary fibrosis
Authors: Kim Hak Su , Moon Su-Jin , Lee Sang Eun , Hwang Gi Won , Yoo Hyun Ju , Song Jin Woo
Published: May 2021

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that are rapidly metabolized into diols by soluble epoxide hydrolase (sEH). sEH inhibition has been shown to increase the biological activity of EETs, which are known to have anti-inflammatory properties. However, the role of EETs in pulmonary fibrosis remains unexplored. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to analyze EETs in the lung tissues of patients with idiopathic pulmonary fibrosis (IPF, n = 29) and controls (n = 15), and the function of 11,12-EET was evaluated in in vitro and in vivo in pulmonary fibrosis models. EET levels in IPF lung tissues, including those of 8,9-EET, 11,12-EET, and 14,15-EET, were significantly lower than those in control tissues. The 11,12-EET/11,12-DHET ratio in human lung tissues also differentiated IPF from control tissues. 11,12-EET significantly decreased transforming growth factor (TGF)-β1-induced expression of α-smooth muscle actin (SMA) and collagen type-I in MRC-5 cells and primary fibroblasts from IPF patients. sEH-specific siRNA and 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU; sEH inhibitor) also decreased TGF-β1-induced expression of α-SMA and collagen type-I in fibroblasts. Moreover, 11,12-EET and TPPU decreased TGF-β1-induced p-Smad2/3 and extracellular-signal-regulated kinase (ERK) expression in primary fibroblasts from patients with IPF and fibronectin expression in Beas-2B cells. TPPU decreased the levels of hydroxyproline in the lungs of bleomycin-induced mice. 11,12-EET or sEH inhibitors could inhibit pulmonary fibrosis by regulating TGF-β1-induced profibrotic signaling, suggesting that 11,12-EET and the regulation of EETs could serve as potential therapeutic targets for IPF treatment.
Application of 3D bioprinting in the prevention and the therapy for human diseases
Authors: Yi Hee-Gyeong , Kim Hyeonji , Kwon Junyoung , Choi Yeong-Jin , Jang Jinah , Cho Dong-Woo
Published: May 2021

Rapid development of vaccines and therapeutics is necessary to tackle the emergence of new pathogens and infectious diseases. To speed up the drug discovery process, the conventional development pipeline can be retooled by introducing advanced in vitro models as alternatives to conventional infectious disease models and by employing advanced technology for the production of medicine and cell/drug delivery systems. In this regard, layer-by-layer construction with a 3D bioprinting system or other technologies provides a beneficial method for developing highly biomimetic and reliable in vitro models for infectious disease research. In addition, the high flexibility and versatility of 3D bioprinting offer advantages in the effective production of vaccines, therapeutics, and relevant delivery systems. Herein, we discuss the potential of 3D bioprinting technologies for the control of infectious diseases. We also suggest that 3D bioprinting in infectious disease research and drug development could be a significant platform technology for the rapid and automated production of tissue/organ models and medicines in the near future.
Bispecific antibody simultaneously targeting PD1 and HER2 inhibits tumor growth via direct tumor cell killing in combination with PD1/PDL1 blockade and HER2 inhibition
Authors: Gu Chang-ling , Zhu Hai-xia , Deng Lan , Meng Xiao-qing , Li Kai , Xu Wei , Zhao Le , Liu Yue-qin , Zhu Zhen-ping , Huang Hao-min
Published: May 2021

Immune checkpoint blockade has shown significant clinical benefit in multiple cancer indications, but many patients are either refractory or become resistant to the treatment over time. HER2/neu oncogene overexpressed in invasive breast cancer patients associates with more aggressive diseases and poor prognosis. Anti-HER2 mAbs, such as trastuzumab, are currently the standard of care for HER2-overexpressing cancers, but the response rates are below 30% and patients generally suffer relapse within a year. In this study we developed a bispecific antibody (BsAb) simultaneously targeting both PD1 and HER2 in an attempt to combine HER2-targeted therapy with immune checkpoint blockade for treating HER2-positive solid tumors. The BsAb was constructed by fusing scFvs (anti-PD1) with the effector-functional Fc of an IgG (trastuzumab) via a flexible peptide linker. We showed that the BsAb bound to human HER2 and PD1 with high affinities (EC50 values were 0.2 and 0.14 nM, respectively), and exhibited potent antitumor activities in vitro and in vivo. Furthermore, we demonstrated that the BsAb exhibited both HER2 and PD1 blockade activities and was effective in killing HER2-positive tumor cells via antibody-dependent cellular cytotoxicity. In addition, the BsAb could crosslink HER2-positive tumor cells with T cells to form PD1 immunological synapses that directed tumor cell killing without the need of antigen presentation. Thus, the BsAb is a new promising approach for treating late-stage metastatic HER2-positive cancers.
STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer
Authors: Zhao Jinlin , Wang Xin , Mi Zeyun , Jiang Xiangli , Sun Lin , Zheng Boyu , Wang Jing , Meng Maobin , Zhang Lu , Wang Zhongqiu , Song Junwei , Yuan Zhiyong , Wu Zhiqiang
Published: May 2021

Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers worldwide but has limited effective therapies. Uncovering the underlying pathological and molecular changes, as well as mechanisms, will improve the treatment. Dysregulated microRNAs (miRNAs) have been proven to play important roles in the initiation and progression of various cancers, including NSCLC. In this manuscript, we identified microRNA-135b (miR-135b) as a tumor-promoting miRNA in NSCLC. We found that miR-135b was significantly upregulated and that its upregulation was associated with poor prognosis in NSCLC patients. miR-135b was an independent prognostic factor in NSCLC. Overexpressing miR-135b significantly promoted the aggressiveness of NSCLC, as evidenced by enhanced cell proliferation, migration, invasion, anti-apoptosis, and angiogenesis in vitro and in vivo, and knockdown of miR-135b had the opposite effects. Mechanistically, our results reveal that miR-135b directly targets the 3′-untranslated region (UTR) of the deubiquitinase CYLD, thereby modulating ubiquitination and activation of NF-κB signaling. Moreover, we found that interleukin-6 (IL-6)/STAT3 could elevate miR-135b levels and that STAT3 directly bound the promoter of miR-135b; thus, these findings highlight a new positive feedback loop of the IL-6/STAT3/miR-135b/NF-κB signaling in NSCLC and suggest that miR-135b could be a potential therapeutic target for NSCLC.
Therapeutic potential of targeting membrane-spanning proteoglycan SDC4 in hepatocellular carcinoma
Authors: Yang Heng , Liu Yang , Zhao Mei-Mei , Guo Qiang , Zheng Xi-Kang , Liu Dan , Zeng Ke-Wu , Tu Peng-Fei
Published: May 2021

Syndecan-4 (SDC4) functions as a major endogenous membrane-associated receptor and widely regulates cytoskeleton, cell adhesion, and cell migration in human tumorigenesis and development, which represents a charming anti-cancer therapeutic target. Here, SDC4 was identified as a direct cellular target of small-molecule bufalin with anti-hepatocellular carcinoma (HCC) activity. Mechanism studies revealed that bufalin directly bond to SDC4 and selectively increased SDC4 interaction with substrate protein DEAD-box helicase 23 (DDX23) to induce HCC genomic instability. Meanwhile, pharmacological promotion of SDC4/DDX23 complex formation also inactivated matrix metalloproteinases (MMPs) and augmented p38/JNK MAPKs phosphorylation, which are highly associated with HCC proliferation and migration. Notably, specific knockdown of SDC4 or DDX23 markedly abolished bufalin-dependent inhibition of HCC proliferation and migration, indicating SDC4/DDX23 signaling axis is highly involved in the HCC process. Our results indicate that membrane-spanning proteoglycan SDC4 is a promising druggable target for HCC, and pharmacological regulation of SDC4/DDX23 signaling axis with small-molecule holds great potential to benefit HCC patients.
Monocytic MDSC mobilization promotes tumor recurrence after liver transplantation via CXCL10/TLR4/MMP14 signaling
Authors: Liu Hui , Ling Chang Chun , Yeung Wai Ho Oscar , Pang Li , Liu Jiang , Zhou Jie , Zhang Wei Yi , Liu Xiao Bing , Ng Tak Pan Kevin , Yang Xin Xiang , Lo Chung Mau , Man Kwan
Published: May 2021

Tumor recurrence is the major obstacle for pushing the envelope of liver transplantation for hepatocellular carcinoma (HCC) patients. The inflammatory cascades activated by acute liver graft injury promote tumor recurrence. We aimed to explore the role and mechanism of myeloid-derived suppressor cell (MDSC) mobilization induced by liver graft injury on tumor recurrence. By analyzing 331 HCC patients who received liver transplantation, the patients with graft weight ratio (GWR, the weight of liver graft divided by the estimated standard liver weight of recipient) <60% had higher tumor recurrence than GWR ≥60% ones. MDSCs and CXCL10/TLR4 levels were significantly increased in patients with GWR <60% or tumor recurrence. These findings were further validated in our rat orthotopic liver transplantation model. In CXCL10−/− and TLR4−/− mice of hepatic ischemia/reperfusion injury plus major hepatectomy (IRH) model, monocytic MDSCs, instead of granulocytic MDSCs, were significantly decreased. Importantly, CXCL10 deficiency reduced the accumulation of TLR4+ monocytic MDSCs, and CXCL10 increased MDSC mobilization in the presence of TLR4. Moreover, MMP14 was identified as the key molecule bridging CXCL10/TLR4 signaling and MDSC mobilization. Knockout or inhibition of CXCL10/TLR4 signaling significantly reduced the tumor growth with decreased monocytic MDSCs and MMP14 in the mouse tumor recurrent model. Our data indicated that monocytic MDSCs were mobilized and recruited to liver graft during acute phase injury, and to promote HCC recurrence after transplantation. Targeting MDSC mobilization via CXCL10/TLR4/MMP14 signaling may represent the therapeutic potential in decreasing post-transplant liver tumor recurrence.
Molecular mechanisms of ion conduction and ion selectivity in TMEM16 lipid scramblases
Authors: Kostritskii Andrei Y. , Machtens Jan-Philipp
Published: May 2021

TMEM16 lipid scramblases transport lipids and also operate as ion channels with highly variable ion selectivities and various physiological functions. However, their molecular mechanisms of ion conduction and selectivity remain largely unknown. Using computational electrophysiology simulations at atomistic resolution, we identified the main ion-conductive state of TMEM16 lipid scramblases, in which an ion permeation pathway is lined by lipid headgroups that directly interact with permeating ions in a voltage polarity-dependent manner. We found that lipid headgroups modulate the ion-permeability state and regulate ion selectivity to varying degrees in different scramblase isoforms, depending on the amino-acid composition of the pores. Our work has defined the structural basis of ion conduction and selectivity in TMEM16 lipid scramblases and uncovered the mechanisms responsible for the direct effects of membrane lipids on the conduction properties of ion channels.
Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint
Authors: Schmidt Nathalie M. , Wing Peter A. C. , Diniz Mariana O. , Pallett Laura J. , Swadling Leo , Harris James M. , Burton Alice R. , Jeffery-Smith Anna , Zakeri Nekisa , Amin Oliver E. , Kucykowicz Stephanie , Heemskerk Mirjam H. , Davidson Brian , Meyer Tim , Grove Joe , Stauss Hans J. , Pineda-Torra Ines , Jolly Clare , Jury Elizabeth C. , McKeating Jane A. , Maini Mala K.
Published: May 2021

Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8+ T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.
Marine snow morphology illuminates the evolution of phytoplankton blooms and determines their subsequent vertical export
Authors: Trudnowska Emilia , Lacour Léo , Ardyna Mathieu , Rogge Andreas , Irisson Jean Olivier , Waite Anya M. , Babin Marcel , Stemmann Lars
Published: May 2021

The organic carbon produced in the ocean’s surface by phytoplankton is either passed through the food web or exported to the ocean interior as marine snow. The rate and efficiency of such vertical export strongly depend on the size, structure and shape of individual particles, but apart from size, other morphological properties are still not quantitatively monitored. With the growing number of in situ imaging technologies, there is now a great possibility to analyze the morphology of individual marine snow. Thus, automated methods for their classification are urgently needed. Consequently, here we present a simple, objective categorization method of marine snow into a few ecologically meaningful functional morphotypes using field data from successive phases of the Arctic phytoplankton bloom. The proposed approach is a promising tool for future studies aiming to integrate the diversity, composition and morphology of marine snow into our understanding of the biological carbon pump.
Silica-copper catalyst interfaces enable carbon-carbon coupling towards ethylene electrosynthesis
Authors: Li Jun , Ozden Adnan , Wan Mingyu , Hu Yongfeng , Li Fengwang , Wang Yuhang , Zamani Reza R. , Ren Dan , Wang Ziyun , Xu Yi , Nam Dae-Hyun , Wicks Joshua , Chen Bin , Wang Xue , Luo Mingchuan , Graetzel Michael , Che Fanglin , Sargent Edward H. , Sinton David
Published: May 2021

Membrane electrode assembly (MEA) electrolyzers offer a means to scale up CO2-to-ethylene electroconversion using renewable electricity and close the anthropogenic carbon cycle. To date, excessive CO2 coverage at the catalyst surface with limited active sites in MEA systems interferes with the carbon-carbon coupling reaction, diminishing ethylene production. With the aid of density functional theory calculations and spectroscopic analysis, here we report an oxide modulation strategy in which we introduce silica on Cu to create active Cu-SiOx interface sites, decreasing the formation energies of OCOH* and OCCOH*—key intermediates along the pathway to ethylene formation. We then synthesize the Cu-SiOx catalysts using one-pot coprecipitation and integrate the catalyst in a MEA electrolyzer. By tuning the CO2 concentration, the Cu-SiOx catalyst based MEA electrolyzer shows high ethylene Faradaic efficiencies of up to 65% at high ethylene current densities of up to 215 mA cm−2; and features sustained operation over 50 h.
Interplay between transforming growth factor-β and Nur77 in dual regulations of inhibitor of differentiation 1 for colonic tumorigenesis
Authors: Niu Boning , Liu Jie , Lv Ben , Lin Jiacheng , Li Xin , Wu Chunxiao , Jiang Xiaohua , Zeng Zhiping , Zhang Xiao-kun , Zhou Hu
Published: May 2021

The paradoxical roles of transforming growth factor-β (TGFβ) signaling and nuclear receptor Nur77 in colon cancer development are known but the underlying mechanisms remain obscure. Inhibitor of differentiation 1 (ID1) is a target gene of TGFβ and a key promoter for colon cancer progression. Here, we show that Nur77 enhances TGFβ/Smad3-induced ID1 mRNA expression through hindering Smurf2-mediated Smad3 mono-ubiquitylation, resulting in ID1 upregulation. In the absence of TGFβ, however, Nur77 destabilizes ID1 protein by promoting Smurf2-mediated ID1 poly-ubiquitylation, resulting in ID1 downregulation. Interestingly, TGFβ stabilizes ID1 protein by switching Nur77 interaction partners to inhibit ID1 ubiquitylation. This also endows TGFβ with an active pro-tumorigenic action in Smad4-deficient colon cancers. Thus, TGFβ converts Nur77’s role from destabilizing ID1 protein and cancer inhibition to inducing ID1 mRNA expression and cancer promotion, which is highly relevant to colon cancer stemness, metastasis and oxaliplatin resistance. Our data therefore define the integrated duality of Nur77 and TGFβ signaling in regulating ID1 expression and provide mechanistic insights into the paradoxical roles of TGFβ and Nur77 in colon cancer progression.
Structure-based engineering of substrate specificity for pinoresinol-lariciresinol reductases
Authors: Xiao Ying , Shao Kai , Zhou Jingwen , Wang Lian , Ma Xueqi , Wu Di , Yang Yingbo , Chen Junfeng , Feng Jingxian , Qiu Shi , Lv Zongyou , Zhang Lei , Zhang Peng , Chen Wansheng
Published: May 2021

Pinoresinol–lariciresinol reductases (PLRs) are enzymes involved in the lignan biosynthesis after the initial dimerization of two monolignols, and this represents the entry point for the synthesis of 8-8′ lignans and contributes greatly to their structural diversity. Of particular interest has been the determination of how differing substrate specificities are achieved with these enzymes. Here, we present crystal structures of IiPLR1 from Isatis indigotica and pinoresinol reductases (PrRs) AtPrR1 and AtPrR2 from Arabidopsis thaliana, in the apo, substrate-bound and product-bound states. Each structure contains a head-to-tail homodimer, and the catalytic pocket comprises structural elements from both monomers. β4 loop covers the top of the pocket, and residue 98 from the loop governs catalytic specificity. The substrate specificities of IiPLR1 and AtPrR2 can be switched via structure-guided mutagenesis. Our study provides insight into the molecular mechanism underlying the substrate specificity of PLRs/PrRs and suggests an efficient strategy for the large-scale commercial production of the pharmaceutically valuable compound lariciresinol.
Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia
Authors: Ochi Yotaro , Yoshida Kenichi , Huang Ying-Jung , Kuo Ming-Chung , Nannya Yasuhito , Sasaki Ko , Mitani Kinuko , Hosoya Noriko , Hiramoto Nobuhiro , Ishikawa Takayuki , Branford Susan , Shanmuganathan Naranie , Ohyashiki Kazuma , Takahashi Naoto , Takaku Tomoiku , Tsuchiya Shun , Kanemura Nobuhiro , Nakamura Nobuhiko , Ueda Yasunori , Yoshihara Satoshi , Bera Rabindranath , Shiozawa Yusuke , Zhao Lanying , Takeda June , Watatani Yosaku , Okuda Rurika , Makishima Hideki , Shiraishi Yuichi , Chiba Kenichi , Tanaka Hiroko , Sanada Masashi , Takaori-Kondo Akifumi , Miyano Satoru , Ogawa Seishi , Shih Lee-Yung
Published: May 2021

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
Revealing pseudorotation and ring-opening reactions in colloidal organic molecules
Authors: Swinkels P. J. M. , Stuij S. G. , Gong Z. , Jonas H. , Ruffino N. , Linden B. van der , Bolhuis P. G. , Sacanna S. , Woutersen S. , Schall P.
Published: May 2021

Colloids have a rich history of being used as ‘big atoms’ mimicking real atoms to study crystallization, gelation and the glass transition of condensed matter. Emulating the dynamics of molecules, however, has remained elusive. Recent advances in colloid chemistry allow patchy particles to be synthesized with accurate control over shape, functionality and coordination number. Here, we show that colloidal alkanes, specifically colloidal cyclopentane, assembled from tetrameric patchy particles by critical Casimir forces undergo the same chemical transformations as their atomic counterparts, allowing their dynamics to be studied in real time. We directly observe transitions between chair and twist conformations in colloidal cyclopentane, and we elucidate the interplay of bond bending strain and entropy in the molecular transition states and ring-opening reactions. These results open the door to investigate complex molecular kinetics and molecular reactions in the high-temperature classical limit, in which the colloidal analogue becomes a good model.