bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression study of Krabbe DiseaseGALCmissense variants – Insights from quantification profiles of residual enzyme activity, secretion and psychosine levels
Authors: Peng Hui , Lam Ying-Wai , Zhou Zitao , Herdt Aimee R. , Gelb Michael H. , Lee Chris W.
Published: October 2024

Krabbe disease (KD) is an autosomal recessive lysosomal storage disorder caused by loss-of-function mutations in theGALCgene, which encodes for the enzyme galactosylceramidase (GALC). GALC is crucial for myelin metabolism. Functional deficiency of GALC leads to toxic accumulation of psychosine, dysfunction and death of oligodendrocytes, and eventual brain demyelination. To date, 46 clinically-relevant, pathogenic GALC missense mutations (MMs) have been identified in KD patients. These MMs are present in ∼70% of KD cases reported over 8 published studies between 1996 – 2019. However, the mechanisms by which these MMs lead to GALC functional deficiency and their correlations with clinical phenotype remain poorly understood.

To address this, we generated aGALC-knockout human oligodendrocytic cell line (MO3.13/GALC-KO) using CRISPR-Cas9 method to assess GALC function and GALC secretion. We evaluated 5 polymorphic and 31 clinically-relevant MM variants (MMVs) using transient expression assays. Our results showed that 26 MMVs, including 10 co-variants with p.I562T, reduced GALC activity by 92% - 100% compared to wild-type GALC (WT-GALC). MMVs from infantile-onset KD patients produced < 2% of WT activity, whereas those associated with juvenile- and adult-onset cases retained up to 7% of WT activity. Residual GALC activity was correlated with mature, lysosomal GALC protein levels (Pearson r = 0.93, P<0.0001). Many low-activity MMVs did not correspondingly impair GALC secretion. Twenty-one of the 26 low-activity MMVs showed a 21% - 100% reduction in sec-GALC levels, indicating varying degrees of GALC mis-trafficking among these variants.

Importantly, GALC activity among MMVs strongly correlates with clinical disease severity, based on the age of symptom onset in patients with either homozygous MM (Pearson r = 0.98, P<0.0001, n = 7) or compound heterozygous (Pearson r = 0.94, P<0.0001, n = 12) MM-null mutation genotypes. Thus, our data suggests that GALC activity could serve as a prognostic disease indicator under specific experimental conditions. We further investigated the impact of pathogenic MMVs on psychosine accumulation, a key biomarker for KD. Psychosine levels were 21-fold higher in mock control cells compared to WT-GALC transfected cells (mock = 0.349 pmol/mg, WT-GALC = 0.016 pmol/mg), but negatively correlated with GALC activity among pathogenic MMVs (Pearson r = −0.63, P < 0.01, n = 15). Although psychosine levels were higher in most MMVs associated with infantile-onset KD, no significant correlations with clinical onset were detected.

Overall, our study provides a comprehensive quantitative analysis of the functional deficits and mis-trafficking associated with clinically-relevant GALC MMVs, enhancing our understanding of the molecular genetics and genotype-phenotype correlations of theGALCgene in Krabbe disease.
Targeted degradation of the HPV oncoprotein E6 reduces tumor burden in cervical cancer
Authors: Smalley Tracess B , Nicolaci Angelo , Tran Kim C. , Lokhandwala Jameela , Obertopp Nina , Matlack Jenet K , Miner Robert E , Teng Michael N. , Pilon-Thomas Shari , Binning Jennifer M
Published: October 2024

Human Papilloma Virus (HPV)-related cancers are a global health burden, yet there are no targeted therapies available for chronically infected patients. The HPV protein E6 is essential for HPV-mediated tumorigenesis and immune evasion, making it an attractive target for antiviral drug development. In this study, we developed an E6-targeting Proteolysis Targeting Chimera (PROTAC) that inhibits the growth of HPV(+) tumors. To develop E6 antagonists, we generated a panel of nanobodies targeting E6 proteins derived from the oncogenic HPV16 subtype. The highest affinity E6 nanobody, A5, was fused to Von Hippel Lindau protein (VHL) to generate a PROTAC that degrades E6 (PROTACE6). Mutational rescue experiments validated specific degradation via the CRL2VHLE3 ligase. Intralesional administration of the PROTACE6using a clinically viable DNA vaccine reduced tumor burden in an immunocompetent mouse model of HPV(+) cancer. The inhibitory effect of the PROTACE6was abrogated by CD4+and CD8+T-cell depletion, indicating that the antitumor function of the PROTACE6relies in part on a host immune response. Overall, these results suggest that the targeted degradation of E6 inhibits its oncogenic function and stimulates a robust immune response against HPV(+) tumors, opening new opportunities for virus-specific therapies in the treatment of HPV-related cancers.
Early spatiotemporal evolution of the immune response elicited by adenovirus serotype 26 vector vaccination in mice
Authors: Blass Eryn , Colarusso Alessandro , Aid Malika , Larocca Rafael A. , Reeves R. Keith , Barouch Dan H.
Published: October 2024

As the first responder to immunological challenges, the innate immune system shapes and regulates the ensuing adaptive immune response. Many clinical studies evaluating the role of innate immunity in initiating vaccine-elicited adaptive immune responses have largely been confined to blood due to inherent difficulty in acquiring tissue samples. However, the absence of vaccine-site and draining lymph node information limits understanding of early events induced by vaccination that could potentially shape vaccine-elicited immunity. We therefore utilized a mouse model to investigate the spatiotemporal evolution of the immune response within the first 24 hours following intramuscular adenovirus serotype 26 (Ad26) vector vaccination in tissues. We show that the Ad26 vaccine-elicited innate immune response commences by one hour and rapidly evolves in tissues and blood within the first 24 hours as reflected by the detection of cytokines, chemokines, cellular responses, and transcriptomic pathways. Furthermore, serum levels of IL-6, MIG, MIP-1α, and MIP-1β at 6 hours post-vaccination correlated with the frequency of vaccine-elicited memory CD8+T cell responses evaluated at 60 days post-vaccination in blood and tissues. Taken together, our data suggests that the immune response to Ad26 vector vaccination commences quickly in tissues by one hour and that events by as early as 6 hours post-vaccination can shape vaccine-elicited CD8+T cell responses at later memory time points.

IMPORTANCE

Prior studies have largely concentrated on innate immune activation in peripheral blood following vaccination. In this study, we report the detailed spatial and temporal innate immune activation in tissues following Ad26 vaccination in mice. We observed rapid innate activation rapidly not only in peripheral blood but also in draining lymph nodes and at the site of inoculation. Our findings provide a more detailed picture of host response to vaccination than previously reported.
The Role of ISG15 in Cancer Biology: Systematic Evaluation of ISG15 Expression and Its Molecular Interactions in a Pan-Cancer Context
Authors: Chatterjee Shrabonti , Mahata Joydeep
Published: October 2024

ISG15’s dual role in cancer biology still remains unclear. One major area requiring further investigation is the molecular mechanisms underlying ISG15’s pro- and anti-tumorigenic roles in different cancer types. In this study, we try to find the probable pathways that could be influenced by ISG15 in different cancers. ISG15, a ubiquitin-like protein is essential in the post-translational modification ISGylation, which involves a series of E1, E2, and E3 enzymes. During viral infections, ISG15 stimulates Type I interferon production and affects key proteins such as STAT1, JAK-1, MDA-5, Mx1, and RIG-1, thus impacting both host immunity and viral evasion strategies. Furthermore, ISG15 exhibits a complex role in cancer, acting as either a tumor suppressor or an oncogene depending on its state—free or conjugated. Intracellular free ISG15 affects protein stability, while extracellular ISG15 has immunomodulatory effects. Despite its significant role in immune regulation and cancer biology, the exact mechanisms through which ISG15 influences cancer progression remain to be fully elucidated. In this study, we examined ISG15’s role in tumor development and progression across 22 cancer types by integrating data from high-throughput databases including TCGA, GTEx, and CPTAC. We evaluated ISG15 expression at both mRNA and protein levels, noting increased mRNA expression in all cancer types except Kidney Chromophobe (KICH) and elevated protein levels in nine out of ten analyzed cancer types, with the exception of liver carcinoma. Analysis of TP53 mutations showed reduced ISG15 mRNA levels in KICH regardless of mutation status. Correlation analyses identified seven highly correlated genes—IFI35, IFI44, OASL, MX1, RSAD2, OAS2, and IRF7 involved in ISG15 downstream signaling. Protein-protein interaction networks revealed hub genes including STAT1, IFIT1, IFIT2, and OASL, which are crucial in cancer pathogenesis and warrant in-depth studies for therapeutic targets and drug repurposing.
Understanding the impact of an applied axial magnetic field on efficient current coupling on the
Z
machine
Authors: Zimmer D. , Gomez M. R. , Bennett N. , Jennings C. A. , Myers C. E. , Lamppa D. C. , Conti F. , Beg F. N.
Published: October 2024

Magnetized liner inertial fusion (MagLIF) is an attractive concept for producing thermonuclear fusion reactions. The MagLIF platform involves the operation of Helmholtz coils to apply a 15 Tesla axial magnetic field to the load region, where a cylindrical, fuel-filled metal liner is imploded by a ∼20  MA current pulse. The fringe field from these coils extends into the transmission line that delivers the current to the target. We investigated the extent to which this applied field disturbs the nominal power flow within that transmission line. A simplified model of the geometry shows that adding the applied magnetic field results in magnetic field lines that connect the cathode to the anode, suggesting electrons may not be magnetically insulated in this region. Particle-in-cell simulations indicated the addition of the applied magnetic field would not significantly impact the current delivery to the load. Velocimetry was used to experimentally assess the current delivery with and without the applied magnetic field. We find no measurable effects of the applied field on current delivery in the configuration investigated in this study.

Published by the American Physical Society
2024
Whole-channel acoustic energy and acoustophoretic efficiency frequency spectrum by the in-flow focusing method
Authors: Baasch Thierry , Qiu Wei , Laurell Thomas
Published: October 2024

The in-flow focusing method, introduced herein, enables rapid and straightforward measurements of the whole-channel acoustic energy of acoustic flow-through devices. The method is applied to assess the whole-channel acoustic energy and acoustophoretic efficiency frequency spectra of a bottom-actuated silicon-glass and a side-actuated glass chip. The input variables are the time-independent geometrical shape of the particle trajectories along the manipulation chamber, the channel cross-section geometry, the physical properties of the reference particles and fluid, and the volumetric flowrate. The outputs are the total acoustic energy, the acoustophoretic efficiency, as well as the acoustic energy density distribution along the channel, which provide a comprehensive overview of the performance of acoustically driven lab-on-a-chip setups. The acoustophoretic efficiency is an important parameter that relates the energy dissipation, and therefore the heat development in the device, to the useful acoustic energy in the channel. Unlike the current state-of-the-art methods such as particle image velocimetry, particle tracking velocimetry, and optical trapping, which are typically limited to small channel areas and are time-consuming, the in-flow focusing method can be applied to long channels and enables rapid measurements of the whole-channel acoustic energy.

Published by the American Physical Society
2024
Unraveling subleading twist GTMDs of proton using light-front quark-diquark model
Authors: Sharma Shubham , Jain Sameer , Dahiya Harleen
Published: October 2024

This study investigates the subleading twist generalized transverse momentum dependent distributions (GTMDs) of a proton within the light-front quark-diquark model framework. We solve the parametrization equations for the Dirac matrix structure, yielding explicit GTMD expressions for both scalar and vector diquark configurations, leading to expressions for active u and d quarks. This analysis addresses the multidimensional nature of GTMDs by exploring their dependencies on one or two variables while keeping others fixed. Additionally, we extract transverse momentum dependent form factors from GTMDs by integrating over the longitudinal momentum fraction x. The study uses three-dimensional plots to illustrate the variation of transverse momentum dependent form factors with the quark’s transverse momentum p⊥ and the transverse momentum transfer to the proton Δ⊥.

Published by the American Physical Society
2024
I=2

ππ

s
-wave scattering length from lattice QCD
Authors: Fu Ziwen , Wang Jun
Published: October 2024

The I=2 ππ elastic s-wave scattering phase shift is measured by lattice quantum chromodynamics with Nf=3 flavors of the Asqtad-improved staggered fermions. The lattice-calculated energy-eigenvalues of ππ systems at one center of mass frame and some moving frames using the moving wall source technique are utilized to secure phase shifts by Lüscher’s formula. Our computations are fine enough to obtain threshold parameters: scattering length a, effective range r, and shape parameter P, which can be extrapolated at the physical point by next-to-leading order in chiral perturbation theory, and our relevant next-to-next-to-leading order predictions from expanding nuclear physics with lattice quantum chromo dynamics collaboration’s works are novelly considered as the systematic uncertainties. Our outcomes are consistent with Roy equation determinations, newer experimental data, and lattice estimations. Numerical computations are performed with a coarse (a≈0.12  fm, L3T=32364), two fine (a≈0.09  fm, L3T=40396) and a superfine (a≈0.06  fm, L3T=483144) lattice ensembles at four pion masses of mπ∼247  MeV, 249 MeV, 275 MeV, and 384 MeV, respectively.

Published by the American Physical Society
2024
Phenomenology of 3-3-1 models with a radiative inverse seesaw mechanism
Authors: Binh V. H. , Bonilla Cesar , Cárcamo Hernández A. E. , Huong D. T. , K. N. Vishnudath , Long H. N. , Thu P. N. , Schmidt Iván
Published: October 2024

We propose two models based on the SU(3)C×SU(3)L×U(1)X gauge symmetry, each incorporating distinct inverse seesaw mechanisms for generating neutrino masses at the radiative level. Therefore, neutrino masses are suppressed by the radiative nature of the mass generation mechanism, which occurs after the spontaneous breaking of the global lepton number symmetry. Both scenarios discussed here are characterized by the presence of vectorlike charged leptons, which are involved in generating the masses of the Standard Model charged leptons. These additional vectorlike fermions also contribute to the anomalous magnetic moments of the muon. We perform a detailed analysis of the scalar sectors, show that these models can successfully accommodate the observed baryon asymmetry through resonant leptogenesis, and compute the rates of charged lepton flavor-violating decays, such as μ→eγ. We discuss the constraints of the model arising from these processes and those associated with the nonunitarity of the lepton mixing matrix.

Published by the American Physical Society
2024
Multifractality in monitored single-particle dynamics
Authors: Yajima Kohei , Oshima Hisanori , Mochizuki Ken , Fuji Yohei
Published: October 2024

We study multifractal properties in time evolution of a single particle subject to repeated measurements. For quantum systems, we consider circuit models consisting of local unitary gates and local projective measurements. For classical systems, we consider models for estimating the trajectory of a particle evolved under local transition processes by partially measuring particle occupations. In both cases, multifractal behaviors appear in the ensemble of wave functions or probability distributions conditioned on measurement outcomes after a sufficiently long time. While the nature of particle transport (diffusive or ballistic) qualitatively affects the multifractal properties, they are even quantitatively robust to the measurement rate or specific protocols. On the other hand, multifractality is generically lost by generalized measurements allowing erroneous outcomes or by postselection of the outcomes with no particle detection. We demonstrate these properties by numerical simulations and also propose several simplified models, which allow us to analytically obtain multifractal properties in the monitored single-particle systems.

Published by the American Physical Society
2024
Audit report lag and the cost of equity capital
Authors: Bhuiyan Md. Borhan Uddin , Man Yimei , Lont David H.
Published: October 2024

Purpose

This research investigates the effect of audit report lag on the cost of equity capital. We argue that an extended audit report lag reduces the value of information and raises concerns for investors, resulting in an increased cost of equity capital.

Design/methodology/approach

We hypothesize that audit report lag increases the firm cost of equity capital. We conduct ordinary least squares (OLS) regression analyses to examine our hypothesis. Finally, we also perform a range of sensitivity tests to examine the hypothesis and robustness of findings.

Findings

Using a sample of the listed US firms from 2003 to 2018, we find that firms with higher audit report lag have a higher cost of equity capital. Our findings are economically significant as one standard deviation increase in audit report lag raises 3.82 basis points of cost of equity capital. Furthermore, our results remain robust to endogeneity concerns and alternative proxies for the cost of equity capital measures. Finally, we confirm that audit report lag increases the firm cost of equity capital through increasing information asymmetry and future financial restatement as a mediating channel.

Originality/value

We contribute to the theoretical discussion about the role of audit report lag and investors' perceptions. Overall, our results suggest that audit report lag affects a firm cost of equity capital.
Building cybersecurity resilience: integrating defense and recovery investment strategies in an expected resilience framework
Authors: Dong Kunxiang , Zhen Jie , Xie Zongxiao , Chen Lin
Published: October 2024

Purpose

To remain competitive in an unpredictable environment where the complexity and frequency of cybercrime are rapidly increasing, a cyber resiliency strategy is vital for business continuity. However, one of the barriers to improving cyber resilience is that security defense and accident recovery do not combine efficaciously, as embodied by emphasizing cyber security defense strategies, leaving firms ill-prepared to respond to attacks. The present study thus develops an expected resilience framework to assess cyber resilience, analyze cyber security defense and recovery investment strategies and balance security investment allocation strategies.

Design/methodology/approach

Based on the expected utility theory, this paper presents an expected resilience framework, including an expected investment resilience model and an expected profit resilience model that directly addresses the optimal joint investment decisions between defense and recovery. The effects of linear and nonlinear recovery functions, risk interdependence and cyber insurance on defense and recovery investment are also analyzed.

Findings

According to the findings, increasing the defense investment coefficient reduces defense and recovery investment while increasing the expected resilience. The nonlinear recovery function requires a smaller defense investment and overall security investment than the linear one, reflecting the former’s advantages in lowering cybersecurity costs. Moreover, risk interdependence has positive externalities for boosting defense and recovery investment, meaning that the expected profit resilience model can reduce free-riding behavior in security investments. Insurance creates moral hazard for firms by lowering defensive investment, yet after purchasing insurance, expanded coverage and cost-effectiveness incentivize firms to increase defense and recovery spending, respectively.

Originality/value

The paper is innovative in its methodology as it offers an expected cyber resilience framework for integrating defense and recovery investment and their effects on security investment allocation, which is crucial for building cybersecurity resilience but receives little attention in cybersecurity economics. It also provides theoretical advances for cyber resilience assessment and optimum investment allocation in other fields, such as cyber-physical systems, power and water infrastructure – moving from a resilience triangle metric to an expected utility theory-based method.
How tie strength and face consciousness moderate the impact of social media on impulsive travel intentions: a social-technical perspective
Authors: Li Lin , Leung Xi Yu , Yang Liyu
Published: October 2024

Purpose

The surge of social media as a pivotal platform for individuals to access travel-related information has become increasingly significant. Drawing upon social-technical theory and weak tie theory, this study aims to delve into the antecedents and moderating variables shaping impulsive travel intentions within social media.

Design/methodology/approach

Data were collected from 696 Chinese social media users and travelers and analyzed using partial least squares structural equation modeling (PLS-SEM).

Findings

The findings indicate that information quality and social network interaction significantly influence spatial presence, thereby increasing users’ impulsive travel intentions. The moderating roles of tie strength and face consciousness are confirmed. For travelers with strong ties, their spatial presence is impacted more by social network interaction. Conversely, for individuals with weak ties, spatial presence is more influenced by information quality. In addition, travelers with heightened face consciousness exhibit a diminished susceptibility to the influence of spatial presence on their travel intentions compared to those with lower face consciousness.

Originality/value

The study endeavors to extend the application of the social-technical theory in the domain of tourism social media marketing by examining the interplay of technological and social attributes on impulsive travel intention. It integrates weak tie theory into the socio-technical perspective, emphasizing the importance of weak ties in the social media environment and their influence on travel behavior. In addition, this study introduces face consciousness to the mechanism, seeking to broaden the research scope and capture the nuances of specific cultural contexts. The insights contribute valuable knowledge for destinations and tourism companies to optimize social media marketing.
Competitive intelligence in tourism: charting future directions through bibliometric analysis
Authors: Aljaafreh Nisreen Abd ALrhman , De-Pablos-Heredero Carmen , Orea-Giner Alicia
Published: October 2024

Purpose

This study explores the crucial role of competitive intelligence (CI) in the tourism sector’s strategic decision-making. CI has significantly transformed the tourism sector through new insights and sophistication in data analysis and strategic planning. The rise in tourism-related competition, due to new destinations, varied tourist preferences and sustainability emphasis, makes competitive intelligence essential for understanding future market trends and making informed strategic choices.

Design/methodology/approach

Utilising PRISMA techniques for bibliometric analysis, the study examines literature from 1998 to 2023 (WoS), focusing on service innovation, customer experience management and sustainable strategies. It presents an analysis of the evolution of CI in tourism, its impact, influential works and future research directions.

Findings

Findings show that the multidisciplinary nature of CI in tourism is further evidenced by studies on quality cues, travellers’ information needs and the utilisation of big data. Future studies need to understand both global trends and regional specifics, as shown in investigations of spatial-temporal tourism dynamics.

Originality/value

This study represents a novel contribution to the field of tourism research by offering a comprehensive bibliometric analysis of CI literature from 1998 to 2023. It uniquely integrates service innovation, customer experience management and sustainable strategies within the context of CI, highlighting its multidisciplinary impacts and evolution. These insights collectively emphasise the need for future innovation and a comprehensive understanding of the global-local nexus to inform future tourism research and practice.
Lactobacillus rhamnosusGG and Bifidobacterium animalis subsp. lactisBB‐12 promote infected wound healing via regulation of the wound microenvironment
Authors: Yin Zhe , Wang Yilin , Feng Xiaojuan , Liu Changqing , Guan Xiaoyang , Liu Shuyan , Long Zhanyi , Miao Zhonghua , He Fang , Cheng Ruyue , Han Yanting , Li Ka
Published: October 2024

Infected wounds can result in complex clinical complications and delayed healing, presenting a significant global public health challenge. This study explored the effects of topical application of two probiotics, Lactobacillus rhamnosus GG (LGG) and Bifidobacterium animalis subsp. lactis BB‐12, on the microenvironment of infected wounds and their impact on wound healing. LGG and BB‐12 were applied separately and topically on the Staphylococcus aureus (S. aureus)‐infected skin wounds of the rat model on a daily basis. Both probiotics significantly accelerated wound healing, demonstrated by enhanced granulation tissue formation and increased collagen deposition, with BB‐12 showing superior efficacy. LGG and BB‐12 both effectively inhibited neutrophil infiltration and decreased the expression of pro‐inflammatory cytokines tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6). Notably, BB‐12 markedly reduced IL‐6 levels, while LGG significantly lowered TNF‐α, transforming growth factor‐β (TGF‐β) and vascular endothelial growth factor (VEGF). Additionally, both probiotics promoted macrophage polarization towards the anti‐inflammatory M2 phenotype. Microbiota analysis revealed that LGG and BB‐12 significantly decreased the abundance of pathogenic bacteria (e.g. Staphylococcus and Proteus) and increased the proportion of beneficial bacteria (e.g. Corynebacterium). Particularly, BB‐12 was more effective in reducing Staphylococcus abundance, whereas LGG excelled in promoting Corynebacterium growth. These findings suggest the ability of LGG and BB‐12 to modulate the wound microenvironment, enhance wound healing and provide valuable insights for the management of infected wounds.
Mass cytometry identifies imbalance of multiple immune‐cell subsets associated with biologics treatment in ankylosing spondylitis
Authors: Lin Li , Luo Jing , Cai Yue , Wu Xin , Zhou Ling , Li Ting , Wang Xiaobing , Xu Huji
Published: October 2024

Objective

This study aims to comprehensively investigate immune‐cell landscapes in ankylosing spondylitis (AS) patients and explore longitudinal immunophenotyping changes induced by biological agents.

Methods

We employed mass cytometry with 35 cellular markers to analyze blood samples from 34 AS patients and 13 healthy controls (HC). Eleven AS patients were re‐evaluated 1 month (4 patients) and 3 months (7 patients) after treatment with biological agents. Flow Self‐Organizing Maps (FlowSOM) clustering was performed to identify specific cellular metaclusters. We compared cellular abundances across distinct subgroups and validated subset differences using gating strategies in flow cytometry scatter plots, visualized with FlowJo software. The proportions of differential subsets were then used for intercellular and clinical correlation analysis, as well as for constructing diagnostic models based on the random forest algorithm.

Results

In AS patients, we identified and validated nine different immune‐cell subsets compared to HC. Three subsets increased: helper T‐cell 17 (Th17), mucosa‐associated invariant T‐cell (MAIT), and classical monocytes (CM). Six subsets decreased: effector memory T‐cell (TEM), naïve B cells, transitional B cells, IL10+ memory B cells, non‐classical monocytes (NCM), and neutrophils. Treatments with biological agents could rectify cellular abnormalities, particularly the imbalance of CM/NCM. Furthermore, these subsets may serve as biomarkers for assessing disease activity and constructing effective diagnostic models for AS.

Conclusion

These findings provide novel insights into the specific patterns of immune cell in AS, facilitating the further development of novel biomarkers and potential therapeutic targets for AS patients.
Possibility of early pregnancy detection in alpacas (Vicugna pacos) based on fecal steroid hormone concentrations
Authors: Egi Toru , Hanada Masaaki , Tokura Yuji , Flores Alejandro Bonifacio , Acosta Tomás J.
Published: October 2024

Early pregnancy detection in alpacas, whose breeding season is limited to the rainy season and has a long gestation period, is important for reproductive management. Conventional detection methods such as ultrasonography cannot be used to detect pregnancy before 30 days after mating. In this study, we examined the feasibility of using fecal steroid hormones as an early detection method in pregnant and non‐pregnant alpacas. Fecal and blood samples were collected from pregnant and non‐pregnant alpacas after mating. Progesterone (P4) and estradiol 17‐β were extracted and quantified from blood and fecal samples. A positive correlation exists between the steroid hormones in serum and feces, indicating that serum steroid hormone concentrations can be estimated from fecal steroid hormones. Within 10 days after mating, both pregnant and non‐pregnant alpacas had fecal P4 concentrations greater than 1.0 ng/mg dry matter (DM), but by 15 days after mating, fecal P4 concentrations decreased to the pre‐mating concentration in non‐pregnant alpacas. From 15 days after mating, non‐pregnant alpacas had a low fecal P4 concentration (< 1 ng/mg DM), whereas a high fecal P4 concentration indicated the possibility of pregnancy, suggesting that this test is clinically beneficial as a supportive test for pregnancy detection.
Drug‐induced liver injury associated with pretomanid, bedaquiline, and linezolid: Insights from FAERS database analysis
Authors: He Qingfeng , Li Yang , Liu Sifan , Xue Hao , Xiang Xiaoqiang , Wang Tao , Feng Zhen
Published: October 2024

Aims

The emergence of drug‐resistant tuberculosis has necessitated novel treatments like the pretomanid, bedaquiline and linezolid (BPaL) regimen. This study investigated the association of drug‐induced liver injury (DILI) with the BPaL regimen compared to first‐line antituberculosis drugs (isoniazid, rifampin, pyrazinamide and ethambutol [HRZE]).

Methods

A retrospective pharmacovigilance analysis was conducted using data from the US Food and Drug Administration Adverse Event Reporting System database from July 2019 to June 2023. Disproportionality analysis was employed to calculate the reporting odds ratio (ROR) of DILI for each component of the BPaL regimen. Onset time and mortality rates of DILI across different regimens were also compared.

Results

We identified 1242 cases of BPaL‐related DILI. Most cases occurred in individuals under 65 years of age (63.8%), with more male patients affected than females (51.4% vs 39.5%). The association between antituberculosis drugs and DILI was stronger for the HRZE regimen (ROR = 7.99, 95% confidence interval [CI] 7.74‐8.25) than the BPaL regimen (ROR = 4.75, 95% CI 4.55‐4.97). The median onset time for DILI was significantly shorter with the BPaL regimen (8 days, interquartile range [IQR] 3‐28) compared to the HRZE regimen (20 days, IQR 6‐48) (P < .001). Additionally, the BPaL regimen was associated with a higher risk of death due to DILI compared to the HRZE regimen (14.1% vs 10.4%, P = .003).

Conclusions

Although the BPaL regimen had a lower overall risk of DILI compared to the HRZE regimen, it was significantly associated with DILI, indicating a need for careful monitoring during treatment.
Recent strategies in target identification of natural products: Exploring applications in chronic inflammation and beyond
Authors: Pan Xian , Jiang Shan , Zhang Xinzhuang , Wang Zhenzhong , Wang Xin , Cao Liang , Xiao Wei
Published: October 2024

Natural products are a treasure trove for drug discovery, especially in the areas of infection, inflammation and cancer, due to their diverse bioactivities and complex, and varied structures. Chronic inflammation is closely related to many diseases, including complex diseases such as cancer and neurodegeneration. Improving target identification for natural products contributes to elucidating their mechanism of action and clinical progress. It also facilitates the discovery of novel druggable targets and the elimination of undesirable ones, thereby significantly enhancing the productivity of drug discovery and development. Moreover, the rise of polypharmacological strategies, considered promising for the treatment of complex diseases, will further increase the demand for target deconvolution. This review underscores strategies for identifying natural product targets (NPs) in the context of chronic inflammation over the past 5 years. These strategies encompass computational methodologies for early target discovery and the anticipation of compound binding sites, proteomics‐driven approaches for target delineation and experimental biology techniques for target validation and comprehensive mechanistic exploration.
Collective bargaining about corporate social responsibility
Authors: Goerke Laszlo , Paulus Nora
Published: October 2024

If a profit‐maximizing firm credibly commits to an employment‐enhancing corporate social responsibility objective in negotiations with a trade union, the union can reduce its wage demands. Lower wages, ceteris paribus, raise profits, while the increase in employment enhances the payoff of a wage‐setting trade union. Therefore, both the firm and the trade union can be better off in the presence of a collectively bargained corporate social responsibility objective than in its absence. Accordingly, establishing a corporate social responsibility objective can give rise to a Pareto improvement and mitigate the inefficiency resulting from collective wage negotiations.
Identification of a Plasma Exosomal lncRNA‐ and circRNA‐Based ceRNA Regulatory Network in Patients With Lung Adenocarcinoma
Authors: Zhu Wangyu , Zhang Huafeng , Tang Liwei , Fang Kexin , Lin Nawa , Huang Yanyan , Zhang Yongkui , Le Hanbo
Published: October 2024

Background

Exosomes have been established to be enriched with various long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) that exert various biological effects. However, the lncRNA‐ and circRNA‐mediated coexpression competing endogenous RNA (ceRNA) regulatory network in exosomes derived from the plasma of patients with lung adenocarcinoma (LUAD) remains elusive.

Methods and Results

This study enrolled nine patients with lung adenocarcinoma and three healthy individuals, and the differential expression of messenger RNAs (mRNAs), lncRNAs, and circRNAs was detected using microarray analysis, while microRNAs (miRNAs) were detected through RNA sequencing. Additionally, bioinformatics algorithms were applied to evaluate the lncRNA–miRNA–mRNAs/circRNA–miRNA–mRNA network. Differentially expressed cicRNAs were identified via quantitative reverse transcription polymerase chain reaction (RT‐qPCR). A total of 1016 lncRNAs, 1396 circRNAs, 45 miRNAs, and 699 mRNAs were differentially expressed in the plasma exosomes of patients with LUAD compared with healthy controls. Among them, 881 lncRNAs were upregulated and 135 were downregulated, 916 circRNAs were upregulated while 480 were downregulated, 45 miRNAs were upregulated while none were downregulated, and 591 mRNAs were upregulated while 108 were downregulated (p ≤ 0.05, and fold change ≥ 2). Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed the biological functions of differentially expressed RNAs. Meanwhile, the RNA networks displayed the regulatory relationship between dysregulated RNAs. Finally, RT‐qPCR validated that the expression of circ‐0033861, circ‐0043273, and circ‐0011959 was upregulated in the plasma exosome of patients with LUAD compared to healthy controls (p = 0.0327, p = 0.0002, p = 0.0437, respectively).

Conclusion

This study proposed a newly discovered ncRNA–miRNA–mRNA/circRNA–miRNA–mRNA ceRNA network and identified that the expression of circulating circ‐0033861, circ‐0043273, and circ‐0011959 was up‐regulated in the plasma exosomes of patients with LUAD, offering valuable insights for exploring the potential function of exosomal noncoding RNA and identifying potential biomarkers for LUAD.
Clinical Examples of the Additive Value of Absolute Quantification of Cell‐Free DNA After Heart Transplantation
Authors: Böhmer Jens , Wåhlander Håkan , Karason Kristjan , Sunnegårdh Jan , Wasslavik Carina , Jonsson Marianne , Asp Julia , Ricksten Anne , Dellgren Göran
Published: October 2024

Objective

Cell‐free DNA (cfDNA) is used as a biomarker after transplantation to detect graft injury, relying on the donor fraction (DF). We have established a PCR‐based approach allowing us to separately quantify absolute values of dd‐cfDNA and recipient‐derived cfDNA (rd‐cfDNA). We aimed to present typical clinical scenarios after heart transplantation (HTx) to illustrate the advantages of absolute cfDNA values over DF.

Methods

We used the cfDNA results of our cohort (509 samples of 52 patients followed during the first year after HTx) as background and determined the trajectories of cfDNA in specific clinical situations. We profiled an uncomplicated clinical course, viral and bacterial infections, acute and chronic rejection, and false‐negative and false‐positive rejections in six patients (five adults, one child).

Results

There was a substantial discrepancy between relative (DF) and absolute cfDNA‐levels in several clinical situations. Rd‐ and dd‐cfDNA were independently elevated during episodes of rejection and infection and were better suited to depict treatment response than DF alone.

Conclusions

Absolute quantification of cfDNA may offer clinically relevant information additive to DF in various situations after HTx and could be helpful for more accurate monitoring of diagnosis and treatment of rejection.
A small, old, and slightly rough mirror: Encountering traumatic experiences in Nanjing Museum of the Site of Lijixiang Comfort Stations
Authors: Sun Hongfang , Liu Guangjian , Yan Jianqiang
Published: October 2024

This paper investigates how traumatic events are curated and narrated in the Nanjing Museum of the Site of Lijixiang Comfort Stations. Drawing on narrative therapy in museology, the paper offers a perspective for understanding and interpreting the narrative practice in public space. It follows the reconstruction of narrative structures through a variety of viewpoints, including spatial narratives, exhibition narratives, public engagement in response to traumatic memories, and the logical and emotional encounters in museums. Visitors' learning of traumatic experiences in the museum shows a kind of indissoluble connection, a type of empathetic mutual understanding, a kind of community engagement that contributed to the recovery, and a kind of responsibility to prevent such traumatic events from happening again.
Computed tomography of the equine caudal spine and pelvis. Pathological findings in 56 clinical cases (2018–2023)
Authors: Ogden Nadine Kristina Elise , Winderickx Katja , Stack John David
Published: October 2024

Background

Computed tomography (CT) of the axial skeleton is increasing across many equine hospitals. CT of the pelvis and caudal spine in a large group of clinical cases has not been reported previously.

Objective

To describe the pathological lesions identified in the caudal spine/pelvis in horses and ponies undergoing CT spine of this region.

Study design

A retrospective case series.

Methods

Horses with CT imaging of the caudal spine/pelvis were included. Horses aged under 6 months and those with CT examinations performed post‐mortem were excluded.

Results

Fifty‐six horses met the inclusion criteria. Ages ranged from 8 months to 20 years and bodyweights from 85 to 680 kg (mean 488 kg). Horses presented predominantly for lameness (30/56) and poor performance (18/56). Osseous pathology was identified in 41/56 horses; including osteoarthritis of the sacroiliac joint(s) (n: 28), pathology of the intervertebral disc joint(s) (n: 12), pelvic fractures (n: 9), osteoarthritis of the coxofemoral joint(s) (n: 8), ventral spondylosis (n: 6), acetabular rim fracture (n: 2), dislocation of coxofemoral joint(s) (n: 2), and dorsal dermal sinus of the sacrum (n: 1).

Main limitations

The relationship between CT imaging findings and clinical signs in horses remains unclear. Further work is required to describe the relationship between congenital, developmental, and acquired changes in the caudal spine and pelvis, and clinical signs.

Conclusions

CT of the caudal spine and pelvis can be utilised in horses and ponies for diagnosing a range of clinical disorders that may be causing ‘lumbosacroiliac pain’, poor performance, hindlimb lameness, and stiffness. The pathologies we observed were diverse and many patients had multiple lesions.
Identification of Potential Hub Genes in Alopecia Areata
Authors: Liu Runqiu , Liu Longdan , Xu Jiandan , Wen Xiaoting , Jiang Yannan , Qi Qi , Qin Jie , Qin Pingping
Published: October 2024

Alopecia areata (AA) is an immune‐mediated chronic alopecia disease, but its specific pathogenesis is unclear. Gene expression data for AA patients (AAs) and healthy controls (HCs) were retrieved from the GEO database, and the differentially expressed genes (DEGs) between AAs and HCs were identified. Then, GO, KEGG and GSEA analysis were performed. A PPI network for the DEGs was then constructed to screen for hub genes, which were validated by three additional datasets. Subsequently, the potential miRNAs interacting with the hub genes were obtained through TarBase and miRNet. The differentially expressed lncRNAs (DElncRs) were obtained for subcellular localisation analysis, and the DElncRs located in the cytoplasm were further screened to identify miRNAs that interact with them. The shared miRNAs interacting with the hub genes and lncRNAs were used to construct a network of mRNA‐miRNA‐lncRNA interactions. Lastly, ROC analysis was performed to evaluate the potential diagnostic value of the hub genes and DElncRs identified. A total of 173 DEGs were obtained, mainly enriched in cytokines, chemokines, hair follicle development and hair cycle related signalling pathways. Through PPI screening and validation based on 3 additional datasets, 24 hub genes were finally yielded. Of them, five hub genes were upregulated and the potential miRNAs that interact with these five hub genes were identified. Additionally, 26 DElncRs were obtained, including 9 upregulated lncRNAs located in the cytoplasm that were predicted to interact with the miRNAs. Finally, an mRNA‐miRNA‐lncRNA regulatory network was constructed using five hub genes, four lncRNAs and their shared five miRNAs. The regulatory relationship between CD8A, mir‐185‐5p and FOXD2‐AS1 might be crucial in AA pathogenesis, with CD8A and FOXD2‐AS1 exhibiting diagnostic potential. CD8A and FOXD2‐AS1 may serve as potential therapeutic targets in AA.
Immigration‐related stress, depression, and positive parenting among undocumented Central American immigrant mothers
Authors: Hernández Dubon Rafael E. , Letiecq Bethany L. , Chaplin Tara , Vesely Colleen K. , Goodman Rachael D. , Marquez Marlene
Published: October 2024

Objective

The purpose of the current study was to examine whether immigration‐related stress is associated with reduced positive parenting and whether this association is mediated by depressive symptoms in undocumented Central American immigrant mothers.

Background

In the context of “illegality,” parents can face myriad stressors related to their immigration status, which may lead to heightened emotions, including depressed mood. These experiences may affect family life, including the ways in which immigrant mothers parent their children.

Method

This study examined survey data generated in 2016–2017 by researchers using a community‐based participatory action research approach in partnership with Central American immigrant mothers residing in the Washington, DC, region. The sample for this study included 117 undocumented Central American immigrant mothers of children aged 3 to 11 years.

Results

Controlling for age of child, mother's education, and relationship status, analyses revealed that immigration‐related stress was associated with heightened levels of depressive symptoms for mothers. However, mothers' symptoms of depression were not associated with positive parenting. Additionally, no association between immigration‐related stress and positive parenting was found.

Conclusions

Findings suggest that mothers, although affected by immigration‐related stress in terms of their own mood symptoms, may deploy mechanisms such as parental self‐sacrifice to protect their children from anti‐immigrant harms.

Implications

Findings hold implications for future research, including research approaches, and practice.
4D pathology: translating dynamic epithelial tubulogenesis to prostate cancer pathology
Authors: Harikumar Hridya , van Royen Martin E , van Leenders Geert JLH
Published: October 2024

The Gleason score is the gold standard for grading of prostate cancer (PCa) and is assessed by assigning specific grades to different microscopical growth patterns. Aside from the Gleason grades, individual growth patterns such as cribriform architecture were recently shown to have independent prognostic value for disease outcome. PCa grading is performed on static tissue samples collected at one point in time, whereas in vivo epithelial tumour structures are dynamically invading, branching and expanding into the surrounding stroma. Due to the lack of models that are able to track human PCa microscopical developments over time, our understanding of underlying tissue dynamics is sparse. We postulate that human PCa expansion utilizes embryonic and developmental tubulogenetic pathways. The aim of this study is to provide a comprehensive overview of developmental pathways of normal epithelial tubule formation, elongation, and branching, and relate those to the static microscopical PCa growth patterns observed in daily clinical practise. This study could provide a rationale for the discerned pathological interobserver variability and the clinical outcome differences between PCa growth patterns.