Scientific Reports最新文献

Voltage-gated sodium channels (Na_V) are complex macromolecular proteins that are responsible for the initial upstroke of an action potential in excitable cells. Appropriate function is necessary for many physiological processes such as heartbeat, voluntary muscle contraction, nerve conduction, and neurological function. Dysfunction can have life-threatening consequences. During the past decade, there have been significant advancements with ion channel structural characterization by CryoEM, yet descriptions of cytosolic components are often lacking. Many investigations have biophysically characterized reconstituted cytosolic components and their interactions. However, extrapolating the structural alterations and allosteric communication within an intact ion channel can be challenging. To address this, we have developed an all-atom model of the human cardiac sodium channel (Na_V1.5) in a lipid bilayer with explicit salt and water. Our simulations contain descriptions of cytosolic components that are poorly predicted by AlphaFold and lacking in many CryoEM structures. Leveraging the latest advancements of the Amber force fields (ff19sb and Lipid21) and water model (OPC), our simulations improved protein backbone torsion angles and generated structural information across time (four independent one-microsecond simulations). Our analysis provided descriptions of lipid and solvent contacts and insight into the C-Terminal Domain - inactivation gate and inactivation gate - latch receptor interactions.

Trifluridine/tipiracil (FTD/TPI) with or without bevacizumab is an effective treatment for metastatic colorectal cancer (mCRC). As this agent is mainly excreted via the kidney, we aimed to evaluate the impact of renal impairment (RI) on the early development of severe neutropenia, a dose-limiting toxicity and whose development reflects better treatment outcomes, in patients with mCRC treated with FTD/TPI. Patients with mCRC receiving FTD/TPI ± bevacizumab (n = 100) were divided into the RI group (creatinine clearance [CCr] < 90 mL/min) or control group (CCr ≥ 90 mL/min), and retrospectively evaluated. Severe neutropenia during the first two cycles occurred in 57.6% and 34.2% of patients in the RI and control groups, respectively, which was significantly different (P = 0.03) and met our primary endpoint. Furthermore, the incidence during the first cycle also differed significantly (52.5% in the RI group and 17.1% in the control group, P = 0.0004). Multivariate logistic regression analysis suggested that baseline RI and neutropenia were significant risk factors for early severe neutropenia (adjusted odds ratio and 95% confidence interval: 3.07, 1.24-7.59, P = 0.02 for RI, and 9.76, 1.08-88.11, P = 0.04 for neutropenia). In conclusion, our study suggested that patients with RI can exhibit early severe neutropenia during real-world FTD/TPI treatment for mCRC.

It is demonstrated that the eXtended Finite Element Method (XFEM) is of remarkable efficiency in simulating crack evolution by eliminating the need for remeshing and refinement. In this paper, it is shown how to enhance the solution efficiency through a comprehensive mathematical investigation of the solution process using XFEM. A typical example is presented to illustrate the disparities in nodal displacements along the two symmetric faces of the crack resulting from the approximation of XFEM. By analysing the structure and components of the global stiffness matrix, the underlying causes of these discrepancies are identified. Building upon these findings, two improvements of the solution are proposed to gain an acceptable accuracy in computing the nodal displacements. The first improvement consists of the subdivision of the enriched elements depending on the characteristic of the distribution of Gauss points. The second improvement is set by determining the optimal number of Gauss points in each sub-element near the crack tip. To calculate the stress intensity factor of the crack under surface pressure, such improvements are applied in conjunction with the interaction integral method, which significantly reduces computational time and eliminates the influence of surface tractions. The numerical solution is validated by comparing it with the analytical solution and the standard XFEM solution. The proposed improvements can enhance both the accuracy of the solution and the computational efficiency of XFEM.

The theory of ion-acoustic solitons in nonrelativistic fully degenerate plasmas and nonrelativistic and ultra-relativistic degenerate plasmas at low temperatures is known. We consider a multi-component relativistic degenerate electron-positron-ion plasma at finite temperatures. Specifically, we focus on the intermediate region where the particle's thermal energy $\left(k_{B}T\right)$ and the rest mass energy $\left(m{c}^2\right)$ do not differ significantly, i.e., $k_{B}T\sim m{c}^2$ . However, the Fermi energy $\left(k_B{T}_F\right)$ is larger than the thermal energy and the normalized chemical energy ( $\xi =\mu /k_{B}T$ ) is positive and finite. Two different parameter regimes with $\beta \equiv k_{B}T/m{c}^2<1$ and $\beta >1$ , relevant for astrophysical plasmas, are defined, and the existence of small amplitude ion-acoustic solitons in these regimes are studied, including the critical cases where the known KdV (Korteweg-de Vries) theory fails. We show that while the solitons with both the positive (compressive) and negative (rarefactive) potentials coexist in the case of $\beta <1$ , only compressive solitons can exist in the other regime $(\beta >1)$ . Furthermore, while the rarefactive solitons within the parameter domains of $\beta$ and $\xi$ can evolve with increasing amplitude and hence increasing energy, the energy of compressive solitons reaches a steady state.

Large carnivore species frequently predate and consume wild or domestic prey, which is referred to as food-related predation. Large carnivores can also hunt and kill prey exceeding their immediate needs (i.e., they do not consume prey), which is referred to as surplus predation. We used 173 records of livestock predations by gray wolves (Canis lupus; n = 133) and Persian leopards (Panthera pardus tulliana; n = 40) reported by governmental organizations of Iran during 2009-2019 to investigate food-related and surplus predation incidents of livestock. We found that for wolves, the number of reported surplus predation incidents was greater than that of food-related predation incidents during all 4 seasons (spring through winter), whereas for leopards, the number of food-related and surplus predation incidents were similar in all seasons. The number of livestock killed per surplus predation incident was greater for wolves than for leopards and that surplus predations by both species occurred more frequently within corrals than on free-range pastures. As corrals in most villages across Iran are poorly constructed and largely accessible to predators, we recommend that livestock owners enhance corral construction, use well-trained dogs during day and particularly at night, employ people to watch livestock at night, and use fire (e.g., torches) during night to scare carnivores. These strategies can mitigate predation incidents and corresponding economic losses, resulting in fewer losses of livestock, wolves, and leopards, as these two carnivore species are mainly killed by humans due to livestock predations across Iran.

For secure network coding to prevent eavesdropping attacks, a general design is used that puts restrictions on the eavesdropping channel set or encryption technology is embedded, which can cause problems in practical applications. Based on random linear network coding technology, in this paper, a transmission strategy to prevent eavesdropping attacks is proposed for single-source multicast networks, without either precondition of restricting the eavesdropping channel set or embedding encryption technology. The data transmission process is divided into three phases, and the global encoding vectors are separated from the encoded data on the channel. The proposed strategy can enable the sink to decode successfully, making it very difficult for eavesdroppers to meet the conditions for successful decoding by randomly selecting the eavesdropping channel set without obtaining network topology knowledge. The feasibility of the proposed method is strictly demonstrated using layered network technology, and its security is analyzed. The simulation results confirm the validity of the theoretical analysis.

The Coma Recovery Scale-revised (CRS-r) is the gold standard for the behavioral assessment of patients with Disorders of Consciousness (DoCs). However, the misdiagnosis rate is around 40%. For this reason, recent guidelines suggested enhancing the assessment with neurophysiological measures: among these, surface electromyography (sEMG) represents a convenient bedside solution. This work presents the use of the STRIVEfc system, a wearable device that allows CRS-r administration while recording four sEMG signals. STRIVEfc was employed in 40 sessions on 33 DoCs patients and the sEMG was analyzed to look for voluntary and consistent over threshold (OT) muscular activities. Their duration, amplitude, and number were retained and compared between patients in Unresponsive Wakefulness Syndrome (UWS) and Minimally Conscious State (MCS), revealing more numerous and significantly longer OTs in the latter group. Lastly, the EMG information was exploited to enrich the behavioral assessment by building the instrumented CRS-r score (ICRS-r). In 9/16 UWS sessions, the ICRS-r score suggested a higher-level functioning, not translated into a behavioral response, compatible with MCS diagnosis. Overall, the use of STRIVEfc allows to reveal hidden muscular patterns not detectable by the clinician, thus improving the characterization of DoCs patient's functional capabilities and supporting the diagnostic process.

Bladder cancer (BCa) poses a significant health challenge, particularly affecting men with higher incidence and mortality rates. Addressing the need for improved predictive models in BCa treatment, this study introduces an innovative 3D in vitro patient-derived bladder cancer tumor model, utilizing decellularized pig bladders as scaffolds. Traditional 2D cell cultures, insufficient in replicating tumor microenvironments, have driven the development of sophisticated 3D models. The study successfully achieved pig bladder decellularization through multiple cycles of immersion in salt solutions, resulting in notable macroscopic and histological changes. This process confirmed the removal of cellular components while preserving the native extracellular matrix (ECM). Quantitative analysis demonstrated the efficacy of decellularization, with a remarkable reduction in DNA concentration, signifying the removal of over 95% of cellular material. In the development of the in vitro bladder cancer model, muscle invasive bladder cancer patients' cells were cultured within decellularized pig bladders, yielding a three-dimensional cancer model. Optimal results were attained using an air-liquid interface technique, with cells injected directly into the scaffold at three distinct time points. Histological evaluations showcased characteristics resembling in vivo tumors derived from bladder cancer patients' cells. To demonstrate the 3D cancer model's effectiveness as a drug screening platform, the study treated it with Cisplatin (Cis), Gemcitabine (Gem), and a combination of both drugs. Comprehensive cell viability assays and histological analyses illustrated changes in cell survival and proliferation. The model exhibited promising correlations with clinical outcomes, boasting an 83.3% reliability rate in predicting treatment responses. Comparison with traditional 2D cultures and spheroids underscored the 3D model's superiority in reliability, with an 83.3% predictive capacity compared to 50% for spheroids and 33.3% for 2D culture. Acknowledging limitations, such as the absence of immune and stromal components, the study suggests avenues for future improvements. In conclusion, this innovative 3D bladder cancer model, combining decellularization and patient-derived cells, marks a significant advancement in preclinical drug testing. Its potential for predicting treatment outcomes and capturing patient-specific responses opens new avenues for personalized medicine in bladder cancer therapeutics. Future refinements and validations with larger patient cohorts hold promise for revolutionizing BCa research and treatment strategies.

The increase in marine diseases, particularly in economically important mollusks, is a growing concern. Among them, the Pacific oyster (Crassostrea gigas) production faces challenges from several diseases, such as the Pacific Oyster Mortality Syndrome (POMS) or vibriosis. The microbial education, which consists of exposing the host immune system to beneficial microorganisms during early life stages is a promising approach against diseases. This study explores the concept of microbial education using controlled and pathogen-free bacterial communities and assesses its protective effects against POMS and Vibrio aestuarianus infections, highlighting potential applications in oyster production. We demonstrate that it is possible to educate the oyster immune system by adding microorganisms during the larval stage. Adding culture based bacterial mixes to larvae protects only against the POMS disease while adding whole microbial communities from oyster donors protects against both POMS and vibriosis. The efficiency of immune protection depends both on oyster origin and on the composition of the bacterial mixes used for exposure. No preferential protection was observed when the oysters were stimulated with their sympatric strains. Furthermore, the added bacteria were not maintained into the oyster microbiota, but this bacterial addition induced long term changes in the microbiota composition and oyster immune gene expression. Our study reveals successful immune system education of oysters by introducing beneficial microorganisms during the larval stage. We improved the long-term resistance of oysters against critical diseases (POMS disease and Vibrio aestuarianus infections) highlighting the potential of microbial education in aquaculture.

With the rapid growth of on-demand delivery, traditional third-party delivery services using electric bicycles face increasing challenges, including increased labor costs and safety issues. To address these issues, we propose two modes for on-demand delivery systems using buses. One is the "bus terminal + professional crowd shippers" (B&P) mode, which involves consolidating parcels from various origins at the bus transfer hub. From there, they are grouped and delivered by buses. The other is the "bus stop + crowdsourced passenger" (B&C) mode, which transports parcels directly from the origin to the destination by passengers without the need for consolidation and sorting at bus transfer hubs. Both modes fully utilize the surplus capacity of buses and employ resources from retail stores and third-party shippers. We evaluated these modes using key performance indicators (KPIs) such as labor costs, cost increases from en-route destination changes, and average delivery time per kilometer. This analysis was based on 18,349 delivery cases in downtown Ningbo, China. Through this evaluation, we identified the strengths, weaknesses, opportunities, and threats associated with each mode. Our findings reveal that both the B&P and B&C modes effectively reduce delivery costs and external impacts while maintaining a user experience and efficiency level comparable to traditional third-party delivery services for mid-to-long-distance (3-10 km) deliveries. However, the use of public transportation may limit the flexibility of the delivery mode. Based on these insights, we provide strategic recommendations for the further development and implementation of B&P and B&C modes.