bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel EGFRvIII-CAR transgenic mice for rigorous preclinical studies in syngeneic mice
Authors: Chuntova Pavlina , Hou Yafei , Naka Ryosuke , Yamamichi Akane , Chen Tiffany , Goretsky Yitzhar , Hatae Ryusuke , Nejo Takahide , Kohanbash Gary , Mende Abigail L , Montoya Megan , Downey Kira M , Diebold David , Skinner Jayne , Liang Hong-Erh , Schwer Bjoern , Okada Hideho
Published: August 2021

Background

Rigorous preclinical studies of chimeric antigen receptor (CAR) immunotherapy will require large quantities of consistent and high-quality CAR-transduced T (CART) cells that can be used in syngeneic mouse glioblastoma (GBM) models. To this end, we developed a novel transgenic (Tg) mouse strain with a fully murinized CAR targeting epidermal growth factor receptor variant III (EGFRvIII).

Methods

We first established the murinized version of EGFRvIII-CAR and validated its function using a retroviral vector (RV) in C57BL/6J mice bearing syngeneic SB28 GBM expressing EGFRvIII. Next, we created C57BL/6J-background Tg mice carrying the anti-EGFRvIII-CAR downstream of a Lox-Stop-Lox cassette in the Rosa26 locus. We bred these mice with CD4-Cre Tg mice to allow CAR expression on T cells and evaluated the function of the CART cells both in vitro and in vivo. To inhibit immunosuppressive myeloid cells within SB28 GBM, we also evaluated a combination approach of CART and an anti-EP4 compound (ONO-AE3-208).

Results

Both RV- and Tg-CART cells demonstrated specific cytotoxic activities against SB28-EGFRvIII cells. A single intravenous infusion of EGFRvIII-CART cells prolonged the survival of glioma-bearing mice when preceded by a lymphodepletion regimen with recurrent tumors displaying profound EGFRvIII loss. The addition of ONO-AE3-208 resulted in long-term survival in a fraction of CART-treated mice and those survivors demonstrated delayed growth of subcutaneously re-challenged both EGFRvIII+ and parental EGFRvIII− SB28.

Conclusion

Our new syngeneic CAR Tg mouse model can serve as a useful tool to address clinically relevant questions and develop future immunotherapeutic strategies.
Utilizing preclinical models to develop targeted therapies for rare central nervous system cancers
Authors: Arakaki Aleena K S , Szulzewsky Frank , Gilbert Mark R , Gujral Taranjit S , Holland Eric C
Published: August 2021

Patients with rare central nervous system (CNS) tumors typically have a poor prognosis and limited therapeutic options. Historically, these cancers have been difficult to study due to small number of patients. Recent technological advances have identified molecular drivers of some of these rare cancers which we can now use to generate representative preclinical models of these diseases. In this review, we outline the advantages and disadvantages of different models, emphasizing the utility of various in vitro and ex vivo models for target discovery and mechanistic inquiry and multiple in vivo models for therapeutic validation. We also highlight recent literature on preclinical model generation and screening approaches for ependymomas, histone mutated high-grade gliomas, and atypical teratoid rhabdoid tumors, all of which are rare CNS cancers that have recently established genetic or epigenetic drivers. These preclinical models are critical to advancing targeted therapeutics for these rare CNS cancers that currently rely on conventional treatments.
Phase I/II trial of vorinostat and radiation and maintenance vorinostat in children with diffuse intrinsic pontine glioma: A Children’s Oncology Group report
Authors: Su Jack M , Kilburn Lindsay B , Mansur David B , Krailo Mark , Buxton Allen , Adekunle Adesina , Gajjar Amar , Adamson Peter C , Weigel Brenda , Fox Elizabeth , Blaney Susan M , Fouladi Maryam
Published: August 2021

Background

A phase I/II trial of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor, was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) through the Children’s Oncology Group (COG) to: 1) determine the recommended phase II dose (RP2D) of vorinostat given concurrently with radiation therapy; 2) document the toxicities of continuing vorinostat as maintenance therapy after radiation; and 3) to determine the efficacy of this regimen by comparing the risk of progression or death with a historical model from past COG trials.

Methods

Vorinostat was given once daily, Monday through Friday, during radiation therapy (54 Gy in 30 fractions), and then continued at 230 mg/m2 daily for a maximum of twelve 28-day cycles.

Results

Twelve patients enrolled in the phase I study; the RP2D of vorinostat given concurrently with radiation was 230 mg/m2/day, Monday through Friday weekly. The six patients enrolled at the RP2D and an additional 64 patients enrolled in the phase II study contributed to the efficacy assessment. Although vorinostat was well-tolerated, did not interrupt radiation therapy, and was permanently discontinued in only 8.6% of patients due to toxicities, risk for EFS-event was not significantly reduced compared with the target risk derived from historical COG data (P = 0.32; 1-sided). The 1-year EFS was 5.85% (95% CI 1.89–13.1%) and 1-year OS was 39.2% (27.8–50.5%).

Conclusions

Vorinostat given concurrently with radiation followed by vorinostat monotherapy was well tolerated in children with newly diagnosed DIPG but failed to improve outcome.
Discovery of carbon-based strongest and hardest amorphous material
Authors: Zhang Shuangshuang , Li Zihe , Luo Kun , He Julong , Gao Yufei , Soldatov Alexander V , Benavides Vicente , Shi Kaiyuan , Nie Anmin , Zhang Bin , Hu Wentao , Ma Mengdong , Liu Yong , Wen Bin , Gao Guoying , Liu Bing , Zhang Yang , Shu Yu , Yu Dongli , Zhou Xiang-Feng , Zhao Zhisheng , Xu Bo , Su Lei , Yang Guoqiang , Chernogorova Olga P , Tian Yongjun
Published: August 2021

Carbon is one of the most fascinating elements due to its structurally diverse allotropic forms stemming from its bonding varieties (sp, sp2 and sp3). Exploring new forms of carbon has been the eternal theme of scientific research. Herein, we report on amorphous (AM) carbon materials with a high fraction of sp3 bonding recovered from compression of fullerene C60 under high pressure and high temperature, previously unexplored. Analysis of photoluminescence and absorption spectra demonstrates that they are semiconducting with a bandgap range of 1.5–2.2 eV, comparable to that of widely used AM silicon. Comprehensive mechanical tests demonstrate that synthesized AM-III carbon is the hardest and strongest AM material known to date, and can scratch diamond crystal and approach its strength. The produced AM carbon materials combine outstanding mechanical and electronic properties, and may potentially be used in photovoltaic applications that require ultrahigh strength and wear resistance.
Search for $\alpha$ condensed states in $^{13}$C using $\alpha$ inelastic scattering
Authors: Inaba K , Sasamoto Y , Kawabata T , Fujiwara M , Funaki Y , Hatanaka K , Itoh K , Itoh M , Kawase K , Matsubara H , Maeda Y , Suda K , Sakaguchi S , Shimizu Y , Tamii A , Tameshige Y , Uchida M , Uesaka T , Yamada T , Yoshida H P
Published: August 2021

We searched for the $\alpha$ condensed state in $^{13}$C by measuring the $\alpha$ inelastic scattering at $E_\alpha = 388$ MeV at forward angles including 0$^\circ$. We performed a distorted-wave Born approximation calculation with the single-folding potential and multipole decomposition analysis to determine the isoscalar transition strengths in $^{13}$C. We found a bump structure around $E_x = 12.5$ MeV due to the isoscalar monopole ($IS0$) transition. A peak-fit analysis suggested that this bump consisted of several $1/2^-$ states. We propose that this bump is due to the mirror state of the 13.5 MeV state in $^{13}$N, which dominantly decays to the $\alpha$ condensed state in $^{12}$C. It was speculated that the $1/2^-$ states around $E_x = 12.5$ MeV were candidates for the $\alpha$ condensed state, but the $3\alpha + n$ orthogonality condition model suggests that the $\alpha$ condensed state is unlikely to emerge as the negative parity states. We also found two $1/2^+$ or $3/2^+$ states at $E_x = 14.5$ and 16.1 MeV excited with the isoscalar dipole ($IS1$) strengths. We suggest that the 16.1 MeV state is a possible candidate for the $\alpha$ condensed state predicted by the cluster model calculations on the basis of the good correspondence between the experimental and calculated level structures. However, the theoretical $IS1$ transition strength for this state is significantly smaller than the measured value. Further experimental information is strongly desired to establish the $\alpha$ condensed state in $^{13}$C.
Type II superstring field theory revisited
Authors: Kunitomo Hiroshi
Published: August 2021

We reconstruct a complete type II superstring field theory with $L_\infty$ structure in a symmetric way concerning the left- and right-moving sectors. Based on the new construction, we show again that the tree-level S-matrix agrees with that obtained using the first-quantization method. Not only is this a simple and elegant reconstruction, but it also enables the action to be mapped to that in the Wess–Zumino–Witten-like superstring field theory, which has not yet been constructed, and fills the only gap in that formulation.
Effectiveness of a Long-Term, Home-Based Aerobic Exercise Intervention on Slowing the Progression of Parkinson Disease: Design of the Cyclical Lower Extremity Exercise for Parkinson Disease II (CYCLE-II) Study
Authors: Alberts Jay L , Rosenfeldt Anson B , Lopez-Lennon Cielita , Suttman Erin , Jansen A Elizabeth , Imrey Peter B , Dibble Leland E
Published: August 2021

Objective

Previous short duration studies have demonstrated that high-intensity aerobic exercise improves aspects of motor and non-motor function in people with Parkinson disease (PwPD); however, the effectiveness of a long-term exercise intervention on slowing disease progression is unknown. The primary aim of this study is to determine the disease-altering effects of high-intensity aerobic exercise, administered on an upright stationary cycle, on the progression of PD. A secondary aim is to develop a prognostic model for 12-month changes in the Movement Disorder Society Unified Parkinson's Disease Rating Scale III (MDS-UPDRS III) of PwPD undergoing an aerobic exercise intervention.

Methods

This pragmatic, multisite, single-rater blinded, randomized controlled trial will recruit PwPD from 2 large, urban, academic medical centers. Participants (N = 250 PwPD) will be randomized to (1) home-based aerobic exercise or (2) usual and customary care. Those in the aerobic exercise arm will be asked to complete in-home aerobic exercise sessions at 60% to 80% of heart rate reserve 3 times per week for 12 months utilizing a commercially available upright exercise cycle. The usual and customary care group will continue normal activity levels. Daily activity will be monitored for both groups throughout the 12-month study period. The primary outcome, both to assess disease-modifying response to aerobic exercise and for prognostic modeling in the aerobic exercise arm, is 12-month rate of change in the MDS-UPDRS III. Clinical and biomechanical measures will also be used to assess upper and lower extremity motor function as well as non-motor functions.

Impact

Should long-term aerobic exercise demonstrate disease-modifying capability, this study will provide evidence that “Exercise is Medicine” for PwPD. Further, the derived prognostic model will inform a patient-specific exercise prescription for PwPD and expected effects on PD progression.
The Active World of Passive Investing
Authors: Easley David , Michayluk David , O’Hara Maureen , Putniņš Tālis J
Published: August 2021

We investigate the new reality of exchange-traded funds (ETFs). We show that most ETFs are active investments in form (designed to generate alpha) or function (serve as building blocks of active portfolios). We define a new activeness index to capture these dimensions, finding that the cross-section of ETFs is now increasingly characterized by highly active investment vehicles. Active-in-form ETFs have positive flow-performance sensitivity, charge the highest fees among ETFs, and have high within-portfolio turnover. Active-in-function ETFs have more concentrated holdings, less within-portfolio turnover, but higher turnover in the secondary market. We show how more active ETFs are gaining market share over less active ETFs, leading to competitive fee pressure both within the ETF space and across the investment management industry. We suggest that the growing activeness of ETFs may assuage concerns about ETFs harming price discovery.
Knowledge networks in Brazil’s health sciences
Authors: Tatsch Ana Lúcia , Ruffoni Janaina , Botelho Marisa dos Reis A , Stefani Rafael
Published: August 2021

This study aims to analyze the network of interactions of Brazilian medical research groups, identifying key actors and their roles in generating and diffusing knowledge. Social network analysis was applied, with data from the Research Groups Directory Census of the National Council of Scientific and Technological Development, from 2016. The main results show (1) the central role of universities, public institutes, and university hospital research groups; (2) the importance of scientific infrastructure and research capability of scientists in knowledge production; (3) the minor role of the industry, denoting the fragility of university–industry interactions; (4) spatial concentration of network actors, mostly located in the south and southeast of Brazil; and (5) a great opportunity to expand flows and cooperation. Regarding these results, the recent budgetary cuts in science and technology resources since 2016 seem to be a misguided and detrimental strategy as these resources are essential for future technological and industrial development.
A Homolog of theArabidopsis TIME FOR COFFEEGene Is Involved in Nonhost Resistance to Wheat Stem Rust inBrachypodium distachyon
Authors: Della Coletta Rafael , Lavell Anastasiya A. , Garvin David F.
Published: August 2021

Plants resist infection by pathogens using both preexisting barriers and inducible defense responses. Inducible responses are governed in a complex manner by various hormone signaling pathways. The relative contribution of hormone signaling pathways to nonhost resistance to pathogens is not well understood. In this study, we examined the molecular basis of disrupted nonhost resistance to the fungal species Puccinia graminis, which causes stem rust of wheat, in an induced mutant of the model grass Brachypodium distachyon. Through bioinformatic analysis, a 1-bp deletion in the mutant genotype was identified that introduces a premature stop codon in the gene Bradi1g24100, which is a homolog of the Arabidopsis thaliana gene TIME FOR COFFEE (TIC). In Arabidopsis, TIC is central to the regulation of the circadian clock and plays a crucial role in jasmonate signaling by attenuating levels of the transcription factor protein MYC2, and its mutational disruption results in enhanced susceptibility to the hemibiotroph Pseudomonas syringae. Our similar finding for an obligate biotroph suggests that the biochemical role of TIC in mediating disease resistance to biotrophs is conserved in grasses, and that the correct modulation of jasmonate signaling during infection by Puccinia graminis may be essential for nonhost resistance to wheat stem rust in B. distachyon.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
Soybean Cyst Nematode Resistance Quantitative Trait Locus cqSCN-006 Alters the Expression of a γ-SNAP Protein
Authors: Butler Katelyn J. , Fliege Christina , Zapotocny Ryan , Diers Brian , Hudson Matthew , Bent Andrew F.
Published: August 2021

Soybean cyst nematode (SCN) is the most economically damaging pathogen of soybean and host resistance is a core management strategy. The SCN resistance quantitative trait locus cqSCN-006, introgressed from the wild relative Glycine soja, provides intermediate resistance against nematode populations, including those with increased virulence on the heavily used rhg1-b resistance locus. cqSCN-006 was previously fine-mapped to a genome interval on chromosome 15. The present study determined that Glyma.15G191200 at cqSCN-006, encoding a γ-SNAP, contributes to SCN resistance. CRISPR/Cas9-mediated disruption of the cqSCN-006 allele reduced SCN resistance in transgenic roots. There are no encoded amino acid polymorphisms between resistant and susceptible alleles. However, other cqSCN-006-specific DNA polymorphisms in the Glyma.15G191200 promoter and gene body were identified, and we observed differing induction of γ-SNAP protein abundance at SCN infection sites between resistant and susceptible roots. We identified alternative RNA splice forms transcribed from the Glyma.15G191200 γ-SNAP gene and observed differential expression of the splice forms 2 days after SCN infection. Heterologous overexpression of γ-SNAPs in plant leaves caused moderate necrosis, suggesting that careful regulation of this protein is required for cellular homeostasis. Apparently, certain G. soja evolved quantitative SCN resistance through altered regulation of γ-SNAP. Previous work has demonstrated SCN resistance impacts of the soybean α-SNAP proteins encoded by Glyma.18G022500 (Rhg1) and Glyma.11G234500. The present study shows that a different type of SNAP protein can also impact SCN resistance. Little is known about γ-SNAPs in any system, but the present work suggests a role for γ-SNAPs during susceptible responses to cyst nematodes.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
Transcriptomic links to muscle mass loss and declines in cumulative muscle protein synthesis during short‐term disuse in healthy younger humans
Authors: Willis Craig R. G. , Gallagher Iain J. , Wilkinson Daniel J. , Brook Matthew S. , Bass Joseph J. , Phillips Bethan E. , Smith Kenneth , Etheridge Timothy , Stokes Tanner , McGlory Chris , Gorissen Stefan H. M. , Szewczyk Nathaniel J. , Phillips Stuart M. , Atherton Philip J.
Published: August 2021

Muscle disuse leads to a rapid decline in muscle mass, with reduced muscle protein synthesis (MPS) considered the primary physiological mechanism. Here, we employed a systems biology approach to uncover molecular networks and key molecular candidates that quantitatively link to the degree of muscle atrophy and/or extent of decline in MPS during short‐term disuse in humans. After consuming a bolus dose of deuterium oxide (D2O; 3 mL.kg−1), eight healthy males (22 ± 2 years) underwent 4 days of unilateral lower‐limb immobilization. Bilateral muscle biopsies were obtained post‐intervention for RNA sequencing and D2O‐derived measurement of MPS, with thigh lean mass quantified using dual‐energy X‐ray absorptiometry. Application of weighted gene co‐expression network analysis identified 15 distinct gene clusters (“modules”) with an expression profile regulated by disuse and/or quantitatively connected to disuse‐induced muscle mass or MPS changes. Module scans for candidate targets established an experimentally tractable set of candidate regulatory molecules (242 hub genes, 31 transcriptional regulators) associated with disuse‐induced maladaptation, many themselves potently tied to disuse‐induced reductions in muscle mass and/or MPS and, therefore, strong physiologically relevant candidates. Notably, we implicate a putative role for muscle protein breakdown‐related molecular networks in impairing MPS during short‐term disuse, and further establish DEPTOR (a potent mTOR inhibitor) as a critical mechanistic candidate of disuse driven MPS suppression in humans. Overall, these findings offer a strong benchmark for accelerating mechanistic understanding of short‐term muscle disuse atrophy that may help expedite development of therapeutic interventions.
Cerebral Macro- and Microcirculation during Ephedrine versus Phenylephrine Treatment in Anesthetized Brain Tumor Patients: A Randomized Clinical Trial Using Magnetic Resonance Imaging
Authors: Koch Klaus U. , Mikkelsen Irene K. , Espelund Ulrick S. , Angleys Hugo , Tietze Anna , Oettingen Gorm V. , Juul Niels , Østergaard Leif , Rasmussen Mads
Published: August 2021

Background

This study compared ephedrine versus phenylephrine treatment on cerebral macro- and microcirculation, measured by cerebral blood flow, and capillary transit time heterogeneity, in anesthetized brain tumor patients. The hypothesis was that capillary transit time heterogeneity in selected brain regions is greater during phenylephrine than during ephedrine, thus reducing cerebral oxygen tension.

Methods

In this single-center, double-blinded, randomized clinical trial, 24 anesthetized brain tumor patients were randomly assigned to ephedrine or phenylephrine. Magnetic resonance imaging of peritumoral and contralateral hemispheres was performed before and during vasopressor infusion. The primary endpoint was between-group difference in capillary transit time heterogeneity. Secondary endpoints included changes in cerebral blood flow, estimated oxygen extraction fraction, and brain tissue oxygen tension.

Results

Data from 20 patients showed that mean (± SD) capillary transit time heterogeneity in the contralateral hemisphere increased during phenylephrine from 3.0 ± 0.5 to 3.2 ± 0.7 s and decreased during ephedrine from 3.1 ± 0.8 to 2.7 ± 0.7 s (difference phenylephrine versus difference ephedrine [95% CI], −0.6 [−0.9 to −0.2] s; P = 0.004). In the peritumoral region, the mean capillary transit time heterogeneity increased during phenylephrine from 4.1 ± 0.7 to 4.3 ± 0.8 s and decreased during ephedrine from 3.5 ± 0.9 to 3.3 ± 0.9 s (difference phenylephrine versus difference ephedrine [95%CI], −0.4[−0.9 to 0.1] s; P = 0.130). Cerebral blood flow (contralateral hemisphere ratio difference [95% CI], 0.3 [0.06 to 0.54]; P = 0.018; and peritumoral ratio difference [95% CI], 0.3 [0.06 to 0.54; P = 0.018) and estimated brain tissue oxygen tension (contralateral hemisphere ratio difference [95% CI], 0.34 [0.09 to 0.59]; P = 0.001; and peritumoral ratio difference [95% CI], 0.33 [0.09 to 0.57]; P = 0.010) were greater during ephedrine than phenylephrine in both regions.

Conclusions

Phenylephrine caused microcirculation in contralateral tissue, measured by the change in capillary transit time heterogeneity, to deteriorate compared with ephedrine, despite reaching similar mean arterial pressure endpoints. Ephedrine improved cerebral blood flow and tissue oxygenation in both brain regions and may be superior to phenylephrine in improving cerebral macro- and microscopic hemodynamics and oxygenation.

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Black goby territorial males adjust their ejaculate's characteristics in response to the presence of sneakers
Authors: Locatello Lisa , Borgheresi Oliviero , Poli Federica , Pilastro Andrea , Rasotto Maria B.
Published: August 2021

In many species, males can rapidly adjust their ejaculate performance in response to changing levels of sperm competition, an ability that is probably mediated by seminal fluid adaptive plasticity. In the black goby,Gobius niger, territorial males attach viscous ejaculate trails to the nest roof, from which sperm are slowly released into the water during the long-lasting spawning events. Sneaker males release their sperm in the vicinity of the nest, and territorial males try to keep them at a distance by patrolling their territory. We show here that territorial males' ejaculate trails released a higher proportion of their sperm in the presence of a single sneaker, but this proportion decreased when there were three sneakers, an effect that is most likely mediated by a change in the seminal fluid composition. Field observations showed that when multiple sneaking attempts occurred, territorial males spent more time outside the nest, suggesting that ejaculation rate and territory defence are traded-off. Altogether, these results suggest that the adjustment of sperm release from the ejaculate may be strategic, guaranteeing a more continuous concentration of the territorial male's sperm in the nest, although at a lower level, when he is engaged in prolonged territory defence outside the nest.
Mesozoic origin and ‘out-of-India’ radiation of ricefishes (Adrianichthyidae)
Authors: Yamahira Kazunori , Ansai Satoshi , Kakioka Ryo , Yaguchi Hajime , Kon Takeshi , Montenegro Javier , Kobayashi Hirozumi , Fujimoto Shingo , Kimura Ryosuke , Takehana Yusuke , Setiamarga Davin H. E. , Takami Yasuoki , Tanaka Rieko , Maeda Ken , Tran Hau D. , Koizumi Noriyuki , Morioka Shinsuke , Bounsong Vongvichith , Watanabe Katsutoshi , Musikasinthorn Prachya , Tun Sein , Yun L. K. C. , Masengi Kawilarang W. A. , Anoop V. K. , Raghavan Rajeev , Kitano Jun
Published: August 2021

The Indian subcontinent has an origin geologically different from Eurasia, but many terrestrial animal and plant species on it have congeneric or sister species in other parts of Asia, especially in the Southeast. This faunal and floral similarity between India and Southeast Asia is explained by either of the two biogeographic scenarios, ‘into-India’ or ‘out-of-India’. Phylogenies based on complete mitochondrial genomes and five nuclear genes were undertaken for ricefishes (Adrianichthyidae) to examine which of these two biogeographic scenarios fits better. We found that
Oryzias setnai
, the only adrianichthyid distributed in and endemic to the Western Ghats, a mountain range running parallel to the western coast of the Indian subcontinent, is sister to all other adrianichthyids from eastern India and Southeast–East Asia. Divergence time estimates and ancestral area reconstructions reveal that this western Indian species diverged in the late Mesozoic during the northward drift of the Indian subcontinent. These findings indicate that adrianichthyids dispersed eastward ‘out-of-India’ after the collision of the Indian subcontinent with Eurasia, and subsequently diversified in Southeast–East Asia. A review of geographic distributions of ‘out-of-India’ taxa reveals that they may have largely fuelled or modified the biodiversity of Eurasia.
State-space aerodynamic model reveals high force control authority and predictability in flapping flight
Authors: Bayiz Yagiz E. , Cheng Bo
Published: August 2021

Flying animals resort to fast, large-degree-of-freedom motion of flapping wings, a key feature that distinguishes them from rotary or fixed-winged robotic fliers with limited motion of aerodynamic surfaces. However, flapping-wing aerodynamics are characterized by highly unsteady and three-dimensional flows difficult to model or control, and accurate aerodynamic force predictions often rely on expensive computational or experimental methods. Here, we developed a computationally efficient and data-driven state-space model to dynamically map wing kinematics to aerodynamic forces/moments. This model was trained and tested with a total of 548 different flapping-wing motions and surpassed the accuracy and generality of the existing quasi-steady models. This model used 12 states to capture the unsteady and nonlinear fluid effects pertinent to force generation without explicit information of fluid flows. We also provided a comprehensive assessment of the control authority of key wing kinematic variables and found that instantaneous aerodynamic forces/moments were largely predictable by the wing motion history within a half-stroke cycle. Furthermore, the angle of attack, normal acceleration and pitching motion had the strongest effects on the aerodynamic force/moment generation. Our results show that flapping flight inherently offers high force control authority and predictability, which can be key to developing agile and stable aerial fliers.
Scaling of urban income inequality in the USA
Authors: Heinrich Mora Elisa , Heine Cate , Jackson Jacob J. , West Geoffrey B. , Yang Vicky Chuqiao , Kempes Christopher P.
Published: August 2021

Urban scaling analysis, the study of how aggregated urban features vary with the population of an urban area, provides a promising framework for discovering commonalities across cities and uncovering dynamics shared by cities across time and space. Here, we use the urban scaling framework to study an important, but under-explored feature in this community—income inequality. We propose a new method to study the scaling of income distributions by analysing total income scaling in population percentiles. We show that income in the least wealthy decile (10%) scales close to linearly with city population, while income in the most wealthy decile scale with a significantly superlinear exponent. In contrast to the superlinear scaling of total income with city population, this decile scaling illustrates that the benefits of larger cities are increasingly unequally distributed. For the poorest income deciles, cities have no positive effect over the null expectation of a linear increase. We repeat our analysis after adjusting income by housing cost, and find similar results. We then further analyse the shapes of income distributions. First, we find that mean, variance, skewness and kurtosis of income distributions all increase with city size. Second, the Kullback–Leibler divergence between a city’s income distribution and that of the largest city decreases with city population, suggesting the overall shape of income distribution shifts with city population. As most urban scaling theories consider densifying interactions within cities as the fundamental process leading to the superlinear increase of many features, our results suggest this effect is only seen in the upper deciles of the cities. Our finding encourages future work to consider heterogeneous models of interactions to form a more coherent understanding of urban scaling.
Uncertainty propagation for deterministic models of biochemical networks using moment equations and the extended Kalman filter
Authors: Kurdyaeva Tamara , Milias-Argeitis Andreas
Published: August 2021

Differential equation models of biochemical networks are frequently associated with a large degree of uncertainty in parameters and/or initial conditions. However, estimating the impact of this uncertainty on model predictions via Monte Carlo simulation is computationally demanding. A more efficient approach could be to track a system of low-order statistical moments of the state. Unfortunately, when the underlying model is nonlinear, the system of moment equations is infinite-dimensional and cannot be solved without a moment closure approximation which may introduce bias in the moment dynamics. Here, we present a new method to study the time evolution of the desired moments for nonlinear systems with polynomial rate laws. Our approach is based on solving a system of low-order moment equations by substituting the higher-order moments with Monte Carlo-based estimates from a small number of simulations, and using an extended Kalman filter to counteract Monte Carlo noise. Our algorithm provides more accurate and robust results compared to traditional Monte Carlo and moment closure techniques, and we expect that it will be widely useful for the quantification of uncertainty in biochemical model predictions.
A novel yeast-based high-throughput method for the identification of protein palmitoylation inhibitors
Authors: Coronel Arrechea Consuelo , Giolito María Luz , García Iris Alejandra , Soria Gastón , Valdez Taubas Javier
Published: August 2021

Protein S-acylation or palmitoylation is a widespread post-translational modification that consists of the addition of a lipid molecule to cysteine residues of proteins through a thioester bond. Palmitoylation and palmitoyltransferases (PATs) have been linked to several types of cancers, diseases of the central nervous system and many infectious diseases where pathogens use the host cell machinery to palmitoylate their effectors. Despite the central importance of palmitoylation in cell physiology and disease, progress in the field has been hampered by the lack of potent-specific inhibitors of palmitoylation in general, and of individual PATs in particular. Herein, we present a yeast-based method for the high-throughput identification of small molecules that inhibit protein palmitoylation. The system is based on a reporter gene that responds to the acylation status of a palmitoylation substrate fused to a transcription factor. The method can be applied to heterologous PATs such as human DHHC20, mouse DHHC21 and also a PAT from the parasite
Giardia lamblia
. As a proof-of-principle, we screened for molecules that inhibit the palmitoylation of Yck2, a substrate of the yeast PAT Akr1. We tested 3200 compounds and were able to identify a candidate molecule, supporting the validity of our method.
Osmolarity-regulated swelling initiates egg activation in
Drosophila
Authors: York-Andersen Anna H. , Wood Benjamin W. , Wilby Elise L. , Berry Alexander S. , Weil Timothy T.
Published: August 2021

Egg activation is a series of highly coordinated processes that prepare the mature oocyte for embryogenesis. Typically associated with fertilization, egg activation results in many downstream outcomes, including the resumption of the meiotic cell cycle, translation of maternal mRNAs and cross-linking of the vitelline membrane. While some aspects of egg activation, such as initiation factors in mammals and environmental cues in sea animals, have been well-documented, the mechanics of egg activation in insects are less well-understood. For many insects, egg activation can be triggered independently of fertilization. In
Drosophila melanogaster
, egg activation occurs in the oviduct resulting in a single calcium wave propagating from the posterior pole of the oocyte. Here we use physical manipulations, genetics and live imaging to demonstrate the requirement of a volume increase for calcium entry at egg activation in
ex vivo
mature
Drosophila
oocytes. The addition of water, modified with sucrose to a specific osmolarity, is sufficient to trigger the calcium wave in the mature oocyte and the downstream events associated with egg activation. We show that the swelling process is regulated by the conserved osmoregulatory channels, aquaporins and DEGenerin/Epithelial Na
+
channels. Furthermore, through pharmacological and genetic disruption, we reveal a concentration-dependent requirement of transient receptor potential M channels to transport calcium, most probably from the perivitelline space, across the plasma membrane into the mature oocyte. Our data establish osmotic pressure as a mechanism that initiates egg activation in
Drosophila
and are consistent with previous work from evolutionarily distant insects, including dragonflies and mosquitos, and show remarkable similarities to the mechanism of egg activation in some plants.
A glitch in the snitch: the role of linker histone H1 in shaping the epigenome in normal and diseased cells
Authors: Saha Ankita , Dalal Yamini
Published: August 2021

Histone H1s or the linker histones are a family of dynamic chromatin compacting proteins that are essential for higher-order chromatin organization. These highly positively charged proteins were previously thought to function solely as repressors of transcription. However, over the last decade, there is a growing interest in understanding this multi-protein family, finding that not all variants act as repressors. Indeed, the H1 family members appear to have distinct affinities for chromatin and may potentially affect distinct functions. This would suggest a more nuanced contribution of H1 to chromatin organization. The advent of new technologies to probe H1 dynamics
in vivo
, combined with powerful computational biology, and
in vitro
imaging tools have greatly enhanced our knowledge of the mechanisms by which H1 interacts with chromatin. This family of proteins can be metaphorically compared to the Golden Snitch from the Harry Potter series, buzzing on and off several regions of the chromatin, in combat with competing transcription factors and chromatin remodellers, thereby critical to the epigenetic endgame on short and long temporal scales in the life of the nucleus. Here, we summarize recent efforts spanning structural, computational, genomic and genetic experiments which examine the linker histone as an unseen architect of chromatin fibre in normal and diseased cells and explore unanswered fundamental questions in the field.
Development of a compact alkynyl-enrichable crosslinker for in-depth in-vivo crosslinking analysis
Authors: Gao Hang , Zhao Lili , Zhao Baofeng , Gong Zhou , Zhao Qun , Zhang Lihua
Published: July 2021

Chemical crosslinking coupled with mass spectrometry (CXMS) has emerged as a powerfμl technique to capture the dynamic information of protein complexes with high sensitivity, throughput and sample universality. To advance the study of in-vivo protein structures and protein-protein interactions on the large scale, a new alkynyl-enrichable crosslinker was developed with high efficiency of membrane penetration, reactivity and enrichment. The crosslinker was successfully used for in-vivo crosslinking of intact human cells, resμlting in 6820 non-redundant crosslinks identified at a false discovery rate (FDR) of 1% using pLink 2.0, which 4898 (71.8%) of the cross-links were assigned as intraprotein and 1922 (28.2%) were interprotein links. To our knowledge, this is also the first time to realize the in-vivo crosslinking with a non-cleavable crosslinker for homo species cells.
Transcriptomic analysis of pathways associated with αv integrin-related non-canonical autophagy in human B cells
Authors: Muir Virginia , Sagadiev Sara , Suchland Emmaline , Meitlis Iana , Giltiay Natalia , Tam Jenny M. , Garner Ethan C. , Wivagg Carl N , Shows Donna , James Richard G. , Lacy-Hulbert Adam , Acharya Mridu
Published: August 2021

Autophagy proteins have been linked with development of immune-mediated diseases including lupus, but the mechanisms for this are unclear. We have previously shown that non-canonical autophagy induced by αv-integrins regulates B cell activation by viral and self-antigens in mice. Here we investigated the involvement of this pathway in B cells from human tissue. Our data revealed that autophagy is specifically induced in germinal-center and memory B cell sub-populations from human tonsil and spleen. Transcriptomic analysis showed that induction of autophagy is related to unique aspects of activated B cells such as mitochondrial metabolism. To understand the function of non-canonical autophagy in B cells, we used CRISPR-mediated knockdown of autophagy genes. Integrating data from primary B cells and knockout cells we found that αv-integrin-related non-canonical autophagy limits activation of specific pathways while promoting others. These data provide new mechanistic links for autophagy and immune dysregulation in diseases such as lupus.
Inhibition of the H3K27 demethylase UTX enhances the epigenetic silencing of HIV proviruses and induces HIV-1 DNA hypermethylation but fails to permanently block HIV reactivation
Authors: Nguyen Kien , Dobrowolski Curtis , Shukla Meenakshi , Cho Won-Kyung , Karn Jonathan
Published: August 2021

One strategy for a functional cure of HIV-1 is “block and lock”, which seeks to permanently suppress the rebound of quiescent HIV-1 by epigenetic silencing. For the HIV LTR, both histone 3 lysine 27 tri-methylation (H3K27me3) and DNA methylation are associated with viral suppression, while H3K4 tri-methylation (H3K4me3) is correlated with viral expression. However, H3K27me3 is readily reversed upon activation of T-cells through the T-cell receptor. To suppress latent HIV-1 in a stable fashion, we depleted the expression or inhibited the activity of UTX/KDM6A, the major H3K27 demethylase, and investigated its impact on latent HIV-1 reactivation in T cells. Inhibition of UTX dramatically enhanced H3K27me3 levels at the HIV LTR and were associated with increased DNA methylation. In latently infected cells from patients, GSK-J4, which is a potent dual inhibitor of the H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A, effectively suppressed the reactivation of latent HIV-1 and induced DNA methylation at specific sites in the 5’LTR of latent HIV-1 by the enhanced recruitment of DNMT3A to HIV-1. Nonetheless, suppression of HIV-1 through epigenetic silencing required the continued treatment with GSK-J4 and was rapidly reversed after removal of the drug. Thus, epigenetic silencing by itself appears to be insufficient to permanently silence HIV-1 proviral transcription.

Author Summary

The “block and lock” strategy for a functional HIV-1 cure is based on the premise that permanent inactivation of the HIV-1 can be achieved by epigenetic silencing of the proviral DNA. For cellular genes, long-term silencing is achieved during cell differentiation by the induction of specific epigenetic modifications involving histone and DNA methylation. During HIV-1 silencing, histone methylation and DNA methylation are observed, but both sets of modifications can be reversed upon activation of T-cells through the T-cell receptor or potent latency reversing agents. In an attempt to enhance silencing of HIV-1 transcription, we used an inhibitor of H3K27 demethylases to increase H3K27 methylation. This in turn led to enhanced DNA methylation of HIV-1. Unfortunately, although the treatment effectively silenced HIV-1 and prevented viral reactivation, the silencing effects were short-lived and quickly reversed after removal of the drug.
Crystal structure, Hirshfeld surface and photophysical analysis of 2-nitro-3-phenyl-9H-carbazole
Authors: Singh Neetu , Noh Ga Hee , Park Hyoung-Ryun , Lee Junseong
Published: August 2021

The title compound, C18H12N2O2, was synthesized from a dinitrobiphenylbenzene derivative using a novel modification of the Cadogan reaction. The reaction has several possible ring-closed products and the title compound was separated as the major product. The X-ray crystallographic study revealed that the carbazole compound crystallizes in the monoclinicP\overline{1} space group and possesses a single closed Cadogan ring. There are two independent molecules in the asymmetric unit. In the crystal, the molecules are linked by N—H...O hydrogen bonding.
Protection of railway infrastructure objects against electrical corrosion
Authors: Trykoz Liudmyla , Kamchatnaya Svetlana , Borodin Dmytro , Atynian Armen , Tkachenko Roman
Published: August 2021

Purpose

The purpose of this paper is to develop a technological method of protection against electrical corrosion. One more way to protect the objects is to prevent the electrical current from getting to them. For example, railway objects are surrounded with a material with raised electrical resistance.

Design/methodology/approach

The railway infrastructure objects (foundations, contact-line supports, reinforced concrete sub-bases, bridge structures, pipelines of engineering networks, supports of passenger platforms and pedestrian bridges, concrete plinth walls of station buildings) are subjected to destruction due to the action of electrical current. One of destruction factors is a corrosion of the concrete constructions which is caused by the leakage current action.

Findings

Leakage currents and stray currents bypass the structure of supports of high passenger platforms or pipes of engineering networks. These currents spread by the line with the least resistance outside of the structures.

Research limitations/implications

Electrical leakage current from the rails gets into such structures through sleepers, ballast and soil and leads to accelerated corrosion leaching of concrete.

Practical implications

The constructions are protected against the destructive effect of electrical corrosion on the metal or concrete of the structure. This scheme is suitable for the construction and reconstruction of railway structures which operate on electrified sections of railways.

Originality/value

Schemes of technological solution are proposed for protection of foundations, supports of high passenger platforms, pipelines of engineering networks, etc. For this, the arrangement of soil-contained screens with big electrical resistance is suggested.
Rethinking free skilled labour migration policies in CLMV countries: a qualitative systematic review
Authors: Daovisan Hanvedes , Phukrongpet Pimporn , Chamaratana Thanapauge
Published: August 2021

Purpose

There is an ongoing debate in the ASEAN Economic Community (AEC) Blueprint 2015 concerning the skilled labour migration policy regimes. This review aims to systematise the free flow of skilled labour migration policies in Cambodia, Lao PDR, Myanmar and Vietnam (CLMV) countries.

Design/methodology/approach

This review utilised a qualitative systematic in peer-reviewed journals for the period 2015–2019. The initial search identified 28,874 articles. Of those articles, 10,612 articles were screened, 738 articles were checked, 150 articles were selected and 18 articles met the criteria. Data were analysed using thematic synthesis (e.g. coding, categorisation, synthesis and summarisation).

Findings

The review suggested that free movement from CLMV countries is the cause of the mass exodus of unskilled migration to high-income countries. The review found that the free flow of migration policy in the AEC Blueprint 2015 is associated with illegal, unauthorised and unskilled workers in the host country.

Research limitations/implications

A systematic review is qualitative in nature, in which the relevant existing literature lacks some empirical studies, and the results must be generalisable.

Practical implications

The current systematic review provides a visual diagram for practical implications to isolate undocumented, illegal, unpermitted and unskilled migrant workers and further reduce the mass exodus of migration from CLMV countries.

Originality/value

To the authors' knowledge, this is the first review to extend the literature to the macro-level determinants of free flow of skilled labour migration policies in CLMV countries. The present review seeks to inform the policy responses of moving freely between sending and receiving countries.