Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer.

Activation of heterotrimeric G-proteins (Gαßγ) by G-protein-coupled receptors (GPCRs) is a quintessential mechanism of cell signaling widely targeted by clinically approved drugs. However, it has become evident that heterotrimeric G-proteins can also be activated via GPCR-independent mechanisms that remain untapped as pharmacological targets. GIV/Girdin has emerged as a prototypical non-GPCR activator of G proteins that promotes cancer metastasis. Here, we introduce IGGi-11, a first-in-class small-molecule inhibitor of noncanonical activation of heterotrimeric G-protein signaling. IGGi-11 binding to G-protein α-subunits (Gαi) specifically disrupted their engagement with GIV/Girdin, thereby blocking noncanonical G-protein signaling in tumor cells and inhibiting proinvasive traits of metastatic cancer cells. In contrast, IGGi-11 did not interfere with canonical G-protein signaling mechanisms triggered by GPCRs. By revealing that small molecules can selectively disable noncanonical mechanisms of G-protein activation dysregulated in disease, these findings warrant the exploration of therapeutic modalities in G-protein signaling that go beyond targeting GPCRs.

An essential protease, FtsH, influences daptomycin resistance acquisition in Enterococcus faecalis.

Daptomycin is a last-line antibiotic commonly used to treat vancomycin-resistant Enterococci, but resistance evolves rapidly and further restricts already limited treatment options. While genetic determinants associated with clinical daptomycin resistance (DAPR) have been described, information on factors affecting the speed of DAPR acquisition is limited. The multiple peptide resistance factor (MprF), a phosphatidylglycerol-modifying enzyme involved in cationic antimicrobial resistance, is linked to DAPR in pathogens such as methicillin-resistant Staphylococcus aureus. Since Enterococcus faecalis encodes two paralogs of mprF and clinical DAPR mutations do not map to mprF, we hypothesized that functional redundancy between the paralogs prevents mprF-mediated resistance and masks other evolutionary pathways to DAPR. Here, we performed in vitro evolution to DAPR in mprF mutant background. We discovered that the absence of mprF results in slowed DAPR evolution and is associated with inactivating mutations in ftsH, resulting in the depletion of the chaperone repressor HrcA. We also report that ftsH is essential in the parental, but not in the ΔmprF, strain where FtsH depletion results in growth impairment in the parental strain, a phenotype associated with reduced extracellular acidification and reduced ability for metabolic reduction. This presents FtsH and HrcA as enticing targets for developing anti-resistance strategies.

Assessment of longitudinal dispersion and flow resistance near floodplains through riparian woodlands.

Riparian woodlands prevent bank erosions, recycle minerals, sustain biodiversity, act as flow resistance on floodplains, and filter pollutants. The emergent trees characterize woodlands with different spacing arrangements that dictate flow resistance and longitudinal dispersion of the pollutants in compound channel flow. The single- and multistage compound channels exist in urban and natural watercourses with riparian and transplanted trees on different stages of the floodplain. This study numerically validates the planting of vegetation in lines on single- and multistage floodplains using a wall-modeled large-eddy simulation model. Post-validation, the focus of the study was to assess the hydrodynamic behavior and mixing around the floodplain and main channel section of different tested configurations. The approximation of flow structures for the various configurations of tree plantations shows stronger vortices with significant characteristic length scales for floodplains closer to the main channel. The intensity of the secondary current is higher for denser planted trees at junctions of floodplains. For higher flow events, drag force contributions for staged floodplains with trees on both stages are 45-41%, and trees on the top stage contribute 27-22% to the total frictional force budget. The subsequent investigation shows that the in-line trees geometrical configuration and spacing arrangement on the floodplain dictates flow resistance and longitudinal dispersion of the pollutants and contamination in channel flow. The results show that the overall reduction in discharge for floodplains with tree planting is 19.8-36.2% for single-stage and 10.4-23.6% for multistage compound channels. The longitudinal dispersion coefficients for each multi-zone model predict a 61% and 41% dispersion reduction, respectively, in single- and multistage floodplains with planted trees. Floodplains with denser tree spacing have a maximum zonal discharge reduction of 45% for a single-stage and 27.2% and 28.0% for multistage channels. These findings strongly suggest that the planting parameters of spacing-to-diameter ratio and floodplain geometry play a pivotal role in floodplain management from the perspective of contaminant dispersion and flood risk reduction during high-flow events.

Immunomodulation of Antibody Glycosylation through the Placental Transfer.

Establishing an immune balance between the mother and fetus during gestation is crucial, with the placenta acting as the epicenter of immune tolerance. The placental transfer of antibodies, mainly immunoglobulin G (IgG), is critical in protecting the developing fetus from infections. This review looks at how immunomodulation of antibody glycosylation occurs during placental transfer and how it affects fetal health. The passage of maternal IgG antibodies through the placental layers, including the syncytiotrophoblast, stroma, and fetal endothelium, is discussed. The effect of IgG subclass, glycosylation, concentration, maternal infections, and antigen specificity on antibody transfer efficiency is investigated. FcRn-mediated IgG transport, influenced by pH-dependent binding, is essential for placental transfer. Additionally, this review delves into the impact of glycosylation patterns on antibody functionality, considering both protective and pathological effects. Factors affecting the transfer of protective antibodies, such as maternal vaccination, are discussed along with reducing harmful antibodies. This in-depth examination of placental antibody transfer and glycosylation provides insights into improving neonatal immunity and mitigating the effects of maternal autoimmune and alloimmune conditions.

Evaluation of infection probability of Covid-19 in different types of airliner cabins.

According to the World Health Organization (https://covid19.who.int/), more than 651 million people have been infected by COVID-19, and more than 6.6 million of them have died. COVID-19 has spread to almost every country in the world because of air travel. Cases of COVID-19 transmission from an index patient to fellow passengers in commercial airplanes have been widely reported. This investigation used computational fluid dynamics (CFD) to simulate airflow and COVID-19 virus (SARS-CoV-2) transport in a variety of airliner cabins. The cabins studied were economy-class with 2-2, 3-3, 2-3-2, and 3-3-3 seat configurations, respectively. The CFD results were validated by using experimental data from a seven-row cabin mockup with a 3-3 seat configuration. This study used the Wells-Riley model to estimate the probability of infection with SARS-CoV-2. The results show that CFD can predict airflow and virus transmission with acceptable accuracy. With an assumed flight time of 4 h, the infection probability was almost the same among the different cabins, except that the 3-3-3 configuration had a lower risk because of its airflow pattern. Flying time was the most important parameter for causing the infection, while cabin type also played a role. Without mask wearing by the passengers and the index patient, the infection probability could be 8% for a 10-h, long-haul flight, such as a twin-aisle air cabin with 3-3-3 seat configuration.

Integrated analysis identified prognostic microRNAs in breast cancer.

BACKGROUND: MicroRNAs (miRNAs) play pivotal roles in the development and progression of breast cancer (BC). In this study, we attempted to identify miRNAs associated with BC prognosis and progression via integrated analysis. METHODS: We first screened 83 differentially expressed miRNAs (DEMs) in 1249 BC samples and 151 normal samples. We then validated their roles in expression and prognosis of BC, identified two survival-related DEMs, and established a risk model. The prediction efficiency was assessed in both the training and validation groups. Tissue and cell experiments were conducted to verify the regulatory effects of miR-127 in BC. RESULTS: The ROC curve indicated good prediction ability with 1-, 3-, and 5-year survival rates of 0.73, 0.72, and 0.72, respectively. Moreover, hsa-miR-127 was found to be an independent prognostic factor of BC. Functional analyses revealed that it is involved in various cancer pathways such as the PI3K-Akt and p53 pathways. miR-127 expression was down-regulated in both BC tissues and cell lines. The knockdown of miR-127 substantially increased, whereas overexpression decreased BC cell proliferation, invasion, and migration. This effect of miR-127 was consistent with its tumorigenic ability and tumor volume in nude mice. CONCLUSIONS: These findings indicate that low expression of miR-127 contributes to BC migration, invasion, and tumorigenesis and that it can be a therapeutic target and prognostic biomarker for BC.

What is suitable social distancing for people wearing face masks during the COVID-19 pandemic?

COVID-19 has caused the global pandemic and had a serious impact on people's daily lives. The respiratory droplets produced from coughing and talking of an infected patient were possible transmission routes of coronavirus between people. To avoid the infection, the US Centers for Disease Control and Prevention (CDC) advised to wear face masks while maintaining a social distancing of 2 m. Can the social distancing be reduced if people wear masks? To answer this question, we measured the mass of inhaled droplets by a susceptible manikin wearing a mask with different social distances, which was produced by coughing and talking of an index "patient" (human subject) also wearing a mask. We also used the computational fluid dynamics (CFD) technology with a porous media model and particle dispersion model to simulate the transmission of droplets from the patient to the susceptible person with surgical and N95 masks. We compared the CFD results with the measured velocity in the environmental chamber and found that the social distancing could be reduced to 0.5 m when people wearing face masks. In this case, the mass concentration of inhaled particles was less than two people without wearing masks and with a social distancing of 2 m. Hence, when the social distancing was difficult, wearing masks could protect people. We also found that the leakage between the face mask and the human face played an important role in the exhaled airflow pattern and particle dispersion. The verified numerical model can be used for more scenarios with different indoor environments and HVAC systems. The results of this study would make business profitable with reduced social distancing in transportation, education, and entertainment industries, which was beneficial for the reopening of the economy.

Virus transport and infection evaluation in a passenger elevator with a COVID-19 patient.

Contaminant transport and flow distribution are very important during an elevator ride, as the reduced social distancing may increase the infection rate of airborne diseases such as COVID-19. Studying the airflow and contaminant concentration in an elevator is not straightforward because the flow pattern inside an elevator changes dramatically with passenger movement and frequent door opening. Since very little experimental data were available for elevators, this investigation validated the use of computational fluid dynamics (CFD) based on the RNG k- ∈ $$ \in $$ turbulence model to predict airflow and contaminant transport in a scaled, empty airliner cabin with a moving passenger. The movement of the passenger in the cabin created a dynamic airflow and transient contaminant dispersion that were similar to those in an elevator. The computed results agreed reasonably well with the experimental data for the cabin. The validated CFD program was then used to calculate the distributions of air velocity, air temperature, and particle concentration during an elevator ride with an index patient. The CFD results showed that the airflow pattern in the elevator was very complex due to the downward air supply from the ceiling and upward thermal plumes generated by passengers. This investigation studied different respiratory activities of the index patient, that is, breathing only, breathing, and coughing with and without a mask, and talking. The results indicated that the risk of infection was generally low because of the short duration of the elevator ride. If the index patient talked in the elevator, two passengers in the closest proximity to distance would be infected.

Recent progress on studies of airborne infectious disease transmission, air quality, and thermal comfort in the airliner cabin air environment.

Airborne transmission of infectious diseases through air travel has become a major concern, especially during the COVID-19 pandemic. The flying public and crew members have long demanded better air quality and thermal comfort in commercial airliner cabins. This paper reviewed studies related to the airliner cabin air environment that have been published in scientific journals since 2000, to understand the state-of-the-art in cabin air environment design and the efforts made to improve this environment. In this critical review, this paper discusses the challenges and opportunities in studying the cabin air environment. The literature review concluded that current environmental control systems for airliner cabins have done little to stop the airborne transmission of infectious diseases. There were no reports of significant air quality problems in cabins, although passengers and crew members have complained of some health-related issues. The air temperature in cabins needs to be better controlled, and therefore, better thermal comfort models for airliners should be developed. Low humidity is a major complaint from passengers and crew members. Gaspers are used by passengers to adjust thermal comfort, but they do not improve air quality. Various personalized and displacement ventilation systems have been developed to improve air quality and thermal comfort. Air cleaning technologies need to be further developed. Good tools are available for designing a better cabin air environment.

Evaluation of SARS-COV-2 transmission and infection in airliner cabins.

Commercial airliners have played an important role in spreading the SARS-CoV-2 virus worldwide. This study used computational fluid dynamics (CFD) to simulate the transmission of SARS-CoV-2 on a flight from London to Hanoi and another from Singapore to Hangzhou. The dispersion of droplets of different sizes generated by coughing, talking, and breathing activities in a cabin by an infected person was simulated by means of the Lagrangian method. The SARS-CoV-2 virus contained in expiratory droplets traveled with the cabin air distribution and was inhaled by other passengers. Infection was determined by counting the number of viral copies inhaled by each passenger. According to the results, our method correctly predicted 84% of the infected/uninfected cases on the first flight. The results also show that wearing masks and reducing conversation frequency between passengers could help to reduce the risk of exposure on the second flight.

Airborne transmission of COVID-19 virus in enclosed spaces: An overview of research methods.

Since the outbreak of COVID-19 in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has spread worldwide. This study summarized the transmission mechanisms of COVID-19 and their main influencing factors, such as airflow patterns, air temperature, relative humidity, and social distancing. The transmission characteristics in existing cases are providing more and more evidence that SARS CoV-2 can be transmitted through the air. This investigation reviewed probabilistic and deterministic research methods, such as the Wells-Riley equation, the dose-response model, the Monte-Carlo model, computational fluid dynamics (CFD) with the Eulerian method, CFD with the Lagrangian method, and the experimental approach, that have been used for studying the airborne transmission mechanism. The Wells-Riley equation and dose-response model are typically used for the assessment of the average infection risk. Only in combination with the Eulerian method or the Lagrangian method can these two methods obtain the spatial distribution of airborne particles' concentration and infection risk. In contrast with the Eulerian and Lagrangian methods, the Monte-Carlo model is suitable for studying the infection risk when the behavior of individuals is highly random. Although researchers tend to use numerical methods to study the airborne transmission mechanism of COVID-19, an experimental approach could often provide stronger evidence to prove the possibility of airborne transmission than a simple numerical model. All in all, the reviewed methods are helpful in the study of the airborne transmission mechanism of COVID-19 and epidemic prevention and control.

HEPA filters for airliner cabins: State of the art and future development.

The airliner cabin environment is very important to the health of passengers and crew members, and the use of high-efficiency particulate air (HEPA) filters for recirculated air in the environmental control systems (ECS) is essential for the removal of airborne particles such as SARS CoV-2 aerosols. A HEPA filter should be high efficiency, low-pressure drop, high dust-holding capacity (DHC), lightweight, and strong for use in aircraft. We conducted an experimental study on 23 HEPA filters with glass fiber media that are used in different commercial airliner models. The tested filters had a median filtration efficiency of >99.97% for particles with a diameter of 0.3-0.5 µm, a pressure drop of 134-412 Pa at rated airflow rate, and a DHC of 32.2-37.0 g/m2 . The use of nanofiber media instead of glass fiber media can reduce the pressure drop by 66.4%-94.3% and significantly increase the quality factor by analysis of literature data. The disadvantages of poor fire resistance and small DHC can be overcome by the use of flame-retardant polymers and fiber structural design. As a new lightweight and environmentally friendly filter material, nanofiber media could be used as air filters in ECS in the future.

Application of data-driven RANS model in simulating indoor airflow.

The indoor environment has a significant impact on our wellbeing. Accurate prediction of the indoor air distribution can help to create a good indoor environment. Reynolds-averaged Navier-Stokes (RANS) models are commonly used for indoor airflow prediction. However, the Boussinesq hypothesis used in the RANS model fails to account for indoor anisotropic flows. To solve this problem, this study developed a data-driven RANS model by using a nonlinear model from the literature. An artificial neural network (ANN) was used to determine the coefficients of high-order terms. Three typical indoor airflows were selected as the training set to develop the model. Four other cases were used as testing sets to verify the generalizability of the model. The results show that the data-driven model can better predict the distributions of air velocity, temperature, and turbulent kinetic energy for the indoor anisotropic flows than the original RANS model. This is because the nonlinear terms are accurately simulated by the ANN. This investigation concluded that the data-driven model can correctly predict indoor anisotropic flows and has reasonably good generalizability.

A model to evaluate ozone distribution and reaction byproducts in aircraft cabin environments.

Ozone and byproducts of ozone-initiated reactions are among the primary pollutants in aircraft cabins. However, investigations of the spatial distribution and reaction mechanisms of these pollutants are insufficient. This study established a computational fluid dynamics-based model to evaluate ozone and byproduct distribution, considering ozone reactions in air, adsorption onto surfaces, and byproduct desorption from surfaces. The model was implemented in an authentic single-aisle aircraft cabin and validated by measurements recorded during the aircraft cruise phase. Ozone concentrations in the supply air-dominated area were approximately 50% higher than that in the passenger breathing zone, suggesting that human surfaces represent a significant ozone sink. The deposition velocity onto human bodies was 21.83 m/h, surpassing 3.97 m/h on other cabin interior surface areas. Our model provides a mechanistic tool to analyze ozone and byproduct concentration distributions, which would be useful for assessing passenger health risks and for developing strategies for healthier aircraft cabin environments.

High-Amylose Corn Starch Regulated Gut Microbiota and Serum Bile Acids in High-Fat Diet-Induced Obese Mice.

High-amylose corn starch is well known for its anti-obesity activity, which is mainly based on the regulatory effects on gut microbiota. Recently, the gut microbiota has been reported to improve metabolic health by altering circulating bile acids. Therefore, in this study, the influence of high-amylose corn starch (HACS) on intestinal microbiota composition and serum bile acids was explored in mice fed with a high fat diet (HFD). The results demonstrated HACS treatment reduced HFD-induced body weight gain, hepatic lipid accumulation, and adipocyte hypertrophy as well as improved blood lipid profiles. Moreover, HACS also greatly impacted the gut microbiota with increased Firmicutes and decreased Bacteroidetes relative abundance being observed. Furthermore, compared to ND-fed mice, the mice with HFD feeding exhibited more obvious changes in serum bile acids profiles than the HFD-fed mice with the HACS intervention, showing HACS might restore HFD-induced alterations to bile acid composition in blood. In summary, our results suggested that the underlying mechanisms of anti-obesity activity of HACS may involve its regulatory effects on gut microbiota and circulating bile acids.

Evaluation of airborne particle exposure for riding elevators.

Social distancing is a key factor for health during the COVID-19 pandemic. In many indoor spaces, such as elevators, it is difficult to maintain social distancing. This investigation used computational-fluid-dynamics (CFD) to study airborne particle exposure in riding an elevator in a typical building with 35 floors. The elevator traveled from the ground floor to the 35th floor with two stops on floor 10 and floor 20, comprising 114 s. The CFD simulated the dispersion of the aerosolized particles exhaled by an index person while breathing in both lobby and elevator areas. The study calculated the accumulated dose of susceptible riders riding in elevators with the index person under different conditions including different ventilation rates, air supply methods, and elevator cab geometries. This investigation also studied a case with a single cough from the index person as the person entered the elevator. The results show that, due to the short duration of the average elevator ride, the number of particles inhaled by a susceptible rider was low. For the reference case with a 72 ACH (air changes per hour) ventilation rate, the highest accumulated particle dose by a susceptible passenger close to the index person was only 1.59. The cough would cause other riders to inhale approximately 8 orders of magnitude higher particle mass than from continuous breathing by the index person for the whole duration of the ride.

Corrigendum to "Evaluation of different air distribution systems in a commercial airliner cabin in terms of comfort and COVID-19 infection risk" Build. Environ., Volume 208, January 2022, 108590.

[This corrects the article DOI: 10.1016/j.buildenv.2021.108590.].

Evaluation of different air distribution systems in a commercial airliner cabin in terms of comfort and COVID-19 infection risk.

The air distribution system in an airliner plays a key role in maintaining a comfortable and healthy environment in the aircraft cabin. To evaluate the performance of a novel displacement ventilation (DV) system and a traditional mixing ventilation (MV) system in an airliner cabin, this study conducted experiments and simulations in a seven-row cabin mockup. This investigation used ultrasonic anemometers and T-thermocouples to measure the air velocity, temperature and distribution of 1 µm and 5 µm particles. Simulation verifications were performed for these operating conditions, and additional scenarios with different occurrence source locations were also simulated. This study combined the Wells-Riley equation with a real case based on a COVID-19 outbreak among passengers on a long-distance bus to obtain the COVID-19 quanta value. Through an evaluation of the airflow organization, thermal comfort, and risk of COVID-19 infection, the two ventilation systems were compared. This investigation found that polydisperse particles should be used to calculate the risk of infection in airliner cabins. In addition, at the beginning of the pandemic, the infection risk with DV was lower than that with MV. In the middle and late stages of the epidemic, the infection risk with MV can be reduced when passengers wear masks, leading to an infection risk approximately equal to that of DV.

Influencing factors in the simulation of airflow and particle transportation in aircraft cabins by CFD.

To control the transport of particles such as the SARS-CoV-2 virus in airliner cabins, which is a significant concern for the flying public, effective ventilation systems are essential. Validated computational fluid dynamics (CFD) models are frequently and effectively used to investigate air distribution and contaminant transportation. The complex geometry and airflow characteristics in airliner cabins pose a challenge to numerical CFD validation. The objective of this investigation was to identify accurate and affordable validation processes for studying the airflow field and particulate contaminant distribution in airliner cabins during the design process for different ventilation systems. This study quantitatively evaluated the effects of ventilation system, turbulence model, particle simulation method, geometry simplification, and boundary condition assignment on airflow and particulate distributions in airliner cabins with either a mixing ventilation (MV) system or a displacement ventilation (DV) system calculated by CFD. The results showed that among four turbulence models, the standard k-ε, RNG k-ε, realizable k-ε and SST k-ω models, the prediction by the realizable k-ε model agreed most closely with the experimental data. Meanwhile, the steady Eulerian method provided a reasonable prediction of the particle concentration field with low computing cost. The computational domain should be simplified differently for the DV system and the MV system with consideration of the simulation accuracy and computing cost. For more accurate modeling results, the boundary conditions should be assigned in greater detail, taking into account the uniformity on the boundary.

Long non-coding RNA MFAT1 promotes skeletal muscle fibrosis by modulating the miR-135a-5p-Tgfbr2/Smad4 axis as a ceRNA.

Fibrosis after skeletal muscle injury is common in sports and can cause irreversible damage to the biomechanical properties of skeletal muscle. Long non-coding RNAs (lncRNAs) have been validated to act as important modulators in the fibrosis of various organs. Here, we reported a novel lncRNA (the skeletal muscle fibrosis-associated transcript 1, lnc-MFAT1), which was highly expressed in skeletal muscle fibrosis. We demonstrate that lnc-MFAT1 knockdown can reduce TGFß-induced fibrosis in vitro and attenuate skeletal muscle fibrosis after acute contusion in mice. Further study showed that lnc-MFAT1 acted as a competitive endogenous RNA of miR-135a-5p. Besides, the miR-135a-5p inhibition obviously promoted TGFß-induced fibrosis in vitro via enhancing its target genes Tgfbr2/Smad4. Moreover, we discovered that lnc-MFAT1 regulates Tgfbr2/Smad4 expression by sponging miR-135a-5p to exert competing endogenous RNA function, resulting in TGFß pathway activation. In conclusion, our study identified a crucial role of lnc-MFAT1-miR-135a-Tgfbr2/Smad4 axis in skeletal muscle fibrosis, providing a promising treatment option against skeletal muscle fibrosis.