bluuebunny/crossref_metadata_2025 huggingface dataset:
Harnessing anti-cytomegalovirus immunity for local immunotherapy against solid tumors
Authors: Çuburu Nicolas , Bialkowski Lukasz , Pontejo Sergio M. , Sethi Shiv K. , Bell Alexander T. F. , Kim Rina , Thompson Cynthia D. , Lowy Douglas R. , Schiller John T.
Published: June 2022

Tumor infiltration by T cells profoundly affects cancer progression and responses to immunotherapy. However, the tumor immunosuppressive microenvironment can impair the induction, trafficking, and local activity of antitumor T cells. Here, we investigated whether intratumoral injection of virus-derived peptide epitopes could activate preexisting antiviral T cell responses locally and promote antitumor responses or antigen spreading. We focused on a mouse model of cytomegalovirus (CMV), a highly prevalent human infection that induces vigorous and durable T cell responses. Mice persistently infected with murine CMV (MCMV) were challenged with lung (TC-1), colon (MC-38), or melanoma (B16-F10) tumor cells. Intratumoral injection of MCMV-derived T cell epitopes triggered in situ and systemic expansion of their cognate, MCMV-specific CD4
+
or CD8
+
T cells. The MCMV CD8
+
T cell epitopes injected alone provoked arrest of tumor growth and some durable remissions. Intratumoral injection of MCMV CD4
+
T cell epitopes with polyinosinic acid:polycytidylic acid (pI:C) preferentially elicited tumor antigen–specific CD8
+
T cells, promoted tumor clearance, and conferred long-term protection against tumor rechallenge. Notably, secondary proliferation of MCMV-specific CD8
+
T cells correlated with better tumor control. Importantly, intratumoral injection of MCMV-derived CD8
+
T cell–peptide epitopes alone or CD4
+
T cell–peptide epitopes with pI:C induced potent adaptive and innate immune activation of the tumor microenvironment. Thus, CMV-derived peptide epitopes, delivered intratumorally, act as cytotoxic and immunotherapeutic agents to promote immediate tumor control and long-term antitumor immunity that could be used as a stand-alone therapy. The tumor antigen–agnostic nature of this approach makes it applicable across a broad range of solid tumors regardless of their origin.
A proposed unified interphase nucleus chromosome structure: Preliminary preponderance of evidence
Authors: Sedat John , McDonald Angus , Cang Hu , Lucas Joseph , Arigovindan Muthuvel , Kam Zvi , Murre Cornelis , Elbaum Michael
Published: June 2022

Cryoelectron tomography of the cell nucleus using scanning transmission electron microscopy and deconvolution processing technology has highlighted a large-scale, 100- to 300-nm interphase chromosome structure, which is present throughout the nucleus. This study further documents and analyzes these chromosome structures. The paper is divided into four parts: 1) evidence (preliminary) for a unified interphase chromosome structure; 2) a proposed unified interphase chromosome architecture; 3) organization as chromosome territories (e.g., fitting the 46 human chromosomes into a 10-μm-diameter nucleus); and 4) structure unification into a polytene chromosome architecture and lampbrush chromosomes. Finally, the paper concludes with a living light microscopy cell study showing that the G1 nucleus contains very similar structures throughout. The main finding is that this chromosome structure appears to coil the 11-nm nucleosome fiber into a defined hollow structure, analogous to a Slinky helical spring [
https://en.wikipedia.org/wiki/Slinky
; motif used in Bowerman
et al.
,
eLife
10, e65587 (2021)]. This Slinky architecture can be used to build chromosome territories, extended to the polytene chromosome structure, as well as to the structure of lampbrush chromosomes.
Mapping functional regions of essential bacterial proteins with dominant-negative protein fragments
Authors: Savinov Andrew , Fernandez Andres , Fields Stanley
Published: June 2022

Massively parallel measurements of dominant-negative inhibition by protein fragments have been used to map protein interaction sites and discover peptide inhibitors. However, the underlying principles governing fragment-based inhibition have thus far remained unclear. Here, we adapted a high-throughput inhibitory fragment assay for use in
Escherichia coli
, applying it to a set of 10 essential proteins. This approach yielded single amino acid resolution maps of inhibitory activity, with peaks localized to functionally important interaction sites, including oligomerization interfaces and folding contacts. Leveraging these data, we performed a systematic analysis to uncover principles of fragment-based inhibition. We determined a robust negative correlation between susceptibility to inhibition and cellular protein concentration, demonstrating that inhibitory fragments likely act primarily by titrating native protein interactions. We also characterized a series of trade-offs related to fragment length, showing that shorter peptides allow higher-resolution mapping but suffer from lower inhibitory activity. We employed an unsupervised statistical analysis to show that the inhibitory activities of protein fragments are largely driven not by generic properties such as charge, hydrophobicity, and secondary structure, but by the more specific characteristics of their bespoke macromolecular interactions. Overall, this work demonstrates fundamental characteristics of inhibitory protein fragment function and provides a foundation for understanding and controlling protein interactions in vivo.
Actin-driven Golgi apparatus dispersal during collective migration of epithelial cells
Authors: Khuntia Purnati , Rawal Simran , Marwaha Rituraj , Das Tamal
Published: June 2022

As a sedentary epithelium turns motile during wound healing, morphogenesis, and metastasis, the Golgi apparatus moves from an apical position, above the nucleus, to a basal position. This apical-to-basal repositioning of Golgi is critical for epithelial cell migration. Yet the molecular mechanism underlying it remains elusive, although microtubules are believed to play a role. Using live-cell and super-resolution imaging, we show that at the onset of collective migration of epithelial cells, Golgi stacks get dispersed to create an unpolarized transitional structure, and surprisingly, this dispersal process depends not on microtubules but on actin cytoskeleton. Golgi–actin interaction involves Arp2/3-driven actin projections emanating from the actin cortex, and a Golgi-localized actin elongation factor, MENA. While in sedentary epithelial cells, actin projections intermittently interact with the apically located Golgi, and the frequency of this event increases before the dispersion of Golgi stacks, at the onset of cell migration. Preventing Golgi–actin interaction with MENA-mutants eliminates Golgi dispersion and reduces the persistence of cell migration. Taken together, we show a process of actin-driven Golgi dispersion that is mechanistically different from the well-known Golgi apparatus fragmentation during mitosis and is essential for collective migration of epithelial cells.
The microstructure and mechanical properties of titanium/copper welded joint by FSW
Authors: Li Jie , Zhou Peng , Wei Guijiang , Huang Jiankang , Shi Hongyuan
Published: June 2022

The dissimilar metal of Ti6Al4V and T2 were joined using a butt joint with and without an intermediate layer Ag by friction stir welding. The interfacial Ti–Cu IMCs of both joints are composed of Ti2Cu, TiCu and Ti3Cu4, and the thicknesses are about 1.5 μm and 3 μm, respectively. The intermediate layer Ag can promote the diffusion of Ti to Cu side, and the diffusion of Ti elements plays a dominant role in the formation of Ti–Cu IMCs. The joint with the intermediate layer Ag presents a higher tensile strength, which is about 70% of the Cu base metal. The fracture characteristics of both types of the joints are brittle fracture, but the tensile fracture regions are different.
Mesoporous NiCo2S4 nanoflakes as an efficient and durable electrocatalyst for non-enzymatic detection of cholesterol
Authors: Rabbani Syeda Sughra , Nisar Amjad , Zafar Amina , Liu Yanguo , Sun Hongyu , Karim Shafqat , Hussain Shafqat , Shah Atta Ullah , Hussain Syed Zahid , Mehboob Nasir , Yu Yanlong , Ahmad Mashkoor
Published: June 2022

The detection of cholesterol is very crucial in clinical diagnosis for rapid and accurate monitoring of multiple disease-biomarkers. There is a great need for construction of a highly reliable and stable electrocatalyst for the efficient detection of cholesterol. In this work, mesoporous NiCo2S4 nanoflakes of enhanced electrochemical properties are prepared through a facile hydrothermal approach. The developed nanoflakes modified nickel foam electrode exhibits outstanding electrocatalytic properties for the detection of cholesterol with high selectivity. The electrode displays excellent sensitivity of 8623.6 μA mM−1 cm−2, in the wide linear range from 0.01 to 0.25 mM with a low detection limit of 0.01 μM. In addition, NiCo2S4 structure reveals good thermal stability and reproducibility over a period of 8 weeks. Moreover, the nanoflakes show good response for detection of cholesterol in real samples. Our results demonstrate the potential use of NiCo2S4 as a catalyst for the development of cost-effective electrochemical sensors for medical and industrial applications.
Optimal analytical and numerical approximations to the (un)forced (un)damped parametric pendulum oscillator
Authors: Alyousef Haifa A , Alharthi M R , Salas Alvaro H , El-Tantawy S A
Published: June 2022

The (un)forced (un)damped parametric pendulum oscillator (PPO) is analyzed analytically and numerically using some simple, effective, and more accurate techniques. In the first technique, the ansatz method is employed for analyzing the unforced damped PPO and for deriving some optimal and accurate analytical approximations in the form of angular Mathieu functions. In the second approach, some approximations to (un)forced damped PPO are obtained in the form of trigonometric functions using the ansatz method. In the third approach, He’s frequency-amplitude principle is applied for deriving some approximations to the (un)damped PPO. In the forth approach, He’s homotopy technique is employed for analyzing the forced (un)damped PPO numerically. In the fifth approach, the p-solution Method, which is constructed based on Krylov–Bogoliúbov Mitropolsky method, is introduced for deriving an approximation to the forced damped PPO. In the final approach, the hybrid Padé-finite difference method is carried out for analyzing the damped PPO numerically. All proposed techniques are compared to the fourth-order Runge–Kutta (RK4) numerical solution. Moreover, the global maximum residual distance error is estimated for checking the accuracy of the obtained approximations. The proposed methodologies and approximations can help many researchers in studying and investigating several nonlinear phenomena related to the oscillations that can arise in various branches of science, e.g. waves and oscillations in plasma physics.
Scheme Design of Xenon Composite Over-wrapped Pressure Vessel for Electric Propulsion System
Authors: YU Bin , ZHAO Lei , ZHAO Jipeng , MA Tianju , GU Sendong , YANG Wenbo , LI Lifeng
Published: June 2022

The composite over-wrapped pressure vessel (COPV), which were made by ultra-thin metal liner and high strength carbon fiber reinforced plastic (CFRP), has high performance factor (PV/W). COPV were widely used in electric propulsion system (EPS) of space system. ANSI/AIAA S-081-2000 is a general standard for pressure vessel of aerospace field at home and abroad, it specified the design elements, references, specifications, requirements in detail. The materials selection of liner, CFRP and skirt are introduced respectively. The design contents of liner and CFRP are explained. The liner is designed in terms of equal strength principle and the composite structure was designed in term of hoop fiber layers and spiral fiber layers alternately over-wrapped. The skirt is composite structure, with X-X carbon fiber over-wrapped the TC4 titanium alloy. The titanium liner thickness is 0.8mm, Cycle life is at last 100 times when the liner thick is ultra-thin. The safe life was designed, including stress-rupture life and low cycle fatigue-life. The leak before burst (LBB)safe failure mode was analyzed. The results show that the structure design meets the technical requirements.
The Design and Development of the Automatic Trigger Device for the High-Speed Photography
Authors: Hou Shengchao
Published: June 2022

At present, there is a problem, which is inconvenient for people to record structure failure data, in some experimental process of special equipment. Focusing on the trigger method of high speed photography recording in the component strength experiment of special equipment, and choosing the feature of vibration in the situation that the strength of specimen is failure, we design two schemes, which are integration vibration switch basing on velocity and voltage comparator vibration switch basing on acceleration, according the design ideas that include analysis, design, specification and verification. Through the verification of the experiment, the method of voltage comparator vibration switch basing on acceleration is feasible, and the successful rate of auto-trigger can reach 100 percent in the situation of usual strength failure. The device has fine trigger stability and accuracy, can effectively solve the problem that manipulation has low rate of successful operation and reliability.
Structural Design of 209 Type Fully Open Lid Mould
Authors: Tan Zhihang , Tan Fenfang , Xu Kai , Fan Lanlan , Xiong Can , Yang Junsheng , Chen Yinlei
Published: June 2022

In this work SolidWorks software was used to design the mold structure of model 209 all-open easy open lid. Firstly, the high-speed forming process of basic lid and finished lid in model 209 all-open easy open lid was analyzed. Then the mold design for its auxiliary engraving line and stop-slip point was carried out, and the convex and concave die of the first station was theoretically analyzed. Finally, the 3D mold structure design for the basic cover, finished cover and pull ring was carried out, and 209 type fully open type easy open cover general assembly drawing was designed. Some practical problems such as interference and position relation ware solved in die design. It has certain guiding significance to the design of easy opening lid.
Rethinking User Experience Design: Sustainability in the Context of the User Centered Innovation Process in Power Tool Design
Authors: Grobelnik Manuel , Cakir Feyyaz , Friedmann Daniel-Philipp , Maul Ludwig
Published: June 2022

Sustainability is becoming increasingly important in product development: both for the manufacturing companies and for the users, who are increasingly questioning the product and its origin. While sustainability is recognised as a strategic factor in many companies, the focus in the operational process is still mainly on desirability, feasibility and profitability, while sustainability is not firmly anchored in the various process steps and thus not effectively operationalised. The aim of this research work is to develop a process that integrates sustainability as a common thread throughout the product development of power tools. For this purpose, a case study at Bosch Power Tools with 10 guideline-supported expert interviews and a workshop with 8 experts shows what requirements are placed on such a process and what such a process should ideally look like. The result is a multi-stage model that integrates the relevant sustainability aspects and thus makes them comprehensible and measurable for practitioners in innovation, design, and product development in medium sized and large organisations.
Dynamic Modeling and Simulation Analysis of Non-explosive Separation Device
Authors: Li Xuemei , Sun Beibei
Published: June 2022

In order to ensure reliable connection and separation between satellites and the launch vehicles, a dynamic modeling method of a certain type of non-explosive separation device based on contact theory is proposed to carry out more accurate results in this paper. After analysis on the actuation principle of the non-explosive separation device, the source of impact response is clarified. Then the contact model is established based on the contact theory and the dynamic simulation model is established. The dynamic simulation results show that the shock acceleration of housing is no more than 300g, it is consistent with the experimental results performed by other workers. The simulation model can be utilized for the design and validation of the non-explosive separation device to provide a reliable basis for subsequent optimization.
Pressure Distribution Prediction of Supercritical Airfoils at Multiple Flight Conditions Using Deep Learning Approach
Authors: MA Tuliang , XIE Hairun , WANG Jing
Published: June 2022

Supercritical airfoils are commonly found in modern civil airplanes. Effective access to pressure distribution around an airfoil under various flight situations is vital for enhancing the quality of supercritical airfoils. With the rapid development of deep learning, the rise of neural networks has provided new powerful tools for obtaining pressure distribution quickly. This paper proposed a deep learning based model to predict the surface pressure distribution around a supercritical airfoil under multiple flight conditions. The airfoil geometry parameters and various flight conditions are taken as input, and the corresponding surface pressure distributions are taken as output. The statistical results show that the proposed method is accurate and generalized in predicting pressure distributions around supercritical airfoils. Our method, in particular, achieves accurate prediction results over the double shock or strong shock area, demonstrating its superiority in handling complex flows.
Research on Parametric Design and Feature Modeling of Freight Ropeway Running Car of Transmission Line
Authors: MinJie ZHU , JianHua LI , KeYang XU , Chen LIU , Fei WANG
Published: June 2022

To improve the freight ropeway components design efficiency, the component structure design is carried out for the components of freight ropeway of transmission line using 3d design software by using parameter modification method. The parametric design and feature modeling of freight ropeway running car is proposed to realize components modelling, and analyse its force conditions to meet the strength requirements. The proposed method can improve the efficiency of freight ropeway structural design.
Integrated Frame Topology Optimization Design of Small Quadrotor UAV
Authors: Qu Jiaqi , Dong Yihao , Gu Xuechen , He Shaoming
Published: June 2022

In recent years, the development of UAV (Unmanned Aerial Vehicle) is rapid, but the development of structural design is slow, and the rack designed according to the experience of engineers still has great redundancy. With the rapid development of topology optimization and additive manufacturing, topology optimization design of integrated rack based on additive manufacturing is carried out. In the design process, manufacturing constraints are added and a variety of typical conditions to obtain the final optimization structure are considered. The influence of human empirical factors on the fuselage structure design is reduced scientifically and effectively by using this method. And the lightweight, topological and integrated design of the quadrotor frame is realized.
Methodological approach to assessing environmental risk (health risk) from air pollution in the Baikal region in a changing climate
Authors: Makosko A A , Matesheva A V
Published: June 2022

The methodological approach to assessing the environmental risk (health risk) from atmospheric pollution in the Baikal region taking into account the changing climate was formulated. It is based on the US EPA's health risk assessment methodology and impurity concentration estimates by solving the adjoint equation for impurities transport and diffusion. The dynamics of health risk for the population of Irkutsk from atmospheric pollution PM10, PM2.5 due to emissions from possible sources located both in the Baikal region and beyond including sources of transboundary pollution in 1980-2050 under various scenarios of climate change was researched. A tendency for a moderate decrease in the considered risk over the past several decades was shown. In the forecast period until 2050, under both climate scenarios, significant changes in the risk were not noted. The spatio-temporal dynamics of the areas of PM10, PM2.5 sources location that create the increased health risk in relation to Irkutsk was studied. The results indicate the moderate narrowing of the increased risk zone for Irkutsk in the first half of the 21st century. In the period until 2050, the main impact on the population health in the Irkutsk area from emission sources located in the southwest, south and southeast is expected. In case of transboundary pollution, the main danger from sources in Kazakhstan, Mongolia, and China is expected. The results are important to develop proposals for ensuring safety for public health, developing health care and planning environmental protection measures in the Baikal and neighboring regions.
Investigation of wind shear structure and turbulence characteristics in a warm front cloud system using a research aircraft
Authors: Volkov V V , Strunin A M , Kirin D V , Kolokutin G E , Strunin M A
Published: June 2022

The manuscript presents the results of study vertical and horizontal wind shears, the spectral characteristics of turbulence in the warm front cloud system with using the Yak-42D aircraft-laboratory. Within the As-Cs clouds at altitudes of 3 - 8 km, vertical wind shear increased sharply to 1.5 ms-1 per 100 m. At altitudes of 8 - 9 km, in the jet stream zone, vertical wind shear increased up to significant values of 3.0 ms-1 per 100 m. The maximum horizontal wind shear of 0.3 ms-1 per km was reached in As-Ns clouds at altitudes of 2 - 4 km. Anisotropy of turbulence with a predominance of horizontal wind fluctuations was observed in the stable layer at the altitude of 6000 m. The normalized spectra of the wind speed fluctuations in the lower part of the cloud system (at an altitude of about 3 km) corresponded to the stable layers of the atmosphere. The maximum value of 0.8 at the coherence spectra between the temperature and the vertical wind speed fluctuations was observed at the scales of 1200 m. It is noted that a solid Cs-As-Ns cloud system could be divided into sub-layers, depending on structure of wind shear and turbulence.
On the ratio of the components of the atmospheric vertical electric current density in fair weather
Authors: Anisimov S V , Galichenko S V , Prokhorchuk A A , Aphinogenov K V
Published: June 2022

This work presents the results of ground-based and tethered balloon observations of altitude profiles of the components of the atmospheric vertical electric current density. The magnitude of the conduction current density was observed in the range 0.2 - 2 pAm−2. The ratio of the negative to positive component of the conduction current density averaged 1.6 outside the layer, where their dependence on the height was noticeable. In the framework of developed numerical model with reasonable values of the parameters it is found that the ratio of the convection current density to the density of the total vertical atmospheric electric current in the atmospheric boundary layer mainly falls in the range 0.2 - 0.6 and tends to increase under strong convection and low electrical conductivity. An exponential parameterization of the dependence of the electromotive force on the ground-level electrical conductivity is proposed.
Aleurite particle concentration profiles in the surface layer of the atmosphere on desertificated areas
Authors: Gushchin R A , Gorchakov G I , Karpov A V
Published: June 2022

The large particle mass flux profile measurement at heights from 0.125 to 16 m and parameters of the size distribution function received by O.E. Semenov on the desertificated areas in the Aral region were analyzed. The technique has been worked out for the large particle height profile characteristic retrieving. The aleurite particle number concentration profiles with sizes less than 50, 73 and 100 μm and sand particle concentration have been retrieved. Power-law approximations of the vertical aleurite and sand particles concentrations profiles are proposed.
Application of wavelet analysis methods to study the climate of the Arctic region
Authors: Solovyev DA , Nefedova LV
Published: June 2022

This paper provides an assessment of the possibilities and advantages of using wavelet analysis methods in the study of regional mechanisms of climate formation in the Arctic region by analyzing the relationship between the values of the air temperature anomalies at the Earth's surface and the North Atlantic Oscillation index. It is shown that the methods of wavelet analysis of climatic indices have certain advantages for identifying cyclical changes in climatic characteristics on local time scales and allow an in-depth spectral assessment. The conducted wavelet analysis of the NAO and SAT index (1950-2020) made it possible to estimate the previously known natural quasi-cyclic oscillations with a typical period of 7-15 years and other dominant components of their spectrum.
Tropical correspondence for smooth del Pezzo log Calabi-Yau pairs
Authors: Graefnitz Tim
Published: June 2022

Consider a log Calabi-Yau pair

(
X
,
D
)

(X,D)

consisting of a smooth del Pezzo surface

X
X

of degree

≥
3

\geq 3

and a smooth anticanonical divisor

D
D

. We prove a correspondence between genus zero logarithmic Gromov-Witten invariants of

X
X

intersecting

D
D

in a single point with maximal tangency and the consistent wall structure appearing in the dual intersection complex of

(
X
,
D
)

(X,D)

from the Gross-Siebert reconstruction algorithm. More precisely, the logarithm of the product of functions attached to unbounded walls in the consistent wall structure gives a generating function for these invariants.
Ultra-Processed Foods Consumption Increases the Risk of Hypertension in Adults: A Systematic Review and Meta-Analysis
Authors: Wang Mei , Du Xinyi , Huang Wei , Xu Yong
Published: June 2022

Background

Effect of ultra-processed foods (UPFs) consumption on health has attracted widespread attention in recent years. However, the relationship between UPFs consumption and hypertension is unclear. This meta-analysis was conducted to analyze the above association.

Methods

We systematically searched PubMed, Embase, and Cochrane Library for all relevant studies published up to 31 January 2022 without language limitation. The random-effects model was selected to pool the effect sizes and 95% confidence intervals (CIs).

Results

Nine observational studies involving 111,594 participants were included. Results from this meta-analysis showed that higher UPFs consumption significantly increased the risk of hypertension (odds ratio: 1.23; 95% CI: 1.11, 1.37; P = 0.034). Furthermore, analyses were performed based on gender, study design, exposure assessment, outcome assessment, body mass index, energy intake, and physical activity, which suggested that the results remained statistically significant.

Conclusions

Our findings suggested that UPFs might have detrimental effects on the incidence of hypertension in the general population. Although current evidence is limited, it cannot be denied that reducing consumption of UPFs may contribute to decrease the risk of chronic noncommunicable diseases.
Proteomic analysis of nascent polypeptide chains that potentially induce translational pausing during elongation
Authors: Shimohata Nobuyuki , Harada Yudai , Hayano Toshiya
Published: June 2022

Currently, proteins equipped with “ribosomal arrest peptides” (RAPs) that regulate the expression of downstream genes and their own activity by pausing their own translation during elongation are extensively studied. However, studies focusing on RAP have been conducted primarily in prokaryotic cells; studies on eukaryotic cells, especially mammalian cells, are limited. In the present study, we comprehensively examined translationally arrested nascent polypeptides to gain novel insights into RAPs in mammalian cells. Cetyltrimethylammonium bromide was used to obtain nascent polypeptide chains that were translationally arrested during translation elongation. After proteomic analysis, additional screening by discriminating according to amino acid residues at the C-terminal end revealed several novel RAP candidates. Our method can be applied for comprehensive RAP studies in mammalian cells.
Glutamate can act as a signaling molecule in mouse preimplantation embryos
Authors: Špirková Alexandra , Kovaříková Veronika , Šefčíková Zuzana , Pisko Jozef , Kšiňanová Martina , Koppel Juraj , Fabian Dušan , Čikoš Štefan
Published: June 2022

Free amino acids are present in the natural environment of the preimplantation embryo, and their availability can influence early embryo development. Glutamic acid is one of the amino acids with the highest concentrations in female reproductive fluids, and we investigated whether glutamic acid/glutamate can affect preimplantation embryo development by acting through cell membrane receptors. Using reverse transcription-polymerase chain reaction, we detected 15 ionotropic glutamate receptor transcripts and 8 metabotropic glutamate receptor transcripts in mouse ovulated oocytes and/or in vivo developed blastocysts. Using immunohistochemistry, we detected the expression of two α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits, three kainate receptor subunits, and member 5 metabotropic glutamate receptor protein in blastocysts. Extracellular concentrations of glutamic acid starting at 5 mM impaired mouse blastocyst development, and this fact may be of great practical importance since glutamic acid and its salts (mainly monosodium glutamate) are widely used as food additives. Experiments with glutamate receptor agonists (in combination with gene expression analysis) revealed that specific AMPA receptors (formed from glutamate receptor, ionotropic, AMPA3 [GRIA3] and/or glutamate receptor, ionotropic, AMPA4 [GRIA4] subunits), kainate receptors (formed from glutamate receptor, ionotropic, kainate 3 [GRIK3] and glutamate receptor, ionotropic, kainate 4 [GRIK4] or glutamate receptor, ionotropic, kainate 5 [GRIK5] subunits), and member 5 metabotropic glutamate receptor (GRM5) were involved in this effect. The glutamic acid-induced effects were prevented or reduced by pretreatment of blastocysts with AMPA, kainate, and GRM5 receptor antagonists, further confirming the involvement of these receptor types. Our results show that glutamic acid can act as a signaling molecule in preimplantation embryos, exerting its effects through the activation of cell membrane receptors.
Endophytic fungi and their bioactive secondary metabolites in medicinal leguminosae plants: nearly untapped medical resources
Authors: Zhou Zhong-Ya , Liu Xi , Cui Jin-Long , Wang Jun-Hong , Wang Meng-Liang , Zhang Gang
Published: June 2022

There are many species of Chinese traditional leguminosae family plants that are well known for their medicinal applications, such as Astragalus membranaceus, Catsia tora, Glycyrrhiza uralensis, Sophora flavescens and Albacia acacia. Their unique bioactive composition and internal phenological environment contribute to the formation of specific and unique endophytic fungal communities, which are important resources for new compounds used in a variety of pharmacological activities. Nonetheless, they have not been systematically studied. In the last decade, nearly 64 genera and thousands of species of endophytic fungi have been discovered from leguminosae plants, as well as 138 secondary metabolites (with 34 new compounds) including flavonoid, alkaloids, phenol, anthraquinone, macrolide, terpenoid, phytohormone and many more. These were shown to have diverse applications and benefits, such as antibacterial, antitumor, antioxidative, immunoregulatory and neuroprotective properties. Here, we provide a summarized overview with the aim of raising awareness of endophytic fungi from medicinal leguminosae plants and providing a comprehensive review of the discoveries of new natural products that may be of medicinal and pharmaceutical importance.
From sink to source: changing climate and disturbance regimes could tip the 21st century carbon balance of an unmanaged mountain forest landscape
Authors: Albrich Katharina , Seidl Rupert , Rammer Werner , Thom Dominik
Published: June 2022

Forests are one of the most important components of the global carbon cycle. Consequently, forest protection as a nature-based climate solution has garnered increasing interest. Protected areas instated to safeguard biodiversity provide an opportunity to maximize carbon storage in situ, with important co-benefits between conservation and climate change mitigation. However, changing climate and disturbance regimes put this carbon storage function at risk. Here we investigated carbon sequestration and storage in a protected landscape in the German Alps (Berchtesgaden National Park) throughout the 21st century. We simulated the impacts of climate change as well as increasing wind and bark beetle disturbances on cumulative Net Ecosystem Production using a process-based forest landscape model. Considering a wide range of potential changes in wind frequency and speed under a variety of climate change scenarios, we addressed the question under which future conditions the landscape will turn from a carbon sink to a carbon source. While the landscape was a net carbon sink at the end of the simulation in 76 per cent of the simulation runs, increasing disturbances and climate change greatly reduced its carbon sink capacity. Under RCP2.6, the landscape remained a robust carbon sink even under elevated disturbance (probability of turning from sink to source between 0 per cent and 25 per cent). In contrast, carbon release was likely under RCP8.5 even with little change in the disturbance regime (probability: 30 per cent to 95 per cent). Productive areas in lower elevations that currently have the highest carbon density on the landscape were contributing most strongly to a reduction of the carbon sink strength. Our study reveals that the effect of protected areas acting as nature-based climate solutions might be overestimated if the risks from changing climate and disturbance regimes are neglected. We therefore call for a more explicit consideration of future forest dynamics in the discussion of the potential role of forests in climate change mitigation.
Altering enhancer–promoter linear distance impacts promoter competition in cis and in trans
Authors: Bateman Jack R , Johnson Justine E
Published: June 2022

In Drosophila, pairing of maternal and paternal homologs can permit trans-interactions between enhancers on one homolog and promoters on another, an example of a phenomenon called transvection. When chromosomes are paired, promoters in cis and in trans to an enhancer can compete for the enhancer’s activity, but the parameters that govern this competition are as yet poorly understood. To assess how the linear spacing between an enhancer and promoter can influence promoter competition in Drosophila, we employed transgenic constructs wherein the eye-specific enhancer GMR is placed at varying distances from a heterologous hsp70 promoter driving a fluorescent reporter. While GMR activates the reporter to a high degree when the enhancer and promoter are spaced by a few hundred base pairs, activation is strongly attenuated when the enhancer is moved 3 kb away. By examining transcription of endogenous genes near the point of transgene insertion, we show that linear spacing of 3 kb between GMR and the hsp70 promoter results in elevated transcription of neighboring promoters, suggesting a loss of specificity between the enhancer and its intended transgenic target promoter. Furthermore, increasing spacing between GMR and hsp70 by just 100 bp can enhance transvection, resulting in increased activation of a promoter on a paired homolog at the expense of a promoter in cis to the enhancer. Finally, cis-/trans-promoter competition assays in which one promoter carries mutations to key core promoter elements show that GMR will skew its activity toward a wild-type promoter, suggesting that an enhancer is in a balanced competition between its potential target promoters in cis and in trans.
ST6Gal1 in plasma is dispensable for IgG sialylation
Authors: Oswald Douglas M , Lehoux Sylvain D , Zhou Julie Y , Glendenning Leandre M , Cummings Richard D , Cobb Brian A
Published: June 2022

The glycosylation of immunoglobulin G (IgG) has attracted increased attention due to the impact of N-glycan modifications at N297 on IgG function, acting primarily through modulation of Fc domain conformation and Fcγ receptor-binding affinities and signaling. However, the mechanisms regulating IgG glycosylation and especially α2,6-sialylation of its N-glycan remain poorly understood. We observed previously that IgG is normally sialylated in mice with B cells lacking the sialyltransferase ST6Gal1. This supported the hypothesis that IgG may be sialylated outside of B cells, perhaps through the action of hepatocyte-released plasma ST6Gal1. Here, we demonstrate that this model is incorrect. Animals lacking hepatocyte expressed ST6Gal1 retain normal IgG α2,6-sialylation despite the lack of detectable ST6Gal1 in plasma. Moreover, we confirmed that B cells were not a redundant source of IgG sialylation. Thus, while α2,6-sialylation is lacking in IgG from mice with germline ablation of ST6Gal1, IgG α2,6-sialylation is normal in mice lacking ST6Gal1 in either hepatocytes or B cells. These results indicate that IgG α2,6-sialylation arises after release from a B cell but is not dependent on plasma-localized ST6Gal1 activity.
Appendix and Ulcerative Colitis: a Key to Explaining the Pathogenesis and Directing Novel Therapies?
Authors: Arjomand Fard Nazanin , Armstrong Heather , Perry Troy , Wine Eytan
Published: June 2022

The vermiform appendix is generally considered a redundant organ, but recent evidence suggests that the appendix could contribute to the pathogenesis of inflammatory bowel diseases, in particular ulcerative colitis (UC), and may even have a therapeutic role; however, mechanisms of the appendix involvement remain unclear. Here, we highlight current evidence on the link between the appendix and UC and consider plausible therapeutic implications. A literature search was conducted using PubMed and PubMed Central from inception to Nov 2021 using the terms “Appendix”, “UC”, “Appendix & UC,” “Appendectomy”, and “Peri-appendicular patch,” including only articles published in English. Reference lists from the selected studies were manually searched and reviewed to gather additional related reports. Inflammation around the appendix (“peri-appendicular patch”) has been frequently observed in UC patients without other cecal involvement, and this inflammation can even precede the onset of UC. Epidemiologic studies propose that appendectomy reduces the risk of developing UC or even the risk of flare after UC is diagnosed, although this remains controversial. We reviewed studies showing altered host-microbe interactions in the appendix in UC, which suggest that the appendix could act as a priming site for disease via alterations in the immune response and changes in microbiota carried distally to the colon. In summary, recent literature suggests a possible role for microbes and immune cells within the appendix; however, the role of the appendix in the pathogenesis of UC remains unclear. Further research could clarify the therapeutic potential related to this organ.
MiRNA-Based Therapies for the Treatment of Inflammatory Bowel Disease: What Are We Still Missing?
Authors: Innocenti Tommaso , Bigagli Elisabetta , Lynch Erica Nicola , Galli Andrea , Dragoni Gabriele
Published: June 2022

Micro-RNAs (miRNAs) are noncoding RNAs usually 24-30 nucleotides long that play a central role in epigenetic mechanisms of inflammatory diseases and cancers. Recently, several studies have assessed the involvement of miRNAs in the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated neoplasia. Particularly, it has been shown that many members of miRNAs family are involved in the pathways of inflammation and fibrogenesis of IBD; therefore, their use as inflammatory and fibrosis biomarkers has been postulated. In light of these results, the role of miRNAs in IBD therapy has been proposed and is currently under investigation with many in vitro and in vivo studies, murine models, and a phase 2a trial. The accumulating data have pushed miRNA-based therapy closer to clinical practice, although many open questions remain.

With this systematic review, we discuss the current knowledge about the therapeutic effects of miRNAs mimicking and inhibition, and we explore the new potential targets of miRNA family for the treatment of inflammation and fibrosis in IBD.
Behavioural responses of wild anadromous Arctic char experimentally infested in situ with salmon lice
Authors: Strøm John Fredrik , Bjørn Pål Arne , Bygdnes Eirik Emil , Kristiansen Lars , Skjold Bjørnar , Bøhn Thomas
Published: June 2022

Salmon lice can impact the marine behaviour, growth, and survival of salmonids, but little is known about their effects on Arctic char. We present behavioural responses from the first dose-response experiment with wild anadromous Arctic char (n = 50) infested in situ with salmon lice (0.0–1.2 lice g−1 fish) in an area with low natural infestations. Infested fish spent less time at sea (mean ± SD = 22 ± 6 d) than non-infested fish (mean ±SD = 33 ± 5 d), and a significant dose response was evident, with even very low louse burdens (<0.05 lice g−1 fish) reducing the marine feeding time. Furthermore, a negative correlation was present between time spent close to their native watercourse and parasite burden, suggesting that salmon lice influence the marine habitat use of Arctic char. No impact of salmon lice was evident on the return probability, i.e. marine survival. However, the presence of louse-induced mortality cannot be excluded as the modest sample size was only sufficient to detect extreme effects. Reduced marine feeding time and altered marine habitat use will likely have substantial negative effects on growth and fitness, suggesting that impacts of salmon lice must be considered in the conservation of anadromous Arctic char.
User Interface Evaluation of Design Alternatives of the Emotion-Libras—An Emotional Self-Report Instrument for Sign Language Users
Authors: Prietch Soraia Silva , Paim Polianna dos Santos , Miranda Flabiéli , Nogueira Camila Soncini , Leite Vanuza
Published: June 2022

For researchers interested in analyzing participants’ self-reflection about their emotional experience during user studies, having an instrument designed for a specific target user can be seen to show empathy for providing socio-cultural elements that involved parties feel a connection with. In user studies, communication mediation between sign language users and non-signers may include a bias; therefore, direct communication between the involved parties is welcome to reduce this risk and expand sign language users’ autonomy. This paper presents the Emotion-Libras, a self-report instrument to collect emotional responses of sign language users after interacting with technology and report findings from a user study. We conducted a focus group with five sign language users to collect their perceptions regarding the three design alternatives of the instrument. As a result, participants selected the best-fitted design interface of the instrument and also found room for improvement in video quality, language choice, written labels and user control.
Creating a framework to align antimicrobial resistance (AMR) research with the global guidance: a viewpoint
Authors: Mitchell Jessica , O’Neill Alex J , King Rebecca
Published: June 2022

We describe here an initial analysis of national and international guidance documents on antimicrobial resistance (AMR) to propose a framework to align AMR research activities with global guidance. The framework provides a summary roadmap for core activities in AMR research and highlights the need for interdisciplinary and One Health collaboration. This analysis also revealed limitations in the current guidance, including a lack of explicit mention of some research activities highly relevant to AMR and a dearth of concrete objectives; consequently, an over-reliance on global guidance could be funnelling research efforts down a generic trajectory without regard to contextual factors. We suggest this framework be used by academics and policymakers to align AMR research and guidance. However, we recommend that deeper exploration be undertaken to fully contextualize the development of meaningful questions based on current knowledge, methodologies and gap analyses.
Fast and Sensitive Method for the Determination of 17 Designer Benzodiazepines in Hair by Liquid Chromatography–Tandem Mass Spectrometry
Authors: DeFreitas Laura , Fonseca Pego Ana Miguel , Kronstrand Robert , Lendoiro Elena , de Castro-Ríos Ana , Concheiro Marta
Published: June 2022

In recent years, identification and analysis of designer benzodiazepines have become a challenge in forensic toxicology. These substances are analogs of the classic benzodiazepines, but their pharmacology is not well known, and many of them have been associated with overdoses and deaths. As a result, there has been a surge in efforts to develop analytical methods to determine these compounds in different biological samples. Our aim was to develop and validate a fast, sensitive and specific method for determining 17 designer benzodiazepines (adinazolam, clobazam, clonazolam, delorazepam, deschloroetizolam, diclazepam, etizolam, flualprazolam, flubromazepam, flubromazolam, flunitrazolam, N-desmethylclobazam, nifoxipam, nitrazolam, meclonazepam, pyrazolam and zolazepam) in hair by liquid chromatography–tandem mass spectrometry (LC–MS-MS). Hair samples were decontaminated and pulverized, and a 20 mg aliquot was incubated in methanol in an ultrasound bath (1 h, 25°C). The supernatant was evaporated and reconstituted in 200 µL of mobile phase, and the extracts were filtered (nano-filter vials) before injection into LC–MS-MS. All analytes were eluted from the chromatographic column in 8 min, and two multiple-reaction monitoring (MRM) transitions were used to identify each compound. The limits of quantification were 5 or 25 pg/mg depending on the analyte, and the calibration functions were linear to 200 pg/mg. Imprecision was <19.2% (n = 15), and bias was from −13.7 to 18.3% (n = 15). All the analytes yielded high extraction efficiencies >70% and displayed ion suppression between −62.8% and −23.9% (n = 10). The method was applied to 19 authentic cases. Five samples were positive for flualprazolam ( 200 pg/mg) and/or etizolam (47.4–88.5 pg/mg). In conclusion, the present validated method has proven to be fast, sensitive, specific and capable of determining 17 designer benzodiazepines in hair using LC–MS-MS.