bluuebunny/crossref_metadata_2025 huggingface dataset:
Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy
Authors: Plewa Natalia , Poncette Lucia , Blankenstein Thomas
Published: February 2023

Background

Adoptive transfer of patient’s T cells, engineered to express a T cell receptor (TCR) with defined novel antigen specificity, is a convenient form of cancer therapy. In most cases, major histocompatibility complex (MHC) I-restricted TCRs are expressed in CD8+T cells and the development of CD4+T cells engineered to express an MHC II-restricted TCR lacks behind. Critical is the choice of the target antigen, whether the epitope is efficiently processed and binds with high affinity to MHC molecules. A mutation in the transforming growth factor β receptor 2 (TGFβR2(-1)) gene creates a frameshift peptide caused by the deletion of one adenine (-1) within a microsatellite sequence. This somatic mutation is recurrent in microsatellite instable colorectal and gastric cancers and, therefore, is a truly tumor-specific antigen detected in many patients.

Methods

ABabDR4 mice, which express a diverse human TCR repertoire restricted to human MHC II molecule HLA-DRA/DRB1*0401 (HLA-DR4), were immunized with the TGFβR2(-1) peptide and TGFβR2(-1)-specific TCRs were isolated from responding CD4+T cells. The TGFβR2(-1)-specific TCRs were expressed in human CD4+T cells and their potency and safety profile were assessed by co-cultures and other functional assays.

Results

We demonstrated that TGFβR2(-1) neoantigen is immunogenic and elicited CD4+T cell responses in ABabDR4 mice. When expressed in human CD4+T cells, the HLA-DR4 restricted TGFβR2(-1)-specific TCRs induced IFNy expression at low TGFβR2(-1) peptide amounts. The TGFβR2(-1)-specific TCRs recognized HLA-DR4+lymphoblastoid cells, which endogenously processed and presented the neoantigen, and colorectal cancer cell lines SW48 and HCT116 naturally expressing the TGFβR2(-1) mutation. No MHC II alloreactivity or cross-reactivity to peptides with a similar TCR-recognition motif were observed, indicating the safety of the TCRs.

Conclusions

The data suggest that HLA-DR4-restricted TCRs specific for the TGFβR2(-1) recurrent neoantigen can be valuable candidates for adoptive T cell therapy of a sizeable number of patients with cancer.
Predictive biomarkers for PD-1/PD-L1 checkpoint inhibitor response in NSCLC: an analysis of clinical trial and real-world data
Authors: So WeiQing Venus , Dejardin David , Rossmann Eva , Charo Jehad
Published: February 2023

Background

Many biomarkers have been proposed to be predictive of response to anti-programmed cell death protein-1 (PD-1)/anti-programmed death ligand-1 (PD-L1) checkpoint inhibitors (CPI). However, conflicting observations and lack of consensus call for an assessment of their clinical utility in a large data set. Using a combined data set of clinical trials and real-world data, we assessed the predictive and prognostic utility of biomarkers for clinical outcome of CPI in non-small cell lung cancer (NSCLC).

Methods

Retrospective cohort study using 24,152 patients selected from 71,850 patients with advanced NSCLC from electronic health records and 9 Roche atezolizumab trials. Patients were stratified into high and low biomarker groups. Correlation with treatment outcome in the different biomarker groups was investigated and compared between patients treated with CPI versus chemotherapy. Durable response was defined as having complete response/partial response without progression during the study period of 270 days.

Results

Standard blood analytes (eg, albumin and lymphocyte) were just prognostic, having correlation with clinical outcome irrespective of treatment type. High expression of PD-L1 on tumors (≥50% tumor cell staining) were specifically associated with response to CPI (OR 0.20; 95% CI 0.13 to 0.30; p<0.001). The association was stronger in patients with non-squamous than squamous histology, with smoking history than non-smokers, and with prior chemotherapy than first-line CPI. Higher tumor mutational burden (TMB) (≥10.44 mut/Mb) was also specifically associated with durable response to CPI (OR=0.40; 95% CI 0.29 to 0.54; p<0.001). The combination of high TMB and PD-L1 expression was the strongest predictor of durable response to CPI (OR=0.04; 95% CI 0.00 to 0.18; p<0.001). There was no significant association between PD-L1 or TMB levels with response to chemotherapy, suggesting a CPI-specific predictive effect.

Conclusions

Standard blood analytes had just prognostic utility, whereas tumor PD-L1 and TMB specifically predicted response to CPI in NSCLC. The combined high TMB and PD-L1 expression was the strongest predictor of durable response. PD-L1 was also a stronger predictor in patients with non-squamous histology, smoking history or prior chemotherapy.
Practical, epistemic and normative implications of algorithmic bias in healthcare artificial intelligence: a qualitative study of multidisciplinary expert perspectives
Authors: Aquino Yves Saint James , Carter Stacy M. , Houssami Nehmat , Braunack-Mayer Annette , Win Khin Than , Degeling Chris , Wang Lei , Rogers Wendy A
Published: February 2023

Background

There is a growing concern about artificial intelligence (AI) applications in healthcare that can disadvantage already under-represented and marginalised groups (eg, based on gender or race).

Objectives

Our objectives are to canvas the range of strategies stakeholders endorse in attempting to mitigate algorithmic bias, and to consider the ethical question of responsibility for algorithmic bias.

Methodology

The study involves in-depth, semistructured interviews with healthcare workers, screening programme managers, consumer health representatives, regulators, data scientists and developers.

Results

Findings reveal considerable divergent views on three key issues. First, views on whether bias is a problem in healthcare AI varied, with most participants agreeing bias is a problem (which we call the bias-critical view), a small number believing the opposite (the bias-denial view), and some arguing that the benefits of AI outweigh any harms or wrongs arising from the bias problem (the bias-apologist view). Second, there was a disagreement on the strategies to mitigate bias, and who is responsible for such strategies. Finally, there were divergent views on whether to include or exclude sociocultural identifiers (eg, race, ethnicity or gender-diverse identities) in the development of AI as a way to mitigate bias.

Conclusion/significance

Based on the views of participants, we set out responses that stakeholders might pursue, including greater interdisciplinary collaboration, tailored stakeholder engagement activities, empirical studies to understand algorithmic bias and strategies to modify dominant approaches in AI development such as the use of participatory methods, and increased diversity and inclusion in research teams and research participant recruitment and selection.
Pacritinib abrogates the lupus phenotype in ABIN1[D485N] mice
Authors: Petrova Tsvetana , Figueras-Vadillo Clara , Nanda Sambit K , Scudamore Cheryl , Cohen Philip
Published: February 2023

Objective

The aim of the study was to investigate whether the IRAK1/JAK2/Flt3 inhibitor pacritinib prevents disease development in the lupus-prone ABIN1[D485N] knock-in mouse.

Methods

ABIN1[D485N] knock-in mice aged 8 weeks were fed for 10 weeks on a diet containing pacritinib. Body weight was monitored, and serum collected at the end to measure pacritinib, autoantibody and immunoglobulin levels. Splenic immune cell populations were analysed, and the kidney, liver and lungs examined for pathology.

Results

Pacritinib prevented multiple facets of the lupus phenotype in ABIN1[D485N] knock-in mice, including splenomegaly, expansion of splenic germinal centre B cells, follicular T helper cells, and neutrophils, elevated serum levels of double-stranded DNA antibodies and immunoglobulins, glomerular IgA and lung inflammation.

Conclusions

Pacritinib may be useful for the treatment of multiorgan inflammation in patients with lupus.
Association between prolonged exposure to long working hours and stroke subtypes in the CONSTANCES cohort
Authors: Fadel Marc , Sembajwe Grace , Li Jian , Leclerc Annette , Pico Fernando , Schnitzler Alexis , Roquelaure Yves , Descatha Alexis
Published: February 2023

Background

Though there is increasing evidence on the effect of long working hours (LWH) and stroke, few studies have distinguished stroke subtypes. We examined the associations between LWH and ischaemic or haemorrhagic stroke after adjusting for cardiovascular risk factors.

Methods

From a national population-based cohort CONSTANCES, baseline questionnaires and initial health examinations were used to retrieve sociodemographic and cardiovascular risk factors from 2012 to 2018. LWH were defined as self-reported working time≥10 hours daily for at least 50 days per year. Incident cases of stroke were collected using International Classification of Disease codes recorded in the National Health Data System. Associations between LWH and stroke were investigated using multinomial models adjusted for cardiovascular risk factors.

Results

Among the 160 751 participants who were free from stroke at baseline, exposure to LWH≥10 years was reported by 20 723 participants, and 190 incident cases of stroke were identified, including 134 ischaemic and 56 haemorrhagic. Exposure to LWH was associated with an elevated odds of ischaemic stroke (OR=1.61 (1.04–2.49)) and haemorrhagic stroke (OR=2.50 (1.38–4.53)) in unadjusted models. In adjusted multivariable models, only the LWH association with haemorrhagic stroke remained significant (aOR=1.92 (1.01–3.09)).

Conclusions

LWH were associated with stroke, though it remained significant for haemorrhagic stroke only after adjustments. Differences in direct and indirect biological pathways and lack of power in the ischaemic subgroup may explain these results and further studies on the impact of mediating and effect measure modifying factors are needed. Nevertheless, policies that attenuate effects of both LWH and cardiovascular risks factor are warranted.
Focal cortical dysplasia: a practical guide for neurologists
Authors: Balestrini Simona , Barba Carmen , Thom Maria , Guerrini Renzo
Published: February 2023

Focal cortical dysplasia (FCD) is a malformation of cortical development characterised by disruption of cortical cytoarchitecture. Classification of FCDs subtypes has initially been based on correlation of the histopathology with relevant clinical, electroencephalographic and neuroimaging features. A recently proposed classification update recommends a multilayered, genotype–phenotype approach, integrating findings from histopathology, genetic analysis of resected tissue and presurgical MRI. FCDs are caused either by single somatic activating mutations in MTOR pathway genes or by double-hit inactivating mutations with a constitutional and a somatic loss-of-function mutation in repressors of the signalling pathway. Mild malformation with oligodendroglial hyperplasia in epilepsy is caused by somatic pathogenicSLC35A2mutations. FCDs most often present with drug-resistant focal epilepsy or epileptic encephalopathy. Most patients respond to surgical treatment. The use of mechanistic target of rapamycin inhibitors may complement the surgical approach. Treatment approaches and outcomes have improved with advances in neuroimaging, neurophysiology and genetics, although predictors of treatment response have only been determined in part.
Nitrous oxide-induced subacute combined degeneration of the cord: diagnosis and treatment
Authors: Paris Alvar , Lake Luke , Joseph Albert , Workman Anna , Walton Joseph , Hayton Tom , Evangelou Nikos , Lilleker James B , Ayling Ruth M , Nicholl David , Noyce Alastair J
Published: February 2023

Recreational use of nitrous oxide (N2O) has increased rapidly in recent years and is now the second most commonly used recreational drug among young people in the UK. There has been a corresponding rise in cases of nitrous oxide-induced subacute combined degeneration of the cord (N2O-SACD), a pattern of myeloneuropathy usually associated with severe vitamin B12deficiency. This can cause serious and permanent disability in young people but, if recognised early, may be effectively treated. All neurologists should be aware of N2O-SACD and its treatment; however, there are currently no agreed guidelines. Based on our experience in East London, an area of high N2O use, we provide practical advice on its recognition, investigation and treatment.
Focused ultrasound-induced inhibition of peripheral nerve fibers in an animal model of acute pain
Authors: Anderson Thomas Anthony , Pacharinsak Cholawat , Vilches-Moure Jose , Kantarci Husniye , Zuchero J Bradley , Butts-Pauly Kim , Yeomans David
Published: February 2023

Background

Moderate-to-severe acute pain is prevalent in many healthcare settings and associated with adverse outcomes. Peripheral nerve blockade using traditional needle-based and local anesthetic-based techniques improves pain outcomes for some patient populations but has shortcomings limiting use. These limitations include its invasiveness, potential for local anesthetic systemic toxicity, risk of infection with an indwelling catheter, and relatively short duration of blockade compared with the period of pain after major injuries. Focused ultrasound is capable of inhibiting the peripheral nervous system and has potential as a pain management tool. However, investigations of its effect on peripheral nerve nociceptive fibers in animal models of acute pain are lacking. In an in vivo acute pain model, we investigated focused ultrasound’s effects on behavior and peripheral nerve structure.

Methods

Focused ultrasound was applied directly to the sciatic nerve of rats just prior to a hindpaw incision; three control groups (focused ultrasound sham only, hindpaw incision only, focused ultrasound sham+hindpaw incision) were also included. For all four groups (intervention and controls), behavioral testing (thermal and mechanical hyperalgesia, hindpaw extension and flexion) took place for 4 weeks. Structural changes to peripheral nerves of non-focused ultrasound controls and after focused ultrasound application were assessed on days 0 and 14 using light microscopy and transmission electron microscopy.

Results

Compared with controls, after focused ultrasound application, animals had (1) increased mechanical nociceptive thresholds for 2 weeks; (2) sustained increase in thermal nociceptive thresholds for ≥4 weeks; (3) a decrease in hindpaw motor response for 0.5 weeks; and (4) a decrease in hindpaw plantar sensation for 2 weeks. At 14 days after focused ultrasound application, alterations to myelin sheaths and nerve fiber ultrastructure were observed both by light and electron microscopy.

Discussion

Focused ultrasound, using a distinct parameter set, reversibly inhibits A-delta peripheral nerve nociceptive, motor, and non-nociceptive sensory fiber-mediated behaviors, has a prolonged effect on C nociceptive fiber-mediated behavior, and alters nerve structure. Focused ultrasound may have potential as a peripheral nerve blockade technique for acute pain management. However, further investigation is required to determine C fiber inhibition duration and the significance of nerve structural changes.
Not all vaping is the same: differential pulmonary effects of vaping cannabidiol versus nicotine
Authors: Bhat Tariq A , Kalathil Suresh G , Goniewicz Maciej L , Hutson Alan , Thanavala Yasmin
Published: February 2023

Rationale

Vaping has become a popular method of inhaling various psychoactive substances. While evaluating respiratory effects of vaping have primarily focused on nicotine-containing products, cannabidiol (CBD)-vaping is increasingly becoming popular. It currently remains unknown whether the health effects of vaping nicotine and cannabinoids are similar.

Objectives

This study compares side by side the pulmonary effects of acute inhalation of vaporised CBD versus nicotine.

Methods

In vivo inhalation study in mice and in vitro cytotoxicity experiments with human cells were performed to assess the pulmonary damage-inducing effects of CBD or nicotine aerosols emitted from vaping devices.

Measurements and main results

Pulmonary inflammation in mice was scored by histology, flow cytometry, and quantifying levels of proinflammatory cytokines and chemokines. Lung damage was assessed by histology, measurement of myeloperoxidase activity and neutrophil elastase levels in the bronchoalveolar lavage fluid and lung tissue. Lung epithelial/endothelial integrity was assessed by quantifying BAL protein levels, albumin leak and pulmonary FITC-dextran leak. Oxidative stress was determined by measuring the antioxidant potential in the BAL and lungs. The cytotoxic effects of CBD and nicotine aerosols on human neutrophils and human small airway epithelial cells were evaluated using in vitro air–liquid interface system. Inhalation of CBD aerosol resulted in greater inflammatory changes, more severe lung damage and higher oxidative stress compared with nicotine. CBD aerosol also showed higher toxicity to human cells compared with nicotine.

Conclusions

Vaping of CBD induces a potent inflammatory response and leads to more pathological changes associated with lung injury than vaping of nicotine.
Cost-effectiveness of home non-invasive ventilation in patients with persistent hypercapnia after an acute exacerbation of COPD in the UK
Authors: Murphy Patrick Brian , Brueggenjuergen Bernd , Reinhold Thomas , Gu Qing , Fusfeld Laura , Criner Gerard , Goss Thomas F , Hart Nicholas
Published: February 2023

Home non-invasive mechanical ventilation (HMV) with home oxygen therapy (HOT) in patients with persistent hypercapnia following an acute exacerbation of chronic obstructive pulmonary disease delays hospital readmission. The economic impact of this treatment is unknown. We evaluated the cost-effectiveness of HMV in the UK healthcare system using data from a previously published efficacy trial. Quality-adjusted life-years (QALYs) were computed from EQ-5D-5L. Accounting for all direct patient costs HOT-HMV was £512 (95%CI £36 to £990) more expensive per patient per year than HOT-alone. This small increase in cost was accompanied by increased quality of life leading to an incremental cost-effectiveness ratio of £10 259 per QALY. HOT-HMV was cost-effective in this clinical population. Trial registration number:NCT00990132.
Hedgehog signal activates AMPK via Smoothened to promote autophagy and lipid degradation in hepatocytes
Authors: Yao Yixing , Li Tianyuan , Yu Tingting , Yang Xin , Wang Yue , Cai Jing , Cheng Steven Y. , Liu Chen , Yue Shen
Published: February 2023

Studies in the past decade have shown that lipid droplets stored in liver cells under starvation are encapsulated by autophagosomes and fused to lysosomes via the endocytic system. Autophagy responds to a variety of environmental factors inside and outside the cell, so it has a complex signal regulation network. To this end, we first explored the role of Hedgehog (Hh) in autophagy and lipid metabolism. Treatment of normal mouse liver cells with SAG and GDC-0449 revealed elevated phosphorylation of AMP-activated protein kinase (AMPK) and increased lipidation of LC3. SAG, and GDC-0449 were agonist and antagonist of Smoothened (Smo) in canonical Hh pathway, respectively, but they played a consistent role in the regulation of autophagy in hepatocytes. Moreover, SAG and GDC-0449 did not affect the expression of glioma-associated oncogene (Gli1) and patched 1, suggesting the absence of canonical Hh signaling in hepatocytes. We further knocked down the Smo and found that the effects of SAG and GDC-0449 disappeared, indicating that the non-canonical Smo pathway was involved in the regulation of autophagy in hepatocytes. In addition, SAG and GDC-0449 promoted lipid degradation and inhibited lipid production signals. Knockdown of Smo slowed down the rate of lipid degradation rather than Sufu or Gli1, indicating that Hh signaling regulated the lipid metabolism via Smo. In summary, activates AMPK via Smo to promote autophagy and lipid degradation.
Bosentan attenuates sickle cell disease erythrocyte HbS polymerization and impaired deformability induced by endothelin-1
Authors: Rosa Teixeira-Alves Lyzes , Guimarães-Nobre Camila Cristina , Mendonça-Reis Evelyn , Miranda-Alves Leandro , Berto-Junior Clemilson
Published: February 2023

The effects of endothelin-1 (ET-1) on erythrocytes from sickle cell disease (SCD) patients have been described, but mechanisms of ET-1 regarding primary erythrocyte functions remain unknown. ET-1 is a vasoconstrictor peptide produced by endothelial cells, and the expression of ET-1 is increased in SCD. The present study used ex vivo experiments with sickle cell erythrocytes, ET-1, and bosentan, a dual antagonist of ETA and ETB receptors. We performed a hemoglobin S (HbS) polymerization assay with three concentrations of ET-1 (1, 20, and 50 pg/mL) and bosentan (100 nmol/L). ET-1 increased HbS polymerization at all concentrations, and this effect was suppressed by bosentan. For the deformability assay, red blood cells (RBCs) were incubated on a Sephacryl column with the same concentrations of ET-1 and bosentan. ET-1 decreased deformability, and this effect was reversed by bosentan. To observe erythrocyte adhesion, ET-1 and bosentan were incubated with RBCs in thrombospondin-coated 96-well plate, which demonstrated that ET-1 decreased adhesion but that bosentan enhanced adhesion. We also assessed erythrocyte apoptosis and observed decreased eryptosis induced by ET-1, and these effects were inhibited bosentan. Thus, these findings demonstrated that ET-1 modulates HbS polymerization, erythrocyte deformability, adhesion to thrombospondin, and eryptosis, and these effects were suppressed or enhanced by bosentan.
Finite temperature energy–momentum tensor in compactified cosmic string spacetime
Authors: dos Santos W. Oliveira , de Mello E. R. Bezerra
Published: February 2023

In this paper we analyze the expectation value of the field squared and the energy–momentum tensor associated with a massive charged scalar quantum field with a nonzero chemical potential propagating in a high-dimensional compactified cosmic string spacetime in thermal equilibrium at finite temperature T. Moreover, we assume that the charged quantum field interacts with a very thin magnetic flux running along the core of the idealized cosmic string, and with a magnetic flux enclosed by the compact dimension. These observables are expressed as the vacuum expectation values and the finite temperature contributions coming from the particles and antiparticles excitations. Due to the compactification, the thermal corrections can be decomposed in a part induced by the cosmic string spacetime without compactification, plus a contribution induced by the compactification. This decompositions explicitly follows from the Abel–Plana formula used to proceed the summation over the discrete quantum number associated with the quasiperiodic condition imposed on the quantum field along the compact dimension. The expectations values of the field squared and the energy–momentum tensor are even periodic functions of the magnetic flux with period being the quantum flux, and also even functions of the chemical potential. Our main objectives in this paper concern in the investigation of the thermal corrections only. In this way we explicitly calculate the behavior of these observables in the limits of low and high temperature. We show that the temperature enhance the induced densities. In addition some graphs are also included in order to exhibit these behaviors.
Asymptotically safe Hilbert–Palatini gravity in an on-shell reduction scheme
Authors: Gies Holger , Salek Abdol Sabor
Published: February 2023

We study the renormalization flow of Hilbert–Palatini gravity to lowest non-trivial order. We find evidence for an asymptotically safe high-energy completion based on the existence of an ultraviolet fixed point similar to the Reuter fixed point of quantum Einstein gravity. In order to manage the quantization of the large number of independent degrees of freedom in terms of the metric as well as the connection, we use an on-shell reduction scheme: for this, we quantize all degrees of freedom beyond Einstein gravity at a given order that remain after using the equations of motion at the preceding order. In this way, we can straightforwardly keep track of the differences emerging from quantizing Hilbert–Palatini gravity in comparison with Einstein gravity. To lowest non-trivial order, the difference is parametrized by fluctuations of an additional abelian gauge field. The critical properties of the ultraviolet fixed point of Hilbert–Palatini gravity are similar to those of the Reuter fixed point, occurring at a smaller Newton coupling and exhibiting more stable higher order exponents.
Signal-background interference effects in Higgs-mediated diphoton production beyond NLO
Authors: Bargieła Piotr , Buccioni Federico , Caola Fabrizio , Devoto Federica , von Manteuffel Andreas , Tancredi Lorenzo
Published: February 2023

In this paper we consider signal-background interference effects in Higgs-mediated diphoton production at the LHC. After reviewing earlier works that show how to use these effects to constrain the Higgs boson total decay width, we provide predictions beyond NLO accuracy for the interference and related observables, and study the impact of QCD radiative corrections on the Higgs width determination. In particular, we use the so-called soft-virtual approximation to estimate interference effects at NNLO in QCD. The inclusion of these effects reduces the NNLO prediction for the total Higgs cross-section in the diphoton channel by about 1.7%. We study in detail the impact of QCD corrections on the Higgs-boson line-shape and its implications for the Higgs boson width extraction. In particular, we find that the shift of the Higgs resonance peak arising from interference effects gets reduced by about 30% with respect to the NLO prediction. Assuming an experimental resolution of about 150 $$\textrm{MeV}$$
MeV
on interference-induced modifications of the Higgs-boson line-shape, our NNLO analysis shows that one could constrain the Higgs-boson total width to about 10–20 times its Standard Model value.
Faster Property Testers in a Variation of the Bounded Degree Model
Authors: Adler Isolde , Fahey Polly
Published: February 2023

Property testing algorithms are highly efficient algorithms that come with probabilistic accuracy guarantees. For a property
P
, the goal is to distinguish inputs that have
P
from those that are
far
from having
P
with high probability correctly, by querying only a small number of local parts of the input. In property testing on graphs, the
distance
is measured by the number of edge modifications (additions or deletions) that are necessary to transform a graph into one with property
P
. Much research has focused on the
query complexity
of such algorithms, i. e., the number of queries the algorithm makes to the input, but in view of applications, the
running time
of the algorithm is equally relevant.

In (Adler, Harwath, STACS 2018), a natural extension of the bounded degree graph model of property testing to relational databases of bounded degree was introduced, and it was shown that on databases of bounded degree and bounded tree-width, every property that is expressible in monadic second-order logic with counting (CMSO) is testable with constant query complexity and
sublinear
running time. It remains open whether this can be improved to constant running time.

In this article we introduce a new model, which is based on the bounded degree model, but the distance measure allows both edge (tuple) modifications and vertex (element) modifications. We show that every property that is testable in the classical model is testable in our model with the same query complexity and running time, but the converse is not true. Our main theorem shows that on databases of bounded degree and bounded tree-width, every property that is expressible in CMSO is testable with constant query complexity and
constant
running time in the new model. Our proof methods include the semilinearity of the neighborhood histograms of databases having the property and a result by Alon (Proposition 19.10 in Lovász, Large networks and graph limits, 2012) that states that for every bounded degree graph

\(\mathcal {G}\)

there exists a constant size graph

\(\mathcal {H}\)

that has a similar neighborhood distribution to 

\(\mathcal {G}\)

.

It can be derived from a result in (Benjamini et al., Advances in Mathematics 2010) that hyperfinite hereditary properties are testable with constant query complexity and constant running time in the classical model (and hence in the new model). Using our methods, we give an alternative proof that hyperfinite hereditary properties are testable with constant query complexity and constant running time in the new model.

We argue that our model is natural and our meta-theorem showing constant-time CMSO testability supports this.
White-Box Fuzzing RPC-Based APIs with EvoMaster: An Industrial Case Study
Authors: Zhang Man , Arcuri Andrea , Li Yonggang , Liu Yang , Xue Kaiming
Published: February 2023

Remote Procedure Call (RPC) is a communication protocol to support client-server interactions among services over a network. RPC is widely applied in industry for building large-scale distributed systems, such as Microservices. Modern RPC frameworks include, for example, Thrift, gRPC, SOFARPC, and Dubbo. Testing such systems using RPC communications is very challenging, due to the complexity of distributed systems and various RPC frameworks the system could employ. To the best of our knowledge, there does not exist any tool or solution that could enable automated testing of modern RPC-based services. To fill this gap, in this article we propose the first approach in the literature, together with an open source tool, for fuzzing modern RPC-based APIs. The approach is in the context of white-box testing with search-based techniques. To tackle schema extraction of various RPC frameworks, we formulate a RPC schema specification along with a parser that allows the extraction from source code of any JVM RPC-based APIs. Then, with the extracted schema we employ a search to produce tests by maximizing white-box heuristics and newly defined heuristics specific to the RPC domain. We built our approach as an extension to an open source fuzzer (i.e.,
EvoMaster
), and the approach has been integrated into a real industrial pipeline that could be applied to a real industrial development process for fuzzing RPC-based APIs. To assess our novel approach, we conducted an empirical study with two artificial and four industrial web services selected by our industrial partner. In addition, to further demonstrate its effectiveness and application in industrial settings, we report results of employing our tool for fuzzing another 50 industrial APIs autonomously conducted by our industrial partner in their testing processes. Results show that our novel approach is capable of enabling automated test case generation for industrial RPC-based APIs (i.e., 2 artificial and 54 industrial). We also compared with a simple gray-box technique and existing manually written tests. Our white-box solution achieves significant improvements on code coverage. Regarding fault detection, by conducting a careful review with our industrial partner of the tests generated by our novel approach in the selected four industrial APIs, a total of 41 real faults were identified, which have now been fixed. Another 8,377 detected faults are currently under investigation.
A WO3-NPs/MEMS NH3 Gas Sensor
Authors: Wen Po Hsiang , Zheng Hao Yuan , Hsueh Ting-Jen
Published: February 2023

This study exhibits WO3 nanoparticles (NPs) by using ultrasonic wave grinding and fabricates a WO3–NPs/MEMS gas sensor. The experimental results show that the WO3– NPs/MEMS gas sensor responds better to NH3 than to CO, CO2, and SO2. In terms of the stability and the reproducibility of the WO3–NPs/MEMS gas sensor, the average sensing response is about 16% and there is an inaccuracy of <±0.5% when the sensor is operated at 142 °C with 1.3 ppm NH3 gas. The WO3–NPs sensor has a better sensing response to NH3 than the WO3-thin film and original-WO3 powder sensors. This study shows that WO3 nanoparticles have a good sensing response to NH3 gas.
3D Stochastic Microsensors Based on Single-Walled Carbon Nanotubes Decorated with Gold Nanoparticles for Molecular Recognition and Determination of Heregulin-α and HER Family (HER1–4) in Biological Samples
Authors: Stefan-van Staden Raluca-Ioana , Cioates Negut Catalina , Sfirloaga Paula
Published: February 2023

Four 3D stochastic microsensors based on single-walled carbon nanotubes decorated with gold nanoparticles and modified with inulins were designed and used for the simultaneous molecular recognition and quantification of heregulin-α and HER family (HER1–4) in tumor brain tissue and whole blood samples. The proposed microsensors presented limits of determination of fg ml−1 magnitude order: for heregulin-α 4.1fg ml−1, for HER1 and HER2 3.9fg ml−1, and for HER3 and HER4 1.0fg ml−1 and wide linear concentration ranges: for heregulin-α 4.10 × 10−9–1.28 × 10−5
μg ml−1, for HER1 and HER2 3.90 × 10−9–3.90 × 10−5
μg ml−1, for HER3 1.00 × 10−9–1.00 × 10−6
μg ml−1, and for HER4 1.00 × 10−9–1.00 × 10−5
μg ml−1. Recoveries higher than 95.00, and %, RSD lower than 1.00 were recorded for the assay of heregulin-α and HER family (HER1–4) when screenings of whole blood and tissue samples were performed.
Development of a Non-Enzymatic Vitamin-C Electrochemical Sensor Based on rGO/Ce2(SO4)3Hierarchical Nanocomposite
Authors: S. Anil Subash , C. Manjunatha , M. Sudeep , Rastogi Chandresh Kumar , Chaudhary Vishal , S. Girish Kumar , Sekhar Praveen
Published: February 2023

The engineering of high-performance functional nanomaterials for efficient monitoring of Vitamin-C/Ascorbic Acid (AA) is highly desirable in the food, chemical, cosmetics, and pharmaceutical industries. In this regard, this report presents the engineering of novel cerous sulfate Ce2(SO4)3nanoflowers, decorated reduced graphene oxide (rGO) through an economic, energy-efficient and rapid one-pot hydrothermal strategy for electrochemical detection of AA. The obtained nanocomposite demonstrates the successful formation of nano Ce2(SO4)3with flower morphology having large surface area and potential to promote the electrolyte accessibility as well as electronic transmission during sensing phenomenon. The Ce2(SO4)3/rGO (CSG) nanoflower composite was drop casted on screen printed carbon electrode (SPCE) and tested for its electrochemical detection of AA. At +0.337 V, a well-defined oxidation peak of AA occurred in phosphate buffer solution of pH 7. A linear response of the CSG electrode was further obtained under optimum conditions, for the AA concentration range of 10 − 1000μM with a sensitivity of 0.2973μAμM−1cm−2and lowest detection limit of 900μM. The excellent Vitamin-C sensing ability of CSG is attributed to the synergistic effect from the dimensional anisotropy of flower-like morphological features of Ce2(SO4)3as well as the interfacial structure. The CSG was also tested for vitamin C tablets, VeeCee-Z, to validate its commercial applicability. Furthermore, fabricated electrochemical sensor exhibited significant reproducibility (98.63%) and optimum stability. Thus, the significant findings of this work are believed to hold the prospect for sensitive and prompt determination of Vitamin-C in the industrial domains.
Traditional Chinese Medicine Compound Preparations Are Associated with Low Disease‐Related Complication Rates in Patients with Rheumatoid Arthritis: A Retrospective Cohort Study of 11,074 Patients
Authors: Fang Yanyan , Liu Jian , Xin Ling , Chen Xiaolu , Ding Xiang , Han Qi , He Mingyu , Li Xu , Sun Yanqiu , Wang Fanfan , Wang Jie , Wang Xin , Wen Jianting , Zhang Xianheng , Zhou Qin , Zhang Junru
Published: February 2023

Objective. To evaluate whether traditional Chinese medicine compound preparations (TCMCPs) are associated with rheumatoid arthritis‐ (RA‐) related complications (including readmission, Sjogren’s syndrome, surgical treatment, and all‐cause death) in patients with RA. Methods. Clinical outcome data were retrospectively collected from patients with RA discharged from the Department of Rheumatology and Immunology of the First Affiliated Hospital of Anhui University of Chinese Medicine from January 2009 to June 2021. The propensity score matching method was used to match baseline data. Multivariate analysis was conducted to analyze sex, age, the incidence of hypertension, diabetes, and hyperlipidemia and identify the risk of readmission, Sjogren’s syndrome, surgical treatment, and all‐cause death. Users of TCMCP and nonusers of TCMCP were defined as the TCMCP and non‐TCMCP groups, respectively. Results. A total of 11,074 patients with RA were included in the study. The median follow‐up time was 54.85 months. After propensity score matching, the baseline data of TCMCP users corresponded with those of non‐TCMCP users, with 3517 cases in each group. Retrospective analysis revealed that TCMCP significantly reduced clinical, immune, and inflammatory indices in patients with RA, and these indices were highly correlated. Notably, the composite endpoint prognosis for treatment failure in TCMCP users was better than that in non‐TCMCP users (HR = 0.75 (0.71‐0.80)). The risk of RA‐related complications in TCMCP users with high‐exposure intensity (HR = 0.669 (0.650‐0.751)) and medium‐exposure intensity (HR = 0.796 (0.691‐0.918)) was significantly lower than those in non‐TCMCP users. An increase in exposure intensity was associated with a concomitant decrease in the risk of RA‐related complications. Conclusion. The use of TCMCPs, as well as long‐term exposure to TCMCPs, may lower RA‐related complications, including readmission, Sjogren’s syndrome, surgical treatment, and all‐cause death, in patients with RA.
Seismic Optimization for Hysteretic Damping-Tuned Mass Damper (HD-TMD) Subjected to White-Noise Excitation
Authors: Xiang Yue , Tan Ping , He Hui , Chen Qianmin
Published: February 2023

The hysteretic damping tuned mass damper (HD-TMD) is composed of a spring element, a hysteretic damping (HD) element, and a mass. The HD force is proportional to the displacement of the tuned mass damper (TMD). Recently, the application of HD-TMD has emerged, but its optimal design is still lacking. To fill this academic gap, numerical solutions for optimal parameters of HD-TMD subjected to white-noise excitation were obtained based on the H2 optimization criterion. Performance balance optimization with a weighting factor was carried out to improve the response of a structure with the HD-TMD system. A set of earthquake records and harmonic excitations were conducted to prove the effectiveness of the optimal numerical solutions and the performance balance design. It was found that the performance of the HD-TMD is slightly better than that of the traditional optimized TMD. As a real TMD application of HD-TMD, the variable friction pendulum TMD (VFP-TMD) was selected to experience earthquakes with the proposed optimal methods. Results showed that the optimal solutions provided the best performance but raised the problem of difficulty in maintaining linearity with a large displacement. Nevertheless, the performance balance design helped reduce this defect and provided impressive seismic mitigation capacity. Compared with the optimal numerical solution results, the performance balance design demonstrated 2.847% of loss in the maximum structural displacement reduction rate and 3.709% of loss in the root mean square reduction rate during the earthquake-excited period, respectively.
Secure Marine Environment Communication: A Multiobject Authentication Protocol Based on Secret Sharing
Authors: Ye Jun , Cao Xinhui , Guo Zhen
Published: February 2023

In the field of marine communication, with the rapid development of the Internet of Things, big data, blockchain, and other new‐generation information technology, marine information security is gradually being attached to more and more coastal countries, and marine information technology has ushered in epoch‐making development opportunities. However, marine communication networks are open, and marine equipment is vulnerable to attacks on communication systems. On the one hand, a malicious adversary can intercept and analyze information, obtain relevant data with high probability, and even obtain the identity information of the equipment. On the other hand, attackers can also maliciously inject false information. At the same time, it is difficult for the existing marine information security technology to guarantee the confidentiality and authenticity of information simultaneously, which will bring substantial potential hidden dangers to the development of the ocean. We propose a multitarget authentication and key exchange protocol for secure communication. Our protocol assigns complex cryptographic operations to servers, thus balancing the system’s security and efficiency. The secret is divided into multiple subsecrets using the secret sharing feature, and the subsecret information is used to manage the identity credentials of resource‐constrained devices. Then, after successful authentication, the server reassigns the subsecret information of the device to achieve the dynamic generation of identity credentials. Meanwhile, a multitarget authentication scheme is proposed based on recovering secrets. In addition, device extension measures are provided to replace or increase devices. Finally, well‐established cryptographic assumptions are used to prove the protocol’s security. Simulation results verify the effectiveness of the protocol in multiobjective authentication.
Nanopore Characteristics of the Cambrian Niutitang Formation Organic-Rich Shales in the Middle Yangtze Region and Its Formation Controlling Factors
Authors: Xu Jie , Guo Weihua , Yang Bin , Ma Dongxu , Zhao Li , Liu Haotian , Ji Hongjie , Tao Huifei
Published: February 2023

The shale of Cambrian Niutitang Formation is one of the most important shale gas reservoirs in the Middle Yangtze region, South China. Nanopores are important reservoir spaces for shale gas. The study of pore characteristics and its formation controlling factors is of great significance for the exploration and development of shale gas in the Niutitang Formation. In this study, two drilling core samples and two profile samples were investigated. The laser Raman, X-ray diffraction analysis, FE-SEM, and low-pressure N2 and CO2 adsorption methods are used to study the geochemical and mineral compositions of the shales, and the nanopore characteristics and its formation controlling factors of the shales are discussed. Results show that the shales have the following features: (1) rich in organic matter (OM) and the total organic carbon (TOC) contents ranging from 2.65 to 11.33%, with an average value of 6.81%. (2) The main mineral components of these shales are quartz, feldspar, clay minerals, calcite, and a small amount of pyrite. (3) The samples from the center of the Middle Yangtze region (EY1 well and BGP profile) have a higher maturity value (

Rmc

R

0

%
=
4.0

%) relatively to the samples from the south of the Middle Yangtze region (XD1 well and JF profile), where the

Rmc

R

0

%

is 2.8%. (4) The maximum N2 adsorption capacity of the four groups of shale samples ranges from 5.090 to 27.333 cm3/g, with an average value of 15.571 cm3/g, while the maximum CO2 adsorption capacity ranges from 2.686 to 5.567 cm3/g, with an average value of 3.776 cm3/g. The higher maturity leads to the EY1 well having the lowest average maximum N2 adsorption capacity, while most of the OM pores in the EY1 well and BGP profile samples are smaller than 10 nm in diameter. The tectonic uplift leads to the profile samples having more meso-macropores than the core samples. The dissolution pores and granular mineral support are the key factors for the better pore structure of the high-evolution stage Niutitang Formation shale.
Descriptive Epidemiology of and Response to the High Pathogenicity Avian Influenza (H5N8) Epidemic in South African Coastal Seabirds, 2018
Authors: Roberts Laura C. , Abolnik Celia , Waller Lauren J. , Shaw Kevin , Ludynia Katrin , Roberts David G. , Kock Alison A. , Makhado Azwianewi B. , Snyman Albert , Abernethy Darrell
Published: February 2023

High pathogenicity avian influenza (HPAI) clade 2.3.4.4b H5N8 virus was detected in coastal seabirds in late 2017 in South Africa, following a devastating epidemic in the commercial poultry and ostrich industries. By May 2018, the infection had been confirmed in fifteen seabird species at 31 sites along the southern coast, with the highest mortality recorded in terns (Family Laridae, Order Charadriiformes). Over 7,500 positive or suspected cases in seabirds were reported. Among those infected were three endangered species: African penguins (Spheniscus demersus Linnaeus, 1758), Cape cormorants (Phalacrocorax capensis Wahlberg, 1855), and Cape gannets (Morus capensis Lichtenstein, 1823). The scale and impact of this outbreak were unprecedented in southern African coastal seabirds and raised logistical challenges in resource allocation, risk mitigation, and outbreak response. It required the collaboration of multiple stakeholder groups, including a variety of government departments and nongovernmental organizations. With another HPAI outbreak in South African seabirds in 2021 and major incursions in seabird species in the northern hemisphere in 2022, it is vital to share and consolidate knowledge on the subject. We describe the epidemic, the lessons learned, and recommendations for developing contingency plans.
[Retracted] Wearable Sensor‐Based Edge Computing Framework for Cardiac Arrhythmia Detection and Acute Stroke Prediction
Authors: Lavanya R. , Vidyabharathi D. , Kumar S. Selva , Mali Manisha , Arunkumar M. , Aravinth S. S. , Zainlabuddin Md. , Jose Triny K. , Sathyendra Bhat J. , Tesfayohanis Miretab
Published: February 2023

Internet of Things‐based smart healthcare systems have gained attention in recent years for improving healthcare services and reducing data management costs. However, there is a requirement for improving the smart healthcare system in terms of speed, accuracy, and cost. An intelligent and secure edge‐computing framework with wearable devices and sensors is proposed for cardiac arrhythmia detection and acute stroke prediction. Latency reduction is highly essential in real‐time continuous assessment, and classification accuracy has to be improved for acute stroke prediction. In this paper, preprocessing and deep learning‐based assessment is performed in the edge‐computing layer, and decisions are communicated instantly to the individuals. In this work, acute stroke prediction is performed by a deep learning model using heart rate variability features and physiological data. Classification accuracy is improved in this approach when compared to other machine learning approaches. Cloud servers are utilized for storing the healthcare data of individuals for further analysis. Analyzed data from these servers are shared with hospitals, healthcare centers, family members, and physicians. The proposed edge computing with wearable sensors approach outperforms existing smart healthcare‐based approaches in terms of execution speed, latency time, and power consumption. The deep learning method combined with DWT performs better than other similar approaches in the assessment of cardiac arrhythmia and acute stroke prediction. The proposed classifier achieves a sensitivity of 99.4%, specificity of 99.1%, and accuracy of 99.3% when compared with other similar approaches.