bluuebunny/crossref_metadata_2025 huggingface dataset:
Valproic acid increases CAR T cell cytotoxicity against acute myeloid leukemia
Authors: Wen Jingjing , Chen Yanxin , Yang Jiajie , Dai Chunye , Yu Shenjie , Zhong Wenting , Liu Lilin , He Chengguanng , Zhang Wenmin , Yang Ting , Liu Lingfeng , Hu Jianda
Published: July 2023

The treatment of B cell malignancies has dramatically changed with the introduction of immunotherapy, especially chimeric antigen receptor T (CAR-T) cell therapy. However, only limited efficacy is observed in acute myeloid leukaemia (AML). In the study, We detected CD123 and CLL-1 expression on leukaemia cells from Relapsed/Refractory AML (R/R AML) patients. Then, we constructed anti-CD123 CAR and CLL-1 CAR with different co-stimulation domains (CD28 or 4-1BB) and detected their anti-AML effects. To increase the efficacy of CAR-T cell therapy, we tested different strategies, including application of combined checkpoint inhibitors and histone deacetylase inhibitors (HDACi)in vivoandin vitro. We found CD123 and CLL-1 were highly expressed on AML cells. The proportions of T cell subsets and NK cells involved in anti-tumour or anti-inflammation processes in AML patients significantly decreased when compared with healthy donors. Both CD123 CAR and CLL-1 CAR displayed specific anti-AML effectsin vitro. To improve the lysis effects of CAR-T cells, we combined CAR-T cell therapy with different agents. PD-1/PD-L1 antibodies only slightly improved the potency of CAR-T cell therapy (CD123 CAR-T 60.92% ± 2.9087% vs. 65.43% ± 2.1893%, 60.92% ± 2.9087% vs. 67.43% ± 3.4973%; 37.37% ± 3.908% vs. 41.89% ± 5.1568%, 37.37% ± 3.908% vs. 42.84% ± 4.2635%). However, one HDACi (valproic acid [VPA]) significantly improved CAR-T cell potency against AML cells (CLL-1 CAR-T 34.97% ± 0.3051% vs. 88.167% ± 1.5327%, p < 0.0001; CD123 CAR-T 26.87% ± 2.7010% vs. 82.56% ± 3.086%, p < 0.0001 in MV411; CLL-1 CAR-T 78.77% ± 1.2061% vs. 93.743% ± 1.2333%, p < 0.0001; CD123 CAR-T 64.10% ± 1.5130% vs. 94.427% ± 0.142%, p = 0.0001 in THP-1). Combination therapy prolonged the overall survival of mice when compared with single CD123 CAR-T cell therapy (median survival: 180 days vs. unfollowed). A possible mechanism is that activated CD8+T cells upregulate natural-killer group 2 member D (NKG2D), and VPA upregulates NKG2D ligand expression in AML cells, contributing to NKG2D-mediated cytotoxicity of CAR-T cells against tumour cells. In conclusion, CD123 and CLL-1 are promising targets for AML CAR-T cell therapy. A combination of VPA pre-treatment and CAR-T against AML exhibits synergic effects.
The digital motor output: a conceptual framework for a meaningful clinical performance metric for a motor neuroprosthesis
Authors: Sawyer Abbey , Cooke Lily , Ramsey Nick F , Putrino David
Published: July 2023

In recent years, the majority of the population has become increasingly reliant on continuous and independent control of smart devices to conduct activities of daily living. Upper extremity movement is typically required to generate the motor outputs that control these interfaces, such as rapidly and accurately navigating and clicking a mouse, or activating a touch screen. For people living with tetraplegia, these abilities are lost, significantly compromising their ability to interact with their environment. Implantable brain computer interfaces (BCIs) hold promise for restoring lost neurologic function, including motor neuroprostheses (MNPs). An implantable MNP can directly infer motor intent by detecting brain signals and transmitting the motor signal out of the brain to generate a motor output and subsequently control computer actions. This physiological function is typically performed by the motor neurons in the human body. To evaluate the use of these implanted technologies, there is a need for an objective measurement of the effectiveness of MNPs in restoring motor outputs. Here, we propose the concept of digital motor outputs (DMOs) to address this: a motor output decoded directly from a neural recording during an attempted limb or orofacial movement is transformed into a command that controls an electronic device. Digital motor outputs are diverse and can be categorized as discrete or continuous representations of motor control, and the clinical utility of the control of a single, discrete DMO has been reported in multiple studies. This sets the stage for the DMO to emerge as a quantitative measure of MNP performance.
Intrinsic motivation
Authors: McNaughton Harry , Fu Vivian
Published: July 2023

The prevailing wisdom in neurological rehabilitation, and particularly for stroke, is that physical therapies are the key to improvements in function. Despite accepting the importance of ‘the motivated patient’, the lack of simple, proven ways to improve intrinsic motivation has hindered efforts to combine physical therapies with motivation. Now there is available a simple, free, well-validated approach to encourage intrinsic motivation (‘Take Charge’). The benefits for people who have had a stroke are well-established but this could be applied to people with a range of neurological and other disorders. We provide the evidential support for this approach and suggest ways of incorporating it into daily practice.
Recent trends in asthma diagnosis, preschool wheeze diagnosis and asthma exacerbations in English children and adolescents: a SABINA Jr study
Authors: Kallis Constantinos , Maslova Ekaterina , Morgan Ann D , Sinha Ian , Roberts Graham , van der Valk Ralf J P , Quint Jennifer K , Tran Trung N
Published: July 2023

Background

Asthma-related burden remains poorly characterised in children in the UK. We quantified recent trends in asthma prevalence and burden in a UK population-based cohort (1‒17-year-olds).

Methods

The Clinical Practice Research Datalink Aurum database (2008‒2018) was used to assess annual asthma incidence and prevalence in 1‒17-year-olds and preschool wheeze in 1‒5-year-olds, stratified by sex and age. During the same period, annual asthma exacerbation rates were assessed in those with either a diagnosis of preschool wheeze or asthma.

Results

Annual asthma incidence rates decreased by 51% from 1403.4 (95% CI 1383.7 to 1423.2) in 2008 to 688.0 (95% CI 676.3 to 699.9) per 105person-years (PYs) in 2018, with the most pronounced decrease observed in 1‒5-year olds (decreasing by 65%, from 2556.9 (95% CI 2509.8 to 2604.7) to 892.3 (95% CI 866.9 to 918.3) per 105PYs). The corresponding decreases for the 6‒11- and 12‒17-year-olds were 36% (1139.9 (95% CI 1110.6 to 1169.7) to 739.9 (95% CI 720.5 to 759.8)) and 20% (572.3 (95% CI 550.4 to 594.9) to 459.5 (95% CI 442.9 to 476.4)) per 105PYs, respectively. The incidence of preschool wheeze decreased over time and was slightly more pronounced in the 1‒3 year-olds than in the 4-year-olds. Prevalence of asthma and preschool wheeze also decreased over time, from 18.0% overall in 2008 to 10.2% in 2018 for asthma. Exacerbation rates increased over time from 1.33 (95% CI 1.31 to 1.35) per 10 PYs in 2008 to 1.81 (95% CI 1.78 to 1.83) per 10 PYs in 2018.

Conclusion

Paediatric asthma incidence decreased in the UK since 2008, particularly in 1–5-year-olds; this was accompanied by a decline in asthma prevalence. Preschool wheeze incidence also decreased in this age group. However, exacerbation rates have been increasing.
Readmission following hospital admission for community-acquired pneumonia in England
Authors: Lawrence Hannah , McKeever Tricia M , Lim Wei Shen
Published: July 2023

Introduction

Readmission rates following hospital admission with community-acquired pneumonia (CAP) have increased in the UK over the past decade. The aim of this work was to describe the cohort of patients with emergency 30-day readmission following hospitalisation for CAP in England and explore the reasons for this.

Methods

A retrospective analysis of cases from the British Thoracic Society national adult CAP audit admitted to hospitals in England with CAP between 1 December 2018 and 31 January 2019 was performed. Cases were linked with corresponding patient level data from Hospital Episode statistics, providing data on the primary diagnosis treated during readmission and mortality. Analyses were performed describing the cohort of patients readmitted within 30 days, reasons for readmission and comparing those readmitted and primarily treated for pneumonia with other diagnoses.

Results

Of 8136 cases who survived an index admission with CAP, 1304 (15.7%) were readmitted as an emergency within 30 days of discharge. The main problems treated on readmission were pneumonia in 516 (39.6%) patients and other respiratory disorders in 284 (21.8%). Readmission with pneumonia compared with all other diagnoses was associated with significant inpatient mortality (15.9% vs 6.5%; aOR 2.76, 95% CI 1.86 to 4.09, p<0.001). A diagnosis of hospital-acquired infection was more frequent in readmissions treated for pneumonia than other diagnoses (22.1% vs 3.9%, p<0.001).

Conclusion

Pneumonia is the most common condition treated on readmission following hospitalisation with CAP and carries a higher mortality than both the index admission or readmission due to other diagnoses. Strategies to reduce readmissions due to pneumonia are required.
Entanglement entropy of Compton scattering with a witness
Authors: Shivashankara Shanmuka
Published: July 2023

Unitarity and the optical theorem are used to derive the reduced density matrices of Compton scattering in the presence of a witness particle. Two photons are initially entangled wherein one photon participates in Compton scattering, while the other is a witness, i.e., does not interact with the electron. Unitarity is shown to require that the entanglement entropy of the witness photon does not change after its entangled partner undergoes scattering. The final mutual information of the electron's and witness particle’s polarizations is shown to be nonzero for low-energy Compton scattering. This indicates that the two particles became correlated in spite of no direct interaction. Assuming an initial maximally entangled state, the change in entanglement entropy of the scattered photon’s polarization is calculated in terms of Stokes parameters. A common ratio of areas occurs in the final reduced density matrix elements, von Neumann entropies, Stokes parameter, and mutual information. This common ratio consists of the Thomson scattering cross-section and an accessible regularized scattering area.
NLO + parton-shower generator for $$\varvec{Wc}$$ production in the POWHEG BOX RES
Authors: Ferrario Ravasio Silvia , Oleari Carlo
Published: July 2023

We present the implementation of a next-to-leading-order plus parton-shower event generator for the hadronic production of a heavy charm quark accompanied by a leptonically-decaying W boson in the framework. We consider both signatures, i.e. $$pp\rightarrow c\, \ell ^- {\bar{\nu }}_{\ell }$$

p
p
→
c

ℓ
-

ν

¯

ℓ

and $$pp\rightarrow {\bar{c}} \,\ell ^+ {\nu }_{\ell }$$

p
p
→

c

¯

ℓ
+

ν
ℓ

, and we include exactly off-shell and spin-correlation effects, as well as off-diagonal Cabibbo–Kobayashi–Maskawa contributions. We present particle-level results, obtained interfacing our code with the and shower Monte Carlo event generators, including hadronization and underlying-event effects, and compare them against the data collected by the CMS Collaboration at $$\sqrt{s}=13$$

s

=
13

 TeV.
Channel capacity: limitation of entropy rate during cell signal transduction
Authors: Tsuruyama Tatsuaki
Published: July 2023

Cellular signal transduction is mediated through chain activation reactions involving signalling molecules. Information thermodynamics may be a promising approach for quantifying signal transduction. A cell signal is transduced through the signal molecule activation as a step of a signal transduction cascade. In each step, two types of entropy can be defined. First, the signal transduction was defined using thermodynamic entropy production during the chemical activation of signal molecules. Second, the chronology was described as a code string, and the logarithm of the number of signal code strings corresponded to the information entropy. Finally, the total entropy during signal transduction was determined by summing the two entropies. When maximising the total entropy, the total entropy rate per signalling molecule concentration was found to be consistent independently of each transduction step (i.e., signal molecule types). Consequently, the speed limit of the entropy rate can be calculated, providing the capacity, which is an essential property of the signal transduction cascade. The theory introduced here is expected to provide a basic framework for understanding new methods of discovering signal cascades and intracellular signal transduction.
The dynamic analysis of discrete fractional-order two-gene map
Authors: Subramani Rajeshkanna , Natiq Hayder , Rajagopal Karthikeyan , Krejcar Ondrej , Namazi Hamidreza
Published: July 2023

The evolutionary processes are based on information transmission by nervous systems and inheritance by genes in DNA. Various continuous and discrete mathematical models have been presented for genes. Discrete gene models are particularly interesting due to their simple analysis and low computational costs. It is imperative to create genetic factors based on gene models that depend on the past. This paper proposes a discrete fractional-order two-gene map model. At first, the gene map is evaluated using the phase plane, bifurcation diagram, and Lyapunov exponent, and the periodic and chaotic behaviors of the system are shown. Then, the fractional-order gene map model is introduced. The system’s dynamic behaviors are investigated using bifurcation diagrams according to system parameters and derivative order. It is shown that increasing the value of the fractional order increases complexity, leading to chaotic behavior in the model. While decreasing the fractional derivative order mostly changes the dynamics to periodic. Finally, the synchronization of two two-gene maps with discrete fractional order is investigated using the electrical connection. The results show that in contrast to the integer-order model, the fractional-order model can reach synchronization.
Dissociative recombination of N$$_2$$$$\hbox {H}^+$$: a revisited study
Authors: Mezei János Zsolt , Ayouz Mehdi A. , Orbán Andrea , Abdoulanziz Abdillah , Talbi Dahbia , Kashinski David O. , Bron Emeric , Kokoouline Viatcheslav , Schneider Ioan F.
Published: July 2023

Dissociative recombination of N$$_2$$

2

H$$^+$$

+

is explored in a two-step theoretical study. In a first step, a diatomic (1D) rough model with a frozen NN bond and frozen angles is adopted, in the framework of the multichannel quantum defect theory (MQDT). The importance of the indirect mechanism and of the bending mode is revealed, in spite of the disagreement between our cross section and the experimental one. In the second step, we use our recently elaborated 3D approach based on the normal mode approximation combined with R-matrix theory and MQDT. This approach results in satisfactory agreement with storage-ring measurements, significantly better at very low energy than the former calculations.
Schisanhenol Attenuates OxLDL-Induced Endothelial Dysfunction via an AMPK-Dependent Mechanism
Authors: Chiu Tsan-Hung , Ku Chang-Wen , Ho Tsung-Jung , Tsai Kun-Ling , Hsu Wei-Ching , Chen Yu-An , Ou Hsiu-Chung , Chen Hsiu-I
Published: July 2023

Atherosclerotic cardiovascular diseases, commonly known as the formation of fibrofatty lesions in the artery wall, are the leading causes of death globally. Oxidized low-density lipoprotein (oxLDL) is one of the major components of atherosclerotic plaques. It is evident that dietary supplementation containing sources of antioxidants can prevent atherogenic diseases. Schisanhenol (SAL), a dibenzocyclooctene lignin, has been shown to attenuate oxLDL-induced apoptosis and the generation of reactive oxygen species (ROS) in endothelial cells. However, the underlying molecular mechanisms are still largely unknown. In this study, human umbilical vein endothelial cells (HUVECs) were pre-treated with SAL and oxLDL. Our results showed that adenosine monophosphate-activated protein kinase (AMPK) phosphorylation was enhanced in cells pre-treated with SAL in time-dependent and dose-dependent manners. Subsequently, oxLDL-induced AMPK dephosphorylation and protein kinase C (PKC) phosphorylation were significantly reversed in the presence of SAL. In addition, SAL treatment led to an inhibiting effect on the oxLDL-induced membrane assembly of NADPH oxidase subunits, and a similar effect was observed in ROS generation. This effect was further confirmed using knockdown AMPK with small interfering RNA (siRNA) and pharmaceutical reagents, such as the AMPK activator (AICAR), PKC inhibitor (Gö 6983), and ROS inhibitor (DPI). Furthermore, the oxLDL-induced intracellular calcium rise and the potential collapse of the mitochondrial membrane reduced the Bcl-2/Bax ratio, and released cytochrome c from the mitochondria, leading to the subsequent activation of caspase-3 in HUVECs, which were also markedly suppressed by SAL pretreatment. The results mentioned above may provide additional insights into the possible molecular mechanisms underlying the cardiovascular protective effects of SAL.
Significance of multi-slips and thermal radiation for unsteady MHD nanofluid flow subject to gyrotactic microorganisms and Cattaneo–Christov heat flux model over a stretching sheet
Authors: Haider Syed Muhammad Ali , Ali Bagh , Wang Qiuwang , Zhao Cunlu
Published: July 2023

This study considered the Cattaneo–Christov heat flux for examining the nanofluid flow with heat transfer towards a stretching sheet involving thermal and solutal buoyancy, activation energy, thermal radiation, and microorganism concentration. It is suggested that the model of Buongiorno nanofluid can be used to sync the influences of thermophoresis and Brownian motion. The 2D boundary layer with non-Fourier PDEs is converted into 1D nonlinear ODEs. Using the RK-4 method, the acquired equations were analyzed numerically. In this regard, the relevant engineering quantities are extensively computed with a higher degree of precision and then tabulated. The motile concentration, temperature, nanoparticles concentration, and velocity decline for numerous values of involved parameters such as slips of microorganism concentration, thermal, solutal, and hydrodynamic, respectively. The temperature field decreased when the parameter of thermal relaxation was imposed, while the reverse behavior was shown for thermophoresis, radiation parameter, and Brownian motion. The current results manifest a reasonable assessment of their existing counterparts.
Change in momentum proportional to the change in angular momentum of the particle
Authors: Zhu Zi-Zhong
Published: July 2023

Recently, Ahn et al. created dumbbell-shaped silica nanoparticles, then optically levitated in vacuum, capable of spinning at 300 billion revolutions per minute, driven only by the force and torque of laser. This is by far the fastest spinning object in the world. We show that in this system, there is an additional change in momentum (or extra force) that is proportional to the change in the angular momentum of the particle (or torque). We suggest that this effect also applies to microscopic particles. In the experiment of Ahn et al., although the angular momentum of the particle itself L is large, the rate of change of the angular momentum [Formula: see text] may not be large. Therefore, experimentally, the physical effects associated with changes in angular momentum can be verified either by applying very strong force and torque to the particle, or by allowing the axis of rotation of the particle to find a way to change very quickly.
Neolearning Methodology Applied to the Networked University
Authors: Bresolin Graziela Grando , de Sá Freire Patricia
Published: July 2023

Neolearning was developed as a teaching and learning methodological platform for the Networked University (NU) model in order to promote experiential and expansive learning for competence development and facilitate the transfer of learning into work practice. The objective of this paper is to analyse the Neolearning as a methodological support for the NU model. To achieve this objective, a qualitative approach was chosen for exploratory and descriptive purposes, through a narrative literature review and multiple case study. This paper presents the main approaches and theories that underlie the NU and the Neolearning methodology. It also presents the guidelines of the NU, the Neolearning cycle, the mechanisms that facilitate the application of Neolearning in the NU, and the analysis of these mechanisms in three case studies. In conclusion, it is confirmed that the Neolearning methodology is aligned with the NU model and attends to the objective of support the teaching and learning processes. Neolearning has been validated in empirical research, both in academic and corporate universities (CUs), as well as in undergraduate courses, graduate programs, and online courses, in face-to-face or remote learning modalities.
Influence of Customer Participation on Co-Creation Intention of Brand Value under Social Media
Authors: Lin Mengfei , Wang Zhihua , Chen Chunfeng
Published: July 2023

The purpose of this paper is to investigate if customer participation has the double-edged sword problem and how it impacts the co-creation intention of brand value under social media. To explore the relationship, we construct a research model from the perspective of value co-creation and cognitive behaviour theory in the context of social media. 385 valid samples were collected through a field questionnaire, and the structural equation model was used to test the research hypotheses. The results indicate that customer participation through social media has a double-edged sword effect, enhancing the perceived prosocial influence, but also causing social media fatigue. Perceived prosocial influence and social media fatigue play a dual mediating effect on the relationship between customer participation and co-creation intention of brand value. Moreover, brand attachment moderates the relationship between perceived prosocial influence and co-creation intention of brand value. Majority of the studies have found that customer participation has positive effect, but a few studies have found that customer participation has a certain “dark side”. This study focuses on the double-edged sword problem of customer participation through social media, as well as its effect on co-creation intention of brand value, thus contribution to the value co-creation theory. This research also analyses the positive effect of perceived prosocial influence and the negative effects of social media fatigue, thus supporting effective social media participation strategies for companies.
What are the main sources of air pollution in Sofia, Bulgaria, and how do they impact human health in the city?
Authors: Shuleva Anna
Published: July 2023

In our modern world, air pollution is a significantly increasing issue. Sofia, the capital city of Bulgaria, is one of the most polluted cities in Europe. It has been a long-standing issue, with pollution levels regularly exceeding the recommended limits set by the World Health Organization.

The main causes of pollution in Sofia include the burning of garbage for residential heating, and emissions from vehicles due to heavy traffic. These factors especially worsen the situation during winter because of low winds and temperature inversions. This can be incredibly harmful to the health of the residents, with long-term exposure causing lung infections or cancer and possibly leading to death.

In recent years, several steps have been taken by the municipality and the residents to address the issue, some of which have proven successful. However, there are still further efforts needed to be undertaken.
Characterization of silicification and dissolution zones by integrating borehole image logs and core samples: a case study of a well from the Brazilian pre-salt
Authors: Basso M. , Chinelatto G. F. , Belila A. M. P. , Mendes L. C. , Souza J. P. P. , Stefanelli D. , Vidal A. C. , Bueno J. F.
Published: July 2023

Precise knowledge of the spatial distribution patterns of non-matrix porosity zones and the establishment of the geological factors controlling their evolution are crucial for building more accurate carbonate reservoir models and improving hydrocarbon production. The occurrence of intervals affected by significant carbonate dissolution may result in drilling fluid loss and time-consuming drawbacks during well construction. Vug or cave-rich reservoirs may exhibit excess permeability and extremely high initial flow rates. Similar situations have been reported in exploration activities in the Brazilian pre-salt plays, where evidence of dissolution and other burial diagenetic processes, such as severe silicification and dolomitization, are common. In this study, we investigate evidence of major post-depositional changes in the lacustrine carbonate reservoirs of the Barra Velha Formation, which comprises the most prolific hydrocarbon play in Brazil. Using a comprehensive database consisting of both core samples and well-log data from a vertical well in the Santos Basin, we have characterized, at multiple scales, reservoir zones affected by silicification and carbonate dissolution. In addition, we have performed a petrophysical evaluation of the reservoir to understand the impact of such processes on porosity and permeability development. The results suggested an intimate relationship between silicification and dissolution processes, which can be associated with late fluid percolation under a deep burial flow regime. The occurrence of silicified and vuggy beds, associated with specific zones and lithofacies, indicates an important degree of stratigraphic control on fluid percolation and lateral migration. Furthermore, the presence of fractures at discrete stratigraphic levels has preferentially influenced the development of high-permeability zones, including metric-scale fracture-related conduits. This study contributes to the general knowledge of carbonate reservoirs affected by silicification and dissolution while providing support for the recognition of such processes in partially- or non-cored wells.
LaF: Labeling-free Model Selection for Automated Deep Neural Network Reusing
Authors: Hu Qiang , Guo Yuejun , Xie Xiaofei , Cordy Maxime , Papadakis Mike , Le Traon Yves
Published: July 2023

Applying deep learning (DL) to science is a new trend in recent years, which leads DL engineering to become an important problem. Although training data preparation, model architecture design, and model training are the normal processes to build DL models, all of them are complex and costly. Therefore, reusing the open-sourced pre-trained model is a practical way to bypass this hurdle for developers. Given a specific task, developers can collect massive pre-trained deep neural networks from public sources for reusing. However, testing the performance (e.g., accuracy and robustness) of multiple deep neural networks (DNNs) and recommending which model should be used is challenging regarding the scarcity of labeled data and the demand for domain expertise. In this article, we propose a labeling-free (LaF) model selection approach to overcome the limitations of labeling efforts for automated model reusing. The main idea is to statistically learn a Bayesian model to infer the models’ specialty only based on predicted labels. We evaluate LaF using nine benchmark datasets, including image, text, and source code, and 165 DNNs, considering both the accuracy and robustness of models. The experimental results demonstrate that LaF outperforms the baseline methods by up to 0.74 and 0.53 on Spearman’s correlation and Kendall’s τ, respectively.
Interruptible Remote Attestation of Low-end IoT Microcontrollers via Performance Counters
Authors: Li Calsi Davide , Zaccaria Vittorio
Published: July 2023

Remote attestation is a method used in distributed systems to detect integrity violations on a target device (prover) through a challenge–response protocol initiated by a verifier device. The prover calculates a hash of its memory, which is compared to a known good state hash by the verifier. We propose a novel technique, called Counters Help Against Roving Malware (CHARM), which uses hardware performance counters on the prover’s side and machine learning on the verifier’s side to make interruptible remote attestation feasible, even for constrained microcontrollers. We will demonstrate the effectiveness of various machine learning tools and data manipulation techniques on prediction accuracy in a variety of scenarios.
How to Use Microdata for Macro-Finance
Authors: Sraer David , Thesmar David
Published: July 2023

Financial frictions generate misallocation of resources across firms by restricting productive firms’ access to capital. This article reviews the literature that estimates the aggregate losses generated by such misallocation. The first approach relies on structural estimations: A model of firm dynamics with financial frictions is typically estimated and used to compare efficiency in the actual economy with a counterfactual with perfect financial markets. We argue that robustness is a central concern for this structural literature and discuss ways to analyze robustness in structural estimation (using well-identified moments and analyzing sensitivity to moments). The second approach relies on sufficient statistics, namely formulas that measure misallocation using simple empirical statistics and that are valid for a class of models. We discuss key contributions in that space, the generality of this approach, and the conditions under which it is valid. Sufficient statistic approaches are simpler and more robust, but they come at a cost: The range of counterfactual analyses that can be explored is more limited.
Reno- and cardioprotective molecular mechanisms of SGLT2 inhibitors beyond glycemic control: from bedside to bench
Authors: Chen Xin , Hocher Carl-Friedrich , Shen Linghong , Krämer Bernhard K. , Hocher Berthold
Published: July 2023

Large placebo-controlled clinical trials have shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) delay the deterioration of renal function and reduce cardiovascular events in a glucose-independent manner, thereby ultimately reducing mortality in patients with chronic kidney disease (CKD) and/or heart failure. These existing clinical data stimulated preclinical studies aiming to understand the observed clinical effects. In animal models, it was shown that the beneficial effect of SGLT2i on the tubuloglomerular feedback (TGF) improves glomerular pressure and reduces tubular workload by improving renal hemodynamics, which appears to be dependent on salt intake. High salt intake might blunt the SGLT2i effects on the TGF. Beyond the salt-dependent effects of SGLT2i on renal hemodynamics, SGLT2i inhibited several key aspects of macrophage-mediated renal inflammation and fibrosis, including inhibiting the differentiation of monocytes to macrophages, promoting the polarization of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype, and suppressing the activation of inflammasomes and major proinflammatory factors. As macrophages are also important cells mediating atherosclerosis and myocardial remodeling after injury, the inhibitory effects of SGLT2i on macrophage differentiation and inflammatory responses may also play a role in stabilizing atherosclerotic plaques and ameliorating myocardial inflammation and fibrosis. Recent studies suggest that SGLT2i may also act directly on the Na+/H+ exchanger and Late-INa in cardiomyocytes thus reducing Na+ and Ca2+ overload-mediated myocardial damage. In addition, the renal-cardioprotective mechanisms of SGLT2i include systemic effects on the sympathetic nervous system, blood volume, salt excretion, and energy metabolism.
Renal and hypothalamic inflammation in renovascular hypertension: role of afferent renal nerves
Authors: Lauar Mariana R. , Evans Louise C. , Van Helden Dusty , Fink Gregory D. , Banek Christopher T. , Menani José V. , Osborn John W.
Published: July 2023

Hypertension resulting from reduced perfusion of the kidney is dependent on renal sensory nerves, which are linked to inflammation in the kidney and hypothalamus. Afferent renal nerves are required for chronic increases in both water intake and vasopressin release observed following renal artery stenosis. Findings from this study suggest an important role of renal sensory nerves that has previously been underestimated in the pathogenesis of 2K1C hypertension.
Sex differences in weight gain, blood pressure control, and responses to melanocortin-4 receptor antagonism in offspring from lean and obese parents
Authors: do Carmo Jussara M. , Dai Xuemei , Aitken Nikaela , Larson Kylie M. , Omoto Ana C. M. , Gulke Rodrigo R. , Wang Zhen , Li Xuan , Mouton Alan J. , Hall John E. , da Silva Alexandre A.
Published: July 2023

We examined potential sex differences in appetite and blood pressure (BP) responses to melanocortin-4 receptor (MC4R) blockade in offspring from lean and obese parents. Offspring from normal (N) diet-fed parents were fed N (NN) or high-fat (H) diets (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were also fed N (HN) or H diets (HH). Adult male and female offspring were implanted with BP telemetry probes and intracerebroventricular cannulas to infuse MC4R antagonist or vehicle. Infusion of the MC4R antagonist SHU-9119 (1 nmol/h) for 7 days caused larger increases in calorie intake and body weight in obese compared with lean offspring. In male offspring, HH and HN groups exhibited higher baseline BP compared with NN and NH, and HH showed a greater reduction in BP during SHU-9119 infusion. In female offspring, HH also showed higher baseline BP and greater reduction in BP during MC4R blockade. SHU-9119 reduced heart rate in all groups, but reductions were more pronounced in offspring from lean parents. Combined α and β-adrenergic blockade reduced BP more in male HH offspring compared with NN controls. Losartan reduced BP more in male NH, HN, and HH offspring compared with NN controls. Losartan and α- and β-adrenergic blockade reduced BP similarly in all female groups. These results suggest that endogenous MC4R activity contributes to elevated BP in obese offspring from obese parents. Our findings also indicate important sex differences in the mechanisms of BP control in male and female offspring of obese parents.
Ponderings on peer review. Part 2. Manuscript critiques
Authors: Seals Douglas R.
Published: July 2023

In part 1 of this Perspective, I discussed general principles of scientific peer review in the biomedical sciences aimed at early-stage investigators (i.e., graduate students, postdoctoral fellows, and junior faculty). Here in part 2, I share my thoughts specifically on the topic of peer review of manuscripts. I begin by defining manuscript peer review and discussing the goals and importance of the concept. I then describe the organizational structure of the process, including the two distinct stages involved. Next, I emphasize several important considerations for manuscript reviewers, both general points and key considerations when evaluating specific types of papers, including original research manuscripts, reviews, methods articles, and opinion pieces. I then advance some practical suggestions for developing the written critique document, offer advice for making an overall recommendation to the editor (i.e., accept, revise, reject), and describe the unique issues involved when assessing a revised manuscript. Finally, I comment on how best to gain experience in the essential academic research skill of manuscript peer review. In part 3 of the series, I will discuss the topic of reviewing grant applications submitted to research funding agencies.
Vibration Analysis of Viscoelastic Timoshenko Cracked Beams with Massless Viscoelastic Rotational Spring Models
Authors: Fu Chao
Published: July 2023

Based on the equivalent bending stiffness of the viscoelastic cracked beam with open cracks, the corresponding complex frequency characteristic equations of a Timoshenko viscoelastic cracked beam are obtained by using the method of separation of variables and the Laplace transform. The vibration characteristics of a viscoelastic Timoshenko cracked beams with the standard linear solid model and Kelvin-Voigt model are investigated. By numerical examples, the effects of the crack location, crack number, crack depth, and slenderness ratio on the vibration characteristics of the viscoelastic cracked beams are revealed.
AD‐Graph: Weakly Supervised Anomaly Detection Graph Neural Network
Authors: Ullah Waseem , Hussain Tanveer , Min Ullah Fath U , Muhammad Khan , Hassaballah Mahmoud , Rodrigues Joel J. P. C. , Baik Sung Wook , Albuquerque Victor Hugo C. de
Published: July 2023

The main challenge faced by video‐based real‐world anomaly detection systems is the accurate learning of unusual events that are irregular, complicated, diverse, and heterogeneous in nature. Several techniques utilizing deep learning have been created to detect anomalies, yet their effectiveness on real‐world data is often limited due to the insufficient incorporation of motion patterns. To address these problems and enhance the traditional functionality of anomaly detection systems for surveillance video data, we propose a weakly supervised graph neural‐network‐assisted video anomaly detection framework called AD‐Graph. To identify temporal information from a series of frames, we extract 3D visual and motion features and represent these in a language‐based knowledge graph format. Next, a robust clustering strategy is applied to group together meaningful neighbourhoods of the graph with similar vertices. Furthermore, spectral filters are applied to these graphs, and spectral graph theory is used to generate graph signals and detect anomalous events. Extensive experimental results over two challenging datasets, UCF‐Crime and ShanghaiTech, show improvements of 0.35% and 0.78% against a state‐of‐the‐art model.
Aptamer-Based Strategies to Address Challenges in COVID-19 Diagnosis and Treatments
Authors: Chang Zi Yuan , Alhamami Falah Abbas Mohamad Salih , Chin Kai Ling
Published: July 2023

Coronavirus disease (COVID-19), a highly contagious and rapidly spreading disease with significant fatality in the elderly population, has swept across the world since 2019. Since its first appearance, the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has undergone multiple mutations, with Omicron as the predominant circulating variant of concern at the moment. The gold standard for diagnosis of COVID-19 by real-time polymerase chain reaction (RT-PCR) to detect the virus is laborious and requires well-trained personnel to perform sophisticated procedures. Also, the genetic variants of SARS-CoV-2 that arise regularly could result in false-negative detection. Meanwhile, the current COVID-19 treatments such as conventional medicine, complementary and alternative medicine, passive antibody therapy, and respiratory therapy are associated with adverse effects. Thus, there is an urgent need to discover novel diagnostic and therapeutic approaches against SARS-CoV-2 and its variants. Over the past 30 years, nucleic acid-based aptamers have gained increasing attention and serve as a promising alternative to the antibodies in the diagnostic and therapeutic fields with their uniqueness of being small, nonimmunogenicity, and thermally stable. Aptamer targeting the SARS-CoV-2 structural proteins or the host receptor proteins represent a powerful tool to control COVID-19 infection. In this review, challenges faced by currently available diagnostic and therapeutic tools for COVID-19 are underscored, along with how aptamers can shed a light on the current COVID-19 pandemic, focusing on the critical factors affecting the discovery of high-affinity aptamers and their potential applications to control COVID-19 infection.
Supplementary Data from Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy–Induced Necrosis
Authors: Ghosh Santanu , Yang Rachel , Duraki Darjan , Zhu Junyao , Kim Ji Eun , Jabeen Musarrat , Mao Chengjian , Dai Xinyi , Livezey Mara R. , Boudreau Matthew W. , Park Ben H. , Nelson Erik R. , Hergenrother Paul J. , Shapiro David J.
Published: July 2023

Supplementary Movie 1
Supplementary Data from Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy–Induced Necrosis
Authors: Ghosh Santanu , Yang Rachel , Duraki Darjan , Zhu Junyao , Kim Ji Eun , Jabeen Musarrat , Mao Chengjian , Dai Xinyi , Livezey Mara R. , Boudreau Matthew W. , Park Ben H. , Nelson Erik R. , Hergenrother Paul J. , Shapiro David J.
Published: July 2023

Supplementary Movie 2
Supplementary Data from Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy–Induced Necrosis
Authors: Ghosh Santanu , Yang Rachel , Duraki Darjan , Zhu Junyao , Kim Ji Eun , Jabeen Musarrat , Mao Chengjian , Dai Xinyi , Livezey Mara R. , Boudreau Matthew W. , Park Ben H. , Nelson Erik R. , Hergenrother Paul J. , Shapiro David J.
Published: July 2023

Supplementary Movie 4
Supplementary Figures from High-Throughput Drug Screening of Primary Tumor Cells Identifies Therapeutic Strategies for Treating Children with High-Risk Cancer
Authors: Mayoh Chelsea , Mao Jie , Xie Jinhan , Tax Gabor , Chow Shu-Oi , Cadiz Roxanne , Pazaky Karina , Barahona Paulette , Ajuyah Pamela , Trebilcock Peter , Malquori Angela , Gunther Kate , Avila Anica , Yun Doo Young , Alfred Stephanie , Gopalakrishnan Anjana , Kamili Alvin , Wong Marie , Cowley Mark J. , Jessop Sophie , Lau Loretta M.S. , Trahair Toby N. , Ziegler David S. , Fletcher Jamie I. , Gifford Andrew J. , Tsoli Maria , Marshall Glenn M. , Haber Michelle , Tyrrell Vanessa , Failes Timothy W. , Arndt Greg M. , Lock Richard B. , Ekert Paul G. , Dolman M. Emmy M.
Published: July 2023

Supplementary Figures
Data from Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy–Induced Necrosis
Authors: Ghosh Santanu , Yang Rachel , Duraki Darjan , Zhu Junyao , Kim Ji Eun , Jabeen Musarrat , Mao Chengjian , Dai Xinyi , Livezey Mara R. , Boudreau Matthew W. , Park Ben H. , Nelson Erik R. , Hergenrother Paul J. , Shapiro David J.
Published: July 2023

Abstract
Several emerging therapies kill cancer cells primarily by inducing necrosis. As necrosis activates immune cells, potentially, uncovering the molecular drivers of anticancer therapy–induced necrosis could reveal approaches for enhancing immunotherapy efficacy. To identify necrosis-associated genes, we performed a genome-wide CRISPR-Cas9 screen with negative selection against necrosis-inducing preclinical agents BHPI and conducted follow-on experiments with ErSO. The screen identified transient receptor potential melastatin member 4 (TRPM4), a calcium-activated, ATP-inhibited, sodium-selective plasma membrane channel. Cancer cells selected for resistance to BHPI and ErSO exhibited robust TRPM4 downregulation, and TRPM4 reexpression restored sensitivity to ErSO. Notably, TRPM4 knockout (TKO) abolished ErSO-induced regression of breast tumors in mice. Supporting a broad role for TRPM4 in necrosis, knockout of TRPM4 reversed cell death induced by four additional diverse necrosis-inducing cancer therapies. ErSO induced anticipatory unfolded protein response (a-UPR) hyperactivation, long-term necrotic cell death, and release of damage-associated molecular patterns that activated macrophages and increased monocyte migration, all of which was abolished by TKO. Furthermore, loss of TRPM4 suppressed the ErSO-induced increase in cell volume and depletion of ATP. These data suggest that ErSO triggers initial activation of the a-UPR but that it is TRPM4-mediated sodium influx and cell swelling, resulting in osmotic stress, which sustains and propagates lethal a-UPR hyperactivation. Thus, TRPM4 plays a pivotal role in sustaining lethal a-UPR hyperactivation that mediates the anticancer activity of diverse necrosis-inducing therapies.
Significance:
A genome-wide CRISPR screen reveals a pivotal role for TRPM4 in cell death and immune activation following treatment with diverse necrosis-inducing anticancer therapies, which could facilitate development of necrosis-based cancer immunotherapies.
Table S5 from Characterizing the Immune Microenvironment and Neoantigen Landscape of Hürthle Cell Carcinoma to Identify Potential Immunologic Vulnerabilities
Authors: Ganly Ian , Kuo Fengshen , Makarov Vladimir , Dong Yiyu , Ghossein Ronald , Xu Bin , Morris Luc G.T. , Chan Timothy A.
Published: July 2023

Neopeptides (10mer) associated with SNV alterations in HCC
Supp Figure S8 from Inhibition of Microsomal Prostaglandin E2 Synthase Reduces Collagen Deposition in Melanoma Tumors and May Improve Immunotherapy Efficacy by Reducing T-cell Exhaustion
Authors: Fukuda Yasunari , Kim Sun-Hee , Bustos Matias A. , Cho Sung-Nam , Roszik Jason , Burks Jared K. , Kim Hong , Hoon Dave S.B. , Grimm Elizabeth A. , Ekmekcioglu Suhendan
Published: July 2023

Figure S8 shows morphological differences between ptgs1-, ptgs2-, and ptges-KO murine BrafV600E melanoma cells by using phase-contrast microscopy
Supp Figure S1 from Inhibition of Microsomal Prostaglandin E2 Synthase Reduces Collagen Deposition in Melanoma Tumors and May Improve Immunotherapy Efficacy by Reducing T-cell Exhaustion
Authors: Fukuda Yasunari , Kim Sun-Hee , Bustos Matias A. , Cho Sung-Nam , Roszik Jason , Burks Jared K. , Kim Hong , Hoon Dave S.B. , Grimm Elizabeth A. , Ekmekcioglu Suhendan
Published: July 2023

Figure S1 shows the selection of ROIs in tumors
FIGURE 3 from Inhibition of Microsomal Prostaglandin E2 Synthase Reduces Collagen Deposition in Melanoma Tumors and May Improve Immunotherapy Efficacy by Reducing T-cell Exhaustion
Authors: Fukuda Yasunari , Kim Sun-Hee , Bustos Matias A. , Cho Sung-Nam , Roszik Jason , Burks Jared K. , Kim Hong , Hoon Dave S.B. , Grimm Elizabeth A. , Ekmekcioglu Suhendan
Published: July 2023

Collagen deposition and distribution of tumor-infiltrating immune cells in tumors derived from ptgs2-KO and ptges-KO murine BrafV600E melanoma cells. A, Left, Representative images of Masson's trichrome staining of tumors derived from scramble, ptgs2-KO, and ptges-KO cells. Scale bar = 100 μm. A, right, Collagen positivity (%) was automatically calculated using Visiopharm software. B–G, Distribution of tumor-infiltrating immune cells was compared between tumors from scramble, ptgs2-KO, and ptges-KO cells. The number of tumor-infiltrating immune cells was automatically calculated using Visiopharm software. Shown are the numbers of tumor-infiltrating CD8a+ cytotoxic T cells (B), tumor-infiltrating GrB+ effector CD8a+ T cells (C), tumor-infiltrating Tim3+ exhausted CD8a+ T cells (D), tumor-infiltrating classic CD8a+ DCs (E), tumor-infiltrating NK1.1+ NK cells (F), and tumor-infiltrating CD19+ B cells (G). Two to five ROIs, depending on tumor size, were randomly selected from each tumor and used for analyses. Graph values represent mean ± SD. Significance in difference between two groups was determined by Student t test. **, P < 0.01; *, P < 0.05.
FIGURE 3 from Characterizing the Immune Microenvironment and Neoantigen Landscape of Hürthle Cell Carcinoma to Identify Potential Immunologic Vulnerabilities
Authors: Ganly Ian , Kuo Fengshen , Makarov Vladimir , Dong Yiyu , Ghossein Ronald , Xu Bin , Morris Luc G.T. , Chan Timothy A.
Published: July 2023

The immune landscape of HCC stratified by the presence of mitochondrial mutations, TERT promoter mutations, and global LOH is shown in A using RNA-seq data. Tumors with global LOH have very low TIS, low CD8 cytotoxic T cells, CD4 helper cells. The immune landscape of tumors with global LOH compared with those without global LOH by IHC is shown in B. The box plots showing each individual change by RNA-seq are illustrated in Supplementary Fig. S4. Tumors with global LOH have very low TIS, low CD8 cytotoxic T cells, CD4 helper cells, central memory T cells, effector memory T cells. Validation by IHC is shown in B.