bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective approaches to gene therapy computational modeling – spotlight on viral gene therapy
Authors: Choules Mary P , Bonate Peter L. , Heo Nakyo , Weddell Jared
Published: October 2023

Clinical studies have found there still exists a lack of gene therapy dose-toxicity and dose-efficacy data that causes gene therapy dose selection to remain elusive. Model informed drug development (MIDD) has become a standard tool implemented throughout the discovery, development, and approval of pharmaceutical therapies, and has the potential to inform dose-toxicity and dose-efficacy relationships to support gene therapy dose selection. Despite this potential, MIDD approaches for gene therapy remain immature and require standardization to be useful for gene therapy clinical programs. With the goal to advance MIDD approaches for gene therapy, in this review we first provide an overview of gene therapy types and how they differ from a bioanalytical, formulation, route of administration, and regulatory standpoint. With this biological and regulatory background, we propose how MIDD can be advanced for AAV-based gene therapies by utilizing physiological based pharmacokinetic modeling and quantitative systems pharmacology to holistically inform AAV and target protein dynamics following dosing. We discuss how this proposed model, allowing for in-depth exploration of AAV pharmacology, could be the key the field needs to treat these unmet disease populations.
Improved survival outcome with not-delayed radiotherapy and immediate PD-1/PD-L1 inhibitor for non-small-cell lung cancer patients with brain metastases
Authors: Yu Yaner , Chen Haiyan , Tian Zhifeng , Zhang Qun , Shui Yongjie , Shen Li , Hu Qiongge , Huang Zhifei , Zhu Shuangqiu , Jiang Hao , Wei Qichun
Published: October 2023

Purpose

To investigate the impact of radiotherapy (RT) and immune checkpoint inhibitor (ICI) sequence on the survival outcome in NSCLC patients with brain metastasis, and decide the best time to initiate RT.

Methods

Patients were managed with delayed RT (ICI delivered over 2 weeks prior to RT), concurrent RT (ICI delivered within 2 weeks prior to or after RT), or upfront RT (RT delivered over 2 weeks prior to ICI). Overall survival (OS), intracranial local progression-free survival (iLPFS), and intracranial distant progression-free survival (iDPFS) were assessed. A meta-analysis was performed to analyze the association between survival outcome and RT/ICI sequence.

Results

A total of 73 NSCLC patients were identified with a median follow-up of 13.9 months. Patients who receive delayed RT demonstrated shorter iLPFS (P = 0.0029), iDPFS (P = 0.016), and OS (P < 0.001). A meta-analysis was conducted and a total of 4 studies, 254 patients were included. The HR was 0.44 for iDPFS (P = 0.03), 0.41 for OS (P < 0.01) when compared concurrent with delayed RT, 0.21 for iDPFS (P < 0.01), 0.32 for OS (P < 0.01) when compared upfront with delayed RT, consistent with our conclusion that delayed RT brought with worst iDPFS and OS. More importantly, the best overall response rate (BOR) decreased in cases with longer RT and ICI intervals. Patients who receive intervals of RT and ICI within 7 days achieve the best median BOR of − 53%.

Conclusions

Delayed RT brought poor survival outcomes including iLPFS, iDPFS, and OS in NSCLC patients. The shorter interval of RT and ICI is associated with better BOR.
Classifying and bounding geomagnetic storms based on the SYM-H and ASY-H indices
Authors: Collado-Villaverde Armando , Muñoz Pablo , Cid Consuelo
Published: October 2023

Geomagnetic storms, which are significant disturbances in Earth’s magnetic field, pose a natural hazard with potentially harmful effects on technological and electrical systems. Various indices such as Kp, Dst, and the newer SYM-H and ASY-H are used to measure storm intensity. However, there is no consensus among researchers regarding storm classification based on intensity and asymmetry for the SYM-H and ASY-H indices, as existing classifications mainly rely on the Dst and Kp indices. This study proposes a classification method based on the cumulative distribution function of the SYM-H and ASY-H indices, applying industry-wide percentiles to determine storm classes. Using percentiles and a superposed epoch analysis, storms are objectively classified based on intensity and occurrence probability. This classification approach has applications in storm forecasting and risk assessment.
Asymptotic behavior of a system of two coupled queues when the content of one queue is very high
Authors: Bruneel Herwig , Devos Arnaud
Published: October 2023

We consider a system of two parallel discrete-time single-server queues, queue 1 and queue 2. The service time of any customer in either queue is equal to 1 time slot. Arrivals during consecutive slots occur independently from slot to slot. However, the arrival streams into both queues are possibly mutually interdependent, i.e., during any slot, the numbers of arrivals in queue 1 and queue 2 need not be statistically independent. Their joint probability generating function (pgf) A(x, y) fully characterizes the queueing model. As a consequence of the possible intra-slot correlation in the arrival process, the numbers of customers present (“system contents”) in queues 1 and 2, at any given slot boundary, are not necessarily independent either. In a previous paper, we have already discussed the mathematical difficulty of computing their steady-state joint pgf $$U(z_1,z_2)$$

U
(

z
1

,

z
2

)

; explicit closed-form results can only be obtained for specific choices of A(x, y). In this paper, we therefore look at the problem from an other angle. Specifically, we study the (asymptotic) conditional steady-state behavior of the system under the condition that the content of queue 1 is (temporarily) very high (goes to infinity). For ease of terminology, we refer to the system as the “asymptotic system” in these circumstances. We prove that the asymptotic system is nearly identical to the original (unconditional) system, but with a modified joint arrival pgf $$A^*(x,y)$$

A
∗

(
x
,
y
)

that can be computed explicitly from A(x, y). This fundamental result allows us to determine the stability condition of queue 2 in the asymptotic system, and explicitly compute the classical queueing performance metrics of queue 2, such as the pgf, the moments and the approximate tail distribution of its system content, when this condition is fulfilled. It also leads to accurate approximative closed-form expressions for the joint tail distribution of the system contents in both queues, in the original (unconditional) system. We extensively illustrate our methodology by means of various specific (popular) choices of A(x, y). In some examples, where an explicit solution for $$U(z_1,z_2)$$

U
(

z
1

,

z
2

)

or for the (approximative) joint tail distribution is known, we retrieve the known results easily. In other cases, new results are found for arrival pgfs A(x, y) for which no explicit results were known until now.
CEO power, corporate risk management, and dividends: disentangling CEO managerial ability from entrenchment
Authors: Adams Mike , Jiang Wei , Ma Tianshu
Published: October 2023

We contribute to the literature on dividend policy by considering two largely ignored, yet important factors, namely CEO power and corporate risk management. We first disentangle CEO managerial ability from entrenchment - the two sources of leadership autonomy that are not normally distinguished in prior literature. Using UK (re)insurance data that allows us to objectively and reliably quantify risk management and to identify powerful stakeholders with monitoring incentives (e.g., shareholders and regulatory body), we find that risk management enables entrenched CEOs to increase dividends to avoid monitoring by shareholders without compromising financial resilience and increasing the risk of regulatory scrutiny. Further, we neither find the degree of CEO managerial ability nor its interaction with risk management to be related to dividends, suggesting that the competing incentives for talented CEOs to pay higher/lower level of dividends cancel out in cross-sectional tests. Nonetheless, we find that the signalling effects of dividends for future accounting earnings only exist in insurers with high ability CEOs. This is consistent with the view that talented CEOs are able to generate sustainable earnings, and when they choose to pay (more) dividends, they do so to externally signal their managerial ability.
Advocacy for Online Proceedings: Features of the Digital World and Their Role in How Communication is Shaped in Remote International Arbitration
Authors: Gómez-Moreno Juan Pablo
Published: October 2023

The Covid-19 pandemic disrupted in-person dispute resolution proceedings, leading to the rapid adoption of digital technologies for remote hearings in international arbitration. The use of these technologies has opened up new possibilities for enhancing procedures, improving efficiency, and streamlining processes. However, it also raises concerns about transparency and authenticity in virtual hearings. This paper explores the impact of digital technologies on the semiotics of law and legal communication in international arbitration, considering the intersections between new technologies and persuasion. Based on practices like the use of e-evidence, debates surrounding remote hearings, and the formulation of standards for stakeholders’ behavior, the study takes a practice-based approach, exploring cognitive processes, such as memory and attention, and their influence on the behavior of counsel, arbitrators, and witnesses in remote hearings. It highlights the key issues, findings, challenges, and future research opportunities arising from the introduction of digital technologies in this field, including considerations on how stakeholders of a virtual hearings are affected by the unique features of the digital environment.
Solar Cycle Observations
Authors: Norton Aimee , Howe Rachel , Upton Lisa , Usoskin Ilya
Published: October 2023

We describe the defining observations of the solar cycle that provide constraints for the dynamo processes operating within the Sun. Specifically, we report on the following topics: historical sunspot numbers and revisions; active region (AR) flux ranges and lifetimes; bipolar magnetic region tilt angles; Hale and Joy’s law; the impact of rogue ARs on cycle progression and the amplitude of the following cycle; the spatio-temporal emergence of ARs that creates the butterfly diagram; polar fields; large-scale flows including zonal, meridional, and AR in-flows; short-term cycle variability; and helioseismic results including mode parameter changes.
A New Fully Implicit Two-Phase Pore-Network Model by Utilizing Regularization Strategies
Authors: Wu Hanchuan , Veyskarami Maziar , Schneider Martin , Helmig Rainer
Published: October 2023

In this paper, we address the expensive computational cost resulting from limited time-step sizes during numerical simulations of two-phase flow in porous media using dynamic pore-network models. To overcome this issue, we propose a numerical method for dynamic pore-network models using a fully implicit approach. The proposed method introduces a regularization strategy considering the historical fluid configuration at the pore throat, which smooths the discontinuities in local conductivity caused by invasion and snap-off events. The results demonstrate the superiority of the proposed method in terms of accuracy, efficiency and consistency in comparison with other numerical schemes. With similar computational cost, determined by time-step sizes and number of Newton iterations, the developed method in this work yields more accurate results compared to similar schemes presented in the literature. Additionally, our results highlight the enhanced robustness of the our scheme, as it exhibits reduced sensitivity to variations in time-step sizes.
Religious Diversity, Islam, and Integration in Western Europe—Dissecting Symbolic, Social, and Institutional Boundary Dynamics
Authors: Koenig Matthias
Published: October 2023

Religious diversity and, in particular, the presence of Islam is often perceived as a threat to national solidarity and social cohesion across Western Europe. Reviewing and synthesizing compartmentalized research literature on religion and immigrant integration, this article scrutinizes symbolic, social, and institutional boundary processes and their underlying micro-level mechanisms. First, it showcases the relative brightness of religiously coded symbolic boundaries that is sustained by anti-Muslim prejudices among the majority as well as by the intergenerational transmission of Muslim religiosity. Second, it discusses whether and how religious differences translate into social boundaries, through both discrimination and religiously based (self-)segregation on the labor market, in education, and in social networks. Third, it traces how interactive sequences of Muslims’ claims for recognition and public policy responses have led to institutional boundary shifts under the influence of constitutional law and European human rights and anti-discrimination directives. The article concludes by discussing scenarios of how macro-level processes of symbolic, social, and institutional boundary transformation interrelate, thus raising broader questions on religious diversity and integration in Western European nation-states.
Massese sheep characteristics and demo-genetic trends in the province of Pisa (Italy)
Authors: Giuliotti Lorella , Benvenuti Maria Novella , Ventura Emilia , Fresi Pancrazio , Preziuso Giovanna , Cecchi Francesca
Published: October 2023

Preserving animal breeds is key to a country’s economy, environment and culture. The present study collects all the available information on the Massese sheep breed and analyzes their demo-genetic trends in Pisa since 1976. Data were provided by Asso.Na.Pa. Descriptive statistics were analysed using Jmp software. The pedigree parameters of a total of 10,393 animals (whole population-WP) were analyzed using CFC, ENDOG and Pedigree viewer software. Animals born in the last fifteen years represented the Reference Population (RP), while animals with one or two unknown parents constituted the Base Population (BP). Demographic results showed an inconstant trend of offspring registration in the Herd book with two periods of a dramatic decline in lamb registrations and a substantially short productivity with a mean number of registered newborns of 1.5 and 18.2 for ewes and rams, respectively. A total of 6456 animals represented the RP, of which only 1059 animals (16.4%) had both known parents. The BP consisted of 7156 animals, thus highlighting the lack of sire and dam registration which prevented an accurate evaluation of the genetic parameters. The average inbreeding coefficient in the WP was 0.78%, and 0.046% in the RP. The number of inbreds was 575 in the WP and 17 in the RP. The present study represents a tool for breeders and technicians aimed at conserving and exploiting the genetic resources of Massese sheep through efficient breeding plans.
The role of sound stimulation in production of plant secondary metabolites
Authors: Wu Li , Yang Ning , Guo Meng , Zhang Didi , Ghiladi Reza A. , Bayram Hasan , Wang Jun
Published: October 2023

Sound vibration is one of natural stimuli trigging physiological changes in plants. Recent studies showed that sound waves stimulated production of a variety of plant secondary metabolites, including flavonoids, in order to enhance seed germination, flowering, growth or defense. In this review, we examine the potential role of sound stimulation on the biosynthesis of secondary metabolites and the followed cascade of physiological changes in plants, from the perspective of transcriptional regulation and epigenetic regulation for the first time. A systematic summary showed that a wide range of factors may regulate the production of secondary metabolites, including plant species, growth stage, sound types, sound frequency, sound intensity level and exposure time, etc. Biochemical and physiological changes due to sound stimulation were thoroughly summarized as well, for secondary metabolites can also act as a free radical scavenger, or a hormone signaling molecule. We also discussed the limits of previous studies, and the future application of sound waves in biosynthesis of plant secondary metabolites.
Laplace transform solution of the time-dependent annular Couette flow with dynamic wall slip
Authors: Ali Ahmed E. K. , Ghaleb A. F. , Abou-Dina M. S. , Helal M. A.
Published: October 2023

The annular Couette flow has several industrial applications, particularly for the characterization of the fluid flow and deformation behavior of fluids. The inclusion of the dynamic wall slip into the flow boundary conditions seems to be necessary for an efficient continuum description of motion of nanofluidics as it reflects the importance of fluid–structure interface related phenomena. Dynamic wall slip introduces a dissipative boundary condition and thus increases the difficulties of finding solutions to related problems. In the present work we investigate the behavior of fluid flow between two infinitely long coaxial circular cylinders, when the inner cylinder is axially moving due to sudden constant velocity, while the outer cylinder is held stationary. The boundary condition on the outer cylinder is that of dynamic wall slip, in addition to the usual Navier slip. The medium considered here is a Newtonian viscous fluid. The solution of the governing equations, initial and boundary conditions for this flow is obtained using the Laplace transform technique and inversion by Laguerre polynomials. This method may be useful, when applied in conjunction with perturbation methods, to solve nonlinear Couette flow problems involving temperature changes. Numerical results are presented and discussed.
Fast and Stable Zinc Anode-Based Electrochromic Displays Enabled by Bimetallically Doped Vanadate and Aqueous Zn2+/Na+ Hybrid Electrolytes
Authors: Song Zhaoyang , Wang Bin , Zhang Wu , Zhu Qianqian , Elezzabi Abdulhakem Y. , Liu Linhua , Yu William W. , Li Haizeng
Published: October 2023

Vanadates are a class of the most promising electrochromic materials for displays as their multicolor characteristics. However, the slow switching times and vanadate dissolution issues of recently reported vanadates significantly hinder their diverse practical applications. Herein, novel strategies are developed to design electrochemically stable vanadates having rapid switching times. We show that the interlayer spacing is greatly broadened by introducing sodium and lanthanum ions into V3O8 interlayers, which facilitates the transportation of cations and enhances the electrochemical kinetics. In addition, a hybrid Zn2+/Na+ electrolyte is designed to inhibit vanadate dissolution while significantly accelerating electrochemical kinetics. As a result, our electrochromic displays yield the most rapid switching times in comparison with any reported Zn-vanadate electrochromic displays. It is envisioned that stable vanadate-based electrochromic displays having video speed switching are appearing on the near horizon. "Image missing"
Research on Time-Based Fare Discount Strategy for Urban Rail Transit Peak Congestion
Authors: Ding Xiaobing , Hong Chen , Wu Jinlong , Zhao Lu , Shi Gan , Liu Zhigang , Hong Haoyang , Zhao Zhengyuan
Published: October 2023

To alleviate peak-hour congestion in urban rail transit, this study proposes a new off-peak fare discount strategy to incentivize passengers to shift their departure time from peak to off-peak hours. Firstly, a questionnaire survey of Shanghai metro passengers is conducted to analyze their willingness to change departure time under different fare strategies. Secondly, based on the survey results, a time-differentiated fare discount model is constructed, considering both the company’s revenue and passengers’ travel benefits, and with the optimization objective of achieving balanced peak-hour and off-peak-hour train loads throughout the day. Subsequently, a genetic algorithm with nested fmincon functions is designed and combined with the actual data of Shanghai rail transit line 9 for arithmetic analysis. Finally, the effectiveness of the model is validated using the survey data. The research results show that the off-peak fare discount strategy can incentivize 6.88% of passengers traveling in the morning peak and 6.66% of passengers traveling in the evening peak to shift to off-peak travel. This research provides theoretical support and decision-making guidance for implementing time-differentiated pricing in urban rail transit systems.
Experimental and numerical investigations of the hot cracking susceptibility during the powder bed fusion of AA 7075 using a laser beam
Authors: Wimmer Andreas , Panzer Hannes , Zoeller Christopher , Adami Stefan , Adams Nikolaus A. , Zaeh Michael F.
Published: October 2023

The variety of processable materials for the powder bed fusion of metals using a laser beam (PBF-LB/M) is still limited. In particular, high-strength aluminum alloys are difficult to process with PBF-LB/M without the occurrence of hot cracks. In situ alloying is a promising method to modify the physical properties of an alloy to reduce its hot cracking susceptibility. In this work, the aluminum alloy 7075 and blends with 2 wt.%, 4 wt.%, and 6 wt.% of Si were processed via PBF-LB/M. The Rappaz–Drezet–Gremaud (RDG) model and the Kou model were investigated regarding their capability of predicting the hot cracking behavior for the aluminum alloy 7075 and the three powder blends. The smoothed-particle hydrodynamics (SPH) method was used to gain the thermal input data for the RDG model. A clear tendency of a reduced hot cracking susceptibility with an increasing amount of Si was observed in the experiments and in the simulations. A detailed analysis of the type of the hot cracking mechanism in the aluminum alloy 7075 provided several indications of the presence of liquation cracking. The Kou model and the RDG model may be applicable for both solidification and liquation cracking. The presented methodology can be used to investigate any material combination and its susceptibility to hot cracking.
Artificial intelligent patient-controlled intravenous analgesia improves the outcomes of older patients with laparoscopic radical resection for colorectal cancer
Authors: Liu Dandan , Li Xiaopei , Nie Xiaohong , Hu Qiangfu , Wang Jiandong , Hai Longzhu , Yang Lingwei , Wang Lin , Guo Peilei
Published: October 2023

Methods

Patients undergoing elective laparoscopic radical resection of colorectal cancer from July 2019 to May 2021 were selected. The patients were assigned to Ai-PCIA group and control group. Ai-PCIA group received postoperative analgesia management and effect evaluation through intelligent wireless analgesia system + postoperative follow-up twice a day, while control group received analgesia management and effect evaluation through ward physician feedback + postoperative follow-up twice a day. The pain numerical score (NRS), Richards–Campbell Sleep Scale (RCSQ), and adverse outcomes were collected and compared.

Results

A total of 60 patients (20 females and 40 males with average (78.26 ± 6.42) years old) were included. The NRS scores at rest and during activity of the Ai-PCA group at 8, 12, and 24 h after the operation were significantly lower than that of the control group (all P < 0.05). The RCSQ score of Ai-PCA group was significantly higher than that of control group on the 1st and 2nd days after operation (all P < 0.05). There were no significant differences in the incidence of dizziness and nausea, vomiting, and myocardial ischemia (all P > 0.05).

Conclusions

Ai-PCIA can improve the analgesic effect and sleep quality of older patients after laparoscopic radical resection, which may be promoted in clinical analgesia practice.
Cultural evolution with uncertain provision of learning resources
Authors: Ladas Konstantinos , Kavadias Stylianos , Hutchison-Krupat Jeremy
Published: October 2023

An essential feature of human progress is the use of different modes of learning so agents acquire the appropriate behaviour to survive in a changing environment. Learning may result from agents who discover new knowledge on their own (individual learning), or imitate the behaviour of others (social learning). Social learning is less costly than discovery, but imitation might yield no benefit. Early theoretical models of a population consisting of purely individual and purely social learners found that both types are present in an evolutionary equilibrium. However, the presence of social learners did not provide any improvement to the average population fitness. Subsequent research showed that the presence of social learners could improve the average population fitness, provided that the pure characterisation of the agents’ learning is relaxed. We return to the pure conceptualisation of agents to challenge an assumption in the early work: agents were guaranteed enough resources to perform their desired learning. We show that, if the resources an agent receives are uncertain, this turns social learning into a source of fitness improvement at the population level. Perhaps counter-intuitively, uncertain provision of resources prompts an increase in the proportion of the population that pursues the costlier individual learning activity in equilibrium.
Preschoolers’ use of cue validities as weights in decision-making: Certainty does not substantially change the world
Authors: Lindow Stefanie , Lehmann Anne , Buttelmann David , Betsch Tilmann
Published: October 2023

A child’s world is full of cues that may help to learn about decision options by providing valuable predictions. However, not all cues are always equally valid. To enhance decision-making, one should use cue validities as weights in decision-making. Prior research showed children’s difficulty in doing so. In 2 conceptual replication studies, we investigated preschoolers’ competencies when they encounter a cue whose prediction is always correct. We assessed 5- to 6-year-olds’ cue evaluations and decision-making in an information-board-game. Participants faced 3 cues when repeatedly choosing between 2 locations to find treasures: A nonprobabilistic, high-validity cue that always provided correct predictions (p = 1) paired with 2 probabilistically correct (Study 1: p = .34, p = .17) or 2 nonprobabilistic, incorrect cues (Study 2: p = 0). Participants considered cue validities—albeit in a rudimentary form. In their cue evaluations, they preferred the high-validity cue, indicating their ability to understand and use cue validity for evaluations. However, in their decision-making, they did not prioritize the high-validity cue. Rather, they frequently searched and followed the predictions of less valid (Study 1) and incorrect cues (Study 2). Our studies strengthen the current state of decision research suggesting that the systematic use of cue validities in decision-making develops throughout childhood. Apparently, having appropriate cue evaluations that reflect cue validities is not sufficient for their use in decision-making. We discuss our findings while considering the importance of learning instances for the development of decision competencies.
The magnetic non-hydrostatic shallow-water model
Authors: Dritschel David G. , Tobias Steven M.
Published: October 2023

We consider the dynamics of a set of reduced equations describing the evolution of a magnetised, rotating stably stratified fluid layer, atop a stagnant dense, perfectly conducting layer. We consider two closely related models. In the first, the layer has, above it, relatively light fluid where the magnetic pressure is much larger than the gas pressure, and the magnetic field is largely force-free. In the second model, the magnetic field is constrained to lie within the dynamical layer by the implementation of a model diffusion operator for the magnetic field. The model derivation proceeds by assuming that the horizontal velocity and the horizontal magnetic field are independent of the vertical coordinate, whilst the vertical components in the layer have a linear dependence on height. The full system comprises evolution equations for the magnetic field, horizontal velocity and height field together with a linear elliptic equation for the vertically integrated non-hydrostatic pressure. In the magneto-hydrostatic limit, these equations simplify to equations of shallow-water type. Numerical solutions for both models are provided for the fiducial case of a Gaussian vortex interacting with a magnetic field. The solutions are shown to differ negligibly. We investigate how the interaction of the vortex changes in response to the magnetic Reynolds number

${Rm}$

, the Rossby deformation radius

$L_D$

, and a Coriolis buoyancy frequency ratio

$f/N$

measuring the significance of non-hydrostatic effects. The magneto-hydrostatic limit corresponds to

$f/N\to 0$

.
Flow over a circular cylinder with a flexible splitter plate
Authors: Shukla S. , Govardhan R.N. , Arakeri J.H.
Published: October 2023

In the present work, we study the flow field around, and forces acting on, a circular cylinder with an attached flexible splitter plate/flap. Two cases of flap length (

$L/D$

), namely,

$L/D = 5$

and

$L/D = 2$

have been investigated focusing on the effect of variations in flap flexural rigidity,

$EI$

. We find that for a range of

$EI$

and Reynolds numbers

$Re = UD/\nu$

, a non-dimensional bending stiffness

$K^{\ast }=EI/((1/2)\rho U^2 L^3)$

collapses flap motion and forces on the system well, as long as

$Re>5000$

. In the

$L/D = 5$

flap case, two periodic flap deformation regimes in the form of travelling waves are identified (modes I and II), with mode I occurring at

$K^{\ast } \approx 1.5\times 10^{-3}$

and mode II at lower

$K^{\ast }$

values (

$K^{\ast }<3\times 10^{-5}$

). In the

$L/D = 2$

flap case, we find a richer set of flapping modes (modes A, B, C and D) that are differentiated by their flapping characteristics (symmetric/asymmetric and amplitude). Force measurements show that the largest drag reduction occurs in mode I (

$L/D = 5$

) and mode C (

$L/D = 2$

), which also correspond to the lowest lift and wake fluctuations, with the mode C wake fluctuations being lower than even the rigid splitter plate case. In contrast, the highest fluctuating lift, in both

$L/D$

cases, occurs at higher

$K^{\ast }$

, when the wake frequency is close to the first structural bending mode frequency of the flap. The observed rich range of flap/splitter plate dynamics could be useful for applications such as drag reduction, vibration suppression, reduction of wake fluctuations and energy harvesting.
ADAM SMITH’S WEALTH OF NATIONS IS STILL RELEVANT TO UK TRADE POLICYMAKING ON INTERNATIONAL TRADE
Authors: Winters L. Alan
Published: October 2023

This article reviews Adam Smith’s clearly articulated views about the desirability of free trade and his equally strong view on the necessity of sound institutions and ‘the tolerable administration of justice’ as key ingredients of successful economic management. It starts with Smith’s views on free trade and shows how pertinent they are to today’s high-level trade policy challenges. It then considers a more detailed day-to-day instrument of policy—the Trade Remedies Authority (TRA). Following Brexit, the TRA was created as an arms-length body for investigating cases for granting temporary import restrictions to specific products according to a reasonably well-defined objective process. The article demonstrates how, over the first 2 years of its life, the TRA has been reduced from a useful administrative instrument to a fig leaf for a political process for granting protection to petitioners. Unfortunately, this tendency to displace analytical approaches to policy by purely political ones can now be observed in many activities of UK governance.
Bacteria associated with ovine gut parasites Trichuris ovis and Haemonchus contortus
Authors: Bhat A. H. , Tak H. , Ganai B. A. , Malik I. M. , Bhat T. A.
Published: October 2023

An associated microbiome of any host helps it in different metabolic processes ranging from the decomposition of food to the maturation of gametes. Organisms with a parasitic mode of life, though present at nutritious sites inside their host, maintain their own microbiome. Nevertheless, the comprehensive characterization and functionality of microbiome in parasitic organisms remain understudied. We selected two nematode parasites of Kashmir Merino sheep viz;Haemonchus contortus and Trichuris ovis based on their higher prevalence, difference in mode of nutrition, habitation site and effect on host. The objective of the study was to explore the bacteria associated with these parasitic nematodes of sheep. We adopted a 16S rRNA metagenomic sequencing approach to estimate and compare the bacterial communities present in these two nematode species. Nematode parasites from Kashmir Merino sheep were identified morphologically and confirmed with DNA characterization. H. contortus was dominated by phylum Proteobacteria (57%), Firmicutes (25%), Bacteroidota (15%) and Actinobacteriota (3%). Conversely, T. ovis showed Proteobacteria (78%) followed by Firmicutes (8%), Bacteroidota (8%), Actinobacteriota (1%), Fusobacteriota (1%) and other phyla (4%). This study provides a comprehensive account of the microbiome composition of H. contortus and T. ovis, both of which are highly prevalent among Kashmir Merino sheep. Additionally, T. ovis exhibited a greater bacterial diversity compared to H. contortus. Notably, these nematodes were found to harbor certain pathogenic bacteria. This study can further be carried forward in gaining insights into the complex relationship between the microbiota of a parasite and its pathogenicity, reproductive potential and host microbiome modification.
Epidemiology and antifungal susceptibilities of clinically isolated Aspergillus species in South China
Authors: Bilal Hazrat , Zhang Dongxing , Shafiq Muhammad , Khan Muhammad Nadeem , chen Canhua , Khan Sabir , Cai Lin , Khan Rahat Ullah , Hu Haibin , Zeng Yuebin
Published: October 2023

Aspergillosis is a rising concern worldwide; however, its prevalence is not well documented in China. This retrospective study determined Aspergillus’s epidemiology and antifungal susceptibilities at Meizhou People’s Hospital, South China. From 2017 to 2022, the demographic, clinical, and laboratory data about aspergillosis were collected from the hospital’s records and analysed using descriptive statistics, chi-square test, and ANOVA. Of 474 aspergillosis cases, A. fumigatus (75.32%) was the most common, followed by A. niger (9.92%), A. flavus (8.86%), and A. terreus (5.91%). A 5.94-fold increase in aspergillosis occurred during the study duration, with the highest cases reported from the intensive care unit (52.74%) – chronic pulmonary aspergillosis (79.1%) and isolated from sputum (62.93%). Only 38 (8.02%) patients used immunosuppressant drugs, while gastroenteritis (5.7%), haematologic malignancy (4.22%), and cardiovascular disease (4.22%) were the most prevalent underlying illnesses. In A. fumigatus, the wild-type (WT) isolates against amphotericin B (99.1%) were higher than triazoles (97–98%), whereas, in non-fumigatus Aspergillus species, the triazole (95–100%) WT proportion was greater than amphotericin B (91–95%). Additionally, there were significantly fewer WT A. fumigatus isolates for itraconazole and posaconazole in outpatients than inpatients. These findings may aid in better understanding and management of aspergillosis in the region.
Party and Party System Institutionalization: Which Comes First?
Authors: Casal Bértoa Fernando , Enyedi Zsolt , Mölder Martin
Published: October 2023

Parties and party systems are treated as separate phenomena in theory, but not in research practice. This is most clearly so in the literature on the institutionalization of party politics, where the party level and the systemic levels are often analyzed through combined fuzzy indices. We 1) propose separate indicators for measuring institutionalization at the party and at the party system level, 2) demonstrate their different dynamics in twentieth and twenty-first century European countries, and 3) investigate the direction of causality. Using a dataset that covers more than 700 elections, 800 parties, and 1,400 instances of government formation in 60 different historical party systems across 45 European countries, we find that party-level institutionalization tends to precede systemic institutionalization. The opposite pattern occurs only in a few countries.
Cap Analysis of Gene Expression Clarifies Transcriptomic Divergence Within Monozygotic Twin Pairs
Authors: Katoh Hirokazu , Asai Hiroaki , Takemoto Keiko , Tomizawa Rie , Honda Chika , Watanabe Mikio ,   Osaka Twin Research Group, Honda Tomoyuki
Published: October 2023

Phenotypic variation is the result of gene expression based on complex interaction between genetic and environmental factors. It is well known that genetic and environmental factors influence gene expression, but our understanding of their relative importance remains limited. To obtain a hint for the understanding of their contributions, we took advantage of monozygotic twins, as they share genetic and shared environmental factors but differ in nonshared factors, such as environmental differences and stochastic factors. In this study, we performed cap analysis of gene expression on three pairs of twins and clustered each individual based on their expression profiles of annotated genes. The dendrogram of annotated gene transcripts showed a monophyletic clade for each twin pair. We also analyzed the expression of retrotransposons, such as human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs), given their abundance in the genome. Clustering analyses demonstrated that HERV and LINE expression diverged even within monozygotic twin pairs. Thus, HERVs and LINEs are more susceptible to nonshared factors than annotated genes. Motif analysis of differentially expressed annotated genes suggests that specificity protein/Krüppel-like factor family transcription factors are involved in the expression divergence of annotated gene influenced by nonshared factors. Collectively, our findings suggest that expressions of annotated genes and retrotransposons are differently regulated, and that the expression of retrotransposons is more susceptible to nonshared factors than annotated genes.
Effect of Regional Marine Cloud Brightening Interventions on Climate Tipping Elements
Authors: Hirasawa Haruki , Hingmire Dipti , Singh Hansi , Rasch Philip J. , Mitra Peetak
Published: October 2023

It has been proposed that increasing greenhouse gas (GHG) driven climate tipping point risks may prompt consideration of solar radiation modification (SRM) climate intervention to reduce those risks. Here, we study marine cloud brightening (MCB) SRM interventions in three subtropical oceanic regions using Community Earth System Model 2 experiments. We assess the MCB impact on tipping element‐related metrics to estimate the extent to which such interventions might reduce tipping element risks. Both the pattern and magnitude of the MCB cooling depend strongly on location of the MCB intervention. We find the MCB cooling effect reduces most tipping element impacts; though differences in MCB versus GHG climate response patterns mean MCB is an imperfect remedy. However, MCB applied in certain regions may exacerbate certain GHG tipping element impacts. Thus, it is crucial to carefully consider the pattern of MCB interventions and their teleconnected responses to avoid unintended climate effects.
An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function
Authors: Cuesta-Hernández Hipólito Nicolás , Contreras Julia , Soriano-Maldonado Pablo , Sánchez-Wandelmer Jana , Yeung Wayland , Martín-Hurtado Ana , Muñoz Inés G. , Kannan Natarajan , Llimargas Marta , Muñoz Javier , Plaza-Menacho Iván
Published: October 2023

Autophosphorylation controls the transition between discrete functional and conformational states in protein kinases, yet the structural and molecular determinants underlying this fundamental process remain unclear. Here we show that c-terminal Tyr 530 is a de facto c-Src autophosphorylation site with slow time-resolution kinetics and a strong intermolecular component. On the contrary, activation-loop Tyr 419 undergoes faster kinetics and a cis-to-trans phosphorylation switch that controls c-terminal Tyr 530 autophosphorylation, enzyme specificity, and strikingly, c-Src non-catalytic function as a substrate. In line with this, we visualize by X-ray crystallography a snapshot of Tyr 530 intermolecular autophosphorylation. In an asymmetric arrangement of both catalytic domains, a c-terminal palindromic phospho-motif flanking Tyr 530 on the substrate molecule engages the G-loop of the active kinase adopting a position ready for entry into the catalytic cleft. Perturbation of the phospho-motif accounts for c-Src dysfunction as indicated by viral and colorectal cancer (CRC)-associated c-terminal deleted variants. We show that c-terminal residues 531 to 536 are required for c-Src Tyr 530 autophosphorylation, and such a detrimental effect is caused by the substrate molecule inhibiting allosterically the active kinase. Our work reveals a crosstalk between the activation and c-terminal segments that control the allosteric interplay between substrate- and enzyme-acting kinases during autophosphorylation.
Endocytosis-mediated entry of a caterpillar effector into plants is countered by Jasmonate
Authors: Yan Zi-Wei , Chen Fang-Yan , Zhang Xian , Cai Wen-Juan , Chen Chun-Yu , Liu Jie , Wu Man-Ni , Liu Ning-Jing , Ma Bin , Wang Mu-Yang , Chao Dai-Yin , Gao Cai-Ji , Mao Ying-Bo
Published: October 2023

Insects and pathogens release effectors into plant cells to weaken the host defense or immune response. While the imports of some bacterial and fungal effectors into plants have been previously characterized, the mechanisms of how caterpillar effectors enter plant cells remain a mystery. Using live cell imaging and real-time protein tracking, we show that HARP1, an effector from the oral secretions of cotton bollworm (Helicoverpa armigera), enters plant cells via protein-mediated endocytosis. The entry of HARP1 into a plant cell depends on its interaction with vesicle trafficking components including CTL1, PATL2, and TET8. The plant defense hormone jasmonate (JA) restricts HARP1 import by inhibiting endocytosis and HARP1 loading into endosomes. Combined with the previous report that HARP1 inhibits JA signaling output in host plants, it unveils that the effector and JA establish a defense and counter-defense loop reflecting the robust arms race between plants and insects.
Identification of errors in draft genome assemblies at single-nucleotide resolution for quality assessment and improvement
Authors: Li Kunpeng , Xu Peng , Wang Jinpeng , Yi Xin , Jiao Yuannian
Published: October 2023

Assembly of a high-quality genome is important for downstream comparative and functional genomic studies. However, most tools for genome assembly assessment only give qualitative reports, which do not pinpoint assembly errors at specific regions. Here, we develop a new reference-free tool, Clipping information for Revealing Assembly Quality (CRAQ), which maps raw reads back to assembled sequences to identify regional and structural assembly errors based on effective clipped alignment information. Error counts are transformed into corresponding assembly evaluation indexes to reflect the assembly quality at single-nucleotide resolution. Notably, CRAQ distinguishes assembly errors from heterozygous sites or structural differences between haplotypes. This tool can clearly indicate low-quality regions and potential structural error breakpoints; thus, it can identify misjoined regions that should be split for further scaffold building and improvement of the assembly. We have benchmarked CRAQ on multiple genomes assembled using different strategies, and demonstrated the misjoin correction for improving the constructed pseudomolecules.
Liquid spherical shells are a non-equilibrium steady state of active droplets
Authors: Bergmann Alexander M. , Bauermann Jonathan , Bartolucci Giacomo , Donau Carsten , Stasi Michele , Holtmannspötter Anna-Lena , Jülicher Frank , Weber Christoph A. , Boekhoven Job
Published: October 2023

Liquid-liquid phase separation yields spherical droplets that eventually coarsen to one large, stable droplet governed by the principle of minimal free energy. In chemically fueled phase separation, the formation of phase-separating molecules is coupled to a fuel-driven, non-equilibrium reaction cycle. It thus yields dissipative structures sustained by a continuous fuel conversion. Such dissipative structures are ubiquitous in biology but are poorly understood as they are governed by non-equilibrium thermodynamics. Here, we bridge the gap between passive, close-to-equilibrium, and active, dissipative structures with chemically fueled phase separation. We observe that spherical, active droplets can undergo a morphological transition into a liquid, spherical shell. We demonstrate that the mechanism is related to gradients of short-lived droplet material. We characterize how far out of equilibrium the spherical shell state is and the chemical power necessary to sustain it. Our work suggests alternative avenues for assembling complex stable morphologies, which might already be exploited to form membraneless organelles by cells.
Beware the myth: learning styles affect parents’, children’s, and teachers’ thinking about children’s academic potential
Authors: Sun Xin , Norton Owen , Nancekivell Shaylene E.
Published: October 2023

Three experiments examine how providing learning style information (a student learns hands-on or visually) might influence thinking about that student’s academic potential. Samples were American and predominately white and middle-class. In Experiment 1, parents (N = 94) and children (N = 73, 6–12 years) judged students who learn visually as more intelligent than hands-on learners. Experiment 2 replicated this pattern with parents and teachers (N = 172). In Experiment 3 (pre-registered), parents and teachers (N = 200) predicted that visual learners are more skilled than hands-on learners at “core” school subjects (math/language/social sciences, except science), whereas, hands-on learners were skilled at non-core subjects (gym/music/art). Together, these studies show that learning style descriptions, resultant of a myth, impact thinking about children’s intellectual aptitudes.
Combined metabolomic and lipidomic analysis uncovers metabolic profile and biomarkers for papillary thyroid carcinoma
Authors: Wang Zipeng , Yang Yiqin , Xing Yurong , Si Dandan , Wang Suhua , Lin Jiashuo , Li Cai , Zhang Ji , Yin Detao
Published: October 2023

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy with a rapidly increasing incidence. The pathogenesis of PTC is unclear, but metabolic and lipidomic reprogramming may play a role in tumor growth. We applied ultra-performance liquid chromatography-tandem mass spectrometry to perform widely targeted metabolomics and lipidomics on plasma samples from 94 patients with PTC and 100 healthy controls. We identified 113 differential metabolites and 236 differential lipids, mainly involved in branched-chain amino acid metabolism, glutamate and glutamine metabolism, tricarboxylic acid cycle, and lipid metabolism. We also screened three potential metabolite biomarkers: sebacic acid, L-glutamine, and indole-3-carboxaldehyde. These biomarkers showed excellent diagnostic performance for PTC in both discovery and validation cohorts, with areas under the receiver operating characteristic curves of 0.994 and 0.925, respectively. Our findings reveal distinct metabolic and lipidomic features of PTC and provide novel targets for diagnosis and treatment.