bluuebunny/crossref_metadata_2025 huggingface dataset:
CXCL17 is an allosteric inhibitor of CXCR4 through a mechanism of action involving glycosaminoglycans
Authors: White Carl W. , Platt Simon , Kilpatrick Laura E. , Dale Natasha , Abhayawardana Rekhati S. , Dekkers Sebastian , Kindon Nicholas D. , Kellam Barrie , Stocks Michael J. , Pfleger Kevin D. G. , Hill Stephen J.
Published: March 2024

CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, and its expression is increased during viral infections of the lung. However, the exact role of CXCL17 in health and disease requires further investigation, and there is a need for confirmed molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET)–based assays, here we demonstrated that CXCL17 inhibited CXCR4-mediated signaling and ligand binding. Moreover, CXCL17 interacted with neuropillin-1, a VEGFR2 coreceptor. In addition, we found that CXCL17 only inhibited CXCR4 ligand binding in intact cells and demonstrated that this effect was mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. Disruption of putative GAG binding domains in CXCL17 prevented CXCR4 binding. This indicated that CXCL17 inhibited CXCR4 by a mechanism of action that potentially required the presence of a glycosaminoglycan-containing accessory protein. Together, our results revealed that CXCL17 is an endogenous inhibitor of CXCR4 and represents the next step in our understanding of the function of CXCL17 and regulation of CXCR4 signaling.
Protein disulfide isomerase 1 is required for RodA assembling-based conidial hydrophobicity of
Aspergillus fumigatus
Authors: Hu Xiaotao , Zhou Yao , Liu Renning , Wang Jing , Guo Lingyan , Huang Xiaofei , Li Jingyi , Yan Yunfeng , Liu Feiyun , Li Xueying , Tan Xinyu , Luo Yiqing , Wang Ping , Zhou Shengmin
Published: March 2024

The hydrophobic layer of
Aspergillus
conidia, composed of RodA, plays a crucial role in conidia transfer and immune evasion. It self-assembles into hydrophobic rodlets through intramolecular disulfide bonds. However, the secretory process of RodA and its regulatory elements remain unknown. Since protein disulfide isomerase (PDI) is essential for the secretion of many disulfide-bonded proteins, we investigated whether PDI is also involved in RodA secretion and assembly. By gene knockout and phenotypic analysis, we found that Pdi1, one of the four PDI-related proteins of
Aspergillus fumigatus
, determines the hydrophobicity and integrity of the rodlet layer of the conidia. Preservation of the thioredoxin-active domain of Pdi1 was sufficient to maintain conidial hydrophobicity, suggesting that Pdi1 mediates RodA assembly through its disulfide isomerase activity. In the absence of Pdi1, the disulfide mismatch of RodA in conidia may prevent its delivery from the inner to the outer layer of the cell wall for rodlet assembly. This was demonstrated using a strain expressing a key cysteine-mutated RodA. The dormant conidia of the Pdi1-deficient strain (Δ
pdi
) elicited an immune response, suggesting that the defective conidia surface in the absence of Pdi1 exposes internal immunogenic sources. In conclusion, Pdi1 ensures the correct folding of RodA in the inner layer of conidia, facilitating its secretion into the outer layer of the cell wall and allowing self-assembly of the hydrophobic layer. This study has identified a regulatory element for conidia rodlet assembly.

IMPORTANCE

Aspergillus fumigatus
is the major cause of invasive aspergillosis, which is mainly transmitted by the inhalation of conidia. The spread of conidia is largely dependent on their hydrophobicity, which is primarily attributed to the self-assembly of the hydrophobic protein RodA on the cell wall. However, the mechanisms underlying RodA secretion and transport to the outermost layer of the cell wall are still unclear. Our study identified a critical role for Pdi1, a fungal protein disulfide isomerase found in regulating RodA secretion and assembly. Inhibition of Pdi1 prevents the formation of correct S-S bonds in the inner RodA, creating a barrier to RodA delivery and resulting in a defective hydrophobic layer. Our findings provided insight into the formation of the conidial hydrophobic layer and suggested potential drug targets to inhibit
A. fumigatus
infections by limiting conidial dispersal and altering their immune inertia.
Irgm proteins attenuate inflammatory disease in mouse models of genital
Chlamydia
infection
Authors: Dockterman Jacob , Reitano Jeffrey R. , Everitt Jeffrey I. , Wallace Graham D. , Hendrix Meghan , Taylor Gregory A. , Coers Jörn
Published: March 2024

Chlamydiae
are obligate intracellular bacterial pathogens that may cause genital pathology via induction of destructive host immune responses. Human-adapted
Chlamydia trachomatis
causes inflammatory disease in human hosts but is easily cleared in mice, and mouse-adapted
Chlamydia muridarum
establishes a productive and pathogenic infection in murine hosts. While numerous anti-chlamydial host resistance factors have been discovered in mice and humans alike, little is known about host factors promoting host fitness independent of host resistance. Here, we show that interferon-inducible immunity-related GTPase M (Irgm) proteins function as such host factors ameliorating infection-associated sequalae in the murine female genital tract, thus characterizing Irgm proteins as mediators of disease tolerance. Specifically, we demonstrate that mice deficient for all three murine Irgm paralogs (pan-
Irgm
−/−
) are defective for cell-autonomous immunity to
C. trachomatis
, which correlates with an early and transient increase in bacterial burden and sustained hyperinflammation
in vivo
. In contrast, upon infection of pan-
Irgm
−/−
mice with
C. muridarum
, bacterial burden is unaffected, yet genital inflammation and scarring pathology are nonetheless increased, demonstrating that Irgm proteins can promote host fitness without altering bacterial burden. Additionally, pan-
Irgm
−/−
mice display increased granulomatous inflammation in genital
Chlamydia
infection, implicating Irgm proteins in the regulation of granuloma formation and maintenance. These findings demonstrate that Irgm proteins regulate pathogenic immune responses to
Chlamydia
infection
in vivo
, establishing an effective infection model to examine the immunoregulatory functions and mechanisms of Irgm proteins.

IMPORTANCE

In response to genital Chlamydia infection, the immune system mounts a proinflammatory response to resist the pathogen, yet inflammation must be tightly controlled to avoid collateral damage and scarring to host genital tissue. Variation in the human IRGM gene is associated with susceptibility to autoinflammatory diseases but its role in ameliorating inflammatory diseases caused by infections is poorly defined. Here, we use mice deficient for all three murine Irgm paralogs to demonstrate that Irgm proteins not only provide host resistance to Chlamydia infections but also limit associated inflammation in the female genital tract. In particular, we find that murine Irgm expression prevents granulomatous inflammation, which parallels inflammatory diseases associated with variants in human IRGM. Our findings therefore establish genital Chlamydia infection as a useful model to study the roles for Irgm proteins in both promoting protective immunity and limiting pathogenic inflammation.
Differentiation of keratinocytes or exposure to type 2 cytokines diminishes
S. aureus
internalization
Authors: Morgenstern Alexis R. , Peterson Liam F. , Arnold Kimberly A. , Brewer Matthew G.
Published: March 2024

Staphylococcus aureus
is a leading cause of skin and soft tissue infections. Colonization by this bacterium is increased in individuals with chronic cutaneous diseases such as atopic dermatitis, psoriasis, and bullous pemphigoid. The greater abundance of
S. aureus
on the skin of subjects with atopic dermatitis in particular has been linked to recurrent cutaneous infections. The primary cell type of the epidermal layer of the skin is the keratinocyte, and it is thought that
S. aureus
internalized in keratinocytes associates with an increased incidence of skin infections. This study addresses whether keratinocyte differentiation and/or inflammation, two important characteristics altered in cutaneous diseases, influence bacterial internalization. To do this,
S. aureus
internalization was measured in immortalized and primary keratinocytes that were differentiated using high Ca
2+
-containing media and/or exposed to cytokines characteristic of atopic dermatitis (IL-4 and IL-13) or psoriasis (IL-17A and IL-22) skin. Our results indicate that
S. aureus
internalization is uniquely decreased upon keratinocyte differentiation, since this was not observed with another skin-resident bacterium,
S. epidermidis
. Additionally, treatment with IL-4 + IL-13 diminished bacterial internalization. We interpret this decrease as a mechanism of keratinocyte-based bacterial killing since a similar number of bacterial genomes were detected in cytokine-treated cells, but less viable internalized
S. aureus
was recovered. Finally, of the receptors reported for
S. aureus
binding/internalizing into keratinocytes, expression of the α
5
component of the α
5
β
1
integrin was in greatest accordance with the number of internalized bacteria in the context of keratinocyte differentiation.

IMPORTANCE

Individuals with chronic cutaneous diseases demonstrate heightened susceptibility for severe and recurrent infections from
Staphylococcus aureus
. What drives this altered susceptibility remains poorly understood. Previous publications have detected
S. aureus
as deep as the dermal layer of skin in subjects with atopic dermatitis, suggesting that the cutaneous environment of this disease enables deeper bacterial infiltration than occurs in healthy individuals. This observation indicates that
S. aureus
has greater opportunity to interact with multiple skin cell types in individuals with chronic inflammatory skin diseases. Identifying the characteristics of the skin that influence bacterial internalization, a common method to establish reservoirs and evade the immune response, is critical for our understanding of
S. aureus
pathogenesis. The significance of this research is the novel identification of epidermal characteristics that influence
S. aureus
internalization. With this knowledge, methods can be developed to identify patient populations at greater risk for cutaneous infections.
Interpretation: use of autoantibodies in children
Authors: King Hayley , Tofias Antonis , Greenhill Abbie , Grimes Aidan , Ng Khuen Foong
Published: March 2024

Judicious use of autoantibodies in paediatrics can be challenging. Autoimmune conditions can present with a wide range of signs and symptoms, many of which are non-specific. In combination with clinical features and laboratory findings, autoantibodies can facilitate diagnosis and in certain cases inform prognosis. Evidence for use of autoantibodies to guide and monitor treatment is limited. Caution is necessary when interpreting adult studies. We summarise the use of autoantibodies in paediatric practice with a guide on how they may be used.
Incidence and predictors of restenosis following successful recanalization of non-acute internal carotid artery occlusion in 252 cases
Authors: Lu Guangdong , Wang Junqing , Wang Tao , Xu Xinjuan , Li Xin , Sun Xinyi , Wang Zhengyu , Luo Jichang , Ma Yan , Yang Bin , Gao Peng , Wang Yabing , Chen Yanfei , Liu Sheng , Jiao Liqun
Published: March 2024

Background

Data concerning restenosis following successful recanalization of non-acute internal carotid artery occlusion (ICAO) are scarce. This study was conducted to identify the incidence and predictors of restenosis following successful recanalization of non-acute ICAO.

Methods

We reviewed the incidence of restenosis (defined as >70% restenosis or reocclusion) among 252 consecutive patients with successful recanalization of non-acute ICAO. Baseline, imaging, and surgery-related characteristics were analyzed to assess their association with restenosis. A scoring system was developed to identify high-risk patients for restenosis.

Results

During a median follow-up of 12.6 months, restenosis occurred in 56 patients (22.2%), including 39 with reocclusion and 17 with >70% restenosis. The cumulative restenosis rate was 18.0% at 12 months and 24.1% at 24 months. The incidence of stroke was higher in patients with restenosis (25.0% vs 1.5%, P<0.01). Multivariate analysis showed occlusion length (5–10 cm vs <5 cm (hazard ratio (HR) 3.15, 95% confidence interval (95% CI) 1.07 to 9.29); ≥ 10 cm vs <5 cm (HR 5.01, 95% CI 1.73 to 14.49)), residual stenosis ≥30% (HR 3.08, 95% CI 1.79 to 5.30), and internal carotid artery (ICA) wall collapse (HR 1.96, 95% CI 1.12 to 3.44) as independent predictors of restenosis. Point scores proportional to model coefficients were assigned, with scores ranging from 0 to 6. Patients scoring 3–6 had a 4.00 times higher chance of developing restenosis (95% CI 2.35 to 6.79) compared with those scoring 0–2.

Conclusions

Nearly one in five patients experienced restenosis following successful recanalization of non-acute ICAO. Occlusion length, residual stenosis ≥30%, and ICA wall collapse were independently associated with restenosis.
Optimizing resources: financial evaluation of flow diverters versus stent assisted coiling in large and giant cerebral aneurysm management in Brazil public health system
Authors: Machado Elias Antônio Tanus , Batista Savio , Braga Fausto de Oliveira , Alves Filho Cesar Augusto Ferreira , Almeida Filho Jose Alberto , Lopes Plínio Gabriel , Cartobei Carlos Leandro , Oliveira Leonardo de Barros , Pereira Paulo José da Mata , Niemeyer Filho Paulo
Published: March 2024

Background

Cerebral aneurysms, especially large and giant aneurysms, pose challenges in neurointerventional surgery. Treatment choices involve clinical presentation, aneurysm details, and global resource variations. Neurointerventional methods, while innovative, may be cost restrictive in certain regions. In public healthcare, cost is crucial, notably in countries like Brazil. This study examines the device specific cost estimation of flow diverters (FD) and traditional stent assisted coiling (SAC) for large and giant cerebral aneurysms, providing insights into optimizing neurosurgical interventions within the Brazilian public health system’s unique challenges.

Methods

A comprehensive retrospective analysis was conducted at our medical center of cases of large and giant aneurysms treated between 2013 and 2023. Determination of the estimated number of coils for aneurysms previously treated with FDs at our center was made, with the cost of each case, and the difference between both treatments was calculated.

Results

We investigated the profiles of 77 patients: 40 had large aneurysms (51.9%) and 37 had giant aneurysms (48.1%). Large aneurysms had a mean cost difference of US$274 (standard deviation (SD) $2071), underscoring the device specific cost estimation of FDs over SAC in their treatment. For giant aneurysms, the mean cost difference increased to $6396 (SD $2694), indicating FDs as the more economically sound choice.

Conclusion

Our study indicated that, for the treatment of giant aneurysms and some large aneurysms, the FD intervention was more economical than SAC.
Circuit-based neuromodulation enhances delayed recall in amnestic mild cognitive impairment
Authors: Ma Jie , Wu Jia-Jia , Xing Xiang-Xin , Xue Xin , Xiang Yun-Ting , Zhen Xiao-Min , Li Jian-Hua , Lu Juan-Juan , Zhang Jun-Peng , Zheng Mou-Xiong , Hua Xu-Yun , Xu Jian-Guang
Published: March 2024

Background

This study aimed to investigate the efficacy of circuits-based paired associative stimulation (PAS) in adults with amnestic mild cognitive impairment (aMCI).

Methods

We conducted a parallel-group, randomised, controlled clinical trial. Initially, a cohort of healthy subjects was recruited to establish the cortical-hippocampal circuits by tracking white matter fibre connections using diffusion tensor imaging. Subsequently, patients diagnosed with aMCI, matched for age and education, were randomly allocated in a 1:1 ratio to undergo a 2-week intervention, either circuit-based PAS or sham PAS. Additionally, we explored the relationship between changes in cognitive performance and the functional connectivity (FC) of cortical-hippocampal circuits.

Results

FCs between hippocampus and precuneus and between hippocampus and superior frontal gyrus (orbital part) were most closely associated with the Auditory Verbal Learning Test (AVLT)_N5 score in 42 aMCI patients, thus designated as target circuits. The AVLT_N5 score improved from 2.43 (1.43) to 5.29 (1.98) in the circuit-based PAS group, compared with 2.52 (1.44) to 3.86 (2.39) in the sham PAS group (p=0.003; Cohen’s d=0.97). A significant decrease was noted in FC between the left hippocampus and left precuneus in the circuit-based PAS group from baseline to postintervention (p=0.013). Using a generalised linear model, significant group×FC interaction effects for the improvements in AVLT_N5 scores were found within the circuit-based PAS group (B=3.4, p=0.017).

Conclusions

Circuit-based PAS effectively enhances long-term delayed recall in adults diagnosed with aMCI, which includes individuals aged 50–80 years. This enhancement is potentially linked to the decreased functional connectivity between the left hippocampus and left precuneus.

Trial registration number

ChiCTR2100053315; Chinese Clinical Trial Registry.
Juçara (Euterpe edulis Martius) improves time-to-exhaustion cycling performance and increased reduced glutathione: a randomized, placebo-controlled, crossover, and triple-blind study
Authors: Copetti Cândice Laís Knöner , Diefenthaeler Fernando , Lanferdini Fábio Juner , Dambrós Betina Fernanda , Marques Bruna Soares , da Silva Edson Luiz , Vieira Francilene Gracieli Kunradi , Willems Mark Elisabeth Theodorus , Pietro Patricia Faria Di
Published: March 2024

To examine the effects of 7-days juçara powder (JP) intake on oxidative stress biomarkers and endurance and sprint cycling performances. In a randomized, placebo-controlled, crossover, and triple-blind study, 20 male trained cyclists were assigned to intake 10 g of JP (240 mg anthocyanins) or placebo (PLA) for 7 days and performed a cycling time-to-exhaustion (TTE). A 5 s cycling sprint was performed before and after the cycling TTE. Blood oxidative stress biomarkers and lactate concentration where evaluated 1 h before (T-1), immediately after (T0), and 1 h after (T1) the cycling TTE. The mean duration time for the cycling TTE was 8.4 ± 6.0% (63 ± 17 s) longer in the JP condition (JP: 751 ± 283 s) compared to PLA (688 ± 266 s) ( P < 0.019). Two-way repeated measures Analysis of variance showed an increase in the JP condition for reduced glutathione (GSH) ( P = 0.049) at T0 ( P = 0.039) and T1 ( P = 0.029) compared to PLA with a moderate effect size at T0 ( d = 0.61) and T1 ( d = 0.57). Blood lactate levels increased over time in both conditions ( P ≤ 0.001). No differences were observed for the post-TTE sprint fatigue index, total phenols, protein carbonyls, and glutathione peroxidase activity. Seven-day intake of JP improved cycling endurance performance and increased GSH levels but had no effect on lactate and cycling sprint-induced fatigue.
Optimising camera and flight settings for ultrafine resolution mapping of artificial night-time lights using an unoccupied aerial system
Authors: Bhattarai Dipendra , Lucieer Arko
Published: March 2024

Light pollution from artificial night-time lights (ANTLs) is a global health, economic, and environmental issue. Remote sensing and unoccupied aerial systems (UASs) provide efficient and cost-effective ways to study ANTL spatial patterns and dynamics over large areas. With ultrahigh-resolution images that can identify individual light sources, UAS offers more detailed image than satellite imagery. However, standardisation and optimisation of camera and flight settings during the acquisition ANTL UAS images is lacking. The aim of this paper is to determine the camera and flight settings to capture high-quality ANTL using a DJI Matrice 300 RTK aircraft with a Zenmuse P1 camera. It emphasises the importance of selecting appropriate camera settings for high-quality ANTL images, which can benefit future research. Results show significant image quality gains when camera and flight settings are chosen appropriately in relation to the lighting conditions. We present three experiments demonstrating a range of camera settings, and we provide practical recommendations for high-quality night-time image collection. The optimal camera settings were determined to be an exposure time of 0.0166 s, ISO of 25600, and aperture of 2.97. This experiment produced outstanding results, with 85% of images having a blur extent below 0.40.
On the Electrodeposition of Zinc in Low Magnetic Fields
Authors: McLeod William T. , Glasco Dalton L. , Boni Tyler N. , Bell Jeffrey G.
Published: March 2024

While aqueous zinc-based batteries have garnered much research on account of their improved safety, lower cost, and easier fabrication over lithium-ion batteries, they remain held back by dendrite growth on the anode. While many different solutions have been proposed, these solutions often greatly complicate the synthesis or materials in the battery. The application of a magnetic field across the battery has been shown to inhibit dendrite formation without the need for any materials or interface engineering. Herein, we provide a study on the effects of low magnetic fields on the electrodeposition and cycling of zinc in various aqueous systems. We demonstrate that although stronger fields have more immediate impacts on the morphology of zinc deposits, low magnetic fields are still suitable for inhibiting dendrite growth over long periods of cycling. Magnetic field strengths as low as 29 mT were shown to decrease charge transfer resistance of zinc ion deposition by up to 54% and to stabilize the cycling of Zn/Zn symmetric cells. Furthermore, the versatility of magnetic field application was demonstrated by affecting the morphology of zinc deposits on both copper and single-walled carbon nanotubes, which are both compatible with anode-free configurations of aqueous zinc-ion batteries.
Oncogenic KRAS Induces Arginine Auxotrophy and Confers a Therapeutic Vulnerability to SLC7A1 Inhibition in Non–Small Cell Lung Cancer
Authors: Gai Xiameng , Liu Yingluo , Lan Xiaojing , Chen Luoyi , Yuan Tao , Xu Jun , Li Yize , Zheng Ying , Yan Yiyang , Yang Liya , Fu Yixian , Tang Shuai , Cao Siyuwei , Dai Xiaoyang , Zhu Hong , Geng Meiyu , Ding Jian , Pu Congying , Huang Min
Published: March 2024

The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation of the underlying mechanism by which oncogenic signaling mediates urea cycle reprogramming could help identify targetable metabolic vulnerabilities. In this study, we discovered that oncogenic activation of KRAS in non–small cell lung cancer (NSCLC) silenced the expression of argininosuccinate synthase 1 (ASS1), a urea cycle enzyme that catalyzes the production of arginine from aspartate and citrulline, and thereby diverted the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication. Specifically, KRAS signaling facilitated a hypoacetylated state in the promoter region of the ASS1 gene in a histone deacetylase 3–dependent manner, which in turn impeded the recruitment of c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cells impaired the biosynthesis of arginine and rendered a dependency on the arginine transmembrane transporter SLC7A1 to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models inhibited KRAS-driven NSCLC growth. Together, these findings uncover the role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability for treating KRAS-mutant NSCLC.

Significance:

ASS1 deficiency is induced by mutant KRAS in NSCLC to facilitate DNA synthesis and creates a dependency on SLC7A1, revealing dietary arginine restriction and SLC7A1 inhibition as potential therapeutic strategies.
ATG-101 Is a Tetravalent PD-L1×4-1BB Bispecific Antibody That Stimulates Antitumor Immunity through PD-L1 Blockade and PD-L1–Directed 4-1BB Activation
Authors: Yuwen Hui , Wang Huajing , Li Tengteng , Ren Yijing , Zhang Yun-kai , Chen Peng , Sun Ao , Bian Gang , Li Bohua , Flowers David , Presler Marc , Subramanian Kalyanasundaram , Xue Jia , Wang Jingjing , Lynch Kevin , Mei Jay , He Xiaowen , Shan Bo , Hou Bing
Published: March 2024

Immune checkpoint inhibitors (ICI) have transformed cancer treatment. However, only a minority of patients achieve a profound response. Many patients are innately resistant while others acquire resistance to ICIs. Furthermore, hepatotoxicity and suboptimal efficacy have hampered the clinical development of agonists of 4-1BB, a promising immune-stimulating target. To effectively target 4-1BB and treat diseases resistant to ICIs, we engineered ATG-101, a tetravalent "2+2″ PD-L1×4-1BB bispecific antibody. ATG-101 bound PD-L1 and 4-1BB concurrently, with a greater affinity for PD-L1, and potently activated 4-1BB+ T cells when cross-linked with PD-L1–positive cells. ATG-101 activated exhausted T cells upon PD-L1 binding, indicating a possible role in reversing T-cell dysfunction. ATG-101 displayed potent antitumor activity in numerous in vivo tumor models, including those resistant or refractory to ICIs. ATG-101 greatly increased the proliferation of CD8+ T cells, the infiltration of effector memory T cells, and the ratio of CD8+ T/regulatory T cells in the tumor microenvironment (TME), rendering an immunologically “cold” tumor “hot.” Comprehensive characterization of the TME after ATG-101 treatment using single-cell RNA sequencing further revealed an altered immune landscape that reflected increased antitumor immunity. ATG-101 was well tolerated and did not induce hepatotoxicity in non-human primates. According to computational semimechanistic pharmacology modeling, 4-1BB/ATG-101/PD-L1 trimer formation and PD-L1 receptor occupancy were both maximized at around 2 mg/kg of ATG-101, providing guidance regarding the optimal biological dose for clinical trials. In summary, by localizing to PD-L1–rich microenvironments and activating 4-1BB+ immune cells in a PD-L1 cross-linking–dependent manner, ATG-101 safely inhibits growth of ICI resistant and refractory tumors.

Significance:

The tetravalent PD-L1×4-1BB bispecific antibody ATG-101 activates 4-1BB+ T cells in a PD-L1 cross-linking–dependent manner, minimizing the hepatotoxicity of existing 4-1BB agonists and suppressing growth of ICI-resistant tumors.

See related commentary by Ha et al., p. 1546
Oncogenic Cell Tagging and Single-Cell Transcriptomics Reveal Cell Type–Specific and Time-Resolved Responses to Vhl Inactivation in the Kidney
Authors: Kurlekar Samvid , Lima Joanna D.C.C. , Li Ran , Lombardi Olivia , Masson Norma , Barros Ayslan B. , Pontecorvi Virginia , Mole David R. , Pugh Christopher W. , Adam Julie , Ratcliffe Peter J.
Published: March 2024

Defining the initial events in oncogenesis and the cellular responses they entrain, even in advance of morphologic abnormality, is a fundamental challenge in understanding cancer initiation. As a paradigm to address this, we longitudinally studied the changes induced by loss of the tumor suppressor gene von Hippel Lindau (VHL), which ultimately drives clear cell renal cell carcinoma. Vhl inactivation was directly coupled to expression of a tdTomato reporter within a single allele, allowing accurate visualization of affected cells in their native context and retrieval from the kidney for single-cell RNA sequencing. This strategy uncovered cell type–specific responses to Vhl inactivation, defined a proximal tubular cell class with oncogenic potential, and revealed longer term adaptive changes in the renal epithelium and the interstitium. Oncogenic cell tagging also revealed markedly heterogeneous cellular effects including time-limited proliferation and elimination of specific cell types. Overall, this study reports an experimental strategy for understanding oncogenic processes in which cells bearing genetic alterations can be generated in their native context, marked, and analyzed over time. The observed effects of loss of Vhl in kidney cells provide insights into VHL tumor suppressor action and development of renal cell carcinoma.

Significance:

Single-cell analysis of heterogeneous and dynamic responses to Vhl inactivation in the kidney suggests that early events shape the cell type specificity of oncogenesis, providing a focus for mechanistic understanding and therapeutic targeting.
Molecular and Clinical Determinants of Acquired Resistance and Treatment Duration for Targeted Therapies in Colorectal Cancer
Authors: Harrold Emily , Keane Fergus , Walch Henry , Chou Joanne F. , Sinopoli Jenna , Palladino Silvia , Al-Rawi Duaa H. , Chadalavada Kalyani , Manca Paolo , Chalasani Sree , Yang Jessica , Cercek Andrea , Shia Jinru , Capanu Marinela , Bakhoum Samuel F. , Schultz Nikolaus , Chatila Walid K. , Yaeger Rona
Published: March 2024

Purpose:

Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance.

Experimental Design:

We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT).

Results:

All patients stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases.

Conclusions:

Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.
Evaluating Hymenoptera Venom Allergy Severity: A Data-Centric Comparison of Grading Instruments
Authors: Kačar Mark , Košnik Mitja
Published: March 2024

Introduction: While a consensus seems to have been reached with regard to the definition of anaphylaxis, there is no universal instrument for scoring allergic reaction severity despite more than 30 having been proposed by the time of writing. This severely hampers comparison of data between studies. While scales have been compared with regard to their utility in grading food-related reactions, no such comparisons have been made for Hymenoptera venom-associated reactions. Methods: The study conducted a retrospective analysis to compare the severity of Hymenoptera venom allergy reactions in 104 participants with suspected Hymenoptera venom allergy. The study applied six grading instruments to each reaction, also evaluating them against the NIAID/FAAN anaphylaxis criteria. Sensitivity, specificity, and receiver operating characteristic area under the curve (AUC) for identifying anaphylaxis were calculated. Severity scales were simplified into “mild,” “moderate,” and “severe” categories. The most common severity grade across the five scales was determined using a custom function to establish a consensus severity grade. Results: The most common culprit insects were honeybees (49.0%). Among the 88 participants with generalized reactions, the highest proportion had involvement of four organ systems. The scales showed high specificity for detecting anaphylaxis, especially when using higher grades of the Mueller, WAO, and Dribin scales. The diagnostic yields (AUC) varied, with the WAO scale having the highest AUC (0.94) for grades 3, 4, and 5. Spearman correlation analysis showed the strongest correlations seen between the Brown and Dribin, Ring and Messmer and Dribin, and Ring and Messmer and Reisman scales. The lowest correlations were observed with the Mueller scale when paired with the WAO, Reisman, and Dribin scales. An inter-rater reliability analysis showed substantial agreement between scales with the same number of grading levels. The agreement was highest for the Brown and Dribin scales, indicating a strong consistency in reaction severity classification across different instruments. Conclusion: While all instruments were effective in stratifying reactions, they showed limitations in differentiating milder phenotypes. The Brown and Dribin scales stood out for their high agreement with the consensus score and sensitivity in identifying anaphylaxis. Our findings suggest that adopting either of these scales could significantly unify the reporting of allergic reactions. We believe the format of an instrument should be tailored to its intended purpose, with clinical decision aids being simpler and research tools being more detailed.
Implementing Approach-Bias Modification as Add-On to Varieties of Clinical Treatment for Alcohol Use Disorders: Results of a Multicenter RCT
Authors: Schenkel Edwin J. , Rinck Mike , Wiers Reinout W. , Becker Eni S. , Muhlig Stephan , Schoeneck Robert , Lindenmeyer Johannes
Published: March 2024

Introduction: Abstinence rates after inpatient treatment for alcohol use disorder (AUD) are modest (1-year rate around 50%). One promising approach is to re-train the automatically activated action tendency to approach alcohol-related stimuli (alcohol-approach bias) in AUD patients, as add-on to regular treatment. As efficacy has been demonstrated in well-controlled randomized controlled trials, the important next step is to add alcohol-approach-bias modification (alcohol-ApBM) to varieties of existing treatments for AUD. Therefore, this prospective, multicenter implementation-RCT examined whether adding alcohol-ApBM to regular treatments (various abstinence-oriented treatments including both individual and group-based interventions) would significantly increase abstinence rates compared to receiving regular treatment only, in a variety of naturalistic settings with different therapeutic approaches. Methods: A total of 1,586 AUD inpatients from 9 German rehabilitation clinics were randomly assigned to receive either ApBM in addition to regular treatment or not. Training satisfaction of patients and therapists was measured after training. Success rates were determined at 3, 6, and 12 months post-treatment. Results: Return rates of the post-treatment assessments varied greatly between clinics, often being low (18–76%). Nevertheless, ApBM significantly increased success rates after 3 months. After 6 and 12 months, the differences were not significant. ApBM was evaluated mostly positively by patients and therapists. Discussion/Conclusion: ApBM was an effective add-on to regular treatment of AUD at 3 months follow-up, across a variety of AUD treatment settings. However, low return rates for the clinical outcomes reduced the effect size of ApBM considerably. The application of ApBM proved feasible in varying clinical settings, offering the opportunity to modify automatic processes and to promote abstinence.
LOX-1 and MMP-9 Inhibition Attenuates the Detrimental Effects of Delayed rt-PA Therapy and Improves Outcomes After Acute Ischemic Stroke
Authors: Arkelius Kajsa , Wendt Trevor S. , Andersson Henrik , Arnou Anaële , Gottschalk Michael , Gonzales Rayna J. , Ansar Saema
Published: March 2024

BACKGROUND:

Acute ischemic stroke triggers endothelial activation that disrupts vascular integrity and increases hemorrhagic transformation leading to worsened stroke outcomes. rt-PA (recombinant tissue-type plasminogen activator) is an effective treatment; however, its use is limited due to a restricted time window and hemorrhagic transformation risk, which in part may involve activation of MMPs (matrix metalloproteinases) mediated through LOX-1 (lectin-like oxLDL [oxidized low-density lipoprotein] receptor 1). This study’s overall aim was to evaluate the therapeutic potential of novel MMP-9 (matrix metalloproteinase 9) ± LOX-1 inhibitors in combination with rt-PA to improve stroke outcomes.

METHODS:

A rat thromboembolic stroke model was utilized to investigate the impact of rt-PA delivered 4 hours poststroke onset as well as selective MMP-9 (JNJ0966) ±LOX-1 (BI-0115) inhibitors given before rt-PA administration. Infarct size, perfusion, and hemorrhagic transformation were evaluated by 9.4-T magnetic resonance imaging, vascular and parenchymal MMP-9 activity via zymography, and neurological function was assessed using sensorimotor function testing. Human brain microvascular endothelial cells were exposed to hypoxia plus glucose deprivation/reperfusion (hypoxia plus glucose deprivation 3 hours/R 24 hours) and treated with ±tPA and ±MMP-9 ±LOX-1 inhibitors. Barrier function was assessed via transendothelial electrical resistance, MMP-9 activity was determined with zymography, and LOX-1 and barrier gene expression/levels were measured using qRT-PCR (quantitative reverse transcription PCR) and Western blot.

RESULTS:

Stroke and subsequent rt-PA treatment increased edema, hemorrhage, MMP-9 activity, LOX-1 expression, and worsened neurological outcomes. LOX-1 inhibition improved neurological function, reduced edema, and improved endothelial barrier integrity. Elevated MMP-9 activity correlated with increased edema, infarct volume, and decreased neurological function. MMP-9 inhibition reduced MMP-9 activity and LOX-1 expression. In human brain microvascular endothelial cells, LOX-1/MMP-9 inhibition differentially attenuated MMP-9 levels, inflammation, and activation following hypoxia plus glucose deprivation/R.

CONCLUSIONS:

Our findings indicate that LOX-1 inhibition and ± MMP-9 inhibition attenuate negative aspects of ischemic stroke with rt-PA therapy, thus resulting in improved neurological function. While no synergistic effect was observed with simultaneous LOX-1 and MMP-9 inhibition, a distinct interaction is evident.
Beyond the Theosophical Paradigm: Ilme kṣnum and the Entangled History of Modern Parsis
Authors: Errichiello Mariano
Published: March 2024

In the early twentieth century, an esoteric interpretation of Zoroastrianism known as Ilme kṣnum became popular among the Parsis of India. Although research on the subject is scant, most scholars suggest that Ilme kṣnum draws largely upon the ideas promoted by the Theosophical Society in India. By examining primary sources in Gujarati, the present article illustrates the interpretation of the Zoroastrian cosmology proposed by Ilme kṣnum. Through a comparative analysis of its main concepts and terms, Ilme kṣnum is historicized in the context of the relations of the Parsi community with the Persianate and Western worlds. By framing Ilme kṣnum as a reconciliation between Persianate and Western forms of knowledge, the present article looks at historical entanglements as resources for the Parsi quest for religious authenticity, placing Zoroastrianism in global religious history.
A bio-economic model for estimating economic values of important production traits in the black soldier fly (Hermetia illucens)
Authors: Zaalberg R.M. , Nielsen H.M. , Noer N.K. , Schou T.M. , Jensen K. , Thormose S. , Kargo M. , Slagboom M.
Published: March 2024

Black soldier fly (BSF) larvae are exceptionally efficient at converting otherwise unusable waste products, while having a minimal impact on the environment. To optimise the production of BSF larvae, selective breeding could be used. With selective breeding, the best individuals to breed the next generation are selected, for example, with a breeding goal. This study aimed to make the first step towards defining such a breeding goal, by estimating the economic values (EV) of traits that are important for the production of BSF larvae. EV were estimated for larval mass on day 15, feed intake, feed conversion ratio, growth rate, dry mass-, protein- and fat content, development time, eggs per fly, egg hatching rate, and larval mortality. A bio-economic model was used to estimate the profit of a BSF production system that produces 1000 kg of wet larvae at harvesting. The EV of a trait was estimated as the increase in profit when the trait value was increased by 10%, whilst the other traits remained unchanged. EV were expressed per 10% increase, and changes in revenues and costs were specified. The results showed traits with the highest EV were related to composition (dry mass-, and protein-content) and growth (larval mass, development time, growth rate). Traits related to reproduction and flies (development from pupa to fly, number of eggs) had the lowest EV. Due to the lack of information on genetic parameters, the EV are expressed per +10% of the mean value of a trait. In the future, when more information is available, the EV should be expressed per genetic standard deviation. In conclusion, this is the first study that estimated EV for an insect species. The results are a first step towards developing a more sophisticated breeding program for optimizing BSF production.
Observed Climatology and Variability of Cattle Heat Stress in Australia
Authors: Cowan Tim , Wheeler Matthew C. , Cobon David H. , Gaughan John B. , Marshall Andrew G. , Sharples Wendy , McCulloch Jillian , Jarvis Chelsea
Published: March 2024

Exposure to weather extremes, such as heatwaves, can cause discomfort, harm, or death in grazing cattle in pastures. While the Australian Bureau of Meteorology issues sheep graziers alerts when there is an exposure risk to chill for livestock, there is no equivalent alert for heat stress for Australian cattle. Before any such alert system can be developed, a robust assessment and comparison of relevant cattle thermal stress indices is required. This study evaluates and compares the multiyear climatology of three cattle thermal heat stress indices across Australia in the warm season months (October–March). The same indices are then used to assess historical Australian heat events where cattle died from heat exposure. These events are based off official records and survey responses from northern Australian graziers. In the seven historical heat events studied, high relative humidity combined with low wind speeds, or high solar exposure combined with high surface temperatures, exacerbated the impact of heat stress on cattle. In the two historic events where multiple compounding weather factors combined (e.g., high humidity, low winds, and high solar exposure), the cattle mortality levels were significantly high. These events were characterized by rainy conditions followed by a rapid warming, meaning cattle were likely unable to acclimatize to such dramatic temperature changes. This study highlights the need for using more than one thermal stress index when verifying cattle heat stress events and, importantly, calls for further research on standardizing the risk classifications of these thermal indices for cattle in Australia’s variable climate.

Significance Statement

Cattle across Australia’s northern tropical and semiarid regions often experience extreme hot and humid conditions in the summer months, which increases the risk of heat stress. This is the first study of its kind to evaluate observations of cattle heat stress across Australia using indices that describe the combined effects of solar exposure, wind speed, relative humidity, and surface temperatures. These cattle heat stress indices can be used to evaluate historical cattle mortality events in feedlots and in grazed pastures. This study lays the groundwork for the development of Australian-wide cattle heat stress forecast products on the 7-day to multiweek time scales.
A simulation of chip formation mechanism in elliptical vibration assisted cutting of nickel-based superalloy Inconel 718
Authors: Tong Guoshun , Yang Lv , Ji Bin , Wu Huaichao , Zou Fengyi
Published: March 2024

This article reveals the chip formation and the reducing of cutting force mechanisms of nickel-based superalloy Inconel 718 under elliptical vibration cutting using finite element analysis software. The results are compared with traditional cutting methods. The elliptical motion trajectory of the tool in elliptical vibration cutting machining is analyzed, and a two-dimensional finite element elliptical vibration cutting model is established. The effects of dynamic impact on the elliptical vibration cutting of Inconel 718 were discussed in terms of the surface morphology, chip formation mechanism, and cutting force reduced mechanism. The simulation results show that (1) compared with traditional cutting, the surface morphology of the workpiece machined by elliptical vibration cutting is better, and the machined surface has obvious elliptic indentation; (2) in traditional cutting, sawtooth chips are formed through shear slip, while in elliptical vibration cutting, the faster relative cutting speed [Formula: see text], higher tool-tip temperature, and smaller material removal cross-sectional area cause a more prominent thermal softening effect in the chip formation process than that in traditional cutting, which leads to the plastic flow to be dominant in the material removal process, resulting in the strip chips; and (3) compared with traditional cutting, the normal cutting force and the tangential cutting force in elliptical vibration cutting are separately reduced about 51.4% and 60.8%.
A knowledge interchange broker composition modeling framework for simulating water, energy, and water-energy nexus systems
Authors: Fard Mostafa D , Sarjoughian Hessam S
Published: March 2024

Understanding the dynamics of complex systems requires developing and combining different kinds of models that can be simulated separately and together. Modeling the interactions as separate models contributes to building flexible hybrid simulation frameworks. In this research, a Discrete Event System Specification–based Interaction Model (DEVS-IM) framework is developed based on the Knowledge Interchange Broker (KIB) approach. This KIB-based RESTful modeling composition framework is shown to enable systematic modeling and simulation of interactions between disparate simulatable models. It supports storing IMs developed for componentized Water Evaluation and Planning System (WEAP) and Low Emissions Analysis Platform (LEAP) tools. It generates the skeleton of DEVS-IMs stored in database for DEVS-Suite simulator. An exemplar model consisting of water, energy, and IMs demonstrates this methodology for developing nexus models of water–energy systems.